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.

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.

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.

SummaryBalance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.Video Abstract

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 (Ͼ40 Hz) power is boosted contralaterally and attenuated ipsilaterally. These modulations must be under top-down control; however, the control mechanisms