Abhishek Datta

Optimized multi-electrode stimulation increases focality and intensity at target

Transcranial direct current stimulation (tDCS) provides a non-invasive tool to elicit neuromodulation by delivering current through electrodes placed on the scalp. The present clinical paradigm uses two relatively large electrodes to inject current through the head resulting in electric fields that are broadly distributed over large regions of the brain. In this paper, we present a method that uses multiple small electrodes (i.e. 1.2 cm diameter) and systematically optimize the applied currents to achieve effective and targeted stimulation while ensuring safety of stimulation. We found a fundamental trade-off between achievable intensity (at the target) and focality, and algorithms to optimize both measures are presented. When compared with large pad-electrodes (approximated here by a set of small electrodes covering 25 cm(2)), the proposed approach achieves electric fields which exhibit simultaneously greater focality (80% improvement) and higher target intensity (98% improvement) at cortical targets using the same total current applied. These improvements illustrate the previously unrecognized and non-trivial dependence of the optimal electrode configuration on the desired electric field orientation and the maximum total current (due to safety). Similarly, by exploiting idiosyncratic details of brain anatomy, the optimization approach significantly improves upon prior un-optimized approaches using small electrodes. The analysis also reveals the optimal use of conventional bipolar montages: maximally intense tangential fields are attained with the two electrodes placed at a considerable distance from the target along the direction of the desired field; when radial fields are desired, the maximum-intensity configuration consists of an electrode placed directly over the target with a distant return electrode. To summarize, if a target location and stimulation orientation can be defined by the clinician, then the proposed technique is superior in terms of both focality and intensity as compared to previous solutions and is thus expected to translate into improved patient safety and increased clinical efficacy.

Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects

•  The diversity of cellular targets of direct current stimulation (DCS), including somas, dendrites and axon terminals, determine the modulation of synaptic efficacy. •  Axon terminals of cortical pyramidal neurons are two–three times more susceptible to polarization than somas. •  DCS in humans results in current flow dominantly parallel to the cortical surface, which in animal models of cortical stimulation results in synaptic pathway‐specific modulation of neuronal excitability. •  These results suggest that somatic polarization together with axon terminal polarization may be important for synaptic pathway‐specific modulation of DCS, which underlies modulation of neuronal excitability during transcranial DCS.

Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: A basis for high-definition tDCS

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 × 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 × 1 montage (4 × cathode, surrounding a single central anode; montage radius ~3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 × 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 × 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 × 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 × 1-Ring montage for cortically targeted neuromodulation.

Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models

Background: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, versatile, and safe neuromodulation technology under investigation for the treatment of neuropsychiatric disorders, adjunct to rehabilitation, and cognitive enhancement in healthy adults. Despite promising results, there is variability in responsiveness. One potential source of variability is the intensity of current delivered to the brain which is a function of both the operator controlled tDCS dose (electrode montage and total applied current) and subject specific anatomy. We are interested in both the scale of this variability across anatomical typical adults and methods to normalize inter-individual variation by customizing tDCS dose. Computational FEM simulations are a standard technique to predict brain current flow during tDCS and can be based on subject specific anatomical MRI. Objective: To investigate this variability, we modeled multiple tDCS montages across three adults (ages 34–41, one female). Results: Conventional pad stimulation led to diffuse modulation with maximum current flow between the pads across all subjects. There was high current flow directly under the pad for one subject while the location of peak induced cortical current flow was variable. The High-Definition tDCS montage led to current flow restricted to within the ring perimeter across all subjects. The current flow profile across all subjects and montages was influenced by details in cortical gyri/sulci. Conclusion: This data suggests that subject specific modeling can facilitate consistent and more efficacious tDCS.

Establishing safety limits for transcranial direct current stimulation

The recent resurgence in the use of transcranial Direct Current Stimulation (tDCS) for electrotherapy and human cognition studies was motivated by studies demonstrating lasting change in cortico-spinal excitability following tDCS (Priori et al., 1998; Nitsche & Paulus, 2000, 2001) including at the University of Gottingen. Subsequent tDCS studies have largely adapted the Gottingen protocols including the use of relatively-large wet sponges with size nominally 25 – 35 cm2 and currents of 1 – 2 mA applied for durations up to 20 minutes (resulting in charge densities of 343–960 C/m2). Reproduction of these protocols across a wide range of applications and subjects (Nitsche et al., 2003a; Fregni et al., 2006; Webster et al., 2006; Boggio et al., 2007), has resulted in only isolated published reports on injury, limited to (acute) skin irritation under the sponges (Poreisz et al., 2007; Dundas et al., 2007; Bikson et al., 2008; Palm et al., 2008) such that current tDCS procedures are considered “safe” (Nitsche & Paulus, 2001; Nitsche et al., 2003b; Nitsche et al., 2003c; Nitsche et al., 2004a; Iyer et al., 2005). None-the-less, the need for continued vigilance in examining potential hazards, combined with the desire by clinicians to explore increasing intensity protocols and duration of after effects (Nitsche et al., 2004b; Fregni et al., 2006) warrants investigation of the thresholds and mechanisms of tDCS hazards. In developing safety guidelines for tDCS, several biophysical qualifications should be made. Firstly, if and what type of injury results from electrical stimulation is wholly dependent on the precise stimulation hardware and waveform applied; thus while one can draw general insights from a broad range of electrical safety studies (Agnew & McCreery et al., 1987; Merrill et al., 2005), it is neither accurate nor prudent to determine quantitative safety standards for tDCS from these reports. Moreover, tDCS itself represents a constellation of technologies and approaches (e.g. sponge salinity, electrode configurations, ramp waveform, intensity) such that safety standards may be tDCS protocol specific. Second, the injurious effects of tDCS on skin and brain are not necessarily linked, and should be considered independently from both the risk and mitigation stand-point. Acute pain and tissue damage of skin can further be distinguished, as should brain cognitive impairment versus brain tissue damage factors. The report in this edition by Liebetanz and colleagues in Gottingen is a valuable contribution towards this last factor. Brain tissue damage was accessed in a rat model following epicranial electrode stimulation (Liebetanz et al., 2009). By fixing the electrode directly on the cranium, and using a large counter electrode on the ventral thorax, the study design maximized the electrode current that crosses directly into the skull; thus in this model the peak current density in the rat brain may approach the current density at the electrode (though some shunting/diffusion as a result of skull resistance is unavoidable). Liebetanz and colleagues report that brain lesions were observed at a minimum cathodal electrode current density 142.9 A/m2 for durations greater than 10 min. For current densities between 142.9 and 285.7 A/m2, lesion size increased linearly with charge density (current density × time); with an extrapolated zero lesion size intercept of 52400 C/m2. Thus Liebetanz and colleagues conclude that both the stated cathodal current density and charge density thresholds must be exceeded to induce histopathologically visible brain tissue damage. These findings must be interpreted in the context of limited understanding of damage mechanisms, and translational issues relating to clinical electrode montages and human anatomy. The authors propose tissue heating (burning) as a probable mechanism for damage. Though temperature measurements were not conducted in the present study, the requirement for a current density threshold, as well as the increased lesion size with time/charge density once current density threshold is exceeded, are consistent with burning. Electrical current generates heat in tissue through joule heat, which is linearly dependent on current density. For analogy: Touching a moderately warm plate, even for a long time, will not induce skin burns when passive (heat conduction) and active (blood flow) mechanisms control peak temperature rise. Similarly, the temperature changes generated by low levels of current density in the brain may be regulated to non-harmful levels. Returning to the hot plate analogy: Even if the plate is heated to a potentially harmful temperature, just touching the plate briefly will not cause a burn, because: 1) it takes time for tissue to heat; and 2) exposure at that temperature only for an extended time will lead to tissue damage (Lee et al., 2000, Kiyatkin, 2004, Elwassif et al.,2006). Hence, damage by heating is critically dependent on exposure time (in contrast for example, immediate instantaneous damage by electroporation), which is consistent with the dependence of tissue lesion size on time/charge density observed by Liebetanz and colleagues. We calculate that a uniform current density of 142.9 A/m2 will increase the temperature of brain tissue to 47.75 °C in 10 minutes (assuming no blood flow and metabolic heat source; initial temperature = 37 °C; electrical conductivity = 0.3 S/m; specific heat = 3650 J/(Kg.°C); density = 1040 Kg/m3). If temperature changes result only from joule heating, without a contribution from electrical alteration in neuronal metabolic activity, then tissue damage thresholds would be polarity independent. However, in the absence of a verified tissue damage mechanism and explicit testing of anodal stimulation, safety results from cathodal stimulation do not necessarily apply for anodal stimulation. In relating the findings of this report to human safety standards, Liebetanz and colleagues acknowledge the (unavoidable) limitations of the animal model but correctly indicate that the epicranial electrode montage may provide a worst case scenario for the fraction of electrode current entering the brain. In clinical studies, it is convenient to report stimulation intensity as average current density: calculated by dividing the current delivered to the electrode by the total sponge contact area. Using sponge electrodes, the current density at the scalp is concentrated near the sponge edges and thus exceeds the average current density (Miranda et al., 2006; Wagner et al., 2007). The skull, however, acts to diffuse current flow such that these concentrations are not reflected on the brain surface (Miranda et al., 2006; Datta et al., 2008; Datta et al.,2009). Moreover, depending on the clinical electrode montage used, a significant portion of the applied current may be ‘shunted’ by the scalp and not enter the brain. Simplistically, if one speculates that average current density at the tDCS electrodes reflects an upper-limit on current density in the brain, then the average electrode current density may be rationally limited to 142.9 A/m2 in order to prevent the tissue damage observed by Liebetanz and colleagues. It would be premature to arbitrarily apply this average electrode current density standard in clinical testing because: 1) as emphasized by the authors, these results “are soley based on morphological [animal data] and do not include studies on long-term morphological changes or behavioral changes”; and 2) details of human anatomy, including cortical folding, will affect current flow and can result in regional cerebral blood flow/current density “clustering” (Lang et al., 2005; Datta et al.,2009). Conversely, this standard does not imply that any tDCS protocol where average electrode current density exceeds this value is necessarily hazardous: Firstly, Liebetanz and colleagues demonstrate a second concurrent charge-density threshold which indicates a pivotal role for exposure time. Second, the reduction in current density from the electrode to brain surface (due to skull diffusion, scalp/CSF shunting) adds an additional safety factor that can be determined for each montage (Wagner et al., 2007; Datta et al., 2008; Datta et al.,2009). Finally, regarding other safety factors: Prevention of brain damage for tDCS electrode montages does not preclude undesirable cognitive side-effects; though to-date, reports of tDCS modulation of cognitive function have generally indicated only transient improvements or impairment in performance, if any change at all (Nitsche et al., 2003a; Antal et al., 2004a; Antal et al., 2004b; Iyer et al., 2005; Kuo et al., 2008). Skin irritation and damage can be readily accessed in human subjects. Especially given the limitation of animal models and the related importance of exactly reproducing electrode montages (e.g. size); a rational approach to skin safety is controlled and incremental evaluation in human subjects. For example, results by our group indicate that with appropriate hardware (electrodes, adapters, and gels), current densities of 25.46 A/m2 can be applied for 20 minutes with minimal sensation and no skin damage (unpublished observations). In these studies, subjects scored pain perception during forearm stimulation under anode and cathode electrodes; in addition pH and temperature changes in the customized stimulation gel were not detected. In summary, the contribution by Liebetanz and colleagues is correctly, a “first estimate of a safety threshold for deleterious DC” transcranial stimulation; the potential of tDCS as a clinical and experimental tool supports further safety studies in both humans and animals as well as the continued development of tDCS technologies.

Electrode montages for tDCS and weak transcranial electrical stimulation: Role of “return” electrode’s position and size

In this issue, Moliadze and colleagues investigate the role of electrode montage in the induction of acute lasting excitability changes by transcranial Direction Current Stimulation (tDCS) and transcranial Random Noise Stimulation (tRNS); specifically they demonstrate that during weak transcranial electrical stimulation, the position of the “return” electrode affects neuromodulation under the “active” electrode. Moliadze and colleagues introduce the development of modern tDCS protocols at the turn of the decade (Priori et al., 1998; Nitsche and Paulus, 2000, 2001; Terney et al., 2008). Despite wide-spread subsequent dissemination of tDCS, there remain significant unknowns about the mechanisms of tDCS and the design of electrode montages, including electrode size and placement. Moliadze and colleagues address the role of “return” electrode’s position (and distance) in the induction of Transcranial Magnetic Stimulation (TMS) evoked excitability changes under an “active” electrode over motor cortex (Moliadze et al., 2010). Understanding and controlling electrotherapy dose is evidently critical in determining behavioral and clinical outcome. The position of stimulating electrodes governs current flow through the body, and hence the distribution of induced electric fields in the brain. These induced cortical currents/electric fields modulate neuronal excitability for DC stimulation and, in turn, determine behavioral and clinical outcomes (Bikson et al., 2008). The most simplistic dose design schemes for tDCS assume a region of “increased excitability” in the cortex directly under the anode electrode, and a region of “decreased excitability’ under the cathode, with intermediary regions largely spared (unaffected). Several studies have suggested limitations in this simplified approach including the need to consider: 1) Current density at the electrode (Nitsche et al., 2007; Miranda et al., 2006; Miranda et al., 2009); 2) Individual differences (Madhavan et al., 2010); 3) Significant current flow in intermediary regions, including the potential for current clustering (Datta et al, 2009); 4) Montages for unidirectional modulation (Rossini et al., 1985; Saypol et al.,1991; Datta et al., 2008); and 5) Relative electrode position, including inter-electrode distance (Stecker et al.,2005; Datta et al., 2008) and the use of extra-cephalic electrodes (Accornero et al., 2007; Ferrucci et al., 2008, Baker et al., 2010). Generally, increasing electrode separation on the head is expected to increase cortical modulation by increased relative amount of current entering the brain rather than “shunted” across the scalp. The report by Moliadze and colleagues provides some of the strongest clinical evidence to-date that the relative position of stimulation electrode can affect neuromodulation under each electrode – namely that in determining electrotherapy dose the two stimulating electrodes cannot be considered separately and independently, even for relatively distant electrode positions. Moreover, increasing electrode distance may decrease the magnitude of neuro-modulation, depending on the specific montage and physiological measure. The current flow through the body is strongly influenced by anatomical details, because of the different electrical conductivities of tissues such as scalp, skull/vertebrae, muscle, CSF, and brain – as a result the induced current profile in the brain may be detailed and complex. Given this, it is thus not surprising that the position of both electrodes determines the resulting current flow distribution through the cortex. Simultaneously, the complexity of current flow indicates that determining electrode montages dose by simplified assumptions may not be prudent, as highlighted by the results of Moliadze et al., 2010. One solution to addressing this complexity in the design of rational stimulation protocols is the prediction of current flow patterns through the brain using computer models. The sophistication of computer models using finite-element-methods (FEM) for this purpose (Butson et al., 2007; De Lucia et al., 2007) has increased to allow high-resolution (e.g. 1 mm; Datta et al., 2009) and individualized modeling (Wagner et al.,2007; Datta et al., in press). Figure 1 illustrates the resulting brain current flow for three electrode montages – in all cases, the size and position of the “active” electrode over motor cortex is fixed, while the position or size of the “return” electrode is varied. The position and size of the “return” electrode affects the electric field distribution across the entire cortex. In addition, changing the position of the “return” electrode affects the electric field distribution in cortex directly under the “active” electrode. Figure 1 Effect of “return” electrode’s position and size on cortical electric fields induced by a 4 cm × 4 cm “active” electrode over the left primary motor cortex. An individualized FEM head model was created from ... Our modeling results support the clinical finding by Moliadze and colleagues that even if the direct actions of the “return” electrode are mitigated by its position (e.g. extracephalic) or size (Nitsche et al., 2007); the “return” electrode will still influence the current path through the brain from the “active” electrode. For example, the repositioning of the return pad from the contralateral forehead to the contralateral upper arm may have shifted the preferential flow of current from across the frontal regions to across the posterior regions of the brain (see Montage A and C versus Montage B in Figure 1). More generally, the regions of brain modulation may not be simply under the “active” electrode (Datta et al., 2009; Sadleir et al., 2010), such that some “surprising” clinical findings, including by Moliadze and colleagues may be understood by considering the concurrent neuro-modulation of multiple cortical and sub-cortical regions. Additional experimental studies investigating the specific role of electrode placements and intensity, and careful consideration of electrode montage in designing therapeutic protocols, is warranted.

tDCS-Induced Analgesia and Electrical Fields in Pain-Related Neural Networks in Chronic Migraine

Objective.— We investigated in a sham‐controlled trial the analgesic effects of a 4‐week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high‐resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation.

Computational models of transcranial direct current stimulation.

During transcranial direct current stimulation (tDCS), controllable dose parameters are electrode number (typically 1 anode and 1 cathode), position, size, shape, and applied electric current. Because different electrode montages result in distinct brain current flow patterns across the brain, tDCS dose parameters can be adjusted, in an application-specific manner, to target or avoid specific brain regions. Though the tDCS electrode montage often follows basic rules of thumb (increased/decreased excitability “under” the anode/cathode electrode), computational forward models of brain current flow provide more accurate insight into detailed current flow patterns and, in some cases, can even challenge simplified electrode-placement assumptions. With the increased recognized value of computational forward models in informing tDCS montage design and interpretation of results, there have been recent advances in modeling tools and a greater proliferation of publications. In addition, the importance of customizing tDCS for potentially vulnerable populations (eg, skull defects, brain damage/stroke, and extremes of age) can be considered. Finally, computational models can be used to design new electrode montages, for example, to improve spatial targeting such as high-definition tDCS. Pending further validation and dissemination of modeling tools, computational forward models of neuromodulation will become standard tools to guide the optimization of clinical trials and electrotherapy.

A Pilot Study of the Tolerability and Effects of High-Definition Transcranial Direct Current Stimulation (HD-tDCS) on Pain Perception

UNLABELLED Several brain stimulation technologies are beginning to evidence promise as pain treatments. However, traditional versions of 1 specific technique, transcranial direct current stimulation (tDCS), stimulate broad regions of cortex with poor spatial precision. A new tDCS design, called high definition tDCS (HD-tDCS), allows for focal delivery of the charge to discrete regions of the cortex. We sought to preliminarily test the safety and tolerability of the HD-tDCS technique as well as to evaluate whether HD-tDCS over the motor cortex would decrease pain and sensory experience. Twenty-four healthy adult volunteers underwent quantitative sensory testing before and after 20 minutes of real (n = 13) or sham (n = 11) 2 mA HD-tDCS over the motor cortex. No adverse events occurred and no side effects were reported. Real HD-tDCS was associated with significantly decreased heat and cold sensory thresholds, decreased thermal wind-up pain, and a marginal analgesic effect for cold pain thresholds. No significant effects were observed for mechanical pain thresholds or heat pain thresholds. HD-tDCS appears well tolerated, and produced changes in underlying cortex that are associated with changes in pain perception. Future studies are warranted to investigate HD-tDCS in other applications, and to examine further its potential to affect pain perception. PERSPECTIVE This article presents preliminary tolerability and efficacy data for a new focal brain stimulation technique called high definition transcranial direct current stimulation. This technique may have applications in the management of pain.

Transcranial Direct Current Stimulation in Patients with Skull Defects and Skull Plates: High-Resolution Computational FEM Study of Factors Altering Cortical Current Flow

Preliminary positive results of transcranial direct current stimulation (tDCS) in enhancing the effects of cognitive and motor training indicate that this technique might also be beneficial in traumatic brain injury or patients who had decompressive craniectomy for trauma and cerebrovascular disease. One perceived hurdle is the presence of skull defects or skull plates in these patients that would hypothetically alter the intensity and location of current flow through the brain. We aimed to model tDCS using a magnetic resonance imaging (MRI)-derived finite element head model with several conceptualized skull injuries. Cortical electric field (current density) peak intensities and distributions were compared with the healthy (skull intact) case. The factors of electrode position (C3-supraorbital or O1-supraorbital), electrode size skull defect size, skull defect state (acute and chronic) or skull plate (titanium and acrylic) were analyzed. If and how electric current through the brain was modulated by defects was found to depend on a specific combination of factors. For example, the condition that led to largest increase in peak cortical electric field was when one electrode was placed directly over a moderate sized skull defect. In contrast, small defects midway between electrodes did not significantly change cortical currents. As the conductivity of large skull defects/plates was increased (chronic to acute to titanium), current was shunted away from directly underlying cortex and concentrated in cortex underlying the defect perimeter. The predictions of this study are the first step to assess safety of transcranial electrical therapy in subjects with skull injuries and skull plates.