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.
Auditory hallucinations are common, transcend diagnoses, and current antipsychotic medications used to attenuate auditory hallucinations are limited by intolerable side effects. Studying the dimension of auditory hallucinations across the psychosis spectrum (schizophrenia, schizoaffective disorder, bipolar psychosis, and psychosis not otherwise specified) may provide better leverage into understanding the pathophysiology of this often distressing symptom, and enable the identification of more targeted treatment interventions. In this proposal, we will examine connectivity abnormalities associated with auditory, speech-related, and cognitive networks using a subject-specific approach in patients with proneness to auditory hallucinations, and this may provide a basis for more personalized pathophysiology-based treatment interventions.
