Leila Chaieb

Increasing Human Brain Excitability by Transcranial High-Frequency Random Noise Stimulation

For >20 years, noninvasive transcranial stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) and direct current stimulation (tDCS) have been used to induce neuroplastic-like effects in the human cortex, leading to the activity-dependent modification of synaptic transmission. Here, we introduce a novel method of electrical stimulation: transcranial random noise stimulation (tRNS), whereby a random electrical oscillation spectrum is applied over the motor cortex. tRNS induces consistent excitability increases lasting 60 min after stimulation. These effects have been observed in 80 subjects through both physiological measures and behavioral tasks. Higher frequencies (100–640 Hz) appear to be responsible for generating this excitability increase, an effect that may be attributed to the repeated opening of Na+ channels. In terms of efficacy tRNS appears to possess at least the same therapeutic potential as rTMS/tDCS in diseases such as depression, while furthermore avoiding the constraint of current flow direction sensitivity characteristic of tDCS.

Comparatively weak after-effects of transcranial alternating current stimulation (tACS) on cortical excitability in humans

OBJECTIVE Interference with brain rhythms by noninvasive transcranial stimulation that uses weak transcranial alternating current may reveal itself to be a new tool for investigating cortical mechanisms currently unresolved. Here, we aim to extend transcranial direct current stimulation (tDCS) techniques to transcranial alternating current stimulation (tACS). BACKGROUND Parameters such as electrode size and position were taken from those used in previous tDCS studies. METHODS Motor evoked potentials (MEPs) revealed by transcranial magnetic stimulation (TMS), electroencephalogram (EEG)-power, and reaction times measured in a motor implicit learning task, were analyzed to detect changes in cortical excitability after 2-10 minutes of AC stimulation and sinusoidal DC stimulation (tSDCS) by using 1, 10, 15, 30, and 45 Hz and sham stimulation over the primary motor cortex in 50 healthy subjects (eight-16 subjects in each study). RESULTS A significantly improved implicit motor learning was observed after 10 Hz AC stimulation only. No significant changes were observed in any of the analyzed frequency bands of EEG and with regard to the MEP amplitudes after AC or tSDCS stimulation. Similarly, if the anodal or cathodal DC stimulation was superimposed on 5, 10, and 15 Hz AC stimulation, the MEP amplitudes did not change significantly. CONCLUSIONS Transcranial application of weak AC current may appear to be a tool for basic and clinical research in diseases with altered EEG activity. However, its effect seems to be weaker than tDCS stimulation, at least in the present context of stimulus intensity and duration. Further studies are required to extend cautiously the safety range and uncover its influence on neuronal circuitries.

Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans

BACKGROUND The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the adult brain. It has been demonstrated that BDNF also plays a significant role in shaping externally induced human brain plasticity. Plasticity induced in the human motor cortex by intermittent theta-burst stimulation (iTBS) was impaired in individuals expressing the Val66Met polymorphism. METHODS To explore whether this polymorphism is also important for other neuroplasticity-inducing tools in humans with modes of action differing from that of iTBS, namely, transcranial direct current (tDCS) and random noise stimulation (tRNS), we retrospectively analyzed the data of 64 subjects studied in our laboratory with regard to BDNF genotype. RESULTS Fifteen subjects with the Val66Met allele, 46 subjects with the Val66Val allele, and 3 Met66Met carriers were identified. The response of the Val66Met allele carriers to stimulation differed in two protocols compared with the response of Val66Val individuals. For iTBS (15 subjects, 5 heterozygotes), plasticity could be only induced in the Val66Val allele carriers. However, for facilitatory tDCS (24 subjects, 10 heterozygotes), as well as for inhibitory tDCS, (19 subjects, 8 heterozygotes), carriers of the Val66Met allele displayed enhanced plasticity, whereas for transcranial random noise stimulation (29 subjects, 8 heterozygotes), the difference between groups was not so pronounced. CONCLUSIONS BDNF polymorphism has a definite impact on plasticity in humans, which might differ according to the mechanism of plasticity induction. This impact of BDNF on plasticity should be taken into account for future studies, as well as having wider ranging implications for the treatment of neuropsychiatric disorders with transcranial stimulation tools, as it may predetermine their efficacy for the treatment of disease and rehabilitation.

Gender-specific modulation of short-term neuroplasticity in the visual cortex induced by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is a non-invasive method of modulating levels of cortical excitability. In this study, data gathered over a number of previously conducted experiments before and after tDCS, has been re-analyzed to investigate correlations between sex differences with respect to neuroplastic effects. Visual evoked potentials (VEPs), phosphene thresholds (PTs), and contrast sensitivity measurements (CSs) are used as indicators of the excitability of the primary visual cortex. The data revealed that cathodally induced excitability effects 10 min post stimulation with tDCS, showed no significant difference between genders. However, stimulation in the anodal direction revealed sex-specific effects: in women, anodal stimulation heightened cortical excitability significantly when compared to the age-matched male subject group. There was no significant difference between male and female subjects immediately after stimulation. These results indicate that sex differences exist within the visual cortex of humans, and may be subject to the influences of modulatory neurotransmitters or gonadal hormones which mirror short-term neuroplastic effects.

Transcranial alternating current stimulation in the low kHz range increases motor cortex excitability

PURPOSE External transcranial electric and magnetic stimulation techniques allow for the fast induction of sustained and measurable changes in cortical excitability. Here we aim to develop a paradigm using transcranial alternating current (tACS) in a frequency range higher than 1 kHz, which potentially interferes with membrane excitation, to shape neuroplastic processes in the human primary motor cortex (M1). METHODS Transcranial alternating current stimulation was applied at 1, 2 and 5 kHz over the left primary motor cortex with a reference electrode over the contralateral orbit in 11 healthy volunteers for a duration of 10 min at an intensity of 1 mA. Monophasic single- pulse transcranial magnetic stimulation (TMS) was used to measure changes in corticospinal excitability, both during and after tACS in the low kHz range, in the right hand muscle. As a control inactive sham stimulation was performed. RESULTS All frequencies of tACS increased the amplitudes of motor- evoked potentials (MEPs) up to 30-60 min post stimulation, compared to the baseline. Two and 5 kHz stimulations were more efficacious in inducing sustained changes in cortical excitability than 1 kHz stimulation, compared to sham stimulation. CONCLUSIONS Since tACS in the low kHz range appears too fast to interfere with network oscillations, this technique opens a new possibility to directly interfere with cortical excitability, probably via neuronal membrane activation. It may also potentially replace more conventional repetitive transcranial magnetic stimulation (rTMS) techniques for some applications in a clinical setting.

Pergolide increases the efficacy of cathodal direct current stimulation to reduce the amplitude of laser-evoked potentials in humans.

Transcranial direct current stimulation (tDCS) was recently reintroduced as a tool for inducing relatively long-lasting changes in cortical excitability in focal brain regions. Anodal stimulation over the primary motor cortex enhances cortical excitability, whereas cathodal stimulation decreases it. Prior studies have shown that enhancement of D2 receptor activity by pergolide consolidates tDCS-generated excitability diminution for up to 24 hours and that cathodal stimulation of the primary motor cortex diminishes experimentally induced pain sensation and reduces the N2-P2 amplitude of laser-evoked potentials immediately poststimulation. In the present study, we investigated the effect of pergolide and cathodal tDCS over the primary motor cortex on laser-evoked potentials and acute pain perception induced with a Tm:YAG laser in a double-blind, randomized, placebo-controlled, crossover study. The amplitude changes of laser-evoked potentials and subjective pain rating scores of 12 healthy subjects were analyzed prior to and following 15 minutes cathodal tDCS combined with pergolide or placebo intake at five different time points. Our results indicate that the amplitude of the N2 component was significantly reduced following cathodal tDCS for up to two hours. Additionally, pergolide prolonged the effect of the cathodal tDCS for up to 24 hours, and a significantly lowered pain sensation was observed for up to 40 minutes. Our study is a further step toward clinical application of cathodal tDCS over the primary motor cortex using pharmacological intervention to prolong the excitability-diminishing effect on pain perception for up to 24 hours poststimulation. Furthermore, it demonstrates the potential for repetitive daily stimulation therapy for pain patients.

Evaluating Aftereffects of Short-Duration Transcranial Random Noise Stimulation on Cortical Excitability

A 10-minute application of highfrequency (100–640 Hz) transcranial random noise stimulation (tRNS) over the primary motor cortex (M1) increases baseline levels of cortical excitability, lasting around 1 hr poststimulation Terney et al. (2008). We have extended previous work demonstrating this effect by decreasing the stimulation duration to 4, 5, and 6 minutes to assess whether a shorter duration of tRNS can also induce a change in cortical excitability. Single-pulse monophasic transcranial magnetic stimulation (TMS) was used to measure baseline levels of cortical excitability before and after tRNS. A 5- and 6-minute tRNS application induced a significant facilitation. 4-minute tRNS produced no significant aftereffects on corticospinal excitability. Plastic after effects after tRNS on corticospinal excitability require a minimal stimulation duration of 5 minutes. However, the duration of the aftereffect of 5-min tRNS is very short compared to previous studies using tRNS. Developing different transcranial stimulation techniques may be fundamental in understanding how excitatory and inhibitory networks in the human brain can be modulated and how each technique can be optimised for a controlled and effective application.

Short-duration transcranial random noise stimulation induces blood oxygenation level dependent response attenuation in the human motor cortex

Manipulation of cortical excitability can be experimentally achieved by the application of transcranial random noise stimulation (tRNS). TRNS is a novel method of non-invasive electrical brain stimulation whereby a random electrical oscillation spectrum is applied over the cortex. A previous study recently reported that application of weak 10-min tRNS over primary motor cortex (M1) enhances corticospinal excitability both during and after stimulation in the healthy human brain. Here, blood oxygenation level dependent (BOLD) MRI was used to monitor modulations in human sensorimotor activity after the application of 4-min tRNS. Activation maps for a right hand index–thumb finger opposition task were obtained for nine subjects after sham and 1-mA tRNS in separate sessions. TRNS of the left-hemispheric sensorimotor cortex resulted in a decrease in the mean number of activated pixels by 17%, in the hand area. Our results indicate that tRNS applied with different durations and/or in combination with a task might result in different outcomes. Application of tRNS to the human cortex allows an unnoticeable and thus painless, selective, non-invasive and reversible activity change within the cortex, its main advantage being the direction insensitivity of the stimulation. TRNS also provides a qualitatively new way of producing and interfering with brain plasticity, although, further research is required to optimise stimulation parameters and efficacy.

Cathodal stimulation of human MT+ leads to elevated fMRI signal: a tDCS-fMRI study.

PURPOSE Transcranial direct current stimulation (tDCS) was reintroduced about a decade ago as a tool for inducing long-lasting changes in cortical excitability. Recently it has been shown that both motor and cognitive functions can be influenced by tDCS. Here, we tested the effect of tDCS on the blood-oxygen level dependent (BOLD) signal evoked by coherent visual motion using functional magnetic resonance imaging (fMRI). METHODS The subjects underwent 10 min of cathodal and sham tDCS, applied over the right MT+. Following stimulation, random dot kinomatograms (RDK) with different percentages (10%, 30%, 50%) of coherently moving dots were presented. RESULTS All motion stimuli activated MT+ in both stimulation conditions. However, cathodal stimulation led to an increase in fMRI signal in MT+ when compared to sham stimulation. This effect did not depend on the coherence level of the visual stimulus. CONCLUSIONS Here, we show for the first time, that cathodal tDCS stimulation leads to elevated fMRI signal in the human visual cortex.

Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

Background: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 min induces a persistent excitability increase lasting for at least 60 min. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1 mA for 10 min stimulation duration and a pharmacological agent (or sham) on eight healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency toward inhibiting MEPs 5–60 min poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0–20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. Conclusions: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.