Paired Associative Stimulation in the Dorsolateral Prefrontal Cortex in Patients With Schizophrenia

The purpose of this study is to 1. assess the effect of PAS in schizophrenia in the dorsolateral prefrontal cortex (DLPFC) 2. assess the effect of PAS induced long-term potentiation (LTP) on the performance of patients with schizophrenia on a cognitive task related to DLFPC.

Neuroplasticity refers to changes in the strength of communication between different neurons. Long-term potentiation (LTP) is one form of neuroplasticity and refers to the strengthening of such communication. LTP is believed to be a cellular substrate of learning and memory. Paired associative stimulation (PAS) is a transcranial magnetic stimulation (TMS) paradigm that is believed to induce LTP in human subjects. However, its effects have been shown to be minimal in patients with schizophrenia suggesting impaired LTP in schizophrenia. The lack of PAS effect in schizophrenia has been observed in the motor cortex (M1). Thus, the investigators propose to assess the effect of PAS in schizophrenia in the dorsolateral prefrontal cortex (DLPFC), an area of the brain that is especially relevant to learning and memory, and to the pathology in schizophrenia. The investigators also propose to assess the effect of PAS induced LTP on the performance of patients with schizophrenia on a cognitive task that is related to DLFPC. Hypothesis 1: Patients with schizophrenia will have reduced PAS-LTP in DLPFC in comparison with healthy controls. Hypothesis 2a: PAS-LTP in patients with schizophrenia and healthy controls randomized to PAS-25 and PAS-100 will correlate with performance on the N-back task at baseline (pre-PAS). Hypothesis 2b: Healthy controls randomized to PAS-25 will perform better after one session of PAS-25 on the 1- and 7-day N-back task compared to healthy controls randomized to PAS-100. Hypothesis 2c: Among healthy controls randomized to PAS-25, the magnitude of improvement on the 1- and 7-day N-back task (compared to pre-PAS) that is in excess of the magnitude of improvement on the 1- and 7-day N-back task among subjects randomized to PAS-100 will correlate with the degree of PAS-LTP. Hypothesis 3a: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have improved PAS-LTP in DLPFC compared to patients with schizophrenia randomized to 2-week course of PAS-100. Hypothesis 3b: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have improved performance on the N-back working memory task compared to patients with schizophrenia randomized to 2-week PAS-100 at 1- and 7-day post-PAS course N-back. Hypothesis 3c: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have increased DLPFC cortical thickness compared to patients with schizophrenia randomized to 2-week PAS-100. Hypothesis 4: Among patients with schizophrenia and healthy controls, PAS-LTP will decrease with age, and the decrease will be more pronounced in healthy controls than in patients.