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.”

Beauty and the Brain: Electrical Stimulation of the Brain Makes You Perceive Faces as More Attractive

The researchers, led by scientists at the California Institute of Technology (Caltech), have used a well-known, noninvasive technique to electrically stimulate a specific region deep inside the brain previously thought to be inaccessible. The stimulation, the scientists say, caused volunteers to judge faces as more attractive than before their brains were stimulated.

Being able to effect such behavioral changes means that this electrical stimulation tool could be used to noninvasively manipulate deep regions of the brain—and, therefore, that it could serve as a new approach to study and treat a variety of deep-brain neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia, the researchers say.

"This is very exciting because the primary means of inducing these kinds of deep-brain changes to date has been by administering drug treatments," says Vikram Chib, a postdoctoral scholar who led the study, which is being published in the June 11 issue of the journal Translational Psychiatry. “But the problem with drugs is that they’re not location-specific—they act on the entire brain.” Thus, drugs may carry unwanted side effects or, occasionally, won’t work for certain patients—who then may need invasive treatments involving the implantation of electrodes into the brain.

So Chib and his colleagues turned to a technique called transcranial direct-current stimulation (tDCS), which, Chib notes, is cheap, simple, and safe. In this method, an anode and a cathode are placed at two different locations on the scalp. A weak electrical current—which can be powered by a nine-volt battery—runs from the cathode, through the brain, and to the anode. The electrical current is a mere 2 milliamps—10,000 times less than the 20 amps typically available from wall sockets. “All you feel is a little bit of tingling, and some people don’t even feel that,” he says.

"There have been many studies employing tDCS to affect behavior or change local neural activity," says Shinsuke Shimojo, the Gertrude Baltimore Professor of Experimental Psychology and a coauthor of the paper. For example, the technique has been used to treat depression and to help stroke patients rehabilitate their motor skills. "However, to our knowledge, virtually none of the previous studies actually examined and correlated both behavior and neural activity," he says. These studies also targeted the surface areas of the brain—not much more than a centimeter deep—which were thought to be the physical limit of how far tDCS could reach, Chib adds.

The researchers hypothesized that they could exploit known neural connections and use tDCS to stimulate deeper regions of the brain. In particular, they wanted to access the ventral midbrain—the center of the brain’s reward-processing network, and about as deep as you can go. It is thought to be the source of dopamine, a chemical whose deficiency has been linked to many neuropsychiatric disorders.

The ventral midbrain is part of a neural circuit that includes the dorsolateral prefrontal cortex (DLPFC), which is located just above the temples, and the ventromedial prefrontal cortex (VMPFC), which is behind the forehead. Decreasing activity in the DLPFC boosts activity in the VMPFC, which in turn bumps up activity in the ventral midbrain. To manipulate the ventral midbrain, therefore, the researchers decided to try using tDCS to deactivate the DLPFC and activate the VMPFC.

To test their hypothesis, the researchers asked volunteers to judge the attractiveness of groups of faces both before and after the volunteers’ brains had been stimulated with tDCS. Judging facial attractiveness is one of the simplest, most primal tasks that can activate the brain’s reward network, and difficulty in evaluating faces and recognizing facial emotions is a common symptom of neuropsychiatric disorders. The study participants rated the faces while inside a functional magnetic resonance imaging (fMRI) scanner, which allowed the researchers to evaluate any changes in brain activity caused by the stimulation.

A total of 99 volunteers participated in the tDCS experiment and were divided into six stimulation groups. In the main stimulation group, composed of 19 subjects, the DLPFC was deactivated and the VMPFC activated with a stimulation configuration that the researchers theorized would ultimately activate the ventral midbrain. The other groups were used to test different stimulation configurations. For example, in one group, the placement of the cathode and anode were switched so that the DLPFC was activated and the VMPFC was deactivated—the opposite of the main group. Another was a “sham” group, in which the electrodes were placed on volunteers’ heads, but no current was run.

Those in the main group rated the faces presented after stimulation as more attractive than those they saw before stimulation. There were no differences in the ratings from the control groups. This change in ratings in the main group suggests that tDCS is indeed able to activate the ventral midbrain, and that the resulting changes in brain activity in this deep-brain region are associated with changes in the evaluation of attractiveness.

In addition, the fMRI scans revealed that tDCS strengthened the correlation between VMPFC activity and ventral midbrain activity. In other words, stimulation appeared to enhance the neural connectivity between the two brain areas. And for those who showed the strongest connectivity, tDCS led to the biggest change in attractiveness ratings. Taken together, the researchers say these results show that tDCS is causing those shifts in perception by manipulating the ventral midbrain via the DLPFC and VMPFC.

"The fact that we haven’t had a way to noninvasively manipulate a functional circuit in the brain has been a fundamental bottleneck in human behavioral neuroscience," Shimojo says. This new work, he adds, represents a big first step in removing that bottleneck.

Using tDCS to study and treat neuropsychiatric disorders hinges on the assumption that the technique directly influences dopamine production in the ventral midbrain, Chib explains. But because fMRI can’t directly measure dopamine, this study was unable to make that determination. The next step, then, is to use methods that can—such as positron emission tomography (PET) scans.

More work also needs to be done to see how tDCS may be used for treating disorders and to precisely determine the duration of the stimulation effects—as a rule of thumb, the influence of tDCS lasts for twice the exposure time, Chib says. Future studies will also be needed to see what other behaviors this tDCS method can influence. Ultimately, clinical tests will be needed for medical applications.

Brain research provides clues to what makes people think and behave differently

Differences in the physical connections of the brain are at the root of what make people think and behave differently from one another. Researchers reporting in the February 6 issue of the Cell Press journal Neuron shed new light on the details of this phenomenon, mapping the exact brain regions where individual differences occur. Their findings reveal that individuals’ brain connectivity varies more in areas that relate to integrating information than in areas for initial perception of the world.

"Understanding the normal range of individual variability in the human brain will help us identify and potentially treat regions likely to form abnormal circuitry, as manifested in neuropsychiatric disorders," says senior author Dr. Hesheng Liu, of the Massachusetts General Hospital.

Dr. Liu and his colleagues used an imaging technique called resting-state functional magnetic resonance imaging to examine person-to-person variability of brain connectivity in 23 healthy individuals five times over the course of six months.

The researchers discovered that the brain regions devoted to control and attention displayed a greater difference in connectivity across individuals than the regions dedicated to our senses like touch and sight. When they looked at other published studies, the investigators found that brain regions previously shown to relate to individual differences in cognition and behavior overlap with the regions identified in this study to have high variability among individuals. The researchers were therefore able to pinpoint the areas of the brain where variable connectivity causes people to think and behave differently from one another.

Higher rates of variability across individuals were also displayed in regions of the brain that have undergone greater expansion during evolution. “Our findings have potential implications for understanding brain evolution and development,” says Dr. Liu. “This study provides a possible linkage between the diversity of human abilities and evolutionary expansion of specific brain regions,” he adds.