Intracortical facilitation and inhibition in human primary motor cortex during motor skill acquisition.

The primary motor cortex (M1) is critical for movement execution, but its role in motor skill acquisition remains elusive. Here, we examine the role of M1 intracortical circuits during skill acquisition. Paired-pulse transcranial magnetic stimulation (TMS) paradigms of short-interval intracortical facilitation (SICF) and inhibition (SICI) were used to assess excitatory and inhibitory circuits, respectively. We hypothesised that intracortical facilitation and inhibition circuits in M1 would be modulated to support acquisition of a novel visuomotor skill. Twenty-two young, neurologically healthy adults trained with their nondominant hand on a skilled and non-skilled sequential visuomotor isometric finger abduction task. Electromyographic recordings were obtained from the nondominant first dorsal interosseous (FDI) muscle. Corticomotor excitability, SICF, and SICI were examined before, at the midway point, and after the 10-block motor training. SICI was assessed using adaptive threshold-hunting procedures. Task performance improved after the skilled, but not non-skilled, task training, which likely reflected the increase in movement speed during training. The amplitudes of late SICF peaks were modulated with skilled task training. There was no modulation of the early SICF peak, SICI, and corticomotor excitability with either task training. There was also no association between skill acquisition and SICF or SICI. The findings indicate that excitatory circuitries responsible for the generation of late SICF peaks, but not the early SICF peak, are modulated in motor skill acquisition for a sequential visuomotor isometric finger abduction task.

Neurochemical balance and inhibition at the subacute stage after stroke.

Stroke is a leading cause of death and disability worldwide with many people left with impaired motor function. Evidence from experimental animal models of stroke indicates that reducing motor cortex inhibition may facilitate neural plasticity and motor recovery. This study compared primary motor cortex (M1) inhibition measures over the first 12 wk after stroke with a cohort of age-similar healthy controls. The excitation-inhibition ratio and gamma-aminobutyric acid (GABA) neurotransmission within M1 were assessed using magnetic resonance spectroscopy and threshold hunting paired-pulse transcranial magnetic stimulation respectively. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Patients with a functional corticospinal pathway had motor-evoked potentials on the paretic side and exhibited better recovery from upper limb impairment and recovery of function than patients without a functional corticospinal pathway. Compared with age-similar controls, the neurochemical balance in terms of the excitation-inhibition ratio was greater within contralesional M1 in patients with a functional corticospinal pathway. There was evidence for elevated long-interval inhibition in both ipsilesional and contralesional M1 compared with controls. Short-interval inhibition measures differed between the first and second phases, with evidence for elevation of the former only in ipsilesional M1 and no evidence of disinhibition for the latter. Overall, findings from transcranial magnetic stimulation indicate an upregulation of GABA-mediated tonic inhibition in M1 early after stroke. Therapeutic approaches that aim to normalize inhibitory tone during the subacute period warrant further investigation.NEW & NOTEWORTHY Magnetic resonance spectroscopy indicated higher excitation-inhibition ratios within motor cortex during subacute recovery than age-similar healthy controls. Measures obtained from adaptive threshold hunting paired-pulse transcranial magnetic stimulation indicated greater tonic inhibition in patients compared with controls. Therapeutic approaches that aim to normalize motor cortex inhibition during the subacute stage of recovery should be explored.

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1.

The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.