Neural plasticity is crucial for understanding the experience-dependent reorganization of brain regulatory circuits and the pathophysiology of schizophrenia. An important circuit-level feature derived from functional magnetic resonance imaging (fMRI) is prefrontalhippocampal seeded connectivity during working memory, the best established intermediate connectivity phenotype of schizophrenia risk to date. The phenotype is a promising marker for the effects of plasticity-enhancing interventions, such as high-frequency repetitive transcranial magnetic stimulation (rTMS), and can be studied in healthy volunteers in the absence of illness-related confounds, but the relationship to brain plasticity is unexplored. We recruited 39 healthy volunteers to investigate the effects of 5 Hz rTMS on prefrontalhippocampal coupling during working memory and rest. In a randomized and sham-controlled experiment, neuronavigation-guided rTMS was applied to the right dorsolateral prefrontal cortex (DLPFC), and fMRI and functional connectivity analyses [seeded connectivity and psychophysiological interaction (PPI)] were used as readouts. Moreover, the test-retest reliability of working-memory related connectivity markers was evaluated. rTMS provoked a significant decrease in seeded functional connectivity of the right DLPFC and left hippocampus during working memory that proved to be relatively time-invariant and robust. PPI analyses provided evidence for a nominal effect of rTMS and poor test-retest reliability. No effects on n-back-related activation and DLPFC-hippocampus resting-state connectivity were observed. These data provide the first in vivo evidence for the effects of plasticity induction on human prefrontalhippocampal network dynamics, offer insights into the biological mechanisms of a well established intermediate phenotype linked to schizophrenia, and underscores the importance of the choice of outcome measures in test-retest designs.

Neuronal plasticity is crucial for flexible interaction with a changing environment and its disruption is thought to contribute to psychiatric diseases like schizophrenia. High-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool to increase local excitability of neurons and induce short-time functional reorganization of cortical networks. While this has been shown for the motor system, little is known about the short-term plasticity of networks for executive cognition in humans. We examined 12 healthy control subjects in a crossover study with fMRI after real and sham 5 Hz rTMS to the right dorsolateral prefrontal cortex (DLPFC). During scanning, subjects performed an n-back working memory (WM) task and a flanker task engaging cognitive control. Reaction times during the n-back task were significantly shorter after rTMS than after sham stimulation. RTMS compared with sham stimulation caused no activation changes at the stimulation site (right DLPFC) itself, but significantly increased connectivity within the WM network during n-back and reduced activation in the anterior cingulate cortex during the flanker task. Reduced reaction times after real stimulation support an excitatory effect of high-frequency rTMS. Our findings identified plastic changes in prefrontally connected networks downstream of the stimulation site as the substrate of this behavioral effect. Using a multimodal fMRI-rTMS approach, we could demonstrate changes in cortical plasticity in humans during executive cognition. In further studies this approach could be used to study pharmacological, genetic and disease-related alterations.