Jacinta O'Shea

Polarity-Sensitive Modulation of Cortical Neurotransmitters by Transcranial Stimulation

Transcranial direct current stimulation (tDCS) modulates cortical excitability and is being used for human studies more frequently. Here we probe the underlying neuronal mechanisms by measuring polarity-specific changes in neurotransmitter concentrations using magnetic resonance spectroscopy (MRS). MRS provides evidence that excitatory (anodal) tDCS causes locally reduced GABA while inhibitory (cathodal) stimulation causes reduced glutamatergic neuronal activity with a highly correlated reduction in GABA, presumably due to the close biochemical relationship between the two neurotransmitters.

Functionally Specific Reorganization in Human Premotor Cortex

After unilateral stroke, the dorsal premotor cortex (PMd) in the intact hemisphere is often more active during movement of an affected limb. Whether this contributes to motor recovery is unclear. Functional magnetic resonance imaging (fMRI) was used to investigate short-term reorganization in right PMd after transcranial magnetic stimulation (TMS) disrupted the dominant left PMd, which is specialized for action selection. Even when 1 Hz left PMd TMS had no effect on behavior, there was a compensatory increase in activity in right PMd and connected medial premotor areas. This activity was specific to task periods of action selection as opposed to action execution. Compensatory activation changes were both functionally specific and anatomically specific: the same pattern was not seen after TMS of left sensorimotor cortex. Subsequent TMS of the reorganized right PMd did disrupt performance. Thus, this pattern of functional reorganization has a causal role in preserving behavior after neuronal challenge.

The neuroethics of non-invasive brain stimulation

Transcranial direct current stimulation (TDCS) is a brain stimulation tool that is portable, painless, inexpensive, apparently safe, and with potential long-term efficacy. Recent results obtained from TDCS experiments offer exciting possibilities for the enhancement and treatment of normal or impaired abilities, respectively. We discuss new neuroethical problems that have emerged from the usage of TDCS, and also focus on one of the most likely future applications of TDCS: enhancing learning and cognition in children with typical and atypical development.

Functional specificity of human premotor-motor cortical interactions during action selection.

Functional connections between dorsal premotor cortex (PMd) and primary motor cortex (M1) have been revealed by paired‐pulse transcranial magnetic stimulation (TMS). We tested if such connections would be modulated during a cognitive process (response selection) known to rely on those circuits. PMd–M1 TMS applied 75 ms after a cue to select a manual response facilitated motor‐evoked potentials (MEPs). MEPs were facilitated at 50 ms in a control task of response execution, suggesting that PMd–M1 interactions at 75 ms are functionally specific to the process of response selection. At 100 ms, PMd–M1 TMS delayed choice reaction time (RT). Importantly, the MEP (at 75 ms) and the RT (at 100 ms) effects were correlated in a way that was hand‐specific. When the response was made with the M1‐contralateral hand, MEPs correlated with slower RTs. When the response was made with the M1‐ipsilateral hand, MEPs correlated with faster RTs. Paired‐pulse TMS confined to M1 did not produce these effects, confirming the causal influence of PMd inputs. This study shows that a response selection signal evolves in PMd early during the reaction period (75–100 ms), impacts on M1 and affects behaviour. Such interactions are temporally, anatomically and functionally specific, and have a causal role in choosing which movement to make.

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.

Individual differences in white-matter microstructure reflect variation in functional connectivity during choice.

The relation between brain structure and function is of fundamental importance in neuroscience. Comparisons between behavioral and brain-imaging measures suggest that variation in brain structure correlates with the presence of specific skills. Behavioral measures, however, reflect the integrated function of multiple brain regions. Rather than behavior, a physiological index of function could be a more sensitive and informative measure with which to compare structural measures. Here, we test for a relationship between a physiological measure of functional connectivity between two brain areas during a simple decision-making task and a measure of structural connectivity. Paired-pulse transcranial magnetic stimulation indexed functional connectivity between two regions important for action choices: the premotor and motor cortex. Fractional anisotropy (FA), a marker of microstructural integrity, indexed structural connectivity. Individual differences in functional connectivity during action selection show highly specific correlations with FA in localized regions of white-matter interconnecting regions, including the premotor and motor cortex. Probabilistic tractography, a technique for identifying fiber pathways from diffusion-weighted imaging (DWI), was used to reconstruct the anatomical networks linking the component brain regions involved in making decisions. These findings demonstrate a relationship between individual differences in functional and structural connectivity within human brain networks central to action choice.

Modulation of movement-associated cortical activation by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor‐related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right‐handed subjects performed a visually cued serial reaction time task with their right hand in a 3‐T MRI scanner both before and after 10 min of 1‐mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short‐lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within‐session linear decreases in activation occurred in all scan sessions. The after‐effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between‐session decrease in task‐related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease.

Contributions of the cerebellum and the motor cortex to acquisition and retention of motor memories

We investigated the contributions of the cerebellum and the motor cortex (M1) to acquisition and retention of human motor memories in a force field reaching task. We found that anodal transcranial direct current stimulation (tDCS) of the cerebellum, a technique that is thought to increase neuronal excitability, increased the ability to learn from error and form an internal model of the field, while cathodal cerebellar stimulation reduced this error-dependent learning. In addition, cathodal cerebellar stimulation disrupted the ability to respond to error within a reaching movement, reducing the gain of the sensory-motor feedback loop. By contrast, anodal M1 stimulation had no significant effects on these variables. During sham stimulation, early in training the acquired motor memory exhibited rapid decay in error-clamp trials. With further training the rate of decay decreased, suggesting that with training the motor memory was transformed from a labile to a more stable state. Surprisingly, neither cerebellar nor M1 stimulation altered these decay patterns. Participants returned 24hours later and were re-tested in error-clamp trials without stimulation. The cerebellar group that had learned the task with cathodal stimulation exhibited significantly impaired retention, and retention was not improved by M1 anodal stimulation. In summary, non-invasive cerebellar stimulation resulted in polarity-dependent up- or down-regulation of error-dependent motor learning. In addition, cathodal cerebellar stimulation during acquisition impaired the ability to retain the motor memory overnight. Thus, in the force field task we found a critical role for the cerebellum in both formation of motor memory and its retention.

Frontal Eye Fields Control Attentional Modulation of Alpha and Gamma Oscillations in Contralateral Occipitoparietal Cortex

Covertly directing visuospatial attention produces a frequency-specific modulation of neuronal oscillations in occipital and parietal cortices: anticipatory alpha (8–12 Hz) power decreases contralateral and increases ipsilateral to attention, whereas stimulus-induced gamma (>40 Hz) power is boosted contralaterally and attenuated ipsilaterally. These modulations must be under top-down control; however, the control mechanisms are not yet fully understood. Here we investigated the causal contribution of the human frontal eye field (FEF) by combining repetitive transcranial magnetic stimulation (TMS) with subsequent magnetoencephalography. Following inhibitory theta burst stimulation to the left FEF, right FEF, or vertex, participants performed a visual discrimination task requiring covert attention to either visual hemifield. Both left and right FEF TMS caused marked attenuation of alpha modulation in the occipitoparietal cortex. Notably, alpha modulation was consistently reduced in the hemisphere contralateral to stimulation, leaving the ipsilateral hemisphere relatively unaffected. Additionally, right FEF TMS enhanced gamma modulation in left visual cortex. Behaviorally, TMS caused a relative slowing of response times to targets contralateral to stimulation during the early task period. Our results suggest that left and right FEF are causally involved in the attentional top-down control of anticipatory alpha power in the contralateral visual system, whereas a right-hemispheric dominance seems to exist for control of stimulus-induced gamma power. These findings contrast the assumption of primarily intrahemispheric connectivity between FEF and parietal cortex, emphasizing the relevance of interhemispheric interactions. The contralaterality of effects may result from a transient functional reorganization of the dorsal attention network after inhibition of either FEF.

Noninvasive associative plasticity induction in a corticocortical pathway of the human brain.

Coincident pairing of presynaptic and postsynaptic activity selectively strengthens synaptic connections, a key mechanism underlying cortical plasticity. Using paired associative transcranial magnetic stimulation (TMS), we demonstrate selective potentiation of physiological connectivity between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1) after repeated paired-pulse TMS of PMv and M1. The effect was anatomically specific: paired stimulation of the presupplementary motor area and M1 did not induce changes in PMv–M1 pathway connectivity. The effect was dependent on stimulation order: repeated stimulation of PMv before M1 led to strengthening of the PMv–M1 pathway, while repeated stimulation of M1 before PMv diminished the strength of the PMv–M1 pathway. The expression of the change in the pathway depended on the cognitive state of the subject at the time of testing: when the subject was tested at rest, paired PMv–M1 stimulation led to an increased inhibitory influence of PMv over M1, but when the subject was tested while engaged in a visuomotor task, PMv–M1 stimulation led to an increased facilitatory influence of PMv over M1. Plasticity evolved rapidly, lasted for at least 1 h, and began to reverse 3 h after intervention.