Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders.Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n ϭ 22) and ephrin-A2A5 In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5Ϫ/Ϫ mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5 Ϫ/Ϫ mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.

Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium-intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test; neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI-rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of α-amino-n-butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, α-amino-n-butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression.

Repetitive transcranial magnetic stimulation (rTMS) induces plasticity in normal and abnormal neural circuitries, an effect that may be influenced by intrinsic brain activity during treatment. Here, we study potential synergistic effects between low-intensity rTMS (LI-rTMS) and concurrent neural activity in promoting circuit reorganization and enhancing visual behavior. We used ephrin-A2A5–/– mice, which are known to possess visuotopic mapping errors that are ameliorated by LI-rTMS, and assessed the impact of stimulation when mice were engaged in a visual learning task. A detachable coil was affixed to each mouse, and animals underwent 2 wk of 10-min daily training in a two-choice visual discrimination task with concurrent LI-rTMS or sham stimulation. No-task controls (+LI-rTMS/sham) were placed in the task arena without visual task training. At the end of the experiment, visuomotor tracking behavior was assessed, and corticotectal and geniculocortical pathway organization was mapped by injections of fluorescent tracers into the primary visual cortex. Consistent with previous results, LI-rTMS alone improved geniculocortical and corticotectal topography, but combining LI-rTMS with the visual learning task prevented beneficial corticotectal reorganization and had no additional effect on geniculocortical topography or visuomotor tracking performance. Unexpectedly, there was a significant increase in the total number of trials completed by task + LI-rTMS mice in the visual learning task. Comparison with wild-type mice revealed that ephrin-A2A5–/– mice had reduced accuracy and response rates, suggesting a goal-directed behavioral deficit, which was improved by LI-rTMS. Our results suggest that concurrent brain activity during behavior interacts with LI-rTMS, altering behavior and different visual circuits in an abnormal system.

Repetitive transcranial stimulation (rTMS) is an increasingly popular method to non-invasively modulate cortical excitability in research and clinical settings. During rTMS, low-intensity magnetic fields reach areas perifocal to the target brain region, however, effects of these low-intensity (LI-) fields and how they interact with ongoing neural activity remains poorly defined. We evaluated whether coordinated neural activity during electromagnetic stimulation alters LI-rTMS effects on cortical excitability by comparing visually evoked potentials (VEP) and densities of parvalbumin-expressing (PV+) GABAergic interneurons in adult mouse visual cortex after LI-rTMS under different conditions: LI-rTMS applied during visually evoked (strong, coordinated) activity or in darkness (weak, spontaneous activity).We also compared response to LI-rTMS in wildtype and ephrin-A2A5−/− mice, which have visuotopic anomalies thought to disrupt coherence of visually-evoked cortical activity. Demonstrating that LI-rTMS effects in V1 require concurrent sensory-evoked activity, LI-rTMS delivered during visually-evoked activity increased PV+ immunoreactivity in both genotypes; however, VEP peak amplitudes changed only in wildtypes, consistent with intracortical disinhibition. We show, for the first time, that neural activity and the degree of coordination in cortical population activity interact with LI-rTMS to alter excitability in a context-dependent manner.