Project Summary/Abstract
Auditory hallucinations associated with schizophrenia (Sz) are pervasive, debilitating, and disturbing.
Unfortunately, they are also difficult to treat – auditory hallucinations persist in about 25% of cases despite
pharmacotherapy1 and treatment of cognitive symptoms (the symptoms most strongly related to global
functioning) is modest at best. We propose a novel, inexpensive, and noninvasive intervention to address
treatment-refractory symptoms, a critical need in Sz. Auditory hallucinations and impaired cognition in
schizophrenia are not independent. Both are associated with system-level dysfunction of the fronto-temporal
auditory control network, comprising auditory/verbal perceptual areas in temporoparietal junction (TPJ) and
cognitive/behavioral control systems in ventrolateral prefrontal cortex (VLPFC). VLPFC traditionally inhibits and
reattributes perceptual misrepresentations in most people2. For those with schizophrenia, impairment of auditory
cognitive control makes this impossible. Data from our lab suggest that auditory control network dysfunction may
be central to the early etiology of the disorder3. Auditory control enhancement (ACE) is designed to improve
auditory control network function, thereby increasing inhibition of spurious auditory system activity in
temporoparietal cortex and reducing auditory hallucinations. ACE combines a time-tested psychotherapeutic
behavioral training program with targeted non-invasive brain stimulation using transcranial Direct Current
Stimulation (tDCS). Our pilot data demonstrate the effectiveness of the behavioral training program and
synergistic effects with tDCS of the auditory control network for treating treatment-refractory auditory
hallucinations in schizophrenia. To further develop ACE for efficacy trials, we plan to investigate neural markers
of target engagement in two sham-controlled experiments. Aim 1 will determine whether tDCS of right vlPFC
(anode) and left TPJ (cathode) during MRI alters electric field measures and blood oxygenation level dependent
(BOLD) response during stimulation to demonstrate that markers of tDCS current flow and BOLD fluctuate with
induced current, and these fluctuations align spatially with computer models. Aim 2 will examine feasibility of
subject retention and blinding for ACE. Aim 3 will examine the degree to which ACE modifies behavioral,
neurophysiological, and hemodynamic markers of target engagement using neural oscillatory and cerebral blood
flow (CBF) measures. Pilot data show feasibility of our aims and provide preliminary evidence that ACE has
strong and lasting effects on auditory hallucinations assessed with the psychotic symptoms rating scale
(PSYRATS), and that changes in cognitive factors associated with auditory hallucinations strongly correlate with
changes in neural oscillatory measures of cognitive control. ACE represents a novel, transformative intervention
with long-lasting effects that has the potential to change the treatment of schizophrenia and vastly improve the
outcome for afflicted individuals.