{17754} Parkinson's vs. normal (midbrain sections)

The result of the neuronal loss is a movement disorder, with "pill-rolling" resting tremor, festinating gait, bradykinesia, cogwheel rigidity, and mask-like face. Many patients become demented (the pathology correlate seems to be beta-amyloid in the striatum J. Neuropath 67: 155, 2008; no correlation with co-existing Alzheimer's). Please remember how to distinguish dementia from depression that is so often seen in Parkinsonism.

Known causes include Von Economo's encephalitis ("post-encephalitic parkinsonism", with neurofibrillary tangles in the substantia nigra neurons instead of Lewy bodies), some cases of chronic traumatic encephalopathy (professional boxers South. Med. J. 82: 543, 1989), and the "designer drug" (MPTP, "Ecstasy") fiasco of a few years ago. Dopaminergic neurons are the only ones that take the drug up, and it produces mitochondrial damage and a permanent Parkinson-like syndrome ("The case of the frozen addicts!")

Most cases of Parkinsonism do not seem to be familial. The known Parkinsonism genes:

• alpha-synuclein, a presynaptic protein involved in synaptic plasticity; in the disease, it twists and accumulates (autosomal dominant PARK1=SNCA; Neurology 43: 69, 1993; Geriatrics 46(S1): 52, 1991; Neurology 45: 502, 1995; Science 256: 2045, 1997 Nat. Genet. 18: 168, 1998; Nat. Med. 8: 564 & 600, 2002); one extra copy gives parkinsonism without dementia, while two extra copies give parkinsonism plus Lewy body dementia: Lancet 364: 1167, 2004.
• tyrosine hydroxylase (autosomal recessive; Neurology 41: 719, 1991).

• Parkin, autosomal recessive (PARK2) early-onset Parkinsonism without Lewy bodies: Nature 392: 544, 1998; NEJM 342: 1560, 2000; Arch. Neuro. 64: 421, 2007; it's the protein that ubiquitinates synphilin-1 which in turn interacts with synuclein (Nat. Med. 7: 1108, 2001; update Science 304: 1328, 2004).
Usually no Lewy bodies
• PARK3 and PARK4 do have Lewy bodies; stay tuned
• tau/MAPT (a variant, Picks-plus-Parkinsonism, no Lewy bodies: Neurology 54: 1787, 2000; Am. J. Path. 153: 1359, 1999; Brain 128: 2645, 2005)
• LRRK2 / PARK8 / dardarin (Brain 128: 2786, 2005. Lewy bodies
• glucocerebrosidase ("GBA", some Ashkenazi alleles; NEJM 351: 1972, 2004); Lewy bodies

In non-familial Parkinsonism having an identical twin with the disease does NOT increase your risk. This is now a robust finding (Neurology 63: 305, 2004). Since environmental risk factors are also elusive, and since twins tend to spend much of their lives together, your lecturer believes that there is a post-zygotic mutation involved -- and since the disease tends to announce itself asymmetrically, perhaps there is also a mitochondrial component.

* The epidemiologic link between insecticide and/or herbicide exposure and Parkinsonism continues to be discussed, especially since MPTP produces permanent Parkinsonism and works like many insecticides on the mitochondrial complex 1 system. Nobody's been looking hard at the epidemiology in recent years; living your life in farmland seems to be a risk, and there was a study where Dieldrin was found in 6 of 20 Parkinson's brains, and none of 14 controls (Ann. Neuro. 36: 100, 1994), and two pretty-good-looking epidemiologic studies (Neurology 43: 1150, 1993; Neurology 42: 1328, 1992). Rotenone, which like other insecticides resembles MPTP chemically and pharmacologically, produces Lewy body parkinsonism in mice (Science 290: 1068, 2000). An animal model showing enhancement of synucleinopathy by insecticides: Am. J. Path. 170: 658, 2007. So far there's no model of the chronic disease using herbicides, though some of these produce acute effects on the dopaminergic system as do many other substances (Science 290: 1068, 2000).

The claim that cigaret smoking is protective against Parkinsonism is by now clearly true (Neurology 45: 1041, 1995; Epidemiology 10: 327, 1999). So is caffeine (Drugs & Aging 18: 797, 2001).

* Nobody knows why, but easiest to believe is that tobacco smoke contains monoamine oxidase inhibitors. Smokers reportedly have only about 40% as much MAO in their brains as do non-smokers, the enzyme generates hydrogen peroxide at the synapses, and this may be what triggers destruction of dopaminergic neurons (JAMA 297: 1419, 2007). This fits with the observation that the nicotine patch works better when combined with the antidepressant bupropion (Zyban).

Most Parkinson's cases are "idiopathic", and begin in later middle age. Look for the distinctive (but not pathognomonic) "Lewy bodies" in dopaminergic (and other) neurons. Big autopsy series: Arch. Neuro. 50: 140, 1993.

* Acupuncture and every other "complementary / alternative remedy" studied for Parkinsonism have been flops (Neurology 57: 790, 2001).

* Around 7% of Parkinson patients taking dopaminergic medications become pathological gamblers (BJM 334: 810, 2007).

The adrenal medulla autotransplantation experiment resulted in non-viable grafts. An animal model of Parkinson's responds dramatically to embryonic stem cell therapy: Proc. Nat. Acad. Sci. 99: 2344, 2002. Update Neurology 66(S4): S89, 2006. Even better Proc. Nat. Acad. Sci. 105: 5856, 2008). The proposal to try stem cells in people has turned into a symbolic political battle which I think most people who have devoted their lives to the battle against disease find disheartening. We await more publications, but it's a hopeful area (Nat. Med. 7: 381, 2001).

Remember the parkinsonism mimics, which include multi-infarct disease, manganese toxicity, Lyme disease (Arch. Path. Lab. Med. 127: 1204, 2003), and now West Nile.

* James Parkinson, the first person to distinguish and describe the illness, was a progressive political activist throughout his life. As a young man, he was implicated in the "pop-gun" plot to assassinate George III with a poisoned dart; thankfully, the business was soon forgotten. Later in life, he was a strong advocate for the protection of the mentally ill and their families, and became interested in the new sciences of paleontology and geology.

CORTICOBASAL DEGENERATION (formerly "Pick's Type B") is a dementing disease with balloon cells, a distinctive tau-based pathologic lesion around astrocytes, and motor problems (notably alien limb, "My hand escaped and is doing its own thing.")

This tends to be rollow a rapid course (Brain 130: 1148, 2007).

Tau-positive inclusions around the astrocytes are the histological hallmark of corticobasal degeneration. They're called "astroglial plaques" and the tau looks like puffs of smoke surrounding the astrocyte body.

* These people often have neurofibrillary tangles, with straight rather than twisted filaments, as in progressive supranuclear palsy. Also look for tau staining immediately around the nucleus.

A few genes are known or suspected, most notably a progranulin allele (Brain 131: 732, 2008).

The disease is notoriously unresponsive to therapy. Reviews: J. Neuro. Neurosurg. Psych. 68: 304, 2000; Arch. Neuro. 55: 957, 1998, pathology J. Neuro. 246 S-2: II 6-15, 1999.

MULTIPLE SYSTEMS ATROPHY is now considered a single disease, because of its distinctive inclusions in the oligodendoglia.

The inclusions (* Papp-Lantos bodies) contain alpha-synuclein. Nobody really understands them.

STRIATONIGRAL DEGENERATION (* multiple system atrophy P for "Parkinson-like") is a degenerative disease in which the caudate and putamen atrophy along with the substantia nigra. Patients have a similar clinical syndrome to Parkinson's, but do not respond to L-Dopa therapy and do not have Lewy bodies.

SHY-DRAGER (* multiple system atrophy A for "autonomic"; see Ann. Int. Med. 125: 194, 1996) is striatonigral degeneration with the loss, in addition, of the intermediolateral neurons of the spinal cord and resulting autonomic disturbances. I've never seen a case, though it's in the differential diagnosis of every patient with orthostatic hypotension, and is perennially discussed.

OLIVOPONTOCEREBELLAR DEGENERATION (* multiple system atrophy C for "cerebellum") is still the name for a grab-bag of diseases with similar anatomic pathology -- loss of neurons from the basis pontis, cerebellar cortex, substantia nigra, and inferior olive. (The inferior olive is reported to disappear whenever the cerebellum is wiped out, due to post-synaptic degeneration.) It still includes the genetic spinocerebellar ataxias I and II. In non-hereditary olivopontocerebellar degeneration, one often sees the oligodendroglial inclusions typical of mutliple systems atrophy.

PROGRESSIVE SUPRANUCLEAR PALSY ("PSP", Steele-Richardson) is an underdiagnosed, fairly-common (Neurology 44: 1015, 1994; Med. Clin. NA 83: 369, 1999; J. Clin. Path. 54: 427, 2001) dementing disorder of older adults with eye movement disorders (especially, problems with downward gaze), other movement disorders, and often dementia.

Neuronal loss is most prominent in the deeper brain structures, and the key to diagnosis is "globose" neurofibrillary tangles found mostly in the oculomotor equipment, basal ganglia, substantia nigra, subthalamic nuclei and various brainstem structures. Abnormal astrocyte-fiber tufts are also quite characteristic distinctive histologic sign: Acta. Neuropath. 96: 401, 1998. NIH workshop, with criteria for diagnosis: Neurology 44: 2015, 1993 (* they want us to call it Steele-Richardson-Olszewski syndrome, nobody's going to...), also Brain 118(3): 759, 1995. * Neurofibrillary tangles in PSP have straight, rather than twisted, filaments. PSP as a taupathy; Lancet 356: 170, 2000.

A parkinsonism/PSP variant that is rampant on the island of Guadeloupe, complete with the NFT's in the substantia nigra and subthalamic nuclei, and astrocyte tufts (Brain 125: 801, 2002) is probably caused by ingestion of the jungle-fruit Annona muricata neurotoxin annonacin (Brain 130: 816, 2007; J. Neurosci. 27: 7827, 2007). "Complementary medicine" folks take note: This is one of the supposedly-good-for-you alkaloids in the herbal cancer remedy "Graviola."

* A mutant tau allele is a feature of at least one kindred with the ultra-rare dementing disorder "progressive subcortical gliosis" (Nat. Med. 5: 454, 1999); another lacks it (Neurology 72: 260, 2009).

FTDP-17 ("frontotemporal dementia with parkinsonism linked to chromosome 17") is caused a mutation of tau itself (Mech. Aging 127: 180, 2006; Brain 128: 2645, 2005) or the nearby protein progranulin (Nature 442: 916, 2006; Arch. Nero. 65: 460, 2008). As with other subcortical taupathies, you might see tau inclusions in the oligodendroglia (J. Neurosci. 25: 9493, 2005).

ARGYROPHILIC GRAIN DISEASE, with silver-staining tau granules in limbic neurons (different from granulovacuolar degeneration, and without other Alzheimer features) is a common, newly-recognized entity seen in older folks, with amnesia, delusions of persecution, and agitation (Acta Neuropath. 111: 320, 2006; now well-known Brain 131: 1416, 2008.) It's been under-recognized since special variants of the silver stains are required to see its lesions.

Pathologists recognize:
• silver-staining 8-micron grains in the dendrites
• hyperphosphorylated tau as coiled bodies in oligodendroglia, and in the astrocytes of the limbic system
• balloon cells in the amygdala
• neurons staining for hyperphosphorylated tau, the tangle precursor, especially in the entorhorhinal cortex (as in early Alzheimer's)

LEWY BODY DEMENTIA features neurons packed with Lewy bodies throughout much of the brain. These patients have a rapid Alzheimer-like illness with some extrapyramidal symptoms (stiff and slow but usually no tremor), visual hallucinations, and (often) exquisite sensitivity to the older neuroleptic drugs (chlorpromazine, etc. -- try one of the newer "atypical antipsychotics" instead.) It's not rare, but seldom diagnosed in life. See Br. Med. J. 305: 673, 1992; Neurology 42: 2131, 1992; clinico-pathologic correlation including tips on how to tell this from Alzheimer's in life Arch. Neuro. 59: 43, 2002.

* Most of these patients also have tangles; the more tangles, the harder it is to tell it from Alzheimer's clinically (Neurology 60: 1586, 2003). * Update on selective involvement of neurons in the caudate, and a correlation with neurophysiology: Neurology 66: 1591, 2006.

TORSION DYSTONIA ("dystonia musculorum deformans") is a disease of children in which the muscle tone increases around the body, twisting it into curious positions. The one known gene is Torsin A (TOR1a / DYT1) which does not always express completely (Neurology 59: 445, 2002; Arch. Neuro. 57: 333, 2000.) The anatomic pathology in the brainstem includes inclusion bodies (not well-characterized; Ann. Neuro. 56: 540, 2004) and since the disease comes on over time, there's probably neurodegeneration involved. Neurosurgical procedures on the deep brain structures has resulted in spectacular recoveries (review Ped. Neuro. 14: 145, 1996).

* HEREDITARY SPASTIC PARAPLEGIA ("familial spastici paraparesis, etc.; Arch. Neuro. 60: 1045, 2003) is a family of thankfully-rare progressive genetic disorders (dominant and recessive) of varying expressivity. For some reason, the long axons in the corticospinal tracts that supply the legs undergo degeneration with the neurons themselves being preserved. At least eight loci are already known (J. Neuro. Neurosurg. Psych. 72: 43, 2002; pathology of the "spastin" mutant variant Neurology 55: 89, 2000).

ESSENTIAL TREMOR ("benign familial tremor") is a very common (1-2% of humankind), usually banal (sometimes severe) intention tremor. It is inherited as an autosomal dominant (possible loci Neurology 68: 790, 2007 and Brain 130: 1456, 2007), first manifests around age 20, and typically vanishes as soon as the "patient" drinks one beer (i.e., here's the three questions you need to ask to pretty-much clinch the diagnosis). If the patient really wants to be treated, or it's severe, try low-dose propranolol or gabapentin (Arch. Neuro. 56: 807, 1999). More important, explain the nature of the process, and that it is NOT Parkinsonism or mental illness.

A group at Columbia NYC finally looked at brain-bank specimens from people with essential tremor and found a couple of different patterns (Brain 130: 3297, 2007).

THE SPINOCEREBELLAR ATAXIAS (update Mayo Clin. Proc. 75: 475, 2000)

This array of autosomal degenerative diseases has recently been sorted out thanks to the Human Genome Project. Except Friedreich's and ataxia with vitamin E deficiency, all are autosomal dominant. The pathologist sees only neuronal loss and maybe gliosis.

TYPE I SPINOCEREBELLAR ATROPHY feature damage to the gene for "ataxin 1", and this also exhibits long tandem repeats and Sherman's paradox (see below; Nat. Neurosci. 3: 157, 2000). So do TYPE II (ataxin 2; Eur. J. Hum. Genet. 7: 841, 1999) and TYPE III (Joseph's, a Portuguese ethnic disease and probably the commonest in this group, ataxin 3). All these do their harm by producing a product whose long repeats gum up the nucleus. (I predicted in 1990 these would prove to be Sherman paradox diseases.) As in the "olivopontocerellar atrophy" variant of multiple systems atrophy, neurons are selectively lost form the basis pontis, inferior olives, cerebellar cortex, and substantia nigra.

FRIEDREICH'S ATAXIA is an autosomal recessive disease with somewhat variable expressivity. Onset is in late childhood, when pes cavus (high-arched feet), clumsiness and speech problems develop. Patients become wheelchair-bound after a few years, and may have a cardiomyopathy with thick walls (not the "classic" hypertrophic cardiomyopathy though). There is gliosis of the posterior columns, dorsal corticospinal tract, and spinocerebellar tracts; the cerebellar cortex and other motor areas may also be involved. The cause is trinucleotide repeats in frataxin, a gene responsible for keeping iron from accumulating in mitochondria; Gene and review: Science 271: 1423, 1996; update Arch. Neuro. 59: 743, 2002.

Unlike other long-repeat diseases, this is a loss-of-function gene, hence the recessive inheritance. Because of Sherman's paradox, Friedreich's used to be considered "often dominant". Any idea how this could have been? A clinician gives the same answer as you did: Arch. Dis. Child. 83: 74, 2000.

Update for clinicians: Arch. Neuro. 64: 558, 2007. The antioxidant idebenone (molecularly similar to CoQ) is the most promising treatment, and seems to slow the disease (how?): big study Neurology 60: 1676 & 1679, 2003.

ATAXIA WITH VITAMIN E DEFICIENCY mimics Friedreich's, but is caused by lack of vitamin-E transfer protein. Of course this is also autosomal recessive. Giving the vitamin in big doses is effective treatment. See NEJM 333: 1313, 1995. Though very rare, it's the only really treatable entity in this group, so be sure to think of it!

* Smith's dentatorubral atrophy is yet another Sherman's-paradox disease ("atrophin"; J. Biol. Chem. 274: 8730, 1999).

* The EPISODIC ATAXIA family includes a mutation in the voltage-gated potassium channel gene; ataxic / dysarthric episodes especially follow a startle.

We've already mentioned ATAXIA-TELANGIECTASIA (gene ATM). The mechanism by which it causes neurodegeneration has remained elusive.

* Men carrying mild alleles of fragile X (i.e., not enough tandem repeats yet) are prone to develop cerebellar ataxias and dementia (Brain 125: 1760, 2002.)

AMYOTROPHIC LATERAL SCLEROSIS ("Lou Gehrig's disease"; "creeping paralysis"; motor neuron disease complex; Am. Fam. Phys. 59: 1489, 1999; NEJM 344: 1688, 2001; BMJ 336: 658, 2008) "Motor neuron disease complex" is actually four diseases, featuring loss of the motor neurons 1. Amyotrophic lateral sclerosis (loss of upper and lower motor neurons); this is the common one 2. Progressive bulbar palsy (cranial nerves are most severely affected) 3. Progressive muscular atrophy (lower motor neurons only) 4. Primary lateral sclerosis (upper motor neurons only)

Lou Gehrig

ALS is a disease of older middle age, progressing to profound disability (usually without mental impairment) in a few years. Most ALS cases are sporadic (but see below). There is a slight male predominance

Current thinking has involved destruction of motor neurons by excitotoxicity (Mayo Clin. Proc. 66: 54, 1991; J. Neurol. 247-S1: I-7, 2000). This is supported by the finding that the anti-glutamate agent riluzole causes a modest slowing of the progression of ALS (NEJM 330: 585, 1994); it's now the only medication approved in the US for ALS and prolongs life by about two months (JAMA 298: 207, 2007; Clin. Pharm. Ther. 83: 718, 2008).

The sick neurons contain ubiquitin-positive inclusions of various sorts, thought to be altered or abnormal proteins that resist degradation (update Acta Neuropath. 113: 535, 2007). Most distinctive is the Bunina body of non-superoxide-dismutase-related disease, which looks like a string of beads, composed largely of cystatin C found in the remaining lower motor neurons.

There are other inclusions as well in most types of ALS; these are cystatin C-negative but stain with ubiquitin and TDP-43 (Science 314: 130, 2006; Am. J. Path. 173: 182, 2008); some of these patients have Bunina bodies, some don't (Arch. Neuro. 66: 121, 2009).

The link between cycad (false sago palm) flour and ALS-dementia-parkinsonism complex of the indigenous Chamorro people of Guam remains speculative. There is now an animal model using the toxin cycasin (Exp. Neurol. 155: 11, 1999). Thankfully the disease is becoming less common, but has not vanished. The locals have always washed the flour, supposedly being aware of the toxin; one group links the disease to the consumption of the ethnic delicacy of the fruit bat that lives on the sago palm (Neurology 58: 956, 2002). Like other ALS syndromes, this one is now known to be TDP-43 positive (Brain 130: 1386, 2007).

About 10% of ALS is hereditary.

The classic gene is a defective superoxide dismutase gene: Science 261: 986 & 1087, 1993; Nature 362: 59, 1993; transgenic mice with the mutant form get sick too Proc. Nat. Acad. Sci. 93: 3155, 1996. The mechanism remains totally obscure; in one model, the protein is misfolded: Brain 127: 73, 2004.

As you'd expect, mutated TDP-43/TARDBP has been discovered as a cause of familial ALS (Arch. Neuro. 65: 1185, 2008).

* Motor neuron disease from mutant dynactin: Nat. Genet. 33: 455, 2003.

* Another locus (alsin, ALS2): Nat. Genet. 298: 160, 2001; Arch. Neuro. 60: 1768, 2003.

Amyotrophic lateral sclerosis is the classic disease cited in considerations of physician-assisted suicide. (Why?) About one Dutch patient in five now chooses this route (NEJM 346: 1638, 2002). And a majority will consider assisted suicide, but most will choose hospice instead (NEJM 339: 967, 1998).

The key illness to rule out in apparent ALS is MULTIFOCAL MOTOR NEUROPATHY, caused by autoantibodies against GM₁ ganglioside. This responds to treatment as other autoantibody diseases (cyclophosphamide, gamma globulin, now rituximab Neurology 63: 2178, 2004).

* KENNEDY'S DISEASE is a bulbospinal atrophy and lack of masculinization of male patients, caused by lack of an androgen receptor. This is yet another trinucleotide repeat disease.

Amyotrphic lateral sclerosis WebPath Photo

Amyotrophic lateral sclerosis WebPath Photo

Amyotrphic lateral sclerosis WebPath Photo

WERDNIG-HOFFMAN DISEASE (spinal muscular atrophy type I) is an autosomal recessive disease causing loss, in the few months before and after birth, of most of the lower motor neurons. It is the most severe of the spinal muscular atrophies, caused by various mutations at the SMN ("survival motor neuron") locus (Nat. Genet. 16: 265, 1997); we covered these under "Muscle".

MENTAL ILLNESS SCHIZOPHRENIA (Lancet 353: 1425, 1999; Mayo Clin. Proc. 77: 1068, 2002) is the most important of the "functional psychoses", supposedly affecting about 1% of humankind in every culture, every bit as devastating as Alzheimer's disease, but under-investigated (i.e., patients don't lobby, there's an awful stigma, and the rich are seldom affected). Schizophrenics consume 2.5% of health care expenditures, constitute 10% of the totally and permanently disabled, and represent around 14% of the homeless (Psych. Clin. N.A. 16: 413, 1993). Schizophrenia reviews: Lancet 346: 477, 1995; NEJM 330: 681, 1994. * There are rumors that schizophrenia is becoming less common among young people in the U.S. Perhaps this is because of 'flu shots, and/or perhaps this is due to fetal monitoring and more frequent cesarean sections (and perhaps this will prove to be the great benefit of fetal monitoring; stay tuned here.)

Brugel's "Mad Meg"

Even in the DSM-IV era, I find Bleuler's "Four A's" helpful: Autism (apparent absorption in self and fantasy), Ambivalence (maintaining contradictory attitudes in logic-tight compartments, with striking lack of insight), loose Associations, and flat Affect. In schizophrenia, these are much more striking even than in us "normal folk".

Don't confuse schizophrenia ("fragmentation of the mind") with "multiple personality", a dissociative state that rarely occurs spontaneously but that is easy to produce iatrogenically using hypnosis. (The fad is over -- induce multiple personalities today, or even talk to one, and you'll end up in court.)

Sensitive physicians know that the negativism, coldness, and lack of motivation of the schizophrenic can be as upsetting to family members as the delusions and hallucinations. Tell them it's nobody's fault and that it isn't that they are not loved.

Reasonably good models for schizophrenia (i.e., both being very crazy and being oriented in the three spheres) include acute intermittent porphyria, lupus, chronic mercury poisoning, ergotism, pellagra, neurosyphilis, frontal lobe meningioma, and some of the psychedelic experiences.

One Flew Over the Cuckoo's Nest

Shakespeare's Ophelia

Until recently, all public discussion of schizophrenia was dominated by ideology. In the 1960's ("B.F. Skinner says..."; "All people are born the same and if you aren't getting what you want, it is society's fault"; etc.), behaviorists wrote dogmatically about "the schizophrenogenic mother" ("She said to the child, 'I love you', but her body language said otherwise, and this prevented the child from distinguishing fantasy from reality"; "the double bind", etc., etc.) In the early 1970's, it was all the fault of "the schizophrenogenic father" instead; as with the "S-mother", evidence was "anecdotal" (i.e., the biological parents of crazy people act screwy themselves; stress sometimes precipitates symptoms) and "based on sound theory" (i.e., "all people are born the same", the left-wing/Skinnerian ideology of the day). Some 'sixties revolutionaries discussed schizophrenia as "a disease caused, more than any other, by our reactionary society", or denied its existence altogether (a Dr. Thomas Szasz, author of The Myth of Mental Illness, described witch-hunts and incarcerating people just for being different). 'Sixties rhetoric emphasized that traditional society was unreasonable and thus the people in the mental hospitals must be the sane ones. "The King of Hearts" put this on the silver screen. Ken Kesey (One Flew Over the Cuckoo's Nest) and Dr. R.D. Laing (The Politics of Experience) wrote their best-sellers. (Dr. Laing's own life-story was not nice.) The ACLU defended the rights of crazy people to refuse treatment (one 1970's study showed 99% were totally grateful after being brought back to earth). And some psychologists inveighed against the use of the obviously-effective phenothiazine drugs, which began cutting through hallucinations and delusions as soon as they were introduced in the 1950's. Confusing fantasy with reality always causes problems, and the beautiful 'sixties rhetoric resulted in disaster for the mentally-ill and their families. Today, only a few psychoanalysts still talk about curing schizophrenia through psychotherapy, and the rest of the world (even the other psychiatrists) just laughs at them (Nature 354: 693, 1991 was the last gasp). There are still occasional complaints from non-physicians about psychiatry being wicked because it is "authoritarian", or obsolete because it is "culture-bound" or "institutionalized" or "modernist rather than postmodernist" (Br. Med. J. 322: 724, 2001). These people ignore the fact that for the past fifty years, free-world psychiatrists have only used coercion when a person cannot take care of himself/herself or a danger to others, and an examination of any psychiatry textbook will show that the discipline is characterized by a variety of perspectives and ways of understanding a particular person's problems.

The end result of all of the "enlightened thinking", of course, was de-institutionalization ("out of the back wards, into the back alleys"). This pleased the Left ("We're for every individual's freedom to be different"; "Even though the inmates got free food, clothing, shelter, medical care, and protection, and were otherwise unemployable, it violated their civil rights to have them work in the laundry and not get minimum wage and benefits"), the Right ("We're against able-bodied people living at public expense"), optimistic physicians ("The grateful patients will come regularly to their community mental health centers to get their medicines refilled"), and real humanitarians (there were, after all, serious abuses in the old "asylum" system). Well, everybody was pleased at first.... Today, the non-compliant mentally-ill whose families can no longer stand them are homeless, and this gets described as a "human rights problem" by the same people who got the asylums closed in the 1970's. Do you think Dr. Szasz ("Mental illness is a myth") has ever talked to his local "bag person"? By the way, schizophrenics ARE more likely to commit crimes, including violent crimes, including murder (Psych. Clin. N.A. 15: 575, 1994; a schizophrenic is 8 times as likely to commit murder as a non-psychotic counterpart: Arch. Gen. Psych. 53: 497, 1996), and only a fool believes that psychiatry can protect the public in today's political-economic "mental-health" environment. I hope that no one was surprised by an enormous study from Duke (Arch. Gen. Psych. 63: 490, 2006) that withdrawn schizophrenics rarely commit crimes but that people raging around and having delusions of persecution are very likely to hurt somebody. The best we're doing nowadays is "leveraging" -- the person doesn't get his/her welfare check if he/she does something violent (Am. J. Psych. 163: 1404, 2006; and the lawyers are all over this; it's emerged that during a six-month period, about 20% of those collecting welfare for mental illness will admit to hurting someone or at least threatening someone with a lethal weapon; same rate as the Duke study above.) The truth is that schizophrenics are more likely than non-schizophrenics to commit all categories of crime except sex crimes (Lancet 355: 614, 2000). In fact, people who stalk strangers (rather than previous sex partners) are usually psychotic (Lancet 355: 199, 2000). Even writers who seem to be advocates for "community mental health" and who emphasize that a majority of stranger-murders result from fights in bars or among druggies cannot hide the reality of senseless violence from schizophrenics (especially against family members and friends: Br. Med. J. 328: 754, 2004). As part of the illness, many schizophrenics do not believe they are sick, and do not want to take their medicine. Thanks mostly to "laws that protect the rights of the specially-challenged", it remains extremely difficult to keep a schizophrenic confined even after multiple episodes of dangerous behavior. The shooting of two guards in the US capitol by a chronically belligerent, chronically threatening, non-compliant schizophrenic named Russell Eugene Weston who had just been given "Greyhound therapy" (a one-way bus ticket out of the state) by the Montana mental-health system should have had an impact, but it didn't. Michael B. Laudor, a schizophrenic who successfully completed the curriculum at Yale Law School and who sold book and movie rights to his success story for $2 million, stopped taking his medicine and a few days later stabbed his pregnant girlfriend to death. In both of these high-profile cases, the families knew there was going to be trouble, but couldn't do anything. A mental patient is most likely to kill a family member when the family denies, misunderstands, or "spiritualizes" the illness (chilling reading: Crim. Behav. Mental Health 15: 154, 2005). The much-hyped recent "study" (Arch. Gen. Psych. 55: 393, 1998) finding that mentally-ill people in the community were no more likely to be violent than their underclass neighbors suffered from serious flaws, including omitting anybody who had been in jail, and not counting threats of violence, swinging-and-missing, fire-setting, or trashing rooms as being violent. More recently, several studies have made it clear that schizophrenics are much more likely to commit violent crimes, especially violent sex crimes (Crim. Behav. Ment. Health 14: 108, 2004 -- note the conflict with some previous studies). A schizophrenic (compared with a non-schizophrenic) is over four times more likely to have been convicted of a crime (21.6% vs. 7.8%), and a violent crime (8.2% vs. 1.8%); the rate of substance abuse among schizophrenics is tremendously high but this doesn't explain all of this (Am. J. Psych. 161: 716, 2004; also JAMA 301: 2016, 2009). At present, there are maybe 300,000 or 400,000 chronically mentally ill Americans confined in jails and prisons. (Many are in jails for vagrancy.) There are only about 80,000 people in long-term mental health facilities. The truth is that this represents a conscious decision by society to turn care of these people over to law enforcement personnel (who are, for the most part, reality-oriented and respectful of the legitimate rights of all people) rather than non-physician (and non-scientifically-oriented) "mental health experts". But the damage has been done. In the past decade, the phenomenon of "mental health courts", judicial-system courts focused on managing these people, has become widespeard; expect continued growth (JAMA 297: 1641, 2007). One of the major moral failures in my life was not speaking up when a group of mental health professionals called a nun a "self-righteous bitch" for no other reason than saying that she preferred -- just for herself -- a celibate lifestyle devoted to caring for the sick and needy. (My course evaluation would probably have been affected adversely, but I'm still ashamed I said nothing. This happened in 1974 or 1975.) On my "psych" rotation, the physicians talked to me again and again about how frustrating it was to have to work with such screwy "fellow-professionals" who wielded so much power. Perhaps things have changed since the mid-1970's. Among my favorite articles from the 1990's was "The Government-Sponsored Revolving Door" in NEJM 333: 777 & 794, 1995. Schizophrenics on welfare learn to act crazy and get admitted while they're broke and waiting for their checks, and recover when the check arrives; and in the study sample, the typical welfare-schizophrenic's largest single expenditure was for cocaine.

It is now perfectly clear that schizophrenia is a major organic nervous system disease. Before the disease fully manifests itself, brain cells die off and brain atrophy occurs (Am. J. Psych. 155: 1661, 1998); this is already well-underway during the first episode (Am. J. Psych. 157: 1829, 2000). Certain association areas in the cortex and thalamus are hit especially hard (Am. J. Psych. 159: 59, 2002; Arch. Gen. Psych. 60: 878, 2003; counting dendritic spines Am. J. Psych. 162: 1200, 2005); the more cortex lost, the worse the outcome (Am. J. Psych. 158: 1140, 2001). For a review of various studies at the light microscopic level, see Brain 122(4): 593, 1999; findings differ in different studies but generally agree that there is neuronal loss and cellular disarray in the cortex, without gliosis. The loss is selective, with the dorsolateral prefrontal cortex severely involved and nearby Broca's area completely spared (Arch. Gen. Psych. 60: 69, 2003; Am. J. Psych. 159: 1983, 2002); the more that's gone, the worse the outcome (Am. J. Psych. 158: 1140, 2001). The volume loss in the superior and middle temporal gyri is by now very well-known and there is talk about its being specific for schizophrenia (Am. J. Psych. 163: 2103, 2006). A rigorous study shows a distinctive pattern of loss in the basal ganglia (Brain 130: 678, 2007). Counting dendrite intersections: Am. J. Psych. 161: 742, 2004. Further, schizophrenics have by-now-well-characterized volumetric loss of the white matter of the frontal, pareital, and fronto-parietal junctions at onset, and these get worse over time (Am. J. Psych. 164: 1082, 2007). Old studies of genetics are now giving way to the discovery of loci. Familial schizophrenia locus Science 288: 678, 2000. Neuregulin 1: Am. J. Hum. Genet. 71: 877, 2002; Am. J. Hum. Genet. 72: 83, 2003. More on the genetics: Lancet 361: 417, 2003. Update JAMA 299: 2017, 2008. Even in cases without simple inheritance, the genes obviously dominate family environment (old work on schizophrenia genetics: Lancet 1: 79, 1989; Nature 339: 305, 1989; Nature 340: 391, 1989; non-schizophrenic relatives tend to be a little-bit screwy and fill DSM criteria for schizophrenia-like illnesses Arch. Gen. Psych. 50: 527, 1993, J. Nerv. Ment. Dis. 182: 443, 1994; the adoption studies from Scandinavia, where they keep good records: Arch. Gen. Psych. 51: 442, 1994; and the neuroimaging studies show similar hippocampal changes Arch. Gen. Psych. 64: 297, 2007). The three best known loci (and all are clearly real) that confer susceptibility to schizophrenia are DYSBINDIN (DTNBP1), a protein expressed on the glutamine neurons (J. Clin. Invest. 113: 1353, 2004); altered forms run especially with schizophrenic negativism (Am. J. Psych. 162: 1824, 2005; Am. J. Psych. 163: 532, 2006). DISC1 ("disrupted in schizophrenia") and NEUREGULIN-1 (NRG1) are also major loci (update Nature 458: 976, 2009). There are conflicting results as to whether RGS4 is a schizophenia locus or not (Curr. Op. Psyc. 22: 154, 2009 -- reviews all the candidate genes and the postmortem brain chemistry.) Same or crazy, your DISC1 alleles seem to have to do with whether you're a socializer or a loner (Arch. Gen. Psych. 66: 134, 2009). KCNH2, a potassium channel: Nat. Med. 15: 448 & 509, 2009. Another locus called PCM1 runs with low orbitofrontal cortical volume and risk of psychosis (Arch. Gen. Psych. 63: 844, 2006). In twins discordant for the disease, magnetic imaging detects distinctive differences in the brains of the schizophrenic twin (NEJM 322: 789 & 842, 1990) which have been confirmed by neuropathologists (Schiz. Res. 3: 295, 1990; Br. Med. J. 305: 327, 1992; South. Med. J. 85: 907, 1992; more on twins J. Nerv. Ment. Dis. 181: 290, 1993). In monozygotic twins who are clearly discordant for schizophrenia, being the crazy twin correlates very strongly with obstetrical complications and/or problems during pregnancy or shortly after birth (Am. J. Psych. 151: 1194, 1994; there was no relation to trauma or to substance abuse; also Am. J. Psych. 157: 196, 2000; pre-eclampsia as a major risk Arch. Gen. Psych. 56: 234, 1999). In the poor nations, where obstetrical catastrophes and infantile brain trauma are more common, the rate of schizophrenia is supposedly no higher, but there's a strong link to these insults (Am. J. Psych. 151: 368, 1994). And prenatal exposure to famine and malnutrition is a strong risk factor: Am. J. Psych. 157: 1170, 2000; strong confirmation JAMA 294: 557, 2005. Currently, there's a lot of interest in obstetrical complications and/or a catastrophe during the second trimester of gestation as the added insult that makes the hereditary trait manifest itself: Br. Med. J. 305: 1256, 1992; Am. J. Psych. 149: 1355, 1992. And so forth. Schizophrenia's gotta be "multifactorial", with etiologies differing from patient to patient, and the psychiatrists had this settled by the early 1990's (Psych. Clin. N.A. 16: 269, 1993; Schiz. Bull. 19: 355, 1993). Also impressive is the finding of a striking increase in sporadic (not familial) schizophrenia following influenza A infection in the fifth month of pregnancy (Lancet 337: 1248, 1991; Arch. Gen. Psych. 47: 869, 1990; Am. J. Med. Genet. 48: 40, 1993). There is a huge excess of schizophrenics born in February and March, and in the city rather than in the country (NEJM 340: 603, 1999). An arcane statistical study of mental and behavioral illnesses that affect primarily the poor (Science 255: 946, 1992) concludes that (in contrast to depression, criminality, and illegal drug abuse), the tendency to schizophrenia causes downward social mobility, and is not the result of bad living conditions.

* Today's neuroleptic-antipsychotic drugs are potent dopamine antagonists, and dopamine-like drugs (notably amphetamine) can make a person act crazy and paranoid (but without the distinctive thought disorder of the schizophrenic). However, the old story about "high dopamine causes schizophrenia, low dopamine causes Parkinsonism, they are two ends of a continuum" just doesn't hold up to today's neuroscience; there are places in the schizophrenic's brain where dopamine is high, and other places where it is low (Am. J. Psych. 148: 1301 & 1474, 1991; striking decrease in D1 receptors in the prefrontal working-memory-processors that in turn correlates with the negative symptoms: Nature 385: 634, 1997). And the newer anti-schizophrenic drugs (clozapine, etc.) are "atypical neuroleptics" that selectively block the subset of dopamine receptors (D4) not involved in the extrapyramidal side effects of the more familiar anti-schizophrenic drugs, as well as 5HT2a receptors. Watch for more about D4 protein, which varies from person to person, and the origins of psychiatric illness: Nature 358: 109 & 149, 1992. D4 allele correlates with novelty-seeking / thrill-seeking (Nat. Genet. 12: 78, 1996). D2 claims flop: Science 264: 1696, 1994.

A Beautiful Mind

* More plausible is the phencyclidine model for schizophrenia (ever see someone go crazy on "angel dust?"), and there's some new evidence that the N-methyl-D-aspartate receptor (blocked by phencyclidine and ketamine) is defective in schizophrenia (Am. J. Psych. 148: 1474, 1991; the ketamine model Arch. Gen. Psych. 51: 199, 1994). Not much more lately, but watch these.

The Caveman's Valentine

De-stigmatize and de-mystify this dread illness -- and explain the hallucinations not as "evidence of being crazy", but as exaggerations of perceptual errors that happen to anyone under stress (J. Nerv. Ment. Dis. 179: 207, 1991). The more the family misunderstands (and therefore criticizes) the patient, the worse the prognosis (Lancet 340: 1007, 1992); your role as educator is extremely important here. Tip: To control "the voices", try one ear plug, or a Walkman, or singing softly to oneself (Br. Med. J. 302: 327, 1991). There was a flap in the early 1990's about neuroleptic treatment causing earlier onset of Alzheimer's in schizophrenics. It's evidently not so (Am. J. Psych. 154: 861, 1997 autopsy studies.)

CHILDHOOD AUTISM (formerly "childhood schizophrenia", semi-glamorized in the film "Rain Man"; reviews Ped. Clin. N.A. 40: 567, 1993; NEJM 347: 302, 2002; Lancet 374: 1627, 2009)

This is an inborn (usually), organic, sometimes-familial, usually sporadic disease of the brain that impacts dramatically on children's ability to imagine, socialize and communicate. The kids show intensive interest in one or two subjects, exhibit a narrow and repetitive lifestyle, lack intonation and body language, and show poor muscular coordination. You'll learn about the way these children think and behave on "Pediatrics".

There's a consensus now that the disease arises from neuronal problems that begin before birth. By now, the morphometric differences between autistic and non-autistic populations are robust and consistent from nation to nation (Brain 128: 268, 2005; Arch. Gen. Psych. 61: 291, 2004; Brain 124: 1317, 2001). There is less gray matter in the fronto-striatal and parietal areas, smaller hippocampus, and less white matter in the cerebellum and fornices. Autistic children's brains actually average larger than those of typically-developing children (Neurology 59: 184, 2002). The neuropathology findings are also being clarified (small cells in places in the limbic system, abnormal microcolumn architecture in the frontal cortex, others: Brain 127: 2572, 2004; Neurology 58: 428, 2002), but this will be much more difficult.

Autism often seems to have an onset sometime during the first three years of life, and this may be fairly sudden. This makes sorting out "possible causes of autism" much more difficult, and makes evaluating anecdotal evidence all the more frustrating. What's more, occasionally there IS a primary cause. Autism developing secondary to a brain tumor: Dev. Med. Child. Neuro. 34: 252, 1992. And exactly what "autism" is remains a question -- kids with common Rett's, Down's, tuberous sclerosis, etc., etc., can have "features of autism".

* One group looked at head circumferences before the onset of symptoms; they found they were unusually small at birth, and unusually large at one year (JAMA 290: 337, 2003). If this turns out to be correct, then autism is one more programmed disease of nervous tissue.

A finding that now seems robust is that members of occupations that do a lot of information-processing (i.e., engineers, scientists, and accounts) are over-represented among parents and grandparents of autistic children (Autism 5: 223, 2001), and to excel, as do the autistic themselves, on the Embededed Figures Test (Neuroimage 35: 283, 2007; J. Aug. 36: 677, 2006; J. Child. Psych. 47: 639, 2006; more). Most physicians will draw the same tentative conclusion that I have -- autism is polygenic, perhaps with an environmental influence, and results from homozygosity for alleles that make heterozygotes into effective student-learners-techies.

Autism is a continuum, with the totally uncommunicative person at one end, and the odd, disliked, clumsy, loner kid who grows up to be a high-functioning, academically-inclined single adult after learning (by trial and error rather than instinct) how to relate to people (Lancet 350: 1761, 1997). In the next few years, watch for a fad for diagnosing super-nerds (young and old) as "suffering from Asperger's disease" and applying for disability privileges. See below.

* Pseudoscientists have been particularly cruel to those who care about autistic children. Bruno ("I'm on the child's side!") Bettelheim, of U. of Chicago, assumed a priori that autism was the result of abuse and neglect, scapegoated the parents, and treated these children in an intensive, lucrative "orthogenic" milieu therapy. Of course, he never published his statistics, and he's now remembered as a charlatan (Pr. Kind. Kind. 41: 316, 1992, abstract 93109943; Skep. Inq. 24(6):12, 2000). More recent autism charlatanism has been reviewed (Dev. Med. Child Neuro 47: 493, 2005), including a $50,000/year technique that falsely claimed cures and was promoted as an "entitlement" that had priority over expenditures on teaching reading and arithmetic to ordinary public school students (J. Autism 28: 91, 1998). The study also reviews what works. (The "behavioral" approach that worked best, unfortunately, in its classic formulation made major use of electric shocks, like training a zoo animal. Asperger's kids and adults can and should be taught social skills. A few Rx's work sometimes. Beyond this, there's no miracles today or on the horizon.) In the 1990's, a technique called "facilitated communication" was developed, in which the operator used the child's hand as the planchette of a Ouija board. Even if the child had never communicated or seemed to understand language, the hand would spell out elaborate stories. If the child was shown one picture and the (unknowing) operator was shown a different picture, and the child was then asked what the picture showed, the "child" would describe only what the operator saw (Ment. Retard. 31: 49, 1993 and many, many more). Gee whiz! The first commentators (1987, also J. Aut. & D.D. 21: 561, 1991) in the refereed literature knew that "facilitated communication" was bunk, but supported it because it would make the public believe that autistic kids, kids with cerebral palsy, and so forth were more like ordinary folks. In other words, politics and propaganda are more important than truth. As you might expect, the "children" often produced stories of elaborate secret sexual abuse, using the vocabulary of sleaze-pornography. Even after the above-referenced article was published, at least one parent in Kansas was sent to prison entirely on this evidence. The literature contains some accounts (notably by a group at SUNY; Arch. Ped. Ad. Med. 148: 1282, 1994) in which "the child's story was proven to be true" by the confession of the accused (no good physical evidence though); however, nowadays it is commonplace for a person accused of a sex crime, often on no real evidence, to be offered leniency in exchange for a confession ("admit you did it and accept counselling, or we'll send you to prison for life"). In 1994, "facilitated communication" (the subject of a media "miracles of healing" hype in the early 1990's) got massive negative TV coverage (for example, PBS, which finished particular folly off. Freeing several dozen imprisoned people, all convicted of child molesting solely on this evidence, will take longer. I am not making this up. How this crock happened: Child Abuse & Neglect 22: 1027, 1998 ("Its proponents' resistance to allowing the technique's validation relying on the paradigm of normal science has resulted in its broad dissemination without support", i.e., all this talk about "Thomas Kuhn paradigm shifts", "postmodernism", and so forth ruins the lives of innocent people).

* The whole MMR-vaccine-and-autism scare resulted from a study in Lancet with obvious selection bias; the kids had been brought forward by parents who believed the MMR vaccine had caused their autism. Lancet 351:637, 1998 also includes some stuff on supposed intestinal pathology; the only "consistent" lesions are normal findings (the authors think that groups of eosinophils in the ileum are abnormal even though everybody's got them) and big lymph nodes with big germinal centers (incredibly, they made a deal out of tingible body macrophages here, everybody's got them too; no controls of course). Were they right to fast-report a possible health hazard? Wrong to rush to publication with no proper controls? Reasonable people will differ. A paper from the Wakefield group with PCR's purporting to show measles virus in the gut lymphoid tissue of autistc children, but not controls (Mol. Path. 55: 84, 2002) remains unreproduced by any other group, and curiously the group itself admitted later that its own data had been corrupted (Mol. Path. 56: 248, 2003). In Feb. 2004, the Lancet apologized for publishing the 1998 paper and revealed that Dr. Wakefield, the principal author, was actually in the pay of a legal-aid service hoping to sue over immunizations. For those who are curious about "autisic enterocolitis", I recommend the paper in Histopathology 50: 371, 2007, which reviews the problems with the work, almost all of which has come from one group; just as I did when I read the article in Lancet almost a decade ago, they point out that the original work called normal findings abnormal and weren't properly controlled; they suggest that the hyperplasia is the result of the constipation seen in autism, just as is seen in chronic constipation from other causes. More about how this particular strangeness happened: West. J. Med. 174: 87, 2001. Dr. Wakefield, who still holds out that he was right, admits that he's most impressed with anecdotal evidence, and perhaps he's actually seeing an ultra-rare phenomenon hidden in statistics (I think he could be right): Br. Med. J. 324: 386, 2002. But the fact that he apparently withheld information about a major conflict of interest will probably ruin him as a scientist. One of my cyberbuddies, a Ph.D. bioscientist who had a child with autism, is confident of Wakefield's essential integrity, other professional people have also written to me defending his genuineness and decency, and it's clear that Wakefield shows none of the signs of charlatanism that you see in most other independent thinkers. Update: In June 2006, a media claim was made that a Dr. Arthur Krisgman, pediatric gastroenterologist at NYU Med, and a Dr. Stephen Walker of Wake Forest University med school (where I did a year of training) had replicated Wakefield's findings. From the media reports, all we have is recovery of vaccine-strain measles from a group of children, without controls. We look forward to publication, peer-reviewed or not. This is a very important question, and as I've said above there may indeed be something real, despite all the politics, lawyering, and emotion. Brain diseases that are reflected only in behavior are the hardest of all diseases to study. And no one questions the devastating impact and gravity of the question. It would please me very much if an important contribution were to come from the school where I trained. Stay tuned.

Update: Formerly portrayed in the popular press as a "persecuted genius", coverage of Wakefield has now become very hostile. Now he is a corrupt, mendacious charlatan wilfully causing the deaths of children (review of media coverage BMJ 336: 479 & 850, 2008). Although the world has plenty of rotten people, I do not believe Wakefield is one of them. Knowing people as I do, I suspect the truth is closer to "the road to ____ is paved with good intentions." I've seen nothing further on the real-science front.

Ileal Lymphoid Hyperplasia
How the Wakefield
MMR business got going


Anyway, in children reported to have autism following MMR or other immunization, there's no dose-response relationship, and no relationship to whether a batch of vaccine actually contained thimerosal (ethylmercury, the supposed toxin): JAMA 290: 1763, 2003. A huge case-controlled in Britain shows no link: Lancet 364: 963, 2004. Thimerosal hasn't been in US vaccines, except for a few 'flu vaccines, since 2001, and there's been no corresponding decrease in autism (Nat. Med. 15: 119, 2009).

The vaccines-and-autism story took a further bizarre twist when the Bush administration granted citizen (i.e., activist) oversight of vaccine safety research (NEJM 358: 2089, 2008). The index case was Hannah Poling, a Hopkins neurology resident's daughter who appeared normal at birth, but had a genetic mitochondriopathy that causes encephalitis and brain damage after common childhood infections. When this happened to the child, the family "was sure" it was the vaccines causing autism. The Bush administration decided to compensate the girl in April 2008. Stay tuned.

ASPERGER'S ("high functioning autism") is a new "disease", supposedly affecting mostly boys, running in families. Asperger's boys tend to be of normal or high intelligence, strongly focused on single topics (for example, math, chess, computers, a musical instrument, train schedules, pathology, skydiving, flattop haircuts, etc., etc.), are physically clumsy, find other people baffling, but don't commit crimes (well usually, the ones that do are refractory to treatment: Med. Sci. Law. 42: 237, 2002). Speech is rapid and lacks intonation. As kids, they are "little professors." After many social failures during adolescent and young adult life, they tend to withdraw and become odd loners. As teens and adults, they have to work hard to learn to use and read body language and to relate to others. Asperger'sseems to be real, and I predict that its study will show something about the wiring of personality. Adults with Asperger's have greatly reduced 5-HT2A receptor density (Brain 125: 1594, 2002), and differences in brain anatomy especially in the frontostriatal connections (Brain 125: 1594, 2002). Properly managed, Asperger's offers a set of unique plusses both for the individual and -- if the interests are useful -- for society.

Of all the patient-care specialties, I am most intrigued by psychiatry. Many other pathologists share my fascination with the life of the mind.

BIOLOGICAL PSYCHIATRY is only now coming of age. Remember that different kinds of synapses may use the same neurotransmitter.

Right now, the study of the very-common OBSESSIVE-COMPULSIVE DISORDERS is a major topic in psychiatry; watch this elucidate different types of serotoninergic synapses (Mayo Clin. Proc. 67: 266, 1992; Postgrad. Med. 91: 171, 1992; Arch. Gen. Psych. 49: 21, 1992; subtle cues to basal ganglia dysfunction Brain 114: 2191 & 2203, 1991; Arch. Gen. Psych. 47: 27, 1990, notably such stuff as visuospatial coordination; this is no surprise because Sydenham chorea produces obsessions and compulsions: Am. J. Psych. 146: 246, 1989; caudate on PET scan display before and after therapy: Arch. Gen. Psych. 49: 681, 1992). For unwanted intrusive thoughts about a past or present problem, set the business down in a cohesive form on paper. When obsessive-compulsive appears suddenly, you'll probably find damage on scan somewhere in the cortex or basal ganglia (Neurology 47: 353, 1996). Moderate catechol O-methyl transferase deficiency and obsessive-compulsive: Proc. Nat. Acad. Sci. 94: 4572, 1997. Psychological tests and scans of patients and family members (who tend to have similar, milder changes): Brain 130: 3223, 2007. Not totally unrelated: Serum from TOURETTE'S patients causes a similar illness in rats if and only if there are antinuclear or antineuronal antibodies (Am. J. Psych. 159: 657, 2002).

BIPOLAR DISORDER is obviously genetic with several distinct syndromes and likely loci (Am. J. Psych. 160: 999, 2003; Arch. Gen. Psych. 60: 497, 2003). The genes remain elusive; Sherman's paradox seems to operate Am. J. Hum. Genet. 53: 385, 1993; the "usual suspects" include tryptophan hydroxylase, and catechol o-methyltransferase (Am. J. Psych. 159: 23, 2002). I'm not the only physician who think that the drug companies have something to do with the greatly increased frequency with which the diagnosis "bipolar" is being made recently. One kind of UNIPOLAR DEPRESSION links nicely to the serotonin transport gene (Lancet 347: 731, 1996 -- I hope no one is surprised).

ATTENTION-DEFICIT DISORDER, with difficulty focusing (even on play), is wired in the caudate and its connections to the frontal lobe (Am. J. Psych. 151: 1791, 1994; update from neuroimaging is impressive: Lancet 362: 1699, 2003). The mouse model is the knockout mouse lacking dopamine transporter: Science 283: 397, 1999.

The big news in DYSLEXIA in 1996 was the discovery that if you help these kids distinguish different phonemes early, they do much better (Br. Med. J. 313: 1096, 1996, Child. Dev. 65: 41, 1994). As I predicted in the 1980's, the US fad to forbid the teaching of phonics resulted in a lot more cases of dyslexia (Psych. Sci. 2(2S): 31, 2001, big review, go figure); sadly, it took neuroscientists rather than people possessed of simple common sense to end this fiasco.

Whatever else we are, humankind is the talking animal. Almost everybody has the same FOXP2 allele, which indicates it swept through the human population rather recently. This includes the Neanderthals (Curr. Bio. 17:1, 2007); any other allele causes severe deficits in speech and language (Nature 413: 519, 2001). Many people are relatively non-verbal (speaking, reading, understanding) despite otherwise normal intellectual function; there's now a few known mutations that cause recipients to be unable to use suffixes or complex grammar. Some have a lot of trouble not only being understood, but moving their faces (Nat. Genet. 18: 168, 1998 -- discovery of the SPCH1 locus, where FOXP2 is located). As a college student in the late 1960's when B.F.Skinner was dogma ("Environment is everything"), I say I'm getting the last laugh.

We await effective therapy for BORDERLINE PERSONALITY ("I hate you, don't leave me!" and more), and I wonder whether it's hard-wired or simply a lack of living skills (which are hard to teach -- and they won't learn if you tolerate their behavior). When talking to a borderline, say "I feel" rather than "you...", and avoid getting entrapped by them.

You will hear plenty of GLOSSOLALIA (i.e., people who believe they are speaking a language they themselves do not understand) among people who are clearly mentally ill, the majority being psychotic; review J. For. Sci. 47: 305, 2002. Whether it is ever really of supernatural/paranormal origin is something you'll need to decide for yourself.

SOMATIZATION DISORDER ("somatoform disorder" JAMA 278: 673, 1997) is still considered "all in your mind" -- I believe this is wrong. The typical patient is a low-achieving young adult with anxiety, depression, and personality problems ("borderline", etc.) However, these folks also have lots of aches, pains, and symptoms that cause substantial disability. This is a patient type well-known across cultures (Am. J. Psych. 154: 989, 1997). I predict (2007) that it will be found to have a strong organic basis and eventually an effective organic therapy. (Uh, doc, you did rule out everything else, right?)

Of course, we all somatize to some extent, especially during difficult times. You'll be impressed by this as a physician. Much of the art of medicine is knowing when to try a workup, and when not to.



Also watch KLEINE-LEVIN SYNDROME (spells of hypersomnia and polyphagia with bizarre behavior), or "sleep-related eating disorder". This in turn may or may not be related to compulsive nighttime icebox-raiding.

SEASONAL AFFECTIVE DISORDER: Arch. Gen. Psych. 41: 72, 1984 (said it all; wavelength Am. J. Psych. 148: 509, 1992; the atypical antidepressant agomelatine, which disrupts circadian rhythms, seems to help: Psychopharmacology 190: 575, 2007; I was surprised that melatonin turned out to be no beter than placebo Neuropsychopharmacology 30: 1345, 2005), though some folks do use it Chronobiol. Int. 23: 403, 2006).

NARCOLEPSY is real (Mayo Clin. Proc. 65: 991, 1990) and affects about 1 person in 5000; patients must have HLA-DR2 / DQ1 (Lancet 341: 406, 1993). They fall asleep without being able to resist, and also drop over suddenly like a rag doll from time to time without falling asleep ("cataplexy"). The brain lacks the neurotransmitter hypocretin, though this is usually not the locus (Nat. Med. 6: 991, 2000; update and additional complexity Lancet 363: 1199, 2004). Most often, the neurons that use hypocretin in the hypothalamus are destroyed (by autoimmunity, we may suppose): Lancet 369: 499, 2007.

* Hypocretin 1 / orexin-A itself is interesting stuff... an injection reverses the cognitive impairment caused by sleep deprivation, at least in monkeys (JAMA 299: 513, 2008).

THE TRANSSEXUAL BRAIN: Ordinary men have huge, and ordinary women have tiny, central divisions of the bed nuclei of the stria terminalis in the hypothalamus (BSTc). Among several male transsexuals (gender-dysphorics, "I'm a woman trapped in a man's body!!"), gay or straight, every one had a tiny BSTc nucleus (Nature 378: 68, 1995). More recent work confirms this even more impressively: J. Clin. End. Metab. 85: 2034, 2000. Despite the politics, some patients find their being unhappy with their sex organs disappears on low doses of medication (Aus. NZ. J. Psych. 30: 422, 1996).

HYPERSEXUALITY seems to be in the wiring (Can. J. Psych. 46: 26, 2001), so it's not surprising that the 1990's push to define "sexual addiction" as an entity to be twelve-stepped was a total failure (Clin. Psych. Rev. 18: 367, 1998). By contrast, the common PARAPHILIAS seem to be acting-out (as common sense would suggest), either a way of dealing with your hatreds or simply avoiding the problems of being "normal". Despite the greater tolerance of (and even promotion of) "minority sexual practices" among consenting adults, these people tend to have overall poor interpersonal skills. If they find real friendship in the "alternative" community, it seems to me it's a good thing, but not the best life could offer.

POST-TRAUMATIC STRESS DISORDER is nothing new ("Skipper Ireson's Ride", shell-shocked WWI veterans), and is serious and real, but is now highly politicized. It is most severe in torture survivors, but any brush with death or bad mistreatment (rape, child abuse) can leave a person jumpy, sleeping poorly, and suffering from flashbacks. Two accounts from physicians appear in BMJ Dec. 2, 2000. One found a deeper appreciation for how delicate and uncertain life is, and spirituality became far more important in his life. Not surprisingly, the policemen with PTSD are the ones whose "worst moment as a cop" involved seeing their own lives in danger (JNMD 194: 591, 2006). The volume of the hippocampus is lower in PTSD patients whose trauma took place in adult life (J. Clin. Psych. 62(S-17): 47, 2001, others), but not when the abuse happened in childhood (Biol. Psych. 50:305, 2001). We don't know whether this identifies people more at risk for PTSD after trauma, or whether this is due to beatings sustained to the head, or whether it is an effect of torture. A prospective study that might have helped didn't get results (Am. J. Psych. 158: 1248, 2001). There are glucocorticoid receptors in the hippocampus, and in some models, glucocorticoid excess itself (Cushing's in humans, mice given high doses) causes atrophy of the hippocampus via glutamate excitotoxicity (Arch. Gen. Psych. 57: 925, 2000; Biol. Psych. 45: 797, 1999). People who have long-term severe depression also have marked atrophy of the hippocampus (Proc. Nat. Acad. Sci. 100: 1387, 2003); interestingly, the volume of the hippocampus is apparently normal at the beginning of these patients' illnesses; another report finds normal volumes but altered shape (Am. J. Psych. 160: 83, 2003). You'll have to decide for yourself about just how prevalent post-traumatic stress disorder is in people whose "stress" seems only part of normal life; lawyers are now alleging PTSD after fender-benders, hearing off-color jokes, etc. (Science 301: 465, 2003). Today there is a strong backlash against "the medicalization of distress" (Lancet 369: 139, 2007): "There is value in focusing on adaptive coping during and after traumas. Striking a balance between a focus on heroism and resiliance versus victimhood and pathological change is a crucial and constant issue after trauma for both clinicians and society."

Must reading (when you have time!): A chilling article entitled "Violence: The Neurological Contribution"; Arch. Neurol. 49: 595, 1992 (it is simplistic to ignore either neurology or sociology). Mice without nitric oxide synthetase are hypersexual and hyperaggressive (Nature 378: 336, 1995).

One current big fad in psychiatry is "debriefing", i.e., they bring a psychiatrist to talk to you after any really bad experience, loads of "counsellors" after a natural or man-made disaster, in the belief that this expensive intervention prevents long term psychopathology; I can't see why it should, and now it's pretty clear that it doesn't work (Br. Med. J. 310: 1479, 1995). Curious exceptions, at least in Britain, home of the stiff-upper-lip: Br. J. Psych. 169: 405, 1996 notes the contrast between the way the system totally ignores kids who've seen their loved ones killed in car wrecks with the flood of "counsellors" who descended on Dunblane in 1996.