Triad-conditioning Transcranial Magnetic Stimulation in Parkinson's Disease

BackgroundTranscranial magnetic stimulation (TMS) has been used to reveal excitability changes of the primary motor cortex (M1) in Parkinson's disease (PD). Abnormal rhythmic neural activities are considered to play pathophysiological roles in the motor symptoms of PD. The cortical responses to external rhythmic stimulation have not been studied in PD. We recently reported a new method of triad-conditioning TMS to detect the excitability changes after rhythmic conditioning stimuli, which induce facilitation by 40-Hz stimulation in healthy volunteers.ObjectiveWe applied a triad-conditioning TMS to PD patients to reveal the motor cortical response characteristics to rhythmic TMS.MethodsThe subjects included 13 PD patients and 14 healthy volunteers. Three conditioning stimuli over M1 at an intensity of 110% active motor threshold preceded the test TMS at various inter-stimulus intervals corresponding to 10–200 Hz.ResultsThe triad-conditioning TMS at 40 Hz induced no MEP enhancement in PD patients in either the On or Off state, in contrast to the facilitation observed in the normal subjects. Triad-conditioning TMS at 20–33 Hz in the beta frequency elicited significant MEP suppression in PD patients. The amount of suppression at 20 Hz positively correlated with the UPDRS III score.ConclusionWe observed abnormal M1 responses to rhythmic TMS in PD. The suppression induced by beta frequency stimulation and no facilitation by 40-Hz stimulation may be related to abnormal beta and gamma band activities within the cortical-basal ganglia network in PD patients. The motor cortical response to rhythmic TMS may be an additional method to detect physiological changes in humans.     

Enhanced intracortical inhibition in cerebellar patients

OBJECTIVE: The aim of the study was to examine intracortical excitability in cerebellar patients. METHODS: Short-latency intracortical inhibition (SICI), long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) to paired transcranial magnetic stimulation (TMS) were investigated in 8 patients with 'pure' cerebellar syndromes and in 14 age-matched normal controls. The conditioning stimulus for short-latency intracortical inhibition and intracortical facilitation was set at 70% of the resting motor threshold (RMT) and preceded the test stimulus (110-120% of the resting motor threshold) by interstimulus intervals (ISIs) of 1-30 ms. For the long-latency intracortical inhibition determinations, the conditioning stimulus was set at 120% of the resting motor threshold and preceded the test stimulus (also 120% of the resting motor threshold) by interstimulus intervals of 30-500 ms. RESULTS: No statistically significant differences were found between patients and controls as regards either short-latency intracortical inhibition or intracortical facilitation. A significant prevalence of long-latency intracortical inhibition was present in cerebellar patients at interstimulus intervals of 200-500 ms (conditioned MEP amplitude=29-41% of test MEP) as compared to controls (71-96% of test MEP). The amplitude of conditioned MEPs was persistently less than 45% of the test MEP in six patients, who were studied at interstimulus intervals up to 1000 ms. CONCLUSIONS: Long-latency intracortical inhibition was prevalent and abnormally longer-lasting in patients. Tonic hyperactivation of a subpopulation of GABAergic interneurons in the motor cortex of patients may be the mechanism responsible for this abnormality. Our findings seem to be specific to cerebellar diseases and are the opposite of those found in movement disorders such as dystonia and Parkinson's disease. These data suggest that the cerebellum and the basal ganglia may have opposite influences in tuning the excitability of the motor cortex.     

Parietal transcranial direct current stimulation modulates primary motor cortex excitability

The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the primary motor cortex (M1). Neuroplastic alterations of neuronal connectivity might be an important basis for learning processes. These have however not been explored for parieto‐motor connections in humans by transcranial direct current stimulation (tDCS). Exploring tDCS effects on parieto‐motor cortical connectivity might be functionally relevant, because tDCS has been shown to improve motor learning. We aimed to explore plastic alterations of parieto‐motor cortical connections by tDCS in healthy humans. We measured neuroplastic changes of corticospinal excitability via motor evoked potentials (MEP) elicited by single‐pulse transcranial magnetic stimulation (TMS) before and after tDCS over the left posterior parietal cortex (P3), and 3 cm posterior or lateral to P3, to explore the spatial specificity of the effects. Furthermore, short‐interval intracortical inhibition/intracortical facilitation (SICI/ICF) over M1, and parieto‐motor cortical connectivity were obtained before and after P3 tDCS. The results show polarity‐dependent M1 excitability alterations primarily after P3 tDCS. Single‐pulse TMS‐elicited MEPs, M1 SICI/ICF at 5 and 7 ms and 10 and 15 ms interstimulus intervals (ISIs), and parieto‐motor connectivity at 10 and 15 ms ISIs were all enhanced by anodal stimulation. Single pulse‐TMS‐elicited MEPs, and parieto‐motor connectivity at 10 and 15 ms ISIs were reduced by cathodal tDCS. The respective corticospinal excitability alterations lasted for at least 120 min after stimulation. These results show an effect of remote stimulation of parietal areas on M1 excitability. The spatial specificity of the effects and the impact on parietal cortex–motor cortex connections suggest a relevant connectivity‐driven effect.     

Somatosensory and transcranial direct current stimulation effects on manual dexterity and motor cortex function: A metaplasticity study

BackgroundNon-invasive neuromodulation may provide treatment strategies for neurological deficits affecting movement, such as stroke. For example, weak electrical stimulation applied to the hand by wearing a “mesh glove” (MGS) can transiently increase primary motor cortex (M1) excitability. Conversely, transcranial direct current stimulation with the cathode over M1 (c-tDCS) can decrease corticomotor excitability.Objective/Hypothesis: We applied M1 c-tDCS as a priming adjuvant to MGS and hypothesised metaplastic effects would be apparent in improved motor performance and modulation of M1 inhibitory and facilitatory circuits.MethodsSixteen right-handed neurologically healthy individuals participated in a repeated measures cross-over study; nine minutes of sham- or c-tDCS followed by 30 min of suprasensory threshold MGS. Dexterity of the non-dominant (left) hand was assessed using the grooved pegboard task, and measures of corticomotor excitability, intracortical facilitation, short-latency afferent inhibition (SAI), short-interval intracortical inhibition (SICI), and SAI in the presence of SICI (SAIxSICI), were obtained at baseline, post-tDCS, and 0, 30 and 60 min post-MGS.ResultsThere was a greater improvement in grooved pegboard completion times with c-tDCS primed MGS than sham + MGS. There was also more pronounced disinhibition of SAI. However, disinhibition of SAI in the presence of SICI was less and rest motor threshold higher compared to sham + MGS.ConclusionsThe results indicate a metaplastic modulation of corticomotor excitability with c-tDCS primed MGS. Further studies are warranted to determine how various stimulation approaches can induce metaplastic effects on M1 neuronal circuits to boost functional gains obtained with motor practice.     

Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest – A bifocal TMS study

ObjectiveIn macaques, intracortical electrical stimulation of ventral premotor cortex (PMv) can modulate ipsilateral primary motor cortex (M1) excitability at short interstimulus intervals (ISIs).MethodsAdopting the same conditioning-test approach, we used bifocal transcranial magnetic stimulation (TMS) to examine intrahemispheric connectivity between left PMv and M1 in humans. A conditioning stimulus (CS) was applied to PMv at intensities of 80% and 90% of active motor threshold (AMT) and 90% and 110% of resting motor threshold (RMT). A supra-threshold test stimulus (TS) was given 2, 4, 6, 8 and 10 ms after the CS and the amplitude of the motor evoked potential (MEP) was measured to probe corticospinal excitability.ResultsThe CS facilitated corticospinal excitability in ipsilateral M1 when PMv was stimulated with 80% AMT 4 or 6 ms before the TS. At the same ISIs, the CS suppressed corticospinal excitability when the stimulus intensity was increased to 90% RMT. Conditioning effects were site-specific because conditioning the dorsal premotor cortex (PMd) at three different sites produced different effects. Using neuronavigated TMS the PMv site where applied CS produced changes in ipsilateral M1 excitability was located at the border between ventral Brodmann area (BA) 6 and BA 44, the human homologue of monkey’s PMv (area F5).ConclusionWe infer that the corticospinal motor output from M1 to contralateral hand muscles can be facilitated or inhibited by a CS over ipsilateral PMv.SignificanceThe fact that conditioning effects following PMd stimulation differ from those after PMv stimulation supports the concept that inputs from premotor cortices to M1 are functionally segregated.     

Acute effects of lithium on excitability of human motor cortex

ObjectiveLithium has been widely used to treat bipolar affective disorder for over 60 years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS).MethodsTen healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450 mg, 900 mg, or 1350 mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration.ResultsTwo hours post drug administration, 450 mg of lithium carbonate increased the slope of the MEP IO-curve while 1350 mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation.ConclusionsThe acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship.SignificanceFindings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.     

Reduced plastic brain responses to repetitive transcranial magnetic stimulation in severe obstructive sleep apnea syndrome

ObjectivesAbnormalities in cortical excitability have been proposed to underlie the pathophysiology of various neurocognitive manifestations of obstructive sleep apnea syndrome (OSAS). Transcranial magnetic stimulation (TMS) provides a noninvasive method for study and modulation of cortical excitability in the human brain, and repetitive TMS (rTMS) has been proven useful for neurophysiologic investigation in various neurologic conditions. We aimed to investigate cortical excitability in patients with OSAS during wakefulness and to determine if rTMS would change the abnormal excitability patterns.MethodsMeasures of motor cortical and corticospinal excitability (resting motor threshold [RMT], motor-evoked potential [MEP] amplitude, and cortical silent period [CSP]) were taken before and after a session of 10-Hz rTMS applied to the motor cortex in 13 individuals with untreated severe OSAS (apnea–hypopnea index [AHI] > 30) and 12 age- and sex-matched healthy controls (HC).ResultsOSAS subjects had a significantly higher RMT (P < .003) and a longer CSP duration (P < .002) compared to HC. No difference was observed between MEP values of OSAS subjects and HC (P > .05). In response to rTMS, the HC group had a significant increase in CSP and MEP values from baseline, which were absent in OSAS subjects.ConclusionsIndividuals with OSAS demonstrated increased motor cortex inhibition, which did not respond to 10-Hz rTMS. As rTMS-induced changes in MEP and CSP involve a separate neurotransmitter system (N-methyl-d-aspartate [NMDA] and gamma-aminobutyric acid [GABA], respectively), these findings suggest a widespread alteration in cortical neurophysiology in severe OSAS subjects that requires clarification with further exploration.     

The Effects of Individualized Theta Burst Stimulation on the Excitability of the Human Motor System

BackgroundTheta burst stimulation (TBS) is a pattern of repetitive transcranial magnetic stimulation that has been demonstrated to facilitate or suppress human corticospinal excitability when applied intermittently (iTBS) or continuously (cTBS), respectively. While the fundamental pattern of TBS, consisting of bursts of 50 Hz stimulation repeated at a 5 Hz theta frequency, induces synaptic plasticity in animals and in vitro preparations, the relationship between TBS and underlying cortical firing patterns in the human cortex has not been elucidated.ObjectiveTo compare the effects of 5 Hz iTBS and cTBS with individualized TBS paradigms on corticospinal excitability and intracortical inhibitory circuits.MethodsParticipants received standard and individualized iTBS (iTBS 5; iTBS I) and cTBS (cTBS 5; cTBS I), and sham TBS, in a randomised design. For individualized paradigms, the 5 Hz theta component of the TBS pattern was replaced by the dominant cortical frequency (4–16 Hz; upper frequency restricted by technical limitations) for each individual.ResultsWe report that iTBS 5 and iTBS I both significantly facilitated motor evoked potential (MEP) amplitude to a similar extent. Unexpectedly, cTBS 5 and cTBS I failed to suppress MEP amplitude. None of the active TBS protocols had any significant effects on intracortical circuits when compared with sham TBS.ConclusionIn summary, iTBS facilitated MEP amplitude, an effect that was not improved by individualizing the theta component of the TBS pattern, while cTBS, a reportedly inhibitory paradigm, produced no change, or facilitation of MEP amplitude in our hands.     

Neuroplastic Modulation of Inhibitory Motor Cortical Networks by Spaced Theta Burst Stimulation Protocols

BackgroundContinuous theta burst stimulation (cTBS) suppresses the excitability of motor networks responsible for generating motor evoked potentials (MEPs), and may also modulates the excitability of inhibitory motor networks. However, its effects on intracortical inhibition are modest in comparison to the effects on MEPs. The repeated, spaced, application of cTBS protocols results in more MEP suppression than seen with a single cTBS protocol, but whether this approach is also effective at modulating intracortical inhibition has not been tested.ObjectiveTo determine whether the paired application of cTBS effectively modulates the excitability of intracortical inhibitory motor networks.MethodsSingle and paired-pulse transcranial magnetic stimulation (TMS) were used to assess resting motor threshold (RMT), MEP amplitude, short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI) before and during two time periods (0–10 and 30–40 min) following application of either a single or paired cTBS protocols.ResultsBoth the single and paired cTBS conditions induced a significant reduction in both MEP amplitudes and the level of SICI. While paired cTBS produced a significantly greater MEP suppression than single cTBS, the effects on SICI were similar. Neither single nor paired cTBS had an effect on RMT or LICI.ConclusionsAlthough the repeated application of cTBS protocols may be effective for enhancing modulation of the MEP-generating excitatory motor networks, these findings suggest that this approach offers little advantage when targeting intracortical inhibitory networks.     

Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer’s disease

ObjectiveSynaptopathy including alterations of synaptic plasticity (long-term potentiation, LTP) may precede neurodegeneration in Alzheimer’s disease (AD). We studied LTP-like corticospinal plasticity induced by paired-associative stimulation (PAS_LTP) in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).Methods15 AD and 15 aMCI patients, and 23 demographically matched healthy controls (HC) were included. Resting motor threshold (RMT) and stimulus intensity needed to evoke motor evoked potentials (MEP) of 1 mV (SI1mV) were obtained as single-pulse transcranial magnetic stimulation (TMS) measures of corticospinal excitability in a hand muscle at baseline, followed by PAS_LTP using standard methodology. MEP amplitude change after PAS_LTP normalized to baseline was defined as plasticity effect. All measures were repeated in two visits for examining test–retest reliability.ResultsSI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test–retest reliability in all groups. PAS_LTP indiscriminately did not induce LTP-like plasticity in any of the groups, and expressed poor test–retest reliability.ConclusionsaMCI shows corticospinal hyperexcitability, consistent with glutamatergic excitotoxicity in early-stage AD. Possible abnormalities of LTP-like plasticity could not be reliably tested with the standard PAS_LTP protocol due to massive inter-subject variability even in HC, and poor test–retest reliability.SignificanceFindings indicate corticospinal hyperexcitability in prodromal AD, and reliability of single-pulse TMS measures for identifying such abnormality. In contrast, the standard PAS_LTP protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test–retest reliability.     

Behavioural exposure and sleep do not modify corticospinal and intracortical excitability in the human motor system

ObjectiveBehavioural exposure and sleep may bidirectionally modify the excitability of cortical networks including those in the motor cortex. Here we tested whether the excitability of intracortical inhibitory and excitatory networks within the primary motor cortex exhibited changes suggestive of a time of day influence.MethodsShort-interval intracortical inhibition (SICI) and facilitation (ICF), and input–output curves (IO curves) were investigated using transcranial magnetic stimulation (TMS). Recordings were made from the resting right first dorsal interosseous (FDI) muscle in 10 healthy subjects on three occasions: 9 A.M. and 4 P.M. of the same day, and 9 A.M. of the following day.ResultsThere was no significant change in any of the measures across the three assessments.ConclusionsThese findings provide evidence that time of day does not significantly influence corticospinal and intracortical excitability in the primary motor cortex.SignificanceThese results provide no support for the hypothesis that synapses within the motor cortex undergo potentiation due to daytime use and behavioural experiences. Additionally, these findings provide evidence that measurement of motor cortical excitability is not systematically biased by time-of-day dependent variability and thus does not pose a confound in studies assessing corticospinal excitability longitudinally.     

Serum levels of carbamazepine and cortical excitability by magnetic brain stimulation

Abstract. We investigated the correlation between serum levels of carbamazepine (CBZ) and motor excitability studied by different parameters of transcranial magnetic stimulation (TMS) in patients at the beginning of antiepileptic treatment. A total of 10 patients with complex partial seizures following stroke were treated with loading doses of CBZ. Motor evoked potential (MEP) was recorded from the thenar eminence (TE) muscles of the unaffected arm. In all patients, we studied rest and active motor threshold (rMT, aMT), MEP amplitude and cortical silent period (CSP). In three patients, intracortical inhibition (ICI) and intracortical facilitation (ICF) were measured using paired TMS at short interstimulus intervals (1–25 ms). The recording sessions were performed before treatment and after 7, 15 and 60 days (SD=16 days). Serum level of CBZ were monitored at each recording session. We observed a progressive increase in rMT and aMT until the serum levels of CBZ reached a steady state condition. No significant changes were observed in MEP amplitude, CSP, ICI and ICF. This study documents the increase of both motor threshold and drug serum levels in patients treated with loading doses of CBZ, suggesting a relationship between drug metabolism and the effect on motor cortical excitability.     

Conditioning the Cortical Silent Period with Paired Transcranial Magnetic Stimulation

BackgroundA single supra-threshold pulse of transcranial magnetic stimulation (TMS) over human motor cortex elicits multiple descending volleys (I-waves) that generate a motor evoked potential (MEP) followed by a period of electromyographic silence in the tonically contracted target muscle (silent period; SP). A sub-threshold conditioning stimulus (CS) delivered at inter-pulse intervals (IPIs) of 1-5 ms after a supra-threshold test stimulus (TS) conditions I-waves elicited by TS and can increase MEP amplitude (short-interval intracortical facilitation; SICF), however its effect on the SP remains unknown.ObjectiveWe investigated whether it is possible to modulate the SP resulting from a TS by delivering a sub-threshold CS 1–5 ms later.MethodsPaired-pulse TMS was delivered while subjects performed slight contraction of the first dorsal interosseous muscle. SICF and SP duration were measured at each IPI and compared to amplitude-matched MEPs evoked by single-pulse TMS.ResultsPaired stimulation at IPI 2–5 ms prolonged the SP by 21 ± 3% (P < 0.001) but had no effect on MEP amplitude. At shorter IPIs the CS increased MEP amplitude (by 170 ± 31%), but the SP was not prolonged when compared to an amplitude-matched single-pulse stimulus.ConclusionThe SP can be modified by a CS applied during the early phase of its genesis. We suggest that this is in keeping with an early GABA_A contribution to the SP, and it is possible that this new conditioning paradigm may offer another means for probing the excitability of cortical inhibitory networks in human motor cortex.     

Sensory afferent inhibition within and between limbs in humans

ObjectiveTo examine the distribution and inter-limb interaction of short-latency afferent inhibition (SAI) in the arm and leg.MethodsMotor evoked potentials (MEPs) in distal and proximal arm, shoulder and leg muscles induced with ranscranial magnetic stimulation (TMS) were conditioned by painless electrical stimuli applied to the index finger (D2) and great toe (T1) at interstimulus intervals (ISIs) of 15, 25–35, 80 ms (D2) and 35, 45, 55, 65 and 100 ms (T1) in 27 healthy human subjects. TMS was delivered over primary motor cortex (M1) arm and leg areas. Electrical stimulus intensities were varied between 1 and 3 times the sensory perception thresholds. We also tested effects of posterior cutaneous brachial nerve (PCBN) stimulation on MEPs in arm muscles at ISIs of 18 and 28 ms.ResultsD2 but not PCBN electrical conditioning reduced MEP amplitudes in upper limb muscles at ISIs of 25 and 35 ms. SAI was more pronounced in distal as compared to proximal arm muscles. Also, SAI following D2 stimulation increased with higher conditioning intensities. D2 stimulation did not change lower limb muscles MEPs. In ontrast, T1 stimulation did not induce SAI in any muscles but caused MEP facilitation in a foot muscle at an ISI of 55 ms and in upper limb muscles at ISIs of 35 and 55 ms. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were not affected by electrical T1 conditioning.ConclusionD2 stimulation causes segmental SAI in upper limb muscles with a distal to proximal attenuation without affecting leg muscles. In contrast, toe stimulation facilitates motor output both in foot and upper arm muscles.SignificanceOur data suggest that cutaneo-motor pathways in arms and legs are functionally organized in a different way with cutaneo-motor interactions induced by toe stimulation probably relayed at a thalamic level. Abnormal cutaneo-motor interactions following electrical toe stimulation may serve as an electrophysiological marker of thalamic dysfunction, e.g. in neurodegenerative diseases.     

Electrophysiological correlates of motor conversion disorder

In patients with a functional (psychogenic) paresis, motor conduction tests are, by definition, normal. We investigated whether these patients exhibit an abnormal motor excitability. Four female patients with a functional paresis of the left upper extremity were studied using transcranial magnetic stimulation (TMS). We investigated motor thresholds, intracortical inhibition and intracortical facilitation at rest. Corticospinal excitability was evaluated by single pulse TMS during rest and during imagination of tonic index finger adductions. Data obtained from the affected first dorsal interosseous muscle were compared with the unaffected hand and with a healthy age‐matched control group. Three patients demonstrated a flaccid paresis, one patient had a psychogenic dystonia. Motor thresholds, short interval intracortical inhibition and intracortical facilitation recorded from the affected side were normal. In healthy subjects, movement imagination produced an increase of corticospinal excitability. In the patients, motor imagery with the affected index finger resulted in a decrease of corticospinal excitability compared to rest, being significantly different from the unaffected side and from the control group. We suggest that suppression of corticospinal excitability during movement imagination is an electrophysiological correlate of the patients' inability to move voluntarily and provides some insight into the pathophysiology of this disorder. © 2008 Movement Disorder Society     

Determination of anodal tDCS duration threshold for reversal of corticospinal excitability: An investigation for induction of counter-regulatory mechanisms

BackgroundTranscranial direct current stimulation (tDCS) is used to induce neuroplasticity in the human brain. Within certain limits of stimulation duration, anodal tDCS (a-tDCS) over the primary motor cortex induces long term potentiation- (LTP) like plasticity. A reversal of the direction of plasticity has however been described with prolonged a-tDCS protocols.ObjectiveWe aimed to systematically investigate the intervention duration threshold for reversal of a-tDCS-induced effects on corticospinal excitability (CSE) and to determine the probable mechanisms involved in these changes.MethodsFifteen healthy participants received a-tDCS of 1 mA for five different durations in pseudo-random session order. Transcranial magnetic stimulation (TMS) was delivered over the left M1, and motor evoked potentials (MEPs) of a contralateral hand muscle were recorded before, immediately and 30 min following intervention to measure CSE changes. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval facilitation (LIF) were assessed via paired-pulse TMS protocols.ResultsA-tDCS significantly increased CSE as expected at stimulation durations of 22 and 24 min. However, this effect of a-tDCS on CSE decreased and even reversed when stimulation duration increased to 26, 28, and 30 min. Respective alterations of ICF, LIF, and SICI indicate the involvement of glutamatergic, and GABAergic systems in these effects.ConclusionsThese results confirm a duration threshold for reversal of the excitability-enhancing effect of a-tDCS with stimulation durations ≥ 26 min. Counter-regulatory mechanisms are discussed as a mechanistic foundation for these effects, which might prevent excessive brain activation.     

Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation.

Single or paired pulse paradigms of transcranial magnetic stimulation (TMS) provide several parameters to test motor cortex excitability, such as motor threshold (MT), motor evoked potential (MEP) amplitude, electromyographic silent period to cortical stimulation (CSP) and intracortical facilitation (ICF) or inhibition (ICI). Various changes in TMS parameters, revealing motor cortex dysfunction, were found in patients with Parkinson's disease (PD). For instance, low MT and increased MEP size disclosed an enhanced corticospinal motor output at rest, while reduced ICF and failure of MEP size increase during contraction suggested defective facilitatory cortical inputs, particularly for movement execution. Inhibitory cortical pathways were also found less excitable at rest (reduced ICI) and sometimes during contraction (shortened CSP). By restoring cortical inhibition, dopaminergic drugs and deep brain stimulation probably overcome the difficulty to focus neuronal activity onto the appropriate network required for a specific motor task. The application of repetitive TMS trains over motor cortical areas also showed some effect on cortical excitability, opening perspectives to consider the motor cortex as a target for therapeutic neuromodulation in PD. However, systematic studies of cortical excitability remained to be performed in large series of patients with PD, taking into account disease stage, clinical symptoms and medication influence.     

Increased motor cortical excitability after whole-hand electrical stimulation: A TMS study

ObjectiveTo examine the neuromodulatory effect of whole-hand mesh-glove (MG) stimulation on motor cortical pathways, we explored motor cortical excitability before and after suprathreshold whole-hand MG stimulation using transcranial magnetic stimulation (TMS).MethodsTwenty-eight healthy volunteers (14 controls) were studied at baseline, immediately post and 1 h post-MG stimulation for 30 min. Motor thresholds (MTs), motor evoked potentials (MEPs) recruitment curve, short intracortical inhibition (SICI) and intracortical facilitation (ICF) after paired magnetic stimuli were evaluated.ResultsAfter MG stimulation the MTs were significantly reduced and slope of MEP recruitment curve significantly increased; furthermore, the stimulation led to a sustained decrease of SICI and increase of ICF in the contralateral motor cortex. These effects lasted for at least 60 min and were stronger 1 h post-stimulation compared with testing immediately after stimulation. A sham group did not show any differences before and after MG stimulation.ConclusionsWe provide a first demonstration that MG whole-hand stimulation induces increases in motor cortical excitability lasting at least 1 h. Both the strength of the corticospinal projections and the inhibitory and facilitatory intracortical mechanisms are involved. Synaptic modifications such as long-term potentiation mechanisms may underlie this stimulation-induced cortical plasticity changes.SignificancePresent results prove the MG stimulation to be a promising tool in neurorehabilitation.     

Multi-modal investigation of transcranial ultrasound-induced neuroplasticity of the human motor cortex

IntroductionThere is currently a gap in accessibility to neuromodulation tools that can approximate the efficacy and spatial resolution of invasive methods. Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate cortical and deep brain structures with more focal stimulation compared to existing NIBS modalities. Theta burst TUS (tbTUS, TUS delivered in a theta burst pattern) is a novel repetitive TUS protocol that can induce durable changes in motor cortex excitability, thereby holding promise as a novel neuromodulation tool with durable effects.ObjectiveThe aim of the present study was to elucidate the neurophysiologic effects of tbTUS motor cortical excitability, as well on local and global neural oscillations and network connectivity.MethodsAn 80-s train of active or sham tbTUS was delivered to the left motor cortex in 15 healthy subjects. Motor cortical excitability was investigated through transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) using paired-pulse TMS. Magnetoencephalography (MEG) recordings during resting state and an index finger abduction-adduction task were used to assess oscillatory brain responses and network connectivity. The correlations between the changes in neural oscillations and motor cortical excitability were also evaluated.ResultstbTUS to the motor cortex results in a sustained increase in MEP amplitude and decreased SICI, but no change in ICF. MEG spectral power analysis revealed TUS-mediated desynchronization in alpha and beta spectral power. Significant changes in alpha power were detected within the supplementary motor cortex (Right > Left) and changes in beta power within bilateral supplementary motor cortices, right basal ganglia and parietal regions. Coherence analysis revealed increased local connectivity in motor areas. MEP and SICI changes correlated with both local and inter-regional coherence.ConclusionThe findings from this study provide novel insights into the neurophysiologic basis of TUS-mediated neuroplasticity and point to the involvement of regions within the motor network in mediating this sustained response. Future studies may further characterize the durability of TUS-mediated neuroplasticity and its clinical applications as a neuromodulation strategy for neurological and psychiatric disorders.     

Normal cortical excitability in Myoclonus-Dystonia — A TMS study

Objective

The aim of the present study is to investigate cortical excitability in patients with DYT 11 positive Myoclonus-Dystonia (M-D), using transcranial magnetic stimulation (TMS).

Methods

Silent period, motor evoked potential (MEP) recruitment curve, short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF), with short interstimulus intervals (ISIs) ranging from 1.2 to 3.2 ms, were studied in 15 DYT 11-positive M–D patients and their matched controls. In four patients and matched controls peripheral double pulse electrical nerve stimulation was performed.

Results

All TMS parameters of cortical excitability were normal compared to healthy controls. In the SICF protocol we observed more variable and polyphasic MEPs in M–D patients. Cross-covariance analysis of MEP area revealed a significant correlation difference at ISI 2.2 and 2.8 ms. This increased variability was not seen in other TMS protocols or with peripheral nerve stimulation.

Conclusions

In contrast with other types of dystonia, no changes in cortical excitability were found in DYT 11 patients. Our findings suggest that M–D is both clinically and pathophysiologically a separate entity from other dystonic disorders. Polyphasic MEPs during the SICF protocol in M–D patients could reflect central neuron membrane instability. Application of the SICF protocol in other patient groups has to prove its value in movement disorders.