User talk:Gerald Ogessa

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Welcome!

Hello Gerald Ogessa, and welcome to Wikiversity! If you need help, feel free to visit my talk page, or contact us and ask questions. After you leave a comment on a talk page, remember to sign and date; it helps everyone follow the threads of the discussion. The signature icon Button sig.png in the edit window makes it simple. All users are expected to abide by our Privacy policy, Civility policy, and the Terms of Use while at Wikiversity.

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Paper 1: Military Mission: Peace corps Mission [edit]

Military Operation: Operational Military Medicine [edit]

Care of the Casualty

  • Tactical Combat Casualty Care
  • Field Trauma Management
  • Emergency War Surgery
  • Military Dermatology
  • Military Psychiatry

Environmental Medicine

  • Hot Environments
  • Cold Environments
  • Jungle Enviornments
  • Mountain Environments
  • Dive Medicine
  • Shipboard Medicine
  • Flight Medicine
  • Chemical Biological Radiological and Nuclear Environments

Medical Operations

  • Medical Operations Planning
  • Special Operations Medicine
  • Humanitarian Medicine
  • Disaster Medicine

Military Preventative Medicine

Military Medical History

Paper 1.1 Peace corps: Welcome to the Department of Military Medicine [edit]

Department Description

Military medicine is focused around health care support to military operations. This encompasses medicine that is before or after an operational deployment (such as care of the service member while in garrison) and medicine while deployed on expeditionary operations.

Many topics in military medicine overlap with civilian medicine and the field of military medicine is interdisciplinary. Most practitioners of military medicine are trained in the realm of civilian medicine first and then undergo training in the various military medicine centric topics.

Topics with a unique focus include:

Military Medicine Pre and Post Deployment

Recruit Medicine

Mobilization and Pre-Deployment Medicine

Military Medical Ethics

Rehabilitation Medicine

Military Occupational Health

Operational Military Medicine

Care of the Casualty

  • Tactical Combat Casualty Care
  • Field Trauma Management
  • Emergency War Surgery
  • Military Dermatology
  • Military Psychiatry

Environmental Medicine

  • Hot Environments
  • Cold Environments
  • Jungle Enviornments
  • Mountain Enviornments
  • Dive Medicine
  • Shipboard Medicine
  • Flight Medicine
  • Chemical Biological Radiological and Nuclear Environments

Medical Operations

  • Medical Operations Planning
  • Special Operations Medicine
  • Humanitarian Medicine
  • Disaster Medicine

Military Preventative Medicine

Military Medical History

The department is a division of the Wikiversity School of Medicine. The department is involved in the teaching of the Level 5 curriculum

Projects, Research and Assignments

No projects, research or assignments have been requested

Department Noticeboard

This department is under construction.

Assessments

No assessments have been requested

Modules Offered

MED5.8 Introduction to Military Medicine

Care of the Casualty

MED5.83 Military Dermatology

Environmental Medicine

MED5.81 Military Medicine in Hot Weather Environments

MED5.82 Military Medicine in Cold Weather Environments

School:Medicine


School Description

The Wikiversity School of Medicine is a free online educational resource for the study of medicine. It is a member of the Faculty of Life Sciences and aims to maximize collaboration with other schools within the faculty and elsewhere. Prospective students may study medicine at Wikiversity by registering with the site and joining the school. Students may study via the proposed curriculum pathway, by picking and choosing modules or lessons from the different departments or by joining the school in creating lessons.

Please read the School of Medicine Disclaimer

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School Noticeboard

This school is currently under construction. Feel free to help in its establishment

Curriculum

The school's medical course is currently divided into pre-clinical and clinical sets of modules. Access to these modules is via the school curriculum. Below are the divisions and departments of the School of Medicine

Pre-clinical Departments



Clinical Departments
v • d • e
Basic medical sciences

Chemistry - Physics - Molecular Biology - Cell Biology - Biochemistry - Anatomy - Psychology - Communication - Philosophy - General Biology - Histology - Medical Microbiology - Pathology - Pharmacology - Physiology - Immunology - Laboratory Techniques - Genetics - Serology - Virology - Community Medicine - Health Informatics - Cytogenetics

Paper 1.2 Peace corps: Welcome to the Wikiversity! [edit]

Paper 1.2 Peace corps: Welcome to the Wikiversity School of Medicine! [edit]

°°°°°Medicine by Correspondence!!°°°°° [edit]

"Education Free at the Point of Delivery"
School Description

The Wikiversity School of Medicine is a free online educational resource for the study of medicine. It is a member of the Faculty of Life Sciences and aims to maximize collaboration with other schools within the faculty and elsewhere. Prospective students may study medicine at Wikiversity by registering with the site and joining the school. Students may study via the proposed curriculum pathway, by picking and choosing modules or lessons from the different departments or by joining the school in creating lessons.

Please read the School of Medicine Disclaimer

Affiliates

The School of Medicine is actively seeking affiliates to collaborate with on projects of mutual interest

School Noticeboard

This school is currently under construction. Feel free to help in its establishment

Curriculum

The school's medical course is currently divided into pre-clinical and clinical sets of modules. Access to these modules is via the school curriculum. Below are the divisions and departments of the School of Medicine

Pre-clinical Departments



Clinical Departments
v • d • e
Basic medical sciences

Chemistry - Physics - Molecular Biology - Cell Biology - Biochemistry - Anatomy - Psychology - Communication - Philosophy - General Biology - Histology - Medical Microbiology - Pathology - Pharmacology - Physiology - Immunology - Laboratory Techniques - Genetics - Serology - Virology - Community Medicine - Health Informatics - Cytogenetics

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http://en.wikiversity.org/wiki/School:Medicine/ [edit]

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°°°°°Wikipedia recommendations°°°°°Welcome! [edit]

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°°°°°Wikipedia recommendations°°°°°Welcome! [edit]

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Hello, Gerald Ogessa, and welcome to Wikipedia! Thank you for your contributions. I hope you like the place and decide to stay. Here are some pages that you might find helpful:

I hope you enjoy editing here and being a Wikipedian! Please sign your messages on discussion pages using four tildes (~~~~); this will automatically insert your username and the date. If you need help, check out Wikipedia:Questions, ask me on my talk page, or ask your question on this page and then place {{help me}} before the question. Again, welcome! Drmies (talk) 20:32, 14 September 2011 (UTC)

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Prescription_costs [edit]

Welcome!

1. http://en.wikipedia.org/wiki/Prescription_costs [edit]

Prescription costs Article Discussion Edit this page History Watch From Wikipedia, the free encyclopedia You have new messages (last change).

Prescription costs are a common health care cost for many people and also the source of considerable economic hardship for some. These costs are sometimes referred to as out-of-pocket prescription costs, since for those with insurance, the total cost of their prescriptions may include expenses covered by a third party, such as an insurance company, as well as the individual. Out-of-pocket prescription costs include deductibles, co-payments, and upper limits in coverage.Contents 1 United States 2 United Kingdom 3 Countries where the cost of drugs is prohibitive 4 Techniques to reduce costs 5 See also 6 References 7 Further information

[edit] United States Main article: Prescription drug prices in the United States

In the period 1994–2004 prescription costs were the most rapidly increasing cost of health care in the United States. These increases, which averaged 12% during some years, are accounted for by increases in the number of drugs per person (treatment intensification), increases in the cost of a “market-basket” of drugs (price inflation), and increases in the use of newer drugs over older, less costly, alternatives.[1] Overall, experts estimate that treatment intensification increased by 68% and price inflation increased by 8.3% between 1994 and 2004.

A substantial body of evidence has documented the association between high out-of-pocket costs and many types of economic and non-economic hardship. Between 20%–30% of patients in the United States report having skipped or stretched a prescription medicine during the previous 12 months because of the cost. Other patients report cutting back on payments for their utilities or food in order to afford their prescription medicines.

There are several barriers that prevent greater patient-provider communication about these costs.[2] Patients may be embarrassed to raise their concerns, concerned that doing so may compromise their quality of care, or under the impression that there is nothing that their health care provider can do to help. Providers may also be embarrassed discussing costs, and feel too much time pressure to discuss these costs with patients. [edit] United Kingdom

A very large number of people in the countries of the United Kingdom get prescriptions partly or totally paid for by National Insurance from the National Health Service.[3] In England prescribed medicines and medical supplies are free of charge to: those under 16 years old; those aged 16–18 in full-time education; those aged 60 or over; holders of a valid Medical Exemption Certificate for a number of chronic conditions such as diabetes, epilepsy, etc.; holders of a Maternity Exemption Certificate; holders of an HC2 certificate (awarded on the basis of low income); those with a War Pension Exemption Certificate; recipients of income related benefits including: Pension Credit, Income Based Job Seekers Allowance and Income Support.

For others each prescribed item, regardless of nature or quantity, costs UK £7.40 (Increased from £7.20 1/3/2011). A prescription pre-payment certificate (or PPC) can be bought for UK £104.00, and covers unlimited prescriptions for 12 months. Alternatively, 3 monthly PPCs may be bought for UK £28.25 (Prices as at February 2010). PPCs are sold to the public by the NHS Business Services Authority.

Other forms of health insurance and private medical care are available, but low income does not prevent access to medical care for most conditions. [edit] Countries where the cost of drugs is prohibitive

In many developing countries the cost of proprietary drugs is beyond the reach of the majority of the population.[4] There have been attempts both by international agreements and by pharmaceutical companies to provide drugs at low cost, either supplied by manufacturers who own the drugs,[5] or manufactured locally as generic versions of drugs which are elsewhere protected by patent.[6] Countries without manufacturing capability may import such generics.

The legal framework regarding generic versions of patented drugs is formalised in the Doha Declaration on Trade-Related Aspects of Intellectual Property Rights and later agreements. [edit] Techniques to reduce costs

Ways to Reduce Prescription Costs Pill splitting

Many pill-form drugs are produced in several different dosages. For example, a medicine may be prescribed at a 25 mg or a 50 mg dose. Some medicines can be prescribed at a higher dose and then the tablets can be split into two or more parts. High-dose pill are often much cheaper per unit weight than their low-dose counterparts. Not all pills can be split, since some come as time release capsules or require very precise dosing. Generic drugs

Generic drugs are much less expensive than brand-name drugs. Many people think that generics are less effective or less safe than a brand name drug, but this is an error. Once a drug is developed, it is protected by patent and sold as a brand name drug for several years, and can be sold as a generic drug or under a different brand when the patent expires. 90-day supply

Some drugs are available in a three-month supply at a lower unit cost than a smaller supply. Stopping medicines that may no longer be needed

Taking a prescription medicine may become so routine that patients continue to take it even when it is no longer necessary. However, many medicines may not be needed indefinitely. Buying from cheaper supplier

Different suppliers may have different prices. There are several government and commercial websites that will compare the prices for a given dosage of a given medication at different pharmacies.

In the USA Wal-Mart has introduced a range of "hundreds" of prescription drugs at a uniform price of US$4 for a 30-day supply.[7] Target followed suit in some locations soon after Wal-Mart. In 2008 Dominick's also began to provide prescription drugs for four dollars.[8] Many other chains have followed their lead, including CVS and Sams Club(owned by walmart). Most chains in the USA now offer some sort of discount plan. This is usually in the form of a special price list, a loyalty discount program, or price matching of other competitors schemes. Prescription pricing has become extremely competitive, with such discounts often resulting in a charge lower than the copay through a patients insurance. Counterfeit medications

There are many counterfeit medicines on the market, posing as both generic and proprietary brands. The counterfeits may be less effective than the real drug, or may have no active ingredients at all. This is a particular problem in countries with poor supervision of the pharmaceutical sector, which often also have many inhabitants with low incomes. Medicines bought over the Internet are also often found to be counterfeit. This can make saving on prescription costs risky. Research regarding out-of-pocket prescription costs

While there are many mechanisms for reducing out-of-pocket prescription costs, pharmaceutical samples actually do not reduce prescription costs. Even after receiving samples, sample recipients remain disproportionately burdened by prescription costs.[9]

For many drugs, especially brand-name antihypertensive fixed-dose medications, the clinical benefits must be balanced with patient financial burden and nonadherence during prescribing.[10]

A study has been done on the cost effectiveness of purchasing a three-month supply, which finds that there is a quantitative cost difference when patients in the U.S. fill larger quantities of a prescription drug for a chronic condition.[11]

Another way to perhaps reduce out-of-pocket costs is to improve physicians' access to health information technology. While physicians with high rates of IT use do not significantly higher knowledge of drug costs, it has been suggested that health IT should be improved to make it easier for physicians to access cost information at the point of care.[12] [edit] See also Generic drug Inverse benefit law Pill splitting Prescription Drug [edit] References This article uses bare URLs for citations, which may be threatened by link rot. Please add information on the author and source, so that the article remains verifiable in the future. The "Reflinks" tool can be used to partially automate this task. (April 2011)

^ Prescription Drug Costs: Background Brief – KaiserEDU.org, Health Policy Education from the Henry J. Kaiser Family Foundation. Kaiseredu.org. Retrieved on 2011-04-23. ^ [1][not in citation given] ^ A quick guide to help with health costs including charges and optical voucher values, Effective from 1 April 2008, NHS ^ Angela Saini Making poor nations pay for drugs, New Scientist, 31 March 2007 ^ GSK tops new ethical ranking for investors – health – 16 June 2008. New Scientist. Retrieved on 2011-04-23. ^ Drugs bust – 13 June 2001. New Scientist. Retrieved on 2011-04-23. ^ 3[verification needed] ^ 7[verification needed] ^ Alexander, G Caleb; Zhang, James; Basu, Anirban (2008). "Characteristics of Patients Receiving Pharmaceutical Samples and Association Between Sample Receipt and Out-of-Pocket Prescription Costs". Medical Care 46 (4): 394–402. doi:10.1097/MLR.0b013e3181618ee0. PMID 18362819. ^ Rabbani, Atonu; Alexander, G. Caleb (2008). "Out-of-pocket and Total Costs of Fixed-dose Combination Antihypertensives and Their Components". American Journal of Hypertension 21 (5): 509–13. doi:10.1038/ajh.2008.31. PMID 18437141. ^ Rabbani, A; Alexander, GC (2009). "Cost Savings Associated with Filling a 3-Month Supply of Prescription Medicines". Applied health economics and health policy 7 (4): 255–64. doi:10.2165/11313610-000000000-00000. PMID 19905039. ^ Tseng, CW; Brook, RH; Alexander, GC; Hixon, AL; Keeler, EB; Mangione, CM; Chen, R; Jackson, EA et al. (2010). "Health information technology and physicians' knowledge of drug costs". The American journal of managed care 16 (4): e105–10. PMID 20370310. [edit] Further information Alexander, G. C.; Casalino, LP; Meltzer, DO (2005). "Physician Strategies to Reduce Patients' Out-of-pocket Prescription Costs". Archives of Internal Medicine 165 (6): 633–6. doi:10.1001/archinte.165.6.633. PMID 15795338. Alexander, G C.; Tseng, C.-W. (2004). "Six strategies to identify and assist patients burdened by out-of-pocket prescription costs". Cleveland Clinic Journal of Medicine 71 (5): 433–7. doi:10.3949/ccjm.71.5.433. PMID 15195778. Alexander, G. Caleb; Casalino, Lawrence P.; Tseng, Chien-Wen; McFadden, Diane; Meltzer, David O. (2004). "Barriers to Patient-physician Communication About Out-of-pocket Costs". Journal of General Internal Medicine 19 (8): 856–60. doi:10.1111/j.1525-1497.2004.30249.x. PMC 1492500. PMID 15242471. Pham, H. H.; Alexander, G. C.; O'Malley, A. S. (2007). "Physician Consideration of Patients' Out-of-Pocket Costs in Making Common Clinical Decisions". Archives of Internal Medicine 167 (7): 663–8. doi:10.1001/archinte.167.7.663. PMID 17420424. Rabbani, Atonu; Alexander, G. Caleb (2008). "Out-of-pocket and Total Costs of Fixed-dose Combination Antihypertensives and Their Components". American Journal of Hypertension 21 (5): 509–13. doi:10.1038/ajh.2008.31. PMID 18437141. Categories: Pharmacology | Drugs | Pharmacy Navigation Main page Contents Featured content Current events Random article Donate to Wikipedia Search

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2. http://en.wikipedia.org/wiki/Medical_procedure [edit]

Medical procedure Article Discussion Edit this page History Watch From Wikipedia, the free encyclopedia

A medical procedure is a course of action intended to achieve a result in the care of persons with health problems.

A medical procedure with the intention of determining, measuring or diagnosing a patient condition or parameter is also called a medical test. Other common kinds of procedures are therapeutic (i.e., with the intention or treating, curing or restoring function or structure), including the large group of surgical procedures. Rehabilitation procedures are included in this group.Contents 1 Definition 2 List of medical procedures 2.1 Propedeutic 2.2 Diagnostic 2.3 Therapeutic 2.4 Surgical 2.5 Other 3 See also 4 References

[edit] Definition "An activity directed at or performed on an individual with the object of improving health, treating disease or injury, or making a diagnosis."[1] "The act or conduct of diagnosis, treatment, or operation."[2] "A series of steps by which a desired result is accomplished."[3] "The sequence of steps to be followed in establishing some course of action."[4] [edit] List of medical procedures [edit] Propedeutic Auscultation Medical inspection Palpation Percussion (medicine) Temperature examination [edit] Diagnostic Cardiac stress test Electrocardiography Electroencephalography Electrocorticography Electromyography Electroneuronography Electronystagmography Electrooculography Electroretinography Endoluminal capsule monitoring Endoscopy Colonoscopy Colposcopy Cystoscopy Gastroscopy Laparoscopy Laryngoscopy Ophthalmoscopy Otoscopy Sigmoidoscopy Esophageal motility study Evoked potential Magnetoencephalography Medical imaging Angiography Aortography Cerebral angiography Coronary angiography Lymphangiography Pulmonary angiography Ventriculography Chest photofluorography Computed tomography Echocardiography Electrical impedance tomography Fluoroscopy Magnetic resonance imaging Diffuse optical imaging Diffusion-weighted imaging Diffusion tensor imaging Functional magnetic resonance imaging Positron emission tomography Radiography Scintillography SPECT Ultrasonography Gynecologic ultrasonography Obstetric ultrasonography Contrast-enhanced ultrasound Intravascular ultrasound Thermography Virtual colonoscopy Neuroimaging Posturography [edit] Therapeutic

See also: Therapy, List of surgical procedures Precordial thump Politzerization Hemodialysis Hemofiltration Plasmapheresis Apheresis Extracorporeal membrane oxygenation (ECMO) Cancer immunotherapy Cancer vaccine Cervical conization Chemotherapy Cytoluminescent therapy Insulin potentiation therapy Low-dose chemotherapy Monoclonal antibody therapy Photodynamic therapy Radiation therapy Targeted therapy Tracheal intubation Unsealed source radiotherapy Virtual reality therapy Physical therapy Speech therapy Phototerapy Hydrotherapy Heat therapy Shock therapy Insulin shock therapy Electroconvulsive therapy Symptomatic treatment Fluid replacement therapy Palliative care Hyperbaric oxygen therapy Oxygen therapy Gene therapy Enzyme replacement therapy Intravenous therapy Kinesiotherapy Phage therapy Respiratory therapy Vision therapy Electrotherapy Transcutaneous electrical nerve stimulation (TENS) Laser therapy Combination therapy Occupational therapy Immunization Vaccination Immunosuppressive therapy Psychotherapy Drug therapy Acupuncture Antivenom Magnetic therapy Craniosacral therapy Chelation therapy Hormonal therapy Hormone replacement therapy Opiate replacement therapy Cell therapy Stem cell treatments Proton therapy Intubation Nebulization[disambiguation needed] Inhalation therapy Ion therapy[disambiguation needed] Fluoride therapy Cold compression therapy Animal-Assisted Therapy Negative Pressure Wound Therapy Nicotine replacement therapy Oral rehydration therapy [edit] Surgical Stereotactic surgery Radiosurgery Endoscopic surgery Lithotomy Image-guided surgery Facial rejuvenation Neovaginoplasty Vaginoplasty Ablation Amputation Cardiopulmonary resuscitation (CPR) Cryosurgery General surgery Hand surgery Laminectomy Hemilaminectomy Laparoscopic surgery Lithotriptor Lobotomy Knee cartilage replacement therapy Xenotransplantation [edit] Other Interventional radiology Screening (medicine) [edit] See also Algorithm (medical) Autopsy Complication (medicine) Consensus (medical) Contraindication Course (medicine) Drug interaction Extracorporeal Guideline (medical) Iatrogenesis Invasive (medical) List of surgical instruments Medical error Medical prescription Medical test Minimally invasive Nocebo Non-invasive Physical examination Responsible drug use Surgical instruments Vital signs [edit] References ^ International Dictionary of Medicine and Biology, Page 2297. ISBN 047101849x ^ Stedman's Medical Dictionary, 27th ed. Page 1446. ISBN 068340007x ^ Dorland's Illustrated Medical Dictionary, 28th ed. Page 1353. ISBN 0721628591 ^ Mosby's Medical, Nursing, & Allied Health Dictionary, Page 1278. ISBN 0801672252 Categories: Medical terms | Medical treatments Navigation Main page Contents Featured content Current events Random article Donate to Wikipedia Search

Interaction Help About Wikipedia Community portal Recent changes Contact Wikipedia Toolbox What links here Related changes Upload file Special pages Permanent link Cite this page Print/export Create a book Download as PDF Printable version GeraldOgessa My talk My preferences My watchlist My contributions Log out

This page was last modified on June 30, 2011 at 13:57.

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3. http://en.wikipedia.org/wiki/Medical_test [edit]

Medical test Article Discussion Edit this page History Watch From Wikipedia, the free encyclopediaMedical test Intervention

X-ray of a hand. X-rays are a common medical test. MeSH D019937


A medical test is a kind of medical procedure performed to detect, diagnose, or evaluate disease, disease processes, susceptibility, and determine a course of treatment.Contents 1 Types of tests 1.1 Diagnostic 1.2 Screening 1.3 Evaluation 2 Risks 3 See also 4 References

[edit] Types of tests [edit] Diagnostic

Lung scintigraphy evaluating lung cancer

A diagnostic test is a procedure performed to confirm, or determine the presence of disease in an individual suspected of having the disease, usually following the report of symptoms, or based on the results of other medical tests.[1][2] Such tests include: Utilizing nuclear medicine techniques to examine a patient having a lymphoma. Measuring the blood sugar in a person suspected of having diabetes mellitus, after periods of increased urination. Taking a complete blood count of an individual experiencing a high fever, to check for a bacterial infection.[1] Monitoring electrocardiogram readings on a patient suffering chest pain, to diagnose or determine any heart irregularities.[3] [edit] Screening

A screening is a medical test or series used to detect or predict the presence of disease in individuals at risk for disease within a defined group, such as a population, family, or workforce.[4] [5] Screenings may be performed to monitor disease prevalence, manage epidemiology, aid in prevention, or strictly for statistical purposes.[6]

Examples of screenings include measuring the level of TSH in the blood of a newborn infant as part of newborn screening for congenital hypothyroidism,[7] checking for Lung cancer in non-smoking individuals who are exposed to second-hand smoke in an unregulated working environment, and Pap smear screening for prevention or early detection of cervical cancer. [edit] Evaluation

Some medical tests are used to evaluate the progress of, or response to medical treatment. They are also used to monitor the course (prognosis) of a disease.[8]

Examples of this may include analyzing the arterial blood gasses of an individual, after chest x-rays confirm the presence of a pneumothorax; or, performing a biopsy of a removed tumor to determine the degree of malignancy. [edit] Risks

Some medical testing procedures have health risks, and even require general anesthesia, such as the mediastinoscopy.[9] Other tests, such as the blood test or pap smear have little to no direct risks.[10] Medical tests may also have indirect risks, such as the stress of testing, and riskier tests may be required as follow-up for a (potentially) false positive test result. Consult the physician prescribing any test for further information. [edit] See also Blood culture Blood test Diagnostic test Genetic testing Nailbed assessment Screening (medicine) Test panel Gold standard (test) [edit] References ^ a b Al-Gwaiz LA, Babay HH (2007). "The diagnostic value of absolute neutrophil count, band count and morphological changes of neutrophils in predicting bacterial infections". Med Princ Pract. 16 (5): 344–347. doi:10.1159/000104806. PMID 17709921. ^ Harvard.edu

Guide to Diagnostic Tests from Harvard Health

^ Harvard.edu ^ Ratcliffe JM, Halperin WE, Frazier TM, Sundin DS, Delaney L, Hornung RW (1986). "The prevalence of screening: a report from the National Institute of Occupational Safety and the Health National Occupational Hazard Survey". Journal of Occupational Medicine 28 (10): 906–912. doi:10.1097/00043764-198610000-00003. PMID 3021937. ^ Osha.gov

US Dept. of Labor - Occupational Safety and Health Admin.

^ Murthy LI, Halperin WE (1995). "Medical Screening and Biological Monitoring: A guide to the literature for physicians". Journal of Occupational and Environmental Medicine 37 (2): 170–184. doi:10.1097/00043764-199502000-00016. PMID 7655958. ^ Moltz KC, Postellon DC (1994). "Congenital hypothyroidism and mental development". Comprehensive Therapy 20 (6): 342–346. PMID 8062543. ^ Pashapour N, Nikibahksh AA, Golmohammadlou S (2007). "Urinary tract infection in term neomates with prolonged jaundice". Urol J. 4 (2): 912–914. PMID 17701928. ^ Harvard.edu ^ Harvard.eduv · d · e Medical testing : Medical imaging · Radiology · (ICD-9-CM V3 87-88, ICD-10-PCS B, CPT 70010-79999)

X-ray/ medical radiography 2D Pneumoencephalography · Dental radiography · Sialography · Myelography · CXR (Bronchography) · AXR / KUB · DXA/DXR · Upper gastrointestinal series/Small bowel follow-through/Lower gastrointestinal series · Cholangiography/Cholecystography · Mammography · Pyelogram · Cystography · Arthrogram · Hysterosalpingography · Skeletal survey

vascular: Angiography (Angiocardiography, Aortography) · Venography · Lymphogram

3D / XCT CT pulmonary angiogram · Cardiac CT · Abdominal and pelvic CT (Virtual colonoscopy) · CT angiography · CT head · pQCT · Spiral computed tomography · High resolution CT Whole body imaging (Full-body CT scan) · Electron beam tomography

Other Fluoroscopy


MRI MRI of brain and brain stem · MR neurography · Cardiac MRI/Cardiac MRI perfusion · MR angiography · MR cholangiopancreatography · Breast MRI Functional MRI · Diffusion MRI

Ultrasound Echocardiography / Doppler echocardiography (TTE · TEE) · Intravascular · Gynecologic · Obstetric · Echoencephalography · Transcranial doppler · Abdominal ultrasonography · Transrectal · Breast ultrasound · Transscrotal ultrasound · Carotid ultrasonography Contrast-enhanced · 3D ultrasound · Endoscopic ultrasound · Emergency ultrasound (FAST) · Duplex

Radionuclide 2D / scintigraphy Cholescintigraphy · Scintimammography · Ventilation/perfusion scan · Radionuclide ventriculography · Radionuclide angiography · Radioisotope renography · Sestamibi parathyroid scintigraphy · Radioactive iodine uptake test · Bone scintigraphy

full body: Octreotide scan · Gallium 67 scan · Indium 111 WBC scan

3D / ECT SPECT (gamma ray): SPECT of brain, Myocardial perfusion imaging PET (positron): Brain PET, Cardiac PET, PET mammography, PET-CT


Optical laser Optical tomography (Optical coherence tomography) · Confocal microscopy

Thermography Breast thermography

v · d · e Medical test: Reference range, Urine tests (CPT 81000-81099)

Protein Albumin · Myoglobin · hCG · Leukocyte esterase · Urine pregnancy test

Small molecules Ketone bodies · Glucose · Urobilinogen · Bilirubin · Creatinine

Blood cells RBC · WBC

Chemical properties Urine specific gravity · Urine osmolality · pH · Urine anion gap

Other Urinary casts


M: URI anat/phys/devp/cell noco/acba/cong/tumr, sysi/epon, urte proc/itvp, drug (G4B), blte, urte


v · d · e Medical test: Serology, reference range: Clinical biochemistry blood tests (including BMP, CMP) (CPT 82000-84999)

Fluid/electrolytes electrolytes (Na+/K+, Cl-/HCO3-) · renal function, BUN-to-creatinine ratio (BUN/Creatinine) · Ca derived values: Plasma osmolality · Serum osmolal gap

Acid-base Arterial blood gas · Base excess · Anion gap · CO2 content

Nutrition Iron tests: Transferrin saturation = Serum iron / Total iron-binding capacity; Ferritin · Transferrin · Transferrin receptor

Endocrine ACTH stimulation test · Thyroid function tests (TSH) Blood sugar: Glucose test · C-peptide · Fructosamine · Glycated hemoglobin

Metabolic Blood lipids

Cardiovascular Cardiac marker: Troponin test · CPK-MB test · LDH · Myoglobin · Glycogen phosphorylase isoenzyme BB

Digestive Liver function tests: protein tests (Human serum albumin, Serum total protein) · ALP · transaminases (ALT, AST, AST/ALT ratio) · Bilirubin (Unconjugated, Conjugated) Amylase · Lipase (Pancreatic lipase)


M: URI anat/phys/devp/cell noco/acba/cong/tumr, sysi/epon, urte proc/itvp, drug (G4B), blte, urte


M: END anat/phys/devp/horm noco(d)/cong/tumr, sysi/epon proc, drug (A10/H1/H2/H3/H5)


M: HRT anat/phys/devp noco/cong/tumr, sysi/epon, injr proc, drug (C1A/1B/1C/1D), blte


M: DIG anat(t, g, p)/phys/devp/enzy noco/cong/tumr, sysi/epon proc, drug(A2A/2B/3/4/5/6/7/14/16), blte


v · d · e Medical test: Myeloid blood tests (CPT 85002-85999)

MEP Clotting

(megakaryocytes)

CBC (Platelet count) · Mean platelet volume · vWF: Ristocetin induced platelet agglutination

clotting factors: Prothrombin time · Partial thromboplastin time · Thrombin time

other/general coagulation: Bleeding time · animal enzyme (Reptilase time, Ecarin clotting time, Dilute Russell's viper venom time) · Thromboelastography fibrinolysis: Euglobulin lysis time · D-dimer

Red blood cell indices

(erythrocytes)

CBC (RBC count, Hematocrit, Hemoglobin)

ratios: Mean corpuscular hemoglobin · Mean corpuscular hemoglobin concentration · Mean corpuscular volume

Fetal hemoglobin: Apt-Downey test · Kleihauer-Betke test · Red blood cell distribution width

Reticulocyte index · Haptoglobin Mentzer index


CFU-GM Nitro blue tetrazolium chloride test · CBC (Absolute neutrophil count)

Other Blood film · Blood viscosity · Erythrocyte sedimentation rate


M: MYL cell/phys (coag, heme, immu, gran), csfs rbmg/mogr/tumr/hist, sysi/epon, btst drug (B1/2/3+5+6), btst, trns


v · d · e Medical test: Reference ranges, CSF tests (CPT 82000-84999)

Albumin CSF albumin · CSF/serum albumin ratio

Glucose CSF glucose · CSF/serum glucose ratio

Other Baricity

see also reference ranges for urine tests M: CNS anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug(N1A/2AB/C/3/4/7A/B/C/D)


v · d · e Medical test: Immunologic techniques and tests (CPT 86000-86849)

Immunologic techniques

and tests ·

serology/ diagnostic immunology Immunoprecipitation Chromatin immunoprecipitation · Immunodiffusion (Ouchterlony double immunodiffusion, Radial immunodiffusion, Immunoelectrophoresis, Counterimmunoelectrophoresis)

Immunoassay ELISA · ELISPOT · Enzyme Multiplied Immunoassay Technique · RAST test · Radioimmunoassay · Radiobinding assay · Immunofluorescence

Agglutination Hemagglutination/Hemagglutinin (Coombs test) · Latex fixation test

Other Nephelometry · Complement fixation test · Immunocytochemistry · Immunohistochemistry (Direct fluorescent antibody) · Epitope mapping · Skin allergy test · Patch test


Inflammation C-reactive protein · Procalcitonin

Total complement activity · MELISA CBC (lymphocyte count)


M: LMC cell/phys/auag/auab/comp, igrc imdf/ipig/hyps/tumr proc, drug(L3/4)


v · d · e Medical test: Antibodies: autoantibodies

Anti-nuclear antibody PBC: Anti-gp210 · Anti-p62 · Anti-sp100

ENA: Anti-topoisomerase/Scl-70 · Anti-Jo1 · ENA4 (Anti-Sm, Anti-nRNP, Anti-Ro, Anti-La)

Anti-centromere Anti-dsDNA

Anti-mitochondrial antibody Anti-cardiolipin

Anti-cytoplasm antibody Anti-neutrophil cytoplasmic (C-ANCA, P-ANCA) · Anti-smooth muscle (Anti-actin) · Anti-TPO/Antimicrosomal

Cell membrane Anti-ganglioside · Anti-GBM

Extracellular Anti-thrombin · Lupus anticoagulant

Gluten sensitivity: Anti-transglutaminase · (Anti-gliadin not autoantibody) RA (Rheumatoid factor/anti-IgG, Anti-citrullinated peptide)

Multiple locations Anti-phospholipid · Anti-apolipoprotein

Ungrouped Anti-glutamate receptor antibodies


M: LMC cell/phys/auag/auab/comp, igrc imdf/ipig/hyps/tumr proc, drug(L3/4)


v · d · e Transfusion medicine

General concepts Apheresis (plasmapheresis, plateletpheresis, leukapheresis) · Blood transfusion · Coombs test (direct and indirect) · Cross-matching · Exchange transfusion · International Society of Blood Transfusion · Intraoperative blood salvage · ISBT 128 · Transfusion reactions

Blood group systems/ blood types ABO · Chido-Rodgers · Colton · Cromer · Diego · Dombrock · Duffy · Gerbich · GIL · Hh · Ii · Indian · JMH · Kell (Xk) · Kidd · Knops · LW · Lewis · Lutheran · MNS · OK · P · Raph · Rh and RHAG · Scianna · T-Tn · Xg · Yt · Other

Blood products/ blood donation Whole blood · Platelets · Red blood cells · Plasma/Fresh frozen plasma/PF24 (Cryoprecipitate + Cryosupernatant) · Blood substitutes


M: MYL cell/phys (coag, heme, immu, gran), csfs rbmg/mogr/tumr/hist, sysi/epon, btst drug (B1/2/3+5+6), btst, trns


v · d · e Medical test: Infectious blood tests (CPT 87001-87999)

Bacterial infection syphilis (VDRL, rapid plasma reagin, Wassermann test, FTA-ABS) · Rickettsia (Weil-Felix test) · Helicobacter (HelicoCARE direct) · Streptococcus (antistreptolysin O titre)

Viral infection HIV (HIV test, BDNA test, mChip) · Epstein-Barr virus (monospot test) · Dengue fever (NS1 antigen test)

Protozoan infection toxoplasmosis (Sabin-Feldman dye test)


M: BAC bact (clas) gr+f/gr+a(t)/gr-p(c)/gr-o drug(J1p, w, n, m, vacc)


M: VIR virs(prot)/clss cutn/syst (hppv/hiva, infl/zost/zoon)/epon drugJ(dnaa, rnaa, rtva, vacc)


M: PRO ambz, excv, chrm (strc) ambz, excv, chrm ambz, excv, chrm


v · d · e Medicine: Pathology

Principles of pathology Disease/Medical condition (Infection, Neoplasia) · Hemodynamics (Ischemia) · Inflammation · Wound healing

Cell death: Necrosis (Liquefactive necrosis, Coagulative necrosis, Caseous necrosis, Fat necrosis) · Apoptosis · Pyknosis · Karyorrhexis · Karyolysis

Cellular adaptation: Atrophy · Hypertrophy · Hyperplasia · Dysplasia · Metaplasia (Squamous, Glandular) accumulations: pigment (Hemosiderin, Lipochrome/Lipofuscin, Melanin) · Steatosis

Anatomical pathology Surgical pathology · Cytopathology · Autopsy · Molecular pathology · Forensic pathology · Dental pathology Gross examination · Histopathology · Immunohistochemistry · Electron microscopy · Immunofluorescence · Fluorescent in situ hybridization

Clinical pathology Clinical chemistry · Hematopathology · Transfusion medicine · Medical microbiology · Diagnostic immunology · Immunopathology Enzyme assay · Mass spectrometry · Chromatography · Flow cytometry · Blood bank · Microbiological culture · Serology

Specific conditions Myocardial infarction

v · d · e Medical test: Electrodiagnosis

Electrocardiography Vectorcardiography · Magnetocardiography

Central nervous system Electroencephalography (Intracranial EEG) · Magnetoencephalography

Peripheral nervous system Electromyography (Facial electromyography) · Nerve conduction study

Eyes Electronystagmography · Electrooculography · Electroretinography

Digestive system Electrogastrogram · Magnetogastrography


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Gerald Ogessa [edit]

Orgz1900@hotmail.de [edit]

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Gerald Ogessa [edit]

Orgz1900@hotmail.de [edit]

German eGovernment]

http://en.wikiversity.org/wiki/Psycholinguistics/Hemispheric_Lateralization#Split_Brain_Studies [edit]

Introduction [edit]

Hemispheric lateralization refers to the distinction between functions of the right and left hemispheres of the brain. If one hemisphere is more heavily involved in a specific function, it is often referred to as being dominant (Bear et al., 2007). Language is a function believed to be heavily lateralized: it is believed that certain aspects of language are localized in the left hemisphere, while others are found in the right, with the left hemisphere most often considered to be dominant. This was initially proposed by early lesion-deficit models and studies with split-brain patients, and has been shown in more recent years through tests like the Wada test and imaging studies. There have been studies which show that there are anatomic asymmetries located near and around the regions associated with language, and each hemisphere has shown to play its own but separate role in the production and comprehension of speech. The hemispheric lateralization of language functions has been suggested to be associated with both handedness, sex, bilingualism, sign-language, and a variance amongst cultures. It has also been proposed that a reorganization occurs following brain injury that involves a shifting of lateralized function, as long as the injury occurs early in life.

The History of Discoveries [edit]

Jean Baptiste Bouillaud and Simon Alexandre Ernest Aubertin [edit]

French physician Jean Baptiste Bouillaud (1796-1881) was one of the earliest proponents of hemispheric language lateralization. On February 21, 1825, Bouillaud presented a paper to the Royal Academy of Medicine in France which suggested that, because so many human tasks are performed using the right hand (such as writing), that the section of the brain which is in control of that hand might be the left hemisphere; this observation implies that language, at the core of writing, would be localized in the left hemisphere. It was already known at this time that motor function was primarily controlled by the hemisphere ipsilateral to the side of the body through lesion studies. Bouillaud also proposed that speech is localized in the frontal lobes, a theory that was carried on by Bouillaud’s son-in-law Simon Alexandre Ernest Aubertin (1825-1893), who went on to work with famed French neurologist Paul Broca in 1861. Together, Aubertin and Broca examined a patient with a left frontal lobe lesion who had lost nearly all ability to speak; this case and several others similar to it became the basis behind the earliest theories of language lateralization.

Paul Broca [edit]

French neurologist Paul Broca (1824-1880) is often credited as being the first to expound upon this theory of language lateralization. In 1861, a 51 year old patient named Leborgne came to Broca; Leborgne was almost completely unable to speak and suffered from cellulitis of the right leg. Leborgne was able to comprehend language but was mostly unable to produce it. He responded to almost everything with the word “tan” and thus came to be known as Tan. Broca theorized that Tan must have a lesion of the left frontal lobe, and this theory was confirmed in autopsy when Tan died later that year (Bear et al., 2007). In 1863, Broca published a paper in which he described the eight cases of patients with damage to the left frontal lobe, all of whom had lost their ability to produce language, and included evidence of right frontal lesions having little effect on articulate speech (Bear et al., 2007). This led Broca to propose in 1864 that the expression of language is controlled by a specific hemisphere, most often the left (Bear et al., 2007). “On parle avec l’hemisphere gauche,” Broca concluded (Purves et al., 2008)- we speak with the left hemisphere.

Carl Wernicke [edit]

German anatomist Carl Wernicke (1848-1904) is also known as an early supporter of the theory of language lateralization. In 1874, Wernicke found an area in the temporal lobe of the left hemisphere, thus distinct from that which Broca had described, which disrupted language capabilities (Bear et al., 2007). He then went on to provide the earliest map of left hemisphere language organization and processing.

Methods of Assessing Lateralization [edit]

Lesion Studies [edit]

A good deal of what we know regarding language lateralization comes from studying the loss of language abilities following brain injury (Bear et al., 2007). Aphasia, the partial or complete loss of language abilities occurring after brain damage, is the source of much of the information on this subject (Bear et al., 2007). As shown in the studies of Bouillaud, Aubertin, Broca and Wernicke described above, lesion studies combined with autopsy reports can tell us a good deal about localization of language, which ultimately has supplied information on lateralization. Lesion studies have shown that, not only is the left cerebral hemisphere most often dominant for language, but also that the right hemisphere generally is not, as lesions in the right hemisphere rarely disturb speech and language function (Bear et al., 2007).

The dangers of using lesion studies are, of course, that they may overemphasize the relevance of particular localized areas and their associated functions. The connection between brain regions and behaviours is not usually quite so simple, and is based on a larger network of connections. This is shown in the fact that the severity of an individual’s aphasia is often related to the amount of tissue damaged around the lesion itself (Bear et al., 2007). It is also known that there is a difference in the severity of the deficit depending on whether the area was removed surgically, or was caused by stroke. This is the case because strokes affect both the cortex and the subcortical structures due to the location of the middle cerebral artery, which supplies blood to the areas associated with language, as well as the basal ganglia, and is often the cause of stroke. As such, surgically produced lesions tend to have milder effects than those resulting from stroke (Bear et al., 2007).

Split Brain Studies [edit]

Studies of patients who have had commissurotomies (split-brain patients) have provided significant information about language lateralization. Commissurotomy is a surgical procedure in which the hemispheres are disconnected by cutting the corpus callosum, the massive bundle of 200 million axons connecting the right and left hemisphere (Bear et al., 2007). Following this procedure, almost all communication between the hemispheres is lost, and each hemisphere then acts independently of the other. What is striking about split-brain patients with regards to the study of language lateralization is that a word may be presented to the right hemisphere of a patient whose left hemisphere is dominant, and when the patient is asked to name the word they will say that nothing is there, because although the right hemisphere “saw” the word, it is the left hemisphere which “speaks.” If that same word is presented to the left hemisphere, the patient is able to verbalize the response (Bear et al., 2007). As such, split-brain patients have presented substantial evidence that language function is generally lateralized in the left hemisphere.

Wada test [edit]

The Wada test was created by Juhn Wada at the Montreal Neurological Institute in 1949, and was designed specifically to study lateralization. A fast-acting barbiturate such as sodium amytal is injected into the carotid artery on one side (although current procedures prefer to use a catheter which is inserted into the femoral artery), and is then transported to the cerebral hemisphere on the opposite side. It then serves to anaesthetize that side of the brain for approximately 10 minutes, after which it begins to wear off and the functions which were disrupted by the anaesthetic gradually return, often displaying aphasic errors (Bear et al., 2007; Wada and Rasmussen, 1960). During the time in which the patient is anaesthetized, they are assessed on their ability to use language. If the left hemisphere is anaesthetized and is the dominant hemisphere, the patient loses all ability to speak, whereas if the left hemisphere is anaesthetized but the right hemisphere is dominant, the patient will continue to speak throughout the procedure (Bear et al., 2007).

In a study published in 1977, Brenda Milner used the Wada test to demonstrate that 98% of left-handed people and 70% of right handed people have a dominant left hemisphere with regards to language and speech function. Her results also showed that 2% of right-handed people have a dominant right hemisphere, which is the same percentage of patients that display aphasia following a lesion to the right hemisphere (Branch et al., 1964).

This procedure is also used prior to brain surgery in order to determine the dominant hemisphere, so as to avoid removal of an area associated with speech and language.

Electrical stimulation, TMS and Imaging [edit]

Electrical stimulation was pioneered by Wilder Penfield and his colleagues at the Montreal Neurological Institute in the 1930’s, and helped to identify certain lateralized areas associated with speech and language. Electrical stimulation is the application of an electrical current directly to the cortical tissue of a patient who is conscious. Penfield found that stimulating the left frontal or temporal regions of the left hemisphere with an electrical current accelerated the production of speech (Penfield, 1961). He also found that stimulation can cause inhibition in complex functions like language, as applying a current to the areas associated with speech production in the left hemisphere while the patient is engaged in speech serves to disrupt this behaviour. This procedure is performed during surgery when the skull is removed, and as such it is not a commonly used method of assessment.

Transcranial Magnetic Stimulation (TMS) is a non-invasive procedure, often combined in studies with MRI, which has helped to map the regions associated with speech, showing lateralization to be dominant in the left hemisphere. TMS has also shown that, following brain injury, it is more likely that it is the tissue surrounding the lesion that acts in a compensatory way rather than the opposite hemisphere providing compensation (Kolb and Whishaw, 2009). The major drawback of TMS is, of course, the fact that the magnetic stimulation must pass through the scalp, skull, and meninges before stimulating the brain region of choice (Kolb and Whishaw, 2009).

Imaging studies have proven to be incredibly useful in determining lateralization of language abilities. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have been able to show the complex circuitry associated with speech and language, and have also proven to be consistent with the findings from previous lesion studies, as well as Penfield’s electric stimulation (Bear et al., 2007). There has been some controversy regarding bilateral activation shown in fMRI studies, the reasons unknown, however it has been suggested that perhaps the right hemisphere is involved in aspects of speech that are not measured by such tests as the Wada procedure (Bear et al., 2007). A significant finding is that fMRI results during developmental years show activation during speech and the use of language mainly in the left hemisphere, providing further evidence in support of left hemisphere dominance (Bear et al., 2007).

Cerebral Dominance and Language Functions of the Left and Right Hemispheres [edit]

The left hemisphere is, in most people, dominant in terms of the capacity for speech. It is thought that areas involved in speech production and comprehension are both localized in the left cerebral hemisphere, around the Sylvian fissure. This may be the result of subtle anatomical asymmetries, discussed in more detail below.

The left hemisphere has been shown to be dominant in speech production and comprehension, represented physiologically in the areas known as Broca's and Wernicke's regions. Electrophysiological recording from George Ojemann and his colleagues at the University of Washington show that the perisylvian cortex of the left hemisphere is involved in language production (localized in Broca's region, at the left end of the left hemisphere's Sylvian fissure, in the inferior frontal gyrus) and comprehension (localized in Wernicke's region, in the right end of the left hemisphere's Sylvian fissure, in the temporal lobe) (Purves et al., 2008). Roger Sperry and his colleagues’ split-brain studies have shown that the left hemisphere is also responsible for lexical and syntactic language capabilities (grammatical rules, sentence structure), writing, and speech (Purves at al., 2008). Other aspects of language which are thought to be governed in most people by the left hemisphere include audition of language-related sounds, recognition of letters and words, phonetics and semantics.

The right hemisphere, though generally not dominant in terms of linguistic ability, has its role in the use of language. Although the right hemisphere has no “speech,” it is still able to understand language through the auditory system, the evidence of which can be found in split-brain studies, and also has shows a small amount of reading ability and word recognition. It is suggested that pitch perception is dependent on areas in the right hemisphere (Zatorre et al., 2002), which plays an important role in the understanding of prosody and emotion in language. Lesion studies of patients who have right hemisphere lesions show a reduction in verbal fluency and deficits in the understanding and use of prosody, indicating tha such functions are likely lateralized in the right hemisphere. Patients who have had their right hemisphere surgically removed (hemispherectomy) show no aphasia, but do show less obvious deficiencies in areas such as verbal selection and understanding of metaphor. It has thus been concluded that the right hemisphere is most often responsible for the prosodic and emotional elements of speech and language (Purves et al., 2008).

It has been suggested by Zatorre et al. (2002) that auditory information is processed in stages, with both cerebral hemispheres contributing to different aspects. Their study (2002)proposes that phonetic decisions are made in Broca's area in the left hemisphere, following which phonetic analysis and comprehension of phonetic segments is made in the left posterior temporal region. Phonetic processing is suggested to occur in the left supramarginal gyrus. According to their study, the right hemisphere controls the judgment of pitch.

Anatomical Asymmetries [edit]

The structural differences between the right and left hemisphere may play a role in the lateralization of language. In the nineteenth century, anatomists observed that the left hemisphere’s sylvian fissure is longer and less steep than that of the right (Bear et al., 2007). In 1980, Graham Ratcliffe and his colleagues used evidence of this asymmetry of the sylvian fissure, shown in carotid angiogram, with results of Wada testing and found that those with speech regions located in the left hemisphere had a mean difference of 27 degrees in the angle of the blood vessels leaving the posterior end of the sylvian fissure, while those with language located in the right hemisphere had a mean angle of zero degrees (Kolb and Whishaw, 2009).

In the 1960s, Norman Geschwind and his colleagues at Harvard Medical School found that the planum temporal, the superior portion of the temporal lobe, is larger in the left hemisphere in almost two thirds of humans, an observation with was later confirmed with MRI (Bear et al., 2007; Purves et al., 2008). This asymmetry exists even in the brain of the human fetus (Bear et al., 2007). The correlation of this asymmetry with the left hemisphere’s language dominance is refuted by many due to the fact that 67% of people show this structural asymmetry, while 97% show left hemispheric dominance.

Proposed Correlations [edit]

Handedness [edit]

The correlation between handedness and hemispheric lateralization is described in the results of the Wada test, described above. The majority of the population is right handed (approximately 90%), and the Wada test results propose that 93% of people’s left hemisphere is dominant for language (Bear et al., 2007). But correlation does not necessarily imply causation, and it is believed that there is no direct relationship between handedness and language, as the majority of left-handers also have their language lateralized in the left hemisphere (Purves et al., 2008). It is, however, a physical example of functional asymmetry, and it is certainly possible that a more substantial connection between handedness and language will be found.

Sex Differences [edit]

The tendency for women to score higher than men on language-related tasks is perhaps the result of the fact that women also tend to have a larger corpus callosum than men, indicating more neural connections between the right and left hemispheres (Jay, 2003). fMRI studies show that women have more bilateral activation than men when performing rhyming tasks, and PET studies show that women have more bilateral activation than men during reading tasks (Jay, 2003). Perhaps the bilateral activation implies the use of what are thought to be right hemisphere language abilities, such as prosody and intonation. Research has also shown that women have a greater ability to recover from left hemisphere brain damage; the evidence provided by the imaging studies in combination with the results of recovery following injury have led to the controversial suggestion that language is more unilateral in men than in women (Jay, 2003).

Sign Language and Bilingualism [edit]

Sign language has shown to be lateralized in the left hemisphere of the brain, in the left frontal and temporal lobes. This is known through the use of lesion studies in which the patient had left hemisphere lesion in the areas associated with language which impaired their ability to sign, while right hemisphere lesions in the same areas show no linguistic deficit (Purves et al., 2008). Lesions in the right hemisphere of signers did, however, show a limited use of spatial information encoded iconically (which is when the sign is similar looking to its referent) (Jay, 2003). This is in keeping with the belief that visuo-spatial ability is a right hemisphere function and suggests that the role of the right hemisphere in sign language is in the non-linguistic features of sign language (Jay, 2003).

Bilingualism is thought to be an overlapping of populations of neurons corresponding to each language, all of which are located in the frontal and temporal regions of the left hemisphere associated with speech comprehension and speech production (Jay, 2003).

Culture and Language Lateralization [edit]

When thinking of language there is a tendency to focus on that language in which you think, however it has been proposed that lateralization of language functions can vary from culture to culture. Asian languages show more bilateral activation during speech than European languages, likely because Asian languages employ a far greater use of right hemisphere abilities, for example prosody, and the use of spatial processing for the more “pictorial” Chinese characters; Native American languages also show a good deal of bilateral activity (Kolb and Whishaw, 2009).

Reorganization following brain injury [edit]

Studies have been done following brain injury to determine the level of recovery of language and speech ability, and whether or not recovery is based on lateralized function. Bryan Woods and Hans-Leukas Teuber looked at patients with prenatal and early postnatal brain injury located in either the right or left hemisphere and drew several conclusions. First, if the injury occurs very early, language ability may survive even after left hemisphere brain damage. Second, they found that an appropriation of language regions by the right hemisphere is responsible for the survival of these abilities, but because of this there is a tendency for visuo-spatial ability to be diminished. Third, right hemisphere lesions have the same effect in prenatal and early postnatal patients as they do in adults (Kolb and Whishaw, 2009). Brenda Milner and Ted Rasmussen used the Wada test to determine that early brain injury can cause either left, right or bilateral speech dominance, and that those who retained left hemisphere dominance had damage that was not in either the anterior (Broca’s) or posterior (Wernicke’s) speech zone (Kolb and Whishaw, 2009). Those whose dominance shifted to the right hemisphere most often had damage to these areas. Milner and Rasmussen also found that brain damage which occurs after the age of 5 does not cause a shift in lateralization but rather reorganizes within the hemisphere, potentially employing surrounding areas to take responsibility for some aspects of speech (Kolb and Whishaw, 2009).

In patients who have had hemispherectomy of the left hemisphere, the right hemisphere can often gain considerable language ability. When performed in adulthood, speech comprehension is usually retained (though speech production suffers severe deficits); reading capability is small, and there is usually no writing capability at all (Kolb and Whishaw, 2009).

References [edit]

Bear, M. F., Connors, B. W., Paradiso, M. A. (2007). Neuroscience: Exploring the Brain, 3rd edition. Lippincott Williams & Wilkins: USA.

Branch, C., Milner, B., Rasmussen, T. (1964). Intracarotid Sodium Amytal for the Lateralization of Cerebral Speech Dominance. Journal of Neurosurgery, Vol. 21, No. 5, pp 399-405.

Jay, T. B. (2003). The Psychology of Language. Prentice Hall: New Jersey, USA.

Kolb, B., Whishaw, I. Q. (2009). Fundamentals of Human Neuropsychology, 6th edition. Worth Publishers: USA.

Penfield, W. (1961). Activation of the Record of Human Experience (Summary of the Lister Oration delivered at the Royal College of Surgeons of England, 27 April, 1961). The British Journal of Surgery, 1954, Vol. 41, pp 77-84.

Purves, D., Augustine, G. J., Fitzpatrick, D., Hall, W. C., LaMantia, A., McNamara, J. O., White, L. E. (2008). Neuroscience, 4th edition. Sinauer Associates, Inc.: Massachusetts, USA.

Wada, J., Rasmussen, T. (1960). Intracarotid Injection of Sodium Amytal for the Lateralization of Cerebral Speech Dominance Experimental and Clinical Observations. Journal of Neurosurgery, Vol. 17, No. 2.

Zatorre, R. J., Evans, A. C., Meyer, E., Gjedde, A. (1992). Lateralization of Phonetic and Pitch Discrimination in Speech Processing. Science, Vol. 256, No. 5058, pp 846-849.


http://en.wikiversity.org/wiki/Artificial_Consciousness/Neural_Correlates/Inter-Organ_Connection_Models [edit]

Inter Organ Connection Models

It is not enough to understand how a brain organ works, we need to understand how they work together as well. Often more than one organ is involved in the execution of a specific function of the brain. While there are hints of connections, that are mappable if we follow the main paths of neurons throughout the brain, mapping connections in the brain has been difficult up until now. However a recent discovery of a means of visualization of connections using a special MRI program suggests that we might soon have a more comprehensive idea of connections on many levels in the brain.

The following models suggest ways in which the different organs of the brain might work together. These are transient expressions of our current understanding of what the organs do, mixed with our current understanding of how they connect to each other. As more research is done into organic operation and their connections within the brain, we will be able to learn more about the functions of the organs, and how they work together, and this will reshape our knowledge about how the brain works.


http://en.wikiversity.org/wiki/Neuroanatomy [edit]

It is the anatomy of the nervous system;which can be divided into the central nervous system (C.N.S) & peripheral nervous system. central nervous system is the brain & spinal cord. which represent the origin of peripheral nerves C.N.S can be divided into following functional areas; 1- cerebral hemispheres 2- cerebellum 3- mid brain 4- pons 5- medulla 6- spinal cord

Cranial Nerves

I = Olfactory
II = Optic
III = Oculomotor
IV = Trochlear
V = Trigeminal
VI = Abducens
VII = Facial
VIII = Vestibulocochlear
IX = Glossopharyngeal
X = Vagus
XI = Accessory
XII = Hypoglossal

Additional resources [edit]



http://en.wikipedia.org/wiki/List_of_regions_in_the_human_brain [edit]

Template:Neuropsychology

Anatomical regions of the brain are listed vertically, following hierarchies that are standard in neuroanatomy. Functional, connective, and developmental regions are listed horizontally in parentheses where appropriate.

Hindbrain (Rhombencephalon) [edit]

Myelencephalon [edit]

Metencephalon [edit]

Midbrain (mesencephalon) [edit]

Forebrain (prosencephalon) [edit]

Diencephalon [edit]

Epithalamus [edit]

Third ventricle [edit]

Thalamus [edit]

Hypothalamus (limbic system) (HPA axis) [edit]

Subthalamus(HPA axis) [edit]

Pituitary gland (HPA axis) [edit]

Telencephalon (cerebrum) Cerebral hemispheres [edit]

Red:Frontal lobe

red:frontal lobe
orange:parietal lobe
yellow:occipital lobe
green: temporal lobe
blue:cerebellum
black:brainstem

White matter [edit]

Subcortical [edit]

Rhinencephalon (paleopallium) [edit]

Lateral ventricles [edit]

Cerebral cortex (neopallium) [edit]

Neural pathways [edit]

Motor systems [edit]

Nerves [edit]

Neuroendocrine systems [edit]

Vascular systems [edit]

Dural meningeal system [edit]

Related topic [edit]

Template:Nervous system

External links [edit]


fr:Liste de régions du cerveau humain ru:Структуры мозга

http://en.wikipedia.org/wiki/Red_Nucleus [edit]

Template:Unref Template:Confuse Template:Infobox Brain The red nucleus is a structure in the rostral midbrain involved in motor coordination. It comprises a caudal magnocellular and a rostral parvocellular part.

Function [edit]

In animals without a significant corticospinal tract, gait is mainly controlled by the red nucleus.

However, where the corticospinal tract is dominant, the rubrospinal tract may be considered to be vestigial. Therefore, here the red nucleus is less important in motor functions than in many other mammals. However, the crawling of babies is controlled by the red nucleus, as is arm-swinging in normal walking. The red nucleus may play an additional role in controlling muscles of the shoulder and upper arm via projections of its magnocellular part. In humans the red nucleus also has sparse control over hands, as the rubrospinal tract is more involved in large muscle movement such as that for arms (but not the legs, as the tract terminates in the superior thoracic region of the spinal cord). Fine control of the fingers is not modified by the functioning of the red nucleus (rather it relies on the corticospinal tract). The majority of red nucleus axons do not project to the spinal cord, but instead (via its parvocellular part) relay information from the motor cortex to the cerebellum through the inferior olivary complex- an important relay center in the medulla.

Input and output [edit]

The red nucleus receives many inputs from the contralateral cerebellum (interposed nucleus and lateral cerebellar nucleus) and an input from the ipsilateral motor cortex.

It sends efferent axons (the rubrospinal projection) to the contralateral half of the rhombencephalic reticular formation and spinal cord. These efferent axons cross just ventral to the anterior tegmental decussation and descend through the midbrain to the spinal cord, where the rubrospinal tract which they make up runs ventral to the lateral corticospinal tract in the lateral funiculus. Second bundle of fibers continues ipsilaterally through the medial tegmental field towards inferior olive.

See also [edit]

Additional images [edit]

  • Schematic representation of the chief ganglionic categories (I to V).

  • Deep dissection of brain-stem. Ventral view.

  • Transverse section through mid-brain.

  • Transverse section of mid-brain at level of superior colliculi.

  • Coronal section of brain immediately in front of pons.

  • Human brain frontal (coronal) section

  • Weber's syndrome.svg

External links [edit]

Template:Mesencephalon Template:Neural tracts

Template:Neuroanatomy-stub

de:Nucleus ruber es:Núcleo rojo fr:Noyau rouge pl:Jądro czerwienne

http://en.wikipedia.org/wiki/Substantia_nigra [edit]

Template:Infobox Brain

The substantia nigra is a brain structure located in the mesencephalon (midbrain) that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in dopaminergic neurons. Parkinson's disease is caused by the death of dopaminergic neurons in the substantia nigra pars compacta.

Although the substantia nigra appears as a continuous band in brain sections, anatomical studies have found that it actually consists of two parts with very different connections and functions, the pars compacta and pars reticulata. The pars compacta serves mainly as an input to the basal ganglia circuit, supplying the striatum with dopamine. The pars reticulata, on the other hand, serves mainly as an output, conveying signals from the basal ganglia to numerous other brain structures.

Anatomy [edit]

Diagram of the main components of the basal ganglia and their interconnections.
Anatomical overview of the main circuits of the basal ganglia. Substantia nigra is shown in black. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.
See also: Primate basal ganglia system

The substantia nigra, along with four other nuclei, is part of the basal ganglia. The substantia nigra lies in the midbrain, dorsal to the cerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline. The substantia nigra is the largest nucleus in the midbrain. The substantia nigra is divided into two parts: the pars reticulata (SNr) and pars compacta (SNc), which lies medial to the pars reticulata. Sometimes a third region, the pars lateralis, is mentioned; however, this is usually classified as part of the pars reticulata. The pars reticulata and the internal globus pallidus are separated by the internal capsule.

Pars reticulata [edit]

Main source: Pars reticulata

The SNr bears a strong resemblance, both structurally and functionally, to the internal part of the globus pallidus (GPi). The two are sometimes considered parts of the same structure, separated by the white matter of the internal capsule. Like those of the globus pallidus, the neurons in SNr are mainly GABAergic.

Afferent connections [edit]

The main input to the SNr derives from the striatum. It comes by two routes, known as the direct and indirect pathways. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to SNr. The indirect pathway consists of three links, first a projection from striatal medium spiny cells to the external part of the globus pallidus (GPe); second a GABAergic projection from GPe to the subthalamic nucleus (STN); third a glutamatergic projection from STN to SNr.[1] Thus, striatal activity exerts an excitatory (or rather disinhibitory) effect on SNr neurons via the direct pathway, but an inhibitory effect via the indirect pathway. The direct and indirect pathways originate from different subsets of striatal medium spiny cells: they are tightly intermingled but express different types of dopamine receptors, as well as showing other neurochemical differences.

Efferent connections [edit]

There are significant projections to the thalamus (ventral lateral and ventral anterior nuclei), superior colliculus, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway).[2] These neurons use GABA as their neurotransmitter. In addition, these neurons form up to five collaterals that branch within both the pars compacta and pars reticulata, likely modulating dopaminergic activity in the pars compacta.[3]

Function [edit]

The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward seeking, learning, and addiction. Many of the substantia nigra's effects are mediated through the striatum. The nigral dopaminergic input to the striatum via the nigrostriatal pathway is intimately linked with the striatum's function.[4] The co-dependence between the striatum and substantia nigra can be seen in this way: when the substantia nigra is electrically stimulated, no movement occurs; however, the symptoms of nigral degeneration due to Parkinson's is a poignant example of the substantia nigra's influence on movement. In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.

Pars Reticulata [edit]

Main source: Pars_reticulata#Function

The pars reticulata of the substantia nigra is an important processing center in the basal ganglia. The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia to the thalamus and superior colliculus. In addition, the pars reticulata also inhibits dopaminergic activity in the pars compacta via axon collaterals, although the functional organization of these connections remains unclear.

The GABAergic neurons of the pars reticulata spontaneously fire action potentials. In rats, the frequency of action potentials is roughly 25 Hz.[5] The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement.[6] The subthalamic nucleus gives excitatory input that modulates the rate of firing of these spontaneous action potentials. However, lesion of the subthalamic nucleus leads to only a 20% decrease in pars reticulata firing rate, suggesting that the generation of action potentials in the pars reticulata is largely autonomous.[7] An example of this inhibitory output is the important role of the pars reticulata in saccadic eye movement. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus. This connection exhibits a high level of sustained, inhibitory activity.[8] Projections from the caudate nucleus to the superior colliculus also modulate saccadic eye movement. Altered patterns of pars reticulata firing such as single-spike or burst firing are found in Parkinson's disease[9] and epilepsy.[10]

Pars Compacta [edit]

Main source: Pars_compacta#Function

The most prominent function of the pars compacta is motor control.[11] However, the substantia nigra's role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement. This is due to the mediation of the striatum in the nigral influence of movement. However, lack of pars compacta neurons clearly has a large influence on movement, as evidenced by the symptoms of Parkinson's. The motor role of the pars compacta may involve fine motor control; this has been confirmed in animal models with lesions in the pars compacta.[12]

The pars compacta is heavily involved in learned responses to stimuli. In primates, dopaminergic neuron activity increases in the nigrostriatal pathway when a new stimulus is presented.[13] Dopaminergic activity decreases with repeated stimulus presentation.[13] However, behaviorally significant stimulus presentation (such as classical conditioning where a reward is presented) continues to activate the dopaminergic neurons. This phenomenon helps explain the role of the dopamine system in the addictiveness of drugs. In addition, the pars compacta is important in "spatial learning," the observations about one's environment and location in space. Lesions in the pars compacta lead to learning deficits in repeating identical movements,[14] and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of the hippocampus, which is traditionally believed to subserve spatial or episodic-like memory functions.[15]

Temporal processing is also an important function of the pars compacta. The pars compacta is activated during time reproduction and lesions in the pars compacta leads to temporal deficits.[16] As of late, the pars compacta has been suspected of regulating the sleep-wake cycle.[17] This is consistent with symptoms such as insomnia and REM sleep disturbances that are reported by patients with Parkinson's disease. Even so, partial dopamine deficits that do not affect motor control can lead to disturbances in the sleep-wake cycle, especially REM-like patterns of neural activity while awake, especially in the hippocampus.[18]

Pathophysiology [edit]

The substantia nigra is critical in the development of many diseases, including Parkinson's disease.

Parkinson's Disease [edit]

Main source: Parkinson's disease

Parkinson's disease is a neurodegenerative disease characterized, in part, by the death of dopaminergic neurons in the pars compacta of the substantia nigra. The major symptoms of Parkinson's disease include tremor, akinesia, bradykinesia, and stiffness.[19] Other symptoms include disturbances to posture, fatigue, sleep abnormalities, and depression.[20]

The cause of death of dopaminergic neurons in the pars compacta is unknown. However, some contributions to the unique susceptibility of dopaminergic neurons in the pars compacta have been identified. For one, dopaminergic neurons show abnormalities in mitochondrial complex 1, causing aggregation of alpha-synuclein. This could result in abnormal protein handling and neuron death.[21] Secondly, dopaminergic neurons in the pars compacta contain less calbindin than other dopaminergic neurons.[22] Calbindin is a protein involved in calcium ion transport within cells, and excess calcium in cells is toxic. The calbindin theory would explain the high cytotoxicity of Parkinson's in the substantia nigra compared to the ventral tegmental area. Regardless of the cause of neuronal death, the plasticity of the pars compacta is very robust; Parkinsonian symptoms do not appear until up to 50-80% of pars compacta dopaminergic neurons have died.[23] Most of this plasticity occurs at the neurochemical level; dopamine transport systems are slowed, allowing dopamine to linger for longer periods of time in the chemical synapses in the striatum.[23]

Schizophrenia [edit]

See also: Dopamine hypothesis of schizophrenia

Increased levels of dopamine have long been implicated in the development of schizophrenia.[24] However, much debate continues to this day surrounding this theory, commonly known as the dopamine hypothesis of schizophrenia. Despite the controversy, dopamine antagonists remain a standard and successful treatment for schizophrenia. These antagonists include first generation (typical) antipsychotics such as butyrophenones, phenothiazines, and thioxanthenes. These drugs have largely been replaced by second generation (atypical) antipsychotics such as clozapine and paliperidone. It should be noted that these drugs generally do not act on dopamine-producing neurons themselves, but on the receptors on the post-synaptic neuron.

Other, non-pharmacological evidence in support of the dopamine hypothesis relating to the substantia nigra include structural changes in the pars compacta, such as reduction in synaptic terminal size.[25] Other changes in the substantia nigra include increased expression of NMDA receptors in the substantia nigra, and reduced dysbindin expression. Increased NMDA receptors may point to the involvement of glutamate-dopamine interactions in schizophrenia. Dysbindin, which has been (controversially) linked to schizophrenia, may regulate dopamine release, and low expression of dysbindin in the substantia nigra may be important in schizophrenia etiology.[26] Due to the changes to the substantia nigra in the schizophrenic brain, it may eventually be possible to use specific imaging techniques (such as melanin-specific imaging) to detect physiological signs of schizophrenia in the substantia nigra.[27]

Chemical Modification of the Substantia Nigra [edit]

Chemical manipulation and modification of the substantia nigra is important in the fields of neuropharmacology and toxicology. Various compounds such as levodopa and MPTP are used in the treatment and study of Parkinson's disease, and many other drugs have effects on the substantia nigra.

Levodopa [edit]

See also: Levodopa

The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease. Levodopa (L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson's disease. Despite controversy concerning the neurotoxicity of dopamine and L-DOPA,[28] it remains the most common treatment for Parkinson's disease. The drug is especially effective in treating patients in the early stages of Parkinson's, although the drug does lose its efficacy over time.[29] Levodopa can cross the blood-brain barrier and increases dopamine levels in the substantia nigra, thus alleviating the symptoms of Parkinson's disease. The drawback of levodopa treatment is that it treats the symptoms of Parkinson's (low dopamine levels), rather than the cause (the death of dopaminergic neurons in the substantia nigra).

MPTP [edit]

See also: MPTP

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), is a neurotoxin specific to dopaminergic cells in the brain, specifically in the substantia nigra. MPTP was brought to the spotlight in 1982 when heroin users in California displayed Parkinson's-like symptoms after using MPPP contaminated with MPTP. The patients, who were rigid and almost completely immobile, responded to levodopa treatment. No remission of the Parkinson's-like symptoms was reported, suggesting irreversible death of the dopaminergic neurons.[30] The proposed mechanism of MPTP involves disruption of mitochondrial function, including disruption of metabolism and creation of free radicals.[31]

Soon after, MPTP was tested in animal models for its efficacy in inducing Parkinson's disease (with success). MPTP induced akinesia, rigidity, and tremor in primates, and its neurotoxicity was found to be very specific to the substantia nigra pars compacta.[32] In other animals, such as rodents, the induction of Parkinson's by MPTP is incomplete or requires much higher and frequent doses than in primates. Today, MPTP remains the most favored model for studying Parkinson's.[31]

Cocaine [edit]

See also: Cocaine

Cocaine's mechanism of action in the human brain includes the inhibition of dopamine reuptake.[33] This blockage of dopamine reuptake explains cocaine's addictive properties, as dopamine is the critical neurotransmitter for reward. However, cocaine is more active in the dopaminergic neurons of the ventral tegmental area than the substantia nigra. Cocaine administration increases metabolism in the substantia nigra, which can explain the altered motor function seen in cocaine-using subjects.[34] The inhibition of dopamine reuptake by cocaine also inhibits the firing of spontaneous action potentials by the pars compacta.[35] The mechanism by which cocaine inhibits dopamine reuptake involves its binding to the dopamine transporter protein, or DAT. However, recent studies show that cocaine can also cause a decrease in DAT mRNA levels.[36] This is probably caused by cocaine's blockade of DAT rather than direct interference with transcriptional or translational pathways.[36]

Inactivation of the substantia nigra could prove to be a possible treatment for cocaine addiction. In a study of cocaine-dependent rats, inactivation of the substantia nigra via implanted cannulae greatly reduced cocaine addiction relapse.[37]

Amphetamines [edit]

See also: Amphetamines

Like cocaine, amphetamine increases the concentrations of dopamine in the synaptic cleft, thereby heightening the response of the post-synaptic neuron.[38] Also like cocaine, the altered dopamine function contributes to the addictiveness of amphetamines.

The mechanism by which amphetamines increase synaptic levels of dopamine is to release dopamine from pre-synaptic vesicles, increasing concentrations of dopamine in the cytosol of the pre-synaptic neuron.[39] The high concentration of dopamine in the pre-synaptic terminal causes the reverse transport of dopamine through the dopamine transporter (DAT) and into the synaptic cleft.[40][41]

Additional images [edit]

  • Schematic representation of the chief ganglionic categories (I to V).

  • Deep dissection of brain-stem. Lateral view.

  • Deep dissection of brain-stem. Ventral view.

  • Coronal section through mid-brain.

  • Transverse section of mid-brain at level of inferior colliculi.

  • Transverse section of mid-brain at level of superior colliculi.

  • Coronal section of brain immediately in front of pons.

  • Human brain frontal (coronal) section

  • Dopamine and serotonin

  • Section through superior colliculus showing path of oculomotor nerve.

  • Periaqueductal MRI.PNG

    MRI section of mid-brain

  • Horizontal MRI (T1 weighted) slice with highlighting indicating location of the substantia nigra.

References [edit]

  1. ↑ Nauta, H J; Cole, M (1978). "Efferent projections of the subthalamic nucleus: an autoradiographic study in monkey and cat.". J Comp Neurol 180 (1): 1–16. doi:10.1002/cne.901800102. PMID 418083. 
  2. ↑ Carpenter, M B; Nakano, K; Kim, R (1976). "Nigrothalamic projections in the monkey demonstrated by autoradiographic technics". J Comp Neurol 165 (4): 401–15. doi:10.1002/cne.901650402. PMID 57125. 
  3. ↑ Deniau, J M; Kitai, S T; Donoghue, J P; Grofova, I (1992). "Neuronal interactions in the substantia nigra pars reticulata through axon collaterals of the projection neurons. An electrophysiological and morphological study.". Exp Brain Res 47 (1): 105–13. PMID 6288427. 
  4. ↑ Nicola, S M; Surmeier, J; Malenka, R C (2000). "Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens". Annu Rev Neurosci 23: 185–215. doi:10.1146/annurev.neuro.23.1.185. PMID 10845063. 
  5. ↑ Gernert, Manuela; Fedrowitz, Maren; Wlaz, Piotr; Loscher, Wolfgang (2004). "Subregional changes in discharge rate, pattern, and drug sensitivity of putative GABAergic nigral neurons in the kindling model of epilepsy.". Eur J Neurosci 20 (9): 2377–86. doi:10.1111/j.1460-9568.2004.03699.x. PMID 15525279. 
  6. ↑ Sato, Makoto; Hikosaka, Okihide (March 15, 2002). "Role of primate substantia nigra pars reticulata in reward-oriented saccadic eye movement.". J Neurosci 22 (6): 2363–73. PMID 11896175. 
  7. ↑ Zahr, Natalie May; Martin, Lynn Pauline; Waszczak, Barbara Lee (2004). "Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia.". Synapse 53 (2): 119–28. doi:10.1002/syn.20064. PMID 15352137. 
  8. ↑ Hikosaka, O; Wurtz, R H (1983). "Visual and oculomotor functions of monkey substantia nigra pars reticulata. III. Memory-contingent visual and saccade responses.". J Neurophysiol 49 (5): 1268–84. PMID 6864250. 
  9. ↑ Tseng, K Y; Riquelme, L A; Belforte, J E; Pazo, J H; Murer, M G (2000). "Substantia nigra pars reticulata units in 6-hydroxydopamine-lesioned rats: responses to striatal D2 dopamine receptor stimulation and subthalamic lesions.". Eur J Neurosci 12 (1): 247–56. doi:10.1046/j.1460-9568.2000.00910.x. PMID 10651879. 
  10. ↑ Deransart, Colin; Hellwig, Bernhard; Heupel-Reuter, Miriam; Leger, Jean-Francois; Heck, Detlef; Lucking, Carl Hermann (2003). "Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy.". Epilepsia 44 (12): 1513–20. doi:10.1111/j.0013-9580.2003.26603.x. PMID 14636321. 
  11. ↑ Hodge, G K; Butcher, L L (1980). "Pars compacta of the substantia nigra modulates motor activity but is not involved importantly in regulating food and water intake.". Naunyn Schmiedebergs Arch Pharmacol 313 (1): 51–67. doi:10.1007/BF00505805. PMID 7207636. 
  12. ↑ Pioli, E Y; Meissner, W; Sohr, R; Gross, C E; Bezard, E; Bioulac, B H (2008). "Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats.". Neuroscience 153 (4): 1213–24. doi:10.1016/j.neuroscience.2008.01.084. PMID 18455318. 
  13. ↑ 13.0 13.1 Ljungberg, T; Apicella, P; Schultz, W (January 1, 1992). "Responses of monkey dopamine neurons during learning of behavioral reactions.". J Neurophysio 67 (1): 145–63. PMID 1552316. 
  14. ↑ Da Cunha, Claudio; Silva, Marcio H C; Wietzikoski, Samantha; Wietzikoski, Evellyn C; Ferro, Marcelo M; Kouzmine, Ivana; Canteras, Newton S (2006). "Place learning strategy of substantia nigra pars compacta-lesioned rats.". Behav Neurosci 120 (6): 1279–84. doi:10.1037/0735-7044.120.6.1279. PMID 17201473. 
  15. ↑ Da Cunha, Claudio; Wietzikoski, Samantha; Wietzikoski, Evellyn C; Miyoshi, Edmar; Ferro, Marcelo M; Anselmo-Franci, Janete A; Canteras, Newton S (2003). "Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system.". Neurobiol Learn Mem 79 (3): 236–42. doi:10.1016/S1074-7427(03)00008-X. PMID 12676522. 
  16. ↑ Matell, M S; Meck, W H (2000). "Neuropsychological mechanisms of interval timing behavior.". Bioessays 22 (1): 94–103. doi:<94::AID-BIES14>3.0.CO;2-E 10.1002/(SICI)1521-1878(200001)22:1<94::AID-BIES14>3.0.CO;2-E. PMID 10649295. 
  17. ↑ Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Vital, Maria A B F; Tufik, Sergio (2007). "The role of the substantia nigra pars compacta in regulating sleep patterns in rats.". PLoS ONE 2 (6). doi:10.1371/journal.pone.0000513. PMID 17551593. 
  18. ↑ Dzirasa, Kafui; Ribeiro, Sidarta; Costa, Rui; Santos, Lucas M; Lin, Shih-Chieh; Grosmark, Andres; Sotnikova, Tatyana D; Gainetdinov, Raul R; Caron, Marc G; Nicolelis, Miguel A L (2006). "Dopaminergic control of sleep-wake states.". J Neurosci 26 (41): 10577–89. doi:10.1523/JNEUROSCI.1767-06.2006. PMID 17035544. 
  19. ↑ Jankovic J (April 2008). "Parkinson's disease: clinical features and diagnosis". J. Neurol. Neurosurg. Psychiatr. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045. PMID 18344392. 
  20. ↑ Adler, CH (2005). "Nonmotor complications in Parkinson's disease.". Movement Disorders 20: S23–9. doi:10.1002/mds.20460. PMID 15822106. 
  21. ↑ Dawson, T; Dawson, V (2003). "Molecular Pathways of Neurodegeneration in Parkinson's Disease". Science 302 (5646): 819–22. doi:10.1126/science.1087753. PMID 14593166. 
  22. ↑ Liang CL, Sinton CM, Sonsalla PK, German DC (1996). "Midbrain dopaminergic neurons in the mouse that contain calbindin-D28k exhibit reduced vulnerability to MPTP-induced neurodegeneration.". Neurodegeneration 5 (4): 313–8. doi:10.1006/neur.1996.0042. PMID 9117542. 
  23. ↑ 23.0 23.1 Interview. Yoland Smith, PhD
  24. ↑ van Rossum, J (1967). "{{{title}}}". Neuropsychopharmacology, Proceedings Fifth Collegium Internationale Neuropsychopharmacologicum: 321–9. 
  25. ↑ N. S. Kolomeets and N. A. Uranova (1997). "Synaptic contacts in schizophrenia: Studies using immunocytochemical identification of dopaminergic neurons". Neuroscience and Behavioral Physiology: 217–21. 
  26. ↑ Kumamoto, N (2006). "Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin.". Biochem Biophys Res Commun 345 (2): 904–9. doi:10.1016/j.bbrc.2006.04.163. PMID 16701550. 
  27. ↑ Shibata, Eri; Sasaki, Makoto; Tohyama, Koujiro; Otsuka, Kotaro; Endoh, Jin; Terayama, Yasuo; Sakai, Akio (2008). "Use of neuromelanin-sensitive MRI to distinguish schizophrenic and depressive patients and healthy individuals based on signal alterations in the substantia nigra and locus ceruleus.". Biol Psychiatry 64 (5): 401–6. doi:10.1016/j.biopsych.2008.03.021. PMID 18452894. 
  28. ↑ Cheng N, Maeda T, Kume T, et al. (December 1996). "Differential neurotoxicity induced by ?-DOPA and dopamine in cultured striatal neurons". Brain research 743 (1-2): 278–83. doi:10.1016/S0006-8993(96)01056-6. PMID 9017256. 
  29. ↑ Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL. (2003). "Limitations of current Parkinson's disease therapy.". Ann Neurol 53 (S3): S3–S15. doi:10.1002/ana.10513. PMID 12666094. 
  30. ↑ JW Langston, P Ballard, JW Tetrud, and I Irwin (1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis". Science 219 (4587): 979–80. doi:10.1126/science.6823561. PMID 6823561. 
  31. ↑ 31.0 31.1 Schmidt, N; Ferger, B (2001). "Neurochemical findings in the MPTP model of Parkinson's disease.". J Neural Transm 108 (11): 1263–82. doi:10.1007/s007020100004. PMID 11768626. 
  32. ↑ Langston, J W; Forno, L S; Rebert, C S; Irwin, I (1984). "Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey.". Brain Res 292 (2): 390–4. doi:10.1016/0006-8993(84)90777-7. PMID 6607092. 
  33. ↑ Heikkila, R E; Cabbat, F S; Duvoisin, R C (1979). "Motor activity and rotational behavior after analogs of cocaine: correlation with dopamine uptake blockade.". Commun Psychopharmacol 3 (5): 285–90. PMID 575770. 
  34. ↑ Joan M. Lakoski, Matthew P. Galloway, Francis J. White (1991). Cocaine. Telford Press. ISBN 0849388139. 
  35. ↑ M. G. Lacey, N. B. Mercuri, and R. A. North (1990). "Actions of cocaine on rat dopaminergic neurones in vitro.". Br J Pharmacol 99 (4): 731–5. PMID 2361170. 
  36. ↑ 36.0 36.1 Yue Xia, Dennis J. Goebel, Gregory Kapatos Michael J. Banno (2006). "Quantitation of Rat Dopamine Transporter mRNA: Effects of Cocaine Treatment and Withdrawal". J Neurochem 59 (3): 1179–82. doi:10.1111/j.1471-4159.1992.tb08365.x. PMID 1494906. 
  37. ↑ See, R E; Elliott, J C; Feltenstein, M W (2007). "The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats.". Psychopharmacology (Berl) 194 (3): 321–31. doi:10.1007/s00213-007-0850-8. PMID 17589830. 
  38. ↑ Kuczenski, R and Segal, D. (1997). "Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine; Comparison with amphetamine.". J Neurochem 68 (5): 2032–7. doi:10.1046/j.1471-4159.1997.68052032.x. PMID 9109529. 
  39. ↑ Rothman, R; Baumann, M. (2006). "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs.". Ann N Y Acad Sci 1074: 245–60. doi:10.1196/annals.1369.064. PMID 17105921. Bibcode: 2006NYASA1074..245R. 
  40. ↑ Johnson, L’Aurelle A. et al. (2005). "Regulation of amphetamine-stimulated dopamine efflux by Protein Kinase C-beta.". J. Biol. Chem. 280 (12): 10914–9. doi:10.1074/jbc.M413887200. PMID 15647254. 
  41. ↑ Kahlig KM, Binda F, Khoshbouei H, et al. (March 2005). "Amphetamine induces dopamine efflux through a dopamine transporter channel". Proc. Natl. Acad. Sci. U.S.A. 102 (9): 3495–500. doi:10.1073/pnas.0407737102. PMID 15728379. 

External links [edit]

Template:Mesencephalon Template:Basal ganglia


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http://en.wikipedia.org/wiki/Neuropharmacology [edit]

For the journal, see Neuropharmacology (journal).

Neuropharmacology is the study of how drugs affect cellular function in the nervous system. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain.[1] Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

History [edit]

Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs, however, that had been found that demonstrated some type of influence on the nervous system. In the 1930’s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson’s disease. This black box method, where an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson’s disease), and serotonin (soon to be recognized as deeply connected to depression). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior.[2] The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential. These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another, but also how a neuron processes this information within itself.

Overview [edit]

Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind drug development, one must first understand how neurons communicate between one another. This article will focus on both behavioral and molecular neuropharmacology; the major receptors, ion channels, and neurotransmitters manipulated through drug action and how people with a neurological disorder benefit from this drug action.

Neurochemical interactions [edit]

To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes.

Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal.

Labeling of different parts of a neuron

These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can effect communication between neurons.[2]

There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGIC’s. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCR’s. These are much slower than LGIC’s due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process.[3]

Molecular neuropharmacology [edit]

Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:

  1. Agonist—this is when a molecule binds to a receptor protein and activates that receptor
  2. Competitive antagonist—this is when a molecule binds to the same site on the receptor protein as the agonist, preventing activation of the receptor.
  3. Non-competitive antagonist—this is when a molecule binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.

The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials.

GABA [edit]

The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell it will bind to a receptor (most likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions.

This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site.[4] Another receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement.

Dopamine [edit]

The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCR's. These five receptor proteins are separated into two classes due to whether the response elicits a excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the blood-brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole.[5]

Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin) which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same process is also used by other illegal stimulant drugs such as cocaine.

Serotonin [edit]

The serotonin neurotransmitter has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. Depending on what part of the brain region serotonin is being acted upon, will depend on whether the output is either increasing or decreasing post-synaptic responses. The most popular and widely used drugs in the regulation of serotonin during depression are known as SSRI's or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap to be used.

Before the discovery of SSRI's, there were also very many drugs that inhibited the enzyme that broke down serotonin. MAOI's or monoamine oxidase inhibitors increased the amount of serotonin in the pre-synaptic cell, but had many side effects including intense migraines and high blood pressure. This was eventually linked to the drug interacting with a common chemical known as tyramine found in many types of food.[6]

Ion channels [edit]

Ion channels located on the surface membrane of the neuron, allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels. Since these channels can not activate, there is no action potential and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic along with sedative properties.[7]

Behavioral neuropharmacology [edit]

Dopamine and serotonin pathway

One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. (see neuropsychopharmacology for human behavior and drug development) Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine and serotonin are projected into this area. Chronic alcohol abuse can cause major dependence and addiction. How this addiction occurs is described below.

Alcoholism [edit]

The behavior effects of alcohol are primarily produced through its actions on the brain. Intoxication is a short-term result of alcohol present in the brain that is attributed to changes in neuronal communication. Tolerance and dependence are more long-term results that involve molecular and cellular changes due to increased exposure to alcohol. Researchers have found many areas in neuronal function that alter due to chronic alcohol exposure. In the GABAergic system, the GABAA receptor is modified effecting the efficiency and timing of inhibitory synaptic transmission.[8] This is also usually accompanied by an increase or decrease in the release of the neurotransmitter GABA causing many of the neurons in the brain to become hyper-excitable during withdrawal from alcohol. Since GABA, for the most part, is an inhibitory neurotransmitter, a decrease in its amount will result in a feeling of anxiety.[3] Along with GABA, there have been many links to other neurotransmitters that are affected by long-term use of alcohol, including dopamine, serotonin, and glutamate.[7]

Research [edit]

Parkinson's disease [edit]

Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood-brain barrier whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long term use of L-dopa will compromise neuroprotection and thus eventually lead to dopaminergic cell death. Though there has been no proof, in-vivo or in-vitro, some still believe that the better long-term use of dopamine agonists be better for the patient.[9]

Alzheimer's disease [edit]

While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease, the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus four anticholinesterases have been developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment in the U.S.A. However, these are not ideal drugs considering their side effects and limited effectiveness. One promising drug, nefiracetam, is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors.[10]

Future [edit]

With an increase in technology and our understanding of the nervous system, the development of drugs will continue to rise with an increase in drug sensitivity and specificity. Structure-activity relationship or SARs is a major area of research within neuropharmacology which tries to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structure.[7]

See also [edit]

References [edit]

  1. ↑ Template:Cite pmid
  2. ↑ 2.0 2.1 Template:Cite pmid
  3. ↑ 3.0 3.1 Lovinger, D. M. (2008). "Communication Networks in the Brain Neurons, Receptors, Neurotransmitters, and Alcohol. [Review].". Alcohol Research & Health 31 (3): 196–214. 
  4. ↑ Template:Cite pmid
  5. ↑ Template:Cite pmid
  6. ↑ Template:Cite pmid
  7. ↑ 7.0 7.1 7.2 Template:Cite pmid
  8. ↑ Template:Cite pmid
  9. ↑ Template:Cite pmid
  10. ↑ Template:Cite pmid

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http://en.wikipedia.org/wiki/Parkinson's_disease [edit]

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Parkinson's disease
Classification and external resources
File:Paralysis agitans (1907, after St. Leger).png
Illustration of Parkinson's disease by William Richard Gowers, which was first published in A Manual of Diseases of the Nervous System (1886)
ICD-10 G20, F02.3
OMIM 168600 Template:OMIM2
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304 Template:EMedicine2 in young
Template:EMedicine2 rehab
GeneReviews Parkinson Disease Overview

Parkinson's disease (also known as Parkinson disease, Parkinson's, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans) is a degenerative disorder of the central nervous system. It results from the death of dopamine-containing cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related, including shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, cognitive and behavioural problems may arise, with dementia commonly occurring in the advanced stages of the disease. Other symptoms include sensory, sleep and emotional problems. PD is more common in the elderly with most cases occurring after the age of 50.

The main motor symptoms are collectively called parkinsonism, or a "parkinsonian syndrome". Parkinson's disease is often defined as a parkinsonian syndrome that is idiopathic (having no known cause), although some atypical cases have a genetic origin. Many risk and protective factors have been investigated: the clearest evidence is for an increased risk of PD in people exposed to certain pesticides and a reduced risk in tobacco smokers. The pathology of the disease is characterized by the accumulation of a protein called alpha-synuclein into inclusions called Lewy bodies in neurons, and from insufficient formation and activity of dopamine produced in certain neurons within parts of the midbrain. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used for confirmation.

Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopamine neurons continue to be lost, a point eventually arrives at which these drugs become ineffective at treating the symptoms and at the same time produce a complication called dyskinesia, marked by involuntary writhing movements. Diet and some forms of rehabilitation have shown some effectiveness at alleviating symptoms. Surgery and deep brain stimulation have been used to reduce motor symptoms as a last resort in severe cases where drugs are ineffective. Research directions include a search of new animal models of the disease and investigations of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents. Medications to treat non-movement-related symptoms of PD, such as sleep disturbances and emotional problems, also exist.

The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817. Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson's disease day on the birthday of James Parkinson, April 11, and the use of a red tulip as the symbol of the disease. People with parkinsonism who have enhanced the public's awareness include Michael J. Fox and Muhammad Ali.

Classification [edit]

The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and parkinson plus syndromes or multiple system degeneration.[1] Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause.[2][3] In recent years several genes that are directly related to some cases of Parkinson's disease have been discovered. As much as this can go against the definition of Parkinson's disease as an idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's disease" can be used to differentiate genetic from truly idiopathic forms of the disease.[4]

PD is usually classified as a movement disorder, although it also gives rise to several non-motor types of symptoms such as sensory deficits,[5] cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features.[2] They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies.[2]

In terms of pathophysiology, PD is considered a synucleinopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer's disease where the brain accumulates tau protein in the form of neurofibrillary tangles.[6] Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of Alzheimer's disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD.[6]

Dementia with Lewy bodies (DLB) is another synucleinopathy that has similarities with PD, and especially with the subset of PD cases with dementia. However the relationship between PD and DLB is complex and still has to be clarified.[7] They may represent parts of a continuum or they may be separate diseases.[7]

Signs and symptoms [edit]

First line of text is "Catherine Metzger" Second line of text is "13 Octobre 1869" (October 13th of 1869; in French).
Handwriting of a person affected by PD in Lectures on the diseases of the nervous system by Charcot (1879). The original description of the text states "The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. (...) the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal — the finer up-strokes, on the contrary, are all tremulous in appearance (...)."
Main source: Signs and symptoms of Parkinson's disease

Parkinson's disease affects movement, producing motor symptoms.[1] Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common.[1]

Motor [edit]

Black and white picture of male with PD stooping forward as he walks. He is viewed from the left side and there is a chair behind him.
A man with Parkinson's disease displaying a flexed walking posture pictured in 1892. Photo appeared in Nouvelle Iconographie de la Salpètrière, vol. 5.
Further information: [[Parkinsonian gait]]

Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.[1]

Tremor is the most apparent and well-known symptom.[1] It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses.[1] It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep.[1] It affects to a greater extent the most distal part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later.[1] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is "pill-rolling", a term used to describe the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement.[1][8] The term derives from the similarity between the movement in PD patients and the earlier pharmaceutical technique of manually making pills.[8]

Bradykinesia (slowness of movement) is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.[1] Performance of sequential and simultaneous movement is hindered.[1] Bradykinesia is the most disabling symptom in the early stages of the disease.[2] Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed.[1] Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet.[2] Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject, to the point that some patients are barely able to walk yet can still ride a bicycle.[1] Generally patients have less difficulty when some sort of external cue is provided.[1][9]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.[1] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).[1][2][10][11] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[12] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[1] In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[13] With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls, and secondarily to bone fractures.[1] Instability is often absent in the initial stages, especially in younger people.[2] Up to 40% of the patients may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.[1]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking),[1] speech and swallowing disturbances including voice disorders,[14] mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large.[1]

Neuropsychiatric [edit]

Parkinson's disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.[1]

Cognitive disturbances can occur in the initial stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.[1][15] The most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. Fluctuations in attention and slowed cognitive speed are among other cognitive difficulties. Memory is affected, specifically in recalling learned information. Nevertheless, improvement appears when recall is aided by cues. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.[15]

A person with PD has two to six times the risk of suffering dementia compared to the general population.[1][15] The prevalence of dementia increases with duration of the disease.[15] Dementia is associated with a reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing nursing home care.[15]

Behavior and mood alterations are more common in PD without cognitive impairment than in the general population, and are usually present in PD with dementia. The most frequent mood difficulties are depression, apathy and anxiety.[1] Impulse control behaviors such as medication overuse and craving, binge eating, hypersexuality, or pathological gambling can appear in PD and have been related to the medications used to manage the disease.[1][16] Psychotic symptoms—hallucinations or delusions—occur in 4% of patients, and it is assumed that the main precipitant of psychotic phenomena in Parkinson’s disease is dopaminergic excess secondary to treatment; it therefore becomes more common with increasing age and levodopa intake.[17][18]

Other [edit]

In addition to cognitive and motor symptoms, PD can impair other body functions. Sleep problems are a feature of the disease and can be worsened by medications.[1] Symptoms can manifest in daytime drowsiness, disturbances in REM sleep, or insomnia.[1] Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence and altered sexual function.[1] Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health.[19] PD is related to several eye and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision.[1][20] Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness).[1] All of these symptoms can occur years before diagnosis of the disease.[1]

Causes [edit]

PDB rendering of Parkin (ligase)

Most people with Parkinson's disease have idiopathic Parkinson's disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationship has been proven.

PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease.[2] At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.[21]

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[4][21] In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD.[4] The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease.[21] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have yielded few positive results, but such studies have been few in number and their size small.[21]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[21] Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD.[21] Missense mutations are rare.[21] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[21] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[21]

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain.[4] Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for up to 10% of individuals with a family history of the disease and 3% of sporadic cases.[4][21] More than 40 different mutations of the gene have been found to be related to PD.[21]

Pathology [edit]

Several brain cells stained in blue. The largest one, a neurone, with a approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears.
A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson's disease. The brown colour is positive immunohistochemistry staining for alpha-synuclein.

Anatomical pathology [edit]

The basal ganglia, a group of "brain structures" innervated by the dopaminergic system, are the most seriously affected brain areas in PD.[22] The main pathological characteristic of PD is cell death in the substantia nigra and, more specifically, the ventral (front) part of the pars compacta, affecting up to 70% of the cells by the time death occurs.[4]

Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of melanin pigmentation in the substantia nigra and locus coeruleus.[23] The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.[23]

Pathophysiology [edit]

Composite of three images, one in top row (described in caption as A), two in second row (described in caption as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". A fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one saggital and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem.
A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's disease, as proposed by Braak and colleagues
B. Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brain stem damage may be the first identifiable stage of PD neuropathology[24]

The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra.[22]

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor, oculo-motor, associative, limbic and orbitofrontal circuits, with names indicating the main projection area of each circuit.[22] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.[22] Scientifically, the motor circuit has been examined the most intensively.[22]

A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.[22] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[22] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.[22]

Brain cell death [edit]

There is speculation of several mechanisms by which the brain cells could be lost.[25] One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies.[4][26] According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.[4] These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective.[25][26] In patients with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented.[23]

Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.[25] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[27]

Diagnosis [edit]

Sagittal PET scan at the level of the striatum. Hottest areas are the cortical grey matter and the striatum.
Fludeoxyglucose (18F) (FDG)] PET scan of a healthy brain. Hotter areas reflect higher glucose uptake. A decreased activity in the basal ganglia can aid in diagnosing Parkinson's disease.

A physician will diagnose Parkinson's disease from the medical history and a neurological examination.[1] There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. Patients may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the patient suffered from Parkinson's disease. The progress of the illness over time may reveal it is not Parkinson's disease, and some authorities recommend that the diagnosis be periodically reviewed.[1][28]

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer's disease, multiple cerebral infarction and drug-induced parkinsonism.[28] Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out.[1] Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson plus syndromes.[1] Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself.[29] Genetic forms are usually classified as PD, although the terms familial Parkinson's disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance.[2]

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson's Disease Society Brain Bank and the US National Institute of Neurological Disorders and Stroke.[1] The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa.[1] Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.[1]

Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.[30] These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus.[30] A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation.[30] Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fludeoxyglucose (18F) for PET.[30] A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.[30]

Management [edit]

Main source: Treatment of Parkinson's disease

There is no cure for Parkinson's disease, but medications, surgery and multidisciplinary management can provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists and MAO-B inhibitors.[31] The stage of the disease determines which group is most useful. Two stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs pharmacological treatment, then a second stage in which an individual develops motor complications related to levodopa usage.[31] Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from enhancement of dopaminergic function. The start of levodopa (or L-DOPA) treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias.[31] In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed.[31] When medications are not enough to control symptoms, surgery and deep brain stimulation can be of use.[32] In the final stages of the disease, palliative care is provided to enhance quality of life.[33]

Levodopa [edit]

Levodopa has been the most widely used treatment for over 30 years.[31] L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase.[31] Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.[31]

Only 5–10% of L-DOPA crosses the blood-brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness.[31] Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors,[31] which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa.[31] Existing preparations are carbidopa/levodopa (co-careldopa) and benserazide/levodopa (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.[16] There are controlled release versions of levodopa in the form intravenous and intestinal infusions that spread out the effect of the medication. These slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.[31][34]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.[31] It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.[31] A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function.[31] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[31]

Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.[31] When this occurs a person with PD can change from phases with good response to medication and few symptoms ("on" state), to phases with no response to medication and significant motor symptoms ("off" state).[31] For this reason, levodopa doses are kept as low as possible while maintaining functionality.[31] Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice.[31] A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now, since it can bring dangerous side effects such as neuroleptic malignant syndrome.[31] Most people with PD will eventually need levodopa and later develop motor side effects.[31]

Dopamine agonists [edit]

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.[31] These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications.[31][35] When used in late PD they are useful at reducing the off periods.[31] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea and constipation.[31] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[31] Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.[31] Nevertheless, they are usually effective enough to manage symptoms in the initial years.[2] They tend to be more expensive than levodopa.[2] Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset.[2] Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset.[2] Agonists have been related to a impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.[16]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[31] It is administered by intermittent injections or continuous subcutaneous infusions.[31] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[31] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) have been recently found to be useful for patients in initial stages and preliminary positive results has been published on the control of off states in patients in the advanced state.[34]

MAO-B inhibitors [edit]

MAO-B inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased L-DOPA in the striatum.[31] Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early disease, but produce more adverse effects and are less effective than levodopa. There are few studies of their effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods.[31] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.[31]

Other drugs [edit]

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments.[31] In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems.[36] Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.[36][37] A 2010 meta-analysis found that non-steroidal anti-inflammatory drugs (apart from acetaminophen and aspirin), have been associated with at least a 15 percent (higher in long-term and regular users) reduction of incidence of the development of Parkinson's disease.[38]

Surgery and deep brain stimulation [edit]

Placement of an electrode into the brain. The head is stabilised in a frame for stereotactic surgery.

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined.[39] Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.[39] Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus.[39] Deep brain stimulation (DBS) is the most commonly used surgical treatment. It involves the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD who suffer from motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems.[32] Other, less common, surgical therapies involve the formation of lesions in specific subcortical areas (a technique known as pallidotomy in the case of the lesion being produced in the globus pallidus).[39]

Rehabilitation [edit]

There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[40][41] Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[41] However, when an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.[42] In terms of improving flexibility and range of motion for patients experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques.[43] As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on but are not limited to improving gait speed, base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).[44] Strengthening exercises have shown improvements in strength and motor function for patients with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson’s disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that patients should perform exercises 45 minutes to one hour after medications, when the patient is at their best.[45] Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson’s disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.[46] Exercise may improve constipation.[19]

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT).[40][47] Speech therapy and specifically LSVT may improve speech.[40] Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[40] There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.[40][48]

Diet [edit]

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period of time than normal).[19] A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction.[19] As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.[19]

Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, thereby competing for access.[19] When they are taken together, this results in a reduced effectiveness of the drug.[19] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.[19] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[19] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[19]

Palliative care [edit]

Palliative care is often required in the final stages of the disease when all other treatment strategies have become ineffective. The aim of palliative care is to maximize the quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative care are: care in the community while adequate care can be given there, reducing or withdrawing drug intake to reduce drug side effects, preventing pressure ulcers by management of pressure areas of inactive patients, and facilitating end-of-life decisions for the patient as well as involved friends and relatives.[33]

Other treatments [edit]

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[49] Its usefulness in PD is an open research topic,[50] although recent studies have shown no effect by rTMS.[51] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[52] There is no evidence to substantiate that acupuncture and practice of Qigong, or Tai chi, have any effect on the course of the disease or symptoms. Further research on the viability of Tai chi for balance or motor skills are necessary.[53][54][55] Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. While they have shown some effectiveness in clinical trials,[56] their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.[57][58]

Prognosis [edit]

See also: Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale
Global burden of Parkinson's disease, measured in disability-adjusted life years per 100,000 inhabitants in 2004
  no data
  < 5
  5–12.5
  12.5–20
  20–27.5
  27.5–35
  35–42.5
  42.5–50
  50–57.5
  57.5–65
  65–72.5
  72.5–80
  > 80

PD invariably progresses with time. Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years.[59] However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability because of the undesired effects of levodopa after years of use.[59] In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.[59] However, it is hard to predict what course the disease will take for a given individual.[59] Age is the best predictor of disease progression.[25] The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.[25]

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.[25] Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.[59] As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage.[59] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.[59] All of these symptoms, especially cognitive decline, greatly increase disability.[25][59]

The life expectancy of people with PD is reduced.[59] Mortality ratios are around twice those of unaffected people.[59] Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival.[59] Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population.[59]

Epidemiology [edit]

PD is the second most common neurodegenerative disorder after Alzheimer's disease.[60] The prevalence (proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to 4% of the population over 80.[60] The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset, begin between the ages of 20 and 50.[2] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[60] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.[60] The incidence of PD is between 8 and 18 per 100,000 person–years.[60]

Many risk factors and protective factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease, however none have been conclusively related to PD by empirical evidence. When epidemiological studies have been carried out in order to test the relationship between a given factor and PD, they have often been flawed and their results have in some cases been contradictory.[60] The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.[60]

Risk factors [edit]

U.S. Army helicopter spraying Agent Orange over Vietnamese agricultural land during the Vietnam war. Agent Orange has been associated with PD.

Injections of the synthetic neurotoxin MPTP produce a range of symptoms similar to those of PD as well as selective damage to the dopaminergic neurons in the substantia nigra. This observation has led to theorizing that exposure to some environmental toxins may increase the risk of having PD.[60] Exposure to toxins that have been consistently related to the disease can double the risk of PD, and include certain pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange.[60][61][62] Indirect measures of exposure, such as living in rural environments, have been found to increase the risk of PD.[62] Heavy metals exposure has been proposed to be a risk factor, through possible accumulation in the substantia nigra; however, studies on the issue have been inconclusive.[60]

Protective factors [edit]

Smoking has been related to a reduced risk of having PD. Smokers' risk of having PD may be reduced down to a third when compared to non-smokers.[60] The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.[60] Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.[63] Caffeine consumption also protects against PD.[64] Antioxidants, such as vitamins C and D, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven.[60] The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-enhancing effects or no effects.[60] Finally there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.[60]

History [edit]

Main source: History of Parkinson's disease
A 1893 photograph of Jean-Martin Charcot, who made important contributions to the understanding of the disease and proposed its current name honoring James Parkinson

Several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise, the Bible, or Galen's writings, describe symptoms resembling those of PD.[65] After Galen there are no references unambiguously related to PD until the 17th century.[65] In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius, Gaubius, Hunter and Chomel.[65][66][67]

In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans.[68] An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.[68][69] Early neurologists who made further additions to the knowledge of the disease include Trousseau, Gowers, Kinnier Wilson and Erb, and most notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a landmark in the understanding of the disease.[68] Among other advances, he made the distinction between rigidity, weakness and bradykinesia.[68] He also championed the renaming of the disease in honor of James Parkinson.[68]

In 1912 Frederic Lewy described microscopic particles in affected brains, later named "Lewy bodies".[68] In 1919 Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938.[68] The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and its role on PD.[70] In 1997, alpha-synuclein was found to be the main component of Lewy bodies.[26]

Anticholinergics and surgery (lesioning of the corticospinal pathway or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically.[66][71] Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century.[70] It entered clinical practice in 1967 and brought about a revolution in the management of PD.[70][72] By the late 1980s deep brain stimulation emerged as a possible treatment.[73]

Research directions [edit]

See also: Parkinson's disease clinical research

There is little prospect of dramatic new PD treatments expected in a short time frame.[74] Currently active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents.[25]

Animal models [edit]

PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The appearance of parkinsonian symptoms in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans.[75] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[76] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[77]

Gene therapy [edit]

Gene therapy involves the use of a non-infectious virus to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage.[25][78] In 2010 there were four clinical trials using gene therapy in PD.[25] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.[25] One of these reported positive results in 2011.[79]

Neuroprotective treatments [edit]

While several chemical compounds such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, none have proven efficacy.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[25] However, none of them have been conclusively demonstrated to reduce degeneration.[25] Agents currently under investigation include anti-apoptotics (TCH346, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[25] Preclinical research also targets alpha-synuclein.[74]

Neural transplantation [edit]

Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[25] Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term benefit.[25] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias.[80] Stem cell transplants are a recent research target, because stem cells are easy to manipulate and stem cells transplanted into the brains of rodents and monkeys have been found to survive and reduce behavioral abnormalities.[25][81] Nevertheless, use of fetal stem cells is controversial.[25] It has been proposed that effective treatments may be developed in a less controversial way by use of induced pluripotent stem cells taken from adults.[25]

Society and culture [edit]

Muhammad Ali at the age of 64 in 2006. He has shown signs of parkinsonism since the age of 38.

Cost [edit]

The costs of PD to society are high, but difficult to calculate exactly due to methodological difficulties in research and differences between countries.[82] The annual cost in the UK is estimated to be between 449 million and 3.3 billion pounds, while the cost per patient per year in the US is probably around $10,000 and the total burden around 23 billion dollars.[82] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medications is substantially lower.[82] Indirect costs are high, due to reduced productivity and the burden on caregivers.[82] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.[82]

Advocacy [edit]

April 11, the birthday of James Parkinson, has been designated as the world's Parkinson's disease day.[68][83] A red tulip was chosen by several international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip cultivar, registered in 1981 by a Dutch horticulturalist.[83] Advocacy organizations on the disease include the National Parkinson Foundation, which has provided more than $155 million in care, research and support services since 1982,[84] Parkinson's Disease Foundation, which has provided more than $85 million for research and $34 million for education and advocacy programs since its foundation in 1957 by William Black;[85][86] the American Parkinson Disease Association, founded in 1961;[87] and the European Parkinson's Disease Association, founded in 1992.[88]

Notable cases [edit]

Main source: List of people diagnosed with Parkinson's disease

Among the many famous people with PD, one who has greatly increased the public awareness of the disease is the actor Michael J. Fox. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from the public for seven years.[89] He has written two autobiographic books in which his fight against the disease plays a major role,[90] and appeared before the United States Congress without medication to illustrate the effects of the disease.[90] The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. In recent years it has been the major Parkinson's fundraiser in the US, providing 140 million dollars in research funding between 2001 and 2008.[90] Fox's work led him to be named one of the 100 people "whose power, talent or moral example is transforming the world" in 2007 by Time magazine,[89] and he received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease.[91] Another foundation that supports Parkinson's research was established by professional cyclist Davis Phinney.[92] The Davis Phinney Foundation strives to improve the lives of those living with Parkinson's disease by providing them with information and tools.[93] Muhammad Ali has been called the "world's most famous Parkinson's patient".[94] He was 42 at diagnosis although he already showed signs of Parkinson's when he was 38.[95] Nevertheless, whether he has PD or a parkinsonian syndrome caused by boxing is still an open question.[95][96]

Support groups [edit]

Gerald Ganglbauer's Parkins(on)line

One of Parkinson's organisations around the world most valuable and popular services is the development and coordination of a network of Parkinson's support groups.[97] A support group, or self-help group is an informal gathering of people who share similar experiences, situations or problems. Parkinson's support group members can offer each other emotional and practical support. Getting together with other people who are facing similar challenges allows everyone to share feelings, resources and experiences. Active participation provides benefits from the exchange of practical information, as well as motivation and inspiration to help members deal positively with the changes to their lifestyle. Support groups also offer a chance to meet new people, which helps to break down any feelings of isolation associated with the disease. Support groups meet in the real world for group discussions, educational sessions by guest speakers, social outings, and, with the popularity of the internet, also in virtual support groups, such as Parkins(on)line.[98]

References [edit]

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 Jankovic J (April 2008). "Parkinson's disease: clinical features and diagnosis". J. Neurol. Neurosurg. Psychiatr. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045. PMID 18344392. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Samii A, Nutt JG, Ransom BR (May 2004). "Parkinson's disease". Lancet 363 (9423): 1783–93. doi:10.1016/S0140-6736(04)16305-8. PMID 15172778. 
  3. ↑ Schrag A (2007). "Epidemiology of movement disorders". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 50–66. ISBN 0-7817-7881-6. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27. doi:10.1093/bmb/ldn013. PMID 18398010. 
  5. ↑ Barnett-Cowan M, Dyde RT, Foxe SH, Moro E, Hutchison WD, Harris LR (June 2010). "Multisensory determinants of orientation perception in Parkinson's disease". Neuroscience 167 (4): 1138–50. doi:10.1016/j.neuroscience.2010.02.065. PMID 20206672. 
  6. ↑ 6.0 6.1 Galpern WR, Lang AE (March 2006). "Interface between tauopathies and synucleinopathies: a tale of two proteins". Ann. Neurol. 59 (3): 449–58. doi:10.1002/ana.20819. PMID 16489609. 
  7. ↑ 7.0 7.1 Aarsland D, Londos E, Ballard C (April 2009). "Parkinson's disease dementia and dementia with Lewy bodies: different aspects of one entity". Int. Psychogeriatr. 21 (2): 216–9. doi:10.1017/S1041610208008612. PMID 19173762. 
  8. ↑ 8.0 8.1 Cooper G, Eichhorn G, Rodnitzky RL (2008). "Parkinson's disease". In Conn PM. Neuroscience in medicine. Totowa, NJ: Humana Press. pp. 508–512. ISBN 978-1-60327-454-8. 
  9. ↑ Rodriguez-Oroz MC, Jahanshahi M, Krack P, et al. (December 2009). "Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms". Lancet Neurol. 8 (12): 1128–39. doi:10.1016/S1474-4422(09)70293-5. PMID 19909911. 
  10. ↑ Banich MT, Compton RJ (2011). "Motor control". Cognitive neuroscience. Belmont, CA: Wadsworth, Cengage learning. pp. 108–44. ISBN 0-8400-3298-6. 
  11. ↑ Longmore, Murray; Wilkinson, Ian B.; Turmezei, Tom; Cheung, Chee Kay (2007-01-04). Oxford Handbook of Clinical Medicine. Oxford University Press. p. 486. ISBN 978-0-19-856837-7. 
  12. ↑ Fung VSC, Thompson PD (2007). "Rigidity and spasticity". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 504–13. ISBN 0-7817-7881-6. 
  13. ↑ O'Sullivan, Susan B; Schmitz, Thomas J (2007). "Parkinson's Disease". Physical Rehabilitation (5th ed.). Philadephia: F.A. Davis. pp. 856–7. 
  14. ↑ Russell JA, Ciucci MR, Connor NP, Schallert T. (2010-06-23). "Targeted exercise therapy for voice and swallow in persons with Parkinson's disease". Brain Res. 1341: 3–11. PMID 20233583. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Caballol N, Martí MJ, Tolosa E (September 2007). "Cognitive dysfunction and dementia in Parkinson disease". Mov. Disord. 22 (Suppl 17): S358–66. doi:10.1002/mds.21677. PMID 18175397. 
  16. ↑ 16.0 16.1 16.2 Ceravolo R, Frosini D, Rossi C, Bonuccelli U (December 2009). "Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management". Parkinsonism Relat. Disord. 15 (Suppl 4): S111–5. doi:10.1016/S1353-8020(09)70847-8. PMID 20123548. 
  17. ↑ Shergill SS, Walker Z, Le Katona C (October 1998). "A preliminary investigation of laterality in Parkinson's disease and susceptibility to psychosis". J. Neurol. Neurosurg. Psychiatr. 65 (4): 610–1. PMID 9771806. 
  18. ↑ Friedman JH (June 2010). "Parkinson's disease psychosis 2010: A review article". Parkinsonism Relat. Disord. 16 (9): 553–60. doi:10.1016/j.parkreldis.2010.05.004. PMID 20538500. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 Barichella M, Cereda E, Pezzoli G (October 2009). "Major nutritional issues in the management of Parkinson's disease". Mov. Disord. 24 (13): 1881–92. doi:10.1002/mds.22705. PMID 19691125. 
  20. ↑ Armstrong RA (March 2008). "Visual signs and symptoms of Parkinson's disease". Clin. Exp. Optom. 91 (2): 129–38. doi:10.1111/j.1444-0938.2007.00211.x. PMID 18271776. 
  21. ↑ 21.00 21.01 21.02 21.03 21.04 21.05 21.06 21.07 21.08 21.09 21.10 Lesage S, Brice A (April 2009). "Parkinson's disease: from monogenic forms to genetic susceptibility factors". Hum. Mol. Genet. 18 (R1): R48–59. doi:10.1093/hmg/ddp012. PMID 19297401. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, et al. (2008). "Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease". Mov. Disord. 23 (Suppl 3): S548–59. doi:10.1002/mds.22062. PMID 18781672. 
  23. ↑ 23.0 23.1 23.2 Dickson DV (2007). "Neuropathology of movement disorders". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 271–83. ISBN 0-7817-7881-6. 
  24. ↑ Jubault T, Brambati SM, Degroot C, et al. (2009). "Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI". PLoS ONE 4 (12): e8247. doi:10.1371/journal.pone.0008247. PMID 20011063. 
  25. ↑ 25.00 25.01 25.02 25.03 25.04 25.05 25.06 25.07 25.08 25.09 25.10 25.11 25.12 25.13 25.14 25.15 25.16 25.17 25.18 Obeso JA, Rodriguez-Oroz MC, Goetz CG, et al. (May 2010). "Missing pieces in the Parkinson's disease puzzle". Nat. Med. 16 (6): 653–61. doi:10.1038/nm.2165. PMID 20495568. 
  26. ↑ 26.0 26.1 26.2 Schulz-Schaeffer WJ (August 2010). "The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia". Acta Neuropathol. 120 (2): 131–43. doi:10.1007/s00401-010-0711-0. PMID 20563819. 
  27. ↑ Hirsch EC (December 2009). "Iron transport in Parkinson's disease". Parkinsonism Relat. Disord. 15 (Suppl 3): S209–11. doi:10.1016/S1353-8020(09)70816-8. PMID 20082992. 
  28. ↑ 28.0 28.1 The National Collaborating Centre for Chronic Conditions, ed (2006). "Diagnosing Parkinson's Disease". Parkinson's Disease. London: Royal College of Physicians. pp. 29–47. ISBN 1-86016-283-5. 
  29. ↑ Poewe W, Wenning G (November 2002). "The differential diagnosis of Parkinson's disease". Eur. J. Neurol. 9 (Suppl 3): 23–30. PMID 12464118. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Brooks DJ (April 2010). "Imaging approaches to Parkinson disease". J. Nucl. Med. 51 (4): 596–609. doi:10.2967/jnumed.108.059998. PMID 20351351. 
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 31.13 31.14 31.15 31.16 31.17 31.18 31.19 31.20 31.21 31.22 31.23 31.24 31.25 31.26 31.27 31.28 31.29 31.30 31.31 31.32 31.33 The National Collaborating Centre for Chronic Conditions, ed (2006). "Symptomatic pharmacological therapy in Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 59–100. ISBN 1-86016-283-5. 
  32. ↑ 32.0 32.1 Bronstein JM, Tagliati M, Alterman RL, et al. (February 2011). "Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues". Arch. Neurol. 68 (2): 165. doi:10.1001/archneurol.2010.260. PMID 20937936. 
  33. ↑ 33.0 33.1 The National Collaborating Centre for Chronic Conditions, ed (2006). "Palliative care in Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 147–51. ISBN 1-86016-283-5. 
  34. ↑ 34.0 34.1 Tolosa E, Katzenschlager R (2007). "Pharmacological management of Parkinson's disease". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 110–45. ISBN 0-7817-7881-6. 
  35. ↑ Goldenberg MM (October 2008). "Medical management of Parkinson's disease". P & T 33 (10): 590–606. PMID 19750042. 
  36. ↑ 36.0 36.1 The National Collaborating Centre for Chronic Conditions, ed (2006). "Non-motor features of Parkinson's disease". Parkinson's Disease. London: Royal College of Physicians. pp. 113–33. ISBN 1-86016-283-5. 
  37. ↑ Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, Pandurangi AK (July 2009). "Pharmacological management of psychosis in elderly patients with parkinsonism". Am. J. Med. 122 (7): 614–22. doi:10.1016/j.amjmed.2009.01.025. PMID 19559160. 
  38. ↑ Gagne JJ, Power MC (Mar 2010). "Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis". Neurology 74 (12): 995-1002. doi:10.1212/WNL.0b013e3181d5a4a3. PMID 20308684. 
  39. ↑ 39.0 39.1 39.2 39.3 The National Collaborating Centre for Chronic Conditions, ed (2006). "Surgery for Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 101–11. ISBN 1-86016-283-5. 
  40. ↑ 40.0 40.1 40.2 40.3 40.4 The National Collaborating Centre for Chronic Conditions, ed (2006). "Other key interventions". Parkinson's Disease. London: Royal College of Physicians. pp. 135–46. ISBN 1-86016-283-5. 
  41. ↑ 41.0 41.1 Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL (April 2008). "The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis". Mov. Disord. 23 (5): 631–40. doi:10.1002/mds.21922. PMID 18181210. 
  42. ↑ Dereli EE, Yaliman A (April 2010). "Comparison of the effects of a physiotherapist-supervised exercise programme and a self-supervised exercise programme on quality of life in patients with Parkinson's disease". Clin Rehabil 24 (4): 352–62. doi:10.1177/0269215509358933. PMID 20360152. 
  43. ↑ O'Sullivan & Schmitz 2007, pp. 873, 876
  44. ↑ O'Sullivan & Schmitz 2007, p. 879
  45. ↑ O'Sullivan & Schmitz 2007, p. 877
  46. ↑ O'Sullivan & Schmitz 2007, p. 880
  47. ↑ Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG (November 2006). "The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders". Semin. Speech. Lang. 27 (4): 283–99. doi:10.1055/s-2006-955118. PMID 17117354. 
  48. ↑ Dixon L, Duncan D, Johnson P, et al. (2007). "Occupational therapy for patients with Parkinson's disease". Cochrane Database Syst. Rev. (3): CD002813. doi:10.1002/14651858.CD002813.pub2. PMID 17636709. 
  49. ↑ Koch G (2010). "rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets". Restor. Neurol. Neurosci. 28 (4): 561–8. doi:10.3233/RNN-2010-0556. PMID 20714078. 
  50. ↑ Platz T, Rothwell JC (2010). "Brain stimulation and brain repair—rTMS: from animal experiment to clinical trials—what do we know?". Restor. Neurol. Neurosci. 28 (4): 387–98. doi:10.3233/RNN-2010-0570. PMID 20714064. 
  51. ↑ Arias P, Vivas J, Grieve KL, Cudeiro J (September 2010). "Controlled trial on the effect of 10 days low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease". Mov. Disord. 25 (12): 1830–8. doi:10.1002/mds.23055. PMID 20669300. 
  52. ↑ Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ (April 2006). "Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 66 (7): 976–82. doi:10.1212/01.wnl.0000206363.57955.1b. PMID 16606908. 
  53. ↑ Lee MS, Lam P, Ernst E (December 2008). "Effectiveness of tai chi for Parkinson's disease: a critical review". Parkinsonism Relat. Disord. 14 (8): 589–94. doi:10.1016/j.parkreldis.2008.02.003. PMID 18374620. 
  54. ↑ Lee MS, Ernst E (January 2009). "Qigong for movement disorders: A systematic review". Mov. Disord. 24 (2): 301–3. doi:10.1002/mds.22275. PMID 18973253. 
  55. ↑ Lee MS, Shin BC, Kong JC, Ernst E (August 2008). "Effectiveness of acupuncture for Parkinson's disease: a systematic review". Mov. Disord. 23 (11): 1505–15. doi:10.1002/mds.21993. PMID 18618661. 
  56. ↑ Katzenschlager R, Evans A, Manson A, et al (2004). "Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study". J. Neurol. Neurosurg. Psychiatr. 75 (12): 1672–7. doi:10.1136/jnnp.2003.028761. PMID 15548480. 
  57. ↑ Ladha SS, Walker R, Shill HA (May 2005). "Case of neuroleptic malignant-like syndrome precipitated by abrupt fava bean discontinuance". Mov. Disord. 20 (5): 630–1. doi:10.1002/mds.20380. PMID 15719433. 
  58. ↑ Raguthu L, Varanese S, Flancbaum L, Tayler E, Di Rocco A (October 2009). "Fava beans and Parkinson's disease: useful 'natural supplement' or useless risk?". Eur. J. Neurol. 16 (10): e171. doi:10.1111/j.1468-1331.2009.02766.x. PMID 19678834. 
  59. ↑ 59.00 59.01 59.02 59.03 59.04 59.05 59.06 59.07 59.08 59.09 59.10 59.11 Poewe W (December 2006). "The natural history of Parkinson's disease". J. Neurol. 253 (Suppl 7): VII2–6. doi:10.1007/s00415-006-7002-7. PMID 17131223. 
  60. ↑ 60.00 60.01 60.02 60.03 60.04 60.05 60.06 60.07 60.08 60.09 60.10 60.11 60.12 60.13 60.14 de Lau LM, Breteler MM (June 2006). "Epidemiology of Parkinson's disease". Lancet Neurol. 5 (6): 525–35. doi:10.1016/S1474-4422(06)70471-9. PMID 16713924. 
  61. ↑ Tanner CM, Kamel F, Ross GW, et al. (January 2011). "Rotenone, Paraquat and Parkinson's Disease". Environ. Health Perspect. doi:10.1289/ehp.1002839. PMID 21269927. 
  62. ↑ 62.0 62.1 IOM (Institute of Medicine), ed (2009). "Neurologic disorders". Veterans and Agent Orange: Update 2008. Washington D.C.: The National Academies press. pp. 510–45. ISBN 0-309-13884-1. 
  63. ↑ Castagnoli K, Murugesan T (2004 Jan). "Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's disease and neuroprotection; are there links?". Neurotoxicology 25 (1–2): 279–91. doi:10.1016/S0161-813X(03)00107-4. PMID 14697903. 
  64. ↑ Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A (2010). "Caffeine exposure and the risk of Parkinson's disease: a systematic review and meta-analysis of observational studies". J. Alzheimers Dis. 20 (Suppl 1): S221–38. doi:10.3233/JAD-2010-091525. PMID 20182023. 
  65. ↑ 65.0 65.1 65.2 García Ruiz PJ (December 2004). "Prehistoria de la enfermedad de Parkinson" (in Spanish; Castilian). Neurologia 19 (10): 735–7. PMID 15568171. 
  66. ↑ 66.0 66.1 Lanska DJ (2010). "Chapter 33: the history of movement disorders". Handb. Clin. Neurol. 95: 501–46. doi:10.1016/S0072-9752(08)02133-7. PMID 19892136. 
  67. ↑ Koehler PJ, Keyser A (September 1997). "Tremor in Latin texts of Dutch physicians: 16th–18th centuries". Mov. Disord. 12 (5): 798–806. doi:10.1002/mds.870120531. PMID 9380070. 
  68. ↑ 68.0 68.1 68.2 68.3 68.4 68.5 68.6 68.7 Lees AJ (September 2007). "Unresolved issues relating to the shaking palsy on the celebration of James Parkinson's 250th birthday". Mov. Disord. 22 (Suppl 17): S327–34. doi:10.1002/mds.21684. PMID 18175393. 
  69. ↑ Louis ED (November 1997). "The shaking palsy, the first forty-five years: a journey through the British literature". Mov. Disord. 12 (6): 1068–72. doi:10.1002/mds.870120638. PMID 9399240. 
  70. ↑ 70.0 70.1 70.2 Fahn S (2008). "The history of dopamine and levodopa in the treatment of Parkinson's disease". Mov. Disord. 23 (Suppl 3): S497–508. doi:10.1002/mds.22028. PMID 18781671. 
  71. ↑ Guridi J, Lozano AM (November 1997). "A brief history of pallidotomy". Neurosurgery 41 (5): 1169–80; discussion 1180–3. doi:10.1097/00006123-199711000-00029. PMID 9361073. 
  72. ↑ Hornykiewicz O (2002). "L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent". Amino Acids 23 (1–3): 65–70. doi:10.1007/s00726-001-0111-9. PMID 12373520. 
  73. ↑ Coffey RJ (March 2009). "Deep brain stimulation devices: a brief technical history and review". Artif. Organs 33 (3): 208–20. doi:10.1111/j.1525-1594.2008.00620.x. PMID 18684199. 
  74. ↑ 74.0 74.1 Script error
  75. ↑ Langston JW, Ballard P, Tetrud JW, Irwin I (February 1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis". Science 219 (4587): 979–80. doi:10.1126/science.6823561. PMID 6823561. 
  76. ↑ Cicchetti F, Drouin-Ouellet J, Gross RE (September 2009). "Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?". Trends Pharmacol. Sci. 30 (9): 475–83. doi:10.1016/j.tips.2009.06.005. PMID 19729209. 
  77. ↑ Harvey BK, Wang Y, Hoffer BJ (2008). "Transgenic rodent models of Parkinson's disease". Acta Neurochir. Suppl. 101: 89–92. doi:10.1007/978-3-211-78205-7_15. PMID 18642640. 
  78. ↑ Feng, LR, Maguire-Zeiss KA (2010). "Gene Therapy in Parkinson's Disease: Rationale and Current Status". CNS Drugs 24 (3): 177–92. doi:10.2165/11533740-000000000-00000. PMID 20155994. 
  79. ↑ Lewitt PA, Rezai AR, Leehey MA, et al. (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". Lancet Neurol 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704. 
  80. ↑ Redmond DE (October 2002). "Cellular replacement therapy for Parkinson's disease—where we are today?". The Neuroscientist 8 (5): 457–88. doi:10.1177/107385802237703. PMID 12374430. 
  81. ↑ Script error
  82. ↑ 82.0 82.1 82.2 82.3 82.4 Findley LJ (September 2007). "The economic impact of Parkinson's disease". Parkinsonism Relat. Disord. 13 (Suppl): S8–S12. doi:10.1016/j.parkreldis.2007.06.003. PMID 17702630. 
  83. ↑ 83.0 83.1 Script error
  84. ↑ Script error
  85. ↑ Script error
  86. ↑ Script error
  87. ↑ Script error
  88. ↑ Script error
  89. ↑ 89.0 89.1 Script error
  90. ↑ 90.0 90.1 90.2 Script error
  91. ↑ Script error
  92. ↑ Script error
  93. ↑ Template:Cite press release
  94. ↑ Brey RL (April 2006). "Muhammad Ali's Message: Keep Moving Forward" 2 (2): 8. American Academy of Neurology. Retrieved on 2011-04-02. 
  95. ↑ 95.0 95.1 Matthews W (April 2006). "Ali's Fighting Spirit" 2 (2): 10–23. American Academy of Neurology. Retrieved on 2011-04-02. 
  96. ↑ Script error
  97. ↑ Parkinson's NSW Inc. Support Groups
  98. ↑ Parkins(on)line Virtual Support Groups

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http://en.wikipedia.org/wiki/Dopamine_hypothesis_of_schizophrenia [edit]

My Substantia nigra Dopamine Malnutrition Syndrome [edit]

Template:Refimprove The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia (like psychoses) to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia.

Introduction [edit]

Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition and alogia.)

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (PCP, Angel Dust)[1], or excess steroids[citation needed], or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D2 receptors in the high-affinity state for dopamine.[2] This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical.

Discussion [edit]

Evidence for the dopamine hypothesis [edit]

Amphetamine, cocaine and similar drugs increase levels of dopamine in the brain and can cause symptoms which resemble those present in psychosis, particularly after large doses or prolonged use. This is often referred to as "amphetamine psychosis" or "cocaine psychosis," but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa for Parkinson's disease can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.[3][4]

Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia.[5]

A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonize dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The link was strengthened by experiments in 1970s which suggested that the binding affinity of antipsychotic drugs for D2 dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.[6][7]

Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way include COMT, DRD4, and AKT1.[8]

Tobacco use is strongly associated with schizophrenia, likely through dopamine modulation by nicotinic acetylcholine receptors.

Evidence against the dopamine hypothesis [edit]

Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2 receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The antipsychotic aripiprazole occupies over 90% of D2 receptors, but this drug is both an agonist and an antagonist at D2 receptors.

Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.[9]

Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotics) were found to be just as effective as older typical antipsychotic drugs in controlling psychosis, particularly the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors.[10] More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D2 receptor.[11]

The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or "Angel Dust") and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis closely resembling schizophrenia, further suggesting that psychosis and schizophrenia cannot fully be explained in terms of dopamine function, but may also involve other neurotransmitters.[12]

Similarly, there is now evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes.[2] It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing.

See also [edit]

References [edit]

  1. ↑ Carlsson, M. and Carlsson, A. (1990). Schizophrenia: A Sub cortical Neurotransmitter Imbalance Syndrome? Schizophrenia Bulletin, 16, (3). P. 425 – 430.
  2. ↑ 2.0 2.1 Template:Cite pmid
  3. ↑ Template:Cite doi
  4. ↑ Template:Cite pmid
  5. ↑ Template:Cite pmid
  6. ↑ Creese I, Burt DR, Snyder SH (April 1976). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs". Science (journal) 192 (4238): 481–3. doi:10.1126/science.3854. PMID 3854. 
  7. ↑ Template:Cite doi
  8. ↑ Template:Cite pmid
  9. ↑ R. Thompson, The Brain, ISBN 0716714620
  10. ↑ Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
  11. ↑ Template:Cite doi
  12. ↑ "Daring to Think Differently about Schizophrenia". New York Times, February 24, 2008. http://www.nytimes.com/2008/02/24/business/24drug.html?_r=1&ei=5087&em=&en=6a0e8fe7296833ff&ex=1204002000&pagewanted=all&oref=slogin.

External links [edit]

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http://en.wikipedia.org/wiki/Levodopa/ [edit]

Dopamine the Natural Dope [edit]

The Dopamine Cycle (Milk and Bread) [edit]

Levodopa [edit]

Template:Drugbox

L-DOPA (L-3,4-dihydroxyphenylalanine) is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc.). As a drug it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Therapeutic use [edit]

L-DOPA crosses the protective blood-brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. This treatment was originally developed by George Cotzias and his coworkers. Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.

Besides the CNS, L-DOPA is also converted into dopamine from within the peripheral nervous system. The resulting hyperdopaminergia causes many of the adverse side effects seen with sole L-DOPA administration. In order to bypass these effects, it is standard clinical practice to co-administer (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines combining L-DOPA and carbidopa are branded as Lodosyn, Sinemet, Parcopa, Atamet, Stalevo) or with a benserazide (combination medicines are branded Madopar, Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Co-administration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration, a phenomenon that historically caused great confusion.

In addition, L-DOPA, co-administered with a peripheral DDCI, has been investigated as a potential treatment for restless leg syndrome. However, studies have demonstrated "no clear picture of reduced symptoms".[1]

There are two types of response seen with administration of L-DOPA:

  • Short-duration response, which is related to the half-life of the drug
  • Longer-duration response, which depends on the accumulation of effects over at least two weeks. This response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.

Dietary supplements [edit]

Herbal extracts containing L-DOPA are available. The most common plant source of L-DOPA marketed in this manner is Mucuna pruriens (Velvet Bean). [2]

Biological role [edit]

Biosynthesis of dopamine

L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH). It is also the precursor for the monoamine or catecholamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of L-DOPA.

L-DOPA can be directly metabolized by catechol-O-methyl transferase (COMT) to 3-O-methyldopa (3-OMD), and then further to vanillactic acid (VLA). This metabolic pathway is non-existent in the healthy body, but becomes important after peripheral L-DOPA administration in patients with PD or in the rare cases of patients with aromatic L-amino acid decarboxylase (AADC) enzyme deficiency.[3]

The prefix L- references its property of levorotation (compared with dextrorotation or D-DOPA).

L-Phenylalanine, L-tyrosine, and L-DOPA, are all are precursors to the biological pigment melanin. The enzyme tyrosinase catalyzes the oxidation of L-DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin oligomers.

Side effects [edit]

The side effects of L-DOPA may include:

Although there are many adverse effects associated with L-DOPA, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.

More serious are the effects of chronic levodopa administration in the treatment of Parkinson disease, which include:

  • End-of-dose deterioration of function
  • On/off oscillations
  • Freezing during movement
  • Dose failure (drug resistance)
  • Dyskinesia at peak dose
  • Possible serotonin depletion: Recent studies have demonstrated that use of L-DOPA without simultaneously giving proper levels of serotonin precursors depletes serotonin
  • Possible dopamine dysregulation: The long-term use of L-DOPA in PD has been linked to the so-called dopamine dysregulation syndrome.[4]

Clinicians will try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.

Toxicity [edit]

Some scientific studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[5] Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with L-DOPA.[6] Other authors have attributed the observed toxic effects of L-DOPA in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.[7][8] Though L-DOPA is generally considered safe, some controversy surrounds its use in the treatment of PD, given some data indicating a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.[9]

History [edit]

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering L-DOPA to animals with Parkinsonian symptoms would cause a reduction in their intensity. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,[10] who greatly increased the dose. The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his book Awakenings, upon which the movie of the same name is based.

The 2001 Nobel Prize in Chemistry was also related to L-DOPA: the Nobel Committee awarded one-fourth of the prize to William S. Knowles for his work on chirally catalysed hydrogenation reactions, the most noted example of which was used for the synthesis of L-DOPA:

L-DOPA synthesis2.png

Marine adhesion [edit]

L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels. It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. L-DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible substrate.

See also [edit]

  • D-DOPA (Dextrodopa)
  • L-DOPS (Droxidopa)
  • Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
  • Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
  • Norepinephrine (Noradrenaline; Levophed, etc.)
  • Epinephrine (Adrenaline; Adrenalin, EpiPen, Twinject, etc.)

References [edit]

  1. ↑ Script error
  2. ↑ http://students.cis.uab.edu/porce/page4.html
  3. ↑ Hyland K, Clayton PT (December 1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology" (PDF). Clinical chemistry 38 (12): 2405–10. PMID 1281049. 
  4. ↑ Merims D, Giladi N (2008). "Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease". Parkinsonism Relat Disord 14 (4): 273–280. doi:10.1016/j.parkreldis.2007.09.007. PMID 17988927. 
  5. ↑ Cheng N, Maeda T, Kume T, et al. (December 1996). "Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons". Brain research 743 (1-2): 278–83. doi:10.1016/S0006-8993(96)01056-6. PMID 9017256. 
  6. ↑ Basma AN, Morris EJ, Nicklas WJ, Geller HM (February 1995). "L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation". Journal of neurochemistry 64 (2): 825–32. doi:10.1046/j.1471-4159.1995.64020825.x. PMID 7830076. 
  7. ↑ Pardo B, Mena MA, Casarejos MJ, Paíno CL, De Yébenes JG (June 1995). "Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants". Brain research 682 (1-2): 133–43. doi:10.1016/0006-8993(95)00341-M. PMID 7552304. 
  8. ↑ Mytilineou C, Han SK, Cohen G (October 1993). "Toxic and protective effects of L-dopa on mesencephalic cell cultures". Journal of neurochemistry 61 (4): 1470–8. doi:10.1111/j.1471-4159.1993.tb13642.x. PMID 8376999. 
  9. ↑ Simuni T, Stern MB (June 1999). "Does levodopa accelerate Parkinson's disease?". Drugs & aging 14 (6): 399–408. doi:10.2165/00002512-199914060-00001. PMID 10408739. 
  10. ↑ (1969) "L-dopa in parkinson's syndrome.". The New England journal of medicine 281 (5): 272. doi:10.1056/NEJM196907312810518. PMID 5791298. 
  • Waite, J. Herbert, et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion 81: 1–21. doi:10.1080/00218460590944602. 
  • Messersmith, Phillip B., et al. (2006). "Rapid Gel Formation and Adhesion in Photocurable and Biodegradable Block Copolymers with High DOPA Content". Macromolecules 39: 1740–1748. doi:10.1021/ma0518959. 

External links [edit]

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ca:L-dopa de:Levodopa et:Levodopa es:Levodopa eu:Lebodopa fa:لوودوپا fr:DOPA ko:L-도파 it:L-DOPA hu:Levodopa nl:Levodopa ja:レボドパ pl:DOPA pt:Levodopa ru:Леводопа simple:L-DOPA sr:L-DOPA fi:L-dopa sv:Levodopa tr:L-DOPA zh:L-多巴

http://en.wikipedia.org/wiki/Methadone [edit]

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Template:Drugbox

Methadone (also known as Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon, Phy and many other names) is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937. Although chemically unlike morphine or heroin, methadone acts on the same opioid receptors as these drugs, and thus has many of the same effects. Methadone is also used in managing severe chronic pain, owing to its long duration of action, extremely powerful effects, and very low cost. Methadone was introduced into the United States in 1947 by Eli Lilly and Company.

Methadone is useful in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine, offering very similar effects and a long duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.

Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-narcotic drugs such as cocaine, methamphetamine, or alcohol.

A number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as the Netherlands, Belgium, France and in the United States, as of March 2008. The tartrate and other salts of the laevorotary form (levomethadone, with trade names including Polamidone and Heptadon) are available in Europe and elsewhere. These are more potent opioid agonists compared to racemic methadone because the dextrorotary form (d-methadone) is not an opioid agonist (it is an NMDA antagonist), therefore by using only the laevorotary form instead of the racemate the opioid agonist potency is doubled. Covidien (formerly Mallinckrodt), is the major racemic methadone producer and sells bulk methadone to producers of generic preparations and distributes its own product in the form of tablets, dispersible tablets and oral concentrate under the brand name Methadose in the United States.[1]

Contents

Medical uses [edit]

Methadone maintenance treatment [edit]

MMT (Methadone Maintenance Treatment), a form of opiate replacement therapy, reduces and/or eliminates the use of illicit opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.[2][3] In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.[2] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.[2] It is also indicated for pregnant women addicted to opiates.[2]

In Russia, methadone treatment is illegal. Health officials there are not convinced of the treatment's efficacy. Instead, doctors encourage immediate abstinence from drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and painkillers to cope with withdrawal symptoms.[4]

Dosage [edit]

Dosing considerations in an outpatient treatment program, where individuals carry a high degree of tolerance to opioids and are closely monitored with witnessed daily dosing, is a separate consideration from the patient with chronic pain requiring analgesia. The intermittent follow up of the pain patient, coupled with the relatively unforgiving nature of the drug (compared with other Long acting opioids), should generate caution in the patient and prescriber alike in an outpatient pain environment. A majority of patients in outpatient treatment programs require 80–125 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for opiate addiction.[2] Lower doses are sometimes not as effective, or do not provide an equivalent blockade effect as higher dosages can. Some patients will be prescribed as much as 750 mg of methadone a day;[5] though a dose as low as 30 mg can prove fatal in an opiate naive individual, or in individuals who lack cross-tolerance to other opioids.[citation needed]

In the United States addiction clinics typically start patients at a low dose, generally only starting patients on methadone when they are in withdrawal and providing a small test dose, after which the patients are observed for possible adverse effects. Assuming there are no complications, the remaining portion of the first day's dose is then given. After this the doses are titrated until they reach either a clinically sufficient level that prevents withdrawal, cravings and possible continued use of illicit opioids, or until they reach a maximum dose set by clinic policy. For example, a clinic may start patients at 30 mg and raise the dosage 5 mg a day until the patient reports feeling comfortable (e.g. free of withdrawal symptoms). Alternatively, the clinic may stop dosage at 80 mg, then allow the patient to move up by 5 mg or 10 mg every 2 or 3 days, until they are free from withdrawal symptoms and intense cravings. Once stabilized, patients may require periodic dose adjustments as their clinical or subjective tolerance changes.

The most common and traditional dosing regimens, however, tend to fall far short of providing optimum or even sufficient results for a number of patients. This is due to the ceilings many clinics place on dose levels.[6][7]

Until recently a 100-mg/d dose was regarded as a 'glass ceiling,' rarely to be penetrated. In practice much lower thresholds were maintained even though the optimal dose varies greatly between patients, often quite higher than this and with no inherent threshold in the possible dose, as the toxic dose for patients with very high tolerance can exceed this tenfold or more. The blood concentrations of patients on an equivalent dose (when adjusted for body weight) can vary as much as 17-fold, or up to 41-fold when influenced by other medications, leading to a vast range of potentially required doses.[8][9]

In the United States, federal law was changed in 2001 to eliminate some restrictions imposed on patients dosed on more than 100 mg per day.

Duration [edit]

While there is much debate generally over treatment schedules and duration, patients can often obtain indefinite treatment at their methadone clinic—lasting as long as the patient requires it. Many factors determine the treatment schedule, including specific clinic policies which sometimes require patients to taper regardless of their desire to do so. In general, methadone maintenance is seen as ongoing symptom management rather than a curative treatment. This has buttressed the arguments of those who view methadone as just another prescription drug taken for a long-term, chronic condition.

Dosage reduction [edit]

A patient's dose of methadone may be reduced by a slow taper with minimal discomfort. Patients undergoing MMT at a clinic where they are given a daily dose have the opportunity to attempt a dose reduction and return to the previous dose if they are feeling discomfort. Policies on dose reduction vary from clinic to clinic, from a focus on eventually tapering the patient off of methadone altogether to a focus on maintaining a high dose to prevent the use of illicit opioids. Many methadone clinics will adjust doses upon personal evaluation of the correct care for the individual patient. A higher methadone dose may be considered preferable by a clinic treating patients addicted to illicit opioids, in order to discourage the use of illegal opioids. This can be due to the large increase in tolerance, a chemical blocking effect caused by methadone above certain doses, or by filling a psychological or physical need that illicit opioids were previously being used for.

To minimize or prevent patient discomfort, the methadone dose must be decreased slowly. Typical reduction rates vary and should be adjusted based on patient response.

Frequently this adjustment is monitored on a daily basis. Most of the literature focuses on methadone maintenance patients visiting clinics daily, focused on heroin substitution. Chronic pain patients wishing to decrease their methadone dose must follow similar titration regimens. However their doctor may substitute alternative opioids during this period, altering what rate is compatible with patient comfort when compared with complete detoxification.

The Centre for Addiction and Mental Health, Ontario, Canada has this recommendation:[10]

Methadone tapering works best when done as a slow and gradual reduction in dose, dropping 5 mg every three to 14 days. At this rate there should be very few, if any, physical symptoms during the taper. Once the dose is lowered to around 20 mg, the tapering may be slowed down to an even more gradual reduction, to reduce or eliminate any symptoms. Nowadays, most methadone providers will allow you to choose the rate at which your dose is reduced.

Aegis Medical Systems Tapering Off of Methadone Maintenance: Evidence-Based Guidelines[11]

recommends regular evaluation of the patient's withdrawal symptoms, counseling where needed, and a generally slow rate, noting:

Dr. J. Thomas Payte, a highly experienced clinician and researcher, has suggested that a 7-10 day period between dose decreases should be adequate time to adjust before the next drop.

Clinical experience reminds us of an important rule in tapering, “THE SLOWER, THE BETTER,”

The College of Pharmacists of British Columbia discusses more specific rates on page 19 of a slide presentation:[12]

Stopping Methadone

  • Greater detox. completion rates with greater time spent in MMT & slower taper.
  • Taper rate
    • < 10 mg or 10% per week.
    • Slower taper below 20-30 mg.

Mallinckrodt, the primary manufacturer of methadone in the US, has guidelines[13] that include

For Medically Supervised Withdrawal After a Period of Maintenance Treatment There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

Other documents discussing the recommended rate of dose reduction can be found from Health Canada[14] and the Canadian Department Of Health And Human Services[15]

Visits to clinics [edit]

Methadone has traditionally been provided to people who are opiate dependent in a highly regulated methadone clinic, generally associated with an outpatient department of a hospital, though this varies country by country. For example in Australia, Methadone maintenance treatment (MMT) is delivered by private pharmacies for a nominal fee to the client (regardless of the fact it is free as it is subsidised by the Federal government). This nominal fee covers the costs of providing the service, such as purchase and maintenance of supplies and equipment like dosing cups and precision measuring devices, supply costs involved in transporting a highly regulated drug from supplier to the pharmacy, extensive record-keeping as per government requirements, and compensation to the pharmacy staff for the time involved in preparing for and dosing a client (none of which are funded by the Federal government).

In many Western countries, new patients are required to visit the clinic daily so that they may be observed taking their dose by the dispensing nurse, but may be allowed to leave the clinic with increasing supplies of "take home doses" or "carries" after several months of adherence to the clinic's regulations, including consistent negative drug-screen results. The way that MMT is delivered in some countries create barriers to scaling up access to the treatment. This can inhibit people's willingness to access treatment due to a lack of confidentiality and anonymity. In most well-designed pharmacies in Australia, however, dosing occurs in a discreet location away from other customers, and may even take place in a room specially designed for this purpose. In some countries or regions, law stipulates that clinics may provide at most one week's worth of methadone (up to 30 days in the USA but states may allow as few as three), except for patients unable to visit the clinic without undue hardship due to a medical disability or infrequent exceptions made for necessary travel to areas without clinics, and this level is only reached after a few years of proper results. A lot of patients report that this type of treatment is the only long term treatment option that has ever continued to be effective for them. A lot of mental issues that come from discontinuing the use of all types of opiates do not cease for years or more. The methadone programs, if correctly monitored, can help the patient get back to their life and be able to function without the constant cravings and insomnia reported after quitting opiates. Methadone can provide a method of stable treatment of the symptoms associated with withdrawal and mental anguish, and, with a proper slow taper, can be discontinued after the patient feels he or she is ready, often after a year or more, which gives the addict time to get away from old habits or triggers.

In the U.S., MMT patients generally receive psycho-social support (i.e. "counseling"), which is provided on site. Although laws vary, this is required in many states and countries regardless of whether a person needs or wants to engage in that kind of intervention (for example, recent changes in Taiwan). Patients are often required to attend 10 hours or more of therapy per week, having their daily dose withheld (thereby inducing withdrawal) for failure to comply. Methadone maintenance is rarely covered by private insurance and patients are encouraged to enroll in public welfare programs or face upwards of $500 USD per month. Since a supervised dose costs more than a take-home dose, and the risk of diversion, clinics are often reluctant to provide take-home privileges.

Cost [edit]

In Germany the annual cost per patient is less than 3000 euros, while heroin assisted treatment costs up to 10,000 euros per year.

Methadone clinics in the U.S. charge anywhere from $50–300 per week, which may be covered by private insurance or Medicaid.

MMT cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.[16][17]

Analgesic [edit]

In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. Due to its activity at the NMDA receptor it may be more effective against neuropathic pain; for the same reason tolerance to the analgesic effects maybe lesser compared to other opioids. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than shorter-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone.[18][19][20]

While the cost for pain patients varies based on many factors, leading to few specifics in the literature, one source[21] states:

Prices vary; however, in some cases monthly costs to patients for oral methadone can be more than 30-fold less than equianalgesic doses of other generic or brand-name opioid analgesics.

A week's supply will typically have a retail cost of $50–$100 in the United States,[citation needed] compared to hundreds of dollars for alternative opioids. Methadone, with its long half-life (and thus long duration of effect) and good oral bioavailability, is a common second-choice drug for pain that does not respond to weaker agonists. A major drawback is that unlike OxyContin (oxycodone continuous release), methadone is not technologically engineered for sustained release of the drug so blood concentrations will fluctuate greatly between dosing. This problem is overcome to a great extent by the practice of dosing methadone two or three times a day in pain patients. Some physicians also choose methadone for treating chronic pain in patients who are thought to have a propensity for addiction, because it causes less of an intoxicated or euphoric "high". The effect is of morphine-equivalent origin.

On November 29, 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat." The advisory went on to say that "the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong narcotic pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heart beat that may not be felt by the patient." The advisory urged that physicians use caution when prescribing methadone to patients who are not used to the drug, and that patients take the drug exactly as directed.[22] As with any strong medication that can be fatal in large doses, methadone must be taken properly and with due care. Otherwise, the accumulation of methadone could potentially reach a level of toxicity if the dose is too high or if the user's metabolism of the drug is slow. In such a situation, a patient who fared fine after the first few doses could reach high levels of the drug in his body without ever taking more than was prescribed. For this reason, it is reasonable to make sure that patients who do not have a tolerance to opiates be prescribed methadone in initially small doses, and that when sent home, patients and their families are made very aware of the symptoms characteristic of opiate overdose. Also, there is some evidence that methadone and other opioids may cause cardiac conduction problems (prolonged QTc interval[23][24]) although there are few documented cases of fatalities resulting from this side effect with methadone.

In an effort to turn the tide on reported increases in methadone-related adverse events, the DEA announced in a recent advisory that manufacturers of methadone hydrochloride 40-mg tablets have agreed to restrict their distribution of that particular formulation of the drug.

As of 1. January 2008, manufacturers will ship the methadone hydrochloride 40-mg formulation only to hospitals and facilities that have been authorized for detoxification and maintenance treatment of patients with opioid addiction. In addition, manufacturers of the drug will instruct their wholesale distributors to stop supplying the formulation to any facility that doesn't meet the criteria.

The DEA advisory stresses that the 40-mg formulation of methadone hydrochloride is indicated only for the detoxification and maintenance treatment of opioid-addicted patients and is not FDA-approved for use in pain management.

Federal law does not restrict the prescribing, dispensing or administration of methadone for the treatment of pain, and the 5-mg and 10-mg methadone formulations will continue to be available as a tool that family physicians can use to treat patients for pain. Despite the FDA directive, many doctors continue to prescribe Methadone as a pain killer, but only to patients which have shown to be responsible in their use of previous pain killers. One reason for use of Methadone is its advantages for opioid rotation.

Patients with long-term pain will sometimes have to perform so-called opioid rotation.[25] By this is meant switching from one opioid to another, usually at intervals of between a few weeks and, more commonly, several months. Opioid rotation is good because switching to another opioid gives lower dose, and because of this less side effects, to achieve the desired effect. Then, with the new opioid, tolerance grows, higher doses are needed, and toxicity in relation to analgesic effects increase. So then it is time rotate again to another opioid. Such opioid rotation is standard practice for managing patients with tolerance development problems. Usually, when doing opioid rotation, one cannot go down to a completely naive dose, because there is cross-tolerance, so some of the high tolerance is brought over to the new opioid. However, Methadone has much lower cross-tolerance, when switching to it from other opioids, than other opioids.[26] This means that Methadone can start at a low dose, and the time for the next switch will be longer.

All opioids have tiredness as a major side effect, which can lead to the patient being in an almost half-awake state, in medical terms known as sedation. Many patients report that Methadone's sedation effect is often less pronounced than with other opioids and cite this as a major argument for preferring Methadone as an analgesic.[27]

Antitussive [edit]

Methadone linctus, which is about one-third the concentration of the liquid methadone used for opioid maintenance, is used where available and approved for such use as a cough syrup for violent coughing. Some studies have shown narcotic cough suppressants to be useful against dry, unproductive coughing, but others have shown questionable or no benefit.

Natural and semi-synthetic opiates with antitussive effects include codeine, ethylmorphine (also known as dionine or codethyline), dihydrocodeine, benzylmorphine, laudanum, dihydroisocodeine, nicocodeine, nicodicodeine, hydrocodone, hydromorphone, acetyldihydrocodeine, thebacon, diamorphine (heroin), acetylmorphone, noscapine and pholcodine and others. Amongst other synthetics are dimemorfan and dextromethorphan in the morphinan group, tipepidine of the thiambutenes, and other drugs of the open-chain (methadone) type with antitussive efficacy include levomethadone, normethadone and levopropoxyphene. There is also the newer synthetic Zipeprol, classified as 'Other' (not available in the U.S. or CA).

Leukemia [edit]

Researchers in Germany have discovered that methadone has surprising killing power against leukemia cells, including treatment-resistant forms of the cancer. Their laboratory study, published in the 1 August 2008 issue of Cancer Research, a journal of the American Association for Cancer Research, suggests that methadone holds promise as a new therapy for leukemia, especially in patients whose cancer no longer responds to chemotherapy and radiation.[28]

Adverse effects [edit]

Adverse effects of methadone include:[29][30][31][32][33]

Detection in biological fluids [edit]

Methadone and its major metabolite, EDDP, are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naive individual. Chronic users often have high methadone and EDDP baseline values.[34]

Mortality [edit]

In the United States, deaths linked to methadone more than quadrupled in the five year period between 1999 and 2004. According to the U.S. National Center for Health Statistics,[35] as well as a 2006 series in the Charleston (West Virginia) Gazette,[36] medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especially benzodiazepines).

Although deaths from methadone are on the rise, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the Substance Abuse and Mental Health Services Administration, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality."[37]

In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled “Methadone Use for Pain Control May Result in Death.” The FDA also revised the drug's package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the 'usual adult dose' was potentially deadly, according to pain specialists."[38]

Driving [edit]

Methadone treatment may impair driving ability.[39] Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by Queensland University. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes.[40] However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.[41]

Tolerance and dependence [edit]

As with other opioid medications, tolerance and dependence usually develop with repeated doses. There is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the NA recepetor. Tolerance to the different physiological effects of methadone varies; tolerance to both analgesic properties and euphoria develops quickly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever).[42]

Withdrawal symptoms [edit]

Physical symptoms[citation needed]

Cognitive symptoms[citation needed]

Withdrawal symptoms have shown to be up to twice as severe than those of morphine or heroin at equivalent doses and are significantly more prolonged; methadone withdrawal symptoms can last for several weeks or more. A general guideline is a 1:1 ratio for trouble free detox. Being on a constant dose of say 100 mg. for one year, can take 18–24 months for safe detoxification. At high maintenance doses, sudden cessation of therapy can result in withdrawal symptoms described as "the worst withdrawal imaginable," lasting from weeks to months.[43]

There is a trend in the management of opiate addiction towards the reduction of a patient's methadone dosage to a point where they can be switched to buprenorphine or another opiate with an easier withdrawal profile. When detoxing at a recommended rate (typically 1-2 mgs per week), withdrawal is either minimal or nonexistent, as the patient's body has time to adjust to each reduction in dose. However, like methadone, buprenorphine produces similar cognitive dehabilitation in multiple areas of mental function in both memory and timed choice task tests, which may persist after cessation of substitution treatment.

Pharmacology [edit]

Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. It is metabolized by the enzymes CYP3A4, CYP2B6 and CYP2D6, with great variability between individuals. Its main route of administration is oral. Adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opiates, spanning anywhere from two weeks to six months.It can also be found in urine samples six to ten weeks after the last dose. It was generally thought it left the system 2–3 days after last use but this is not the case, many factors contribute to how long it will stay in the system. It depends an individual's body weight, metabolism, history of use/abuse and many more factors. In studies done on Methadone users going through detox, individuals experienced different withdrawal symptoms and withdrawal periods even though they received their last dose at the same time. When they gave blood and urine samples the methadone showed up in some individuals samples as much as four weeks after it was not evident in other individuals samples.

Mechanism of action [edit]

Ball-and-stick model of methadone

Methadone is a full µ-opioid agonist. Methadone also binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[44]

Metabolism [edit]

Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,[45][46] ranging from as few as 4 hours to as many as 130 hours,[47] or even 190 hours.[48] This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.[47] This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.[citation needed]

The toxic effects of an overdose can be treated with naloxone.[29] Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite Methadone's much longer duration of action compared to either heroin and other shorter-acting agonists, and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half-life, it is more difficult to titrate. If too large a dose of opioid antagonist is given to a dependent patient, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short lived. Doses of naltrexone take longer to be eliminated from the patient's system. A common problem in treating methadone overdoses is that, given the short action of Naloxone (versus the extremely longer-acting Methadone), a dosage of Naloxone given to a Methadone-overdosed patient will initially work to bring the patient out of overdose, but once the Naloxone wears off, if no further Naloxone is administered, the patient can go right back into overdose (based upon time and dosage of the Methadone ingested).

Route of administration [edit]

The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.[47] This is becoming less common due to the higher production costs.

Methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the patient to drink. Drinkable forms include ready-to-dispense liquid, and "Disket" which is a tablet designed to disperse itself in water for oral administration, used in a similar fashion to Alka-Seltzer. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone does not result in a "rush" as with some other strong opioids such as morphine or hydromorphone, because its extraordinarily high volume of distribution causes it to diffuse into other tissues in the body, particularly fatty tissue; the peak concentration in the blood is achieved at roughly the same time, whether the drug is injected or ingested. When injecting Methadone, only pills have the least-dangerous cautions although it can easily cause collapsed veins, bruising, swelling and possibly other harmful effects. Methadone pills often contain talc[49][50] that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease.[51][52][53] Methadose/Methadone should not be injected either.[54] While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported as well as damaged veins from sugar and other ingredients (Sugar-Free syrups also should not be injected). Oral medication offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs.[55]

History [edit]

40mg of Methadone

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst (it is synthesised from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium shortage problem.[56] The reason for its swift abandonment as an alternative to morphine was due to the adverse effects it had on german soldiers during early trials. In contrast to morphine, which was used to alleviate pain in the injured but also to boost the esteem, stamina, and drive of german soldiers in combat, methadone had effects that have been described as such; "Dolophine (Methadone) had many adverse effects on the soldiers to whom it was given, leading to apathy, lethargy, and decreased willingness to engage in combat".

On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or polamidon (a name still in regular use in Germany) and whose structure had only slight relation to morphine or the opiate alkaloids (Bockmühl and Ehrhart, 1949).

After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US.

It was only in 1947 that the drug was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association (COUNCIL...1947). Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could buy the rights for commercial production of methadone for just one dollar (MOLL 1990).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic (they gave it the trade name Dolophine, which is now registered to Roxane Laboratories). Since then, it has been best known for its use in treating narcotic addiction. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and it had even been used in some hospitals. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.

Methadone (as Dolophine) was first manufactured in the USA by Eli Lilly and Company Pharmacueticals, who first obtained FDA approval on August 14, 1947, for their Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmacueticals did not receive approval until December 15, 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for their branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.[57]

The results of the early major studies showed methadone could effectively interrupt illicit opioid use and reduce the associated costs to society, findings which have been consistent with later research and backed up by modern knowledge of the psychological, social and pharmacological mechanisms of illicit opioid addiction.

Origin of Dolophine name [edit]

A persistent but untrue urban legend claims that the trade name "Dolophine" was coined in tribute to Adolf Hitler by its German creators, and it is sometimes even claimed that the drug was originally named "adolphine" or "adolophine" or "Dolphamine". The claim is still presented as fact by Church of Scientology literature and was repeated by actor and vocal Scientologist Tom Cruise in a 2005 Entertainment Weekly interview.[58] However, as the magazine pointed out, this is not true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly,[59] and the pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.[60]

Similar drugs [edit]

See also: Heroin-assisted Treatment and Buprenorphine

There are two methadone isomers that form the racemic mixture which is more common as it is cheaper to produce. The laevorotary isomer, which is isolated by several recrystalisations from racemic methadone, is more expensive to produce than the racemate. It is more potent at the opioid receptor than the racemic mixture and is marketed especially in continental Europe as an analgesic under the trade names Levo-Polamidone, Polamidone, Heptanone, Heptadone, Heptadon and others. It is used as the hydrochloride salt almost exclusively with some uncommon pharmaceuticals and research subjects consisting of the tartrate. The dextrorotary isomer d-methadone is not commercially available. It is devoid of opioid activity and it acts as an NMDA antagonist. It has been shown to be analgesic in experimental models of chronic pain. Clinical trials of d-methadone, to test its analgesic efficacy against neuropathic pain are in progress.

The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and in Schedule II of the United States Controlled Substances Act. LAAM has since been removed from the US and European markets due to reports of rare cardiac side effects.

Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone). In the NL, Switzerland, the UK and a few other European countries, however, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical diamorphine (heroin) or other opioids may be used for outpatient maintenance treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. In the United Kingdom, diamorhpine is used extremely selectively and is not available on prescription to addicts; except in specialist trials which involved no more than 300 participants. A study from Austria indicated that oral morphine (in the form of MS-Contin) under the trade name Substitol-Retard provides better results than oral methadone, and studies of heroin maintenance have indicated that a low background dose of methadone combined with heroin maintenance may significantly improve outcomes for less-responsive patients.[61] Slow release oral morphine is readily used alongside methadone and buprenorphine for OMT in Austria, Slovakia, and Bulgaria, and to a limited extent in other EU nations including the United Kingdom. Different nations within the EU have different regulations, and in some nations general practitioners have the right to maintain addicts with whatever they deem to be most efficacious in maintaining their health and well being. Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.[62]

Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. Since dextropropoxyphene produces relatively modest pain relief compared to other opioids but still produces severe respiratory depression at high doses, it is particularly dangerous when abused, as drug users may take dangerously high doses in an attempt to achieve narcotic effects. This narcotic is among the top 10 drugs reported by medical examiners in recreational drug use deaths. However, dextropropoxyphene is still prescribed for the short term relief of opiate withdrawal symptoms, particularly when the aim of treatment is to smooth detoxification to a drug free state rather than a switch to maintenance treatment.

Other analogues of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter-lasting but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. These drugs have a high potential for abuse and dependence and were notorious for being widely abused and sought after by drug addicts in the 1970s. They are still rarely used for the relief of severe pain in the treatment of terminal cancer or other serious medical conditions.

Notes [edit]

  1. ↑ Pharmaceuticals.Mallinckrodt.com
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Joseph H, Stancliff S, Langrod J (2000). "Methadone maintenance treatment (MMT): a review of historical and clinical issues". Mt. Sinai J. Med. 67 (5-6): 347–64. PMID 11064485. 
  3. ↑ Connock M, Juarez-Garcia A, Jowett S, et al. (2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health technology assessment (Winchester, England) 11 (9): 1–171, iii–iv. PMID 17313907. 
  4. ↑ M Schwirtz. "Russia Scorns Methadone for Heroin Addiction." The New York Times. July 22, 2008.
  5. ↑ Template:Cite doi
  6. ↑ Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL (2005). "Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers". Addiction 100 (10): 1496–509. doi:10.1111/j.1360-0443.2005.01232.x. PMID 16185211. 
  7. ↑ Latowsky M (2006). "Methadone death, dosage and torsade de pointes: risk-benefit policy implications". Journal of psychoactive drugs 38 (4): 513–9. PMID 17373567. 
  8. ↑ Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P (2000). "When "Enough" Is Not Enough: New Perspectives on Optimal Methadone Maintenance Dose". Mount Sinai Journal of Medicine 67 (5&6): 404–411. 
  9. ↑ Faggiano F, Vigna-Taglianti F, Versino E, Lemma P (2003). "Methadone maintenance at different dosages for opioid dependence". Cochrane database of systematic reviews (3): CD002208. doi:10.1002/14651858.CD002208. PMID 12917925. 
  10. ↑ Script error
  11. ↑ Script error
  12. ↑ "Methadone Maintenance Program Overview". The College Of Pharmacists Of British Columbia. "The College Of BC Pharmacists". 
  13. ↑ Script error
  14. ↑ Script error
  15. ↑ Script error
  16. ↑ Script error
  17. ↑ Script error
  18. ↑ Template:Cite pmid
  19. ↑ Template:Cite pmid
  20. ↑ Template:Cite pmid
  21. ↑ Script error
  22. ↑ Script error
  23. ↑ Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A (2005). "QTc interval prolongation in patients on long-term methadone maintenance therapy". European addiction research 11 (1): 44–9. doi:10.1159/000081416. PMID 15608471. 
  24. ↑ 24.0 24.1 Template:Cite doi
  25. ↑ Script error
  26. ↑ Script error
  27. ↑ Script error
  28. ↑ Claudia Friesen, Mareike Roscher, Andreas Alt and Erich Miltner (2008). "Methadone, Commonly Used as Maintenance Medication for Outpatient Treatment of Opioid Dependence, Kills Leukemia Cells and Overcomes Chemoresistance". Cancer Research 68 (15): 6059–64. doi:10.1158/0008-5472.CAN-08-1227. PMID 18676827. 
  29. ↑ 29.0 29.1 Public Health Issue: Methadone Maintenance Therapy RICHARD SADOVSKY, M.D. - Anderson IB, Kearney TE. Use of methadone. West J Med January 2000;172:43-6.
  30. ↑ Script error
  31. ↑ Script error
  32. ↑ Script error
  33. ↑ Script error
  34. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 941-945.
  35. ↑ Script error
  36. ↑ "The Killer Cure" The Charleston Gazette 2006
  37. ↑ Script error
  38. ↑ [1] Charleston Gazette, "New warning issued on methadone", Nov. 28, 2006
  39. ↑ Giacomuzzi SM, Ertl M, Vigl A, et al. (July 2005). "Driving capacity of patients treated with methadone and slow-release oral morphine". Addiction 100 (7): 1027. doi:10.1111/j.1360-0443.2005.01148.x. PMID 15955021. 
  40. ↑ Reece AS (2008). "Experience of road and other trauma by the opiate dependent patient: a survey report". Subst Abuse Treat Prev Policy 3: 10. doi:10.1186/1747-597X-3-10. PMID 18454868. 
  41. ↑ [2]
  42. ↑ Addiction Treatment Forum
  43. ↑ Script error
  44. ↑ Xiao Y, Smith RD, Caruso FS, Kellar KJ (October 2001). "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs". J. Pharmacol. Exp. Ther. 299 (1): 366–71. PMID 11561100. 
  45. ↑ Kell MJ (1994). "Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting". Journal of addictive diseases: the official journal of the ASAM, American Society of Addiction Medicine 13 (1): 5–26. PMID 8018740. 
  46. ↑ Eap CB, DeglonJ-J, Boumann P. (1999). "Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance". Heroin Addiction and Related Clinical Problems: the official journal of EUROPAD, European Opiate Addiction Treatment Association 1 (1): 19–34. 
  47. ↑ 47.0 47.1 47.2 Eap CB, Buclin T, Baumann P (2002). "Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence". Clinical pharmacokinetics 41 (14): 1153–93. PMID 12405865. 
  48. ↑ Manfredonia, John (March 2005). "Prescribing Methadone for Pain Management in End-of-Life Care". JAOA The Journal of the American Osteopathic Association 105. 
  49. ↑ Script error
  50. ↑ Script error
  51. ↑ Script error
  52. ↑ Script error
  53. ↑ Script error
  54. ↑ Nicholas Lintzeris, Michael Lenne, Alison Ritter (1999). "Methadone injecting in Australia: A Tale of Two Cities". Addiction 94 (8): 1175–1178. doi:10.1046/j.1360-0443.1999.94811757.x. PMID 10615732. 
  55. ↑ Code of Federal Regulations, Title 42, Sec 8.
  56. ↑ M. Bockmuhl, Über eine neue Klasse von analgetisch wirkenden Verbindungen Ann. Chem. 561, 52 (1948)
  57. ↑ Accessdata.FDA.gov
  58. ↑ Tom Responds, Entertainment Weekly, May 11, 2005
  59. ↑ Script error
  60. ↑ Indro-Online.de (PDF format)
  61. ↑ Michels II, Stöver H, Gerlach R (2007). "Substitution treatment for opioid addicts in Germany". Harm Reduct J 4: 5. doi:10.1186/1477-7517-4-5. PMID 17270059. 
  62. ↑ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A (December 2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID 17156174. 

External links [edit]

Template:Analgesics Template:Drugs used in addictive disorders Template:Cholinergics Template:Serotonergics


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http://en.wikipedia.org/wiki/Nuclear_science [edit]

A figurative depiction of the helium-4 atom. In the nucleus, the two protons are shown in red and neutrons blue. This depiction shows the particles as separate, whereas in an actual helium atom, the protons are superimposed in space and most likely found at the very center of the nucleus, and the same is true of the two neutrons. Thus all four particles are most likely found in exactly the same space. Classical images of separate particles thus fail to model known charge distributions in very small nuclei

The nucleus is the very dense region consisting of nucleons (protons and neutrons) at the center of an atom. Almost all of the mass in an atom is made up from the protons and neutrons in the nucleus, with a very small contribution from the orbiting electrons. It was discovered in 1911, as a result of Ernest Rutherford's interpretation of the famous 1909 Rutherford experiment performed by Hans Geiger and Ernest Marsden, under the direction of Rutherford. The proton–neutron model of nucleus was proposed by Dmitry Ivanenko in 1932.[citation needed]

The diameter of the nucleus is in the range of 1.75 fm (femtometre) (1.75×10−15
 m) for hydrogen (the diameter of a single proton)[1] to about 15 fm for the heaviest atoms, such as uranium. These dimensions are much smaller than the diameter of the atom itself (nucleus + electronic cloud), by a factor of about 23,000 (uranium) to about 145,000 (hydrogen).

The branch of physics concerned with studying and understanding the atomic nucleus, including its composition and the forces which bind it together, is called nuclear physics.

Introduction [edit]

Etymology [edit]

The term nucleus is from the Latin word nucleus ("nut"). In 1844, Michael Faraday used the term to refer to the "central point of an atom". The modern atomic meaning was proposed by Ernest Rutherford in 1912.[2] The adoption of the term "nucleus" to atomic theory, however, was not immediate. In 1916, for example, Gilbert N. Lewis stated, in his famous article The Atom and the Molecule, that "the atom is composed of the kernel and an outer atom or shell"[3]

Nuclear makeup [edit]

The nucleus of an atom consists of protons and neutrons (two types of baryons) bound by the nuclear force (also known as the residual strong force). These baryons are further composed of subatomic fundamental particles known as quarks bound by the strong interaction. Which chemical element an atom represents is determined by the number of protons in the nucleus. Each proton carries a single positive charge, and the total electrical charge of the nucleus is spread fairly uniformly throughout its body, with a fall-off at the edge.

Major exceptions to this rule are the light elements hydrogen and helium, where the charge is concentrated most highly at the single central point (without a volume of uniform charge), as would be expected for fermions (in this case, protons) in 1s states without orbital angular momentum.[4]

As each proton carries a unit of charge, the charge distribution is indicative of the proton distribution. The neutron distribution probably is similar.[4]

Protons and neutrons [edit]

Protons and neutrons are fermions, with different values of the isospin quantum number,Template:Dubious so two protons and two neutrons can share the same space wave function since they are not identical quantum entities. They sometimes are viewed as two different quantum states of the same particle, the nucleon.[5][6] Two fermions, such as two protons, or two neutrons, or a proton + neutron (the deuteron) can exhibit bosonic behavior when they become loosely bound in pairs.

In the rare case of a hypernucleus, a third baryon called a hyperon, with a different value of the strangeness quantum number can also share the wave function. However, the latter type of nuclei are extremely unstable and are not found on Earth except in high energy physics experiments.

The neutron has a positively charged core of radius ≈ 0.3 fm surrounded by a compensating negative charge of radius between 0.3 fm and 2 fm. The proton has an approximately exponentially decaying positive charge distribution with a mean square radius of about 0.8 fm.[7]

Forces [edit]

Nuclei are bound together by the residual strong force (nuclear force). The residual strong force is minor residuum of the strong interaction which binds quarks together to form protons and neutrons. This force is much weaker between neutrons and protons because it is mostly neutralized within them, in the same way that electromagnetic forces between neutral atoms (such as van der Waals forces that act between two inert gas atoms) are much weaker than the electromagnetic forces that hold the parts of the atoms internally together (for example, the forces that hold the electrons in an inert gas atom bound to its nucleus).

The nuclear force is highly attractive at the distance of typical nucleon separation, and this overwhelms the repulsion between protons which is due to the electromagnetic force, thus allowing nuclei to exist. However, because the residual strong force has a limited range because it decays quickly with distance (see Yukawa potential), only nuclei smaller than a certain size can be completely stable. The largest known completely stable (e.g., stable to alpha, beta, and gamma decay) nucleus is lead-208 which contains a total of 208 nucleons (126 neutrons and 82 protons). Nuclei larger than this maximal size of 208 particles are unstable and (as a trend) become increasingly short-lived with larger size, as the number of neutrons and protons which compose them increases beyond this number. However, bismuth-209 is also stable to beta decay and has the longest half-life to alpha decay of any known isotope, estimated at a billion times longer than the age of the universe.

The residual strong force is effective over a very short range (usually only a few fermis; roughly one or two nucleon diameters) and causes an attraction between any pair of nucleons. For example, between protons and neutrons to form [NP] deuteron, and also between protons and protons, and neutrons and neutrons.

Halo nuclei and strong force range limits [edit]

The effective absolute limit of the range of the strong force is represented by halo nuclei such as lithium-11 or boron-14, in which dineutrons, or other collections of neutrons, orbit at distances of about ten fermis (roughly similar to the 8 fermi radius of the nucleus of uranium-238). These nuclei are not maximally dense. Halo nuclei form at the extreme edges of the chart of the nuclides—the neutron drip line and proton drip line—and are all unstable with short half-lives, measured in milliseconds; for example, lithium-11 has a half-life of less than 8.6 milliseconds.

Halos in effect represent an excited state with nucleons in an outer quantum shell which has unfilled energy levels "below" it (both in terms of radius and energy). The halo may be made of either neutrons [NN, NNN] or protons [PP, PPP]. Nuclei which have a single neutron halo include 11Be and 19C. A two-neutron halo is exhibited by 6He, 11Li, 17B, 19B and 22C. Two-neutron halo nuclei break into three fragments, never two, and are called Borromean because of this behavior (referring to a system of three interlocked rings in which breaking any ring frees both of the others). 8He and 14Be both exhibit a four-neutron halo. Nuclei which have a proton halo include 8B and 26P. A two-proton halo is exhibited by 17Ne and 27S. Proton halos are expected to be more rare and unstable than the neutron examples, because of the repulsive electromagnetic forces of the excess proton(s).

Nuclear models [edit]

There are many different historical models of the atomic nucleus, none of which to this day completely explains experimental data on nuclear structure. A useful review of 37 known models of the atomic nucleus is provided by Cook.[8]

The nuclear radius (R) is considered to be one of the basic things that any model must predict. For stable nuclei (not halo nuclei or other unstable distorted nuclei) the nuclear radius is roughly proportional to the cube root of the mass number (A) of the nucleus, and particularly in nuclei containing many nucleons, as they arrange in more spherical configurations:

The stable nucleus has approximately a constant density and therefore the nuclear radius R can be approximated by the following formula,

R = r_0 A^{1/3} \,

where A = Atomic mass number (the number of protons, Z, plus the number of neutrons, N) and r0 = 1.25 fm = 1.25 × 10−15 m. In this equation, the constant r0 varies by 0.2 fm, depending on the nucleus in question, but this is less than 20% change from a constant.[9]

In other words, packing protons and neutrons in the nucleus gives approximately the same total size result as packing hard spheres of a constant size (like marbles) into a tight spherical or semi-spherical bag (some stable nuclei are not quite spherical, but are known to be prolate).[citation needed]

Liquid drop models [edit]

Main source: Liquid-drop model

Early models of the nucleus viewed the nucleus as a rotating liquid drop. In this model, the trade-off of long-range electromagnetic forces and relatively short-range nuclear forces, together cause behavior which resembled surface tension forces in liquid drops of different sizes. This formula is successful at explaining many important phenomena of nuclei, such as their changing amounts of binding energy as their size and composition changes (see semi-empirical mass formula), but it does not explain the special stability which occurs when nuclei have special "magic numbers" of protons or neutrons.

Shell models and other quantum models [edit]

Main source: Nuclear shell model

A number of models for the nucleus have also been proposed in which nucleons occupy orbitals, much like the atomic orbitals in atomic physics theory. These wave models imagine nucleons to be either sizeless point particles in potential wells, or else probability waves as in the "optical model", frictionlessly orbiting at high speed in potential wells.

In these models, the nucleons may occupy orbitals in pairs, due to being fermions, but the exact nature and capacity of nuclear shells differs from those of electrons in atomic orbitals, primarily because the potential well in which the nucleons move (especially in larger nuclei) is quite different from the central electromagnetic potential well which binds electrons in atoms. Some resemblance to atomic orbital models may be seen in a small atomic nucleus like that of helium-4, in which the two protons and two neutrons separately occupy 1s orbitals analogous to the 1s orbital for the two electrons in the helium atom, and achieve unusual stability for the same reason. Nuclei with 5 nucleons are all extremely unstable and short-lived, yet, helium-3, with 3 nucleons, is very stable even with lack of a closed 1s orbital shell. Another nucleus with 3 nucleons, the triton hydrogen-3 is unstable and will decay into helium-3 when isolated. Weak nuclear stability with 2 nucleons {NP} in the 1s orbital is found in the deuteron hydrogen-2, with only one nucleon in each of the proton and neutron potential wells. While each nucleon is a fermion, the {NP} deuteron is a boson and thus does not follow Pauli Exclusion for close packing within shells. Lithium-6 with 6 nucleons is highly stable without a closed second 1p shell orbital. For light nuclei with total nucleon numbers 1 to 6 only those with 5 do not show some evidence of stability. Observations of beta-stability of light nuclei outside closed shells indicate that nuclear stability is much more complex than simple closure of shell orbitals with magic numbers of protons and neutrons.

For larger nuclei, the shells occupied by nucleons begin to differ significantly from electron shells, but nevertheless, present nuclear theory does predict the magic numbers of filled nuclear shells for both protons and neutrons. The closure of the stable shells predicts unusually stable configurations, analogous to the noble group of nearly-inert gases in chemistry. An example is the stability of the closed shell of 50 protons, which allows tin to have 10 stable isotopes, more than any other element. Similarly, the distance from shell-closure explains the unusual instability of isotopes which have far from stable numbers of these particles, such as the radioactive elements 43 (technetium) and 61 (promethium), each of which is preceded and followed by 17 or more stable elements.

There are however problems with the shell model when an attempt is made to account for nuclear properties well away from closed shells. This has led to complex post hoc distortions of the shape of the potential well to fit experimental data, but the question remains whether these mathematical manipulations actually correspond to the spatial deformations in real nuclei. Problems with the shell model have led some to propose realistic two-body and three-body nuclear force effects involving nucleon clusters and then build the nucleus on this basis. Two such cluster models are the Close-Packed Spheron Model of Linus Pauling and the 2D Ising Model of MacGregor.[8]

Consistency between models [edit]

Main source: Nuclear structure

As with the case of superfluid liquid helium, atomic nuclei are an example of a state in which both (1) "ordinary" particle physical rules for volume and (2) non-intuitive quantum mechanical rules for a wave-like nature apply. In superfluid helium, the helium atoms have volume, and essentially "touch" each other, yet at the same time exhibit strange bulk properties, consistent with a Bose-Einstein condensation. The latter reveals that they also have a wave-like nature and do not exhibit standard fluid properties, such as friction. For nuclei made of hadrons which are fermions, the same type of condensation does not occur, yet nevertheless, many nuclear properties can only be explained similarly by a combination of properties of particles with volume, in addition to the frictionless motion characteristic of the wave-like behavior of objects trapped in Schrödinger quantum orbitals.

See also [edit]

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Notes [edit]

  1. ↑ Geoff Brumfiel (July 7, 2010). "The proton shrinks in size". Nature. doi:10.1038/news.2010.337. 
  2. ↑ Script error
  3. ↑ G.N. Lewis (1916). "The Atom and the Molecule". Journal of the American Chemical Society 38. doi:10.1021/ja02261a002. 
  4. ↑ 4.0 4.1 J.-L. Basdevant, J. Rich, M. Spiro (2005). Fundamentals in Nuclear Physics. Springer. p. 13, Fig. 1.1. ISBN 0387016724. http://books.google.com/?id=OFx7P9mgC9oC&pg=PA375&dq=helium+%22nuclear+structure%22. 
  5. ↑ A.G. Sitenko, V.K. Tartakovskiĭ (1997). Theory of Nucleus: Nuclear Structure and Nuclear Interaction. Kluwer Academic. p. 3. ISBN 0792344235. http://books.google.com/?id=swb9QpqOqtAC&pg=PA464&dq=isbn=0792344235#PPA3,M1. 
  6. ↑ M.A. Srednicki (2007). Quantum Field Theory. Cambridge University Press. pp. 522–523. ISBN 9780521864497. 
  7. ↑ J.-L. Basdevant, J. Rich, M. Spiro (2005). Fundamentals in Nuclear Physics. Springer. p. 155. ISBN 0387016724. http://books.google.com/?id=OFx7P9mgC9oC&pg=PA375&dq=helium+%22nuclear+structure%22. 
  8. ↑ 8.0 8.1 N.D. Cook (2010). Models of the Atomic Nucleus (2nd ed.). Springer. p. 57 ff.. ISBN 978-3-642-14736-4. 
  9. ↑ K.S. Krane (1987). Introductory Nuclear Physics. Wiley-VCH. ISBN 0-471-80553-X. 

References [edit]

External links [edit]

Template:Particles Template:Nuclear Technology

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http://en.wikipedia.org/wiki/Nebula [edit]

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The "Pillars of Creation" from the Eagle Nebula
The Triangulum Emission Garren Nebula NGC 604
The Crab Nebula video by NASA

A nebula (from Latin: "cloud";[1] pl. nebulae or nebulæ, with ligature or nebulas) is an interstellar cloud of dust, hydrogen gas, helium gas and other ionized gases. Originally, nebula was a general name for any extended astronomical object, including galaxies beyond the Milky Way (some examples of the older usage survive; for example, the Andromeda Galaxy was referred to as the Andromeda Nebula before galaxies were discovered by Edwin Hubble). Nebulae often form star-forming regions, such as in the Eagle Nebula. This nebula is depicted in one of NASA's most famous images, the "Pillars of Creation". In these regions the formations of gas, dust, and other materials "clump" together to form larger masses, which attract further matter, and eventually will become massive enough to form stars. The remaining materials are then believed to form planets, and other planetary system objects.

History [edit]

Around A.D. 150, Claudius Ptolemaeus (Ptolemy) recorded, in books VII-VIII of his Almagest, five stars that appeared nebulous. He also noted a region of nebulosity between the constellations Ursa Major and Leo that was not associated with any star.[2] The first true nebula, as distinct from a star cluster, was mentioned by the Persian astronomer, Abd al-Rahman al-Sufi, in his Book of Fixed Stars (964).[3] He noted "a little cloud" where the Andromeda Galaxy is located.[4] He also cataloged the Omicron Velorum star cluster as a "nebulous star" and other nebulous objects, such as Brocchi's Cluster.[3] The supernova that created the Crab Nebula, the SN 1054, was observed by Arabic and Chinese astronomers in 1054.[5][6]

For reasons unknown, Al-Sufi failed to note the Orion Nebula, which is at least as prominent as the Andromeda galaxy in the night sky. On November 26, 1610, Nicolas-Claude Fabri de Peiresc discovered the Orion Nebula using a telescope. This nebula was also observed by Johann Baptist Cysat in 1618. However, the first detailed study of the Orion Nebula wouldn't be performed until 1659 by Christian Huygens, who also believed himself to be the first person to discover this nebulosity.[4]

In 1715, Edmund Halley published a list of six nebulae.[7] This number steadily increased during the century, with Jean-Philippe de Cheseaux compiling a list of 20 (including eight not previously known) in 1746. From 1751–53, Nicolas Louis de Lacaille cataloged 42 nebulae from the Cape of Good Hope, with most of them being previously unknown. Charles Messier then compiled a catalog of 103 nebulae by 1781, although his primary goal in doing so was to avoid the false detection of comets.[8]

The number of nebulae was then greatly expanded by the efforts of William Herschel and his sister Caroline Herschel. Their Catalogue of One Thousand New Nebulae and Clusters of Stars was published in 1786. A second catalog of a thousand was published in 1789 and the third and final catalog of 510 appeared in 1802. During much of their work, William Herschel believed that these nebulae were merely unresolved clusters of stars. In 1790, however, he discovered a star surrounded by nebulosity and concluded that this was a true nebulosity, rather than a more distant cluster.[8]

Beginning in 1864, William Huggins examined the spectra of about 70 nebulae. He found that roughly a third of them had the absorption spectra of a gas. The rest showed a continuous spectrum and thus were thought to consist of a mass of stars.[9][10] A third category was added in 1912 when Vesto Slipher showed that the spectrum of the nebula that surrounded the star Merope matched the spectra of the Pleiades open cluster. Thus the nebula radiates by reflected star light.[11]

Slipher and Edwin Hubble continued to collect the spectra from many diffuse nebulae, finding 29 that showed emission spectra and 33 had the continuous spectra of star light.[10] In 1922, Hubble announced that nearly all nebulae are associated with stars, and their illumination comes from star light. He also discovered that the emission spectrum nebulae are nearly always associated with stars having spectral classifications of B1 or hotter (including all O-type main sequence stars), while nebulae with continuous spectra appear with cooler stars.[12] Both Hubble and Henry Norris Russell concluded that the nebulae surrounding the hotter stars are transformed in some manner.[10]

Formation [edit]

NGC 2024, The Flame Nebula
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Many nebulae or stars form from the gravitational collapse of gas in the interstellar medium or ISM. As the material collapses under its own weight, massive stars may form in the center, and their ultraviolet radiation ionises the surrounding gas, making it visible at optical wavelengths. Examples of these types of nebulae are the Rosette Nebula and the Pelican Nebula. The size of these nebulae, known as HII regions, varies depending on the size of the original cloud of gas. These are sites where star formation occurs. The formed stars are sometimes known as a young, loose cluster.

Some nebulae are formed as the result of supernova explosions, the death throes of massive, short-lived stars. The materials thrown off from the supernova explosion are ionized by the energy and the compact object that it can produce. One of the best examples of this is the Crab Nebula, in Taurus. The supernova event was recorded in the year 1054 and is labelled SN 1054. The compact object that was created after the explosion lies in the center of the Crab Nebula and is a neutron star.

Other nebulae may form as planetary nebulae. This is the final stage of a low-mass star's life, like Earth's Sun. Stars with a mass up to 8-10 solar masses evolve into red giants and slowly lose their outer layers during pulsations in their atmospheres. When a star has lost enough material, its temperature increases and the ultraviolet radiation it emits can ionize the surrounding nebula that it has thrown off. The nebula is 97% Hydrogen and 3% Helium with trace materials.

Types of nebulae [edit]

Classical types [edit]

Nebulae are classified in four major groups(stars). Galaxies and globular clusters were previously thought to be other types of nebulae. Spiral nebula were used to explain the spiral structures of galaxies.

  • H II regions, which encompass diffuse nebulae, bright nebulae, and reflection nebulae.
  • Planetary nebulae
  • Supernova remnant
  • Dark nebula

This classification does not encompass all known cloud-like structures. An example is a Herbig–Haro object.

Diffuse nebulae [edit]

The Omega Nebula, an example of an emission nebula.
The Horsehead Nebula, an example of a dark nebula.

The diffuse nebulae near the stars are examples of reflection nebula.

Most nebulae can be described as diffuse nebulae, which means that they are extended and contain no well-defined boundaries.[13] In visible light these nebulae may be divided into emission nebulae and reflection nebulae, a classification that depends on how the light we see is created. Emission nebulae contain ionized gas (mostly ionized hydrogen) that produces spectral line emission.[14] These emission nebulae are often called HII regions; the term "HII" is used in professional astronomy to refer to ionized hydrogen. In contrast to emission nebulae, reflection nebulae do not produce significant amounts of visible light by themselves but instead reflect light from nearby stars.[14]

Dark nebulae are similar to diffuse nebulae, but they are not seen by their emitted or reflected light. Instead, they are seen as dark clouds in front of more distant stars or in front of emission nebulae.[14]

Although these nebulae appear differently at optical wavelengths, they are all bright sources of emission at infrared wavelengths. This emission comes chiefly from the dust within the nebulae.[14]

Planetary nebulae [edit]

The Cat's Eye Nebula, an example of a planetary nebula.

Planetary nebulae are nebulae that form from the gaseous shells that are ejected from low-mass asymptotic giant branch stars when they transform into white dwarfs.[14] These nebulae are emission nebulae with spectral emission that is similar to the emission nebulae found in star formation regions.[14] Technically, they are an HII region because most hydrogen will be ionized. However, planetary nebulae are denser and more compact than the emission nebulae in star formation regions.[14] Planetary nebulae are so called because the first astronomers who observed these objects thought the nebulae resembled the disks of planets, although they are not related to planets. Our Sun is believed to become one of these 12 billion years after the Sun's formation.[15]