Catecholaminergic consolidation of motor cortical neuroplasticity in humans

Amphetamine, a catecholaminergic re-uptake-blocker, is able to improve neuroplastic mechanisms in humans. However, so far not much is known about the underlying physiological mechanisms. Here, we study the impact of amphetamine on NMDA receptor-dependent long-lasting excitability modifications in the human motor cortex elicited by weak transcranial direct current stimulation (tDCS). Amphetamine significantly enhanced and prolonged increases in anodal, tDCS-induced, long-lasting excitability. Under amphetamine premedication, anodal tDCS resulted in an enhancement of excitability which lasted until the morning after tDCS, compared to approximately 1 h in the placebo condition. Prolongation of the excitability enhancement was most pronounced for long-term effects; the duration of short-term excitability enhancement was only slightly increased. Since the additional application of the NMDA receptor antagonist dextromethorphane blocked any enhancement of tDCS-driven excitability under amphetamine, we conclude that amphetamine consolidates the tDCS-induced neuroplastic effects, but does not initiate them. The fact that propanolol, a beta-adrenergic antagonist, diminished the duration of the tDCS-generated after-effects suggests that adrenergic receptors play a certain role in the consolidation of NMDA receptor-dependent motor cortical excitability modifications in humans. This result may enable researchers to optimize neuroplastic processes in the human brain on the rational basis of purpose-designed pharmacological interventions.     

Abnormal changes of synaptic excitability in migraine with aura

Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded simultaneously in migraineurs and healthy subjects. In order to investigate the homeostatic-like plasticity in the visual cortex, cortical excitability was modified using transcranial direct current stimulation (tDCS). Before any stimulation, migraineurs showed significantly higher glutamate/creatine ratios (Glx/Cr) than healthy subjects. In healthy subjects, excitatory (anodal) tDCS caused an increase and inhibitory (cathodal) tDCS a decrease in the Glx/Cr ratio. Subsequent photic stimulation (PS) reversed the changes in Glx/Cr ratios, which returned back to baseline, demonstrating homeostatic-like metaplasticity in the control group. In migraine patients, both anodal and cathodal tDCS decreased the Glx/Cr ratio, which did not return to baseline after PS. While healthy subjects showed an increase in VEP amplitude under anodal and a reduction under cathodal tDCS, the modifiability of VEP under tDCS was reduced in migraineurs. The results demonstrate a reduced responsiveness of the occipital cortex to interventions that change cortical excitability in migraine. Moreover, altered glutamatergic neurotransmission seems to mediate the relation between abnormal cortical information processing and excitability in migraineurs.     

Homeostatic metaplasticity of the motor cortex is altered during headache-free intervals in migraine with aura

Preconditioning of the human primary motor cortex (M1) with transcranial direct current stimulation (tDCS) can shape the magnitude and direction of excitability changes induced by a subsequent session of repetitive transcranial magnetic stimulation (rTMS). Here, we examined this form of metaplasticity in migraine patients with visual aura and healthy controls. In both groups, facilitatory preconditioning of left M1 with anodal tDCS increased the mean amplitudes of motor-evoked potentials (MEPs) elicited in the contralateral hand, whereas inhibitory preconditioning with cathodal tDCS produced a decrease in amplitude. Following cathodal tDCS, a short train of low-intensity 5-Hz rTMS antagonized the suppression of the mean MEP amplitude in both groups. In contrast, the homeostatic effects of 5-Hz rTMS differed between groups when rTMS was given after anodal tDCS. In controls 5-Hz rTMS induced a marked decrease in MEP amplitudes, whereas in migraineurs rTMS induced only a modest decrease in MEP amplitudes, which were still facilitated after rTMS when compared with baseline amplitudes. These findings indicate that short-term homeostatic plasticity is altered in patients with visual aura between the attacks.     

Dissociating the roles of the cerebellum and motor cortex during adaptive learning: the motor cortex retains what the cerebellum learns

Adaptation to a novel visuomotor transformation has revealed important principles regarding learning and memory. Computational and behavioral studies have suggested that acquisition and retention of a new visuomotor transformation are distinct processes. However, this dissociation has never been clearly shown. Here, participants made fast reaching movements while unexpectedly a 30-degree visuomotor transformation was introduced. During visuomotor adaptation, subjects received cerebellar, primary motor cortex (M1) or sham anodal transcranial direct current stimulation (tDCS), a noninvasive form of brain stimulation known to increase excitability. We found that cerebellar tDCS caused faster adaptation to the visuomotor transformation, as shown by a rapid reduction of movement errors. These findings were not present with similar modulation of visual cortex excitability. In contrast, tDCS over M1 did not affect adaptation, but resulted in a marked increase in retention of the newly learnt visuomotor transformation. These results show a clear dissociation in the processes of acquisition and retention during adaptive motor learning and demonstrate that the cerebellum and primary motor cortex have distinct functional roles. Furthermore, they show that is possible to enhance cerebellar function using tDCS.     

Lie-specific involvement of dorsolateral prefrontal cortex in deception

Lies are intentional distortions of event knowledge. No experimental data are available on manipulating lying processes. To address this issue, we stimulated the dorsolateral prefrontal cortex (DLPFC) using transcranial direct current stimulation (tDCS). Fifteen healthy volunteers were tested before and after tDCS (anodal, cathodal, and sham). Two types of truthful (truthful selected: TS; truthful unselected: TU) and deceptive (lie selected: LS; lie unselected: LU) responses were evaluated using a computer-controlled task. Reaction times (RTs) and accuracy were collected and used as dependent variables. In the baseline task, the RT was significantly longer for lie responses than for true responses ([mean +/- standard error] 1153.4 +/- 42.0 ms vs. 1039.6 +/- 36.6 ms; F(1,14) = 27.25, P = 0.00013). At baseline, RT for selected pictures was significantly shorter than RT for unselected pictures (1051.26 +/- 39.0 ms vs. 1141.76 +/- 41.1 ms; F(1,14) = 34.85, P = 0.00004). Whereas after cathodal and sham stimulation, lie responses remained unchanged (cathodal 5.26 +/- 2.7%; sham 5.66 +/- 3.6%), after anodal tDCS, RTs significantly increased but did so only for LS responses (16.86 +/- 5.0%; P = 0.002). These findings show that manipulation of brain function with DLPFC tDCS specifically influences experimental deception and that distinctive neural mechanisms underlie different types of lies.     

A review of burn symptoms and potential novel neural targets for non-invasive brain stimulation for treatment of burn sequelae

Burn survivors experience myriad associated symptoms such as pain, pruritus, fatigue, impaired motor strength, post-traumatic stress, depression, anxiety, and sleep disturbance. Many of these symptoms are common and remain chronic, despite current standard of care. One potential novel intervention to target these post burn symptoms is transcranial direct current stimulation (tDCS). tDCS is a non-invasive brain stimulation (NIBS) technique that modulates neural excitability of a specific target or neural network. The aim of this work is to review the neural circuits of the aforementioned clinical sequelae associated with burn injuries and to provide a scientific rationale for specific NIBS targets that can potentially treat these conditions. We ran a systematic review, following the PRISMA statement, of tDCS effects on burn symptoms. Only three studies matched our criteria. One was a feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury, one looked at the effects of tDCS to reduce pain anxiety during burn wound care, and one assessed the effects of tDCS to manage pain and pruritus in burn survivors. Current literature on NIBS in burn remains limited, only a few trials have been conducted. Based on our review and results in other populations suffering from similar symptoms as patients with burn injuries, three main areas were selected: the prefrontal region, the parietal area and the motor cortex. Based on the importance of the prefrontal cortex in the emotional component of pain and its implication in various psychosocial symptoms, targeting this region may represent the most promising target. Our review of the neural circuitry involved in post burn symptoms and suggested targeted areas for stimulation provide a spring board for future study initiatives.     

Temporary occlusion of associative motor cortical plasticity by prior dynamic motor training

A novel Hebbian stimulation paradigm was employed to examine physiological correlates of motor memory formation in humans. Repetitive pairing of median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex (paired associative stimulation, PAS) may decrease human motor cortical excitability at interstimulus intervals of 10 ms (PAS10) or increase excitability at 25 ms (PAS25). The properties of this plasticity have previously been shown to resemble associative timing-dependent long-term depression (LTD) and long-term potentiation (LTP) as established in vitro. Immediately after training a novel dynamic motor task, the capacity of the motor cortex to undergo plasticity in response to PAS25 was abolished. PAS10-induced plasticity remained unchanged. When retested after 6 h, PAS25-induced plasticity recovered to baseline levels. After training, normal PAS25-induced plasticity was observed in the contralateral training-naive motor cortex. Motor training did not reduce the efficacy of PAS25 to enhance cortical excitability when PAS10 was interspersed between the training and application of the PAS25 protocol. This indicated that the mechanism supporting PAS25-induced plasticity had remained intact immediately after training. Behavioral evidence was obtained for continued optimization of force generation at a time when PAS25-induced plasticity was blocked in the training motor cortex. Application of the PAS protocols after motor training did not prevent the consolidation of motor skills evident as performance gains at later retesting. The results are consistent with a concept of temporary suppression of associative cortical plasticity by neuronal mechanisms involved in motor training. Although it remains an open question exactly which element of motor training was responsible for this effect, our findings may link dynamic properties of LTP formation, as established in animal experiments, with human motor memory formation and possibly dynamic motor learning.     

Circadian modulation of GABA-mediated cortical inhibition

Circadian rhythms exert powerful influence on various aspects of human physiology and behavior. Here, we tested changes of human cerebral cortex excitability over the course of the day with transcranial magnetic stimulation (TMS). At different times of the day, intracortical and corticospinal excitability of the primary motor cortex (M1) was evaluated in 15 healthy subjects by TMS of left M1. While motor thresholds, short-interval intracortical inhibition and facilitation and input/output curves remained unchanged, we found that a specific form of γ-aminobutyric acid (GABA)-mediated intracortical inhibition, revealed by long-interval intracortical inhibition and cortical silent periods, progressively decreased during the course of the day. Additional experiments demonstrated that morning inhibition persisted irrespective of previous sleep or sleep deprivation. Corticotropin-releasing hormone (CRH) infusions in the evening lead to morning cortisol levels but did not restore levels of morning inhibition, whereas suppression of endogenous CRH release by repeated oral dexamethasone intake over 24 h prevented morning inhibition. The findings suggest a specific modulation of GABAergic motor cortex inhibition within the circadian cycle, possibly linked to the CRH system, and may indicate a neurobiological basis for variable neuroplasticity over the course of the day.     

Modification of practice-dependent plasticity in human motor cortex by neuromodulators

Practice-dependent plasticity underlies motor learning in everyday life and motor relearning after lesions of the nervous system. Previous studies showed that practice-dependent plasticity is modifiable by neuromodulating transmitters such as norepinephrine (NE), dopamine (DA) or acetylcholine (ACh). Here we explored, for the first time comprehensively and systematically, the modifying effects of an agonist versus antagonist in each of these neuromodulating transmitter systems on practice-dependent plasticity in healthy subjects in a placebo-controlled, randomized, double-blind crossover design. We found that the agonists in all three neuromodulating transmitter systems (NE: methylphenidate; DA: cabergoline; ACh: tacrine) enhanced practice-dependent plasticity, whereas the antagonists decreased it (NE: prazosin; DA: haloperidol; ACh: biperiden). Enhancement of plasticity under methylphenidate and tacrine was associated with an increase in corticomotoneuronal excitability of the prime mover of the practice, as measured by the motor evoked potential amplitude, but with a decrease under cabergoline. Our findings demonstrate that agonists and antagonists in various neuromodulating transmitter systems produce significant and oppositely directed modifications of practice-dependent plasticity in human motor cortex. Enhancement of plasticity occurred through different strategies that either favoured extrinsic (NE, ACh) or intrinsic (DA) modulating influence on the motor cortical output network.     

A New Cortical Electrode for Neuronavigation-Guided Intraoperative Neurophysiological Monitoring: Technical Note

Intraoperative neurophysiological mapping and monitoring of eloquent brain areas can be combined with image-guided localisation to enhance the safety and efficacy of surgical procedures in the motor cortex. We designed a new type of cortical electrode which can be repeatedly placed on the cortical surface and allows accurate and reproducible stimulation by means of a navigation pointer. The newly designed device consists of a monopolar electrode contact for direct cortical stimulation, housed in a holder which allows placement, easy removal, and precise repeated placement of a surgical navigation pointer. It can be used for navigation-guided, high-frequency anodal monopolar cortical stimulation (MCS) for the mapping of eloquent cortex, and for monitoring of motor pathways. While the cortex is stimulated, compound muscle action potentials (CMAP) are recorded from muscles of the contralateral extremities and are assessed both qualitatively and quantitatively. When the device is used in combination with intraoperative navigation, the stimulation sites may optionally be registered or displayed on the system monitor. This allows repeated pinpointing and obviates the need for strip or grid electrodes in the operative field; although such electrodes may be useful for continuous monitoring, they often are in the surgeon's way. In addition, the primary and supplementary motor cortex can be mapped by determining the location of the sites of stimulation on surface-projected images of the cerebral cortex.     

Enhanced rapid-onset cortical plasticity in CADASIL as a possible mechanism of preserved cognition

Ischemic small vessel disease (SVD) may lead to cognitive impairment, but cognitive deficits with a given burden of SVD vary significantly. The underlying mechanisms of impaired or preserved cognition are unknown. Here, we investigated the impact of ischemic SVD on rapid-onset cortical plasticity, as induced with a paired-associative stimulation protocol. To exclude concomitant effects of aging, we examined 12 middle-aged patients (48.3 ± 8.3 years) with cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) who suffered from severe ischemic SVD and a group of 12 age-matched controls (49.9 ± 8.3 years). Cognitive status, motor performance and learning, and motor cortex excitability in response to cathodal transcranial direct current stimulation (ctDCS) were assessed. White matter integrity was analyzed by conventional magnetic resonance imaging and diffusion tensor imaging. We found that cognitive and motor functions were largely preserved in CADASIL patients, while rapid-onset cortical plasticity was significantly higher in the CADASIL group compared with controls (repeated measures analysis of variance [group × time] interaction: P = 0.03). This finding was even more pronounced in patients with higher white matter lesion load. ctDCS revealed no evidence of cortical dysplasticity. We conclude that increased rapid-onset cortical plasticity may contribute to largely preserved cognitive and motor function despite extensive ischemic SVD.     

Intra-Operative Mapping of the Motor Cortex During Surgery in and Around the Motor Cortex

The intra-operative use of neurophysiological techniques allows reliable identification of the sensorimotor region, and constitutes a prerequisite for its anatomical and functional preservation. The present prospective study combines monopolar cortical stimulation (MCS) with the recording of phase reversal of somatosensory evoked potentials (SEP-PR) in a protocol for the intra-operative mapping of the motor cortex. Functional mapping of the motor cortex by SEP-PR and MCS was performed in 70 patients during surgery in and around the motor cortex. The central sulcus was identified by SEP-PR. Cortical motor mapping was then performed by monopolar anodal (400 Hz) stimulation. Motor responses were recorded by needle electrodes placed in the muscles of the contralateral extremities. Surgery was performed under general anaesthesia without muscle relaxants. Intra-operative localization of the central sulcus by SEP-PR was possible in 68 patients (97.14%). Motor evoked potentials (MEP) were elicited following MCS in 67 cases (95.7%). In 3 cases no MEP was recorded, not even after maximal stimulation intensity, the central sulcus being localized by SEP-PR only. On the other hand, MCS allowed localizing the motor cortex in the 2 cases with no recordable SEP-PR. Thus, combining SEP-PR and MCS allowed intra-operative localization of the sensorimotor cortex in 100% of the cases.     

Comparison Between Monopolar and Bipolar Electrical Stimulation of the Motor Cortex

Intra-operative neurophysiological techniques allow reliable identification of the sensorimotor region and make their anatomical and functional preservation feasible. Monopolar cortical stimulation has recently been described as a new mapping technique. In the present study this method was compared to the "traditional" technique of bipolar stimulation. Functional mapping of the motor cortex was performed in 35 patients during surgery in the central region. The central sulcus (CS) was identified by somatosensory evoked potential (SEP) phase reversal. Cortical motor mapping was first performed by monopolar anodal stimulation with a train of 500 Hz (7-10 pulses) followed by bipolar stimulation (pulses at 60 Hz with max. 4 sec train duration). Surgery was performed under general anaesthesia without muscle relaxants. Of 280 motor responses elicited by bipolar cortical stimulation, 54.23% [152] were located in the primary motor cortex (PMC), 37.85% 106[ outside the motor strip in the secondary motor cortex (SMC), and 8% 22[ posterior to the CS. Of 175 motor responses elicited by monopolar cortical stimulation. 68.57% 120[ were located in the SMC, 23.42% 41[ in the SMC and 8% 14[ posterior to the CS. Contrary to the general clinical view, there is considerable overlapping of primary motor units over a cortical area much broader than the "classical" narrow motor strip along the CS. Bipolar cortical stimulation is more sensitive than monopolar for mapping motor function in the premotor frontal cortex. Both methods are equally sensitive for mapping the primary motor cortex.     

Dopamine modulation of prefrontal cortex interneurons occurs independently of DARPP-32

Dopamine (DA) exerts a strong influence on inhibition in prefrontal cortex. The main cortical interneuron subtype targeted by DA are fast-spiking gamma-aminobutyric acidergic (GABAergic) cells that express the calcium-binding protein parvalbumin. D1 stimulation depolarizes these interneurons and increases excitability evoked by current injection. The present study examined whether this direct DA-dependent modulation of fast-spiking interneurons involves DARPP-32. Whole-cell patch-clamp recordings were made from fast-spiking interneurons in brain slices from DARPP-32 knockout (KO) mice, wild-type mice, and rats. Low concentrations of DA (100 nM) increased interneuron excitability via D1 receptors, protein kinase A, and cyclic adenosine 3',5'-monophosphate in slices from both normal and DARPP-32 KO mice. Immunohistochemical staining of slices from normal animals revealed a lack of colocalization of DARPP-32 with calcium-binding proteins selective for fast-spiking interneurons, indicating that these interneurons do not express DARPP-32. Therefore, although DARPP-32 impacts cortical inhibition through a previously demonstrated D2-dependent regulation of GABAergic currents in pyramidal cells, it is not involved in the direct D1-mediated regulation of fast-spiking interneurons.     

Transcranial direct current stimulation (tDCS) paired with massed practice training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: A pilot study

Objective: Our goal was to determine if pairing transcranial direct current stimulation (tDCS) with rehabilitation for two weeks could augment adaptive plasticity offered by these residual pathways to elicit longer-lasting improvements in motor function in incomplete spinal cord injury (iSCI).

Design: Longitudinal, randomized, controlled, double-blinded cohort study.

Setting: Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Participants: Eight male subjects with chronic incomplete motor tetraplegia.

Interventions: Massed practice (MP) training with or without tDCS for 2 hrs, 5 times a week.

Outcome Measures: We assessed neurophysiologic and functional outcomes before, after and three months following intervention. Neurophysiologic measures were collected with transcranial magnetic stimulation (TMS). TMS measures included excitability, representational volume, area and distribution of a weaker and stronger muscle motor map. Functional assessments included a manual muscle test (MMT), upper extremity motor score (UEMS), action research arm test (ARAT) and nine hole peg test (NHPT).

Results: We observed that subjects receiving training paired with tDCS had more increased strength of weak proximal (15% vs 10%), wrist (22% vs 10%) and hand (39% vs. 16%) muscles immediately and three months after intervention compared to the sham group. Our observed changes in muscle strength were related to decreases in strong muscle map volume (r=0.851), reduced weak muscle excitability (r=0.808), a more focused weak muscle motor map (r=0.675) and movement of weak muscle motor map (r=0.935).

Conclusion: Overall, our results encourage the establishment of larger clinical trials to confirm the potential benefit of pairing tDCS with training to improve the effectiveness of rehabilitation interventions for individuals with SCI.

Trial Registration: NCT01539109     

Demonstration of Cerebral Plasticity by Intra-Operative Neurophysiological Monitoring: Report of an Uncommon Case

Summary  It has been postulated long ago that “eloquent” areas shift their location in patients with arteriovenous malformations (AVM). Obviously the “motor region” in not located in the precentral gyrus in a patient with an AVM in the “motor region”.  We report on the case of a 15-year old boy with an AVM in the left sensorimotor cortex, in whom intra-operative mapping showed an inexcitability of the precentral gyrus, while stimulation of the cortex anterior to the primary motor cortex elicited motor responses. This indicates that motor function was translocated from the primary to the supplementary motor cortex. Surgery was performed under general anaesthesia. Neurophysiological monitoring was performed throughout surgery. The central sulcus was identified by phase reversal of the somatosensory evoked potentials. The motor cortex was mapped by direct high-frequency (500 Hz) monopolar anodal stimulation.  In the patient herein reported, stimulation of the “anatomically” defined primary motor cortex induced no motor response, as expected. Motor response was elicited only by stimulation of the cortex anterior to the precentral gyrus. There was no postoperative deterioration of motor function. These observations indicate that the precentral gyrus was functionally “useless”. The motor region was relocated into more rostral areas in the supplementary motor cortex. This translocation of function in the presence of an AVM indicates cerebral plasticity.     

Imagery-induced cortical excitability changes in stroke: a transcranial magnetic stimulation study

Focal transcranial magnetic stimulation (TMS) was employed in a population of hemiparetic stroke patients in a post-acute stage to map out the abductor digiti minimi (ADM) muscle cortical representation of the affected (AH) and unaffected (UH) hemisphere at rest, during motor imagery and during voluntary contraction. Imagery induced an enhancement of the ADM map area and volume in both hemispheres in a way which partly corrected the abnormal asymmetry between AH and UH motor output seen in rest condition. The voluntary contraction was the task provoking maximal facilitation in the UH, whereas a similar degree of facilitation was obtained during voluntary contraction and motor imagery in the AH. We argued that motor imagery could induce a pronounced motor output enhancement in the hemisphere affected by stroke. Further, we demonstrated that imagery-induced excitability changes were specific for the muscle 'prime mover' for the imagined movement, while no differences were observed with respect to the stroke lesion locations. Present findings demonstrated that motor imagery significantly enhanced the cortical excitability of the hemisphere affected by stroke in a post-acute stage. Further studies are needed to correlate these cortical excitability changes with short-term plasticity therefore prompting motor imagery as a 'cortical reservoir' in post-stroke motor rehabilitation.     

Activity-dependent modulation of synaptic transmission in the intact human motor cortex revealed with transcranial magnetic stimulation

Activity-dependent modulation of cortical synaptic transmission is a fundamental mechanism involved in learning and memory storage. This modulation has been widely studied in in vitro brain slices and in vivo animal models. More recently, transcranial magnetic stimulation has allowed detection of activity-dependent excitability modulation occurring in the intact human primary motor cortex (MI) after execution of different kinds of motor tasks. Both increased and decreased MI excitability have been described after exercise. While increased MI excitability is generally considered direct expression of cortical synaptic plasticity, a controversy still exists as to whether decreased MI excitability reflects fatigue of central nervous system (CNS) structures or cortical neuronal reorganization taking place after exercise. Here, we extend previous findings in order to provide further support for the latter hypothesis. Abduction- adduction movements of the thumb performed for 1 min at 2 Hz frequency rate produce a 55% decrease in MI excitability of mean 30 min duration. Similar decrements in amplitude and duration of motor evoked potentials (MEPs) are not reached if the same task is performed once again during the maximal inhibition phase (10 min post-exercise) produced by a previous activation. Moreover, the same task performed at a lower (1 Hz) frequency rate produces no significant MEP changes but can transiently reverse activity-dependent depression obtained after previous 2 Hz movements. Repeated execution of the same task (2 Hz), each being performed after recovery from a previously induced MEP depression, ceases to produce an MEP decrement, suggesting adaptation in MI excitability modulation. This adaptation is long lasting and task-specific, since a different motor task (1 min circular movement of the thumb) restores activity-dependent modulation. Overall, these findings suggest that the dynamic modulation of MEPs occurring after execution of different kinds of simple motor skills reflects some form of activity-dependent, plastic neuronal reorganization instead of CNS fatigue. Possible anatomo-functional mechanisms involved in this activity-dependent modulation of MI excitability are discussed.     

Intracortical hyperexcitability in humans with a GABAA receptor mutation

A missense mutation of the gamma2 subunit of the gamma-aminobutyric acid A (GABA(A)) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 +/- 15 years) and 24 controls (11 males, mean age: 38 +/- 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 +/- 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net short-interval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.     

Spinal cord responses to feline transcranial brain stimulation: evidence for involvement of cerebellar pathways

The physiological characteristics of spinal cord responses recorded from the spinal epidural space of the cat to transcranial brain stimulation were studied, in comparison with the spinal cord responses to direct stimulation of the motor cortex or cerebellum. The conduction velocity of the initial wave of the responses to transcranial brain stimulation (122.3 +/- 16.3 m/sec mean +/- SD, n = 5) was much faster than the conduction velocity of the initial wave of the responses to motor cortex stimulation (68.3 +/- 14.7, n = 5) and similar to the conduction velocity of the initial wave of the responses to cerebellar stimulation (120.2 +/- 16.2, n = 5). Furthermore, the conduction velocity of any component in the subsequent polyphasic waves at any intensity was not similar to the conduction velocity of the initial wave of the responses to motor cortex stimulation. All components of the responses to motor cortex stimulation disappeared after intercollicular transection. In contrast, the initial wave of the responses to cerebellar stimulation and transcranial brain stimulation remained unaffected by intercollicular transection. The initial wave caused by anodal transcranial brain stimulation was eliminated by ablation of the cerebellum. However, cathodal transcranial brain stimulation sometimes can produce an initial wave that can be eliminated only by transection at the medullospinal junction. The initial wave of the responses to cerebellar stimulation was largest in amplitude when the vicinity of the dentate nucleus was stimulated. These results suggest that responses to activation of the cerebellum, rather than corticospinal neurons arising from the motor cortex, represent a major component of the spinal cord responses to transcranial brain stimulation in cats. The data obtained indicate that it is difficult to activate the motor cortex selectively by transcranial brain stimulation in cats.