Modulation of excitability in human primary somatosensory and motor cortex by paired associative stimulation targeting the primary somatosensory cortex.

Input from primary somatosensory cortex (S1) to primary motor cortex (M1) is important for high-level motor performance, motor skill learning and motor recovery after brain lesion. This study tested the effects of manipulating S1 excitability with paired associative transcranial stimulation (S1-PAS) on M1 excitability. Given the important role of S1 in sensorimotor integration, we hypothesized that changes in S1 excitability would be directly paralleled by changes in M1 excitability. We applied two established protocols (S1-PAS(LTP) and S1-PAS(LTD) ) to the left S1 to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like plasticity. S1 excitability was assessed by the early cortical components (N20-P25) of the median nerve somatosensory-evoked potential. M1 excitability was assessed by motor-evoked potential amplitude and short-interval intracortical inhibition. Effects of S1-PAS(LTP) were compared with those of a PAS(LTP) protocol targeting the left M1 (M1-PAS(LTP) ). S1-PAS(LTP) and S1-PAS(LTD) did not result in significant modifications of S1 or M1 excitability at the group level due to substantial interindividual variability. The individual S1-PAS-induced changes in S1 and M1 excitability showed no correlation. Furthermore, the individual changes in S1 and M1 excitability induced by S1-PAS(LTP) did not correlate with changes in M1 excitability induced by M1-PAS(LTP) . This demonstrates that the effects of S1-PAS in S1 are variable across individuals and, within a given individual, unrelated to those induced by S1-PAS or M1-PAS in M1. Potentially, this extends the opportunities of therapeutic PAS applications because M1-PAS 'non-responders' may well respond to S1-PAS.

Interactions between short-interval intracortical inhibition and short-latency afferent inhibition in human motor cortex.

Transcranial magnetic stimulation (TMS) allows the testing of various inhibitory processes in human motor cortex. Here we aimed at gaining more insight into the underlying physiology by studying the interactions between short-interval intracortical inhibition (SICI) and short-latency afferent inhibition (SAI). SICI and SAI were examined in a slightly contracting hand muscle of healthy subjects by measuring inhibition of a test motor-evoked potential conditioned by a sub-threshold motor cortical magnetic pulse (S1) or an electrical pulse (P) applied to the ulnar nerve at the wrist, respectively. SICI alone and SAI alone had similar magnitude when S1 intensity was set to 90% active motor threshold and P intensity to three times the perceptual sensory threshold. SICI was reduced or even disinhibited when P was co-applied, and SAI was reduced or disinhibited when S1 was co-applied. These interactions did not depend on the exact timing of arrival of P and S1 in motor cortex. A control experiment with a S1 intensity lowered to 70% active motor threshold excluded a contribution by short-interval intracortical facilitation. Finally, SICI with co-applied P correlated linearly with SICI alone with a slope of the regression line close to 1 whereas SAI did not correlate with SAI when S1 was co-applied with a slope of the regression line close to zero. Data indicate that S1 largely eliminates the effects of P when applied together, suggesting dominance of S1 over P. Findings strongly support the idea that SICI and SAI are mediated through two distinct and reciprocally connected subtypes of GABAergic inhibitory interneurons with convergent projections onto the corticospinal neurons. Furthermore, dominance of S1 over P is compatible with the notion that the SICI interneurons target the corticospinal neurons closer to their axon initial segment than the SAI interneurons.

Deleterious effects of a low amount of ethanol on LTP-like plasticity in human cortex.

Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input-output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation.

Relation of brain stimulation induced changes in MEP amplitude and BOLD signal.

BACKGROUND: Non-invasive human brain stimulation can induce long-term plasticity reflected by changes in putative markers of synaptic activation, such as the motor evoked potential (MEP) amplitude elicited by transcranial magnetic stimulation or the task-dependent blood oxygenation level-dependent (BOLD) signal measured by functional magnetic resonance imaging. OBJECTIVE: To study the relationship between brain stimulation induced changes in MEP amplitude and BOLD signal. METHODS: Paired associative stimulation of the hand area of the left primary somatosensory cortex (S1-PAS) was applied in 15 healthy subjects to induce excitability change in the adjacent primary motor cortex (M1) [Kriváneková et al. 2011, Eur J Neurosci 34:1292-1300]. Before and after S1-PAS, MEP amplitude in a right hand muscle, and the BOLD signal during a right hand motor or somatosensory activation task were measured. RESULTS: S1-PAS resulted in substantial individual MEP and BOLD signal changes, but these changes did not correlate in M1 or S1. CONCLUSIONS: Findings indicate that MEP amplitude and BOLD signal within the tested M1 reflect physiologically distinct aspects of synaptic excitability change. Therefore, it is suggested that MEP amplitude and BOLD signal are complementary rather than interchangeable markers of synaptic excitability.

Lithium: a switch from LTD- to LTP-like plasticity in human cortex.

Lithium, a simple cation, is the mainstay treatment of bipolar disorder. Deficient synaptic plasticity is considered one important mechanism of this disease. Lithium inhibits glycogen synthase kinase-3beta (GSK-3ß), which is involved in the regulation of synaptic plasticity. In animal preparations, inhibition of GSK-3ß by lithium up-regulated long-term potentiation (LTP) of excitatory synapses but down-regulated long-term depression (LTD). The effects of lithium on plasticity in the human brain are unexplored. We tested the effects of a single oral dose of 900 mg of lithium on LTP-/LTD-like plasticity in human motor cortex induced by established paired associative transcranial magnetic stimulation (PAS(LTP), PAS(LTD)) protocols. We studied 10 healthy adults in a placebo-controlled double-blind randomized crossover design. PAS-induced plasticity was indexed by change in motor evoked potential amplitude recorded in a hand muscle. In the placebo session, subjects were stratified, according to the known variability of the PAS(LTP) response, into PAS(LTP) 'LTP responders' and PAS(LTP) 'LTD responders' (n = 5 each). Lithium did not affect the PAS(LTP)-induced LTP-like plasticity in the 'LTP responders', but switched the PAS(LTP)-induced LTD-like plasticity in the 'LTD responders' to LTP-like plasticity. In contrast, lithium had no effect on the PAS(LTD)-induced LTD-like plasticity in the 'LTD responders'. We provide first-time evidence that lithium significantly modulates brain stimulation induced plasticity in human cortex. The switch from LTD- to LTP-like plasticity is best explained by the inhibitory action of lithium on GSK-3ß. This conclusion is necessarily circumstantial because GSK-3ß activity was not directly measured. We discuss that other important plasticity-related modes actions of lithium cannot explain our findings.