Changes In Cortical Excitability Research Articles

P 157. Anodal tDCS during skill learning preconditioned by cathodal tDCS improves motor memory – A TMS study

Question Weak anodal tDCS applied to the primary motor cortex during motor learning is known to increase synaptic activity in specific cortical areas involved in learning and thus to improve motor performance and memory formation. According to the rules of homeostatic metaplasticity (Ziemann and Siebner, 2008) it has been proposed that decrease of the threshold for induction of synaptic plasticity by experimental lowering the neuronal activity before practice may also facilitate learning. The study aimed to examine if anodal transcranial direct current stimulation (atDCS) applied during learning preconditioned by cathodal tDCS (ctDCS) proves to be more effective then atDCS alone in order to boost performance gains and to extend retention of motor memory. Methods To prove this hypothesis three matched study groups (n = 12) were recruited: a group receiving 15 min sham preconditioning stimulation before learning and atDCS during learning (atDCS), a group receiving 15 min preconditioning ctDCS before learning and atDCS during learning (c/atDCS) and a group receiving sham stimulation (sham). Grooved pegboard test (GPT) was employed as a learning paradigm. For evaluation of the learning and tDCS-induced effects, behavioural measures and transcranial magnetic stimulation (TMS) assessments were considered. Time to complete the GPT was evaluated across four blocks; task retention was tested after two weeks. Cortical excitability changes were assessed with single and paired-pulse TMS at baseline (T0), post preconditioning stimulation (T1), post training (T2) and 60 min post training (T3). Results Anodal tDCS applied to the motor cortex during execution of the grooved pegboard test improved significantly motor performance compared to the sham group. This effect was even enhanced when the motor cortex was preconditioned with ctDCS. Importantly in this case also the motor memory was improved as tested after two weeks. The observed effects correlated with changes in motor cortical excitability. Application of ctDCS induced decrease in motor evoked potential (MEP) amplitude and intracortical facilitation (ICF) and increase in intracortical inhibition (SICI). However application of atDCS resulted in increased MEP amplitude and ICF and decreased SICI. When atDCS was preceeded by 15 min ctDCS the facilitatory effects were retained for 1 h. Conclusion Decreased neuronal activity by ctDCS increase subsequent facilitation of learning-dependent plasticity resulting in improved performance gains and retention. The results provide better understanding on the ability to modulate motor learning and memory with non-invasive brain stimulation through gating and homeostatic metaplasticity. This holds potential for clinical applications, specifically for the development of learning-stimulation protocols.

IS 17. Effects of focal static magnetic fields on the human cortex

The non-invasive modulation of motor cortex excitability by the application of static magnetic fields through the scalp was investigated in healthy humans. Static magnetic fields were obtained by using cylindrical NdFeB magnets. (tSMS) in conscious subjects. We observed an average reduction of motor cortex excitability of up to 25%, as revealed by TMS, which lasted for several minutes after the end of 10min of static magnetic field stimulation (tSMS). The effect of tSMS was dose-dependent (intensity of the magnetic field) and duration dependent, but not polarity-dependent. We used transcranial electric stimulation (TES) to establish that the tSMS-induced reduction of motor cortex excitability was not due to corticospinal axon and/or spinal excitability, but specifically involved intracortical networks. We further explored the tSMS effects on EEG oscillations in the visual cortex and during visual attentional performance in healthy humans. We specifically examined the hypothesis that these effects could be related to an increase of alpha band activity, and therefore, associated to an inhibitory effect. During real but not sham tSMS over the visual cortex, there was a significant increase of the alpha band power. Moreover, we observed a similar reaction time (RTs) pattern during real and sham tSMS for most of trials. However, a significant slowing of RTs emerged across those trials with a higher difficulty levels during real in comparison to sham tSMS . Further studies using tSMS are required to extend the knowledge of the functional significance of cortical excitability changes and brain oscillations changes induced by the application of small magnets over the scalp. These results suggest that tSMS using small static magnets may be a promising tool to modulate cerebral excitability in a non-invasive, painless, and reversible way.

IS 15. Flashes of insight: Non-conventional NIBS reveals novel ways to stimulate the brain

Modulating, disrupting or otherwise interfering with the activity of the cerebral cortex by non-invasive, external stimulation methods not only offers the possibility of clinical intervention in neurological and psychiatric diseases, but provides us with a powerful research tool for understanding the workings of the intact human brain. In the past years new non-conventional, non-invasive brain stimulation (NIBS) techniques have been developed. Application of near-infrared light to the scalp has recently been introduced in order to treat neurological conditions such as stroke and the treatment of traumatic brain disorders ( Hashmi et al., 2010 ). Another very simple method, the application of static magnetic fields (tSMS) through the scalp by using small cylindrical magnets, has been shown to induce robust effects on levels of cortical excitability in healthy subjects ( Oliviero et al., 2011 ). Nevertheless, a deeper knowledge of the mechanisms of how these methods work on a neuronal level, is required. In our laboratory we have demonstrated that applying near-infrared light at a wavelength of 810 nm for 10 min to the primary motor cortex (M1), results in cortical excitability changes, assessed by means of motor-evoked potentials (MEP). MEP amplitudes showed a 20–40% decrease compared to sham stimulation, for up to 1 h post-stimulation. Furthermore, it was observed that the stimulation modified the long intracortical inhibition. Similarly, with the application of tSMS to the M1, an inhibition could be observed. On the functional level it has been demonstrated that both of these methods can modify implicit motor learning. These non-conventional NIBS techniques may thus be opening new research domains for influencing brain activity and to treat neurological and psychiatric disorders in a non-invasive way.

P 84. High-frequency neuronavigated cerebellar repetitive Transcranial Magnetic stimulation (rTMS) increases human pharyngeal motor cortex excitability

Animal studies, human brain imaging and more recently Transcranial Magnetic Stimulation (TMS) suggest a role for the cerebellum in human swallowing. Moreover, paired-pulse cerebellar-cortical TMS delivered in rapid succession (50–200 ms intervals) facilitates pharyngeal motor cortex excitability ( Jayasekeran et al., 2011 ). The aim of this study was to determine if longer trains of rTMS can induce long-lasting changes in pharyngeal cortical excitability that may prove to be therapeutically useful for dysphagia after stroke. In 17 healthy adults (6 female, age range 18–61 yrs), anatomical MR brain scans were acquired. Thereafter participants were intubated with an intraluminal catheter to record pharyngeal electromyography and underwent TMS cortical mapping with neuronavigation to co-localise pharyngeal motor representation bilaterally, hand motor cortex and the cerebellar site which evoked the largest pharyngeal motor response. Subjects were then randomised to receive one of 5 neuronavigated cerebellar rTMS interventions (Sham, 1 Hz, 5 Hz, 10 Hz and 20 Hz, at least 1 week apart) to the cerebellar site evoking the largest baseline pharyngeal responses to single-pulse cerebellar TMS. Bihemispheric pharyngeal cortical excitability (ipsilateral and contralateral cortex to cerebellum site) was measured at baseline and for up to 1 h post cerebellar rTMS intervention. Abductor pollicis brevis (APB) recordings were used as control. Interventional data were compared to sham using repeated measures ANOVA. Cerebellar rTMS was tolerated well and delivered at an average intensity of 55% of stimulator output. Compared to Sham, 10 Hz cerebellar rTMS increased pharyngeal cortical excitability ( F (1,16) = 8.3, ∗ p = 0.01), with maximal size and durational effects seen primarily in the contralateral pharyngeal cortex (+72%, ∗∗ p = 0.02, Fig. 1 ). By contrast, 1 Hz ( F (1,16) = 0.3, p = 0.60), 5 Hz ( F (1,16) = 0.5, p = 0.48), and 20 Hz rTMS ( F (1,16) = 1.3, p = 0.27) cerebellar conditioning did not significantly alter pharyngeal excitability compared to Sham. APB responses were not significantly different to sham after any intervention. Our data show for the first time that high-frequency (10 Hz) cerebellar stimulation can produce long-lasting increases in human pharyngeal motor cortex excitability, with larger and longer-lasting effects of the intervention primarily seen in the contralateral projection. Hence 10 Hz cerebellar rTMS may play a therapeutic role in the treatment of dysphagia after hemispheric stroke.

Alterations of cortical excitability and central motor conduction time in Wilson's disease

Wilson's disease (WD) leads to widespread structural alterations of central nervous system and our objectives were to determine the cortical excitability changes in WD by using transcranial magnetic stimulation (TMS). Thirteen patients with WD, diagnosed by the presence of Kayser–Fleischer ring and biochemical tests, were studied. TMS was performed using a figure-of-eight coil attached to Magstim 200 stimulator. Motor evoked potentials (MEP) were recorded from right first dorsal interosseous at rest. Resting motor threshold (RMT) was determined using standard techniques and central motor conduction time (CMCT) by ‘F’ wave method. Comparison was made with control data of our laboratory. Dysarthria was the presenting symptom in 5 patients (38.5%) and chorea, tremors, dystonia and abnormal gait in 2 patients each (15.4%). RMT was recordable in 10 patients and not recordable in 3. Compared to controls, patients in whom RMT was recordable, had significantly higher mean RMT (80.9±14.8 vs. 41.1±7, p<0.0001) and CMCT (6.7±0.5ms vs. 4.8±0.6ms; p<0.0001). In 2 of the 3 patients with non-recordable RMT, MEP could be obtained with active contraction. CMCT in these 2 patients was also prolonged. Patients with WD have reduced cortical excitability and prolonged CMCT which may be due to the intracortical presynaptic motor dysfunction.

Excitability modulation of the motor system induced by transcranial direct current stimulation: A multimodal approach

Anodal and cathodal transcranial direct current stimulations (tDCS) are both established techniques to induce cortical excitability changes. Typically, in the human motor system, such cortical modulations are inferred through changes in the amplitude of the motor evoked potentials (MEPs). However, it is now possible to directly evaluate tDCS-induced changes at the cortical level by recording the transcranial magnetic stimulation evoked potentials (TEPs) using electroencephalography (EEG).The present study investigated the modulation induced by the tDCS on the motor system. The study evaluates changes in the MEPs, in the amplitude and distribution of the TEPs, in resting state oscillatory brain activity and in behavioral performance in a simple manual response task. Both the short- and long-term tDCS effects were investigated by evaluating their time course at ~0 and 30min after tDCS.Anodal tDCS over the left primary motor cortex (M1) induced an enhancement of corticospinal excitability, whereas cathodal stimulation produced a reduction. These changes in excitability were indexed by changes in MEP amplitude. More interestingly, tDCS modulated the cortical reactivity, which is the neuronal activity evoked by TMS, in a polarity-dependent and site-specific manner. Cortical reactivity increased after anodal stimulation over the left M1, whereas it decreased with cathodal stimulation. These effects were partially present also at long term evaluation.No polarity-specific effect was found either on behavioral measures or on oscillatory brain activity. The latter showed a general increase in the power density of low frequency oscillations (theta and alpha) at both stimulation polarities.Our results suggest that tDCS is able to modulate motor cortical reactivity in a polarity-specific manner, inducing a complex pattern of direct and indirect cortical activations or inhibitions of the motor system-related network, which might be related to changes in synaptic efficacy of the motor cortex.

AGE-RELATED DIFFERENCES ON THE ENHANCEMENT OF NON- DOMINANT HAND MOTOR FUNCTION AFTER PARALLEL INTERVENTION OF ANODAL TDCS AND MOTOR TASK: A TMS STUDY

BackgroundHealthy ageing is accompanied by cognitive and functional deficits which result in decreased ability to respond quickly and accurately to different stimuli. Whilst a general decline is observed in manual...

Motor Cortex Excitability in Acute Cerebellar Infarct

Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired-pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age-matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery.

Polarity Independent Effects of Cerebellar tDCS on Short Term Ankle Visuomotor Learning

BackgroundTranscranial direct current stimulation (tDCS), an emerging technique of noninvasive brain stimulation, has shown to produce beneficial neural effects in consequence with improvements in motor behavior. There are not many studies examining the use of tDCS for lower limb motor control and learning. Most studies using tDCS for facilitating lower limb motor coordination have applied tDCS to the lower limb motor cortex (M1). As the cerebellum is also critically involved in movement control, it is important to dissociate the effect of tDCS on the cerebellum and M1 with respect to lower limb motor control before we begin the application of tDCS as a neuromodulatory tool. Objective/HypothesisThe purpose of this study was to determine the effects of cerebellar vs. motor cortical tDCS on short term ankle visuomotor learning in healthy individuals. MethodsEight healthy individuals practiced a skilled ankle motor tracking task while receiving either facilitatory anodal tDCS to cerebellum, inhibitory cathodal tDCS to cerebellum, facilitatory anodal tDCS to M1, inhibitory cathodal tDCS to M1 or sham stimulation. Pre- and post-measures of changes in cortical excitability of the tibialis anterior muscle and measures of tracking accuracy were assessed. ResultsAnodal cerebellar, cathodal cerebellar, and anodal M1 stimulation improved target-tracking accuracy of the ankle. This was not dependent on the observed changes in motor cortical excitability of the tibialis anterior muscle. Conclusion(s)Polarity independent effects of tDCS on cerebellum were observed. The present study shows that modulation effects of tDCS can occur because of changes in the cerebellum, a structure implicated in several forms of motor learning, providing an additional way in which tDCS can be used to improve motor coordination.

Unilateral cortical hyperexcitability in congenital hydrocephalus: A TMS study

Introduction: Changes in cortical excitability are considered to play an important role in promoting brain plasticity both in healthy people and in neurological diseases. Hydrocephalus is a brain development disorder related to an excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. The functional relevance of cortical structural changes described in this disease is largely unexplored in human. We investigated cortical excitability using multimodal transcranial magnetic stimulation (TMS) in a case of congenital hydrocephalus with almost no neurological signs. Methods: A caucasian 40 years old, ambidextrous and multilingual woman affected by occult spina bifida and congenital symmetrical hydrocephalous underwent a TMS study. The intracortical and interhemispheric paired pulse paradigms were used, together with the mapping technique. Results: No significant differences were found in the resting motor thresholds between the two hemispheres. Instead, the intracortical excitability curves were statistically different between the two hemispheres (with short intracortical inhibition (SICI) being strongly reduced and intracortical facilitation (ICF) enhanced in the right one), and the interhemispheric curves showed a general hyper-excitability on the right hemisphere (when conditioned by the left one) and a general hypo-excitability in the left hemisphere (when conditioned by the right one). It is noteworthy that an asymmetric right hemisphere (RH) change of excitability was observed by means of mapping technique. Conclusion: We hypothesize that in this ambidextrous subject, the observed RH hyper-excitability could represent a mechanism of plasticity to preserve functionality of specific brain areas possibly devoted to some special skills, such as multilingualism.

Synaptic and Intrinsic Homeostatic Mechanisms Cooperate to Increase L2/3 Pyramidal Neuron Excitability during a Late Phase of Critical Period Plasticity

Visual deprivation profoundly affects visual cortical response properties, but the activity-dependent plasticity mechanisms that underlie these changes are poorly understood. Monocular deprivation (MD) induces ocular dominance (OD) shifts through biphasic changes in cortical excitability, first decreasing responsiveness to the deprived eye, and then slowly increasing responsiveness to both the deprived and spared eyes. It has been suggested that this slow gain of responsiveness is due to homeostatic synaptic scaling, but this prediction has not been tested directly. Here we show that, in rat monocular and binocular primary visual cortex (V1m and V1b), postsynaptic strength onto layer 2/3 (L2/3) pyramidal neurons is modulated in a biphasic manner by MD, first undergoing a net decrease after 1 and 2 d MD, increasing back to baseline after 3 d, and finally undergoing a net potentiation between 3 and 6 d. The time course and direction of these synaptic changes match well the known changes in visual responsiveness during OD plasticity. Viral-mediated delivery of the GluA2 C-tail in vivo blocked these synaptic changes, indicating that, like synaptic scaling in vitro, AMPA receptor trafficking via the GluA2 C-tail is required for the delayed increase in postsynaptic strength. Finally, we also observed a delayed increase in the intrinsic excitability of L2/3 pyramidal neurons following prolonged MD. These data indicate that synaptic and intrinsic homeostatic mechanisms cooperate to increase excitability of L2/3 pyramidal neurons following prolonged MD, and suggest that these homeostatic mechanisms contribute to the delayed gain of visual responsiveness during OD plasticity.

Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.

H‐coil repetitive transcranial magnetic stimulation for pain relief in patients with diabetic neuropathy

Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to study changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H-coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower-limb representation relieves pain in patients with diabetic neuropathy. Patients were randomly assigned to receive daily real or sham H-coil rTMS for 5 consecutive days. After a 5-week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex). Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p=0.01), and so did RIII reflex area (p<0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS-induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well. Deep H-coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.

Effect of expectancy and personality on cortical excitability in Parkinson's disease

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Botulinum toxin modulates cortical maladaptation in post‐stroke spasticity

Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity.

Cortical excitability changes correlate with fluctuations in glucose levels in patients with epilepsy

ObjectiveWe used transcranial magnetic stimulation (TMS) to investigate motor cortical excitability changes in relation to blood glucose levels. MethodsTwenty-two drug-naïve patients with epilepsy [11 generalized and 11 focal] and 10 controls were studied twice on the same day; first after 12h of fasting and then 2h postprandial. Motor threshold and paired-pulse TMS at a number of short and long interstimulus intervals were measured. Serum glucose levels were measured each time. ResultsDecreased long intracortical inhibition was seen in patients and controls during fasting compared to postprandial studies. This effect was much more prominent in patients with generalized epilepsy (with effect sizes of up to 0.8) in whom there was also evidence of increased intracortical facilitation (effect size: 0.3). ConclusionCortical excitability varies with fluctuations in blood glucose levels. This variation is more prominent in patients with epilepsy. Decreased glucose levels may be an important physiological seizure trigger.

The Modulation of Error Processing in the Medial Frontal Cortex by Transcranial Direct Current Stimulation.

Background. In order to prevent future errors, we constantly control our behavior for discrepancies between the expected (i.e., intended) and the real action outcome and continuously adjust our behavior accordingly. Neurophysiological correlates of this action-monitoring process can be studied with event-related potentials (error-related negativity (ERN) and error positivity (Pe)) originating from the medial prefrontal cortex (mPFC). Patients with neuropsychiatric diseases often show performance monitoring dysfunctions potentially caused by pathological changes of cortical excitability; therefore, a modulation of the underlying neuronal activity might be a valuable therapeutic tool. One technique which allows us to explore cortical modulation of neural networks is transcranial direct current stimulation (tDCS). Therefore, we tested the effect of medial-prefrontal tDCS on error-monitoring potentials in 48 healthy subjects randomly assigned to anodal, cathodal, or sham stimulation. Results. We found that cathodal stimulation attenuated Pe amplitudes compared to both anodal and sham stimulation, but no effect for the ERN. Conclusions. Our results indicate that cathodal tDCS over the mPFC results in an attenuated cortical excitability leading to decreased Pe amplitudes. We therefore conclude that tDCS has a neuromodulatory effect on error-monitoring systems suggesting a future approach to modify the sensitivity of corresponding neural networks in patients with action-monitoring deficits.

Évaluation électrophysiologique de l’excitabilité corticale dans la migraine

IntroductionNeurophysiological studies point to altered cortical neuronal excitability in migraine patients. State of artBetween attacks, migraine brain seems to be “hyperresponsive” to repetitive stimuli, as suggested by evoked potential studies that show a lack of habituation to sensory stimuli. Transcranial magnetic stimulation suggests an impairment of intracortical inhibitory circuits in migraine, especially in migraine with aura. Controversial results are obtained in migraineurs without aura. Repetitive transcranial magnetic stimulation also shows in migraine with aura a paradoxical enhancement of intracortical facilitation by low frequency stimulation and greater increased facilitatory mechanisms by high-frequency stimulation. Importantly, cortical excitability level fluctuates over time in relation to the migraine cycle. The interictal lack of habituation to sensory stimuli normalizes before and during a migraine attack. Changes of cortical excitability consistent with the theory of cortical spreading depression are also observed during migraine aura with magnetoencephalography. PerspectivesThe exact role of cortical excitability changes in migraine pathophysiology and possibly in chronic migraine is still unknown. Further studies are also necessary to clarify the role of migraine preventive drugs on brain excitability. ConclusionsIn this review, the results of neurophysiological studies conducted in migraine patients will be described and the associated pathophysiological hypotheses will be discussed.

Brain Activation in Motor Sequence Learning Is Related to the Level of Native Cortical Excitability

Cortical excitability may be subject to changes through training and learning. Motor training can increase cortical excitability in motor cortex, and facilitation of motor cortical excitability has been shown to be positively correlated with improvements in performance in simple motor tasks. Thus cortical excitability may tentatively be considered as a marker of learning and use-dependent plasticity. Previous studies focused on changes in cortical excitability brought about by learning processes, however, the relation between native levels of cortical excitability on the one hand and brain activation and behavioral parameters on the other is as yet unknown. In the present study we investigated the role of differential native motor cortical excitability for learning a motor sequencing task with regard to post-training changes in excitability, behavioral performance and involvement of brain regions. Our motor task required our participants to reproduce and improvise over a pre-learned motor sequence. Over both task conditions, participants with low cortical excitability (CElo) showed significantly higher BOLD activation in task-relevant brain regions than participants with high cortical excitability (CEhi). In contrast, CElo and CEhi groups did not exhibit differences in percentage of correct responses and improvisation level. Moreover, cortical excitability did not change significantly after learning and training in either group, with the exception of a significant decrease in facilitatory excitability in the CEhi group. The present data suggest that the native, unmanipulated level of cortical excitability is related to brain activation intensity, but not to performance quality. The higher BOLD mean signal intensity during the motor task might reflect a compensatory mechanism in CElo participants.

Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique to modulate cortical excitability. Although increased/decreased excitability under the anode/cathode electrode is nominally associated with membrane depolarization/hyperpolarization, which cellular compartments (somas, dendrites, axons and their terminals) mediate changes in cortical excitability remains unaddressed. Here we consider the acute effects of DCS on excitatory synaptic efficacy. Using multi-scale computational models and rat cortical brain slices, we show the following. (1) Typical tDCS montages produce predominantly tangential (relative to the cortical surface) direction currents (4-12 times radial direction currents), even directly under electrodes. (2) Radial current flow (parallel to the somatodendritic axis) modulates synaptic efficacy consistent with somatic polarization, with depolarization facilitating synaptic efficacy. (3) Tangential current flow (perpendicular to the somatodendritic axis) modulates synaptic efficacy acutely (during stimulation) in an afferent pathway-specific manner that is consistent with terminal polarization, with hyperpolarization facilitating synaptic efficacy. (4) Maximal polarization during uniform DCS is expected at distal (the branch length is more than three times the membrane length constant) synaptic terminals, independent of and two-three times more susceptible than pyramidal neuron somas. We conclude that during acute DCS the cellular targets responsible for modulation of synaptic efficacy are concurrently somata and axon terminals, with the direction of cortical current flow determining the relative influence.