title: Application of high-frequency repetitive transcranial magnetic stimulation to the DLPFC alters human prefrontal-hippocampal functional interaction.
abstract: 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 prefrontal-hippocampal 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 prefrontal-hippocampal 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 prefrontal-hippocampal 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.
authors.affiliation: Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, 68159 Mannheim, Germany.
authors.forename: Edda
authors.initials: E
authors.lastname: Bilek
authors.forename: Axel
authors.initials: A
authors.lastname: Schäfer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ochs
authors.forename: Christine
authors.initials: C
authors.lastname: Esslinger
authors.forename: Maria
authors.initials: M
authors.lastname: Zangl
authors.forename: Michael M
authors.initials: MM
authors.lastname: Plichta
authors.forename: Urs
authors.initials: U
authors.lastname: Braun
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001931:Brain Mapping; D005260:Female; D006624:Hippocampus / Q000098:blood supply / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D009434:Neural Pathways / Q000098:blood supply / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000098:blood supply / Q000502:physiology*; D015203:Reproducibility of Results; D050781:Transcranial Magnetic Stimulation; D055815:Young Adult
chemical_list: D010100:Oxygen