Posts tagged OCD
Articles and news from the latest research reports.
Evidence Supports Deep Brain Stimulation for Obsessive-Compulsive Disorder
Available research evidence supports the use of deep brain stimulation (DBS) for patients with obsessive-compulsive disorder (OCD) who don’t respond to other treatments, concludes a review in the October issue of Neurosurgery, official journal of the Congress of Neurological Surgeons (CNS). The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
Based on evidence, two specific bilateral DBS techniques are recommended for treatment of carefully selected patients with OCD, according to a new clinical practice guideline endorsed by the CNS and the American Association of Neurological Surgeons. While calling for further research in key areas, Dr. Clement Hamani of Toronto Western Hospital and coauthors emphasize that patients with OCD symptoms that don’t respond to other treatments should continue to have access to DBS.
Deep Brain Stimulation for OCD—What’s the Evidence?
Dr. Hamani led a multispecialty expert group in performing a systematic review of research on the effectiveness of DBS for OCD. Deep brain stimulation—placement of electrodes in specific areas of the brain, followed by electrical stimulation of those areas—has become an important treatment for patients with Parkinson’s disease and other movement disorders.
Although many patients with OCD respond well to medications and/or psychotherapy, 40 to 60 percent continue to experience symptoms despite treatment. Over the past decade, a growing number of reports have suggested that DBS may be an effective alternative in these “medically refractory” cases.
Dr. Hamani and colleagues were tasked with analyzing the supporting evidence and developing an initial clinical practice guideline for the use of DBS for patients with OCD. The review and guideline development process was sponsored by the American Society of Stereotactic and Functional Neurosurgery and the CNS. Out of more than 350 papers, the reviewers identified seven high-quality studies evaluating DBS for OCD.
Based on that evidence, they conclude that bilateral stimulation (on both sides of the brain) of two brain “targets”—areas called the subthalamic nucleus and the nucleus accumbens—can be regarded as effective treatments for OCD. In controlled clinical trials, both techniques improved OCD symptoms by around 30 percent on a standard rating scale.
While Research Proceeds, well-selected treatment-resistant severe OCD Patients Should Have Access to DBS
That evidence forms the basis for a clinical guideline stating that bilateral DBS is a “reasonable therapeutic option” for patients with severe OCD that does not respond to other treatments. The guideline also notes that there is “insufficient evidence” supporting the use of any type of unilateral DBS target (one side of the brain) for OCD.
The review highlights the difficulties of studying the effectiveness of DBS for OCD—because most patients respond to medical treatment, studies of this highly specialized treatment typically include only small numbers of patients. Dr. Hamani and coauthors identify some priorities for future research: particularly to identify the most effective brain targets and the subgroups of patients most likely to benefit.
Despite the limited evidence base, DBS therapy for OCD has been approved by the Food and Drug Administration under a humanitarian device exemption. Dr. Hamani and coauthors note that various safeguards are in place to ensure appropriate use, and prevent overuse, of DBS for OCD.
While research continues, they believe that functional neurosurgeons should continue to work with other specialists to ensure that patients with severe, medically refractory OCD continue to have access to potentially beneficial DBS therapy.
(Source: wolterskluwerhealth.com)
Creatures of habit: disorders of compulsivity share common pattern and brain structure
In a study published in the journal Molecular Psychiatry and primarily funded by the Wellcome Trust, researchers show that people who are affected by disorders of compulsivity have lower grey matter volumes (in other words, fewer nerve cells) in the brain regions involved in keeping track of goals and rewards.
In our daily lives, we make decisions based either on habit or aimed at achieving a specific goal. For example, when driving home from work, we tend to follow habitual choices – our ‘autopilot’ mode – as we know the route well; however, if we move to a nearby street, we will initially follow a ‘goal-directed’ choice to find our way home – unless we slip into autopilot and revert to driving back to our old home. However, we cannot always control the decision-making process and make repeat choices even when we know they are bad for us – in many cases this will be relatively benign, such as being tempted by a cake whilst slimming, but extreme cases it can lead to disorders of compulsivity.
In order to understand what happens when our decision-making processes malfunction, a team of researchers led by the Department of Psychiatry at the University of Cambridge compared almost 150 individuals with disorders including methamphetamine dependence, obesity with binge eating and obsessive compulsive disorder, comparing them with healthy volunteers of the same age and gender.
Study participants first took part in a computerised task to test their ability to make choices aimed a receiving a reward over and above making compulsive choices. In a second study, the researchers compared brain scans taken using magnetic resonance imaging (MRI) in healthy individuals and a subset of obese individuals with or without binge eating disorder (a subtype of obesity in which the person binge eats large amounts of food rapidly).
The researchers demonstrated that all of the disorders were connected by a shift away from goal-directed behaviours towards automatic habitual choices. The MRI scans showed that obese subjects with binge eating disorder have lower grey matter volumes – a measure of the number of neurons – in the orbitofrontal cortex and striatum of the brain compared to those who do not binge eat; these brain regions are involved in keeping track of goals and rewards. Even in healthy volunteers, lower grey matter volumes were associated with a shift towards more habitual choices.
Dr Valerie Voon, principal investigator of the study, says: “Seemingly diverse choices – drug taking, eating quickly despite weight gain, and compulsive cleaning or checking – have an underlying common thread: rather that a person making a choice based on what they think will happen, their choice is automatic or habitual.
“Compulsive disorders can have a profoundly disabling effect of individuals. Now that we know what is going wrong with their decision making, we can look at developing treatments, for example using psychotherapy focused on forward planning or interventions such as medication which target the shift towards habitual choices.”
Dealing with negative thinking
Is it ‘normal’ to think about pushing someone in front of a train or to fantasise about driving your car into oncoming traffic?
The answer is yes says Victoria University of Wellington researcher Dr Kirsty Fraser who graduated with a PhD in Psychology last week.
“It’s common for people to occasionally have those kind of negative thoughts, but then most of us realise it’s a bit ridiculous and move on,” says Dr Fraser.
For some people, however, those negative thoughts may persist, leading to anxiety and depression.
“It’s how we react to, and process, those negative intrusions that can make the difference between brushing them off and developing obsessive compulsive symptoms, such as severe anxiety and depression.
“For example, some people could be so anxious about those kind of thoughts that they go out of their way to avoid catching a train or driving.”
Dr Fraser’s thesis focused on two ways of processing negative thoughts—inflated responsibility (IR) and thought action fusion (TAF), and the way each relates to mental disorders.
“TAF is when you believe that thinking about an action is equivalent to actually carrying out that action, while IR is one of the driving forces behind obsessive compulsive disorder (OCD), where you believe you can prevent something happening by what you do or don’t do.
“My research demonstrates that both types of beliefs play important roles in the development and maintenance of psychological symptoms related to anxiety, depression and OCD.”
Dr Fraser’s research also looked at how childhood experiences, critical events in one’s life and religious beliefs could impact upon thoughts.
She surveyed more than 1,000 people and divided them into four groups: undergraduate students, so called ‘normal’ citizens, patients from an anxiety clinic and those with religious and atheist beliefs.
“Overall,” she says, “my research provided strong support for existing theories about the role of cognitive processes in the maintenance of symptoms and distress.”
When Kirsty arrived at Victoria in 2002, she began studying human resources. She took a psychology paper out of interest and “never left”.
“The lecturer was John McDowall, who introduced me to how interesting the subject is. He ended up being my supervisor for my PhD.”
For the past three years, Kirsty has combined doctoral study with teaching a second year psychology paper at Victoria, marking for another tertiary institution and being a full-time mother.
“Now I’m starting to think about other challenges, including possible research positions. I’d like to publish my PhD research and continue lecturing.”
Researchers Identify Genetic Marker Linked to OCD
A group of researchers led by Johns Hopkins scientists say they have identified a genetic marker that may be associated with the development of obsessive-compulsive disorder (OCD), whose causes and mechanisms are among the least understood among mental illnesses.
The results of the research are published online May 13 by the journal Molecular Psychiatry.
“If this finding is confirmed, it could be useful,” says study leader Gerald Nestadt, M.D., M.P.H., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of Johns Hopkins’ Obsessive-Compulsive Disorder Program. “We might ultimately be able to identify new drugs that could help people with this often disabling disorder, one for which current medications work only 60 to 70 percent of the time.”
Nestadt and his team conducted what is known as a genome-wide association study, scanning the genomes of more than 1,400 people with OCD and more than 1,000 close relatives of people with the mental disorder. A significant association was identified in OCD patients near a gene called protein tyrosine phosphokinase (PTPRD).
OCD is a condition marked by thoughts and images that chronically intrude in the mind and by repetitive behaviors aimed at reducing the associated anxiety. Some of the least disabling forms of the disorder can add an extra hour to the day’s routine, causing distress and interfering with daily life. Some people are so disabled that they can’t leave their homes.
Experts say OCD affects an estimated 1 to 2 percent of the U.S. population, and the World Health Organization has called it one of the more disabling medical conditions worldwide. Antidepressants known as SSRIs work for some people, but not everyone; the same is true of behavioral therapy.
Nestadt says the genome-wide association study findings of a PTRPD-OCD link add to evidence that the genetic region they identified is important. The gene has already been shown in animals to be possibly involved in learning and memory, traits influenced by OCD in humans. Moreover, some cases of attention-deficit hyperactivity disorder (ADHD) have been associated with the gene, and OCD and ADHD have some symptoms in common. He says the gene also works with another gene family, SLITRK, which has also been associated with OCD in animals.
“OCD research has lagged behind other psychiatric disorders in terms of genetics,” Nestadt says. “We hope this interesting finding brings us closer to making better sense of it — and helps us find ways to treat it.”
(Image credit: Jennifer Soo)
Deep Brain Stimulation for Obsessive-Compulsive Disorder Releases Dopamine in the Brain
Some have characterized dopamine as the elixir of pleasure because so many rewarding stimuli – food, drugs, sex, exercise – trigger its release in the brain. However, more than a decade of research indicates that when drug use becomes compulsive, the related dopamine release becomes deficient in the striatum, a brain region that is involved in reward and behavioral control.
New research now published in Biological Psychiatry from the Academic Medical Center in Amsterdam suggests that dopamine release is increased in obsessive-compulsive disorder (OCD) and may be normalized by the therapeutic application of deep brain stimulation (DBS).
To conduct the study, the authors recruited clinically stable outpatients with OCD who had been receiving DBS therapy for greater than one year. The patients then underwent three single photon emission computerized tomography (SPECT) imaging scans to measure dopamine availability in the brain.
In order to evaluate the effect of DBS, these scans were conducted during chronic DBS, 8 days after DBS had been discontinued, and then after DBS was resumed. Designing the study in this manner also allowed the researchers to measure the relationship between dopamine availability and symptoms.
During the chronic DBS phase, patients showed increased striatal dopamine release compared to healthy volunteers. When DBS was turned off, patients showed worsening of symptoms and reduced dopamine release, which was reversed within one hour by the resumption of DBS. This observation suggests that enhancing striatal dopamine signaling may have some therapeutic effects for treatment-resistant symptoms of OCD.
First author Dr. Martijn Figee further explained, “DBS of the nucleus accumbens decreased central dopamine D2 receptor binding potential indicative of DBS-induced dopamine release. As dopamine is important for reward-motivated behaviors, these changes may explain why DBS is able to restore healthy behavior in patients suffering from OCD, but potentially other disorders involving compulsive behaviors, such as eating disorders or addiction.”
The patients selected for participation in this study had previously been non-responsive to traditional pharmacological therapies that target the dopamine system. These findings suggest that the effectiveness of DBS for OCD may be related to its ability to compensate for an underlying dysfunction of the dopaminergic system. The DBS-related stimulatory increase in dopamine appears to aid patients by improving their control over obsessive-compulsive behaviors.
“It is exciting to see circuit-based DBS linked to molecular brain imaging. This is a strategy that may shed light into the mechanisms through which this treatment can produce positive clinical change,” said Dr. John Krystal, Editor of Biological Psychiatry.
He also noted, “It would be interesting to know whether the patients who do respond to dopamine-blocking antipsychotic medications commonly prescribed for OCD symptoms have a different underlying disturbance in dopamine function than the patients enrolled in this study who failed to respond to these medications. Nonetheless, the findings of this study raise the possibility that some deficits in dopamine signaling in the brain that might be targeted by novel treatments may prevent adequate response to conventional treatments for this disorder.”
(Image: © Thom Graves)
Genetic analysis reveals insights into the genetic architecture of OCD, Tourette syndrome
An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS), providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders. Their report is being published in the October issue of the open-access journal PLOS Genetics.
"Both TS and OCD appear to have a genetic architecture of many different genes – perhaps hundreds in each person – acting in concert to cause disease,” says Jeremiah Scharf, MD, PhD, of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology, senior corresponding author of the report. “By directly comparing and contrasting both disorders, we found that OCD heritability appears to be concentrated in particular chromosomes – particularly chromosome 15 – while TS heritability is spread across many different chromosomes.”
An anxiety disorder characterized by obsessions and compulsions that disrupt the lives of patients, OCD is the fourth most common psychiatric illness. TS is a chronic disorder characterized by motor and vocal tics that usually begins in childhood and is often accompanied by conditions like OCD or attention-deficit hyperactivity disorder. Both conditions have been considered to be heritable, since they are known to often recur in close relatives of affected individuals, but identifying specific genes that confer risk has been challenging.
Two reports published last year in the journal Molecular Psychiatry (1, 2), with leadership from Scharf and several co-authors of the current study, described genome-wide association studies (GWAS) of thousands of affected individuals and controls. While those studies identified several gene variants that appeared to increase the risk of each disorder, none of the associations were strong enough to meet the strict standards of genome-wide significance. Since the GWAS approach is designed to identify relatively common gene variants and it has been proposed that OCD and TS might be influenced by a number of rare variants, the research team adopted a different method. Called genome-wide complex trait analysis (GCTA), the approach allows simultaneous comparision of genetic variation across the entire genome, rather than the GWAS method of testing sites one at a time, as well as estimating the proportion of disease heritability caused by rare and common variants.
"Trying to find a single causative gene for diseases with a complex genetic background is like looking for the proverbial needle in a haystack,” says Lea Davis, PhD, of the section of Genetic Medicine at the University of Chicago, co-corresponding author of the PLOS Genetics report. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to TS or OCD at once, we’re actually testing the whole haystack and asking where we’re more likely to find the needles.”
Using GCTA, the researchers analyzed the same genetic datasets screened in the Molecular Psychiatry reports – almost 1,500 individuals affected with OCD compared with more than 5,500 controls, and nearly TS 1,500 patients compared with more than 5,200 controls. To minimize variations that might result from slight difference in experimental techniques, all genotyping was done by collaborators at the Broad Institute of Harvard and MIT, who generated the data at the same time using the same equipment. Davis was able to analyze the resulting data on a chromosome-by-chromosome basis, along with the frequency of the identified variants and the function of variants associated with each condition.
The results found that the degree of heritability for both disorders captured by GWAS variants is actually quite close to what previously was predicted based on studies of families impacted by the disorders. “This is a crucial point for genetic researchers, as there has been a lot of controversy in human genetics about what is called ‘missing heritability’,” explains Scharf. “For many diseases, definitive genome-wide significant variants account for only a minute fraction of overall heritability, raising questions about the validity of the approach. Our findings demonstrate that the vast majority of genetic susceptibility to TS and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for TS and OCD than for any other complex trait studied to date.”
Nancy Cox, PhD, section chief of Genetic Medicine at the University of Chicago and co-senior author of the PLOS Genetics report, adds, “Despite the fact that we confirm there is shared genetic liability between these two disorders, we also show there are notable differences in the types of genetic variants that contribute to risk. TS appears to derive about 20 percent of genetic susceptibility from rare variants, while OCD appears to derive all of its susceptibility from variants that are quite common, which is something that has not been seen before.”
In terms of the potential impact of the risk-associated variants, about half the risk for both disorders appears to be accounted for by variants already known to influence the expression of genes in the brain. Further investigation of those findings could lead to identification of the affected genes and how the expression changes contribute to the development of TS and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could identify the biologic pathways disrupted in the disorder, potentially leading to new therapeutic approaches.
(Source: medicalxpress.com)
Power of precision medicine in successful treatment of patient with disabling OCD
A multidisciplinary team led by a geneticist and psychiatrist from Cold Spring Harbor Laboratory’s (CSHL) Stanley Institute for Cognitive Genomics today publish a paper providing a glimpse of both the tremendous power and the current limitations of what is sometimes called “precision medicine.”
Precision medicine is an approach to diagnosis and treatment that tailors therapeutic care to individuals in a highly specific manner, and which brings to bear powerful new technologies that have not yet made it into the mainstream of clinical medicine, in part because they remain unproven.
Gholson J. Lyon, M.D., Ph.D., a CSHL researcher in molecular genetics and also a practicing psychiatrist, and collaborators at the University of Utah, the Utah Foundation for Biomedical Research (UFBR) and the companies Omicia, Inc. and AssureRx, report on their recruitment and treatment of a single patient with severe psychiatric illness. The man, identified as a 37-year-old U.S. military veteran, suffered from a form of obsessive-compulsive disorder (OCD) that rendered him completely disabled – profoundly compulsive and anxious, occasionally paranoid, and unable to hold a job or form meaningful relationships.
Over the past three years, the team successfully treated the man with an experimental form of electrical brain stimulation, called deep-brain stimulation (DBS). To date, DBS has been used most frequently to lessen symptoms in people with advanced Parkinson’s disease and also on an experimental basis to help lift otherwise untreatable, severe depression. Worldwide, only around 100 other people with OCD have been reported to have received DBS treatment on a trial basis. This was the first such instance, however, in which an individual with such severe mental illness, being treated with DBS, also consented to and received whole-genome sequencing, and rigorous post-sequencing analysis of the results, accompanied by genetic counseling.
Integrating the results
Each phase of the study generated significant data; but never had such data been integrated in the context of a single clinical psychiatric case. The results, which appear online today in the journal PeerJ, show that the patient was greatly helped by DBS. Over the treatment period, symptoms associated with OCD diminished to the point that the individual was able to “regain a quality of life that he had not previously experienced in over 15 years,” Dr. Lyon and colleagues report. As the electrical stimulation of his brain via DBS was optimized over time (this involved gradually increasing the voltage used in electrical stimulation), he was able to participate in regular exercise, work as a volunteer, and eventually meet someone and get married.
The researchers noted that several times during the treatment, when power from the battery that drives the DBS signals was either drained or not activated by the patient, symptoms of severe OCD returned over the course of 12-24 hours and rapidly became debilitating. This was both a powerful lesson to the patient to keep the device charged (the battery is rechargeable) and vivid evidence to the scientists regarding the device’s role in producing the patient’s observed symptomatic improvements.
Whole-genome sequencing, meantime, revealed that the patient carries at least three gene variants, or alleles, that have been associated in other studies with neuropsychiatric illness. These variants were in genes that encode proteins called BDNF, MTHFR and ChAT. The BDNF gene variant is of particular interest. Its protein is a prime growth factor essential in the early development and subsequent healthy function of the brain and nervous system. The other two variants have also been associated in past studies with possibly increasing the risks of mental illness.
Other gene variants were found that have implications for the way the patient is either able or unable to metabolize particular kinds of drugs. These and literally thousands of other bits of personal genomic information had no immediate impact on his treatment or prognosis, but were archived by Dr. Lyon’s team in the hope that at some later date they might be useful. One of the gene variants did prompt a referral for an eye exam, which revealed bilateral cataracts and poor night vision in this person, which the investigators are currently following up.
“Although we believe in archiving and managing all genetic results and not just a small subset of presently-known ‘risk genes,’ we did analyze the 57 genes in our subject’s genome that are currently recommended for ‘return of results’ to patients by the American College of Medical Genetics,” Dr. Lyon and the team notes.
“I met with this individual to go over the results with him” Dr. Lyon adds, “along with adding some of the findings into his paper-based medical record. We also contacted physicians and other officials at the US Veterans Administration office to offer to incorporate these data into the VA electronic medical record for this patient. We were told, however, that there is no current capacity at the VA to incorporate any genomic variant data.”
The inability even to enter the data in existing electronic health record databases points to the practical problems that remain in using comprehensive data sets to help evaluate and treat patients in a clinical context.
The team, however, believes its results demonstrate that “one can learn a substantial amount from detailed study of particular individuals,” and argues that “we are entering an era of precision medicine in which we can learn from and collect substantial data on informative individual cases.” They further note: “The genomic data we gathered would have been more helpful if obtained much earlier in the patient’s medical course, as it could have provided guidance on which medications to avoid or to provide in increased doses.”
Video: The animation describes the paths of traveling performed by an OCD patient who is about to leave his apartment (left) and by a co-morbid OCD and schizophrenia patient performing the same behavior (right). Black circles indicate the number of acts performed in each location. As shown, the COD patient is mostly stationary, while the schizo-OCD patient travels all over the apartment.
The Difference Between Obsession and Delusion
TAU researchers use a zoological method to classify symptoms of OCD and schizophrenia in humans
Because animals can’t talk, researchers need to study their behavior patterns to make sense of their activities. Now researchers at Tel Aviv University are using these zoological methods to study people with serious mental disorders.
Prof. David Eilam of TAU’s Zoology Department at The George S. Wise Faculty of Life Sciences recorded patients with obsessive-compulsive disorder and “schizo-OCD” — which combines symptoms of schizophrenia and OCD — as they performed basic tasks. By analyzing the patients’ movements, they were able to identify similarities and differences between two frequently confused disorders.
Published in the journal CNS Spectrums, the research represents a step toward resolving a longstanding question about the nature of schizo-OCD: Is it a combination of OCD and schizophrenia, or a variation of just one of the disorders?
The researchers concluded that schizo-OCD is a combination of the two disorders. They noted that the behavioral differences identified in the study could be used to help diagnose patients with OCD and other obsessive-compulsive disorders, including schizo-OCD.
The taxonomy of mental disorders
"I realized my methodology for studying rat models could be directly applied to work with humans with mental disorders," Prof. Eilam said. "Behavior is the ultimate output of the nervous system, and my team and I are experts in the fine-grained analysis of behavior, be it of humans or of other animals."
The main features of OCD are, of course, obsessions and compulsions. Obsessions are recurring and persistent thoughts, impulses, or images that are experienced as intrusive and unwanted and cause marked distress or anxiety. In contrast, compulsions are repetitive motor behaviors, such as counting, that occur in response to obsessions and are performed according to strictly applied rules. Schizophrenia is marked by delusions, hallucinations, disorganized speech, abnormal motor behavior, and diminished emotional expression, among other symptoms.
Eilam and graduate student Anat Gershoni of the Zoology Department and Prof. Haggai Hermesh of TAU’s Sackler Faculty of Medicine set out with Dr. Naomi Fineberg of the Queen Elizabeth II Hospital in England to resolve the controversy. To this end, they recorded and compared videos of diagnosed OCD and schizo-OCD patients performing 10 different mundane tasks, like leaving home, making tea, or cleaning a table. The patients met the criteria of the widely used Diagnostic and Statistical Manual of Mental Disorders.
A matter of space
The researchers found that both OCD and schizo-OCD patients exhibited OCD-like behavior in performing the tasks, excessively repeating and adding actions. But schizo-OCD patients additionally acted like schizophrenics.
For a typical OCD patient in the study, the task of leaving home involved standing in one place and repeatedly checking the contents of his pockets before finally taking his keys and cell phone and going to the door. In contrast, a typical schizo-OCD patient traveled around the apartment — switching the lights in the bathroom on and off, then taking his keys and phone to the door, going to scan the bedroom, then taking his keys and phone to the door, going to empty the ashtray, then taking his keys and phone to the door and so on. A typical healthy person would simply pick up his keys and phone and walk out.
Overall, the researchers found that the level of obsessive-compulsive behavior was the same in OCD and schizo-OCD patients. This suggests that both types of patients had the difficulty shifting attention from one task to another that helps define OCD. The schizo-OCD patients, though, did more divergent activity over a larger area than did OCD patients. This suggests that the schizo-OCD patients were continuously shifting attention, which happens in schizophrenia but not OCD.
"While the obsessive compulsive is obsessed with one idea; the schizophrenic’s mind is drifting," said Eilam. "We found that this is reflected in their paths of locomotion. So instead of tracking the thoughts of the patients, we can simply trace their paths of locomotion."
Eilam plans to conduct research comparing repetitive behavior in OCD and autism patients.
Brain circuit links obsessive-compulsive behavior and obesity
Findings may have implications for treating compulsive behavior associated with psychiatric disease and eating disorders
What started as an experiment to probe brain circuits involved in compulsive behavior has revealed a surprising connection with obesity.
The University of Iowa-led researchers bred mice missing a gene known to cause obesity, and suspected to also be involved in compulsive behavior, with a genetic mouse model of compulsive grooming. The unexpected result was offspring that were neither compulsive groomers nor obese.
The study, published the week of June 10 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), suggests that the brain circuits that control obsessive-compulsive behavior are intertwined with circuits that control food intake and body weight. The findings have implications for treating compulsive behavior, which is associated with many forms of psychiatric disease, including obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.
UI neuro-psychiatrists Michael Lutter, M.D., Ph.D. and Andrew Pieper, M.D., Ph.D. led the study. The team also included researchers from Stanford University School of Medicine, University of Texas Southwestern Medical Center, Beth Israel Deaconess Medical Center, and Harvard Medical School.
Lutter, an assistant professor of psychiatry, and Pieper, an associate professor of psychiatry and neurology at the UI Carver College of Medicine, both recently arrived at the UI and use mouse models in their laboratories to study human disorders and conditions.
Pieper is interested in compulsive behavior. His mouse model of compulsivity lacks a brain protein called SAPAP3. These mice groom themselves excessively to the point of lesioning their skin, and their compulsive behavior can be effectively treated by fluoxetine, a drug that is commonly used to treat OCD in people.
Lutter works with a mouse that genetically mimics an inherited form of human obesity. This mouse lacks a brain protein known a MC4R. Mutations in the MC4R gene are the most common single-gene cause of morbid obesity and over-eating in people.
“I study MC4R signaling pathways and their involvement in the development of obesity,” Lutter explains. “I’m also interested in how these same molecules affect mood and anxiety and reward, because it’s known that there is a connection between depression and anxiety and development of obesity.”
An old study hinted that in addition to its role in food intake and obesity, MC4R might also play a role in compulsive behavior, which got Lutter and Pieper thinking of ways to test the possible interaction.
"We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different pathway (SAPAP3) caused compulsive grooming," Lutter says. "So, we decided to breed the two mice together to see if it would have an effect on compulsive grooming."
The experiment proved their original hypothesis—knocking out the MC4R protein in the OCD mouse normalized grooming behavior in the animals. In addition, chemically blocking MC4R in the OCD mice also eliminated compulsive grooming. The rescued behavior is mirrored by normalization of a particular pattern of brain cell communication linked to compulsive behavior.
However, the breeding experiment revealed another totally unexpected result. Loss of the SAPAP3 protein from the mice that were obese due to lack of MC4R produced mice of normal weight.
"We had this other, completely shocking finding—we completely rescued body weight and food intake in the double null mouse," Lutter says. "So, not only were we affecting the brain regions involved in grooming and behavior, but we also affected the brain regions involved in food intake and body weight."
Although obesity and obsessive-compulsive behavior may seem unrelated, Lutter suggests that the connection may be rooted in the evolutionary need to eat safe, clean food in times of a food abundance, and to lessen this drive when food is scarce.
"Food safety has been an issue through the entire course of human evolution—refrigeration is a relatively recent invention," he says. "Obsessive behavior, or fear of contamination, may be an evolutionary protection against eating rotten food."
Oils and fats have lots of calories and nutrients but they also spoil much more easily than less nutrient- and calorie-dense foods like potatoes, onions, or apples.
"I think this circuit that we have uncovered is probably involved in determining whether or not people should eat calorically dense foods," he says.
Lutter suggests that slight perturbations in this system might lead, on one hand, to disorders that link anxiety and obsessive behavior to limited food selection or intake, such as anorexia nervosa, Tourette syndrome, or OCD, and on the other hand, to obesity, where people over-consume high-fat foods and may have decreased obsessive behavior and anxiety.
“The next step will be to determine how these two pathways communicate with one another, in hopes of identifying new ways to develop drugs to treat either of these disorders,” says Pieper.
(Source: now.uiowa.edu)
Mice Give New Clues to Origins of OCD
Columbia Psychiatry researchers have identified what they think may be a mechanism underlying the development of compulsive behaviors. The finding suggests possible approaches to treating or preventing certain characteristics of OCD.
OCD consists of obsessions, which are recurrent intrusive thoughts, and compulsions, which are repetitive behaviors that patients perform to reduce the severe anxiety associated with the obsessions. The disorder affects 2–3 percent of people worldwide and is an important cause of illness-related disability, according to the World Health Organization.
Using a new technology in a mouse model, the researchers found that repeated stimulation of specific circuits linking the brain’s cortex and striatum produces progressive repetitive behavior. By targeting this region, it may be possible to stop abnormal circuit changes before they become pathological behaviors in people at risk for obsessive-compulsive disorder (OCD). The study, which was led by Susanne Ahmari, MD, PhD, assistant professor of clinical psychiatry at Columbia Psychiatry and the New York State Psychiatric Institute, was published in the June 7 issue of Science.
While the obsessions and compulsions that are the hallmarks of OCD are thought to be centered in the cortex, which controls thoughts, and the striatum, which controls movements, little is known about how abnormalities in these brain regions lead to compulsive behaviors in patients.
To simulate the increased activity that takes place in the brains of OCD patients, Dr. Ahmari and her colleagues used a new technology called optogenetics, in which light-activated ion channels are expressed in subsets of neurons in mice, and neural circuits are then selectively activated using light delivered through fiberoptic probes.
“What we found was really surprising,” said Dr. Ahmari. “That activation of cortico-striatal circuits did not lead directly to repetitive behaviors in the mice. But if we repeatedly stimulated for multiple days in a row for only five minutes a day, we saw a progressive development of repetitive behaviors—in this case, repetitive grooming behavior—that persisted up to two weeks after the stimulation was stopped.”
She added, “And not only that, when we treated the mice with fluoxetine, one of the most common medications used for OCD, their behavior went back to normal.” The current study, as well as others currently being performed by Dr. Ahmari and her team, may ultimately provide clues for new treatment targets in terms of both novel drug development and direct stimulation techniques, including deep brain stimulation (DBS).