A.F. Leuchter, R. Espinoza, N. Suthana, A. Hunter, I.A. Cook
University of California Los Angeles, USA
DOI: http://dx.doi.org/10.1016/j.brs.2017.01.438

Introduction: Repetitive Transcranial Magnetic Stimulation (rTMS) applied to dorsolateral prefrontal cortex (DLPFC) causes acute changes in neuronal excitability in this region as well as changes in functional connectivity of brain circuitry involving DLPFC. Theta burst stimulation (TBS) has particularly strong effects on cortical excitability: intermittent pulsing of left DLPFC (iTBS) increases excitability, while continuous pulsing of the right DLPFC (cTBS) reduces excitability. TBS modulation of cortical excitability is known to be dependent upon glutamatergic neurotransmission through the N-Methyl-D-aspartate receptor (NMDAR).

Methods: We used the NMDAR antagonist ketamine (KET) to probe glutamatergic mediation of functional connectivity changes seen with TBS. Excitability in, and neurophysiologic connectivity of, DLPFC during iTBS and cTBS was monitored using TMS-compatible quantitative electroencephalography (qEEG). Subjects were pretreated with KET or placebo (PBO) prior to administration of TBS. Baseline functional magnetic resonance imaging (fMRI) and Diffusion Tensor Imaging (DTI) were performed to examine functional and structural connectivity measures, with follow-up scans to examine changes associated with treatment.

Results: Both TBS and KET had robust effects on cortical excitability. TBS was associated with local changes in excitability involving DLPFC, while KET (but not placebo) was associated with more global changes in excitability. Pretreatment with KET modulated the excitability effects of iTBS in left DLPFC and the inhibitory effects of cTBS in right DLPFC. Changes in excitability were correlated with connectivity of DLPFC, anterior cingulate cortex, medial frontal cortex, and orbitofrontal cortex.

Discussion: Ketamine constitutes a useful neurochemical probe of the mechanisms underlying the physiologic effects of TBS on excitability, connectivity, and neuroplastic processes. Future studies should examine the potential clinical impact of combining these treatment modalities.

TMS Center of SWFL finds a combination of ketamine and TBS can be an effective treatment of Major Depressive Disorder in some patients.