Boosting brain excitability by transcranial high frequency stimulation in the ripple range

Abstract

Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80–250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation.

Figure 1. tAC stimulation under complete muscle relaxation

A, 140 Hz AC stimulation significantly increased MEPs at the ST2–ST10 and PST0–PST60 time points compared to the sham stimulation (*P < 0.05). B, controls by sham and 80 Hz stimulation were without any effect. C, 250 Hz AC stimulation significantly increased MEPs at the ST6–ST10 and PST0–PST5. The figure shows mean amplitudes of MEPs and their s.e.m. during 10 min and after tAC stimulation up to 60 min. Filled symbols indicate significant deviations of the during- and post-measurements of MEP amplitudes from baseline values; *P < 0.05. D, recalculated data of A, B and C in order to sum up the 1 mA tACS induced effects on cortical excitability. Different frequencies show different behaviours. Using 140 Hz stimulation MEP amplitudes increased most. Post hoc tests showed that the 140 Hz tACS applied with 1 mA intensity induced a significant elevation in MEP compared to 80 Hz and 250 Hz stimulation (Fisher's LSD test, P < 0.05). Error bars indicate s.e.m. The bar graphs show the MEP value from ST1 to PST60. *P < 0.05.

Figure 2. tACS of 140 Hz under complete muscle relaxation shifts the slope of the input–output curve

The MEP amplitudes (means ±s.e.m.) at 110, 130 and 150% of resting MT (RMT) are shown for sham, 80, 140 and 250 Hz tAC stimulations. *P < 0.05, Fisher's LSD test.

Figure 3. Intracortical inhibition and facilitation is modulated by tACS

The single-pulse standardized double-stimulation MEP amplitude ratios ±s.e.m. are depicted for ISIs revealing inhibitory (ISIs of 2 and 4 ms) and facilitatory (ISIs of 7, 9 and 12 ms) effects for the different tACS protocols. A and C, 80 Hz (A) and 250 Hz (C) stimulation do not shift inhibition and facilitation relative to the sham stimulation. B, 140 Hz stimulation reduces SICI. D, bar graphs show the mean of MEP value (±s.e.m.) for SICI (ISI 2 and 4 ms) and ICF (ISI 7, 9 and 12 ms) for each condition. *P < 0.05, Fisher's LSD test.

Figure 4. Motor task-related modulation of different frequency tACS

The figure shows mean amplitudes of MEPs and their s.e.m. after tAC stimulation under motor activation up to 60 min. Stimulation of 80 Hz AC and 250 Hz did not modify the MEP amplitudes significantly, when compared with sham stimulation. In contrast, 140 Hz stimulation during contraction still induced a significant elevation in MEP amplitude compared to sham stimulation. According to the post hoc analysis, significantly increased MEPs were observed in 140 Hz at the PST5–PST50 time points compared to the time point using sham stimulation. Filled symbols indicate significant deviations of the post-measurements of MEP amplitudes from baseline values. *P < 0.05, Fisher's LSD test.

Figure 5. Serial reaction time task (SRTT) and tACS

Stimulation at 80 Hz and 140 Hz of the primary motor cortex did not improve implicit motor learning. Interestingly, with 250 Hz a slight but non-significant improvement was evident in Blocks 2–5. Reduced RTs in Blocks 7 and 8 have been identified in two tACS frequency conditions: 80 and 250 Hz, compared to the sham condition. This effect was missing in the 140 Hz tACS condition.