Jessica D. Richardson

Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016.

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

Left Hemisphere Plasticity and Aphasia Recovery

A recent study by our group revealed a strong relationship between functional brain changes in the left hemisphere and anomia treatment outcome in chronic stroke patients (N=26) with aphasia (Fridriksson, 2010). The current research represents a continuation of this work in which we have refined our methods and added data from four more patients (for a total sample size of 30) to assess where in the left hemisphere treatment-related brain changes occur. Unlike Fridriksson (2010) which only focused on changes in correct naming as a marker of treatment outcome, the current study examined the relationship between changes in left hemisphere activity and changes in correct naming, semantic paraphasias, and phonemic paraphasias following treatment. We also expanded on the work by Fridriksson by examining whether neurophysiological measures taken at baseline (defined henceforth as the time-point before the start of anomia treatment) predict treatment outcome. Our analyses revealed that changes in activation in perilesional areas predicted treatment-related increases in correct naming in individuals with chronic aphasia. This relationship was most easily observed in the left frontal lobe. A decrease in the number of semantic and phonemic paraphasias was predicted by an activation change in the temporal lobe involving cortical areas that were shown to be active during picture naming in 14 normal subjects. In contrast, a far less certain relationship was found between baseline neurophysiological measures and anomia treatment outcome. Our findings suggest that improved naming associated with behavioral anomia treatment in aphasia is associated with modulation of the left frontal lobe whereas a reduction in naming errors is mediated by left posterior regions that classically are thought to be involved in language processing.

Re-Establishing Broca's Initial Findings.

The importance of the left inferior pre-frontal cortex (LIPC) for speech production was first popularized by Paul Broca, providing a cornerstone of behavioral neurology and laying the foundation for future research examining brain-behavior relationships. Although Brocas findings were rigorously challenged, comprehensive contradictory evidence was not published until 130years later. This evidence suggested that damage to left anterior insula was actually the best predictor of motor speech impairment. Using high-resolution structural magnetic resonance imaging (MRI) in patients with chronic stroke, we reveal that LIPC involvement more accurately predicts acquired motor speech impairment than insula damage. Perfusion-weighted MRI provides complementary evidence, highlighting how damage to left inferior pre-frontal gyrus often includes insula involvement, and vice versa. Our findings suggest that Brocas initial conclusions associating acquired motor speech impairment with LIPC damage remain valid nearly 150years after his initial report on this issue.

Mechanisms and Effects of Transcranial Direct Current Stimulation

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose–response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.

Cerebral perfusion in chronic stroke: Implications for lesion-symptom mapping and functional MRI

Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke.

Feasibility of using high-definition transcranial direct current stimulation (HD-tDCS) to enhance treatment outcomes in persons with aphasia

BACKGROUND Transcranial direct current stimulation (tDCS) enhances treatment outcomes post-stroke. Feasibility and tolerability of high-definition (HD) tDCS (a technique that increases current focality and intensity) for consecutive weekdays as an adjuvant to behavioral treatment in a clinical population has not been demonstrated. OBJECTIVE To determine HD-tDCS feasibility outcomes: 1) ability to implement study as designed, 2) acceptability of repeated HD-tDCS administration to patients, and 3) preliminary efficacy. METHODS Eight patients with chronic post-stroke aphasia participated in a randomized crossover trial with two arms: conventional sponge-based (CS) tDCS and HD-tDCS. Computerized anomia treatment was administered for five consecutive days during each treatment arm. RESULTS Individualized modeling/targeting procedures and an 8-channel HD-tDCS device were developed. CS-tDCS and HD-tDCS were comparable in terms of implementation, acceptability, and outcomes. Naming accuracy and response time improved for both stimulation conditions. Change in accuracy of trained items was numerically higher (but not statistically significant) for HD-tDCS compared to CS-tDCS for most patients. CONCLUSIONS Regarding feasibility, HD-tDCS treatment studies can be implemented when designed similarly to documented CS-tDCS studies. HD-tDCS is likely to be acceptable to patients and clinicians. Preliminary efficacy data suggest that HD-tDCS effects, using only 4 electrodes, are at least comparable to CS-tDCS.

Main concepts for three different discourse tasks in a large non-clinical sample

Background: Semi-spontaneous speech production tasks are commonly elicited to assess discourse ability. When knowledge of a topic, story, or event is shared, it is possible to gauge the informativeness of discourse by evaluating how accurately and completely an individual produces the concepts considered to be essential to the shared topic. This analysis, main concept analysis (MCA), quantifies the degree to which speakers are able to communicate the overall gist of an event. Though MCA is an easy-to-perform, informative, and reliable measure of discourse adequacy, its widespread adoption depends on the development of standardisation and normative reference. Given the large collection of control discourse transcripts available on the AphasiaBank database, it is possible to generate main concept lists based upon a large sample of control speakers and to characterise their performance to establish preliminary normative reference. Aims: The first aim of this study was to develop main concept checklists drawn from a control population for three semi-spontaneous discourse tasks included in the AphasiaBank protocol—a picture sequence narrative (Broken Window), storytelling (Cinderella), and a procedure (Peanut Butter and Jelly). The second aim was to report MCA results for control speakers to provide a normative reference and to stratify the normative information by age. Methods & Procedures: Ninety-two control transcripts, stratified into four age groups (20–39 years; 40–59 years; 60–79 years; 80+ years), were downloaded from the AphasiaBank database. Relevant concepts were identified, and those spoken by at least one-third of the control sample were considered to be main concepts. A multilevel coding system was used to determine the accuracy and completeness of the main concepts produced by control speakers. Outcomes & Results: Main concept checklists for three discourse tasks are provided. Descriptive statistics are reported and examined to assist readers with evaluation of the normative data. No differences between age groups were observed for the Broken Window narrative. For the remaining discourse tasks, the younger half of the sample generally performed differently than the older half of the sample. Additionally, the two younger age groups did not differ significantly from each other, nor did the two older groups. Conclusions: This study provides main concept checklists drawn from a large control sample. Normative information for main concept production is provided for three discourse tasks. The sample distribution is evaluated relative to the normal probability distribution and the sample composition is described, enabling readers to determine the adequacy of normative characteristics of the sample and also the fit between their patient or client and the normative sample. This study also provides information about main concept or event production for four age groups.

On the role of electric field orientation in optimal design of transcranial current stimulation

Transcranial current stimulation (tCS) is a promising noninvasive technique to elicit neuromodulation by passing weak electrical currents through scalp electrodes. While significant effort has been devoted towards designing stimulation protocols which “steer” current to regions of interest, previous work has been almost exclusively focused on the magnitude of the electric field, while ignoring the effects of direction. This is despite previous in vitro studies demonstrating that the angle between the field orientation and the cell axis of symmetry has significant effects on the resulting membrane polarization presumably underlying therapeutic effects. To that end, here we examine the impact of the desired electric field orientation on the optimal placement of electrodes for a given target region. Based on high-resolution head models derived from magnetic resonance scans of patients enrolled in a clinical trial examining the use of tCS in rehabilitation after stroke, we derive and employ an optimization algorithm which computes the montage maximizing directed current flow at the target. The results reveal a strong dependence of the optimal montage on the desired orientation; moreover, the magnitude of the induced electric field at the target region varies widely with the preferred direction. This suggests that identifying the desired electric field orientation at the region of interest is a crucial step in the development of rational electrical stimulation paradigms.

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop

Background Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. Objective This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. Methods The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Results Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. Conclusions These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders.

Response to letter to the editor: Safety of transcranial direct current stimulation: Evidence based update 2016

We respond to concerns raised by Godinho et al. about the Bikson et al. tDCS safety review [1]. As stated in the opening sentence, our report provided an update “based on published Serious Adverse Effects in human trials and irreversible brain damage in animal models”. Further, we carefully defined the scope of the review, “In this review, tDCS safety indicates the absence of a Serious Adverse Effect including brain tissue injury related to tDCS application.” We developed precise criteria for a Serious Adverse Effect. A systematic review of all adverse events, includingminor side effects that may affect the acceptability and tolerability of tDCS (as suggested by Godhino et al.) was outside the scope of our review, and addressed elsewhere including recently by our coauthors [2]. Adverse event underreporting occurs in most medical fields. We dedicated our assessment to published reports specifically of Serious Adverse Events, assuming reporting a Serious Adverse Event (e.g. hospitalization) is more reliable than mild well-known tDCS side effects (e.g. itching). Speculation regarding unpublished adverse events was not incorporated into our evidence-based approach. Causality was explicit to our definition of Serious Adverse Effect namely: “based on scientific judgment is determined to be caused or aggravated by the application of direct current to the head.” Exact methodology to estimate the volume of tDCS sessions was indicated in the relevant section, but safety considerations were based on the complete tDCS literature as assessed by authors with domain expertise. We underscore that our conclusions are derived from, and are explicitly limited to, stated definitions such that the discourse by Godinho et al. does not affect the validity of our methodology. To the extent that Godinho et al. do not provide evidence for a Serious Adverse Effect by tDCS, the review conclusion is unchanged. -Marom Bikson, Pnina Grossman, Greg Kronberg, Paulo S ergio Boggio, Andre R. Brunoni, Leigh Charvet, Felipe Fregni, Brita Fritsch, Bernadette Gillick, Roy H. Hamilton, Benjamin M. Hampstead, Adam Kirton, Helena Knotkova, David Liebetanz, Anli Liu, Colleen Loo, Michael A. Nitsche, Janine Reis, Jessica D. Richardson, Alexander Rotenberg, Peter Turkeltaub, Adam Woods.