Epicranial Direct Current Stimulation Suppresses Harmaline Tremor in Rats.

INTRODUCTION: Essential tremor (ET) is the most common neurologic movement disorder worldwide. It is characterized by a postural tremor, mostly in the upper extremities, causing difficulties in daily activities that may lead to social exclusion. Some patients with ET do not respond well to or do not tolerate medication. Thus, deep brain stimulation can be offered. In a recent study, we proposed a novel neuromodulation technique called epicranial current stimulation (ECS) that works in a minimally invasive way by placing the electrodes subcutaneously under the skin and directly over the skull. In this study, we investigated the feasibility of using epicranial direct current stimulation (EDCS) to suppress tremor in a rat harmaline ET model. MATERIALS AND METHODS: In experiment 1, seven Sprague Dawley rats were implanted with ECS electrodes placed over the motor cortex (MC) and the cerebellum to investigate whether stimulating between them could suppress tremor. In experiments 2 and 3, eight rats were implanted with ECS electrodes placed over the MC, cerebellum, and the rostral skull to separate the effects on tremor caused by stimulating each target. During each experiment, the rats were injected with harmaline, which induced tremor that was quantified using an accelerometer. EDCS was then applied through the different electrode configurations to evaluate their tremor suppression effectiveness. RESULTS: Results from experiment 1 showed that MCcathode-Cerebellaranode suppressed tremor compared with stimulation-OFF but MCanode-Cerebellarcathode did not. Furthermore, experiments 2 and 3 showed that it was the cerebellar anodal electrode that was driving tremor suppression. CONCLUSION: Cerebellar EDCS suppressed harmaline tremor in rats in a polarity-dependent manner. EDCS could be a promising neuromodulation method for patients with ET.

Frequency-Specific Modulation of Slow-Wave Neural Oscillations via Weak Exogeneous Extracellular Fields Reveals a Resonance Pattern.

Single neurons often exhibit endogenous oscillatory activity centered around a specific frequency band. Transcranial alternating current stimulation (tACS) can generate a weak oscillating extracellular field in the brain that causes subthreshold membrane potential shifts that can affect spike timing at the single neuron level. Many studies have now shown that the endogenous oscillation can be entrained when the tACS frequency matches that of the exogenous extracellular field. However, the effect of tACS on the amplitude of the endogenous oscillation has been less well studied. We investigated this by using exogenous extracellular fields to modulate slow-wave neural oscillations in the ketamine anesthetized male Wistar rat. We applied spatially broad extracellular fields of different frequencies while recording spiking activity from single neurons. The effect of the exogenous extracellular field on the slow-wave neural oscillation amplitude (NOA) followed a resonance pattern: large modulations were observed when the extracellular frequency matched the endogenous frequency of the neuron, while extracellular fields with frequencies far away from the endogenous frequency had little effect. No changes in spike-rate were observed for any of the extracellular fields applied. Our results demonstrate that in addition to the previously reported entrainment and Arnold tongue patterns, weak oscillating extracellular fields modulate the amplitude of the endogenous neural oscillation without any changes in spike-rate, and that this modulation follows a frequency-specific resonance pattern.SIGNIFICANCE STATEMENT Neural activity often oscillates around specific endogenous frequencies. Transcranial alternating current stimulation (tACS) is a neuromodulation method which biases spike-times and alter endogenous activity. Most tACS studies focus on entrainment effects which occur when tACS and endogenous neural frequencies are matched. In this study we varied the frequency of the applied tACS and investigated its effect on amplitude of the neural oscillation. Our results revealed a resonance pattern where tACS frequencies close to the endogenous frequency caused an increase in neural oscillation amplitude (NOA) specifically at the applied tACS frequency, while applying tACS frequencies farther away caused little or no change in NOA. Furthermore, applying tACS at differing frequencies caused the amplitude of the neural oscillation at the prestimulation endogenous frequency to decrease.

Detection of tACS Entrainment Critically Depends on Epoch Length.

Neural entrainment is the phase synchronization of a population of neurons to an external rhythmic stimulus such as applied in the context of transcranial alternating current stimulation (tACS). tACS can cause profound effects on human behavior. However, there remain a significant number of studies that find no behavioral effect when tACS is applied to human subjects. To investigate this discrepancy, we applied time sensitive phase lock value (PLV) based analysis to single unit data from the rat motor cortex. The analysis revealed that detection of neural entrainment depends critically on the epoch length within which spiking information is accumulated. Increasing the epoch length allowed for detection of progressively weaker levels of neural entrainment. Based on this single unit analysis, we hypothesized that tACS effects on human behavior would be more easily detected in a behavior paradigm which utilizes longer epoch lengths. We tested this by using tACS to entrain tremor in patients and healthy volunteers. When the behavioral data were analyzed using short duration epochs tremor entrainment effects were not detectable. However, as the epoch length was progressively increased, weak tremor entrainment became detectable. These results suggest that tACS behavioral paradigms that rely on the accumulation of information over long epoch lengths will tend to be successful at detecting behavior effects. However, tACS paradigms that rely on short epoch lengths are less likely to detect effects.

Biophysical mechanisms of electroconvulsive therapy-induced volume expansion in the medial temporal lobe: A longitudinal in vivo human imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) applies electric currents to the brain to induce seizures for therapeutic purposes. ECT increases gray matter (GM) volume, predominantly in the medial temporal lobe (MTL). The contribution of induced seizures to this volume change remains unclear. METHODS: T1-weighted structural MRI was acquired from thirty patients with late-life depression (mean age 72.5 ± 7.9 years, 19 female), before and one week after one course of right unilateral ECT. Whole brain voxel-/deformation-/surface-based morphometry analyses were conducted to identify tissue-specific (GM, white matter: WM), and cerebrospinal fluid (CSF) and cerebral morphometry changes following ECT. Whole-brain voxel-wise electric field (EF) strength was estimated to investigate the association of EF distribution and regional brain volume change. The association between percentage volume change in the right MTL and ECT-related parameters (seizure duration, EF, and number of ECT sessions) was investigated using multiple regression. RESULTS: ECT induced widespread GM volume expansion with corresponding contraction in adjacent CSF compartments, and limited WM change. The regional EF was strongly correlated with the distance from the electrodes, but not with regional volume change. The largest volume expansion was identified in the right MTL, and this was correlated with the total seizure duration. CONCLUSIONS: Right unilateral ECT induces widespread, bilateral regional volume expansion and contraction, with the largest change in the right MTL. This dynamic volume change cannot be explained by the effect of electrical stimulation alone and is related to the cumulative effect of ECT-induced seizures.

A Computational Modeling Study to Investigate the Use of Epicranial Electrodes to Deliver Interferential Stimulation to Subcortical Regions.

Background: Epicranial cortical stimulation (ECS) is a minimally invasive neuromodulation technique that works by passing electric current between subcutaneous electrodes positioned on the skull. ECS causes a stronger and more focused electric field in the cortex compared to transcranial electric stimulation (TES) where the electrodes are placed on the scalp. However, it is unknown if ECS can target deeper regions where the electric fields become relatively weak and broad. Recently, interferential stimulation (IF) using scalp electrodes has been proposed as a novel technique to target subcortical regions. During IF, two high, but slightly different, frequencies are applied which sum to generate a low frequency field (i.e., 10 Hz) at a target subcortical region. We hypothesized that IF using ECS electrodes would cause stronger and more focused subcortical stimulation than that using TES electrodes. Objective: Use computational modeling to determine if interferential stimulation-epicranial cortical stimulation (IF-ECS) can target subcortical regions. Then, compare the focality and field strength of IF-ECS to that of interferential Stimulation-transcranial electric stimulation (IF-TES) in the same subcortical region. Methods: A human head computational model was developed with 19 TES and 19 ECS disk electrodes positioned on a 10-20 system. After tetrahedral mesh generation the model was imported to COMSOL where the electric field distribution was calculated for each electrode separately. Then in MATLAB, subcortical targets were defined and the optimal configurations were calculated for both the TES and ECS electrodes. Results: Interferential stimulation using ECS electrodes can deliver stronger and more focused electric fields to subcortical regions than IF using TES electrodes. Conclusion: Interferential stimulation combined with ECS is a promising approach for delivering subcortical stimulation without the need for a craniotomy.

tDCS peripheral nerve stimulation: a neglected mode of action?

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method widely used by neuroscientists and clinicians for research and therapeutic purposes. tDCS is currently under investigation as a treatment for a range of psychiatric disorders. Despite its popularity, a full understanding of tDCS's underlying neurophysiological mechanisms is still lacking. tDCS creates a weak electric field in the cerebral cortex which is generally assumed to cause the observed effects. Interestingly, as tDCS is applied directly on the skin, localized peripheral nerve endings are exposed to much higher electric field strengths than the underlying cortices. Yet, the potential contribution of peripheral mechanisms in causing tDCS's effects has never been systemically investigated. We hypothesize that tDCS induces arousal and vigilance through peripheral mechanisms. We suggest that this may involve peripherally-evoked activation of the ascending reticular activating system, in which norepinephrine is distributed throughout the brain by the locus coeruleus. Finally, we provide suggestions to improve tDCS experimental design beyond the standard sham control, such as topical anesthetics to block peripheral nerves and active controls to stimulate non-target areas. Broad adoption of these measures in all tDCS experiments could help disambiguate peripheral from true transcranial tDCS mechanisms.

Investigating the Feasibility of Epicranial Cortical Stimulation Using Concentric-Ring Electrodes: A Novel Minimally Invasive Neuromodulation Method.

BACKGROUND: Invasive cortical stimulation (ICS) is a neuromodulation method in which electrodes are implanted on the cortex to deliver chronic stimulation. ICS has been used to treat neurological disorders such as neuropathic pain, epilepsy, movement disorders and tinnitus. Noninvasive neuromodulation methods such as transcranial magnetic stimulation and transcranial electrical stimulation (TES) show great promise in treating some neurological disorders and require no surgery. However, only acute stimulation can be delivered. Epicranial current stimulation (ECS) is a novel concept for delivering chronic neuromodulation through subcutaneous electrodes implanted on the skull. The use of concentric-ring ECS electrodes may allow spatially focused stimulation and offer a less invasive alternative to ICS. OBJECTIVES: Demonstrate ECS proof-of-concept using concentric-ring electrodes in rats and then use a computational model to explore the feasibility and limitations of ECS in humans. METHODS: ECS concentric-ring electrodes were implanted in 6 rats and pulsatile stimulation delivered to the motor cortex. An MRI based electro-anatomical human head model was used to explore different ECS concentric-ring electrode designs and these were compared with ICS and TES. RESULTS: Concentric-ring ECS electrodes can selectively stimulate the rat motor cortex. The computational model showed that the concentric-ring ECS electrode design can be optimized to achieve focused cortical stimulation. In general, focality was less than ICS but greater than noninvasive transcranial current stimulation. CONCLUSION: ECS could be a promising minimally invasive alternative to ICS. Further work in large animal models and patients is needed to demonstrate feasibility and long-term stability.

Validation of the Fetal Lamb Model of Spina Bifida.

A randomized trial demonstrated that fetal spina bifida (SB) repair is safe and effective yet invasive. New less invasive techniques are proposed but are not supported by adequate experimental studies. A validated animal model is needed to bridge the translational gap to the clinic and should mimic the human condition. Introducing a standardized method, we comprehensively and reliably characterize the SB phenotype in two lamb surgical models with and without myelotomy as compared to normal lambs. Hindbrain herniation measured on brain magnetic resonance imaging (MRI) was the primary outcome. Secondary outcomes included gross examination with cerebrospinal fluid (CSF) leakage test, neurological examination with locomotor assessment, whole-body MRI, motor and somatosensory evoked potentials; brain, spinal cord, hindlimb muscles, bladder and rectum histology and/or immunohistochemistry. We show that the myelotomy model best phenocopies the anatomy, etiopathophysiology and symptomatology of non-cystic SB. This encompasses hindbrain herniation, ventriculomegaly, posterior fossa anomalies, loss of brain neurons; lumbar CSF leakage, hindlimb somatosensory-motor deficit with absence of motor and somatosensory evoked potentials due to loss of spinal cord neurons, astroglial cells and myelin; urinary incontinence. This model obtains the highest validity score for SB animal models and is adequate to assess the efficacy of novel fetal therapies.

Analytical bias accounts for some of the reported effects of tACS on auditory perception.

BACKGROUND: Transcranial alternating current stimulation (tACS) has been shown to modulate auditory, visual, cognitive and motor function. However, tACS effects can often be small and difficult to reproduce. Thus, the establishment of robust experimental and analysis procedures is of high importance. We reviewed the analysis used in six studies that investigated if tACS can phase-modulate auditory perception. All studies used analytical methods that introduce bias and could produce false positive results. Four studies corrected for this bias but two did not. OBJECTIVE: Our objectives were two-fold: 1) Use simulated null hypothesis datasets, where no tACS effect is present, to determine if uncorrected analytical bias could account for some of the reported effects on auditory perception. 2) Help establish best practices to correct for bias when analyzing tACS phase-effects on perception. METHODS: We simulated null hypothesis datasets (i.e. no tACS effect) by drawing samples for all tACS and sham conditions from the same normal distribution. We then applied the reported analyses to the null hypothesis datasets. RESULTS: Reported results from studies that did not correct for analytical bias could be reproduced from the null hypothesis datasets. However, results for studies that did correct for analytical bias could not be reproduced from the null hypothesis datasets. CONCLUSION: True effects of tACS on auditory perception can be detected if analytical bias is accounted for by using correction procedures. However, to fully establish the effects of tACS on auditory perception a reanalysis of the data for the studies that used biased analysis without correction procedures is needed.

tACS motor system effects can be caused by transcutaneous stimulation of peripheral nerves.

Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method which has been shown to modulate hearing, motor, cognitive and memory function. However, the mechanisms underpinning these findings are controversial, as studies show that the current reaching the cortex may not be strong enough to entrain neural activity. Here, we propose a new hypothesis to reconcile these opposing results: tACS effects are caused by transcutaneous stimulation of peripheral nerves in the skin and not transcranial stimulation of cortical neurons. Rhythmic activity from peripheral nerves then entrains cortical neurons. A series of experiments in rats and humans isolated the transcranial and transcutaneous mechanisms and showed that the reported effects of tACS on the motor system can be caused by transcutaneous stimulation of peripheral nerves. Whether or not the transcutaneous mechanism will generalize to tACS effects on other systems is debatable but should be investigated.

Publisher Correction: Using high-amplitude and focused transcranial alternating current stimulation to entrain physiological tremor.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Using high-amplitude and focused transcranial alternating current stimulation to entrain physiological tremor.

Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that can entrain physiological tremor in healthy volunteers. We conducted two experiments to investigate the effectiveness of high-amplitude and focused tACS montages at entraining physiological tremor. Experiment 1 used saline-soaked sponge electrodes with an extra-cephalic return electrode and compared the effects of a motor (MC) and prefrontal cortex (PFC) electrode location. Average peak-amplitude was 1.925 mA. Experiment 2 used gel-filled cup-electrodes in a 4 × 1 focused montage and compared the effects of MC and occipital cortex (OC) tACS. Average peak-amplitude was 4.45 mA. Experiment 1 showed that unfocused MC and PFC tACS both produced phosphenes and significant phase entrainment. Experiment 2 showed that focused MC and OC tACS produced no phosphenes but only focused MC tACS caused significant phase entrainment. At the group level, tACS did not have a significant effect on tremor amplitude. However, with focused tACS there was a significant correlation between phase entrainment and tremor amplitude modulation: subjects with higher phase entrainment showed more tremor amplitude modulation. We conclude that: (1) focused montages allow for high-amplitude tACS without phosphenes and (2) high amplitude focused tACS can entrain physiological tremor.

Quantitative analysis of motor evoked potentials in the neonatal lamb.

Evoking motor potentials are an objective assessment method for neuromotor function, yet this was to our knowledge never done in neonatal lambs. There is neither a method for standardized quantification of motor evoked potentials (MEPs). We first aimed to evaluate the feasibility of MEP recording in neonatal lambs and test its validity. Second we aimed to develop an algorithm for its quantification and test its reliability since manual input is required. We recorded myogenic MEPs after transcranial motor cortex stimulation in 6 lambs aged 1-2 days. MEPs were also measured in one lamb undergoing Neuro-Muscular Blockade (NMB) and another undergoing lumbar spinal cord (SC) transection, both serving as controls. We computed 5 parameters using a custom-made algorithm: motor threshold, latency, area-under-the-curve, peak-to-peak amplitude and duration. Intra- and inter-observer reliability was analyzed. MEPs could be easily recorded, disappearing after NMB and SC transection. The algorithm allowed for analysis, hence physiologic readings of the parameters in all 4 limbs of all lambs were obtained. Our method was shown to have high intra- and inter-observer ( ≥70%) reliability for latency, area-under-the-curve and peak-to-peak amplitude. These results suggest that standardized MEP recording and analysis in neonatal lambs is feasible, and can reliably assess neuromotor function.

Simultaneously Excitatory and Inhibitory Effects of Transcranial Alternating Current Stimulation Revealed Using Selective Pulse-Train Stimulation in the Rat Motor Cortex.

Transcranial alternating current stimulation (tACS) uses sinusoidal, subthreshold, electric fields to modulate cortical processing. Cortical processing depends on a fine balance between excitation and inhibition and tACS acts on both excitatory and inhibitory cortical neurons. Given this, it is not clear whether tACS should increase or decrease cortical excitability. We investigated this using transcranial current stimulation of the rat (all males) motor cortex consisting of a continuous subthreshold sine wave with short bursts of suprathreshold pulse-trains inserted at different phases to probe cortical excitability. We found that when a low-rate, long-duration, suprathreshold pulse-train was used, subthreshold cathodal tACS decreased cortical excitability and anodal tACS increased excitability. However, when a high-rate, short-duration, suprathreshold pulse-train was used this pattern was inverted. An integrate-and-fire model incorporating biophysical differences between cortical excitatory and inhibitory neurons could predict the experimental data and helped interpret these results. The model indicated that low-rate suprathreshold pulse-trains preferentially stimulate excitatory cortical neurons, whereas high-rate suprathreshold pulse-trains stimulate both excitatory and inhibitory neurons. If correct, this indicates that suprathreshold pulse-train stimulation may be able to selectively control the excitation-inhibition balance within a cortical network. The excitation-inhibition balance then likely plays an important role in determining whether subthreshold tACS will increase or decrease cortical excitability.SIGNIFICANCE STATEMENT Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that uses weak sinusoidal electric fields to modulate cortical activity. In healthy volunteers tACS can modulate perception, cognition, and motor function but the underlying neural mechanism is poorly understood. In this study, using rat motor cortex, we found that tACS effects are highly variable: applying the same tACS waveform to the same cortical area does not always give the same change in cortical excitability. An integrate-and-fire model incorporating excitatory pyramidal and inhibitory interneurons indicated that tACS effects likely depend on the cortical excitation-inhibition balance. When cortical activity is excitation dominated one particular tACS phase increases excitability, but when the cortical activity is inhibition dominated the same tACS phase actually decreases excitability.