A Comparison of Two Methods in Acquiring Stimulus–Response Curves with Transcranial Magnetic Stimulation

BackgroundThe stimulus–response (S–R) curve is a well accepted constituent in transcranial magnetic stimulation (TMS) studies. However, it has been suggested that parameters of the S–R curve differ when stimuli are provided in a “ramped” (measured steps from low to high intensity), or “random” fashion.HypothesisWe hypothesized that there would be no difference in the parameters of the S–R curve between either methodologies.MethodsUsing a randomised cross-over design, 10 healthy participants (29.6 ± 6.4 yrs, 3 f) completed “ramped” or “random” curves in biceps brachii (BB) and first dorsal interosseous (FDI) muscles of both limbs. Curves were compared using mixed-factor ANOVA and correlated between limbs and methodologies.ResultsNo differences (P > 0.05) and high correlations (range 0.71–0.97; P < 0.001) were observed in BB and FDI data between curves.ConclusionsThis study demonstrated that either methodology provides similar parameters of the S–R curve in healthy participants.     

Reduced motor cortex plasticity following inhibitory rTMS in older adults

ObjectiveAgeing is accompanied by diminished practice-dependent plasticity. We investigated the effect of age on another plasticity inducing paradigm, repetitive transcranial magnetic stimulation (rTMS).MethodsHealthy young (n = 15; 25 ± 4 years) and old (n = 15; 67 ± 5 years) adults participated in two experiments. Motor evoked potentials (MEPs) were measured in the target muscle (first dorsal interosseus, FDI) and a remote muscle (abductor digiti minimi) during a set of single stimuli. Subjects then received real or sham inhibitory rTMS (intermittent subthreshold trains of 6 Hz stimulation for 10 min). MEPs were measured for 30 min after rTMS.ResultsIn young adults, MEPs in the target FDI muscle were ∼15% smaller in the real rTMS experiment than in the sham rTMS experiment (P < 0.026). In old adults, FDI MEP size did not differ between experiments.ConclusionsAdvancing age is associated with reduced efficacy of inhibitory rTMS.SignificanceThis work has important implications for the potential therapeutic use of rTMS in stroke and neurological disease.     

Hysteresis effects on the input–output curve of motor evoked potentials

ObjectiveInput–output (IO) curves of motor evoked potentials (MEP) are widely used to assess corticospinal excitability by transcranial magnetic stimulation (TMS). Here we sought to determine hysteresis effects on IO curves, i.e. their short-term dependence on prior corticospinal activation.MethodsIO curves were measured from the first dorsal interosseous (FDI) muscle of 14 healthy volunteers in three different conditions of stimulus intensity order: increase from lowest to highest, decrease from highest to lowest, and random. Intensities ranged from 80% to 170% of the resting motor threshold (RMT). IO curves were measured in the resting vs. active FDI and at two different intertrial intervals (ITI, 5 s and 20 s).ResultsIn the resting FDI and at ITI = 5 s, the IO curve in condition “decrease” shifted significantly to the left compared to condition “increase”. The IO curve in condition “random” ran in between the other two curves. Hysteresis was most pronounced in the high intensity part of the IO curves. Hysteresis did not occur at ITI = 20 s or in the active FDI.ConclusionsFindings implicate that hysteresis can influence IO curves significantly. One possible underlying mechanism might be short-term synaptic enhancement.SignificanceConsideration of IO curve hysteresis effects is important to avoid systematic data bias in clinical and research TMS applications.     

Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex.

OBJECTIVE: To study the after effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on corticospinal excitability. METHODS: Eight healthy volunteers received either 150 or 1800 stimuli of 5 Hz rTMS on two separate days in a counterbalanced order. rTMS was given over the 'motor hot spot' of the right first dorsal interosseus (FDI) muscle using an intensity of 90% of resting motor threshold (referred to as subthreshold rTMS). We evaluated the amplitude of the motor-evoked potential (MEP), short-latency intracortical inhibition (SICI), short-latency intracortical facilitation (SICF), and cortical silent period (CSP) before and for about 30 min after rTMS. MEPs were recorded from the right FDI muscle and abductor digiti minimi (ADM) muscle. RESULTS: 1800 stimuli induced an increase in MEP amplitude in the relaxed FDI muscle, but not in the relaxed ADM muscle. This facilitatory after effect was stable for at least 30 min. Prolonged 5 Hz rTMS had no effect on the relative magnitude of SICI and SICF. 150 stimuli caused no lasting modulation of MEP amplitudes in either muscle. In a subgroup of 5 subjects, 900 conditioning stimuli caused only a short-lived MEP facilitation. 5 Hz rTMS did not modify the duration of the CSP during tonic contraction. CONCLUSIONS: A single session of subthreshold 5 Hz rTMS to the M1 can induce a long-lasting and muscle-specific increase in resting corticospinal excitability. However, a sufficient number of conditioning stimuli is necessary to produce persistent corticospinal facilitation.     

Effect of slow rTMS of motor cortex on the excitability of the Blink Reflex: A study in healthy humans

ObjectiveTo evaluate the after-effects of low frequency, sub-threshold repetitive Transcranial Magnetic Stimulation (rTMS) of primary motor cortex, on the excitability of Blink Reflex (BR) in healthy subjects.MethodsThe BR recovery cycle was carried out in 10 healthy volunteers in basal conditions, immediately after rTMS (30 s), 15 and 60 min later. A paired electric supraorbital stimulus paradigm with inter-stimulus intervals (ISI) of 100–600–1000–1500 ms was used. The “real” rTMS consisted of a 200 stimuli long train delivered at 1 Hz and intensity 80% of rest Motor Threshold of the FDI muscle, using a focal coil applied over the primary motor cortex region. The basal BR recovery cycle was also compared with that obtained after a “sham” rTMS.ResultsThe recovery of the R2 component of the BR was significantly suppressed 30 s after rTMS. This effect was also observed at 15 min, though of lower magnitude and only at long ISIs (1000-1500 ms). No significant effect on R2 recovery was observed 60 min after real rTMS as well as after sham rTMS.ConclusionsrTMS of motor cortex modulates the excitability of BR through its action on cortical excitability and on the cortical facilitatory drive to the brainstem reflex pathways.SignificanceSlow (1 Hz), sub-threshold rTMS of motor cortex determines a long-lasting reduction of excitability of BR.     

D-cycloserine normalizes long-term motor plasticity after transcranial magnetic intermittent theta-burst stimulation in major depressive disorder

ObjectivesMajor Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD.MethodsWe conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day.ResultsAcute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC.ConclusionMDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism.SignificanceAgonism of NMDA receptors rescues iTBS motor plasticity in MDD.     

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.     

Slow (1 Hz) repetitive transcranial magnetic stimulation (rTMS) induces a sustained change in cortical excitability in patients with Parkinson’s disease

ObjectiveLow-frequency (⩽1 Hz) rTMS (LF-rTMS) can reduce excitability in the underlying cortex and/or promote inhibition. In patients with Parkinson’s disease (PD) several TMS elicited features of motor corticospinal physiology suggest presence of impaired inhibitory mechanisms. These include shortened silent period (SP) and slightly steeper input–output (I–O) curve of motor evoked potential (MEP) size than in normal controls. However, studies of LF-rTMS effects on inhibitory mechanisms in PD are scarce.In this companion paper to the clinical paper describing effects of four consecutive days of LF-rTMS on dyskinesia in PD (Filipović et al., 2009), we evaluate the delayed (24 h) effects of the LF-rTMS treatment on physiological measures of excitability of the motor cortex in the same patients. There are very few studies of physiological follow up of daily rTMS treatments.MethodsNine patients with PD in Hoehn and Yahr stages 2 or 3 and prominent medication-induced dyskinesia were studied. This was a placebo-controlled, crossover study, with two treatment arms, “real” rTMS and “sham” rTMS (placebo). In each of the treatment arms, rTMS (1800 pulses; 1 Hz rate; intensity of the real stimuli just-below the active motor threshold) was delivered over the motor cortex for four consecutive days. Motor cortex excitability was evaluated at the beginning of the study and the next day following each of the four-day rTMS series (real and sham) with patients first in the practically defined “off” state, following 12 h withdrawal of medication, and subsequently in a typical “on” state following usual morning medication dose.ResultsThe SP was significantly longer following real rTMS in comparison to both baseline and sham rTMS. The effect was independent from the effects of dopaminergic treatment. There was no difference in MEP size, rest and active motor threshold. The I–O curve, recorded from the relaxed muscle, showed a trend towards diminished slope in comparison to baseline, but the difference was not significant. There was no consistent correlation between prolongation of SP and concomitant reduction in dyskinesia following real rTMS.ConclusionsLow-frequency rTMS delivered over several consecutive days changes the excitability of motor cortex by increasing the excitability of inhibitory circuits. The effects persist for at least a day after rTMS.SignificanceThe results confirm the existence of a residual after-effect of consecutive daily applications of rTMS that might be relevant to the clinical effect that was observed in this group of patients and could be further exploited for potential therapeutic uses.     

Altered response to repetitive transcranial magnetic stimulation in patients with chronic primary insomnia

BackgroundWe aimed at evaluating the amplitude changes of the motor evoked potentials (MEPs) induced by of low-frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) in10 patients with primary insomnia (PI) and in 10 age-matched healthy controls.MethodsMedian peak-to-peak MEP amplitudes were assessed in all subjects at three times: at baseline (T₀), after the first train of a single rTMS session (T₁), and after the whole rTMS procedure (T₂). This consists of 20 trains of 1 Hz stimulation with 50 stimuli per train and an intertrain interval of 30 s.ResultsResting motor threshold (RMT) and MEPs amplitude did not differ between the two groups at T₀. A reduction of MEP size was observed at both T₁ and T₂ in all subjects, but this was significantly less pronounced in patients than in control subjects.ConclusionsThe lack of MEP inhibition reflects an altered response to LF rTMS in patients with PI. These rTMS findings are indicative of an altered cortical plasticity in inhibitory circuits within M1 in PI. Subjects with PI exhibited an impairment of the LTD-like mechanisms induced by inhibitory rTMS, thus providing further support to the involvement of GABA neurotransmission in the pathophysiology of PI.     

Effect of repetitive transcranial magnetic stimulation combined with robot-assisted training on wrist muscle activation post-stroke

ObjectiveTo compare the effects of active assisted wrist extension training, using a robotic exoskeleton (RW), with simultaneous 5 Hz (rTMS + RW) or Sham rTMS (Sham rTMS + RW) over the ipsilesional extensor carpi radialis motor cortical representation, on voluntary wrist muscle activation following stroke.MethodsThe two training conditions were completed at least one week apart in 13 participants >1-year post-stroke. Voluntary wrist extensor muscle activation (motor unit (MU) recruitment thresholds and firing rate modulation in a ramp-hold handgrip task), ipsilesional corticospinal excitability (motor evoked potential [MEP] amplitude) and transcallosal inhibition were measured Pre- and Post-training.ResultsFor MUs active both Pre and Post training, greater reductions in recruitment thresholds were found Post rTMS + RW training (p = 0.0001) compared to Sham rTMS + RW (p = 0.16). MU firing rate modulation increased following both training conditions (p = 0.001). Ipsilesional MEPs were elicited Pre and Post in only 5/13 participants. No significant changes were seen in ipsilesional corticospinal excitability and transcallosal inhibition measures (p > 0.05).ConclusionsFollowing a single rTMS + RW session in people >1-year post-stroke, changes were found in voluntary muscle activation of wrist extensor muscles. Alterations in ipsilesional corticospinal or interhemispheric excitability were not detected.SignificanceThe effects of rTMS + RW on muscle activation warrant further investigation as post-stroke rehabilitation strategy.     

ALS pathophysiology: Insights from the split-hand phenomenon

ObjectiveThe aim of the present study was to assess whether peripheral mechanisms, mediated through axonal dysfunction, may contribute to development of the split-hand in amyotrophic lateral sclerosis (ALS).MethodsMedian and ulnar nerve motor axonal excitability studies were undertaken on 21 ALS patients with motor responses recorded over the abductor pollicis brevis (APB), abductor digit minimi (ADM) and first dorsal interosseous (FDI) muscles, and results compared to 24 controls.ResultsThe split-hand index (SI), an objective biomarker of preferential atrophy of APB and FDI muscles, was significantly reduced in ALS (SI_ALS 7.8 ± 1.7, SI_CONTROLS 13.1 ± 1.1, P < 0.0001). Axonal excitability studies identified significant prolongation of strength-duration time constant in ALS patients when recording over the APB (P < 0.05) and ADM axons (P < 0.05) but not FDI axons (P = 0.22). Greater changes in depolarising threshold electrotonus were also evident across the range of intrinsic hand muscles and were accompanied by increases of superexcitability in APB (P < 0.01) and FDI (P < 0.05) axons.ConclusionThe present study reinforces the significance of the split-hand phenomenon in ALS and argues against a significant peripheral contribution in the underlying development.SignificanceAxonal dysfunction may appear as a downstream process that develops secondary to the intrinsic pathophysiological origins of ALS.     

The Effect of rTMS on Auditory Processing in Adults with Chronic,Bilateral Tinnitus: A Placebo-Controlled Pilot Study

BackgroundOn the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated the use of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as a potential modulator of this hyperactivity. While these investigations show promise, investigations to date have neglected to consider the possible effect of 1 Hz rTMS on other functions of the auditory cortex of these individuals, such as auditory processing.Objective/hypothesisThis placebo-controlled pilot study aimed to determine whether 1 Hz rTMS applied to the primary auditory cortex (PAC), specifically Brodmann Area 41 (BA41), of adults with chronic, bilateral tinnitus would influence their auditory processing abilities.MethodsEight participants with bilateral, chronic tinnitus were randomized to receive a 10-day course of neuronavigationally guided active rTMS (n = 4) or placebo rTMS (n = 4) treatment applied to a focal region of the left PAC (BA41). Participants' auditory processing was measured using Time Compressed Reverberant Speech and three-pair Dichotic Digits (DD). Their tinnitus was measured using the Tinnitus Handicap Inventory (THI) and a psychoacoustic measure of tinnitus perception. All outcome measures were administered at baseline (1 week prior to rTMS), 1 week, 1, 2 and 3 months post-rTMS.ResultsAll four participants in the active rTMS (A) group, and none of the participants in the sham (placebo) rTMS (S) group, showed improved auditory processing scores at multiple assessment points post-stimulation, with the group differences in median normalized gain scores reaching significance at the 5% level from 1 week or 1 month post-stimulation onwards. Three of the four participants in the active rTMS (A) group, and none of the participants in the sham rTMS (S) group, showed improved tinnitus scores at multiple assessment points post-stimulation, with some of the group differences in median normalized gain scores reaching significance at the 5% level.ConclusionsThe results of this preliminary study suggest that 1 Hz rTMS applied to the PAC (BA41) has the capacity to improve both auditory processing and tinnitus perception in some adults with chronic, bilateral tinnitus.     

Different short-term modulation of cortical motor output to distal and proximal upper-limb muscles during painful sensory nerve stimulation

The pattern of upper-limb muscle activation following painful stimulation has not been clarified in detail. We investigated the short-term inhibitory and excitatory effects of painful electrical digital stimulation on the motoneuron pools of distal and proximal upper-limb muscles. Transcranial magnetic stimulation (TMS) was used as test stimulus, and painful digital nerve stimulation as conditioning stimulus for motor evoked potential (MEP) recordings over the abductor digiti minimi (ADM), abductor pollicis brevis (APB), biceps brachii (BB), and deltoid muscles. Inhibition of the conditioned MEP response was most prominent in the distal muscles, whereas BB and deltoid muscles were only weakly inhibited. The mean MEP response over APB decreased with painful cutaneous stimuli, showing maximum inhibition (by 82%) at interstimulus intervals (ISIs) of 50 ms. Inhibition in the ADM was maximal (49%) but less pronounced at an ISI of 40 ms. The BB and deltoid muscles showed inhibition by 25% and 29%, respectively. Significant facilitation was present in BB and deltoid muscles by 43% and 41% at an ISI of 100 ms, but not in the smaller hand muscles. The observed pattern of upper-limb muscle activation corresponds to the protective withdrawal reflex and the neuronal basis of the observed short-term modulation of motor activity is compatible with a spinal or brainstem pathway.     

Modulation of motor cortex excitability by paired peripheral and transcranial magnetic stimulation

Objective

Repetitive application of peripheral electrical stimuli paired with transcranial magnetic stimulation (rTMS) of M1 cortex at low frequency, known as paired associative stimulation (PAS), is an effective method to induce motor cortex plasticity in humans. Here we investigated the effects of repetitive peripheral magnetic stimulation (rPMS) combined with low frequency rTMS (‘magnetic-PAS’) on intracortical and corticospinal excitability and whether those changes were widespread or circumscribed to the cortical area controlling the stimulated muscle.

Relationship Between Motor Function,DTI, and Neurophysiological Parameters in Patients with Stroke in the Recovery Rehabilitation unit

ObjectivesWe investigated the relationship between pyramidal tract evaluation indexes (i.e., diffusion tensor imaging, transcranial magnetic stimulation (TMS)-induced motor-evoked potential (MEP), and central motor conduction time (CMCT) on admission to the recovery rehabilitation unit) and motor functions at discharge in patients with ischemic or hemorrhagic stroke.Materials and MethodsSeventeen patients were recruited (12 men; 57.9 ± 10.3 years). The mean fractional anisotropy (FA) values of the right and left posterior limbs of the internal capsule were estimated using a computer-automated method. We determined the ratios of FA values in the affected and unaffected hemispheres (rFA), TMS-induced MEP, and the ratios of CMCT in the affected and unaffected hemispheres (rCMCT) and examined their association with motor functions (Fugl–Meyer Assessment (FMA) and Action Research Arm Test (ARAT)) at discharge.ResultsHigher rFA values of the posterior limb of the internal capsule on admission to the recovery rehabilitation unit led to a better recovery of upper limb function (FMA: r = 0.78, p < 0.001; ARAT: r = 0.74, p = 0.001). Patients without MEP had poorer recovery of upper limb function than those with MEP (FMA: p < 0.001; ARAT: p = 0.001). The higher the rCMCT, the poorer the recovery of upper limb function (ARAT: r = ?0.93, p < 0.001). However, no association was observed between the pyramidal tract evaluation indexes and recovery of lower limb motor function.ConclusionsEvaluating the pyramidal tract is useful for predicting upper limb function prognosis, but not for lower limb function prognosis.     

Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway

BackgroundInvestigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response.ObjectiveWe aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS.MethodsTwenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed.ResultsFor high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed.ConclusionOpposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted.     

Jitter of Corticospinal Neurons During Repetitive Transcranial Magnetic Stimulation. Method and Possible Clinical Implications

BackgroundRepetitive transcranial magnetic stimulation (rTMS) of the motor cortex activates corticospinal neurons mainly through the depolarization of cortico-cortical axons belonging to interneurons of superficial layers.ObjectiveWe used single-fiber electromyography (SFEMG) to estimate the “central jitter” of activation latency of interneural pools from one pulse of TMS to another.MethodsWe evaluated 10 healthy subjects and one patient with multiple sclerosis. By recording SFEMG evoked activity from the left first dorsal interosseous (FDI), we first used a standard repetitive electrical 3 Hz stimulation of the ulnar nerve at the wrist to calculate the mean consecutive difference from at least 10 different potentials. The same procedure was applied during 3 Hz repetitive TMS of the contralateral motor cortex. The corticospinal monosynaptic connection of the FDI and the selectivity of SFEMG recording physiologically justified the subtraction of the “peripheral jitter” from the whole cortico-muscular jitter, obtaining an estimation of the actual “central jitter.”ResultsAll subjects completed the study. The peripheral jitter was 28 μs ± 6 and the cortico-muscular jitter was 344 μs ± 97. The estimated central jitter was 343 ± 97 μs. In the patient the central jitter was 846 μs, a value more than twice the central jitter in healthy subjects.ConclusionCurrent results demonstrate that the evaluation of the central component of the cumulative cortico-muscular latency variability in healthy subjects is feasible with a minimally invasive approach. We present and discuss this methodology and provide a “proof of concept” of its potential clinical applicability in a patient with multiple sclerosis.     

Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has been widely used in non-invasive treatments for different neurological disorders. Few biomarkers are available for treatment response prediction. This study aims to analyze the correlation between changes in long-term potentiation (LTP)-like cortical plasticity and cognitive function in patients with Alzheimer’s disease (AD) that underwent rTMS treatment.MethodsA total of 75 AD patients were randomized into either 20 Hz rTMS treatment at the dorsolateral prefrontal cortex (DLPFC) group (n = 37) or a sham treatment group (n = 38) for 30 sessions over six weeks (five days per week) with a three-month follow-up. Neuropsychological assessments were conducted using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment-Cognitive Component (ADAS-Cog). The cortical plasticity reflected by the motor-evoked potential (MEP) before and after high-frequency repetitive TMS to the primary motor cortex (M1) was also examined prior to and after the treatment period.ResultsThe results showed that the cognitive ability of patients who underwent the MMSE and ADAS-Cog assessments showed small but significant improvement after six weeks of rTMS treatment compared with the sham group. The cortical plasticity improvement correlated to the observed cognition change.ConclusionsCortical LTP-like plasticity could predict the treatment responses of cognitive improvements in AD patients receiving rTMS intervention. This warrants future clinical trials using cortical LTP as a predictive marker.     

Corticomotor excitability in drug-naive patients with Parkinson disease

Background and purposeThis study aimed to assess the indices of corticomotor excitability (CE) in drug-naive Parkinson disease (PD) patients and to investigate its relationship with asymmetry and severity of clinical symptoms.Material and methodsEleven (4 men) drug-naive PD patients (mean age: 53.1 ± 9.8 years) and 13 (7 men) healthy controls (mean age: 51.7 ± 4.2 years) were included. All PD patients were rated on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) with measurement of the side-specific score separately for arms and legs. Resting motor threshold (RMT), central silent period (CSP), amplitude of motor evoked potential (MEP) and central motor conduction time (CMCT) evoked by a single pulse of the transcranial magnetic stimulation were recorded in all subjects from the left and right abductor digiti minimi (ADM) and extensor digitorum brevis (EDB).ResultsParkinson disease patients showed higher MEP (1.8 ± 0.9 vs. 1.1 ± 0.8 mV, p < 0.05) and shorter CMCT (6.1 ± 0.9 vs. 7.4 ± 1.0 ms, p < 0.05) recorded from the ADM on the more affected side. CSP recorded from the more affected ADM was under the normal range in five and from the less affected ADM in four PD patients. For CSP recorded from the EDB, respective values are four for the more affected side and three for the less affected side. The rigidity from the more affected arm and leg correlated negatively with the respective CSP recorded from the ADM (r = –0.74, p < 0.01) and EDB (r = –0.68, p < 0.04).ConclusionsIn the early stage of untreated PD the CE parameters are altered only on the more affected side. The shortening of CSP reflects the severity of rigidity on the more affected side.     

Treatment of Executive Function Deficits in autism spectrum disorder with repetitive transcranial magnetic stimulation: A double-blind,sham-controlled,pilot trial

BackgroundIn youth and young adults with autism spectrum disorder (ASD), executive function (EF) deficits may be a promising treatment target with potential impact on everyday functioning.ObjectiveTo conduct a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for EF deficits in ASD.MethodIn Toronto, Ontario (November 2014 to June 2017), a 20-session, 4-week course of 20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) (90%RMT) was compared to sham stimulation in 16–35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n = 20 active/n = 20 sham). Outcome measures evaluated protocol feasibility and clinical effects of active vs. sham rTMS on EF performance. The moderating effect of baseline functioning was explored.ResultsOf eligible participants, 95% were enrolled and 95% of randomized participants completed the protocol. Adverse events across treatment arms were mild-to-moderate. There was no significant difference between active vs. sham rTMS on EF performance. Baseline adaptive functioning moderated the effect of rTMS, such that participants with lower baseline functioning experienced significant EF improvement in the active vs. sham group.ConclusionsOur pilot RCT demonstrated the feasibility and acceptability of using high frequency rTMS targeting DLPFC in youth and young adults with autism. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, we found promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits. Future work could focus on examining efficacy of rTMS in this higher-need population.Clinical trial registrationRepetitive Transcranial Magnetic Stimulation (rTMS) for Executive Function Deficits in Autism Spectrum Disorder and Effects on Brain Structure: A Pilot Study; https://clinicaltrials.gov/ct2/show/NCT02311751?term = ameis&rank = 1; NCT02311751. The trial was funded by: an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award, the Innovation Fund from the Alternate Funding Plan of the Academic Health Sciences Centres of Ontario, and an Ontario Mental Health Foundation (OMHF) Project A Grant and New Investigator Fellowship.