Lisa M. McTeague - US grants

DESCRIPTION (provided by applicant): The proposed research will examine emotional reactivity among individuals with varying levels of potentially traumatic exposure to motor vehicle accidents (MVAs) and associated stress. This proposal was motivated by the prominence in the diagnostic nosology of emotional dysregulation and physiological symptoms (i.e., physiological hyper-reactivity to traumarelevant cues, exaggerated startle) as hallmark components of the posttraumatic presentation. The specific goals of this research are both methodological and conceptual. Employing parametric manipulations will allow examination of specific hypotheses regarding emotional modulation among individuals with traumatic exposure with and without PTSD symptoms. Self-report and physiological responses will be measured during two laboratory paradigms; a narrative imagery task and a picture-viewing task, thereby allowing comparison of the utility of the two different tasks and stimuli in eliciting emotional reactivity in this sample.

DESCRIPTION (provided by applicant): This is a K23 Career Development Award application for Lisa M. McTeague, Ph.D., a clinical psychologist and Instructor in the Department of Psychiatry at Stanford University. Dr. McTeague's long-term career goal is to understand the neural basis of emotional reactivity impairments in severe affective illness in the service of identifying multimodal approaches to better remediate these deficits. This K23 award would enable Dr. McTeague to gain proficiency in 1) cutting-edge functional neuroimaging (fMRI), 2) transcranial magnetic stimulation (TMS) as a direct tool for investigating intact and disordered brain activation, 3) translating the principles of experimental medicine to psychosocial treatment toward ameliorating emotional dysfunction, and 4) leveraging these new techniques in conjunction with her established expertise in cognitive- behavioral treatment and psychophysiology for a series of grant submissions to help solidify her independence. This project focuses on posttraumatic stress disorder (PTSD) as a syndrome with well-characterized emotion deficits that may be susceptible to exogenous stimulation (i.e., TMS), which could, in turn, be utilized to enhance conventional psychotherapy outcomes. Trauma-focused exposure-based therapies are the first-line treatments for PTSD but half of patients meet diagnostic criteria upon completion. A fundamental component of exposure is the process of thorough emotional engagement-both subjectively and objectively-ensuring that the ultimate experience of habituation is optimally powerful. Dr. McTeague previously observed that chronic PTSD is marked by stark blunting of defensive mobilization, foremost in startle reflex responding during aversive imagery, suggestive of deficient limbic (and associated network) activation. To meaningfully advance these conclusions and point to intervention targets, Dr. McTeague proposes to assess brain activation and autonomic responding in 40 patients with PTSD and 20 trauma-exposed healthy participants during neutral and aversive as well as equally high arousing appetitive imagery. The inclusion of the latter will inform on whether PTSD is marked by core deficiencies in emotion networks as opposed to strategic avoidance-either outcome integral to intervention planning (Aim 1). To assess whether aberrant, state-dependent, interactions between limbic and prefrontal circuitry characterize PTSD, single pulses of TMS will be administered to two prefrontal regions during imagery (Aim 2). Finally, prefrontal-limbic circuits will be excited in patients with a single (non-therapeutic) session of rTMS to assess for (potentially normalizing) effects on emotional processing in an immediately subsequent imagery session (Aim 3). Successful completion would provide a more sophisticated neurobiological circuit understanding to Dr. McTeague's prior observation of blunted responding while furnishing essential guidance on the feasibility of using TMS to enhance emotional reactivity and regulation neurocircuitry as a preamble to imaginal exposure for PTSD (planned R01 application).

Abstract The Research Domain Criteria (RDoC) initiative prompts us to consider ?dimensional constructs integrating elements of psychology and biology? interrogated with multiple units of analysis toward better understanding mental illness (1). However, such an approach, agnostic to traditional discrete diagnostic classification, does not come with prescribed analytical approaches. Rather, part of the RDoC challenge is to determine appropriate statistical techniques for identifying alternative, meaningful subtypes or clusters defined by bio- psychological profiles. At the same time, there are inherent methodological challenges to clustering with the multiple units of analysis proposed for RDoC approaches. These include 1) highly skewed biological and psychological variables, 2) multi-dimensional, and often high-dimensional datasets, and 3) multiple statistically plausible clustering solutions. Traditional clustering methods most readily accessible and most frequently used in psychiatric research cannot accommodate these issues; their application can produce misleading findings. We propose to utilize cutting-edge finite mixture modeling clustering approaches, robust to these issues, in a large sample of anxiety spectrum disorder patients and matched control participants (n=518) who completed psychophysiological assessment during narrative imagery. Consistent with RDoC constructs within both the Negative and Positive Valence System Domains, participants imagined unpleasant (e.g., threat) and pleasant (e.g., affiliation/reward) as well as neutral narratives while autonomic, facial expressivity, acoustic startle reflex responding and subjective ratings of engagement were recorded. On the basis of the DSM, defensive hyper- reactivity might be expected 1) across anxiety disorders and 2) across response channels. In fact, defensive hypo- and hyper-reactivity were often observed in different channels, within individuals (e.g., exaggerated startle reflex, facial expressivity, and subjective arousal coupled with blunted heart rate and skin conductance responding). The hypothesis of this study is that utilizing cutting-edge clustering approaches will reveal novel transdiagnostic subtypes based on multimodal, dimensional response coordination (or lack thereof) during emotional engagement. These subtypes are expected to cut across traditional diagnostic boundaries, while revealing that the extent of coordination among certain channels is most predictive of emotional health and functional status. The long-term goal is to identify potential novel targets for tailoring interventions, particularly emotion-focused psychotherapy, to coordination among specific response channels. The shorter-term goal is to identify analytical approaches that leverage the rich information in multimodal datasets?applicable to a wide range of RDoC approaches.

Nearly 70% of chronic stroke patients have impairment in at least one cognitive domain. Many of these deficits are subtle, not directly assessed by therapists, and yet are barriers to achieving optimal recovery. While cognitive deficits can be parsed into unique subdomains (e.g., working memory, response inhibition, set shifting), diverse processes are supported by a common neural network: the Multiple Demand Network (MDN). The MDN consists of ?core? nodes: bilateral dorsolateral (dlPFC) and ventrolateral prefrontal cortex, intraparietal sulcus, pre-supplementary motor area (preSMA), dorsal anterior cingulate and bilateral insula. The left dlPFC node includes the site typically targeted with therapeutic repetitive transcranial magnetic stimulation (rTMS) for depression. Thus, it is not surprising that cognitive improvements have been a reported outcome of therapeutic rTMS to left dlPFC among neuropsychiatric disorders and a wide range of neurological conditions including mild to moderate cognitive impairment, dementia, and Alzheimer?s and Parkinson?s diseases. Targeting this cognitive network with rTMS may be a fruitful and innovative therapeutic adjuvant for cognitive rehabilitation in chronic stroke. Additionally, the preSMA, which also is a node in this network, is easily accessible to TMS. Since it is integrally involved in motor control, it could be an especially promising target for remediating deficits as it may affect both cognitive and motor control. Before proceeding to a clinical trial of MDN-guided rTMS as a therapeutic tool for stroke patients, it is critical to determine the functional integrity of the MDN in chronic stroke patients. Aim 1 is to test whether chronic stroke patients engage the MDN in a manner similar to control participants for endogenous cognitive tasks, specifically working memory and response inhibition. While these tasks both engage the MDN, response inhibition preferentially activates the preSMA. Furthermore, response inhibition represents the intersection of cognitive and motor control, underscoring its relevance in functional recovery in chronic stroke. Assessing both tasks will provide information on MDN functional integrity across task domains, as well as whether preSMA deficits are particularly prominent. Aim 2 is to determine which of these two nodes of the MDN (dlPFC versus preSMA) shows stronger activation of the MDN. This will be achieved by applying a series of TMS pulses to each location while the participant is in the MRI scanner, i.e., concurrent TMS-fMRI, a unique tool that was first developed here at the Medical University of South Carolina. The results from these endogenous and exogenous probes will be used to determine which site is a more promising target for cognitive improvement via rTMS.

SUMMARY With advances in opto-/chemo-genetic stimulation techniques, preclinical studies have demonstrated that activity in frontal-striatal neural circuits has a causal influence on heavy alcohol drinking and relapse-like behavior. Similar findings using modern fMRI imaging techniques in humans have confirmed some of these findings. Clinically, however, we have not yet translated this research into a neural circuit based therapeutic technique for patients with alcohol use disorder (AUD). The long term goal of our multidisciplinary research team is to determine the optimal parameters through which non-invasive transcranial magnetic stimulation (TMS) can be used to improve alcohol drinking outcomes (abstinence, heavy drinking days) among individuals seeking behavioral treatment for AUD. Building on a foundation of several TMS brain target identification studies and a small double-blinded clinical trial in treatment-engaged AUD patients performed by our group in the Charleston Alcohol Research Center (ARC), here we propose a double-blind placebo controlled, randomized study to evaluate the efficacy of theta burst stimulation (TBS) to ventromedial prefrontal cortex (vmPFC) as a treatment to decrease drinking and brain reactivity to alcohol cues among treatment-seeking individuals with AUD. Individuals will be screened initially by the ARC Clinical Intake and Assessment Core, then given an opportunity to enroll in this study, provide informed consent, and be randomized to receive real or sham TBS to the vmPFC 36 sessions (3x/day on each of 3 days/week over 4 weeks, i.e., 12 days). Prior to randomization and again after 4 weeks of TBS treatment, they will receive a well-established and validated alcohol-cue stimulation BOLD fMRI procedure. The scientific premise of this ARC research proposal is that, by modulating the neural circuits that regulate alcohol cue-reactivity, it will be possible to increase alcohol abstinence rates and decrease heavy drinking days over a 4-month period. Accordingly, we will explore the relationship of TBS-induced changes in brain reactivity to alcohol cues as mediators of the TBS treatment response. Also, brain activation to natural reward and threat cues will be studies as a means to probe potential effects of TBS treatment on negative affect/emotionality associated with AUD. With our combined scientific expertise in brain stimulation, neuroimaging, clinical (and preclinical) alcohol-related research in the Charleston ARC, and AUD clinical trial expertise, MUSC is uniquely suited to develop this critical line of research. The outcomes of the proposed Aims will provide an evidence-based foundation for a multisite clinical trial and will hasten progress towards developing a new neural circuit-based treatment for individuals with AUD.