Inter-individual Variability in Response to Non-invasive Brain Stimulation Paradigms

BackgroundNon-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms.HypothesisInter-individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed.MethodsIn three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS₂₅), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern.ResultsAll three paradigms show similar efficacy over the first hour post stimulation – there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS₂₅. Cluster analysis reveals a bimodal response pattern – but only 39%, 45% and 43% of subjects responded as expected to PAS₂₅, AtDCS, and iTBS respectively. Pre-stimulation SICI accounted for 10% of the variability in response to PAS₂₅, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment.ConclusionThe implications of the high rate of ‘dose-failure’ for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field.     

Electrical Stimulation of the Human Brain in Epilepsy

The concordance between the epileptogenic area as determined by intracranially recorded spontaneous seizure onset and that determined by electrically induced auras or seizures in 126 patients with medically intractable epilepsy was studied. Four to 11 multicontact depth electrodes were chronically implanted in patients as part of a preoperative investigation procedure. Localization of the epileptic area was obtained from the recording of three spontaneous seizures and from stimulation data including self-reported auras, seizures, and intracranial EEG afterdischarges recorded during an incremental stimulation sequence at all cortical pairs of contacts. Positive responses to stimulation were obtained in 63% of patients. Concordance between spontaneous and induced auras or seizures was greater than 90% with single unilateral foci and less with multiple foci. Stimulation data reliably predicted the resection area in unilateral and bilateral temporal foci but not in other locations. Afterdischarge thresholds were not reliable predictors of the spontaneous seizure focus. The intracranial stimulation procedure used appears to provide useful confirmatory and complementary localizing information in relation to that obtained from spontaneous seizures.     

Cutaneous perception thresholds of electrical stimulation methods: Comparison of tDCS and tRNS

Objective

Controlled blinded studies using transcranial electrical stimulation (tES) paradigms need a validated sham stimulation paradigm since an itching or tingling sensation on the skin surface under the electrode can be associated with current flow.

Methods

Here we investigated the skin perception thresholds of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) for current intensities ranging from 200 to 2000 μA and additional non-stimulation trials using a motor cortex–contralateral orbit montage in three different healthy subject groups: subjects naïve to tES methods, subjects with previous experience with these techniques and investigators, who use these methods in their research.

Results

Taking the whole sample into consideration the 50% perception threshold for both tDCS conditions was at 400 μA while this threshold was at 1200 μA in the case of tRNS. Anodal and cathodal tDCS are indistinguishable regarding sites of perception. Experienced investigators show a significantly higher anodal stimulation detection rate when compared to the naïve group, furthermore investigators performed significantly better than naïve subjects in non-stimulation discrimination.

Conclusions

tRNS has the advantage of higher cutaneous perception thresholds and lower response rates in when compared with tDCS. Further investigation in blinding methods (such as placebo itching) is warranted in order to improve sham control.

Significance

As tRNS has been shown to have similar aftereffects as anodal tDCS, this finding points to the application of tRNS as a possible alternative with a better blinding control.     

Transcranial Direct Current Stimulation Enhances Sucking of a Liquid Bolus in Healthy Humans

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive technique used for modulating cortical excitability in vivo in humans. Here we evaluated the effect of tDCS on behavioral and electrophysiological aspects of physiological sucking and swallowing.MethodsTwelve healthy subjects underwent three tDCS sessions (anodal, cathodal and sham stimulation) on separate days in a double-blind randomized order. The active electrode was placed over the right swallowing motor cortex. Repeated sucking and swallowing acts were performed at baseline and at 15 and 60 min after each tDCS session and the mean liquid bolus volume ingested at each time point was measured. We also calculated average values of the following electrophysiological parameters: 1) area and 2) duration of the rectified EMG signal from the suprahyoid/submental muscles related to the sucking and swallowing phases; 3) EMG peak amplitude for the sucking and swallowing phases; 4) area and peak amplitude of the laryngeal-pharyngeal mechanogram; 5) oropharyngeal delay.ResultsThe volume of the ingested bolus significantly increased (by an average of about 30% compared with the baseline value) both at 15 and at 60 min after the end of anodal tDCS. The electrophysiological evaluation after anodal tDCS showed a significant increase in area and duration of the sucking phase-related EMG signal.ConclusionsAnodal tDCS leads to stronger sucking of a liquid bolus in healthy subjects, likely by increasing recruitment of cortical areas of the swallowing network. This finding might open up interesting perspectives for the treatment of patients suffering from dysphagia due to various pathological conditions.     

Electroencephalographic Effects of Transcranial Random Noise Stimulation in the Auditory Cortex

BackgroundTranscranial random noise stimulation (tRNS) is an innovative technique of non-invasive electrical stimulation. tRNS over the parietal cortex has improved cognitive function in healthy controls and, applied to the auditory cortex, tRNS has shown beneficial effects on tinnitus.Objective/hypothesisHere we aimed to investigate the effects of tRNS over the auditory cortex on resting state and evoked activity in healthy subjects.MethodsWe used EEG to measure tRNS induced changes in resting state activity and in auditory steady state responses (ASSRs). Stimuli were 1000 Hz carrier frequency tones, amplitude modulated at 20 Hz and 40 Hz and applied in randomized order. Fourteen subjects participated in a placebo-controlled randomized design study; each received 20 min of tRNS applied over auditory cortices with 2 mA, with a one week interval between real and sham stimulation.ResultsWe found a significant increase in the ASSR in response to 40 Hz frequency modulated tone and a non-significant trend toward an increase in mean theta band power and variability of the theta band power for the resting state data.ConclusionsOur finding of tRNS induced increased excitability in the auditory cortex parallels previous findings of tRNS effects on motor cortex excitability and is in line with current concepts of tRNS mechanisms such as increase of stochastic resonance.     

Brain Electrical Activity After Acute Hippocampal Stimulation in Awake Rats

Objective: We describe the electrocorticographic findings after hippocampal stimulation in normal awake rats. Methods: Six male Wistar rats were implanted bilaterally with neocortical and hippocampal electrodes. The animals were submitted to hippocampal low‐ and high‐frequency stimulation. Results: Recruiting responses were seen in the ipsilateral hippocampus after unilateral low‐frequency (6 Hz) hippocampal stimulation with low voltage (0.3 V). These recruiting responses could be seen at the contralateral hippocampus with slightly higher voltage (0.5 V) and over the ipsilateral neocortex with stimulation with 1.2 V. Bilateral neocortical recruiting responses were noted at stimuli voltage of 1.5 V. There were no recruiting responses after high‐frequency stimulation (130 Hz). A dorsal column (DC) shift, characterized by baseline oscillation without brain activity modification, was noted in all animals after hippocampal stimulation with frequency higher than 60 Hz. The increase of stimulation frequency from 6 to 130 Hz (1.2 V, 300 µsec) showed progressive reduction in the amplitude and disappearance of the time‐locked recruiting responses, especially from around 60 Hz. Conclusions: Bilateral hippocampal and cortical recruiting responses were easily obtained in all animals after low‐frequency hippocampal unilateral stimulation. High‐frequency stimulation did not give rise to recruiting response, although a DC shift was noted. The fact that unilateral hippocampal stimulation might lead to bilateral limbic system modulation suggested that unilateral stimulation might be enough in many situations. Our findings suggested that high‐frequency stimulation was more likely to be effective than low‐frequency stimulation regarding the potential inactivation of the hippocampus. These findings might prove relevant to the determination of the adequate parameters for stimulation using hippocampal deep brain stimulation (DBS) in the future. An increase in our knowledge on the physiologic mechanisms underlying DBS might be translated into more rational clinical approaches.     

Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease

OBJECTIVES: Cognitive impairment is a common feature in Parkinson's disease (PD) and is an important predictor of quality of life. Past studies showed that some aspects of cognition, such as working memory, can be enhanced following dopaminergic therapy and transcranial magnetic stimulation. The aim of our study was to investigate whether another form of noninvasive brain stimulation, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability, is associated with a change in a working memory task performance in PD patients. METHODS: We studied 18 patients (12 men and 6 women) with idiopathic PD. The patients performed a three-back working memory task during active anodal tDCS of the left dorsolateral prefrontal cortex (LDLPFC), anodal tDCS of the primary motor cortex (M1) or sham tDCS. In addition, patients underwent two different types of stimulation with different intensities: 1 and 2 mA. RESULTS: The results of this study show a significant improvement in working memory as indexed by task accuracy, after active anodal tDCS of the LDLPFC with 2 mA. The other conditions of stimulation: sham tDCS, anodal tDCS of LDLPFC with 1 mA or anodal tDCS of M1 did not result in a significant task performance change. CONCLUSION: tDCS may exert a beneficial effect on working memory in PD patients that depends on the intensity and site of stimulation. This effect might be explained by the local increase in the excitability of the dorsolateral prefrontal cortex.     

Intracellular Calcium Deposition in Brain Following Electrical Stimulation

The effects of electrical stimulation of the cat cerebral cortex have been evaluated by light and electron microscopy following a wide variety of stimulation parameters (QD/ph of 10 – 300 μc/cm²/ph). Platinum or rhodium disc electrode arrays were bilaterally implanted subdurally on the parietal cortex and subjected to 36-hour stimulations (9 hrs./day for 4 days). Prominent among the degenerative changes shown by electron microscopy were dense crystalline inclusions that were identified as calcium hydroxyapatite (CHA) crystals by electron diffraction and energy dispersive X-ray analysis. The appearance of intracellular calcification generally paralleled the onset of other degenerative changes in stimulated tissue, including gliosis, mitochondrial swelling, lipid inclusions, degenerating cells, neuronal loss, and phagocytic activity. A preferential deposition of calcium was noted in mitochondria of several cell types and in postsynaptic dendrites. The mechanism of the apparently electroresponsive calcium deposition is obscure; however, a plausible explanation is that increased cyclic AMP levels, known to occur with electrical stimulation of nervous tissue, result in enhanced calcium plasmalemmal permeability.     

Evidence for a Role of the Right Dorsolateral Prefrontal Cortex in Controlling Stimulus-response Integration: A Transcranial Direct Current Stimulation (tDCS) Study

BackgroundActing coherently upon stimuli requires some kind of integration of stimulus and response features across various distinct cortical feature maps (one aspect of the binding problem). Although the process of feature binding proper seems rather automatic, recent studies revealed that the management of stimulus-response bindings is less efficient in populations with impaired cognitive-control processes.ObjectiveHere, we investigated whether the cognitive control of stimulus-response feature bindings (“event files”) in healthy participants is affected by non-invasive brain stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC)—a main component of the cognitive-control network.MethodIn different sessions, participants received anodal, cathodal, or sham tDCS (2 mA, 20 min) while performing an audio-visual event-file task assessing the creation and retrieval of stimulus–stimulus and stimulus-response feature bindings. The general findings from this task indicate that performance suffers when some, but not all of the features are repeated (the so-called partial repetition cost).ResultsStimulation over the right, but not the left DLPFC reduced control of stimulus-response bindings and produced outcome patterns similar to those previously observed in autistic children, people with lower fluid intelligence, and older adults.ConclusionsThis finding provides empirical support for a role of the right DLPFC in feature-binding management, which might consist in preventing the stimulus-induced activation of previously created, but now task-irrelevant, episodic bindings. From a methodological perspective, the finding may suggest that tDCS could be used as a temporary, reversible “brain lesion” generator in healthy subjects, enabling experimental investigation of how the brain works.     

Increased Transcranial Direct Current Stimulation After Effects During Concurrent Peripheral Electrical Nerve Stimulation

In this study we tested the hypothesis whether a lasting change in the excitability of cortical output circuits can be obtained in healthy humans by combining a peripheral nerve stimulation during a concomitant depolarization and/or hyperpolarization of motor cortex. To reach this aim we combined two different neurophysiological techniques each of them able to induce a lasting increase of cortical excitability by them self: namely median nerve repetitive electrical stimulation (rEPNS) and transcranial direct current stimulation (tDCS). Ten normal young volunteers were enrolled in the present study. All subjects underwent five different protocols of stimulation: (1, 2) tDCS alone (anodal or cathodal); (3) Sham tDCS plus rEPNS; (4, 5) anodal or cathodal tDCS plus rEPNS. The baseline MEP amplitude from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscle, the FCR H-reflex were compared with that obtained immediately after and 10, 20, 30, 60 min after the stimulation protocol. Anodal tDCS alone induced a significant transient increase of MEP amplitude immediately after the end of stimulation while anodal tDCS + rEPNS determined MEP changes which persisted for up 60 min. Cathodal tDCS alone induced a significant reduction of MEP amplitude immediately after the end of stimulation while cathodal tDCS + rEPNS prolonged the effects for up to 60 min. Sham tDCS + rEPNS did not induce significant changes in corticospinal excitability. Anodal or cathodal tDCS + rEPNS and sham tDCS + rEPNS caused a lasting facilitation of H-reflex. These findings suggest that by providing afferent input to the motor cortex while its excitability level is increased or decreased by tDCS may be a highly effective means for inducing an enduring bi-directional plasticity. The mechanism of this protocol may be complex, involving either cortical and spinal after effects.     

Effects of bilateral dorsolateral prefrontal cortex high-definition transcranial direct-current stimulation on time-trial performance in cyclists with type 1 diabetes mellitus

BackgroundHD-tDCS is capable to increase the focality of neuromodulation and has been recently applied to improve endurance performance in healthy subjects.Objective/hypothesisWhether these putative advantages could be exploited in active subjects with type 1 diabetes mellitus (T1D) remains questionable.MethodsIn a double-blind, randomized crossover order, 11 high-level cyclists (27 ± 4.3 years; weight: 65.5 ± 8.6 kg; height: 180 ± 8 cm; VO₂peak: 67.5 ± 2.9 mL min^?1 kg^?1) with T1D underwent either HD-tDCS (F3, F4) or control (SHAM) and completed a constant-load trial (CLT) at 75% of the 2nd ventilatory threshold plus a 15-km cycling time-trial (TT).ResultsAfter HD-tDCS, the total time to cover the TT was 3.8% faster (P < 0.01), associated with a higher mean power output (P < 0.01), and a higher rate of power/perception of effort (P < 0.01) and power/heart rate at iso-time (P < 0.05) than the SHAM condition. Physiological parameters during CLT and TT did not differ in both conditions.ConclusionsThese findings suggest that upregulation of the prefrontal cortex could enhance endurance performance in high-level cyclists with T1D, without altering physiological and perceptual responses at moderate intensity. Present data open to future applications of HD-tDCS to a wider population of active T1D-subjects.     

Motor Evoked Potentials Improve Targeting in Deep Brain Stimulation Surgery

ObjectivesOne of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects.Materials and MethodsMotor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated.ResultsIntraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects.ConclusionsIntraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.     

Analgesic Effects of Noninvasive Brain Stimulation in Rodent Animal Models: A Systematic Review of Translational Findings

Objectives: Noninvasive brain stimulation (NIBS) interventions have demonstrated promising results in the clinical treatment of pain, according to several preliminary trials, although the results have been mixed. The limitations of clinical research on NIBS are the insufficient understanding of its mechanisms of action, a lack of adequate safety data, and several disparities with regard to stimulation parameters, which have hindered the generalizability of such studies. Thus, experimental animal research that allows the use of more invasive interventions and creates additional control of independent variables and confounders is desirable. To this end, we systematically reviewed animal studies investigating the analgesic effects of NIBS. In addition, we also explored the investigation of NIBS in animal models of stroke as to compare these findings with NIBS animal pain research. Methods: Of 1916 articles that were found initially, we identified 15 studies (stroke and pain studies) per our eligibility criteria that used NIBS methods, such as transcranial direct current stimulation, paired associative stimulation, transcranial magnetic stimulation, and transcranial electrostimulation. We extracted the main outcomes on stroke and pain, as well as the methods and electrical parameters of each technique. Results: NIBS techniques are effective in alleviating pain. Similar beneficial clinical effects are observed in stroke. The main insights from these animal studies are the following: 1) combination of NIBS with analgesic drugs has a synergistic effect; 2) effects are dependent on the parameters of stimulation, and in fact, not necessarily the strongest stimulation parameter (i.e., the largest intensity of stimulation) is associated with the largest benefit; 3) pain studies show an overall good quality as indexed by Animals in Research: Reporting In Vivo Experiments guidelines of the reporting of animal experiments, but insufficient with regard to the reporting of safety data for brain stimulation; 4) these studies suggest that NIBS techniques have a primary effect on synaptic plasticity, but they also suggest other mechanisms of action such as via neurovascular modulation. Conclusions: We found a limited number of animal studies for both pain and stroke NIBS experimental research. There is a lack of safety data in animal studies in these two topics and results from these studies have not been yet fully tested and translated to human research. We discuss the challenges and limitations of translating experimental animal research on NIBS into clinical studies.