Velicia Bachtiar

The role of GABA in human motor learning.

Summary GABA modification plays an important role in motor cortical plasticity [1–4]. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. We assessed GABA responsiveness by transcranial direct current stimulation (tDCS), an intervention known to decrease GABA [5, 6]. The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.

Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke

Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment (n = 13) or a functional magnetic resonance imaging experiment (n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5–10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke.

What are we measuring with GABA magnetic resonance spectroscopy

A number of recent papers1-3 have demonstrated a relationship between in vivo concentration of GABA, as assessed using Magnetic Resonance Spectroscopy (MRS), and an individual’s task performance, giving a unique insight into the relationship between physiology and behavior. However, interpretation of the functional significance of the MRS GABA measure is not straightforward. Here we discuss some of the outstanding questions as to how total concentration of GABA within a cortical region relates to phasic and tonic GABA activity within the cortical volume studied.

Local GABA concentration is related to network-level resting functional connectivity

Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies. DOI: http://dx.doi.org/10.7554/eLife.01465.001

Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation

We previously demonstrated that network level functional connectivity in the human brain could be related to levels of inhibition in a major network node at baseline (Stagg et al., 2014). In this study, we build upon this finding to directly investigate the effects of perturbing M1 GABA and resting state functional connectivity using transcranial direct current stimulation (tDCS), a neuromodulatory approach that has previously been demonstrated to modulate both metrics. FMRI data and GABA levels, as assessed by Magnetic Resonance Spectroscopy, were measured before and after 20 min of 1 mA anodal or sham tDCS. In line with previous studies, baseline GABA levels were negatively correlated with the strength of functional connectivity within the resting motor network. However, although we confirm the previously reported findings that anodal tDCS reduces GABA concentration and increases functional connectivity in the stimulated motor cortex; these changes are not correlated, suggesting they may be driven by distinct underlying mechanisms. DOI: http://dx.doi.org/10.7554/eLife.08789.001

The role of inhibition in human motor cortical plasticity

Over recent years evidence from animal studies strongly suggests that a decrease in local inhibitory signaling is necessary for synaptic plasticity to occur. However, the role of GABAergic modulation in human motor plasticity is less well understood. Here, we summarize the techniques available to quantify GABA in humans, before reviewing the existing evidence for the role of inhibitory signaling in human motor plasticity. We discuss a number of important outstanding questions that remain before the role of GABAergic modulation in long-term plasticity in humans, such as that underpinning recovery after stroke, can be established.

Two‐voxel spectroscopy with dynamic B0 shimming and flip angle adjustment at 7 T in the human motor cortex

The aim of this study was to acquire high‐quality in vivo 1H spectra concurrently from two voxels at ultra‐high field (7 T) without specialized hardware. To this end, an acquisition scheme was developed in which first‐order shims and flip angles are dynamically updated to acquire spectra from both of the brains motor cortices in an alternating fashion. To validate this acquisition scheme, separate, static, single‐voxel acquisitions were also performed for comparison. Six subjects were examined using semi‐LASER spectroscopy at 7 T. Barium titanate pads were used to increase the extent of the effective transmit field (B1+). Spectra were obtained from the hand area of both motor cortices for both acquisition schemes. LCModel was used to determine neurochemical profiles in order to examine variations between acquisition schemes and volumes of interest. The dynamic two‐voxel acquisition protocol produced water linewidths (full width at half‐maximum between 11.6 and 12.8 Hz) and signal‐to‐noise ratios similar to those from static single‐voxel measurements. The concentrations of 13 individual and 3 combined metabolites with Cramér–Rao lower bounds below 30% were reliably detected for both acquisition schemes, and agreed well with previous postmortem assay and spectroscopy studies. The results show that high spectral quality from two voxels can be acquired concurrently without specialized hardware. This practical technique can be applied to many neuroscience applications. Copyright

Interindividual Differences in Behavior and Plasticity

Considerable differences exist between individuals both in the way the brain functions normally and how it recovers from injury. Plasticity can be defined as the reorganization of brain connectivity through experience, and animal studies have shown that modulation of intracortical inhibitory circuits is necessary for plasticity induction to occur. There is significant interest among both the clinical and neuroscience communities in investigating the role of inhibitory processes in normal brain function and in how this can help us understand pathophysiology in disease. The ability to measure GABAergic inhibition in vivo using MRS has sparked interest into investigating interindividual differences in the role of GABA in behavior and the effects on GABA concentrations following plasticity-induction paradigms. This chapter will summarize what has been learned about interindividual differences in behavior from MRS studies and explore its potential use in the future. The use of MRS approaches is still in its infancy for applications in neuroscience and many important questions remain to be answered. However, despite these unanswered questions MRS is increasingly being recognized as a robust and powerful tool for the in vivo investigations of neurophysiological changes in humans.