Identifying Optimal Targets and Stimulation Protocols for the Treatment of Psychiatric Disorders

Emad Eskandar, M.D.

Massachusetts General Hospital

Funded in December, 2012: $250000 for 3 years


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Behaviorally-guided DBS may treat psychiatric conditions involving impaired decision-making

This neurosurgical research team will explore, at the neuronal level, how two brain networks normally drive the balance between safe and risky decision-making behaviors, and use the findings to design deep brain stimulation (DBS) strategies for modifying excessively risky or risk-adverse behaviors.
Ordinarily, people balance drives for making a conservative safe choice versus those for making a risky but potentially rewarding choice. Imbalances in these drives characterize psychiatric conditions such as the risk-averseness of obsessive compulsive disorder (OCD) and the excessive riskiness in alcoholism. Based on their prior research combining physiological measures with deep brain stimulation (DBS) electrical recordings of single neurons in brain circuits, the investigators hypothesize that two networks that connect the brain’s striatal and cortical areas explain the processes that drive balanced and imbalanced decision-making. Specifically, they anticipate that a dorsal compartment (composed of the cingulate cortex, caudate, and prefrontal cortex) is involved in driving decisions that are safe, with delayed gratification, while a ventral compartment (composed of nucleus accumbens and orbital-frontal cortex) mediates reward-seeking and often risky decision-making.    
This hypothesis arose from their pioneering efforts to study learning and its enhancement, using a combination of neurophysiological techniques (fMRI imaging), surgical ablation (cutting) of certain neural connections to interrupt detrimental signaling, deep brain stimulation (DBS) to obtain electrical recordings from single neurons, and behavioral assessments.  Then, using combined neurophysiological and DBS techniques to study decision-making, the investigators found that neurons in the nucleus accumbans encode two decision-making signals involved in safe versus risky decisions, while neurons in the subthalamic nucleus (STN) encode these same signals but at different times in the decision-making process. During surgery, patients participated in the classic card game “war.” The patient is dealt a card, the computer is dealt the next card, and the highest card wins. When intermittent DBS stimulation was delivered only at a neurophysiologically-determined crucial time period, patients’ altered their decision-making processes toward more impulsive and risky decisions.  
Now, the investigators will use these findings to guide stimulation of DBS electrodes in the two networks at the critical time points in a total of about 60 patients who are undergoing DBS implantation for treatment of depression, OCD, and Parkinson’s disease. Patients will participate in decision-making tasks involving reward and those involving delayed-gratification during DBS surgery and then again six-months following surgery. The neurosurgical researchers will determine whether DBS stimulation in different brain area compartments in these networks is associated with decisions that represent excessive perfectionism, as is seen in OCD, or impulsivity, as seen in alcohol addiction.  If so, the approach will pave the way for developing DBS treatment for conditions involving excessively risky or risk-averse decision-making based on neurophysiological data that guides intermittent DBS stimulation within the two involved brain networks.
Significance:  The findings could lead to development of behaviorally-guided DBS devices for treating psychiatric conditions that impair decision-making processes. 


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Emad Eskandar, M.D.

Dr. Emad Eskandar is a scientist and neurosurgeon at the Massachusetts General Hospital (MGH). He is also an Associate Professor at Harvard Medical School (HMS). He obtained his MD at the University of Southern
California, and completed his residency training at MGH/Harvard. He was an NIH research scholar for two
years during medical school, received an NRSA award for an additional two years research fellowship at HMS
during residency, and a K08 research award at the completion of residency with John Asaad PhD as his
mentor at Harvard Medical School. He has subsequently maintained an active primate physiology laboratory.
Dr. Eskandar is director of Functional Neurosurgery (Parkinson Disease, Epilepsy) at MGH. He also heads a
large and active research laboratory investigating the basal ganglia, a group of centrally located nuclei in the
brain. The basal ganglia play a central role in theories of learning, motivation, memory, and drug addiction.
The laboratory uses microelectrode recordings and electrical micro-stimulation to evaluate the role of the basal
ganglia in both primates and humans performing complex behavioral tasks. The laboratory is uniquely
positioned in that ideas from the bench can quickly be tested in the clinical arena and vice-versa. Dr Eskandar
is also interested in developing new MRI safe electrodes and more sophisticated electronics for closed-loop
stimulation to treat a variety of disorders such as traumatic brain injury.
The Eskandar lab has made important scientific contributions over the past years. For example, one recent
study, published in Nature, found that the cingulate cortex plays an important role in adapting to varying
degrees of cognitive difficulty. Another recent paper in Nature Neuroscience, found that delivering microstimulation
in one part of the basal ganglia, the caudate nucleus, significantly increases the rate of learning
beyond baseline rates. These findings suggest that the caudate plays a critical role in learning, and that
learning can be enhanced to promote recovery after traumatic brain injury or stroke. Numerous other studies
have been published in Nature Neuroscience, J. Neuroscience, Brain, Cerebral Cortex, PNAS and other high
impact journals.
Dr. Eskandar has been the recipient of numerous honors and awards including the Howard Hughes Medical
Institute Physician Scientist Early Career Award and an award from the Klingenstein Foundation. He was also
awarded the Grass Neuroscience Fellowship, a National Research Service Award, the Excellence in Teaching
Award at Harvard Medical School, and Excellence in Teaching Award from MGH Residents. In addition Dr.
Eskandar has successfully obtained R01 funding from the National Institutes of Health (NIH) and the National
Science Foundation (NSF). Recently, Dr. Eskandar has been awarded a national K12 award to train junior
neurosurgery faculty members.
Dr. Eskandar has mentored many fellows that have successfully transitioned to the appropriate stages in their
careers. A few of the trainees and their current positions are as follows: Ziv Williams MD, Assistant Professor,
Harvard Medical School; Sameer Sheth, MD, PhD Assistant Professor, Columbia University; Wael Asaad MD,
PhD, Assistant Professor, Brown University, Jason Gerrard, MD PhD, Assistant Professor, Yale University
John Gale PhD, Assistant Professor, Cleveland Clinic Foundation;.