Dorsal Anterior Cingulate and Anterior Insula computations during threat avoidance in Humans - Project Summary Anxiety disorders are the most common mental illnesses in the world. One in 14 people worldwide currently suffer from dysregulated anxiety. People with dysregulated anxiety report poor quality of life, loss of independence and are at an increased risk of suicide attempts. A key component of anxiety disorder is a persistent and disruptive state of aversion, high arousal, and negatively valenced perception even in the absence of threat. Remarkably, up to 30 percent of those who suffer from anxiety disorders do not respond to currently available pharmacologic and behavioral therapies. Part of the reason for this treatment gap is because we do not have a mechanistic understanding of anxiety related brain circuits in humans. Noninvasive neuroimaging techniques, mainly fMRI, have been used to study anxiety related brain circuits. However, fMRI may not capture dynamics and other aspects of the neural mechanisms of anxiety that require greater temporal and spatial resolution. Extensive work in rodent models has identified brain circuits associated with anxiety, in the context of simple experiences. Causal manipulations at the level of specific brain regions and individual neurons have defined their contributions to anxiety-like behavior with potential implications for the treatment of dysregulated anxiety. However, studies in rodent systems may not capture the relationship of anxiety to human subjectivity or the complexities of higher-order human cognition. Circuit-level work in humans is required. The goal of this proposal is to mechanistically uncover neuroanatomical substrates of anxiety related brain circuits that will be candidates for neural circuit reprogramming in future studies. Two reciprocally connected brain regions that have been implicated in top down and bottom-up control of anxiety are the dorsal Anterior Cingulate (Area 24) and the anterior insula. Here we propose a theoretical model where safety assessment and aversive outcomes are dissociably represented in the dorsal Anterior Cingulate Cortex and anterior Insula, respectively. To determine how this circuit operates in humans requires causal manipulations which are difficult due to their deep location. We will take a two-level approach in dissecting these anxiety related brain circuits in epilepsy patients implanted with intracranial depth electrodes, for the sole purpose of seizure onset localization and functional brain mapping. First, using multiregional invasive neurophysiology, we will outline the individual and complementary roles these brain regions play in safety assessment and outcomes response as subjects engage in a spatial avoidance of threat task. This will be done at single neuron, population activity, and network oscillation levels. Next, transient disruption of key nodes of this network, using direct electrical brain stimulation, will provide a mechanistic understanding and causal relationships across these brain regions. This scientific approach—linking single neuron activity to behavior through large scale brain oscillations will set the stage for outlining the fundamental circuit level organization of anxiety in humans.
