Desmond J. Oathes, Ph.D. - US grants

DESCRIPTION (provided by applicant): Despite its high prevalence, generalized anxiety disorder (GAD) has been relatively under studied compared with other anxiety disorders. Patients with GAD worry excessively about an uncertain future that they believe will be aversive. Despite evidence that worry concerns the future, most experimental paradigms studying GAD focus only on direct responses to evocative material. With the advent of increasingly sophisticated assessments of neural responsivity, it is now essential to probe the anticipatory nature of GAD alongside responses to affective stimuli. Another important factor in this form of psychopathology is the chronic nature of anxiety and difficulty controlling negative thoughts once they are initiated. Difficulty controlling worry is one of the diagnostic criteria for GAD well supported by self-report data in these patients. To provide evidence for the neurobiological substrate of chronic, difficult to control aversive experiences in GAD, the measurement of physiological responses in the aftermath of aversive stimulus presentations (recovery) is warranted. The work planned will focus on the neural signature of processing negative emotional information in GAD using functional magnetic resonance brain imaging (fMRI). The paradigm will take an innovative approach in examining emotional reactivity including anticipation of, response to, and recovery from aversive visual stimuli in a single study. Comparisons will be made between GAD and control subjects with no current or past psychiatric disorder. Contrasts will also be made between GAD patients and major depressive disorder (MDD) patients as well as patients with both conditions. GAD patients are expected to show greater amygdala activity as well as activity in the insula and several key areas implicated in the anticipation of aversion during anticipation of emotional stimuli than non-anxious controls. In response to aversive stimuli, GAD patients are expected to show less reactivity in these regions than non-anxious controls. For recovery, GAD patients are expected to be similar to MDD patients in showing sustained neural responding in the targeted brain regions following aversive stimuli. PUBLIC HEALTH RELEVANCE: By better understanding the processes of anticipation, response, and recovery in anxious and depressive populations, new strategies for treatment may benefit individuals and reduce the societal burden of their symptoms. These data will allow clinicians to know which stage of emotional processing for a particular group of patients might most benefit from interventions targeting that stage. These data may also suggest sensitive precursors of affective disorders in individuals with genetic susceptibility to anxious and depressive traits with the goal to ultimately prevent the clinical syndrome from developing in these individuals.

Project Summary / Abstract In an exciting era of growth in the use of non-invasive brain stimulation, new methods and applications are being disseminated widely with an increasing number of FDA approvals and equipment designed to probe or modulate the brain in fascinating new ways. The problem with this growing enthusiasm is that there are too few studies that have evaluated how tools such as transcranial magnetic stimulation (TMS) induce functional activation throughout a human brain, especially outside of the motor system. Neuromodulation made possible by administering trains of repetitive TMS (rTMS) is even more poorly understood since it requires capturing dynamic changes in the brain that are at the root of proposed changes in function. We have developed a protocol for assaying circuit communication by single pulse TMS delivered while recording functional MRI to follow brain wide effects of TMS to various prefrontal cortex targets. We are beginning to measure this circuit- specific communication flow before and after neuromodulatory rTMS to the same circuit to quantify changes in dynamics resulting from these acute brain interventions. With the proposed research, we plan to optimize targeting of two brain networks with TMS: inferior frontal gyrus to amygdala and lateral prefrontal to subgenual anterior cingulate cortex. By individualizing targeting from each person's functional MRI mapping, we believe that we can optimize our ability to affect the brain and ultimately better understand variability in behavioral response to TMS. A key set of proposed metrics for establishing a firmer understanding of TMS effects on the brain will be two different hypothesized dose/response relationships: 1) Circuit activation will increase as a function of absolute stimulation level and 2) Circuit communication will be modulated as a function of the cumulative number of rTMS pulses delivered during neuromodulatory brain stimulation. 3) Finally, to increase our chances of capturing a stratified sample of circuit integrity in the targeted pathways that are thought to be disrupted in affective disorders, a sub-sample of the recruited participants (who will otherwise be healthy) will be recently diagnosed with major depressive disorder. Significance: Our comprehensive assay of brain response to TMS will include TMS probe responses as well as resting fMRI recorded before, during, and after application of neuromodulatory TMS. This strategy will yield a significant step forward in understanding how non-invasive brain stimulation affects human brain functioning that can be a methodological and theoretical base for tool development and novel brain-based therapeutics.

Project Summary / Abstract In an exciting era of growth in the use of non-invasive brain stimulation, new methods and applications are being disseminated widely with an increasing number of FDA approvals and equipment designed to probe or modulate the brain in fascinating new ways. The problem with this growing enthusiasm is that there are too few studies that have evaluated how tools such as transcranial magnetic stimulation (TMS) induce functional activation throughout a human brain, especially outside of the motor system. Neuromodulation made possible by administering trains of repetitive TMS (rTMS) is even more poorly understood since it requires capturing dynamic changes in the brain that are at the root of proposed changes in function. We have developed a protocol for assaying circuit communication by single pulse TMS delivered while recording functional MRI to follow brain wide effects of TMS to various prefrontal cortex targets. We are beginning to measure this circuit- specific communication flow before and after neuromodulatory rTMS to the same circuit to quantify changes in dynamics resulting from these acute brain interventions. With the proposed research, we plan to optimize targeting of two brain networks with TMS: inferior frontal gyrus to amygdala and lateral prefrontal to subgenual anterior cingulate cortex. By individualizing targeting from each person's functional MRI mapping, we believe that we can optimize our ability to affect the brain and ultimately better understand variability in behavioral response to TMS. A key set of proposed metrics for establishing a firmer understanding of TMS effects on the brain will be two different hypothesized dose/response relationships: 1) Circuit activation will increase as a function of absolute stimulation level and 2) Circuit communication will be modulated as a function of the cumulative number of rTMS pulses delivered during neuromodulatory brain stimulation. 3) Finally, to increase our chances of capturing a stratified sample of circuit integrity in the targeted pathways that are thought to be disrupted in affective disorders, a sub-sample of the recruited participants (who will otherwise be healthy) will be recently diagnosed with major depressive disorder. Significance: Our comprehensive assay of brain response to TMS will include TMS probe responses as well as resting fMRI recorded before, during, and after application of neuromodulatory TMS. This strategy will yield a significant step forward in understanding how non-invasive brain stimulation affects human brain functioning that can be a methodological and theoretical base for tool development and novel brain-based therapeutics.

ABSTRACT Despite the increasing use of transcranial magnetic stimulation (TMS) in both research and clinical practice, the field nonetheless lacks a theoretical framework to predict the impact of TMS on circuits. In this application, we propose to test the over-arching hypothesis that brain responses to TMS are governed by both the network control properties of the stimulation site and the functional context of the network during stimulation. Recent advances in network control theory have provided quantitative diagnostics of network controllability, which collectively define how external input (e.g., TMS) to network nodes (e.g., brain regions) can move the entire system. In Aim 1, we will test the hypothesis that TMS targeted to regions of high network control will produce greater brain responses than TMS targeted to regions of low network control. Specifically, we will recruit healthy young adults (n=40) and use ultra-high resolution diffusion imaging to identify control points that are topologically situated to drive network reconfiguration. We will use cutting-edge interleaved TMS/fMRI to test the hypothesis that individually-targeted TMS at control points will produce greater network segregation, consisting of fronto-parietal network activation, DMN de-activation, and reduced connectivity between the two. In Aim 2, we will examine the impact of the functional context of TMS. We predict that TMS simulation during conditions of high working memory (WM) load will result in greater network segregation responses than in conditions of lower load. In Aims 3 & 4, we will examine the degree to which individually targeted stimulation during WM task performance augments behavioral WM performance following repetitive TMS. We predict that the behavioral impact of neuromodulation on WM performance will scale with observed increases in network segregation versus baseline in both our sample of healthy young adults as well as age-matched patients with ADHD who have documented executive deficits (n=35). This proposal leverages our group's unique expertise in advanced TMS/fMRI, network science, and multi-modal imaging. Together, this research will elucidate basic mechanisms of neuromodulation that will accelerate translation of these therapies to clinical practice and more definitive links between brain functional modules and brain functioning.

ABSTRACT The proposed project is designed to increase precision and responsiveness in transcranial magnetic stimulation therapies across the neuropsychiatric spectrum and specifically in working memory deficits which are common across a variety of neuropsychiatric conditions. Cutting edge functional imaging studies suggest that using multiple types of imaging datasets yield more reliable estimates of brain network communication. Our methods yield a combined resting and task fMRI functional network mapping individualized for each participant that will allow precise identification of brain stimulation targets associated with optimal working memory performance (Aim 1). To close the loop in designing TMS protocols that respond to an individual person's brain activation state, we will also develop and test a real-time brain decoder to determine when optimal working memory states are online (Aim 2). By iteratively testing excitatory neuromodulation frequencies at this stimulation site and capturing the relative movement of brain states towards or away from optimal working memory states, we will settle on the optimal frequency for augmenting working memory performance in each individual (Aim 3). We will validate this approach by administering either the `best' or `worst' (random assignment to each participant) neuromodulation protocol across several days then testing working memory performance and brain activation in a final MRI scan session. The multi-modal based TMS targeting and individualized frequency optimization techniques will be based on our findings and packaged into a combined software suite in Docker containers made available to the scientific and clinical community at the conclusion of this project (Aim 4).