Niranjan Khadka

Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS)

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the rings diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be controlled while balancing other design factors such as intensity at the target and uni-directionality. Furthermore, the evaluated concentric HD-tDCS approaches can provide categorical improvements in targeting compared to conventional tDCS. Hypothesis driven clinical trials, based on specific target engagement, would benefit by this more precise method of stimulation that could avoid potentially confounding brain regions.

Modeling sequence and quasi-uniform assumption in computational neurostimulation.

Computational neurostimulation aims to develop mathematical constructs that link the application of neuromodulation with changes in behavior and cognition. This process is critical but daunting for technical challenges and scientific unknowns. The overarching goal of this review is to address how this complex task can be made tractable. We describe a framework of sequential modeling steps to achieve this: (1) current flow models, (2) cell polarization models, (3) network and information processing models, and (4) models of the neuroscientific correlates of behavior. Each step is explained with a specific emphasis on the assumptions underpinning underlying sequential implementation. We explain the further implementation of the quasi-uniform assumption to overcome technical limitations and unknowns. We specifically focus on examples in electrical stimulation, such as transcranial direct current stimulation. Our approach and conclusions are broadly applied to immediate and ongoing efforts to deploy computational neurostimulation.

The Influence of Skin Redness on Blinding in Transcranial Direct Current Stimulation Studies: A Crossover Trial

To evaluate whether and to which extent skin redness (erythema) affects investigator blinding in transcranial direct current stimulation (tDCS) trials.

Tolerability of Repeated Application of Transcranial Electrical Stimulation with Limited Outputs to Healthy Subjects

BACKGROUND The safety and tolerability of limited output transcranial electrical stimulation (tES) in clinical populations support a non-significant risk designation. The tolerability of long-term use in a healthy population had remained untested. OBJECTIVE We tested the tolerability and compliance of two tES waveforms, transcranial direct current stimulation (tDCS) and modulated high frequency transcranial pulsed current stimulation (MHF-tPCS) compared to sham-tDCS, applied to healthy subjects for three to five days (17-20 minutes per day) per week for up to six weeks in a communal setting. MHF-tPCS consisted of asymmetric high-frequency pulses (7-11 kHz) having a peak amplitude of 10-20 mA peak, adjusted by subject, resulting in an average current of 5-7 mA. METHOD A total of 100 treatment blind healthy subjects were randomly assigned to one of three treatment groups: tDCS (n = 33), MHF-tPCS (n = 30), or sham-tDCS (n = 37). In order to test the role of waveform, electrode type and montage were fixed across tES and sham-tDCS arms: high-capacity self-adhering electrodes on the right lateral forehead and back of the neck. We conducted 1905 sessions (636 sham-tDCS, 623 tDCS, and 646 MHF-tPCS sessions) on study volunteers over a period of six weeks. RESULTS Common adverse events were primarily restricted to influences upon the skin and included skin tingling, itching, and mild burning sensations. The incidence of these events in the active tES treatment arms (MHF-tPCS, tDCS) was equivalent or significantly lower than their incidence in the sham-tDCS treatment arm. Other adverse events had a rarity (<5% incidence) that could not be significantly distinguished across the treatment groups. Some subjects were withdrawn from the study due to atypical headache (sham-tDCS n = 2, tDCS n = 2, and MHF-tPCS n = 3), atypical discomfort (sham-tDCS n = 0, tDCS n = 1, and MHF-tPCS n = 1), or atypical skin irritation (sham-tDCS n = 2, tDCS n = 8, and MHF-tPCS n = 1). The rate of compliance, elected sessions completed, for the MHF-tPCS group was significantly greater than the sham-tDCS groups compliance (p = 0.007). There were no serious adverse events in any treatment condition. CONCLUSION We conclude that repeated application of limited output tES across extended periods, limited to the hardware, electrodes, and protocols tested here, is well tolerated in healthy subjects, as previously observed in clinical populations.

Minimal Heating at the Skin Surface During Transcranial Direct Current Stimulation

To assess if transcranial direct current stimulation (tDCS) produces a temperature change at the skin surface, if any change is stimulation polarity (anode or cathode) specific, and the contribution of passive heating (joule heat) or blood flow on such change.

Methods for Specific Electrode Resistance Measurement During Transcranial Direct Current Stimulation

BACKGROUND Monitoring of electrode resistance during tDCS is considered important for tolerability and safety. Conventional resistance measurement methods do not isolate individual electrode resistance and for HD-tDCS devices, cross talk across electrodes makes concurrent resistance monitoring unreliable. OBJECTIVE We propose a novel method to monitor individual electrode resistance during tDCS, using a super-position of direct current with a test-signal (low intensity and low frequency sinusoids with electrode-specific frequencies) and a sentinel electrode (not used for DC). METHODS We developed and solved lumped-parameter models of tDCS electrodes with or without a sentinel electrode to validate this methodology. Assumptions were tested and parameterized in participants using forearm stimulation combining tDCS (2 mA) and test-signals (38 and 76 μA pk-pk at 1 Hz, 10 Hz, & 100 Hz) and an in vitro test (creating electrode failure modes). DC and AC component voltages across the electrodes were compared and participants were asked to rate subjective pain. RESULTS A sentinel electrode is required to isolate electrode resistance in a two-electrode tDCS system. Cross talk aggravated with electrode proximity and resistance mismatch in multi-electrode resistance tracking could be corrected using proposed approaches. Average voltage and pain scores were not significantly different across test current intensities and frequencies. CONCLUSION Using our developed method, a test signal can predict DC electrode resistance. Since unique test frequencies can be used at each tDCS electrode, specific electrode resistance can be resolved for any number of stimulating channels - a process made still more robust by the use of a sentinel electrode.

Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

Involuntary movements as seen in repetitive disorders such as Tourette Syndrome (TS) results from cortical hyperexcitability that arise due to striato-thalamo-cortical circuit (STC) imbalance. Transcranial direct current stimulation (tDCS) is a stimulation procedure that changes cortical excitability, yet its relevance in repetitive disorders such as TS remains largely unexplored. Here, we employed the dopamine transporter-overexpressing (DAT-tg) rat model to investigate behavioral and neurobiological effects of frontal tDCS. The outcome of tDCS was pathology dependent, as anodal tDCS decreased repetitive behavior in the DAT-tg rats yet increased it in wild-type (wt) rats. Extensive deep brain stimulation (DBS) application and computational modeling assigned the response in DAT-tg rats to the sensorimotor pathway. Neurobiological assessment revealed cortical activity changes and increase in striatal inhibitory properties in the DAT-tg rats. Our findings show that tDCS reduces repetitive behavior in the DAT-tg rat through modulation of the sensorimotor STC circuit. This sets the stage for further investigating the usage of tDCS in repetitive disorders such as TS.

Principles of Within Electrode Current Steering

tDCS is a neuromodulation technique that involves noninvasive delivery of weak direct current (1–2 mA) to the brain. Conventionally, tDCS employs rectangular saline-soaked sponge pads (25–35 cm) placed on the scalp, with an internal electrode connected to the current source. Impedance measurement across the current source output may fail to recognize nonuniform conditions at the skin interface such an uneven content or saturation. tDCS is well tolerated with minor adverse effects limited to transient skin irritation [1]. Nonetheless, technology that enhances the sophistication of electrode design would further enhance tolerability and promote broad (e.g., home) use. In order to enhance the reliability and tolerability of tDCS, we describe a novel method called WECS. This concept is distinct from (across electrode) current steering, as developed for implanted devices such as deep brain stimulation (DBS), where current is steered between electrodes that are each in contact with tissue, with the goal of changing desired brain regions that are activated [2]. WECS adjusts current between electrodes not in contact with tissue but rather embedded in an electrolyte on the body surface. The goal here is not to alter brain current flow, but rather compensate for nonideal conditions at the surface. This technology leverages our technique for independently isolating electrode impedance and overpotential during multichannel stimulation [3]. With a novel approach, the objective of this first paper was to demonstrate the principles of WECS using an exemplary electrode design typical for tDCS (four rivet-electrode sponge) and extremes of current steering (from uniform in all rivets to a single rivet). Through FEM simulation of this illustrative case, we validate the underlying assumptions of WECS: steering current within electrodes but without altering current distribution in brain target. Having presented this novel idea through an exemplary case, this report supports future studies in optimization of electrode design, automation of algorithms to control current (including using impedance measurement), and ultimately validation under experimental conditions. 2 Methods

Higher-order power harmonics of pulsed electrical stimulation modulates corticospinal contribution of peripheral nerve stimulation

It is well established that electrical-stimulation frequency is crucial to determining the scale of induced neuromodulation, particularly when attempting to modulate corticospinal excitability. However, the modulatory effects of stimulation frequency are not only determined by its absolute value but also by other parameters such as power at harmonics. The stimulus pulse shape further influences parameters such as excitation threshold and fiber selectivity. The explicit role of the power in these harmonics in determining the outcome of stimulation has not previously been analyzed. In this study, we adopted an animal model of peripheral electrical stimulation that includes an amplitude-adapted pulse train which induces force enhancements with a corticospinal contribution. We report that the electrical-stimulation-induced force enhancements were correlated with the amplitude of stimulation power harmonics during the amplitude-adapted pulse train. In an exploratory analysis, different levels of correlation were observed between force enhancement and power harmonics of 20–80 Hz (r = 0.4247, p = 0.0243), 100–180 Hz (r = 0.5894, p = 0.0001), 200–280 Hz (r = 0.7002, p < 0.0001), 300–380 Hz (r = 0.7449, p < 0.0001), 400–480 Hz (r = 0.7906, p < 0.0001), 500–600 Hz (r = 0.7717, p < 0.0001), indicating a trend of increasing correlation, specifically at higher order frequency power harmonics. This is a pilot, but important first demonstration that power at high order harmonics in the frequency spectrum of electrical stimulation pulses may contribute to neuromodulation, thus warrant explicit attention in therapy design and analysis.

Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury

Cervical injuries are the most common form of SCI. In this study, we used a neuromodulatory approach to promote skilled movement recovery and repair of the corticospinal tract (CST) after a moderately severe C4 midline contusion in adult rats. We used bilateral epidural intermittent theta burst (iTBS) electrical stimulation of motor cortex to promote CST axonal sprouting and cathodal trans-spinal direct current stimulation (tsDCS) to enhance spinal cord activation to motor cortex stimulation after injury. We used Finite Element Method (FEM) modeling to direct tsDCS to the cervical enlargement. Combined iTBS-tsDCS was delivered for 30min daily for 10days. We compared the effect of stimulation on performance in the horizontal ladder and the Irvine Beattie and Bresnahan forepaw manipulation tasks and CST axonal sprouting in injury-only and injury+stimulation animals. The contusion eliminated the dorsal CST in all animals. tsDCS significantly enhanced motor cortex evoked responses after C4 injury. Using this combined spinal-M1 neuromodulatory approach, we found significant recovery of skilled locomotion and forepaw manipulation skills compared with injury-only controls. The spared CST axons caudal to the lesion in both animal groups derived mostly from lateral CST axons that populated the contralateral intermediate zone. Stimulation enhanced injury-dependent CST axonal outgrowth below and above the level of the injury. This dual neuromodulatory approach produced partial recovery of skilled motor behaviors that normally require integration of posture, upper limb sensory information, and intent for performance. We propose that the motor systems use these new CST projections to control movements better after injury.