Alpha power increase after transcranial alternating current stimulation at alpha frequency (α-tacs) reflects plastic changes rather than entrainment

Background: Periodic stimulation of occipital areas using transcranial alternating current stimulation (tACS) at alpha (α) frequency (8–12 Hz) enhances electroencephalographic (EEG) α-oscillation long after tACS-offset. Two mechanisms have been suggested to underlie these changes in oscillatory EEG activity: tACS-induced entrainment of brain oscillations and/or tACS-induced changes in oscillatory circuits by spike-timing dependent plasticity.<p></p> Objective: We tested to what extent plasticity can account for tACS-aftereffects when controlling for entrainment “echoes.” To this end, we used a novel, intermittent tACS protocol and investigated the strength of the aftereffect as a function of phase continuity between successive tACS episodes, as well as the match between stimulation frequency and endogenous α-frequency.<p></p> Methods: 12 healthy participants were stimulated at around individual α-frequency for 15–20 min in four sessions using intermittent tACS or sham. Successive tACS events were either phase-continuous or phase-discontinuous, and either 3 or 8 s long. EEG α-phase and power changes were compared after and between episodes of α-tACS across conditions and against sham.<p></p> Results: α-aftereffects were successfully replicated after intermittent stimulation using 8-s but not 3-s trains. These aftereffects did not reveal any of the characteristics of entrainment echoes in that they were independent of tACS phase-continuity and showed neither prolonged phase alignment nor frequency synchronization to the exact stimulation frequency.<p></p> Conclusion: Our results indicate that plasticity mechanisms are sufficient to explain α-aftereffects in response to α-tACS, and inform models of tACS-induced plasticity in oscillatory circuits. Modifying brain oscillations with tACS holds promise for clinical applications in disorders involving abnormal neural synchrony

Phase Dependency of the Human Primary Motor Cortex and Cholinergic Inhibition Cancelation during Beta tACS

The human motor cortex has a tendency to resonant activity at about 20 Hz so stimulation should more readily entrain neuronal populations at this frequency. We investigated whether and how different interneuronal circuits contribute to such resonance by using transcranial magnetic stimulation (TMS) during transcranial alternating current stimulation (tACS) at motor (20 Hz) and a nonmotor resonance frequency (7 Hz). We tested different TMS interneuronal protocols and triggered TMS pulses at different tACS phases. The effect of cholinergic short-latency afferent inhibition (SAI) was abolished by 20 Hz tACS, linking cortical beta activity to sensorimotor integration. However, this effect occurred regardless of the tACS phase. In contrast, 20 Hz tACS selectively modulated MEP size according to the phase of tACS during single pulse, GABAAergic short-interval intracortical inhibition (SICI) and glutamatergic intracortical facilitation (ICF). For SICI this phase effect was more marked during 20 Hz stimulation. Phase modulation of SICI also depended on whether or not spontaneous beta activity occurred at ~20 Hz, supporting an interaction effect between tACS and underlying circuit resonances. The present study provides in vivo evidence linking cortical beta activity to sensorimotor integration, and for beta oscillations in motor cortex being promoted by resonance in GABAAergic interneuronal circuits

State-Dependent Variability of Neuronal Responses to Transcranial Magnetic Stimulation of the Visual Cortex

SummaryElectrical brain stimulation is a promising tool for both experimental and clinical applications. However, the effects of stimulation on neuronal activity are highly variable and poorly understood. To investigate the basis of this variability, we performed extracellular recordings in the visual cortex following application of transcranial magnetic stimulation (TMS). Our measurements of spiking and local field potential activity exhibit two types of response patterns which are characterized by the presence or absence of spontaneous discharge following stimulation. This variability can be partially explained by state-dependent effects, in which higher pre-TMS activity predicts larger post-TMS responses. These results reveal the possibility that variability in the neural response to TMS can be exploited to optimize the effects of stimulation. It is conceivable that this feature could be utilized in real time during the treatment of clinical disorders

Motor system plasticity induced by non-invasive stimuli

MD ThesisPrecisely timed paired stimulation protocols can change cortical and subcortical excitability. In the first study, induction of plastic changes in the long-latency stretch reflex (LLSR) by pairing non-invasive stimuli was attempted, at timings predicted to cause spiketiming dependent plasticity (STDP) in the brainstem. LLSR in human elbow muscles depends on multiple pathways; one possible contributor is the reticulospinal tract. The stimuli used are known to activate reticulospinal pathways. In healthy human subjects, reflex responses in flexor muscles were recorded following extension perturbations at the elbow. Subjects were then fitted with a portable device which delivered auditory click stimuli, and electrical stimuli to biceps muscle. The LLSR was significantly enhanced or suppressed in the biceps muscle depending on the intervention protocol. No changes were observed in the unstimulated brachioradialis muscle. Although contributions from the spinal or cortical pathways cannot be excluded, the results were consistent with STDP in reticulospinal circuits. In the second study, baseline TMS responses were recorded from two intrinsic hand muscles, flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC). In the first phase, paired associative stimulation (PAS) was delivered by pairing motor point stimulation of FDS or EDC with TMS. Responses were then remeasured. Increases were greatest in the hand muscles, smaller in FDS, and non-significant in EDC. In the second phase, intermittent theta-burst rapid-rate TMS was applied instead of PAS. In this case, all muscles showed similar increases in TMS responses. This study showed that potential plasticity in motor cortical output has a gradient: hand muscles > flexors > extensors. However, this was only seen in a protocol which requires integration of sensory input (PAS), and not when plasticity was induced purely by cortical stimulation (rapid rate TMS). In the third study, motor imagery was paired with TMS in healthy human subjects. They were asked to imagine wrist flexion or extension movement, while TMS was delivered to the motor cortex. Six different protocols were tested, but only flexor imagination with TMS and extensor imagination with TMS showed significant facilitation following the test. Flexor imagination with TMS increased motor evoked potential (MEP) in all four Abstract 2 muscles with maximum changes towards flexor, whereas extensor imagination with TMS increased MEP only in extensor. Above changes in the cortical or subcortical excitability evoked by non-invasive stimulation protocols were consistent with long term potentiation and long-term depression mediated plastic change

Dissecting two distinct interneuronal networks in M1 with transcranial magnetic stimulation

Interactions from both inhibitory and excitatory interneurons are necessary components of cortical processing that contribute to the vast amount of motor actions executed by humans daily. As transcranial magnetic stimulation (TMS) over primary motor cortex is capable of activating corticospinal neurons trans-synaptically, studies over the past 30 years have provided how subtle changes in stimulation parameters (i.e., current direction, pulse width, and paired-pulse) can elucidate evidence for two distinct neuronal networks that can be probed with this technique. This article provides a brief review of some fundamental studies demonstrating how these networks have separable excitatory inputs to corticospinal neurons. Furthermore, the findings of recent investigations will be discussed in detail, illustrating how each network’s sensitivity to different brain states (i.e., rest, movement preparation, and motor learning) is dissociable. Understanding the physiological characteristics of each network can help to explain why interindividual responses to TMS exist, while also providing insights into the role of these networks in various human motor behaviors

Sensorimotor integration in dystonia: pathophysiology and possible non-invasive approaches to therapy

Dystonia is a condition characterized by excessive and sustained muscle contractions causing abnormal postures and involuntary movements. The pathophysiology of dystonia includes loss of inhibition and abnormal plasticity in the somatosensory and motor systems; however, their contribution to the phenomenology of dystonia is still uncertain, and the possibility to target these abnormalities in an attempt to devise new treatments has not been thoroughly explored. This thesis describes how abnormal inhibition and plasticity in the somatosensory system of dystonic patients can be manipulated to ameliorate motor symptoms by means of peripheral stimulation. First, we characterized electrophysiological and behavioural markers of inhibition in the primary somatosensory cortex in a group of patients with idiopathic cervical dystonia (CD). Outcome measures included a) somatosensory temporal discrimination threshold (STDT); b) paired-pulse somatosensory evoked potentials (PP-SEP) tested with interstimulus intervals (ISIs) of 5, 20 and 40 ms; c) spatial somatosensory inhibition ratio (SIR) by measuring SEP interaction between simultaneous stimulation of the digital nerves in thumb and index finger; d) high-frequency oscillations (HFO) extracted from SEP obtained with stimulation of digital nerves of the index finger. This first investigation demonstrated that increased STDT in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex, as reflected by reduced PP-SEP inhibition at ISI of 5 ms and reduced area of the late part of the HFO (l-HFO). In a second set of experiments, we applied high frequency repetitive somatosensory stimulation (HF-RSS), a patterned electric stimulation applied to the skin through surface electrodes, to the index finger in a sample of healthy subjects, with the aim to manipulate excitability and inhibition of the primary somatosensory (S1) and motor (M1) cortices. The former was assessed by the same methods used before (STDT, PP-SEP, HFO), with the addition of two psychophysical tasks designed to assess tactile spatial discrimination (grating orientation and bumps tests). Assessment of physiology of M1 was performed by means of short intracortical inhibition (SICI) assessed with TMS; this was performed with multiple conditioning stimulus (CS) intensities (70%, 80%, 90% of the active motor threshold) and with a insterstimulus interval (ISI) between conditioning and test stimulus of 3 ms. It was found that HF-RSS increased inhibition in S1 tested by PP-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally, there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Overall, these findings demonstrated that HF-RSS is able to modify the effectiveness of inhibitory circuitry in S1 and M1. The results obtained so far led us to hypothesize that HF-RSS could restore inhibition in dystonic patients, similar to what observed in healthy subjects. To test this, we applied HF-RSS on the index finger in a sample of patients with CD, and tested its effects with some of the outcome measures used before (STDT, PP-SEP, HFO, SIR, SICI). Unexpectedly, the results were opposite to what was predicted. Patients with CD showed a consistent, paradoxical response: after HF-RSS, they had reduced suppression of PP-SEP, as well as decreased HFO area and SICI, and increased SIR. STDT deteriorated after the stimulation protocol, and correlated with reduced measures of inhibition within S1 (PP-SEP at 5 ms ISI, l-HFO area). It was hypothesized that patients with CD have abnormal homeostatic inhibitory plasticity within the sensorimotor cortex and that this is responsible for their abnormal response to HF-RSS. Interestingly, this alteration in plasticity seems to be specific to idiopathic dystonia: when the same protocol was applied to patients with dystonia caused by lesions in the basal ganglia, the response was similar to healthy controls. This result suggests that reduced somatosensory inhibition and abnormal cortical plasticity are not strictly required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. We then directed our attention to another form of peripheral electrical stimulation, delivered at low frequency (LF-RSS). Previous literature demonstrated that this pattern of stimulation had effects opposite to HF-RSS on tactile performance in healthy subjects; therefore, given the previous findings of abnormal response to HF-RSS in CD, we hypothesized that an inverse response might occur in these patients following LF-RSS as well. Our hypothesis was confirmed by the observation that LF-RSS, applied to the fingers in patients with CD, induced an increase in inhibition in the primary somatosensory and motor cortices. This was reflected by an improvement of STDT and an increase in PP-SEP suppression, HFO area and SICI. With this in mind, in the final project of the thesis, we tested the effects of HF-RSS and LF-RSS applied directly over two affected muscles in different groups of patients with focal hand dystonia (FHD), in an attempt to modulate involuntary muscle activity and, consequently, to ameliorate motor symptoms. Whereas HF-RSS was delivered synchronously over the two muscles, LF-RSS was given either synchronously or asynchronously. Outcome measures included a) PP-SEP obtained by direct stimulation of affected muscles, with ISIs of 5 and 30 ms; b) quantification of electromyographic (EMG) activity from tested muscles; c) SICI recorded from the affected muscles, with CS intensities ranging from 50% to 100% RMT and with an ISI of 3 ms; d) evaluation of hand function, assessed by the box and blocks test (BBT) and the nine-hole peg test (NHPT); e) SIR by measuring SEP interaction between simultaneous stimulation of the two muscles receiving repetitive stimulation. We confirmed the paradoxical response of dystonic patients to HF-RSS, which was reflected in decreased PP-SEP suppression and SICI and increased SIR. Importantly, this was paralleled by an increase in involuntary EMG activity and worse scores at the BBT and NHPT. This results were opposite when LF-RSS was delivered, either in its synchronous or asynchronous version, the latter being slightly more effective. Thus, LF-RSS was able to increase PP-SEP suppression and SICI, decrease SIR and reduce involuntary EMG activity, with consequent improvement in performance in the BBT and NHPT. Overall, our data provide novel insight into the neural mechanisms underlying loss of inhibition and deranged somatosensory plasticity in idiopathic dystonia and bring preliminary evidence that peripheral electrical stimulation can be used as a treatment in idiopathic focal hand dystonia

Associative Stimulation of the Supraorbital Nerve Fails to Induce Timing-Specific Plasticity in the Human Blink Reflex

BACKGROUND: Associative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger, 2001). HFS given at the onset of the R2 component of the blink reflex (HFS(LTP)) produced a lasting facilitation of the R2, whereas HFS given shortly before R2 (HFS(LTD)) caused a lasting suppression of the R2. In patients with benign essential blepharospasm (BEB), a focal dystonia affecting the orbicularis oculi muscles, HFS(LTP) induced excessive LTP-like associative plasticity relative to healthy controls, which was normalized after botulinum toxin (BTX) injections (Quartarone et al, 2006). METHODOLOGY/PRINCIPAL FINDINGS: We used HFS conditioning of the supraorbital nerve to study homeostatic metaplasticity of the blink reflex circuit in healthy subjects and dystonic patients. On separate days, we tested the conditioning effects on the R2 response and paired-pulse R2 inhibition after (i) HFS(LTP), (ii) HFS(LTP) followed by HFS(LTP), and (iii) HFS(LTP) followed by HFS(LTD). Controls also received (iv) HFS(LTD) alone and (v) a non-intervention protocol. In BEB patients, HFS(LTP) followed by HFS(LTD) was given before and after BTX treatment. We were not able to replicate the bidirectional timing-dependent effects of HFS(LTP) and HFS(LTD) alone. All HFS protocols produced a non-specific reduction of the R2 response and a relative decrease in paired-pulse inhibition. These R2 changes also occurred in controls when no HFS was applied. There was also no trace of a homeostatic response pattern in BEB patients before or after BTX treatment. CONCLUSION/SIGNIFICANCE: Our data challenge the efficacy of associative HFS to produce bidirectional plasticity in the human blink reflex circuit. The non-specific decrease of the R2 response might indicate habituation of the blink reflex following repeated electrical supraorbital stimulation. The increase of inhibition after paired pulse stimulation might reflect homeostatic behaviour to prevent further down regulation of the R2 response to preserve the protection of this adverse-effects reflex

Lasting EEG/MEG aftereffects on human brain oscillations after rhythmic transcranial brain stimulation: Level of control over oscillatory network activity

A number of rhythmic protocols have emerged for non-invasive brain stimulation (NIBS) in humans, including transcranial alternating current stimulation (tACS), oscillatory transcranial direct current stimulation (otDCS) and repetitive (also called rhythmic) transcranial magnetic stimulation (rTMS). With these techniques, it is possible to match the frequency of the externally applied electromagnetic fields to the intrinsic frequency of oscillatory neural population activity ("frequency-tuning"). Mounting evidence suggests that by this means tACS, otDCS, and rTMS can entrain brain oscillations and promote associated functions in a frequency-specific manner, in particular during (i.e. online to) stimulation. Here, we focus instead on the changes in oscillatory brain activity that persist after the end of stimulation. Understanding such aftereffects in healthy participants is an important step for developing these techniques into potentially useful clinical tools for the treatment of specific patient groups. Reviewing the electrophysiological evidence in healthy participants, we find aftereffects on brain oscillations to be a common outcome following tACS/otDCS and rTMS. However, we did not find a consistent, predictable pattern of aftereffects across studies, which is in contrast to the relative homogeneity of reported online effects. This indicates that aftereffects are partially dissociated from online, frequency-specific (entrainment) effects during tACS/otDCS and rTMS. We outline possible accounts and future directions for a better understanding of the link between online entrainment and offline aftereffects, which will be key for developing more targeted interventions into oscillatory brain activity