Pilot Study: Evaluating the Feasibility of Repetitive Transcranial Magnetic Stimulation Treatment Delivered at Individual-based, SCC-determined Frequency in Subjects Suffering From Major Depressive Disorder

The therapeutic benefit of repetitive Transcranial Magnetic Stimulation (rTMS) for the treatment of Major Depressive Disorder (MDD) is thought to depend upon engagement of brain functional networks (FNs). Engagement is dependent upon an interaction between the rTMS stimulation frequency and the preferred oscillatory frequency of the target network for that individual. We report here on a novel method to interrogate the left dorsolateral prefrontal cortex (DLPFC) treatment target to identify the optimal frequency for engagement of the frontoparietal control network (FCN) for each individual. 23 subjects with MDD were stimulated with 40 pulse rTMS trains at frequencies varying from 3-17 Hz at 0.2 Hz increments, plus a separate intermittent theta burst (iTBS) stimulation, for a total of 70 frequency interrogations. FN engagement was assessed using continuous high-density array TMS-EEG recordings and measurement of the change in the density of the spectral correlation coefficient (SCC) between left DLPFC and other brain areas following each interrogation. All subjects had one or more frequency bands that showed high SCC values across multiple FNs, regardless of the frequency of interrogation. Those subjects who showed clinical response to 10 Hz rTMS showed increases in SCCD over FCN connections across in response to 10 Hz interrogation, but not in response to interrogation in other bands. There was a strong association between the increase in SCCD in FCN and degree of improvement in depressive symptoms after both 2 and 6 weeks of treatment. These findings suggest that SCC density may be useful for identifying rTMS stimulation frequencies that are associated with therapeutic benefit in MDD. This study will examine the feasibility using these findings to determine if SCC-determined rTMS treatment can benefit subjects with Major Depressive Disorder.

INTRODUCTION AND RATIONALE

Repetitive Transcranial Magnetic Stimulation (rTMS) has been reported to relieve symptoms of Major Depressive Disorder (MDD) when administered at a number of different stimulation frequencies: 1, 5, 10, 15, 18, and 50 Hz (theta burst stimulation, or TBS) all have reported to provide clinical benefit. It is difficult to compare the efficacy of these different frequencies of stimulation because of differences in study design and limitations of sample size, but there is significant evidence of efficacy for each of these frequencies when applied to one or more stimulation targets.1 There have not been head-to-head studies to compare different stimulation frequencies in individual subjects to determine whether individuals have similar clinical responses to more than one frequency of stimulation.

One feature that is shared by all frequencies of rTMS is that while stimulation is ongoing, both neuronal spiking and ongoing oscillations are synchronized to the frequency of stimulation (Fröhlich and McCormick, 2010 ; Thut et al., 2011 ). This modulation of cerebral oscillatory activity is hypothesized to underlie the therapeutic effects of rTMS for MDD. , Entrainment of brain oscillations has been shown to modify brain activity in a variety of functional networks (FNs), with changes in oscillations associated with alterations in task performance, local oscillatory activity, connectivity patterns and in the case of motor networks, corticospinal coupling.

Different frequencies of rTMS stimulation have distinct effects on FN engagement and task performance. These differential effects are consistent with the fact that FNs have one or more preferred resonant frequencies that mediate connectivity both within and across networks (Hacker et al., 2017 , , , The effects of rTMS stimulation depends upon the interaction between the frequency of stimulation and the ongoing oscillatory activity of the target FN(s): the oscillatory pattern of the specific brain region being stimulated (as measured with electroencephalography [EEG]) is a major determinant of rTMS engagement with the associated FN(s)3, and the effects on network performance.