Effects of high-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex on motor recovery in severe hemiplegic stroke: A randomized clinical trial

BackgroundThe contralesional hemisphere compensation may play a critical role in the recovery of stroke when there is extensive damage to one hemisphere. There is little research on the treatment of hemiplegia by high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the contralesional cortex.ObjectiveWe conducted a 2-week randomized, sham-controlled, single-blind trial to determine whether high-frequency rTMS (HF-rTMS) over the contralesional motor cortex can improve motor function in severe stroke patients.MethodsForty-five patients with ischemic or hemorrhagic stroke in the middle cerebral artery territory were randomly assigned to treatment with 10 Hz rTMS (HF group), 1 Hz rTMS (LF group) or sham rTMS (sham group) applied over the contralesional motor cortex (M1) before physiotherapy daily for two weeks. The primary outcome was the change in the Fugl-Meyer Motor Assessment (FMA) Scale score from baseline to 2 weeks. The secondary endpoints included root mean square of surface electromyography (RMS-SEMG), Barthel Index (BI), and contralesional hemisphere cortical excitability.ResultsThe HF group showed a more significant improvement in FMA score (p < 0.05), BI (p < 0.005), contralesional hemisphere cortical excitability and conductivity (p < 0.05), and RMS-SEMG of the key muscles (p < 0.05) compared with the LF group and sham group. There were no significant differences between the LF group and sham group. There was a positive correlation between cortical conductivity of the uninjured hemisphere and recovery of motor impairment (p = 0.039).ConclusionsHF-rTMS over the contralesional cortex was superior to low-frequency rTMS and sham stimulation in promoting motor recovery in patients with severe hemiplegic stroke by acting on contralesional cortex plasticity.Trial registrationClinical trial registered with the Chinese Clinical Trial Registry at http://www.chictr.org.cn/showproj.aspx?proj=23264 (ChiCTR-IPR-17013580).     

Chronic treatment with rivastigmine in patients with Alzheimer's disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic stimulation

ObjectiveTo investigate changes in cortical excitability and short-term synaptic plasticity we delivered 5 Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in 11 patients with mild-to-moderate Alzheimer’s disease (AD) before and after chronic therapy with rivastigmine.MethodsResting motor threshold (RMT), motor evoked potential (MEP), cortical silent period (CSP) after single stimulus and MEP facilitation during rTMS trains were tested three times during treatment. All patients underwent neuropsychological tests before and after receiving rivastigmine. rTMS data in patients were compared with those from age-matched healthy controls.ResultsAt baseline, RMT was significantly lower in patients than in controls whereas CSP duration and single MEP amplitude were similar in both groups. In patients, rTMS failed to induce the normal MEP facilitation during the trains. Chronic rivastigmine intake significantly increased MEP amplitude after a single stimulus, whereas it left the other neurophysiological variables studied unchanged. No significant correlation was found between patients’ neuropsychological test scores and TMS measures.ConclusionsChronic treatment with rivastigmine has no influence on altered cortical excitability and short-term synaptic plasticity as tested by 5 Hz-rTMS.SignificanceThe limited clinical benefits related to cholinesterase inhibitor therapy in patients with AD depend on factors other than improved plasticity within the cortical glutamatergic circuits.     

The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation

BackgroundThe use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC).HypothesisIt was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity.Methods29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis.ResultsIn females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males.ConclusionsThese preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.     

Determining optimal rTMS parameters through changes in cortical inhibition

ObjectivesEvidence shows that repetitive transcranial magnetic stimulation (rTMS) changes cortical inhibition (CI) and excitability and that these changes may relate to its therapeutic effects. This study aimed to investigate the effects of differing durations or ‘doses’ of rTMS on cortical inhibition and excitability in healthy subjects.MethodsFour different experiments were conducted: 1 session of 1200 pulses of 1 or 20 Hz active or sham rTMS; 10 sessions of 1 or 20 Hz active or sham rTMS, 1200 pulses/session; 1 session of 3600 pulses of 1 or 20 Hz active or sham rTMS; 1 session of 6000 pulses of 20 Hz active or sham rTMS. Measures of cortical inhibition and excitability included short-interval intracortical inhibition, long interval cortical inhibition, cortical silent period (CSP), motor evoked potential amplitude, resting motor threshold and intracortical facilitation.ResultsOnly 6000 pulses of 20 Hz rTMS lead to a significant lengthening of the CSP and therefore potentiation of CI. There were no changes to excitability measures.ConclusionOnly high frequency rTMS potentiated CI. Longer treatment durations are required to produce such changes.SignificanceStudies investigating the therapeutic effects of rTMS may benefit from extended dosing with increased number of pulses per session. CSP lengthening may be used to guide treatment response.     

The Effects of High-Frequency rTMS Over the Left Dorsolateral Prefrontal Cortex on Reward Responsiveness

BackgroundHigh-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the prefrontal region has been shown to increase endogenous dopamine release in the striatum, which is closely associated with probabilistic reward learning.ObjectiveWe attempted to investigate whether HF-rTMS over the dorsolateral prefrontal cortex (DLPFC) would modulate reward responsiveness using a probabilistic reward task.MethodsEighteen healthy volunteers participated in this study using a randomized within-subject crossover design. Each participant received a single session of 10 Hz high-frequency rTMS over the left DLPFC and another session of sham stimulation, with an interval of 1 week between sessions. Nine hundred magnetic stimuli were delivered in three blocks 10 min apart, for a total duration of 30 min. After each stimulation session, participants performed a probabilistic reward task where two different stimuli were rewarded with different probabilities (i.e., rich vs. lean) to produce a response bias toward the more frequently rewarded stimulus.ResultsParticipants showed faster and more accurate responses toward the rich stimulus than the lean stimulus. Participants developed a greater response bias toward the rich stimulus after HF-rTMS during the early learning trials versus after sham stimulation. No differences in response bias were observed during the later learning trials. Reaction time did not differ between the active HF-rTMS and sham stimulation conditions.ConclusionHF-rTMS over the left DLPFC increased responsiveness toward rewarding stimuli. This facilitation effect of HF-rTMS might be associated with changes in dopaminergic neurotransmission in the striatum. Our findings contribute to our understanding of the effects HF-rTMS can have on reward learning.     

Repetitive Transcranial Magnetic Stimulation With H-Coil Coupled With Cycling for Improving Lower Limb Motor Function After Stroke: An Exploratory Study

Background/ObjectivesRepetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke.Materials and MethodsTwelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study. Eleven sessions of HF-rTMS (40 2s-trains of 20 Hz at 90% resting leg motor threshold) were delivered over the LE motor areas using the H-coil during active cycling for three weeks. Each subject underwent both real and sham rTMS treatments separated by a four-week washout period, in a random sequence. Vital signs were recorded before and after each rTMS session. Any discomfort related to stimulation and side effects were recorded. LE function was also evaluated with Fugl-Meyer assessment (FMA-LE), spasticity was assessed with modified-Ashworth scale and measures of gait speed and endurance (10-meter and 6-min walk tests, respectively) were recorded.ResultsNo participant reported serious adverse effects. During real rTMS, 4 of 12 subjects reported mild side effects including transitory dizziness and muscle twitches on shoulder, so that intensity of stimulation initially set at 90% of RMT was reduced to 80% of RMT on average in these four subjects. Only real treatment was associated with a significant and sustained improvement in FMA-LL (67% responders vs. 9% of the sham). Spasticity significantly ameliorated only after the real rTMS. Real treatment did not offer advantages on walking timed measures when compared with sham.ConclusionsThis exploratory study suggests that bilateral HF-rTMS combined with cycling is safe and potentially effective in ameliorating paretic LE motor function and spasticity, rather than gait speed or endurance, in chronic stroke.     

High-Frequency Repetitive Transcranial Magnetic Stimulation over the Primary Foot Motor Area in Parkinson's Disease

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been reported to be clinically effective for treating motor symptoms in Parkinson's disease (PD). Few studies have been performed reporting the effects of rTMS on non-motor symptoms such as depression and apathy in PD.ObjectiveWe assessed the effects of high-frequency (HF) rTMS over the primary motor (M1) foot area on motor symptoms, depression and apathy scales, and sensory symptoms in PD.MethodsWe investigated the efficacy of 3 consecutive days of HF-rTMS over the M1 foot area in 21 patients with PD using a randomized, double-blind cross-over trial compared with sham stimulation. Motor effects were evaluated using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), the self-assessment motor score, the visual analog scale (VAS), the 10-m walking test, and finger tapping. Non-motor effects were analyzed using the Montgomery Asberg Depression Rating Scale, the Apathy Scale, and quantitative sensory testing.ResultsHF-rTMS significantly improved UPDRS-III (P < 0.001), VAS (P < 0.001), the walking test (P = 0.014), self-assessment motor score (P = 0.010), and finger tapping measurement (P < 0.05) compared to sham stimulation. In contrast, no significant improvement was observed in depression and apathy scales. Consecutive days of rTMS did not significantly increase the improvement in motor symptoms. There were no adverse effects following rTMS on patients with PD.ConclusionsWe confirmed that HF-rTMS over the M1 foot area significantly improved motor symptoms in patients with PD. In addition, daily repeated stimulation was not significantly more effective than a single session of stimulation, but may be effective for maintaining the improvement in motor symptoms in patients with PD.     

Neurophysiological effects of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant depression

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is effective for treatment resistant depression (TRD), but little is known about rTMS’ effects on neurophysiological markers. We previously identified neurophysiological markers in depression (N45 and N100) of GABA receptor mediated inhibition. Here, we indexed TMS-electroencephalographic (TMS-EEG) effects of rTMS.MethodsTMS-EEG data was analyzed from a double blind 2:1 randomized active (10 Hz left/bilateral):sham rTMS TRD trial. Participants underwent TMS-EEG over left dorsolateral prefrontal cortex (DLPFC) before and after 6 weeks of rTMS. 30 had useable datasets. TMS-evoked potentials (TEP) and components (N45, N100, P60) were examined with global mean field analysis (GMFA) and locally in DLPFC regions of interest.ResultsThe N45 amplitude differed between active and sham groups over time, N100 amplitude did not. N45 (t = 2.975, p = 0.007) and N100 amplitudes (t = 2.177, p = 0.042) decreased after active rTMS, demonstrating alterations in cortical inhibition. TEP amplitudes decreased after active rTMS in left (t = 4.887, p < 0.001) and right DLPFC (t = 4.403, p < 0.001) not sham rTMS, demonstrating alterations in cortical excitability.ConclusionsOur results provide important new knowledge regarding rTMS effects on TMS-EEG measures in TRD, suggesting rTMS reduces neurophysiological markers of inhibition and excitability.SignificanceThese findings uncover potentially important neurophysiological mechanisms of rTMS action.     

Effect of repetitive transcranial magnetic stimulation on altered perception of One’s own face

BackgroundChronic orofacial pain (COP) patients often perceive the painful face area as “swollen” without clinical signs; such self-reported illusions of the face are termed perceptual distortion (PD). The pathophysiological mechanisms underlying PD remain elusive.ObjectiveTo test the neuromodulatory effect of repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals, to gain insight into the cortical mechanisms underlying PD.MethodsPD was induced experimentally by injections of local anesthetic (LA) around the infraorbital nerve and measured as perceived size changes of the affected area. Participants were randomly allocated to inhibitory rTMS (n = 26) or sham rTMS (n = 26) group. The participants rated PD at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. The rTMS (inhibitory and sham) was applied to face (lip) representation area of primary somatosensory cortex (SI) as an intervention at 10 min after the LA, when the magnitude of PD is large. As inhibitory rTMS, continuous theta-burst stimulation paradigm (50 Hz) for 40s was employed to inhibit cortical activity.ResultsWe demonstrated a significant decrease in the magnitude of PD immediately and 20 min after the application of inhibitory rTMS compared with sham rTMS (P < 0.006). In two control experiments, we also showed that peripheral muscle stimulation and stimulation of a cortical region other than the lip representation area had no effect on the magnitude of the PD.ConclusionsInhibitory rTMS applied to a somatotopical-relevant cortical region modulates PD of the face in healthy individuals and could potentially have therapeutic implications for COP patients.     

Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain

ObjectiveTo assess the modulation of acute provoked pain by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic neuropathic pain.MethodsIn 32 patients with chronic neuropathic pain affecting one upper limb, laser-evoked potentials (LEPs) (N2 and P2 components) were recorded in response to laser stimulation of the painful or painless hand, before and after active or sham rTMS applied at 10 Hz over the motor cortex corresponding to the painful hand. Laser-induced pain was scored on a visual analogue scale.ResultsBoth active and sham rTMS reduced N2–P2 amplitude of the LEPs in response to painful or painless hand stimulation, likely due to the decline of attention during the sessions. However, active rTMS, but not sham rTMS, specifically reduced N2 amplitude and N2/P2 amplitude ratio of the painful hand LEPs. Painful hand LEP attenuation correlated with the magnitude of pain relief produced by active rTMS.ConclusionMotor cortex rTMS delivered at high frequency (10 Hz) was able to reduce LEP amplitude in parallel with laser-induced pain scores in patients with chronic neuropathic pain. The preferential change in the N2 component suggested a modulation of the sensori-discriminative aspect of laser-induced pain.SignificancePrevious studies have shown that rTMS delivered to various cortical targets by different protocols could modulate experimental pain, primarily in healthy subjects. The present results demonstrate the ability of motor cortex rTMS to interfere with the processing of acute provoked pain, even if there is an underlying chronic neuropathic pain.     

Effects of different frequencies of repetitive transcranial magnetic stimulation in stroke patients with non-fluent aphasia: a randomized,sham-controlled study

Objective: The purpose of this study was to compare the efficacy of repetitive transcranial magnetic stimulation (rTMS) applied at different frequencies to the contra-lesional hemisphere to optimize the treatment of post-stroke non-fluent aphasia.

Method: Patients with post-stroke non-fluent aphasia were divided randomly into four groups: a high-frequency rTMS (HF-rTMS) group (10 Hz), a low-frequency rTMS (LF-rTMS) group (1 Hz), a sham stimulation group, and a control group. All groups received the standard treatment (consisting of drug therapy, conventional physical exercises, and speech training); in the HF-rTMS and LF-rTMS, this was supplemented with magnetic stimulation that targeted the mirror area within the right hemispheric Broca’s area. Patients’ language ability was assessed prior to, immediately after, and at 2 months post-treatment by the Chinese version of the Western Aphasia Battery (WAB).

Results: When measured immediately post-treatment, as well as at 2 months post-treatment, the LF-rTMS group exhibited a more marked improvement than the HF-rTMS group in spontaneous speech, auditory comprehension, and aphasia quotients (AQ). Compared to the control group, the HF-rTMS cohort exhibited significant improvement at 2-months post-treatment in repetition and AQ.

Conclusions: LF-rTMS and HF-rTMS are both beneficial to the recovery of linguistic function in patients with post-stroke non-fluent aphasia. LF-rTMS produced immediate benefits that persisted long-term, while HF-rTMS only produced long-term benefits. In addition, the benefits produced with LF-rTMS were more marked than those produced by HF-rTMS.     

Effect of electroconvulsive therapy on cortical excitability in patients with major depression: a transcranial magnetic stimulation study.

OBJECTIVE: The antidepressant action of electro-convulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) may be related to their ability to modulate cortical excitability. The aim of this study was to investigate changes in cortical excitability following ECT in patients with major depression (MD) and to compare therapeutic efficacy of ECT combined with rTMS to that of ECT alone. METHODS: Twenty-two patients with MD were assigned to receive ECT and right prefrontal 1 Hz rTMS (n=12) or ECT with sham rTMS (n=10). ECT was given twice weekly and rTMS was applied on the remaining 4 days, throughout 3 weeks. The resting motor threshold (rMT) and motor evoked potential (MEP)/M-wave area ratio were evaluated before and 6 h after the first, third and sixth ECT session. The active motor threshold (aMT), intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF) were measured at baseline and 24 h after the last ECT. RESULTS: There were no significant differences in the degree of clinical improvement and measures of cortical excitability in the ECT+active rTMS group as compared to the ECT+sham rTMS group. Marked clinical improvement observed in 19 out of the 22 patients was associated with a significant increase of the MEP/M-wave area ratio, decrease of the aMT and reduction of the ICI in the left hemisphere. CONCLUSIONS: The antidepressant effect of ECT was associated with an enhancement of left hemispheric excitability. rTMS did not add to the beneficial effect of ECT. However, the small sample size and the robust effect of ECT might have obscured a potential therapeutic effect of rTMS. SIGNIFICANCE: Measures of cortical excitability may provide insight to our understanding of the mechanism of action of ECT and might be useful for the assessment of treatment response.     

Cerebellar repetitive transcranial magnetic stimulation (rTMS) for essential tremor: A double-blind,sham-controlled,crossover, add-on clinical trial

BackgroundThere is controversial evidence about the effect of cerebellar low-frequency stimulation in patients with essential tremor (ET).ObjectivesIn this study we assessed safety and effectiveness of 1 Hz (low-frequency) cerebellar repetitive transcranial magnetic stimulation (rTMS) on tremor severity in patients with essential tremor in a sham-controlled crossover trial.MethodsA total of 23 patients assigned into two groups to receive either sham (n = 10) or rTMS (n = 13) treatment, with crossing over after a two-month washout period. Intervention consisted of 900 pulses of 1 Hz rTMS at 90% resting motor threshold or the same protocol of sham stimulation over each cerebellar hemisphere for 5 consecutive days. Tremor severity was assessed by Fahn-Tolosa-Marin (FTM) scale at baseline and at days 5, 12 and 30 after intervention. The FTM consists of 3 subscales including tremor severity rating, performance of motor tasks, and functional disability. Carry-over and treatment effects were analyzed using independent samples t-test.ResultsThere was no significant improvement in the total FTM scores in rTMS compared to the sham stimulation on day 5 (p = 0.132), day 12 (p = 0.574), or day 30 (p = 0.382). Similarly, FTM subscales, including tremor severity rating, motor tasks, and functional disability did not improve significantly after rTMS treatment. Mild headache and local pain were the most frequent adverse events.ConclusionAlthough cerebellar rTMS seems to have acceptable safety when used in ET patients, this study could not prove any efficacy for it in reduction of tremor in these patients. Larger studies are needed to evaluate efficacy of this therapeutic intervention and to provide evidence about the optimal stimulation parameters.     

High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression

Studies of repetitive transcranial magnetic stimulation (rTMS) in depression have found antidepressant effects when high frequency stimulation (HF-rTMS; >1 Hz) is applied over the left prefrontal cortex (LPF). A few studies have also reported success with low frequency stimulation (LF-rTMS) to the right prefrontal cortex (RPF). Both HF-rTMS and LF-rTMS have been reported to work better in areas with cerebral hypometabolism or hypermetabolism, respectively. Thirty medication-resistant patients with major depression were randomized into three groups. The first group received sham rTMS and the second group received active rTMS (20-Hz rTMS to the LPF and 1-Hz rTMS to the RPF). The third group, however, received active rTMS that was focused on different regions of the brain after examination with single photon emission computed tomography (20-Hz rTMS to an area of relatively low activity and 1-Hz rTMS to an area showing relatively high activation). Patients and raters were blind to the treatment condition. Comparison of the sham rTMS group with the overall group that received active rTMS revealed statistically significant changes on the Hamilton Rating Scale for Depression after 10 sessions. This study demonstrated that combined 20+1-Hz rTMS was effective, but no additional advantages were obtained by focusing rTMS on areas identified by single photon emission tomography as showing high versus low levels of functional activity.     

Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects.

BACKGROUND: Rapid-rate repetitive transcranial magnetic stimulation (rTMS) can produce a lasting increase in cortical excitability in healthy subjects or induce beneficial effects in patients with neuropsychiatric disorders; however, the conditioning effects of rTMS are often subtle and variable, limiting therapeutic applications. Here we show that magnitude and direction of after-effects induced by rapid-rate rTMS depend on the state of cortical excitability before stimulation and can be tuned by preconditioning with transcranial direct current stimulation (tDCS). METHODS: Ten healthy volunteers received a 20-sec train of 5-Hz rTMS given at an intensity of individual active motor threshold to the left primary motor hand area. This interventional protocol was preconditioned by 10 min of anodal, cathodal, or sham tDCS. We used single-pulse TMS to assess corticospinal excitability at rest before, between, and after the two interventions. RESULTS: The 5-Hz rTMS given after sham tDCS failed to produce any after-effect, whereas 5-Hz rTMS led to a marked shift in corticospinal excitability when given after effective tDCS. The direction of rTMS-induced plasticity critically depended on the polarity of tDCS conditioning. CONCLUSIONS: Preconditioning with tDCS enhances cortical plasticity induced by rapid-rate rTMS and can shape the direction of rTMS-induced after-effects.     

Effects of theta burst stimulation on motor cortex excitability in Parkinson's disease

ObjectiveLong-term potentiation (LTP)-like plasticity induced by paired associative stimulation (PAS) is impaired in Parkinson’s disease (PD). Intermittent theta burst stimulation (iTBS) is another rTMS protocol that produces LTP-like effects and increases cortical excitability but its effects are independent of afferent input. The aim of the present study was to examine the effects of iTBS on cortical excitability in PD.MethodsiTBS was applied to the motor cortex in 10 healthy subjects and 12 PD patients ON and OFF dopaminergic medications. Motor evoked potential (MEP) before and for 60 min after iTBS were used to examine the changes in cortical excitability induced by iTBS. Paired-pulse TMS was used to test whether intracortical circuits, including short interval intracortical inhibition, intracortical facilitation, short and long latency afferent inhibition, were modulated by iTBS.ResultsAfter iTBS, the control, PD ON and OFF groups had similar increases in MEP amplitude compared to baseline over the course of 60 min. Changes in intracortical circuits induced by iTBS were also similar for the different groups.ConclusionsiTBS produced similar effects on cortical excitability for PD patients and controls.SignificanceSpike-timing dependent heterosynaptic LTP-like plasticity induced by PAS may be more impaired in PD than frequency dependent homosynaptic LTP-like plasticity induced by iTBS.     

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.     

Electroencephalography quadratic phase self-coupling correlates with consciousness states and restoration in patients with disorders of consciousness

ObjectiveThe objective of this study was to explore the role for quadratic phase coupling within electroencephalography (EEG) oscillations in the diagnosis of consciousness and consciousness restoration for disorders of consciousness (DOC).MethodsFifty-one DOC patients were enrolled in this study. For each patient, a Coma Recovery Scale-Revised (CRS-R) score and 20-min resting-state EEG were recorded. Consciousness recovery was assessed with a CRS-R score at a three-month follow-up. Twenty healthy subjects were included as controls. General harmonic wavelet transform-based bicoherence was used to quantify the quadratic phase coupling characteristics of the EEG oscillations.ResultsQuadratic phase self-coupling (QPSC) at the delta (QPSC_delta), theta (QPSC_theta) and alpha (QPSC_alpha) bands were closely correlated with patient CRS-R scores. Particularly, the QPSC_theta value could significantly differentiate between vegetative state (VS) patients, minimally conscious state (MCS) patients and healthy control subjects. As compared to VS patients, patients with MCS had a lower QPSC_theta value on the left as well as a higher QPSC_alpha value in right frontal regions. The frontal QPSC_theta value showed significant differences between recovered and unrecovered patients.ConclusionQPSC characteristics could differentiate between consciousness states and show a predictive ability for the recovery of consciousness in DOC patients.SignificanceChanges in QPSC accompany consciousness injury and restoration in DOC patients. A QPSC assessment is helpful in the diagnosis and prognosis of DOC patients.     

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.     

Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers

Although repetitive transcranial magnetic stimulation (rTMS) is established in the treatment of depression, there is little knowledge about the underlying molecular mechanisms. In the last decade, the neurotrophic hypothesis of depression entailed a plethora of studies on the role of neurogenesis-associated factors in affective disorders and rTMS treatment. In the present study, we hypothesised a sham-controlled increase of peripheral brain-derived neurotrophic factor (BDNF) levels following serial rTMS stimulations in healthy individuals. We investigated the influence of a cycle of nine daily high-frequency (HF)-rTMS (25 Hz) stimulations over the left dorsolateral prefrontal cortex (DLPFC) on serum levels of BDNF in 44 young healthy male volunteers. BDNF serum concentrations were measured at baseline, on day 5 and on day 10. Overall, the statistical analyses showed that the active and sham group differed significantly regarding their responses of BDNF serum levels. Contrary to our expectations, there was a significant decrease of BDNF only during active treatment. Following the treatment period, significantly lower BDNF serum levels were quantified in the active group on day 10, when compared to the sham group. The participants’ smoking status affected this effect. Our results suggest that serial HF-rTMS stimulations over the left DLPFC decrease serum BDNF levels in healthy male volunteers. This provides further evidence for an involvement of BDNF in clinical rTMS effects.