Prefrontal Cortical Engagement Through Non-Invasive Brain Stimulation in Schizophrenia

Cognitive deficits are a strong predictor of functional outcome in schizophrenia, yet poorly
remediated by current treatments. Disturbances in dorsolateral prefrontal cortex (DLPFC)
function underlie core impairments such as in cognitive control and thus represent a critical
target for novel therapeutics. Initial studies indicate transcranial direct-current
stimulation (tDCS) may be effective in reducing symptoms due to DLPFC dysfunction. While tDCS
potentially represents an exciting, novel therapeutic advance, a number of basic questions
should be addressed prior to conducting larger-scale clinical trials, including: verifying
therapeutic target engagement, optimizing treatment parameters, and evaluating for meaningful
clinical effects. Recent studies employing tDCS to enhance prefrontal cortical function in
schizophrenia applied stimulating electrodes over the left frontal scalp region, putatively
targeting the left DLPFC. However, explicit confirmation of such target engagement is
lacking. Further, EEG studies have demonstrated close links of frontal cortical gamma
oscillations to cognitive control processes but modulation of this critical physiologic
process has not been investigated. Accordingly, the primary aim of this study is to employ
multimodal imaging to explicitly test for the assumed DLPFC engagement (fMRI) and modulation
of frontal gamma activity (EEG) by tDCS. This study will also investigate the optimization of
tDCS application parameters. Analogous to dose-finding investigations in drug studies, we
will conduct a parametric investigation of optimal current strengths. Also, while there is
extensive evidence for tolerability of single session tDCS, confirmation of feasibility of
multisession optimized protocols in schizophrenia is lacking and so will be explicitly
evaluated.

In summary, a successful outcome of this study would provide tDCS the sound mechanistic and
methodologic basis for more definitive testing in large-scale clinical trials as a highly
innovative therapeutic intervention for cognitive impairments in schizophrenia.

Inclusion Criteria:

1. ages 18-35 years;

2. within first five years of antipsychotic treatment;

3. on stable doses of second-generation antipsychotic medication for at least one month;

4. Clinically stable as defined by Clinical Global Impression−Severity scale (CGI−S) less
than or equal to 4 (moderately ill);

5. Mild to severe cognitive impairment in MATRICS Consensus Cognitive Battery (composite
scores <40);

6. DSM-5 criteria for schizophrenia or schizoaffective by patient SCID

Exclusion Criteria:

1. DSM-5 mental retardation;

2. significant head injury;

3. History of severe medical or neurological illnesses

4. pregnancy or postpartum (<6 weeks after delivery or miscarriage);

5. inability to provide informed consent;

6. significant color blindness that affects task performance;

7. Positive urine drug screen (exception for marijuana) or presence of substance use
disorder within 3 months;

8. Currently on benzodiazepines or mood stabilizers affecting GABA