Adaptive threshold hunting for the effects of transcranial direct current stimulation on primary motor cortex inhibition

Abstract

Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA)-mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior-anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior-posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 ± 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICI was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICI and LICI modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after-effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA-mediated inhibitory circuits.

Preferential Activation of Unique Motor Cortical Networks With Transcranial Magnetic Stimulation: A Review of the Physiological, Functional, and Clinical Evidence

“…Consequently, conventional recruitment theory suggests that increasing the relative contribution of the late I‐waves to the descending volley by applying AP stimulation will increase the sensitivity of the associated MEP to activation of these intracortical circuits, producing greater inhibition (76). In support of this, several studies have reported that assessing SICI (9,77–81) and LICI (79) with an AP current results in greater levels of inhibition. While these findings support conventional recruitment theory, Cirillo and Byblow (79) also reported that preferential activation of late I‐waves (assessed using MEP onset latencies) only correlated with the magnitude of SICI measured with AP currents, whereas there was no relationship between SICI and I‐wave recruitment for PA currents.…”

“…These include spinal cord recordings from the cervical epidural space (a, recreated from reference (8), with permission. Individual subject data shown), SMU recordings (b, recreated from reference (9), with permission. Individual subject data shown), SICF (c, recreated from reference (10), with permission.…”

Can genetic polymorphisms predict response variability to anodal transcranial direct current stimulation of the primary motor cortex?

“…One such mechanism is the role other GABA receptors involved in motor cortex plasticity such as GABA‐B receptors (McDonnell et al., 2006) may play in the categorization of responders and non‐responders following a‐tDCS. It has been recently reported that both GABA‐A and GABA‐B mediated inhibition may be associated with the modulation of CSE following a‐tDCS and ultimately the observed inter‐individual variability following a‐tDCS (Mooney et al., 2018). To our knowledge, investigation into differences in GABA‐B receptor activity in a‐tDCS responders versus non‐responders is yet to be conducted and may provide deeper insight in mechanisms behind inter‐individual variability to a‐tDCS.…”

“…Albeit small, the slightly greater SICI values in GABRA3 gene rs1112122 and rs4828696 SNPs ‘Variant expression’ subgroup compared to the ‘Normal expression’ subgroup following a‐tDCS may highlight a trend towards reduced ICI, the non‐significant findings do not support this (Figures 4c and 5c). With ICI mediated by GABA receptors other than GABA‐A (McDonnell et al., 2006; Mooney et al., 2018), investigation into SNPs in genes that encode for other GABA receptors, such as GABA‐B, may offer additional insight into this potential relationship between a reduced capacity for ICI and a‐tDCS responder categorization.…”

“…With a fine balance between excitation and inhibition required to avoid excitotoxicity and to maintain normal neuronal network functioning, GABAergic inhibitory neurons play an important role in the ongoing regulation of excitatory Glutamatergic/NMDA neurons and therefore in LTP consolidation (Chapman et al., 1998; Rozov et al., 2017; Tatti et al., 2017). It is this regulatory role of GABAergic inhibitory neurons that has led to reports of GABAergic neurons playing a key regulatory role in the after‐effect changes in CSE following a‐tDCS (Mooney et al., 2018; Nitsche, et al., 2004). With previous reports that specific SNPs in genes encoding for GABA receptors may be associated with excitotoxicity and a reduced capacity for ICI (Hung et al., 2013), investigations into their involvement in inter‐individual variability following a‐tDCS is warranted.…”