Preet Minhas

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.

Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation.

Transcranial direct current stimulation in pediatric brain: A computational modeling study

Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation which uses weak electric currents applied on the scalp to modulate activity of underlying brain tissue. In addition to being used as a tool for cognitive neuroscience investigations, tDCS has generated considerable interest for use as a therapeutic modality for neurologic disorders. Though the safety and tolerability of tDCS in adults is well-established, there is little information on the safety of tDCS in children. Because there are differences between children and adults in several key parameters (such as skull thickness and cerebrospinal fluid volume) which affect current flow through the brain, special consideration should be given to the stimulation parameters which are used in a pediatric study population. In this study we present cortical electrical field maps at different stimulation intensities and electrode configurations using a high-resolution-MRI derived finite element model of a typically developing, anatomically normal 12 year old child. The peak electrical fields for a given stimulus intensity in the adolescent brain were twice as high as in the adult brain for conventional tDCS and nearly four times as high for a 4×1 High-Definition tDCS electrode configuration. These data suggest that acceptable tDCS stimulation parameters may be different in children compared to adults, and that further modeling studies are needed to help guide decisions about applied current intensity.

Pediatric stroke and transcranial direct current stimulation: methods for rational individualized dose optimization

Background: Transcranial direct current stimulation (tDCS) has been investigated mainly in adults and doses may not be appropriate in pediatric applications. In perinatal stroke where potential applications are promising, rational adaptation of dosage for children remains under investigation. Objective: Construct child-specific tDCS dosing parameters through case study within a perinatal stroke tDCS safety and feasibility trial. Methods: 10-year-old subject with a diagnosis of presumed perinatal ischemic stroke and hemiparesis was identified. T1 magnetic resonance imaging (MRI) scans used to derive computerized model for current flow and electrode positions. Workflow using modeling results and consideration of dosage in previous clinical trials was incorporated. Prior ad hoc adult montages vs. de novo optimized montages provided distinct risk benefit analysis. Approximating adult dose required consideration of changes in both peak brain current flow and distribution which further tradeoff between maximizing efficacy and adding safety factors. Electrode size, position, current intensity, compliance voltage, and duration were controlled independently in this process. Results: Brain electric fields modeled and compared to values previously predicted models (Datta et al., 2011; Minhas et al., 2012). Approximating conservative brain current flow patterns and intensities used in previous adult trials for comparable indications, the optimal current intensity established was 0.7 mA for 10 min with a tDCS C3/C4 montage. Specifically 0.7 mA produced comparable peak brain current intensity of an average adult receiving 1.0 mA. Electrode size of 5 × 7 cm2 with 1.0 mA and low-voltage tDCS was employed to maximize tolerability. Safety and feasibility confirmed with subject tolerating the session well and no serious adverse events. Conclusion: Rational approaches to dose customization, with steps informed by computational modeling, may improve guidance for pediatric stroke tDCS trials.

Cutaneous perception during tDCS: Role of electrode shape and sponge salinity

Transcranial direct current stimulation (tDCS) is a noninvasive method of brain modulation that is increasingly tested for the treatment of neuropsychiatric disorders (Murphy et al 2009) and cognitive enhancement (Paulus, 2004; Talelli and Rothwell, 2006). Conventional tDCS protocols apply 1–2 mA of current, for several minutes, through conductive-rubber electrodes inserted in sponge wrappers, which are typically soaked in saline, before being placed on the scalp. tDCS has many useful characteristics including low cost, ease of use, portability, and absence of significant side-effects. Indeed, during tDCS, mild tingling or itching sensation are the most common adverse effects (Poreisz et al., 2007), and though isolated cases of skin burns have been reported (Lagopoulos and Degabriele, 2008; Palm et al., 2008), relatively large scale experiences from several active centers, including at Gottingen, suggest that under proper protocols, significant adverse events are avoided (Dundas et al., 2007; Loo et al., 2010; Poreisz et al., 2007). Acute sensation under electrodes during DC stimulation is well established (Leeming et al 1970, Mason and Mackay, 1976) and is highly dependent on both stimulation intensity and electrode design (Dundas et al., 2007; Forrester and Petrofsky, 2004); Martinsen et al., 2004; Minhas et al., 2010). Though generally increasing applied current increases all physiological responses, sensation does not simply correlate with either skin damage or brain modulation (Bikson et al., 2009) because of importance of electrode design and montage (for example increasing the proximity of electrodes decreases total brain but not skin current). None-the-less, sensation is clinically significant in itself for several reasons including tolerability (especially in vulnerable populations), confounding of experimental and clinical results, and blinding. The report in this edition by Ambrus and colleagues in Gottingen evaluated sensation differences for surface-area matched (35 cm2) rectangular and round electrodes. For anodal and cathodal tDCS, as well as tRNS, they found no substantial differences in detection threshold, detection rate, false-positive rate, or quality of sensation. It is well established, including through computational modeling studies, that during electrical stimulation, current distribution at the electrode-tissue (skin) interface is not uniform, with high concentration of current density at the electrode edges (Miranda et al., 2006). The concentration of current density at an electrode edge is generally undesired for safety reasons (especially for implanted electrodes; (Merrill et al., 2005)) and may increase sensation during trancutaneous stimulation. Note that during transcranial electrical stimulation, subsequent current dispersion across deeper tissues results in no electrode-edge related current concentrations at the brain (Miranda et al., 2006, Datta et al., 2008, Datta et al., 2009a,b). Various strategies for normalizing current distribution at the electrode-tissue interface have been developed focusing on the materials and/or shape of the electrode (Krasteva and Papazov, 2002; Gilad et al., 2007; Minhas et al., 2010) - motivating the tDCS/tRNS electrode shape study by Ambrus et al (2010). We modeled the current density at the electrode-skin interface under conditions approximating those tested by Ambrus et al. (2010). Consistent with previous results, for both rectangular and round electrodes, the current density was significantly higher at the electrode edges (Figure 1). For the same average current density (total current applied to equally sized electrodes), there was a moderately higher peak concentration of current for the rectangular electrodes than for the circular electrodes (Figure 1 a2, b3), but only at the rectangular electrode corners (Figure 1 a3, b3). Given the scale (peak) and nature (distribution) of these differences, it is not surprising that difference in sensation could not be resolved clinically by Ambrus and colleagues – especially when considering that, practically, the effect of sharp rectangular edges would be reduced by hair wetting. We further modeled changing the saline concentration in the electrode; as expected decreasing sponge salinity significantly decreased peak current density at the electrode corners (Figure 1 a4, b4), consistent with the clinical finding by Dundas et al. (2007) – peak current densities for the circular and rectangular electrode were relatively matched. Figure 1 Comparison of the skin current density profiles for area matched rectangular and circular pads a1,b1: Modeled finite element geometry. The head model comprised of 4 concentric blocks (skin, skull, CSF, brain). The electrode and sponge pad had 0.5 mm and ... To allow direct comparisons across electrode shapes, our simplified (planar) model does not address: 1) realistic head shapes and anatomy (leading to asymmetric current distribution at electrode edges); 2) potential difference in skin properties (skin micro-architecture). Indeed, Ambrus and colleagues report significant differences in sensitivity of perception across stimulation sites. The simplest explanation for sensation and discomfort during transcutaneous electrical stimulation is the excitation of peripheral nerves; electrochemical processes (Minhas 2010), but not heating, (Nitsche and Paulus, 2000; Datta et al., 2009) may contribute during tDCS. Regardless of the mechanism(s), hot spots of current density around the electrode edges, and perhaps around skin inhomogeneities (e.g. sweat glands), are considered to increase sensitivity, and thus approaches to increase uniformity of current density at the electrode-skin interface are rational. In conclusion, it is important to emphasize that current technologies and protocols in transcranial stimulation, which have been largely incrementally and empirically derived, can likely be further optimized and refined. For example, electrolyte fluids and gels optimized specifically for tDCS have only recently been explored (Dundas et al., 2007; Minhas 2010). The ultimate goal of such design efforts would be electrodes that minimize (if not eliminate) all sensation and prevent skin irritation, even under non-optimal conditions, while maintaining the simplicity and cost-effectiveness of existing designs. The report in this issue by Ambrus and colleagues is a valuable step toward that goal.

Axon terminal polarization induced by weak uniform DC electric fields: A modeling study

Uniform steady state (DC) electric fields, like those generated during transcranial direct current stimulation (tDCS), can affect neuronal excitability depending on field direction and neuronal morphology. In addition to somatic polarization, subthreshold membrane polarization of axon compartments can play a significant role in modulating synaptic efficacy. The aim of this study is to provide an estimation of axon terminal polarization in a weak uniform subthreshold electric field. Simulations based on 3D morphology reconstructions and simplified models indicate that for axons having long final branches compared to the local space constant (L>;4λ) the terminal polarization converges to Eλ for electric fields oriented in the same direction as the branch. In particular we determined how and when analytical approximations could be extended to real cases when considering maximal potential polarization during weak DC stimulation.

Reduced discomfort during high-definition transcutaneous stimulation using 6% benzocaine

Background: High-Definition transcranial Direct Current Stimulation (HD-tDCS) allows for non-invasive neuromodulation using an array of compact (approximately 1 cm2 contact area) “High-Definition” (HD) electrodes, as compared to conventional tDCS (which uses two large pads that are approximately 35 cm2). In a previous transcutaneous study, we developed and validated designs for HD electrodes that reduce discomfort over >20 min session with 2 mA electrode current. Objective: The purpose of this study was to investigate the use of a chemical pretreatment with 6% benzocaine (topical numbing agent) to further reduce subjective discomfort during transcutaneous stimulation and to allow for better sham controlled studies. Methods: Pre-treatment with 6% benzocaine was compared with control (no pretreatment) for 22 min 2 mA of stimulation, with either CCNY-4 or Lectron II electroconductive gel, for both cathodal and anodal transcutaneous (forearm) stimulation (eight different combinations). Results: Results show that for all conditions and polarities tested, stimulation with HD electrodes is safe and well tolerated and that pretreatment further reduced subjective discomfort. Conclusion: Pretreatment with a mild analgesic reduces discomfort during HD-tDCS.

Computational Modeling Assisted Design of Optimized and Individualized Transcranial Direct Current Stimulation Protocols

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity currents facilitating or inhibiting spontaneous neuronal activity. Such non-invasive electrotherapies have a number of advantages that have been exploited in clinical practice; in particular, tDCS dose is easily customized by varying electrode number, position, size, shape, and current. Recent developments in computational models have further personalized dose to individual subjects/cases. Finite element method models developed from high-resolution MRI scans are among the tools available today. Designing and interpreting these models while aware of their limitations can affect the rational design of electrotherapy, as evidenced in studies combining computer modeling and clinical data. Though modeling for non-invasive brain stimulation is still in its development phase, it is predicted that, with increased validation, dissemination, simplification, and democratization of modeling tools, computational forward models of neuromodulation will become useful tools to guide the optimization of clinical electrotherapy. Essential for this process is an appreciation by clinicians of the uses and limitation of computational models, and understanding by engineers and programmers of what predictions are in fact relevant to clinical practice.

A Role of Computational Modeling in Customization of Transcranial Direct Current Stimulation for Susceptible Populations

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity currents facilitating or inhibiting spontaneous neuronal activity. Such noninvasive electrotherapies have a number of advantages that have been exploited in clinical practice; in particular, tDCS dose is easily customized by varying electrode number, position, size, shape, and current. Recent developments in computational models have further customized dose to individual subjects and cases. Finite Element Method models developed from high-resolution magnetic resonance imaging (MRI) scans are among the tools available today. Designing and interpreting these models while aware of their limitations can affect the rational design of electrotherapy as evidenced in studies combining computer modeling and clinical data. Though modeling for noninvasive brain stimulation is still in its development phase, it is predicted that with increased validation, dissemination, simplification, and democratization of modeling tools, computational forward models of neuromodulation will become useful tools to guide the optimization of clinical electrotherapy. As an example of tDCS customization and dose design, case studies of computational modeling in susceptible populations are discussed in the final section.