Darin Dougherty - US grants

This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K23) titled "Physiologic Studies of Anger in Depressed Patients". It allows the candidate, who has experience with clinical psychopharmacology and positron emission tomography (PET) activation studies, to gain expertise in psychophysiology and in vivo neuroreceptor imaging techniques in the study of affective dysregulation in major depressive disorder (MDD). Numerous PET studies have demonstrated abnormal metabolic patterns in anterior paralimbic structures in patients with MDD. Numerous PET studies following negative emotion induction paradigms in healthy controls have demonstrated that anterior paralimbic structures are involved in the processing of negative emotions such as sadness and disgust. Few studies have utilized these paradigms to study emotional processing in subjects with MDD, a disorder characterized by profound disturbances of affect regulation. Patients with a well-characterized subtype of MDD, MDD with anger attacks, present with sudden uncharacteristic spells of anger accompanied by autonomic activation. This subtype of MDD provides an opportunity to characterize affect dysregulation of a specific type (anger) in a well-defined clinical population, ultimately helping to elucidate the pathophysiology of MDD. We propose to study three populations: MDD with anger attacks, MDD without anger attacks, and healthy control subjects. We will utilize narrative scripts to induce emotional states (angry, sad, and neutral states) and assess physiologic responses in the study populations utilizing psychophysiologic measures, PET activation studies, and PET in vivo neuroreceptor imaging techniques. By this proposal, the candidate seeks training in (1) clinical studies of MDD, (2) affective neuroscience, (3) statistics relevant to functional neuroimaging, and (4) neuroreceptor imaging with PET. This rigorous training plan, integrating strong didactics and multidisciplinary expertise, will teach the candidate how to synthesize information from diverse fields in studying affect dysregulation in MDD. This integrated program of training and research will advance our knowledge of the pathophysiology of MDD, yield new tools for studying emotional processing, and give the candidate the skills needed to achieve independence in a highly complex field.

Project Abstract This project is a pilot clinical trial of a new brain stimulation treatment for obsessive-compulsive disorder. OCD is a mental illness that affects 4-7 million people in the US. Of those, 50-70% still have substantial symptoms after being treated with medication or talk therapy. Recently, clinicians have started trying to treat OCD with deep brain stimulation (DBS). DBS involves surgically placing electrodes into the brain, then sending electrical stimulation currents through those electrodes. Most investigators think that DBS for OCD works by affecting brain circuits called the cortico-striato-thalamo-cortical loops, or CSTC loops. The belief is that OCD is caused by the CSTC loops being too strongly connected, so that signals get stuck in them and become the stuck, perseverative, obsessional thinking of OCD. To interrupt these loops, investigators have placed DBS into the ventral capsule/ventral striatum (VC/VS), the S of CSTC. VC/VS DBS has helped several patient who had very treatment-resistant OCD. However, about half do not get better. We hypothesize that this is because DBS does not always influence cortico-striatal loops correctly, because it only affects a single area in this multi-area circuit. Our main objective (Aim 1) is to test a stimulator that affects the deep brain and the cortex (brain surface) at once and tries to break the abnormal CSTC synchrony. It drives two brain areas at slightly different frequencies, keeping them out of sync. Our second objective is to test whether activity in the CSTC loop correlates to the symptoms of OCD. No study has proven that these two are linked in humans, because it is difficult to record from the human brain, especially over long periods of time and from deep brain areas. We will use a novel technology, the Medtronic PC+S sensing DBS, to record the brain's activity while delivering the stimulation treatment (Aim 2a). As patients' symptoms improve, we expect to see that connectivity and synchrony between the surface and deep brain decreases along the same trajectory. We will also capture recordings during symptom flares and as patients participate in symptom-triggering activities such as exposure therapy sessions. This will help us further determine how well this brain activity correlates to symptoms. Finally, to help capture clearer signals, we will also collect those recordings while patients do a fear task that is linked to OCD severity, using EEG to further understand the cortico-striatal response to DBS (Aim 2b). This study leverages a broad interdisciplinary team of psychiatrists, statisticians, a neurosurgeon, and electrophysiologists, all with experience in OCD and brain stimulation.

This project will transfer a computational modeling technology, StimVision, from the McIntyre Lab at Case Western Reserve University to the deep brain stimulation (DBS) group at Massachusetts General Hospital (MGH). DBS is currently used to treat severe obsessive-compulsive disorder (OCD) through high-frequency electrical stimulation of the ventral internal capsule/ventral striatum (VC/VS). VC/VS is a complex brain region containing white matter tracts projecting to multiple frontal cortical regions. It is not understood which VC/VS fibers matter most to DBS' clinical effects on OCD, in part because we do not know how the stimulator's electrical field propagates through and activates this electrically irregular tissue. This leads to very inconsistent clinical effects (about 50% of patients respond poorly or not at all) for this invasive and expensive procedure. StimVision is designed to model those electric fields, but has not been adapted to or deployed in this specific application. As part of the BRAIN Initiative's efforts to transfer methods between laboratories, the McIntyre group will adapt StimVision for VC/VS modeling and train the MGH team in its use. We will then deploy it as part of our ongoing analysis of neurophysiologic and behavioral data in our existing patient cohort. We expect to show that the use of these advanced modeling techniques clarifies neural mechanisms underlying known behavioral effects, by compensating for heterogeneous VC/VS anatomy. Our Objective is to achieve that technology transfer and demonstrate MGH's successful uptake of the methods to the point that we can use them independently going forward. We approach this through two Aims. Aim 1 represents the Case group's alterations to the user interface and algorithms of StimVision to be compatible with MGH's imaging and analysis workflows. This includes improvements to the electrical models that may be necessary for properly capturing VC/VS effects and incorporating novel tractography algorithms originally developed by MGH/Brigham collaborators. Aim 2 then transfers initial and revised versions of StimVision to MGH and demonstrates their successful use for data analysis. We will re-analyze two MGH datasets, one concerning hypomania (a major DBS side effect) and one concerning behavioral effects from DBS manipulation during a psychophysical task. In both cases, we hypothesize that use of StimVision modeling will further clarify the cortical circuits underpinning these effects, and further hypothesize that this will primarily implicate the anterior cingulate. The goal of this Aim, however, is not necessarily to prove these hypotheses. It is demonstration of technology transfer, the core success criterion of this BRAIN RFA.

ABSTRACT Obsessive-compulsive disorder (OCD) is a chronic mental illness affecting 4-7 million people in the US. Patients are impaired in multiple Research Domain constructs. Medication and behavioral therapies yield inadequate symptom relief in 50-70% of patients. As a result, OCD remains a leading worldwide cause of disability, equivalent to more visible disorders such as schizophrenia. Roughly 1/3 of patients are unable to work due to their symptoms and their caregivers report profound, life-impairing stress. More recently, the field has focused on deep brain stimulation (DBS). However, about a third of the patients who undergo DBS receive no meaningful benefit. We propose a primarily retrospective investigation of imaging-based targeting for Deep Brain Stimulation (DBS) for severe obsessive-compulsive disorder (OCD). We aim to increase response rates while testing imaging biomarkers that could guide therapeutic intervention. Our hospital is the highest-volume site in the US using DBS at the ventral capsule/ventral striatum (VC/VS) for the treatment of intractable OCD. A major contributor to imperfect response is that DBS is implanted at standard coordinates across patients, without accounting for variation in VC/VS anatomy. Our investigation will study imaging markers that may target ventral capsule/ventral striatum (VC/VS) for DBS to patient-specific brain circuitry. We hypothesize that clinical response will be related to the degree that the DBS electrical field influences orbitofronto-thalamic fibers and the nucleus accumbens grey matter. If we are successful in identifying a biomarker during this three-year retrospective study, a future prospective clinical trial will target DBS implants to the newly identified structures in a patient-specific fashion.

PROJECT SUMMARY (PROJECT 2, Project Leader: Dougherty, Massachusetts General Hospital) The goal of Project 2 is to causally probe the role of cortico-striatal circuits in approach-avoidance conflict using invasive recording and neurostimulation in awake, behaving humans. Invasive studies in humans serve as a bridge between the complementary invasive animal and non-invasive human studies in other Projects. Noninvasive human functional imaging studies provide valuable insights into the circuitry underlying specific brain functions but ? fundamentally ? are correlative in nature. Invasive measurements in humans during tasks provide markedly better spatial resolution (down to the single neuron) and temporal resolution (down to 5-10 milliseconds). More critically, the ability to stimulate using the same electrodes allows for unique ?backwards neuroimaging?. Instead of performing a task and observing which brain networks are involved, one can stimulate different brain regions at different amplitudes, frequencies and task epochs to observe effects on task performance all while simultaneously recording. In this project we propose to study approach-avoidance conflict in two human models: (1) deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) and (2) surgical epilepsy monitoring. Over five years, we will recruit 20 DBS patients with chronic DBS electrodes in the VC/VS for treatment of neuropsychiatric disorders and 20 patients with epilepsy with acute depth electrodes for seizure monitoring. We will investigate the behavioral and neural effects of DBS on approach-avoidance behavior in patients with major depressive disorder (MDD) with implanted DBS electrodes in the VC/VS. Capitalizing on our prior studies and extensive set of preliminary data we will use an approach/avoidance decision making task to assess behavioral and neural changes associated with stimulation of the ventral striatum (as opposed to no stimulation) in neuropsychiatric patients with implanted DBS depth electrodes. We will also investigate the large- scale neural network of approach-avoidance behavior in epilepsy patients implanted with depth electrodes, and test the hypothesis that closed-loop stimulation targeting key cortico-striatal nodes will bidirectionally modulate approach-avoidance behaviors in depressed patients. Building on our extensive experience in this area we will record simultaneous activity of multiple prefrontal structures and, in some cases, striatum, in patients admitted to the MGH Epilepsy Monitoring Units following implantation of depth electrodes. To maximize synergies across Projects, the task will be identical to the one used in Project 1 (with unmedicated individuals with MDD or anxiety disorders) and functionally analogous to the one in Project 3 (with non-human primates). Contribution to Overall Center Goals & Interactions with Other Center Components. By testing that direct stimulation of both approach-related (e.g., striatum) and avoidance-related (e.g., pregenual anterior cingulate cortex) areas affects approach-avoidance behavior in humans, Project 2 will directly link the non-invasive fMRI studies in individuals with unmedicated MDD (Project 1) with the non-human primate (Project 3) and rodent (Project 4) studies that will mechanistically dissect neurobiological mechanisms governing approach/avoidance behaviors.