The impact of brain lesions on tDCS-induced electric fields.

Transcranial direct current stimulation (tDCS) can enhance motor and language rehabilitation after stroke. Though brain lesions distort tDCS-induced electric field (E-field), systematic accounts remain limited. Using electric field modelling, we investigated the effect of 630 synthetic lesions on E-field magnitude in the region of interest (ROI). Models were conducted for two tDCS montages targeting either primary motor cortex (M1) or Broca's area (BA44). Absolute E-field magnitude in the ROI differed by up to 42% compared to the non-lesioned brain depending on lesion size, lesion-ROI distance, and lesion conductivity value. Lesion location determined the sign of this difference: lesions in-line with the predominant direction of current increased E-field magnitude in the ROI, whereas lesions located in the opposite direction decreased E-field magnitude. We further explored how individualised tDCS can control lesion-induced effects on E-field. Lesions affected the individualised electrode configuration needed to maximise E-field magnitude in the ROI, but this effect was negligible when prioritising the maximisation of radial inward current. Lesions distorting tDCS-induced E-field, is likely to exacerbate inter-individual variability in E-field magnitude. Individualising electrode configuration and stimulator output can minimise lesion-induced variability but requires improved estimates of lesion conductivity. Individualised tDCS is critical to overcome E-field variability in lesioned brains.

tDCS induced GABA change is associated with the simulated electric field in M1, an effect mediated by grey matter volume in the MRS voxel.

BACKGROUND AND OBJECTIVE: Transcranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during anodal tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. METHODS: Data from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1 mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual structural MR images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. RESULTS: In M1, higher mean E-field magnitude was associated with greater anodal tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = -3.55, p = 0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. CONCLUSIONS: Our data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to anodal tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects.

Differences in outcomes following an intensive upper-limb rehabilitation program for patients with common central nervous system-acting drug prescriptions.

Background: Difficulty using the upper-limb is a major barrier to independence for many patients post-stroke or brain injury. High dose rehabilitation can result in clinically significant improvements in function even years after the incident; however, there is still high variability in patient responsiveness to such interventions that cannot be explained by age, sex, or time since stroke. Methods: This retrospective study investigated whether patients prescribed certain classes of central nervous system-acting drugs-γ-aminobutyric acid (GABA) agonists, antiepileptics, and antidepressants-differed in their outcomes on the three-week intensive Queen Square Upper-Limb program. For 277 stroke or brain injury patients (167 male, median age 52 years (IQR: 21), median time since incident 20 months (IQR: 26)) upper-limb impairment and activity was assessed at admission to the program and at six months post-discharge, using the upper limb component of the Fugl-Meyer, Action Research Arm Test, and Chedoke Arm and Hand Activity Inventory. Drug prescriptions were obtained from primary care physicians at referral. Specification curve analysis was used to protect against selective reporting results and add robustness to the conclusions of this retrospective study. Results: Patients with GABA agonist prescriptions had significantly worse upper-limb scores at admission but no evidence for a significant difference in program-induced improvements was found. Additionally, no evidence of significant differences in patients with or without antiepileptic drug prescriptions on either admission to, or improvement on, the program was found in this study. Although no evidence was found for differences in admission scores, patients with antidepressant prescriptions experienced reduced improvement in upper-limb function, even when accounting for anxiety and depression scores. Conclusions: These results demonstrate that, when prescribed typically, there was no evidence that patients prescribed GABA agonists performed worse on this high-intensity rehabilitation program. Patients prescribed antidepressants, however, performed poorer than expected on the Queen Square Upper-Limb rehabilitation program. While the reasons for these differences are unclear, identifying these patients prior to admission may allow for better accommodation of differences in their rehabilitation needs.

Reassessing associations between white matter and behaviour with multimodal microstructural imaging.

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2∗). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40-200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM's relationship with behaviour, suggesting that variable biological effects may be shaping their interaction.

A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning.

KEY POINTS: Baclofen is a GABAB agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. Overall baclofen did not alter transcranial magnetic stimulation-measured GABAB inhibition, although the change in GABAB inhibition correlated with aspects of visuomotor learning retention. Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients. ABSTRACT: The GABAB agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double-blind, placebo-controlled study, we investigated whether a single 10 mg dose of the GABAB agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABAA (short-interval intracortical inhibition, 2.5 ms) and GABAB (long-interval intracortical inhibition, 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F1,137.8  = 6.133, P = 0.014) and retention (F1,130.7  = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABAB inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.

Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices.

Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke.SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.

Neurochemical changes underpinning the development of adjunct therapies in recovery after stroke: A role for GABA?

Stroke is a leading cause of long-term disability, with around three-quarters of stroke survivors experiencing motor problems. Intensive physiotherapy is currently the most effective treatment for post-stroke motor deficits, but much recent research has been targeted at increasing the effects of the intervention by pairing it with a wide variety of adjunct therapies, all of which aim to increase cortical plasticity, and thereby hope to maximize functional outcome. Here, we review the literature describing neurochemical changes underlying plasticity induction following stroke. We discuss methods of assessing neurochemicals in humans, and how these measurements change post-stroke. Motor learning in healthy individuals has been suggested as a model for stroke plasticity, and we discuss the support for this model, and what evidence it provides for neurochemical changes. One converging hypothesis from animal, healthy and stroke studies is the importance of the regulation of the inhibitory neurotransmitter GABA for the induction of cortical plasticity. We discuss the evidence supporting this hypothesis, before finally summarizing the literature surrounding the use of adjunct therapies such as non-invasive brain stimulation and SSRIs in post-stroke motor recovery, both of which have been show to influence the GABAergic system.