Functional and effective connectivity between dorsolateral prefrontal and subgenual anterior cingulate cortex depends on the timing of transcranial magnetic stimulation relative to the phase of prefrontal alpha EEG

Abstract

The communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited. Here, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Results in healthy volunteers (n=11) were compared to those from patients with major depressive disorder (MDD) (n=17) collected as part of a ongoing clinical trial investigation. In both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC effective connectivity (EC) was moderated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS onsets during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group. Results demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest clinical applications whereby TMS is synchronized to internal rhythms of the brain in order to more efficiently engage deep therapeutic targets.

Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression

“…Before recruitment, all patients were screened for all inclusion and exclusion criteria described in [27], [25], and [28]. Then the pre-treatment scan (scan#1) was done with our integrated fMRI-EEG-TMS (fET) system to determine the pre-treatment preferred phase ϕ pre of each subject [19, 25]. For patients assigned to the SYNC group, the ϕ pre measured for each patient was used as their target phase ϕ tar for the entire closed-loop EEG-rTMS treatment (i.e., ϕ tar = ϕ pre ).…”

“…The pretreatment scan (scan #1) was done with an fMRI-EEG-TMS (fET) system to determine the subject specific “preferred” phase ϕ pre for each patient [23, 25, 26]. ϕ pre is defined as the alpha phase that evoked the strongest activity in the dorsal anterior cingulate cortex (dACC) after the TMS administration [19, 26]. If the patient was assigned to the SYNC group, this phase was the target phase ϕ tar during the treatment.…”

Circular Clustering With Polar Coordinate Reconstruction

“…In a previous clinical study, we measured the inter-trial phase coherence (ITPC) of the quasi-alpha oscillation (6-13Hz) from participants' EEG signals [9,22,38]. In this study, we hypothesized that stronger and more precise intertrial coherence would be a biomarker of the efficacy of a neurostimulation therapeutic.…”

“…For instance, the rhythmically synchronized activity in the brain is widely believed to play a fundamental role in coordinating information transfer during goaldirected behavior [5,6]. Recent studies suggest that the phase of ongoing oscillatory activity relative to endogenous or exogenous cues will facilitate coordinated information transfer within circuits and between distributed brain areas and provide windows for optimal communication between two or more brain areas [7,8,9]. Investigating phase synchronization, which is represented with polar coordinates, requires appropriate analysis tools to characterize aspects of the oscillatory activity, and one approach to do this is via unsupervised clustering.…”

Biomarkers predict the efficacy of closed-loop rTMS treatment for refractory depression

“…The pretreatment scan (scan #1) was done with an fMRI-EEG-TMS (fET) system to determine the subject specific "preferred" phase φpre for each patient [23,25,26]. φpre is defined as the alpha phase that evoked the strongest activity in the dorsal anterior cingulate cortex (dACC) after the TMS administration [19,26]. If the patient was assigned to the SYNC group, this phase was the target phase φ tar during the treatment.…”