Non-synaptic mechanisms underlie the after-effects of cathodal transcutaneous direct current stimulation of the human brain

Abstract

Although cathodal transcranial direct current stimulation (tDCS) decreases cortical excitability, the mechanisms underlying DC-induced changes remain largely unclear. In this study we investigated the effect of cathodal DC stimulation on spontaneous neural activity and on motor responses evoked by stimulation of the central and peripheral nervous system. We studied 17 healthy volunteers. Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the motor area were used to study the effects of cathodal tDCS (1.5 mA, 10 min) on resting motor threshold and motor evoked potentials (MEPs) recorded from the contralateral first dorsal interosseous muscle (FDI). The electroencephalographic (EEG) activity in response to cathodal tDCS was analysed by power spectral density (PSD). Motor axonal excitability changes in response to transcutaneous DC stimulation of the ulnar nerve (0.3 mA, 10 min) were assessed by testing changes in the size of the compound muscle action potential (CMAP) elicited by submaximal nerve stimulation. Cathodal tDCS over the motor area for 10 min increased the motor threshold and decreased the size of MEPs evoked by TMS for at least 60 min after current offset (t(0) 71.7 +/- 5%, t(20) 50.8 +/- 11%, t(40) 47.7 +/- 7.7%, and t(60) 39.7 +/- 6.4%, P < 0.01). The tDCS also significantly decreased the size of MEPs elicited by TES (t(0) 64 +/- 16.4%, P = 0.09; t(20) 67.6 +/- 10.8%, P = 0.06; and t(40) 58.3 +/- 9.9%, P < 0.05). At the same time in the EEG the power of delta (2-4 Hz) and theta (4-7 Hz) rhythms increased (delta 181.1 +/- 40.2, P < 0.05; and theta 138.7 +/- 27.6, P = 0.07). At the peripheral level cathodal DC stimulation increased the size of the ulnar nerve CMAP (175 +/- 34.3%, P < 0.05). Our findings demonstrate that the after-effects of tDCS have a non-synaptic mechanism of action based upon changes in neural membrane function. These changes apart from reflecting local changes in ionic concentrations, could arise from alterations in transmembrane proteins and from electrolysis-related changes in [H(+)] induced by exposure to constant electric field.

Figures

Figure 1. Effect of cathodal transcranial direct current stimulation (tDCS) on resting motor threshold (A) and on motor evoked potentials (MEP amplitude) (B,C) elicited by transcranial magnetic stimulation (TMS)

MEP amplitude is expressed as a percentage of the control unconditioned response; resting motor threshold is expressed as a percentage of control threshold; error bars show s.e.m. Time axis shows minutes after the end of tDCS or sham stimulation; □, tDCS (n = 7 subjects); Δ, sham stimulation (n = 5). *P < 0.05, **P < 0.01 Wilcoxon signed rank test. MEP recordings from a representative subject (C) showing the decrease in MEP amplitude after cathodal tDCS. Each trace is the average of 24 sweeps. t0 (0 min after tDCS), t20 (20 min after tDCS), t40 (40 min after tDCS), t60 (60 min after tDCS). Note the persistent decrease in MEP amplitude and persistent increase in resting motor threshold after cathodal tDCS but not after sham stimulation.

Figure 2. Effect of cathodal transcranial direct current stimulation (tDCS) on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES)

Consecutive non-averaged MEP recordings from a representative subject showing the persistent decrease in MEP amplitude 40 min after cathodal tDCS offset. A and B MEPs evoked by TMS. C and D MEPs evoked by TES. Note that the level of EMG activity in the 40 ms before test stimulus was similar in C and D.

Figure 3. Effect of transcranial direct current stimulation (tDCS) and sham tDCS on the power of EEG rhythms

▪: power spectral density (PSD) after tDCS offset (tDCS: right hemisphere cathodal polarity, left hemisphere anodal polarity, six subjects); Δ, PSD after sham stimulation (five subjects). Y-axes: power expressed as a percentage of the control value estimated on the EEG signal acquired for 30 min before scalp tDCS. Error bars show the s.e.m. Note the increased delta and theta rhythms after cathodal tDCS.

Figure 4. Effect of cathodal transcutaneous direct current (DC) stimulation and sham stimulation on the excitability of ulnar motor axons

A, CMAP recordings from a representative subject showing the increase in CMAP amplitude just above the threshold in ulnar nerve after cathodal transcutaneous DC stimulation. B, Δ: cathodal polarization (n = 7 subjects); □: sham stimulation (n = 6); Y-axis: compound muscle action potential (CMAP) size expressed as a percentage of the control unconditioned response; X-axis: test stimulation strength expressed as percentage (%) of motor threshold; error bars: s.e.m. Note the increased excitability of low-threshold motor axons after cathodal DC offset. *P < 0.05 Wilcoxon signed rank test. Note the persistent increase in CMAP size after cathodal transcutaneous DC stimulation but not after sham stimulation.