Cerebellar Agenesis: Life without a Cerebellum

Many people are familiar with the famous patient H.M., the man who, in an attempt to control his intractable epilepsy, underwent surgical resection of both his medial temporal lobes.

There is another patient who is less famous, known the by initials H.C. He died in 1939 when H.M. was just entering adolescence. Unlike H.M., this patient did not undergo radical resection surgery. In fact, he never underwent brain surgery at all. His contribution to neurology did not begin until after his death at the age of 76.

In what was supposed to have been a routine autopsy, H.C. was discovered to have had no cerebellum (see pictured brain above). H.C. had a very rare neurological condition known as cerebellar agenesis. When I was in graduate school, I was taught that the neuroplasticity of the brain was so remarkable, that even a child born without his or her cerebellum could grow-up to have no deficits and live a normal life. As it turns out, that was only partly true. H.C. was in fact, not without deficits. His tale is recounted briefly in two articles from the March 2010 issue of Brain:

"It was clear that there were indeed clinical signs included right external strabismus (i.e., misaligned eyes), slow and slurred articulation and an unsteady gait." (1)

However, he did live a "normal life":

H.C. "had employment, that he was able to work in a manual job and that his working life was not curtailed by his cerebellar agenesis." (1)

What is interesting about H.C. compared to H.M., is that H.C.'s agenesis was discovered only after he died. Very little clinical history about his life exists, making this story a great neurological detective case. Most of what is known about H.C. comes from hospital notes during his last years of life, just before he developed dementia:

"The social history describes him as 'single.' The notes contained a record of his assessment by a neurologist, Dr. Jacobson, who described him as 'a simple man with some hearing loss and slow slurred speech; he has a fair memory for recent and remote events concerning himself, but with limited general knowledge. There is no hallucination or delusions nor emotional defect. He is clean in his habits and able to attend to his person. He is able to get around unassisted." (1)

The human brain is estimated to have approximately 85 billion neurons (2). The cerebellum, which is typically 1/4 the size of the rest of brain, contains a full 50% of all our neurons. If you pay close attention to the image above, you will notice that, in addition to not having a cerebellum, H.C. was also missing his pons, the bulbous structure that is typically adjacent to the cerebellum and is responsible for arousal and alertness.

Many of the patients I have seen with cerebellar strokes typically have severe and irreversible deficits. While H.C. did have some cognitive and functional deficits, that he lived a full and functional life is nothing less than remarkable. His case is an example of how extraordinary the human brain actually is.

I encourage you to read more about the mysterious case of H.C. here.



Boyd, C. (2009). Cerebellar agenesis revisited Brain, 133 (3), 941-944 DOI: 10.1093/brain/awp265

Lemon, R., & Edgley, S. (2010). Life without a cerebellum Brain, 133 (3), 652-654 DOI: 10.1093/brain/awq030

Detroit SWAT Team Kill 7 Year-Old Girl

There has to be a better way to do this....full story here.



UPDATE: As luck would have it, this particular raid was being filmed for a reality show known as "The First 48." Base on the footage, the family lawyer is alleging a cover up (1).

Draw Muh...er...Comedy Central Executives Day

May 20th has been declared "Everybody Draw Muhammad Day" (1). By now, many should be aware of the controversy surrounding South Park's 200th and 201st episodes.

Shortly after the airing of episode 200, a group known as Revolution Muslim posted the following message on their site:

"We have to warn Matt and Trey that what they are doing is stupid and they will probably wind up like Theo Van Gogh for airing this show...this is not a threat, but a warning of the reality of what will likely happen to them." (2).

Thereafter, the media got wind of this post and ran with it. All major news networks and outlets had something to say about this "controversy". A week later, the 201st episode aired. It was, against the wishes of Matt Stone and Trey Parker, heavily edited by the douche bags at Comedy Central/Viacom.

As a result of the ignorant and spineless actions by the douche bags at Comedy Central/Viacom, a self-proclaimed idiot (3) and artist, Molly Norris, declared May 20th to be "Everybody Draw Muhammad Day." She had created a poster showing many objects, such as a tea cup, claiming to be the likeness of Muhammad. She sent this poster to different media outlets, who took it seriously, and then it went viral.

Ms. Norris has since distanced her self from "Draw Muhammad Day" and suggested that we should draw Al Gore instead (4).

After reading and listening to the media, I decided to do some research. To me, all this "controversy" seemed a bit contrived. After all, this was nothing like the Danish cartoon hysteria. If you were paying attention at all, it appears that this "controversy" had fallen on deaf ears in the Muslim world (5).

The true extent of Muslim hysteria was this: one post, by one Islamic group, Revolution Muslim.

I read about the group on Wikipedia (6). It turned out to be an interesting read:

"The group of 5-10 members....run by Yousef al-Khattab, born Joseph Cohen, an American Jew who converted to Islam in 2000 after living in Israel and attending an orthodox rabbinical school."

More about Joseph Cohen from LoonWatch.com :

"He was born and raised in the United States as a Jew, and holds both American and Israeli citizenship.   In the late eighties, Cohen embraced an ultra-orthodox interpretation of Judaism, and began attending a yeshiva (rabbinical school).  In 1998, Cohen hearkened to the Zionist call, and packed up his bags to relocate to the Israeli Occupied Territories where he became an Israeli settler.  As an ardent and extreme Zionist, Joseph Cohen fell in with the Jewish fundamentalist group Shas, an extreme right-wing political party that believes in flouting international law based on their religious beliefs.  Less than three years later, Cohen 'converted' to Islam, moved back to the United States, and founded the most radical Islamic group in the country." (7, 8)

A radical in one religion will be a radical in another religion.

Maybe, just maybe, it was not the Muslims who were over reacting, but rather, the American Media. Now many people across this country are angry, and on May 20th, people will take pencil to paper and draw the Prophet Muhammad.

Perhaps this anger is misplaced. After all, it was Comedy Central/Viacom that censored the cartoon. It was also Comedy Central/Viacom that censored people who criticized their spineless behavior (9). Perhaps the true enemies of free speech are the people responsible for actual censorship: the executives/lawyers at Comedy Central/Viacom.

Woman Hospitalized Following Botched Raid

How many armed, anonymous, men does it take to give an old woman a heart attack? The answer:

"An elderly Polk County woman is hospitalized in critical condition after suffering a heart attack when drug agents swarm the wrong house. Machelle Holl tells WSB her 76-year-old mother, Helen Pruett, who lives alone, was at home when nearly a DOZEN local and federal agents swarmed her house, thinking they were about to arrest suspected drug dealers." (1)

There Are 40,000 of These Each Year

Here's what happened (1):

"SWAT team breaks into home, fires seven rounds at family's pit bull and corgi (?!) as a seven-year-old looks on.

They found a "small amount" of marijuana, enough for a misdemeanor charge. The parents were then charged with child endangerment.

So smoking pot = "child endangerment." Storming a home with guns, then firing bullets into the family pets as a child looks on = necessary police procedures to ensure everyone's safety.

Just so we're clear."

Transcranial Magnetic Stimulation: Does it Live Up to the Hype?

Repetitive Transcranial Magnetic Stimulation (rTMS) is a treatment for depression that was approved by the FDA in October of 2008 (1). Repetitive TMS involves a device (pictured right), which is noninvasive, that excites the neurons in the brain. When this done over the left dorsolateral prefrontal cortex (an area of the brain supposedly less active in depressed patients), brain activity increases. The major selling point is that it has very few side-effects compared to standard antidepressant treatment (most common effects are headache and tingling at the stimulation site).

The FDA approval of this device has been controversial (2). The initial study submitted to the FDA was rejected. The folks at Neurostar (the manufacturers of the device) did a post-hoc analysis of that data. They discovered that patients, who failed to respond to only 1 antidepressant, subsequently responded to rTMS greater than sham (27.3% versus 10.5%). Based on this analysis, the FDA approved rTMS for the treatment of MDD in patients who have failed only 1 antidepressant trial.

In this month's Archives of General Psychiatry, is an article titled "Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder" (3). This study was funded by the NIMH and is the first nonindustry funded multisite study of rTMS (though some of the researchers are paid consultants of the TMS manufacturer). It involved 190 people.

What supposedly separates this study from all others, is the sham treatment. One major criticism of the previous TMS research is that the sham treatment was not convincing enough to prevent unblinding (for example, sham did not cause scalp irritation or facial twitching). The researchers went to great lengths to develop a sham treatment which produced the similar physical sensations of rTMS to prevent unblinding.

(Click to Enlarge)

Unfortunately, approximately 50% of the active treatment group correctly guessed which treatment condition they were in. A full 66% of placebo participants correctly guessed their condition. In truth, the level of unblinding is not a whole lot different from standard antidepressant drug trials (since placebos are inactive). The patients, on average, were similar to the patients in the Neurostar post-hoc analysis. The participants failed 1.51 antidepressant trials. 
 
The primary outcome was remission, defined as a score of 3 or less on the HAM-D or 2 consecutive HAM-D scores less than 10 during phase 1 of the study. Phase 1 was three weeks in duration. Patients received rTMS once a day for 50 minutes (5 days a week).

(Click to Enlarge)

Unfortunately, the results were negative. During the three week period (the right side of the chart) only 6 patients (11%) met criteria for remission. The average drop in HAM-D score for active treatment was only 5 points (26 to 21). The researchers then extended the the length of phase 1 by two weeks. The number of patients who went into remission during this extension phase was 13 (14%). By increasing the length of the phase 1, they obtained statical significance. Sounds fishy to me, but at least they provide all the data.
 
Similar to the Neurostar analysis, those who did remit were less treatment resistance (i.e., failed only 1 antidepressant trial). The number needed to treat (NNT) was 12. That means, 12 people will need to be treated with rTMS before another person, who otherwise would have not remitted without intervention, finally does remit. That's not very good. However, that number is not far off from standard antidepressant drug trials.
 
Does rTMS have any practical value as a future treatment for depression? Based on these results, one will need to attend a 50 minutes session everyday (excluding weekends) for 3-5 weeks to see some sort of result. That is in stark contrast to attending psychotherapy 1-2 times a week or visiting a psychiatrist once every 4-6 weeks. As Daniel Carlat points out in his monthly report (1), each treatment session would cost approximately $400. Insurance companies do not currently cover this treatment (and probably never will). Moreover, the group of patients who did remit (i.e., those who failed only 1 antidepressant trial) is not very marketable. Odds are they will try a second antidepressant instead. According to the Star-D results, the odds of improvement are 30% on a second antidepressant compared to 14% of rTMS. Presently, rTMS just does not make economic sense.



George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, & Sackeim HA (2010). Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Archives of general psychiatry, 67 (5), 507-16 PMID: 20439832

Psychosis Among Substance Users

Psychosis among drug users is quite common. Often, it is difficult to determine which came first, substance use or psychosis. Frequently, they co-occur. In cases where drugs are causally related (i.e., substance-induced psychosis), the condition is typically transient with a duration of 1 month or less. In rare cases, the length of psychosis can last longer. And in even rarer cases, symptoms such as hallucinations can be permanent.

Psychosis can be associated with the use many legal (e.g., alcohol) or illicit substance such as stimulants (amphetamines and cocaine), cannabis, and hallucinogens. An article by Thirthalli and Benegal (1) reviews the evidence that these drugs can cause psychosis in nonpsychotic persons. 

Alcohol

The neurochemical effects of alcohol are complex. "Common knowledge" states that alcohol acts in a similar fashion to other sedatives (e.g., diazepam). In other words, it is an agonist of GABA receptors. In reality, the alcohol molecule is very simple. It has the ability to cross cell membranes (e.g., blood-brain barrier) easily and can exert its effects on the brain within minutes. Alcohol also influences the phospholipid bilayer that make up cell membranes. This ability has a widespread impact on normal cell functions and also enables alcohol to modify the action of many neurotransmitter systems, such glutamate, dopamine, and norepinephrine in addition to GABA.

Alcohol-induced psychosis can occur during different drug states such intoxication or withdrawal (e.g., delirium tremens, alcoholic hallucinosis). In general, the risk of psychosis is two-fold greater than in the general adult population.

Stimulants (click to enlarge picture; 2)
Cocaine and Amphetamines are widely known to lead to psychosis. The psychosis produced by both cocaine and amphetamines is similar to schizophrenia. The risk of psychosis from amphetamine use is quite high; greater than 70% in chronic users. Users who develop first episode psychosis use an average of 20 times years. Psychosis typically lasts for the duration the drug is in the system. However, it can last more than a month in more severe cases.

For cocaine, typically 50% of chronic users experience paranoia and hallucinations. Cocaine-induced psychosis has a stereotypical form; Users believe that their drug use is being watched and that they are being followed. This paranoia is typically accompanied by hallucinations. Cocaine-induced psychosis also shows sensitization; that is, psychosis becomes more severe and occurs more rapidly with continued use. Unlike amphetamine-induced psychosis, cocaine induced-persistent psychosis is very rare.

Cocaine has the highest affinity and binds most strongly to the serotonin (5HT)reuptake pump, followed by the dopamine (DA) reuptake pump, then the norepinephrine (NE) reuptake pump (FYI-Effexor is cocaine with a PG-rating; effexor's affinities are for serotonin, then NE, and then DA). Contrary to popular belief, amphetamines do not act by blocking the dopamine reuptake pump. Amphetamines are indirect agnonist of the catecholaminergic systems (i.e., dopamine and norepinephrine). First, amphetamines go inside the neuron and release both DA and NE from their vesicles into the cell cytoplasm (i.e., catecholamins are released inside the neurone). Second, The catecholamines are subsequently transported outside of the neuron by a reversal of the reuptake pumps. This results in a MASSIVE increase in synaptic DA and NE. Lastly, at higher doses, amphetamines inhibit catecholamine metabolism, leading to even higher concentrations in the synapse. 

Cannabis
There has been a boom in the current research of cannabis and psychosis. There appears to be a temporal correlation between early cannabis use and onset of schizophrenia. This association is stronger than for any other substance. Why the association exists is unclear. In general, cannabis has the same risk of inducing psychosis as alcohol (i.e., two-fold).

There are two cannabinoid receptors in the human body: CB1 and CB2. The CB2 receptor is not expressed in the brain, and is primarily found in the immune system. The CB1 receptor is typically found in the basal ganglia, cerebellum, hippocampus, and the cortex. CB1 receptors exist on the axon terminal instead of the post-synaptic cell. In others words, CB1 receptors are autoreceptors that can inhibit the release of many different neurotransmitters.

Hallucinogens
Many different drugs fall under this category: mushrooms, peyote buttons, and LSD, for example. Many hallucinogenic drugs are either synthesized by plants or are based on plant-derived compounds. The main active compound in peyote is mescaline, while psilocin in found mushrooms. LSD is actually a synthetic compound, but is based on a fungal alkaloid taken from ergot.

Hallucinogenic compounds have a catecholamine-like structure (most are similar in shape to serotonin). Hallucinogens are primarily 5-HT2a receptor agonists. While these drugs do not lead to dependence, withdrawal, or cravings, they still can lead to serious problems for some users. Some people experience acute anxiety or panic attacks in responses to the drugs' hallucinogenic effects. There is a disorder known as hallucinogen persisting perception disorder (HPPD), which is the fancy name for "flashbacks." The most severe reactions, of course, are psychotic breakdowns. However, similar to the above mentioned drugs, psychosis is typically transient. Most prolonged episodes of hallucinogen-induced psychosis involve individuals who have already been diagnosed with a psychotic disorder or who have manifested prepsychotic (e.g., prodromal) symptoms before taking these drugs.

Treatment
In most cases, substance induced psychosis does not need medical treatment per se. It usually disappears when the drug's affects are gone. However, there are cases when treatment is necessary. Alcohol dependent individuals in withdrawal do need medical treatment because alcohol withdrawal can be lethal. Typically, sedatives (benzodiazepines) are the drugs of choice. For either cocaine or amphetamine induced psychosis, first or second generation antipsychotics are the drugs of choice because of their potent D2 receptor antagonism. In general, it is common for anyone presenting with psychotic symptoms to be prescribed antipsychotics. Occasionally, patients who are addicted to amphetamines will be prescribed antipsychotics in hopes that they will reduce the risk of subsequent psychosis or reduce euphoria, making the drug less reinforcing. Drugs that antagonize the 5HT2a receptor such as risperidone (or any second generation antipsychotic), ketanserin, and ritanserin have been shown to reverse hallucinogenic-induced psychosis.

In rare cases when psychosis persists, there are a few things to consider, such as, is their another cause for the psychosis? For example, does the person have schizophrenia or is there a physical cause for the psychosis (e.g., tumor, metabolic, etc)? Often times, doctors not knowing what to do, will double down on the antipsychotics. This is unlikely to work because the mechanism of action (D2 or 5HT2a blockade) does not necessarily increase with the addition of a second drug. Simply upping the does of the current drug should suffice. Side effects, however, are always additive. Antipsychotics with higher affinities for both D2 and 5HT2a receptors are preferable (e.g., risperidone).

Risk Factors
The risk factors for substance-induced psychosis are similar across all substances. Pre-morbid psychiatric history or a family history of schizophrenia put an individual at risk. Also, the longer a substance is consumed and the larger the quantities consumed are also risk factors. Polysubstance use or consuming drugs that contain other compounds increases the risk of psychosis too. Unfortunately, the research into the neurobiological and genetic underpinnings is substance-related psychosis are quite poor. A useful theory for substance-related psychosis which could lead to better acute treatment is lacking.



Thirthalli, J & Benegal, V. (2006). Psychosis Among Substance Users Current Opinion in Psychiatry

"Anatomy of an Epidemic" or The Same Story Told Over and Over Again

On Salon.com, there is an interview with Robert Whitaker, the author of Mad in America, about his new book titled "Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America."

The article/interview at Salon is devoid of any context:

"In the past few months, the perennial controversy over psychiatric drug use has been growing considerably more heated. A January study showed a negligible difference between antidepressants and placebos in treating all but the severest cases of depression. The study became the subject of a Newsweek cover story, and the value of psychiatric drugs has recently been debated in the pages of the New Yorker, the New York Times and Salon...The timing of Robert Whitaker’s "Anatomy of an Epidemic," a comprehensive and highly readable history of psychiatry in the United States, couldn’t be better."

That study in JAMA is hardly a first (1, 2, 3), nor is Mr. Whitaker's book a first (4, 5, 6, and anything written by Peter Breggin). Timing couldn't be better? Sure, if by timing you mean, when can one cash in on anti-psychiatry sentiment.

I have not read this book. I did read his previous book, Mad in America, which surveyed the history of the treatment of mental illness in American and the rise of psychiatric drugs. Based on that book, which was sensationalistic and misrepresented research, I think I know what to expect in his new book. My focus, instead, will be on his interview. Comments in red.

"Psychiatric drug use is a notoriously tough subject for writers, because of all the contradictory research. Why wade into it? In 1998, I was writing a series for the Boston Globe on abuse of psychiatric patients in research settings. I came across the World Health Organization’s outcomes study for schizophrenia patients, and found that outcomes were better for poor countries of the world -- like India, Colombia, Nigeria -- than for the rich countries. And I was startled to find that only a small percentage of patients in those countries were medicated. I also discovered that the number of people on disability for mental illness in this country has tripled over the last 20 years..."

 He doesn't provide an actual number for "only a small percentage of patients." However, according to the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO;7), which surveyed Europe, Asia, Africa, and Latin America, it revealed that a not so small 40% of patients where on antipsychotic medications. The real differences between rich and poor counties is that patients in developing countries were primarily on first generation antipsychotics (60%) and on monotherapy (75%). The reasons for outcome differences are many.

"...If our psychiatric drugs are effective at preventing mental illness, I thought, why are we getting so many people unable to work?"

I don't think anyone of real importance claimed that psychiatric drugs were aimed at "preventing mental illness." Again, there is no context. For example, one explanation for the increase of those on disability is that entitlement programs have increased their coverage over the years to include those with mental illnesses.

"What's so risky about Ritalin? For one, a significant percentage -- between 10 and 25 percent -- of kids prescribed medication for ADHD will have a manic episode or psychotic episode and deteriorate in such a way that they’re diagnosed with bipolar disorder..."

He is misrepresenting the data. That study (8), examined the comorbidity of ADHD and mania, not the association of stimulant medication use and risk of mania. It's quite possible that those who eventually develop bipolar disorder have an ADHD appearance during childhood.

"But if these studies are so groundbreaking, why have they gone unreported in the media? Because the NIMH didn’t announce it. Just as they didn’t announce the 2007 outcome study for schizophrenia patients. In that study, the recovery rate was 40 percent for those off meds, but only 5 percent for those on meds. I checked all the NIMH press releases for 2007, and found no release on this study. I found no announcement of it in any American Psychiatric Association publication or textbook. Not a single newspaper published an account of the study. And that’s because the psychiatric establishment -- the NIMH, the APA, even the National Alliance on Mental Illness, an advocacy organization -- did not put out any press release about it or try to alert the media in any way."

Either he's lying or had a lobotomy. I have reviewed that study as well as it's follow-up (9). Here is what the researchers actually discovered :

"Looking at it from a different viewpoint, the data suggests that schizophrenia patients with good prognostic features, with better premorbid developmental achievements and with more favorable personality characteristics are the subgroup more likely to stay off antipsychotics for a prolonged period"

That's why the NIMH, APA, and NAMI didn't sound the alarm about that supposed discovery. Here's another way to highlight the absurdity of his conclusion: Two women have been diagnosed with breast cancer. One has a strong family history of breast cancer and tested positive for the BRCA gene (i.e., she has a poor prognosis). The other woman has no family history nor the BRCA gene. Both were treated with chemo. One recovered quickly stopped treatment. The other woman, while still being treated, died. The chemotherapy killed her, right?

 I could continue, but what's the point. His book has one intended audience: People who already hate psychiatry. If one cares to fully fact check the entire interview, you'll find one misleading statement after another. Whitaker is biased and has no scruples about misrepresenting facts and data to suit his narrative.

He is no different than the very industry that he is attacking.