Chips Coming to a Brain Near You

By Lakshmi Sandhana

In this era of high-tech memory management, next in line to get that memory upgrade isn't your computer, it's you.

Professor Theodore W. Berger, director of the Center for Neural Engineering at the University of Southern California, is creating a silicon chip implant that mimics the hippocampus, an area of the brain known for creating memories. If successful, the artificial brain prosthesis could replace its biological counterpart, enabling people who suffer from memory disorders to regain the ability to store new memories.

And it's no longer a question of "if" but "when." The six teams involved in the multi-laboratory effort, including USC, the University of Kentucky and Wake Forest University, have been working together on different components of the neural prosthetic for nearly a decade. They will present the results of their efforts at the Society for Neuroscience's annual meeting in San Diego, which begins Saturday.

The hippocampus of the intact brain (left) receives neural impulses from the environment. The microchip (right), which may be able to help humans build long-term memories, processes the signals from the brain as electrical impulses and sends them back into the hippocampus.

While they haven't tested the microchip in live rats yet, their research using slices of rat brain indicates the chip functions with 95 percent accuracy. It's a result that's got the scientific community excited.

"It's a new direction in neural prosthesis," said Howard Eichenbaum, director of the Laboratory of Cognitive Neurobiology at Boston University. "The Berger enterprise is ambitious, aiming to provide a prosthesis for memory. The need is high, because of the prevalence of memory disorder in aging and disease associated with loss of function in the hippocampus."

Forming new long-term memories may involve such tasks as learning to recognize a new face, or remembering a telephone number or directions to a new location. Success depend on the proper functioning of the hippocampus. While this part of the brain doesn't store long-term memories, it re-encodes short-term memory so it can be stored as long-term memory.

It's the area that's often damaged as a result of head trauma, stroke, epilepsy and neurodegenerative disorders such as Alzheimer's disease. Currently, no clinically recognized treatments exist for a damaged hippocampus and the accompanying memory disorders.

Berger's team began its research by studying the re-encoding process performed by neurons in slices of rat hippocampi kept alive in nutrients. By stimulating these neurons with randomly generated computer signals and studying the output patterns, the group determined a set of mathematical functions that transformed any given arbitrary input pattern in the same manner that the biological neurons do. And according to the researchers, that's the key to the whole issue.

"It's an impossible task to figure out what your grandmother looks like and how I would encode that," said Berger. "We all do a lot of different things, so we can't create a table of all the things we can possibly look at and how it's encoded in the hippocampus. What we can do is ask, 'What kind of transformation does the hippocampus perform?'

"If you can figure out how the inputs are transformed, then you do have a prosthesis. Then I could put that into somebody's brain to replace it, and I don't care what they look at -- I've replaced the damaged hippocampus with the electronic one, and it's going to transform inputs into outputs just like the cells of the biological hippocampus."

Dr. John J. Granacki, director of the Advanced Systems Division at USC, has been working on translating these mathematical functions onto a microchip. The resulting chip is meant to simulate the processing of biological neurons in the slice of rat hippocampus: accepting electrical impulses, processing them and then sending on the transformed signals. The researchers say the microchip is doing exactly that, with a stunning 95 percent accuracy rate.

"If you were looking at the output right now, you wouldn't be able to tell the difference between the biological hippocampus and the microchip hippocampus," Berger said. "It looks like it's working."

The team next plans to work with live rats that are moving around and learning, and will study monkeys later. The researchers will investigate drugs or other means that could temporarily deactivate the biological hippocampus, and implant the microchip on the animal's head, with electrodes into its brain.

"We will attempt to adapt the artificial hippocampus to the live animal and then show that the animal's performance -- dependent in these tasks on an intact hippocampus -- will not be compromised when the device is in place and we temporarily interrupt the normal function of the hippocampus," said Sam A. Deadwyler, "thus allowing the neuro-prosthetic device to take over that normal function." Deadwyler, a professor at Wake Forest University, is working on measuring the hippocampal neuron activity in live rats and monkeys.

The team expects it will take two to three years to develop the mathematical models for the hippocampus of a live, active rat and translate them onto a microchip, and seven or eight years for a monkey. They hope to apply this approach to clinical applications within 10 years. If everything goes well, they anticipate seeing an artificial human hippocampus, potentially usable for a variety of clinical disorders, in 15 years.

Overall, experts find the results promising.

"We are nowhere near applicability," said Boston University's Eichenbaum. "But the next decade will prove whether this strategy is truly feasible."

"There is a big gap in making the microchip work in a slice preparation and getting it to work in a human being," added Norbert Fortin, a neuroscientist from the Cognitive Neurobiology Lab at Boston University. "However, their approach is very methodical, and it is not unreasonable to think that in 15 to 20 years such a chip could help, to some degree, a patient who suffered from hippocampal damage."

Free Will vs. the Programmed Brain

If our actions are determined by prior events, then do we have a choice about anything—or any responsibility for what we do?

By Shaun Nichols

Many scientists and philosophers are convinced that free will doesn’t exist at all. According to these skeptics, everything that happens is determined by what happened before—our actions are inevitable consequences of the events leading up to the action—and this fact makes it impossible for anyone to do anything that is truly free. This kind of anti-free will stance stretches back to 18th century philosophy, but the idea has recently been getting much more exposure through popular science books and magazine articles. Should we worry? If people come to believe that they don’t have free will, what will the consequences be for moral responsibility?

In a clever new study, psychologists Kathleen Vohs at the University of Minnesota and Jonathan Schooler at the University of California at Santa Barbara tested this question by giving participants passages from The Astonishing Hypothesis, a popular science book by Francis Crick, a biochemist and Nobel laureate (as co-discoverer, with James Watson, of the DNA double helix). Half of the participants got a passage saying that there is no such thing as free will. The passage begins as follows: “‘You,’ your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules. Who you are is nothing but a pack of neurons.”
The passage then goes on to talk about the neural basis of decisions and claims that “…although we appear to have free will, in fact, our choices have already been predetermined for us and we cannot change that.” The other participants got a passage that was similarly scientific-sounding, but it was about the importance of studying consciousness, with no mention of free will.

After reading the passages, all participants completed a survey on their belief in free will. Then comes the inspired part of the experiment. Participants were told to complete 20 arithmetic problems that would appear on the computer screen. But they were also told that when the question appeared, they needed to press the space bar, otherwise a computer glitch would make the answer appear on the screen, too. The participants were told that no one would know whether they pushed the space bar, but they were asked not to cheat.

The results were clear: those who read the anti-free will text cheated more often! (That is, they pressed the space bar less often than the other participants.) Moreover, the researchers found that the amount a participant cheated correlated with the extent to which they rejected free will in their survey responses.

Varieties of Immorality

Philosophers have raised questions about some elements of the study. For one thing, the anti-free will text presents a bleak worldview, and that alone might lead one to cheat more in such a context (“OMG, if I’m just a pack of neurons, I have much bigger things to worry about than behaving on this experiment!”). It might be that one would also find increased cheating if you gave people a passage arguing that all sentient life will ultimately be destroyed in the heat death of the universe.

On the other hand, the results fit with what some philosophers had predicted. The Western conception idea of free will seems bound up with our sense of moral responsibility, guilt for misdeeds and pride in accomplishment. We hold ourselves responsible precisely when we think that our actions come from free will. In this light, it’s not surprising that people behave less morally as they become skeptical of free will. Further, the Vohs and Schooler result fits with the idea that people will behave less responsibly if they regard their actions as beyond their control. If I think that there’s no point in trying to be good, then I’m less likely to try.

Even if giving up on free will does have these deleterious effects, one might wonder how far they go. One question is whether the effects extend across the moral domain. Cheating in a psychology experiment doesn’t seem too terrible. Presumably the experiment didn’t also lead to a rash of criminal activity among those who read the anti-free will passage. Our moral revulsion at killing and hurting others is likely too strong to be dismantled by reflections about determinism. It might well turn out that other kinds of immoral behavior, like cheating in school, would be affected by the rejection of free will, however.

Is the Effect Permanent?

Another question is how long-lived the effect is. The Vohs and Schooler study suggests that immediately after people are made skeptical of free will, they cheat more. But what would happen if those people were brought back to the lab two weeks later? We might find that they would continue to be skeptical of free will but they would no longer cheat more.

There is no direct evidence on this question, but there is recent evidence on a related issue. Philosopher Hagop Sarkissian of the City Univeristy of New York and colleagues had people from Hong Kong, India, Colombia and the U.S. complete a survey on determinism and moral responsibility. Determinism was described in nontechnical terms, and participants were asked (in effect): whether our universe was a deterministic universe and whether people in a deterministic universe are morally responsible for their actions.
Across cultures, they found that most people said that our universe is not deterministic and also that people in the deterministic universe are not responsible for their actions. Although that isn’t particularly surprising—people want to believe they have free will—something pretty interesting emerges when you look at the smaller group of people who say that our universe is deterministic. Across all of the cultures, this substantial minority of free will skeptics were also much more likely to say that people are responsible even if determinism is true. One way to interpret this finding is that if you come to believe in determinism, you won’t drop your moral attitudes. Rather, you’ll simply reverse your view that determinism rules out moral responsibility.

Many philosophers and scientists reject free will and, while there has been no systematic study of the matter, there’s currently little reason to think that the philosophers and scientists who reject free will are generally less morally upright than those who believe in it. But this raises yet another puzzling question about the belief in free will. People who explicitly deny free will often continue to hold themselves responsible for their actions and feel guilty for doing wrong. Have such people managed to accommodate the rest of their attitudes to their rejection of free will? Have they adjusted their notion of guilt and responsibility so that it really doesn’t depend on the existence of free will? Or is it that when they are in the thick of things, trying to decide what to do, trying to do the right thing, they just fall back into the belief that they do have free will after all?

Alzheimer's vaccine stopped plaque, not dementia

By Maria Cheng,

Posted: 2008-07-17 19:11:02
AP

LONDON (AP) - Some doctors have long suspected that if the plaque that builds up in the brains of patients with Alzheimer's disease could be removed, they could be saved. But a new vaccine that did just that suggests the theory is wrong.

British researchers gave 64 patients with moderate Alzheimer's disease an experimental vaccine designed to eliminate plaque from their brains. Some patients were followed for up to six years.

Autopsies on seven patients who died of Alzheimer's during the study showed that nearly all of the sticky beta-amyloid protein thought to be dangerous had been removed. But all patients still had severe dementia.

"It may be that these toxic plaques trigger the neurodegeneration, but don't have an ongoing role," said Clive Holmes of the University of Southampton, lead author, in a press statement. The study was published Friday in the medical journal, The Lancet.

The study was paid for by the Alzheimer's Research Trust, a British charity.

Alzheimer's disease is the most common cause of dementia and affects about 25 million people worldwide.

Other experts said that the study's findings pointed to a major gap in our understanding of the disease. Doctors have never been sure whether the brain plaques are the cause of Alzheimer's disease or just a side effect.

"We still don't have enough understanding of what we should target," said Dr. Bengt Winblad, director of the Alzheimer's Centre at Sweden's Karolinska Institute. Winblad was not connected to the study.

Aside from the plaque build-up, scientists also think that tangles of another brain protein called tau play a major role in Alzheimer's. Because those tangles form later than the plaque, some experts think they should be the focus instead.

"It may be harder to get a response from targeting plaque because that forms years before people actually have Alzheimer's," said Dr. Simon Lovestone, professor of Old Age Psychiatry at King's College in London. "By the time you do something, it may be too late."

Winblad said there was a better connection between brain tangles and Alzheimer's symptoms, but that no studies so far had looked at whether removing tangles might improve or even reverse Alzheimer's disease in patients.

Still, experts say that attacking toxic plaque in the brain shouldn't be abandoned just yet, since the formation of such plaques might be what sparks Alzheimer's disease in the first place.

"Removal of the initial motor for the disease might slow progression," wrote Peter H. St. George-Hyslop and John C. Morris of the University of Cambridge and the University of Toronto in an accompanying commentary in the Lancet.

Mechanism Behind Mind-body Connection Discovered

ScienceDaily (July 16, 2008)

Every cell contains a tiny clock called a telomere, which shortens each time the cell divides. Short telomeres are linked to a range of human diseases, including HIV, osteoporosis, heart disease and aging. Previous studies show that an enzyme within the cell, called telomerase, keeps immune cells young by preserving their telomere length and ability to continue dividing.

UCLA scientists found that the stress hormone cortisol suppresses immune cells' ability to activate their telomerase. This may explain why the cells of persons under chronic stress have shorter telomeres.

The study reveals how stress makes people more susceptible to illness. The findings also suggest a potential drug target for preventing damage to the immune systems of persons who are under long-term stress, such as caregivers to chronically ill family members, as well as astronauts, soldiers, air traffic controllers and people who drive long daily commutes.

Rita Effros, professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA, and a member of the Jonsson Cancer Center, Molecular Biology Institute and UCLA AIDS Institute, is available for interviews.

"When the body is under stress, it boosts production of cortisol to support a "fight or flight" response," explains Effros. "If the hormone remains elevated in the bloodstream for long periods of time, though, it wears down the immune system. We are testing therapeutic ways of enhancing telomerase levels to help the immune system ward off cortisol's effect. If we're successful, one day a pill may exist to strengthen the immune system's ability to weather chronic emotional stress."

The research was published in the May issue of the peer-reviewed journal Brain, Behavior and Immunity.

The study was supported by the National Institute of Aging, National Institute of Allergy and Infectious Disease, the Geron Corp. and TA Therapeutics, Ltd.

The Genetics of Cognitive Impairment in Schizophrenia

June 2008

by Philip D. Harvey, PhD

Dr. Harvey is Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.

Schizophrenia and other psychotic conditions have a substantial genetic component, although the patterns of heritability are clearly not consistent with standard patterns of inheritance. Heritability estimates for schizophrenia are fairly substantial, with considerable increases in risk for concordance across monozygotic as compared to dizygotic twin pairs. As a result, the study of genetics of schizophrenia and bipolar disorder has headed in the direction of attempting to identify heritable phenotypes for the illnesses. Since both of these conditions are clearly quite heterogeneous, this approach appears to have some intrinsic appeal. Thus, the search for heritable phenotypes has been ongoing for the last two to three decades.

There is an intrinsic relationship between cognitive impairments and vulnerability to schizophrenia. It has been known for decades that first-degree relatives of people with schizophrenia have cognitive impairments of the same type seen in people with schizophrenia.[1] These impairments are present even in individuals with no other evidence of behavioral abnormalities, but are often more severe in people who have additional features of psychopathology related to schizophrenia (such as schizotypal symptoms). Individuals with disorders related to schizophrenia, such as schizotypal personality disorder, also have cognitive impairments that are qualitatively similar to those seen in people with schizophrenia. These impairments are not related to global aspects of maladjustment, because they are more substantial than those seen in individuals with other severe personality disorders, such as borderline personality.[2]

Even more striking is the finding that cognitive impairments present in children whose parents have schizophrenia predicts increased risk for the illness. As reported by Cornblatt, et al.,[3] the more impaired the attentional performance of children of mothers with schizophrenia, the more likely that they would develop schizophrenia. Children with minimal attentional impairments have the smallest risk for developing schizophrenia themselves. Thus, cognitive impairments seem to be a marker of not only the presence of schizophrenia in the family, but of increased individual risk development of the illness.

Given the centrality of cognitive impairment in both the familial characteristics of schizophrenia and in risk transmission for the illness, it is no surprise that cognitive impairments have been given consideration as potential phenotypes for the illness. One recent, large-scale, NIH-funded study, the Consortium on the Genetics of Schizophrenia (COGS)[4] project, examined the heritable nature of cognitive impairments in families with members who had schizophrenia.

Cognitive performance tends to be heritable in general. This should not be a surprise as evidence has accrued for years that elements of cognitive functioning, namely intelligence, tend to be quite consistent in family members and have been shown to be heritable in studies of members of the same family who were reared apart. Further, many of the elements of cognitive functioning that are impaired in schizophrenia have been shown to be heritable in families with and without psychopathology.

The COGS study used several criteria to select specific elements of cognitive performance as potential endophenotypes. These included the following:
I. Association with illness
State independent:
(a) adequate test-retest stability
(b) adequate between-site reliability
(c) evidence that impairments in patients are not due to medications
(d) evidence that impairments are observed regardless of the illness state;
Heritability:
(a) in healthy populations
(b) in schizophrenia families;
II. A known neurobiological substrate relevant to schizophrenia
III. Practicality of task administration in a large multisite protocol.
After careful review of the literature, the COGS research team decided that the following cognitive ability areas met the above criteria:
• Attention and, in particular, vigilance
• Verbal learning and memory
• Working memory.
In addition, several subtests from a computerized cognitive assessment battery were examined, including face memory and affect recognition, spatial memory, spatial reasoning, and problem solving.

The review of the literature on these tests revealed very important findings.[5] For instance, across these different cognitive ability domains, heritability estimates for performance on most tests was in the range of h=0.50, with higher estimates in populations with more variance in scores, such as older adults. These data indicate that, in general, cognitive abilities share considerable variance across family members and the correlation within family members in terms of cognitive performance is much closer than many other traits.

All of these cognitive potential endophenotypes were tested in a preliminary study.[6] The study was based on 183 nuclear families ascertained by the presence of a schizophrenic member. Each family was required to have both parents available for assessment, the index case, and at least one unaffected full sibling. All of the cases in the study were tested with an assessment battery based on the cognitive domains described above.

As might be expected from a systematic, large-scale study, the estimates of heritability were slightly lower than the smaller studies that preceded it. The range of heritabilites was 0.24 to 0.55 for performance-based cognitive measures and lower for putative psychophysiological measures (0.10 for p50 suppression and 0.32 for prepulse inhibition). That said, these data still suggest substantial levels of genetic influence on various aspects of cognitive functioning. The conclusion from the first stage of COGS is that the classical cognitive impairments seen in schizophrenia manifest substantial heritability.

These findings are even more interesting because of the nature of the assessments performed. The tests with higher heritabilities were standard neuropsychological measures, not specialized neuroscience tests. As we described in a previous column, the NIH is very interested in the translation of experimental cognitive science procedures into repeatable measures suitable for use in clinical trials. It is not clear if the higher heritability of the standard measures is because of their standardization or because they measure content that is inherently more heritable. Later research will clearly be focused on identification of genetic variation in experimental procedures as well as clinical neuropsychological tests.
An even more clinically relevant point is related to the idea of treatment of cognitive impairments and the contributions of genetic variation to cognitive treatment response. With the advent of genome wide association studies, there will be attempts to identify specific genetic loci that are quantitatively linked to specific cognitive abilities. With more efforts to treat cognitive impairments and the promise of eventual successes in pharmacological and remediation interventions, identification of genetic predictors of treatment response to cognitively oriented treatments will be a goal of genomics research. As soon as genetic factors that predict cognitive impairments are detected, they can then be used to predict treatment response.

In conclusion, cognitive performance is a highly heritable trait. The most common cognitive impairments seen in schizophrenia manifest considerable heritability and clearly meet criteria for genetically mediated endophenotypes. These cognitive impairments are present across the schizophrenia spectrum and across the course of illness in people with schizophrenia. They also show evidence of being associated with increased risk for schizophrenia in people who are related to people with the illness. The detection of patterns of genetic variation that are associated with cognitive impairments may also hold promise for the prediction of treatment response, when treatments for cognitive impairment are developed and commonly available.

REFERENCES

1. Harvey PD, Walker E, Wielgus M. Psychological markers of vulnerability to schizophrenia. In: Maher BH, Maher WB (eds). Progress in Experimental Personality Research, Volume 14. New York: Academic Press, 1986:231–267.
2. Mitropoulou V, Harvey PD, Maldari M, et al. Neuropsychological performance in schizotypal personality disorder: evidence regarding diagnostic specificity. Biol Psychiat. 2002;52:1175–1182.
3. Cornblatt B, Obuchowski M, Roberts S, et al. Cognitive and behavioral precursors of schizophrenia. Dev Psychopathol. 1999;11:487–508.
4. Calkins ME, Dobie DJ, Cadenhead KS, et al. The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration. Schizophr Bull. 2007;33:33–48.
5. Gur RE, Calkins ME, Gur RC, et al. The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophr Bull. 2007;33:49–68.
6. Greenwood TA, Braff DL, Light GA, et al. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia Arch Gen Psychiatry. 2007;64(11):1242–1250.

Pramipexole and Compulsive Masturbation

September 2007

by Randy A. Sansone, MD; and Mark Ferlan, DO

Dr. Sansone is a Professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio. Dr. Ferlan is a resident in the Department of Internal Medicine at Kettering Medical Center in Kettering, Ohio.

Abstract

Objective: Exploration of a possible relationship between pramipexole and compulsive masturbation.
Methods: We present a case report.
Results: Given the temporal overlap between pramipexole prescription and its discontinuation, and the onset and cessation of the patient’s hypersexual behavior, there appears to be a strong likelihood of association.
Conclusions: Like other dopamine agonists, pramipexole may precipitate compulsive behaviors, including hypersexual behavior in the form of compulsive masturbation.

Key Words: dopamine agonists, hypersexual behavior, compulsive sexual behavior, masturbation, adverse effects

Introduction

Pramipexole is a non-ergot dopamine agonist that binds to D2 and D3 dopamine receptors in the striatum and substantia nigra. This drug is a full dopamine agonist (bromocriptine and pergolide are partial agonists) and is more selective for the D3 receptor than either bromocriptine or pergolide. Pramipexole has no significant effects on adrenergic or serotonergic receptor sites and is primarily prescribed for the treatment of Parkinson’s disease and restless legs syndrome.

In the empirical literature, there are a number of reports of compulsive behaviors in association with dopamine agonist therapy. For example, there are several case reports of dopamine agonist therapy and pathological gambling.[1-9] In one series of 388 patients, 4.4 percent developed pathological gambling.[2] In a sample of Italian patients, the prevalence of pathological gambling was 6.1 percent, compared with 0.25 percent among controls.[3]

In addition to pathological gambling, other compulsive behaviors have been reported with the use of dopamine agonists. For example, there are several case reports of patients compulsively using dopamine agonist drugs, a phenomenon that is identified as “dopamine dysregulation syndrome”[10] or “hedonistic homeostatic dysregulation.”[11] Pezzella and colleagues describe this behavior as “self-medication and addiction to dopaminergic drugs.”[11] Punding, a stereotypic behavior characterized by the repetitive handling and examination of mechanical objects, has also been reported in association with dopamine agonist therapy.[12,13] In one case, punding manifested as “computer addiction.”[13] There have also been case reports of compulsive eating with dopamine agonist therapy.[14]

Although infrequently reported, hypersexual behavior has also been described in patients on dopamine agonists. Weintraub and colleagues found that 2.6 percent of their patient series reported compulsive sexual behaviors while on dopamine agonist therapy.[7] In their discussion of findings, the authors never explicitly describe these behaviors. However, pramipexole was the most frequently implicated drug. In a retrospective review of medical records, Klos and colleagues described 15 cases of hypersexuality associated with dopamine agonist therapy.[15] These hypersexual behaviors included the compulsive use of pornography, extramarital affairs, and delusions of spouse infidelity. One-third of the patients were prescribed pramipexole.

While all dopamine agonists are generally associated with diverse compulsive behaviors, some investigators believe that pramipexole is more likely to be causative.[8,9] Some studies support this suspicion. For example, while the precise neurophysiology of this association remains unknown, rats treated chronically with a D2/D3 agonist developed compulsive checking of specific locations.[16] By being a full and selective D3 agonist, pramipexole may pose a heightened risk for the development of compulsive behaviors. These behaviors may be mediated through ventral-striatal over-stimulation, and manifest as novelty and reward-seeking.17 While compulsive behaviors associated with dopamine agonists may appear to have overtones of obsessive-compulsive disorder, comparative examination does not appear to support a relationship between the two.[18]

In the following case report, we describe a male patient who was treated with pramipexole for restless legs syndrome. While on treatment with dopamine agonist therapy, he developed relentless compulsive masturbation.

Case Report

Mr. T. was a 67-year-old white man with medical diagnoses of hypertension, complex-partial epilepsy, liver cancer (status-post resection), hemochromatosis, gastroesophageal reflux, sleep apnea, restless legs syndrome, and major depression. His medications were lisinopril 10mg daily, clonidine transdermal 0.2mg daily, amlodipine 10mg daily, oxcarbazepine 600mg twice per day, clopidogrel 75mg daily, allopurinol 100mg daily, aspirin daily, hydrochlorothiazide 25mg daily, ranitidine 75mg daily, pramipexole 0.5mg at bedtime, and escitalopram 10mg daily.

During an appointment, Mrs. T. voiced her concern about her husband’s hypersexuality. She stated that for the past 3 to 4 years, Mr. T. had experienced a very high libido and was masturbating approximately 6 to 8 times a day. Mrs. T. explained that he would also wake her up in the middle of the night to satisfy his needs. In addition, he would excuse himself from the dinner table at home, in restaurants, or at the homes of friends to masturbate. The patient acknowledged these behaviors but was unable to explain them. Upon careful inquiry, the patient affirmed that his symptoms began shortly after starting pramipexole for restless legs syndrome. A literature search indicated a possible relationship between compulsive behaviors and pramipexole, and the temporal association was convincing. The patient was advised to discontinue the pramipexole. Mr. T. and his wife returned for a follow-up encounter two weeks later and indicated that since the discontinuation of the pramipexole, there had been a marked decrease in his masturbatory behavior, which was no longer daily.

Conclusions

It appears that dopamine agonists may, in susceptible patients, result in various types of compulsive behaviors. We have previously discussed some possible neurophysiological substrates that may account for these unusual behaviors. However, a number of questions remain unanswered. For example, are there specific dopamine subreceptors that, when stimulated, are more likely to cause compulsive behaviors (e.g., D3 receptors)? Will the various dopamine agonists evidence differing rates of risk for compulsive behaviors based upon their dopamine receptor profiles? Are there any predisposing factors in the patient’s premorbid history that partially account for the specific type of compulsive behavior manifested? Only further investigation will clarify these intriguing issues. For the time being, however, it seems prudent to recommend that clinicians who see patients on dopamine agonists routinely inquire about the unusual side effect of compulsive behavior, including hypersexuality and masturbation. In addition, these drugs should be used very cautiously and with great discretion in sex offenders.

References
1. Voon V, Thomsen T, Miyasaki JM, et al. Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. Arch Neurol 2007;64:212–6.
2. Grosset KA, Macphee G, Pal G, et al. Problematic gambling on dopamine agonists: Not such a rarity. Mov Disord 2006;21:2206–8.
3. Avanzi M, Baratti M, Cabrini S, et al. Prevalence of pathological gambling in patients with Parkinson’s disease. Mov Disord 2006;21:2068-72.
4. Quickfall J, Suchowersky O. Pathological gambling associated with dopamine agonist use in restless legs syndrome. Parkinsonism Relat Disord Jan 29 2007 (Epub ahead of print).
5. Spengos K, Grips E, Karachalios G, et al. Reversible pathological gambling under treatment with pramipexole. Nervenarzt 2006;77:958–60.
6. Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:969-73.
7. Molina JA, Sainz-Artiga MJ, Fraile A, et al. Pathological gambling in Parkinson’s disease: A behavioral manifestation of pharmacologic treatment? Mov Disord 2000;15:869–72.
8. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurol 2003;61:422–3.
9. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377–81.
10. Evans AH, Lawrence AD, Potts J, et al. Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease. Neurol 2005;65:1570–4.
11. Pezzella FR, Colosimo C, Vanacore N, et al. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson’s disease. Mov Disord 2005;20:77–81.
12. Shapiro MA, Chang YL, Munson SK, et al. Hypersexuality and paraphilia induced by selegiline in Parkinson’s disease: Report of 2 cases. Parkinsonism Relat Disord 2006;12:392–5.
13. Fasano A, Elia AE, Soleti F, et al. Punding and computer addiction in Parkinson’s disease. Mov Disord 2006;21:1217–8.
14. Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use. Mov Disord 2006;21:524–9.
15. Klos KJ, Bower JH, Josephs KA, et al. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord 2005;11:381–6.
16. Dvorkin A, Perreault ML, Szechtman H. Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder. Behav Brain Res 2006;169:303–11.
17. Voon V. Repetition, repetition, and repetition: Compulsive and punding behaviors in Parkinson’s disease. Mov Disord 2004;19:367–70.
18. Harbishettar V, Pal PK, Janardhan Reddy YC, Thennarasu K. Is there a relationship between Parkinson’s disease and obsessive-compulsive disorder? Parkinsonism Relat Disord 2005;11:85–8.

A Quandary on Blood Drops in the Brain

July 1, 2008

By GINA KOLATA

On Dec. 18, 2005, Ariel Sharon, then Israel’s prime minister, was taken to a Jerusalem hospital with symptoms of a stroke, unable to speak or understand what others were saying.

Over the next 36 hours, his doctors found themselves in a quandary. Mr. Sharon had two conditions that might lead to a new and devastating stroke. And treating one condition could make the other one worse.

First, he was susceptible to blood clots that could be swept from his heart to his brain, causing a major stroke. Anticlotting drugs might protect him.

But his brain scans showed microbleeds, pinpoint drops of blood that leaked from blood vessels in the brain. The fear was that an anticlotting drug might turn a new microbleed into a life-threatening, incapacitating hemorrhagic stroke.

Until recently, microbleeds were all but unknown. Now, with improved scans, they are turning up constantly; one recent study found them in the brains of 1 out of 5 people age 60 and older. And they are leading to a classic conundrum of modern medicine: Just because something turns up on an M.R.I. scan, is it significant? And if it may or may not be significant, what to do about it?

With strokes, the stakes can be life or death. Or, as happened with Mr. Sharon, somewhere in between.

His doctors decided that blood clots were his biggest risk, so they gave him heparin, an anticlotting drug. Two weeks later, he had a major bleeding stroke. Mr. Sharon remains in a persistent vegetative state to this day, awake but not aware, unable to respond, unable to communicate, able to breathe but unable to think.

It can never be proved that an anticlotting drug caused a stroke in an individual case. But it is known that when patients taking such drugs have hemorrhagic strokes, the strokes are much worse, with double the normal fatality rate.

The microbleed story began when neurologists, using newer magnetic resonance imaging techniques, began seeing them in patients who had symptoms of a stroke or, in some cases, signs of an electrical disturbance in the brain. A patient might have numbness or tingling in part of the face that then migrated to a hand and went away.

On scans, neurologists would see a few drops of blood in the patient’s brain, smaller than the tip of a pen. Or they would see tiny drops in routine scans in patients with dementia, or in patients who had had a serious stroke.

Now, neurologists are seeing microbleeds even in some patients who seemed free of neurological problems — people who were given a scan because of a blow to the head, or memory problems, or headaches.

“They clearly are being picked up more often,” said Dr. Steven M. Greenberg, a neurologist at Massachusetts General Hospital who studies microbleeds. “That’s one reason why we all get nervous about getting scans on people who don’t necessarily need them. You have to be able to deal with the consequences.”

With microbleeds, that can be difficult. At a loss as to what to do, doctors call specialists like Dr. Greenberg, asking for advice.

“I get a lot of calls I didn’t used to get,” Dr. Greenberg says. “And they mostly involve questions I can’t answer.”

When the bleeds are on the outer surface of the brain, they often seem associated with a condition in which blood vessels are damaged by the protein amyloid. This is the same protein that piles up in the brains of patients with Alzheimer’s disease; microbleeds from amyloid can be associated with dementia.

Other times, the microbleeds are deep in the brain and may be linked to high blood pressure, a leading cause of strokes. But it is not clear whether microbleeds, especially those deep in the brain, are of any real consequence. Until recently, no one asked how often they turn up in healthy people, nor whether they predict strokes or other serious brain damage.

That changed when Dr. Monique M. B. Breteler, a neuroepidemiologist at Erasmus University in Rotterdam, the Netherlands, decided to look for microbleeds among residents of her city.

“If there were more than we knew of in the general population, that might — and I want to stress might — have important consequences,” Dr. Breteler said. “That is why we started to look for them.”

For more than a decade, Dr. Breteler and her colleagues have followed a group of Rotterdam residents age 45 and older. The goal is to do repeated brain scans on 8,000 people; so far they have scanned nearly 4,000 and are analyzing those data.

“What we found came as a big surprise,” Dr. Breteler said. Previous estimates were that 5 to 7 percent of healthy older people had microbleeds. The Rotterdam study found them in more than 20 percent. And the older the person, the more likely the microbleeds. They were present in 18 percent of 60-year-olds and nearly 40 percent of those over 80.

“We now know that these changes are there and that they are frequent,” Dr. Breteler said. “But we don’t know yet what their clinical impact is, what their prognosis is.”

Still, she and other experts say, there is reason for concern.

Dr. Greenberg has found that if the microbleed is near the brain’s surface, where it might be associated with amyloid, then anticlotting drugs are more likely to precipitate a brain hemorrhage. But sometimes a patient is at such grave risk of a stroke that the balance tips in favor of an anticlotting drug anyway, he says.

If the microbleed is deep in the brain, it is not clear whether anticlotting drugs are dangerous.

Even patients who come in with symptoms that might be caused by microbleeds can pose a problem.

Edward Reynolds, 74, of Beverly, Mass., was referred to Dr. Greenberg after an episode in which part of his face went numb, then his hand, and then the numbness faded and he felt fine. He had an abnormal heart rhythm, which meant that anticlotting drugs might help him avoid a stroke caused by blood clots in his heart.

But an M.R.I. scan found microbleeds on the surface of his brain, which meant they were probably associated with amyloid. And that meant powerful anticlotting drugs like warfarin could be dangerous for him.

“Here’s a guy on a knife edge of being anticoagulated or not,” Dr. Greenberg said. “There really are major risks on both sides. You can see bad things happening either way.”

Dr. Greenberg decided in the end that the risk from drug like warfarin was not justified. He advised Mr. Reynolds to take baby aspirin, with its mild anticlotting properties.

“It’s only one decision, but it’s a big one,” Dr. Greenberg said.

So far, Mr. Reynolds has done well, with no recurrence of the numbness and no signs of a stroke.

“I’m feeling pretty good,” he said.