It has been suggested that the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are mediated through changes in cortical inhibition (CI). However, in healthy human subjects the effects of rTMS on CI have been inconsistent. Therefore, this study sought to improve on the methodological limitations of previous studies by exploring several different rTMS-stimulus conditions on inhibition in the human motor cortex. In the first experiment, 12 healthy control subjects were randomly assigned to receive regular 1, 10 or 20 Hz rTMS in a counterbalanced order with sessions separated by at least 1 week. In the second experiment, 10 of these 12 subjects received priming rTMS (600 stimuli at 6 Hz followed by 600 stimuli at 1 Hz). Cortical inhibition was indexed using short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Corticospinal excitability was indexed using motor threshold and MEP amplitude. We found no significant overall change in SICI, although there was a significant correlation between changes in SICI with baseline SICI. Subjects with greater SICI at baseline tended to have reduction in SICI post-rTMS, whereas subjects with less SICI tended to have increase in SICI post-rTMS. There was also a significant lengthening of the CSP with higher stimulation frequencies compared to lower stimulation frequencies. These findings suggest that rTMS increases CI, particularly in subjects with reduced baseline inhibition, a finding consistent with the concept of homeostatic plasticity. Baseline physiological characteristics may be further explored as a method to select patients who may benefit from rTMS treatment.

Several lines of evidence suggest that schizophrenia (SCZ) is associated with disrupted plasticity in the cortex. However, there is little direct neurophysiological evidence of aberrant long-term potentiation (LTP)-like plasticity in SCZ and little human evidence to establish a link between LTP to learning and memory. LTP was evaluated using a neurophysiological paradigm referred to as paired associative stimulation (PAS). PAS involves pairing of median nerve electric stimulation with transcranial magnetic stimulation (TMS) over the contralateral motor cortex (for abductor pollicis brevis muscle activation) delivered at 25-ms interstimulus interval. This pairing was delivered at a frequency of 0.1 Hz for 30 min. LTP was reflected by the change in motor evoked potentials (MEPs) before and after PAS. In addition, motor skill learning was assessed using the rotary pursuit task. Compared with healthy subjects, patients with SCZ demonstrated significant MEP facilitation deficits following PAS and impaired rotary-pursuit motor learning. Across all subjects there was a significant association between LTP and motor skill learning. These data provide evidence for disrupted LTP in SCZ, whereas the association between LTP with motor skill learning suggests that the deficits in learning and memory in SCZ may be mediated through disordered LTP.

It has been previously demonstrated that unmedicated persons with schizophrenia have deficits in cortical inhibition (CI) as indexed with transcranial magnetic stimulation (TMS). This inhibition is largely mediated by cortical GABAergic mechanisms. It has also been demonstrated that these inhibitory deficits may be normalized with the use of atypical antipsychotic medications. The purpose of this study, therefore, was to examine the effects of clozapine on TMS measures of CI and to compare these effects to unmedicated persons with schizophrenia and healthy subjects. We used two TMS inhibitory paradigms: short interval intra-cortical inhibition (SICI) and the cortical silent period (CSP) to evaluate CI in 10 clozapine-treated persons with schizophrenia, 6 unmedicated persons with schizophrenia and 10 healthy subjects. Clozapine-treated persons with schizophrenia had significantly longer CSPs compared with healthy subjects and unmedicated persons with schizophrenia. There were no significant differences in SICI between groups, however, the severity of psychotic symptoms was correlated with reduced SICI across all persons with schizophrenia. Our findings suggest that clozapine treatment is associated with greater CI in persons with schizophrenia and this increase may be related to potentiation of cortical GABAergic receptor mediated inhibitory neurotransmission. Our results also confirm previous findings suggesting that deficits in CI are related to the severity of psychotic symptoms in persons with schizophrenia.