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.

A systematic review and meta-analysis of transcranial direct-current stimulation effects on cognitive function in patients with Alzheimer's disease.

Transcranial direct-current stimulation (tDCS) appears to enhance cognitive function in Alzheimer's disease (AD). Accordingly, over the last two decades, the number of studies using tDCS for AD has grown. This study aimed to provide a quantitative assessment of the efficacy of tDCS in improving cognitive function in patients with AD. We systematically searched the literature until May 2021 to identify relevant publications for inclusion in our systematic review and meta-analysis. Eligible studies were sham-controlled trials assessing the impacts of anodal or cathodal tDCS on cognitive function in patients with AD. The outcome measure of this study was the effects of tDCS on distinct cognitive domains including memory, attention, and global cognitive function. The initial search yielded a total of 323 records. Five other articles were found using manual search of the databases. Of these, 13 publications (14 different studies) with a total of 211 patients of various degrees of AD severity underwent meta-analysis. Meta-analysis revealed the non-significant effects of tDCS on attention (0.425 SMD, 95% CI, -0.254 to 1.104, p = 0.220), and significant positive impacts on the amelioration of general cognitive measures (1.640 SMD, 95% CI, 0.782 to 2.498, p < 0.000), and memory (1.031 SMD, 95% CI, 0.688 to 1.373, p < 0.000) dysfunction in patients with AD. However, the heterogeneity of the studies were high in all subdomains of cognition (Ï°2 = 22.810, T2 = 0.552, d.f. = 5, I2 = 78.80%, p < 0.000 for attention, Ï°2 = 96.29, T2 = 1.727, d.f. = 10, I2 = 89.61%, p < 0.000 for general cognition, and Ï°2 = 7.253, T2 = 0.085, d.f. = 5, I2 = 31.06%, p = 0.203 for memory). Improved memory and general cognitive function in patients with AD was shown in this meta-analysis. However, due to the small number of studies and the high heterogeneity of the data, more high-quality studies using standardized parameters and measures are needed before tDCS can be considered as a treatment for AD.

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.

Interphase Gaps in Symmetric Biphasic Pulses Reduce the Therapeutic Window in Ventral Intermediate Nucleus of the Thalamus-Deep Brain Stimulation for Essential Tremor.

INTRODUCTION: Symmetric biphasic pulses enlarge the therapeutic window in thalamic deep brain stimulation in patients with essential tremor. Adding an interphase gap to these symmetric biphasic pulses may further affect the therapeutic window. MATERIALS AND METHODS: Nine patients (16 hemispheres) were included in this study. Biphasic pulses (anodic phase first) with interphase gaps of 0, 10, 20, 50, and 100 µs were tested, in random order. The outcome parameters were the therapeutic threshold (TT) and side-effect threshold (SET), and thus also the therapeutic window (TW). RESULTS: Increasing interphase gaps lowered both SET and TT (linear mixed-effects model; p < 0.001 and p < 0.001). Because SET decreased predominantly, increasing interphase gaps resulted in smaller TWs (linear mixed-effects model; p < 0.001). DISCUSSION AND CONCLUSIONS: Introducing an interphase gap in a symmetric biphasic pulse may lead to less selectivity in fiber or neuronal activation. Our findings show that, in the context of anode-first biphasic pulses, the use of zero-interphase gaps results in the largest TW. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT05177900.

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease.

OBJECTIVES: Deep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway-a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks. MATERIALS AND METHODS: We measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD. RESULTS: A short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001). CONCLUSIONS: Our results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming. CLINICAL TRIAL REGISTRATION: The ClinicalTrials.gov registration number for the study is NCT04658641.

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.

Aligning Dentato-Rubro-Thalamic Tract and Subthalamic Nucleus Targets in a Patient with Comorbid Essential Tremor and Parkinson's Disease: Case Report.

Deep brain stimulation is an established treatment option for both essential tremor (ET) and Parkinson's disease (PD), although typically targeting different brain structures. Some patients are diagnosed with comorbid ET and PD. Selecting the optimal stimulation target in these patients is challenging. We present a patient with comorbid ET and PD in whom we used bilaterally a single parietal trajectory to align the dentato-rubro-thalamic tract and the subthalamic nucleus. Although parietal trajectories are challenging, we reached satisfactory outcomes for both conditions without complications. Single-electrode deep brain stimulation of the dentato-rubro-thalamic tract and the subthalamic nucleus through a parietal approach may represent a feasible treatment option in this patient group.

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.

A model of the medial superior olive explains spatiotemporal features of local field potentials.

Local field potentials are important indicators of in vivo neural activity. Sustained, phase-locked, sound-evoked extracellular fields in the mammalian auditory brainstem, known as the auditory neurophonic, reflect the activity of neurons in the medial superior olive (MSO). We develop a biophysically based model of the neurophonic that accounts for features of in vivo extracellular recordings in the cat auditory brainstem. By making plausible idealizations regarding the spatial symmetry of MSO neurons and the temporal synchrony of their afferent inputs, we reduce the challenging problem of computing extracellular potentials in a 3D volume conductor to a one-dimensional problem. We find that postsynaptic currents in bipolar MSO neuron models generate extracellular voltage responses that strikingly resemble in vivo recordings. Simulations reproduce distinctive spatiotemporal features of the in vivo neurophonic response to monaural pure tones: large oscillations (hundreds of microvolts to millivolts), broad spatial reach (millimeter scale), and a dipole-like spatial profile. We also explain how somatic inhibition and the relative timing of bilateral excitation may shape the spatial profile of the neurophonic. We observe in simulations, and find supporting evidence in in vivo data, that coincident excitatory inputs on both dendrites lead to a drastically reduced spatial reach of the neurophonic. This outcome surprises because coincident inputs are thought to evoke maximal firing rates in MSO neurons, and it reconciles previously puzzling evoked potential results in humans and animals. The success of our model, which has no axon or spike-generating sodium currents, suggests that MSO spikes do not contribute appreciably to the neurophonic.

Frequency selectivity in Old-World monkeys corroborates sharp cochlear tuning in humans.

Frequency selectivity in the inner ear is fundamental to hearing and is traditionally thought to be similar across mammals. Although direct measurements are not possible in humans, estimates of frequency tuning based on noninvasive recordings of sound evoked from the cochlea (otoacoustic emissions) have suggested substantially sharper tuning in humans but remain controversial. We report measurements of frequency tuning in macaque monkeys, Old-World primates phylogenetically closer to humans than the laboratory animals often taken as models of human hearing (e.g., cats, guinea pigs, chinchillas). We find that measurements of tuning obtained directly from individual auditory-nerve fibers and indirectly using otoacoustic emissions both indicate that at characteristic frequencies above about 500 Hz, peripheral frequency selectivity in macaques is significantly sharper than in these common laboratory animals, matching that inferred for humans above 4-5 kHz. Compared with the macaque, the human otoacoustic estimates thus appear neither prohibitively sharp nor exceptional. Our results validate the use of otoacoustic emissions for noninvasive measurement of cochlear tuning and corroborate the finding of sharp tuning in humans. The results have important implications for understanding the mechanical and neural coding of sound in the human cochlea, and thus for developing strategies to compensate for the degradation of tuning in the hearing-impaired.

Testing of symmetric biphasic stimulation in Vim-DBS ET patients: a randomized-controlled pilot study.

Introduction: Symmetric biphasic pulses have been shown to increase the therapeutic window compared to standard cathodic pulses in ET Vim-DBS patients. Furthermore, three hours of stimulation with biphasic pulses caused less stimulation-induced ataxia compared to cathodic pulses. Therefore, an investigation of the longer-term safety of biphasic pulses is warranted. Methods: Seven ET patients were included in a randomized double-blind, cross-over design of one week home-use of symmetric biphasic stimulation (anodic phase first) versus cathodic stimulation. Amplitude was set in a double-blinded way, at the tremor arrest threshold. The primary outcome was safety assessed by documenting the adverse events. Secondary outcome parameters were stimulation amplitude, tremor (Fahn-Tolosa-Marin Tremor Rating Scale) and ataxia (International Cooperative Ataxia Rating Scale) severity, quality of life (Quality of Life in Essential Tremor Questionnaire) and cognition (Montreal Cognitive Assessment). Three patients continued in the open-label extension phase for 3 months, during which biphasic stimulation-only was further assessed by the same outcome parameters. Results: During the 1 week testing, no adverse effects were reported. To obtain equivalent tremor control, the amplitude of the biphasic pulse was significantly higher compared to that of the cathodic pulse (p = 0.003). The other outcome parameters were not significantly different. During the open-label study, one patient used the remote control to increase the amplitude, leading to two falls caused by stimulation-induced ataxia. No other adverse effects occurred. Discussion and conclusion: In a small cohort, when tested for one week, symmetric biphasic pulses suggest to be safe, but require higher stimulation amplitudes. Further follow-up studies are needed to investigate long-term effects and safety.

Electrophysiological sweet spot mapping in deep brain stimulation for Parkinson's disease patients.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-millisecond peak (P3) relating to clinical benefit, and a 10-millisecond peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping. METHODS: EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients' individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs. RESULTS: In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra. CONCLUSION: This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.

Rate and onset cues can improve cochlear implant synthetic vowel recognition in noise.

Understanding speech-in-noise is difficult for most cochlear implant (CI) users. Speech-in-noise segregation cues are well understood for acoustic hearing but not for electric hearing. This study investigated the effects of stimulation rate and onset delay on synthetic vowel-in-noise recognition in CI subjects. In experiment I, synthetic vowels were presented at 50, 145, or 795 pulse/s and noise at the same three rates, yielding nine combinations. Recognition improved significantly if the noise had a lower rate than the vowel, suggesting that listeners can use temporal gaps in the noise to detect a synthetic vowel. This hypothesis is supported by accurate prediction of synthetic vowel recognition using a temporal integration window model. Using lower rates a similar trend was observed in normal hearing subjects. Experiment II found that for CI subjects, a vowel onset delay improved performance if the noise had a lower or higher rate than the synthetic vowel. These results show that differing rates or onset times can improve synthetic vowel-in-noise recognition, indicating a need to develop speech processing strategies that encode or emphasize these cues.

Reinterpreting published tDCS results in terms of a cranial and cervical nerve co-stimulation mechanism.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation method that has been used to alter cognition in hundreds of experiments. During tDCS, a low-amplitude current is delivered via scalp electrodes to create a weak electric field in the brain. The weak electric field causes membrane polarization in cortical neurons directly under the scalp electrodes. It is generally assumed that this mechanism causes the observed effects of tDCS on cognition. However, it was recently shown that some tDCS effects are not caused by the electric field in the brain but rather via co-stimulation of cranial and cervical nerves in the scalp that also have neuromodulatory effects that can influence cognition. This peripheral nerve co-stimulation mechanism is not controlled for in tDCS experiments that use the standard sham condition. In light of this new evidence, results from previous tDCS experiments could be reinterpreted in terms of a peripheral nerve co-stimulation mechanism. Here, we selected six publications that reported tDCS effects on cognition and attributed the effects to the electric field in the brain directly under the electrode. We then posed the question: given the known neuromodulatory effects of cranial and cervical nerve stimulation, could the reported results also be understood in terms of tDCS peripheral nerve co-stimulation? We present our re-interpretation of these results as a way to stimulate debate within the neuromodulation field and as a food-for-thought for researchers designing new tDCS experiments.

Understanding Neuromodulation Pathways in tDCS: Brain Stem Recordings in Rat During Trigeminal Nerve Direct Current Stimulation.

Background: Recent evidence suggests that transcranial direct current stimulation (tDCS) indirectly influences brain activity through cranial nerve pathways, particularly the trigeminal nerve. However, the electrophysiological effects of direct current (DC) stimulation on the trigeminal nerve (DC-TNS) and its impact on trigeminal nuclei remain unknown. These nuclei exert control over brainstem centers regulating neurotransmitter release, such as serotonin and norepinephrine, potentially affecting global brain activity. Objectives: To investigate how DC-TNS impacts neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV). Methods: Twenty male Sprague Dawley rats (n=10 each nucleus) were anesthetized with urethane. DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve's marginal branch. Simultaneously, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, comprising three one-minute intervals: pre-stimulation, DC stimulation, and post-stimulation. Xylocaine was administered to block the trigeminal nerve as a control. Results: DC-TNS significantly increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. When the trigeminal nerve was blocked with xylocaine, the robust 3 mA trigeminal nerve DC stimulation failed to induce increased spiking activity in the trigeminal nuclei. Conclusion: Our results offer initial empirical support for trigeminal nuclei activity modulation via DC-TNS. This discovery supports the hypothesis that cranial nerve pathways may play a pivotal role in mediating tDCS effects, setting the stage for further exploration into the complex interplay between peripheral nerves and neural modulation techniques. Highlights: Direct current stimulation of the trigeminal nerve (DC-TNS) modulates neural activity in rat NVsnpr and MeV.Xylocaine administration reversibly blocks the DC-TNS effect on neural responses.Trigeminal nerve stimulation should be considered a possible mechanism of action of tDCS.

Deep brain stimulation for the treatment of Alzheimer's disease: A systematic review and meta-analysis.

Background: One of the experimental neuromodulation techniques being researched for the treatment of Alzheimer's disease (AD) is deep brain stimulation (DBS). To evaluate the effectiveness of DBS in AD, we performed a systematic review and meta-analysis of the available evidence. Methods: From the inception through December 2021, the following databases were searched: Medline via PubMed, Scopus, Embase, Cochrane Library, and Web of Science. The search phrases used were "Alzheimer's disease," "AD," "deep brain stimulation," and "DBS." The information from the included articles was gathered using a standardized data-collecting form. In the included papers, the Cochrane Collaboration methodology was used to evaluate the risk of bias. A fixed-effects model was used to conduct the meta-analysis. Results: Only five distinct publications and 6 different comparisons (one study consisted of two phases) were included out of the initial 524 papers that were recruited. DBS had no impact on the cognitive ability in patients with AD [0.116 SMD, 95% confidence interval (CI), -0.236 to 0.469, p = 0.518]. The studies' overall heterogeneity was not significant (κ2 = 6.23, T 2 = 0.053, df = 5, I 2 = 19.76%, p = 0.284). According to subgroup analysis, the fornix-DBS did not improve cognitive function in patients with AD (0.145 SMD, 95%CI, -0.246 to 0.537, p = 0.467). Unfavorable neurological and non-neurological outcomes were also reported. Conclusion: The inconsistencies and heterogeneity of the included publications in various target and age groups of a small number of AD patients were brought to light by this meta-analysis. To determine if DBS is useful in the treatment of AD, further studies with larger sample sizes and randomized, double-blinded, sham-controlled designs are required.

Acute stimulation with symmetric biphasic pulses induces less ataxia compared to cathodic pulses in DBS for essential tremor.

BACKGROUND: Symmetric biphasic pulses have been shown to acutely increase the therapeutic window of ventralis intermedius deep brain stimulation (Vim-DBS) for essential tremor (ET) compared to cathodic pulses. Acute supratherapeutic stimulation can induce ataxic side effects in Vim-DBS. OBJECTIVE: To investigate the effect on tremor, ataxia and dysarthria of 3 h of biphasic stimulation in patients with DBS for ET. METHODS: A randomized, doubled-blind, cross-over design was used to compare standard cathodic pulses with symmetric biphasic pulses (anode-first) during a 3-h period per pulse shape. During each 3-h period, all stimulation parameters were identical, except for the pulse shape. Tremor (Fahn-Tolosa-Marin Tremor Rating Scale), ataxia (International Cooperative Ataxia Rating Scale) and speech (acoustic and perceptual measures) were assessed hourly during the 3-h periods. RESULTS: Twelve ET patients were included. During the 3-h stimulation period, tremor control was equivalent between the two pulse shapes. Biphasic pulses elicited significantly less ataxia than cathodic pulses (p = 0.006). Diadochokinesis rate of speech was better for the biphasic pulse (p = 0.048), but other measures for dysarthria were not significantly different between the pulses. CONCLUSION: Symmetric biphasic pulses induce less ataxia than conventional pulses after 3 h of stimulation DBS in ET patients.

EEG-based biomarkers for optimizing deep brain stimulation contact configuration in Parkinson's disease.

Objective: Subthalamic deep brain stimulation (STN-DBS) is a neurosurgical therapy to treat Parkinson's disease (PD). Optimal therapeutic outcomes are not achieved in all patients due to increased DBS technological complexity; programming time constraints; and delayed clinical response of some symptoms. To streamline the programming process, biomarkers could be used to accurately predict the most effective stimulation configuration. Therefore, we investigated if DBS-evoked potentials (EPs) combined with imaging to perform prediction analyses could predict the best contact configuration. Methods: In 10 patients, EPs were recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. In two patients, we recorded from both hemispheres, resulting in recordings from a total of 12 hemispheres. A monopolar review was performed by stimulating on each contact and measuring the therapeutic window. CT and MRI data were collected. Prediction models were created to assess how well the EPs and imaging could predict the best contact configuration. Results: EPs at 3 ms and at 10 ms were recorded. The prediction models showed that EPs can be combined with imaging data to predict the best contact configuration and hence, significantly outperformed random contact selection during a monopolar review. Conclusion: EPs can predict the best contact configuration. Ultimately, these prediction tools could be implemented into daily practice to ease the DBS programming of PD patients.

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.