Ann Shinn - US grants

DESCRIPTION (provided by applicant): This K23 proposal aims to understand auditory, speech, and cognitive networks underlying proneness to auditory hallucinations (AH) across the continuum of psychosis. The PI, Dr. Shinn, is a clinically trained psychiatrist with four years of post-residency training in psychosis functional connectivity (FC) research. She proposes to investigate both structural and dynamic aspects of connectivity, focusing on dorsal anterior cingulate cortex (dACC), auditory cortex (A1), voice perception (Vper), and voice production (Vpro) areas in AH- prone patients across the diagnostic categories of schizophrenia, schizoaffective disorder, bipolar psychosis, and DSM-IV psychotic disorder not otherwise specified (NOS). There is a clinical need to understand AH pathophysiology better, as AH are often distressing and associated with increased suicide risk. While antipsychotic medications can reduce their severity, in 25-30% of patients AH are refractory to antipsychotic medications. More effective interventions targeted at underlying AH pathophysiology are necessary. However, patient heterogeneity presents a major challenge to biological research in this area. Dr. Shinn proposes to directly address the issue of patient heterogeneity by: (a) Taking a dimensional and cross-diagnostic approach. AH are more homogeneous than diagnoses, and the current proposal aims to identify a neurobiological AH signature that transcends diagnosis. (b) Identifying subject- and functionally specific brain regions of interest and conducting analyses at the individual subject level; (c) Using multimodal neuroimaging within a single cohort to generate more cohesive understanding. Her approach, combining stochastic tractography, resting state fMRI (rsfMRI), and fMRI during a cognitive interference task, can inform about structural, baseline, and dynamic task-related aspects of connectivity. Dr. Shinn's hypothesis, which attempts to reconcile conflicting cognitive models of AH, is that AH-prone patients have increased baseline connectivity between A1, Vper, Vpro, and dACC, and an inability to modulate these connections during the auditory Stroop, a task that requires suppression of attention to irrelevant aspects of auditory stimuli. Such tonic hyper- and phasic hypo- connectivity may reflect a network that is biased towards hearing internally generated voices and less able to allocate resources when challenged. The current proposal may provide better understanding of circuitry abnormalities in AH, and expand possibilities for AH treatment using interventions such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), or neurofeedback, with an eye towards personalized medicine approaches. In parallel with the research proposed, Dr. Shinn will engage in multiple career development activities to vertically and horizontally expand her ability to develop mechanistic insights about AH. These include new training in cognitive neuroscience, better understanding of mechanisms involved in auditory and speech/language processing, and a stronger grasp of basic neuroscience. She will also receive advanced training in rsfMRI and new training in stochastic tractography.

PROJECT SUMMARY/ABSTRACT This R21 proposal aims to provide detailed understanding of how finely parcellated subareas of the auditory cortex (AC) are functionally connected with one another and with cerebellar regions in schizophrenia (SZ) patients with auditory hallucinations (AH). AH can be disabling, and do not always respond to existing treatments. A clear understanding of AH pathophysiology is needed to guide the development of more effective treatments for AH, but such knowledge is currently lacking. Previous research suggests that the AC is abnormal in AH, suggesting a possible perceptual basis for AH. The AC, however, is one of many brain regions implicated in AH pathogenesis, and a better understanding of how AC interacts with other critical brain areas is needed. The cerebellum coordinates a host of cerebral cortical functions?including higher-level cognitive, affective, and perceptual processes?rather than just motor functions, as traditionally believed. Consistent with this framework, the myriad symptoms of psychosis have been proposed to reflect ?dysmetria,? or incoordination, of mental activity due to disruptions in cerebro-cerebellar circuits (Andreasen, et al., 1996; Schmahmann, 1998). Given evidence that the cerebellum is reciprocally connected to AC and coordinates auditory processing, there is motivation to understand how abnormal AC-cerebellar circuitry might lead to `auditory dysmetria', and AH. We propose to examine features of local AC circuitry and AC-cerebellar circuitry underlying AH by utilizing an innovative and highly reliable AC parcellation strategy based on resting state functional magnetic resonance imaging (rsfMRI). This parcellation method, which computes functional connectivity (FC) between voxels in AC and the rest of the brain, will be used to segment AC into multiple subareas. Subdividing the AC at this fine- grained a level could only be achieved before with postmortem (e.g., cytoarchitectonic) methods. Here, these individual-specific and functionally defined AC subareas will serve as the seeds for FC between AC subareas and between AC and cerebellum. Our aims are to identify features of AC inter-subarea FC (Aim 1) and features of AC-cerebellar FC (Aim 2) that track with AH severity in SZ. We also aim to validate how these markers change with intra-subject variations in AH (Aim 3), using data from an independent interventional longitudinal study. Our hypotheses are two-fold: (1) The AC is comprised of a complex local network of both primary sensory and association subareas, and FC between AC subareas is meaningfully associated with AH. (2) The cerebellum plays a key role in coordinating activity in AC subareas, and this process is `dysmetric' in AH. This project is significant because it is the first step in a continuum of research that is expected to lead to the development of more targeted and personalized treatments for AH. Repetitive transcranial magnetic stimulation (rTMS) is a promising non-pharmacological treatment for AH. We propose that stimulation of cerebellar regions that are connected to association subareas of AC may provide access to circuits that are dysmetric in AH. We expect that this proposal will identify potential cerebellar targets for rTMS that can be tested in a future clinical trial.