Thursday, May 16, 2024
5/16/2024
PROJECT SUMMARY Emotion-regulatory deficits are a hallmark of mood and anxiety disorders, which afflict over 20% of adults in the United States. Poor emotion regulation is often characterized by the context-inappropriate expression of emotion, including the unwarranted persistence and influence of negative states outside their temporal context. Therefore, the ability to respond to emotional events in a temporally and contextually sensitive manner is paramount to mental health and wellbeing. Evidence from cognitive control studies indicates that function of the lateral prefrontal cortex (LPFC), including lateral frontal pole and mid-LPFC, is essential for temporally organized cognitive control and behavior sensitive to goals and context. However, mechanistic studies of LPFC function in emotion are lacking, even though there are strong indications of a prominent but little-understood role for LPFC in promoting adaptive emotional functioning, including hypoactivation and reduced LPFC connectivity in mood and anxiety disorders, associations between LPFC lesions and incidence of major depression, and the use of transcranial magnetic stimulation (TMS) to LPFC to treat depression. The central goal of this proposal is therefore to elucidate the organization, representational and causal contributions of distinct LPFC regions for adaptive time and context sensitive emotional responding. This proposal tests the central hypothesis that the human lateral frontal pole (FPl) integrates emotional and temporal information to promote goal-oriented and context-sensitive responses via downstream mid-LPFC function. This hypothesis is informed by documented neuroanatomical projections, insights into the organization of temporal control in LPFC, and recent work unveiling functional specificity in distinct LPFC regions during emotion-dependent cognitive control. Using an innovative combination of multivariate analysis of fMRI data and information-guided TMS, the proposed studies examine the representational and causal roles of distinct LPFC regions for (1) goal-oriented action that requires accurate tracking of temporally extended emotional information (Aim 1) and (2) temporal- context sensitive regulation of affect (Aim 2). Full-factorial representational similarity analysis will permit quantifying emotional valence, temporal, and contextual goal signals—as well as, critically, their interaction. Information-guided TMS, followed by task fMRI acquisition, will establish functional and representational specificity of distinct LPFC regions—FPl and mid-LPFC—with causal inference (Aims 1b-2b). Task-based functional connectivity analysis will uncover the topology of amygdala-LPFC interactions (including intermediary mPFC nodes) associated with emotion-temporal integration and affect regulation (Aim 3). Collectively, these Aims will advance a directional model of how LPFC function and amygdala-LPFC interactions support adaptive time-and-context appropriate responses in the face of emotional challenges.
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