Bilateral theta-burst stimulation on emotional processing in major depressive disorder: A functional neuroimaging study from a randomized, double-blind, sham-controlled trial.

AIM: Bilateral theta-burst stimulation (biTBS; intermittent TBS over the left dorsolateral prefrontal cortex [DLPFC] and continuous TBS over the right DLPFC) has demonstrated efficacy in improving symptoms in patients with major depressive disorder (MDD). However, the underlying brain mechanisms remain unknown. The authors aimed to investigate the antidepressant efficacy of biTBS monotherapy and its effects on the brain responses measured by functional magnetic resonance imaging (fMRI) during emotional processing in MDD. METHODS: The authors conducted a double-blind, randomized, sham-controlled trial of patients with MDD who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode. Recruited patients were randomly assigned to 10 biTBS monotherapy or sham stimulation sessions. The fMRI scans during performing emotional recognition task were obtained at baseline and after 10 sessions of treatment. Depressive symptoms were assessed using the 21-item Hamilton Rating Scale for Depression at baseline and the weeks 4, 8, 12, 16, 20, and 24 week. RESULTS: The biTBS group (n = 17) exhibited significant decreases in depression scores compared with the sham group (n = 11) at week 8 (70% vs 40%; P = 0.02), and the significant differences persisted during the 24-week follow-up periods. At week 4, when the treatment course was completed, patients in the biTBS group, but not in the sham group, exhibited increased brain activities over the left superior and middle frontal gyrus during negative emotional stimuli. CONCLUSION: The authors' findings provide the first evidence regarding the underlying neural mechanisms of biTBS therapy to improve clinical symptoms in patients with MDD.

Low-frequency oscillations in cortical level to help diagnose task-specific dystonia.

Task-specific dystonia is a neurological movement disorder that abnormal contractions of muscles result in the twisting of fixed postures or muscle spasm during specific tasks. Due to the rareness and the pathophysiology of the disease, there is no test to confirm the diagnosis of task-specific dystonia, except comprehensive observations by the experts. Evidence from neural electrophysiological data suggests that enhanced low frequency (4-12 Hz) oscillations in the subcortical structure of the globus pallidus were associated with the pathological abnormalities concerning ß and γ rhythms in motor areas and motor cortical network in patients with task-specific dystonia. However, whether patients with task-specific dystonia have any low-frequency abnormalities in motor cortical areas remains unclear. In this study, we hypothesized that low-frequency abnormalities are present in core motor areas and motor cortical networks in patients with task-specific dystonia during performing the non-symptomatic movements and those low-frequency abnormalities can help the diagnosis of this disease. We tested this hypothesis by using EEG, effective connectivity analysis, and a machine learning method. Fifteen patients with task-specific dystonia and 15 healthy controls were recruited. The machine learning method identified 8 aberrant movement-related network connections concerning low frequency, ß and γ frequencies, which enabled the separation of the data of patients from those of controls with an accuracy of 90%. Importantly, 7 of the 8 aberrant connections engaged the premotor area contralateral to the affected hand, suggesting an important role of the premotor area in the pathological abnormities. The patients exhibited significantly lower low frequency activities during the movement preparation and significantly lower ß rhythms during movements compared with healthy controls in the core motor areas. Our findings of low frequency- and ß-related abnormalities at the cortical level and aberrant motor network could help diagnose task-specific dystonia in the clinical setting, and the importance of the contralesional premotor area suggests its diagnostic potential for task-specific dystonia.

Antidepressant efficacy and immune effects of bilateral theta burst stimulation monotherapy in major depression: A randomized, double-blind, sham-controlled study.

Inflammation theory has been consolidated by accumulating evidence, and many studies have suggested that the peripheral cytokine levels could be biomarkers for disease status and treatment outcome in major depressive disorder (MDD). Theta burst stimulation (TBS), a new form of repetitive transcranial magnetic stimulation (TMS) for MDD, has been demonstrated to improve depression via modulating dysfunctional neural network or hypothalamic­pituitary­adrenal axis hyperactivities in MDD. However, there is lack of exploratory studies investigating its effect on serum inflammatory cytokines. Here, we aimed to investigate the antidepressant efficacy of bilateral TBS monotherapy and its effects on the serum cytokine levels in MDD. We conducted a double-blind, randomized, sham-controlled trial, with 53 MDD patients who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode assigned randomly to one of two groups: bilateral TBS monotherapy (n = 27) or sham stimulation (n = 26). The TBS treatment period was 22 days. Blood samples from 31 study subjects were obtained for analyses. The bilateral TBS group exhibited significantly greater decreases in depression scores than the sham group at week 4 (56.5% vs. 33.1%; p < 0.001 [effect size (Cohen ' s d) = 1.00]) and during the 20-week follow-up periods. Significantly more responders were also found at week 4 (70.3% vs. 23.1%, p = 0.001) and during the 20-week follow-up periods. However, we did not detect any significant effects of TBS on the cytokine panels or any correlations between improvement in depressive symptoms and changes in serum inflammatory markers. Our findings provided the first evidence that the antidepressant efficacy of bilateral TBS monotherapy might not work via immune-modulating mechanisms.

Sonographic Clue in Non-traumatic Carotid-cavernous Fistula: Report of a Case and Literature Review.

BACKGROUND: Failure to recognize a carotid-cavernous fistula (CCF) promptly may lead to worse prognosis due to a setback in providing proper treatment. To promote early diagnosis of non-traumatic CCF, we report a case with classic clinical symptoms and signs that was diagnosed and followed up with carotid Doppler sonography (CDS) and transcranial color-coded duplex (TCD). CASE REPORT: A 45-year-old woman developed an intermittent headache, pulsatile tinnitus, and double vision sequentially within ten days. Progressive left retro-orbital pain, continuous ringing in the left ear, sensory impairment of trigeminal nerve and abducens nerve palsy were also noted on examination. Despite insignificant findings on computed tomography (CT) of the brain, TCD revealed an aberrant flow pattern with high velocity and low resistance at the left carotid siphon. Digital subtraction angiography (DSA) later confirmed a left direct type CCF by illustrating a quick opacification of left cavernous sinus via the internal carotid artery. CONCLUSION: In addition to invasive DSA, non-invasive CDS and TCD may serve as useful apparatus during the initial evaluation and subsequent follow-ups. The positive sonographic clues, including abnormal turbulent and hemodynamic parameters, are quite exhibitive in the existence of CCFs.

Bilateral subthalamic stimulation for advanced Parkinson disease: early experience at an Eastern center.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can improve the life quality of patients with advanced Parkinson disease (PD). However, previous studies have stemmed mainly from Western centers. Present study analyzed the 6-month outcomes of bilateral STN-DBS therapy that were observed during a 9-year period at a Taiwanese institute. We retrospectively reviewed 72 consecutive patients, whose mean disease history was 8 years when they underwent surgery. The median "drug-off" Hoehn and Yahr stage was 3. The STN was targeted using T2-weighted magnetic resonance imaging and electrophysiological guidance. The over-time mean differences in the Unified PD Rating Scale (UPDRS) scores and daily levodopa-equivalent dose (LED) were assessed using the repeated measurements ANOVA at 3 and 6 months relative to those of presurgical drug-off baseline. At 6 months postsurgery, the mean UPDRS total, Part II and Part III subscores significantly decreased by 27, 30 and 25 %, respectively, with clinically high effect size. Tremors were markedly (66 %) ameliorated. Moreover, problems of akinesia, rigidity, and locomotion were significantly improved by 20 %. The mean daily LED needs decreased by 25 %; thus, drug-induced dyskinesia was markedly (80 %) diminished. STN-DBS therapy could provide similarly effective impacts to Eastern and Western PD patients. Preoperative optimal selection of patients and postoperative delicate programming ensure a better surgical improvement.

Activation of N-methyl-D-aspartate receptor glycine site temporally ameliorates neuropsychiatric symptoms of Parkinson's disease with dementia.

AIM: We have previously found that sarcosine, a glycine transporter I inhibitor, can improve the psychiatric symptoms of schizophrenia. In this study, we aimed to investigate whether the agent can also ameliorate neuropsychiatric symptoms of Parkinson's disease (PD) patients with dementia. METHODS: An 8-week, double-blind, placebo-controlled trial was conducted in patients who had PD with dementia (PD-D). Neuropsychiatric manifestations were measured before and at week 2 (V1), week 4 (V2) and week 8 (V3) after treatment. Linear regression with the generalized estimating equations was applied for data analysis. RESULTS: Fifteen patients were randomized into a sarcosine group; the other 15 into a placebo group. The generalized estimating equations model revealed significant differences in Hamilton Depression Rating Scale score (P = 0.049) at V1 and Neuropsychiatry Inventory (P = 0.039) at V2 between the treatment and placebo groups. By excluding the advanced patients from analysis, there were significant differences in Unified Parkinson's Disease Rating Scale V2 (P = 0.004) and V3 (P = 0.040), Hamilton Depression Rating Scale V1 (P = 0.014) and V2 (P = 0.047), Neuropsychiatry Inventory V1 (P = 0.002) and V2 (P < 0.001) and Behavior Pathology in Alzheimer's Disease Rating Scale V2 (P = 0.025) in favor of sarcosine. CONCLUSION: Sarcosine temporally improved depression and neuropsychiatric symptoms in PD-D patients without exacerbating the motor or cognitive features; the beneficial effects were more prominent in patients with mild-moderate severity. Enhancement of N-methyl-D-aspartate receptor-glycine cascade may lead to a novel path for the management of PD-D.

Spatiotemporal dynamics of bimanual integration in human somatosensory cortex and their relevance to bimanual object manipulation.

Little is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration.

Anatomical and electrophysiological manifestations in a patient with congenital corpus callosum agenesis.

The corpus callosum is the major brain structure responsible for the transferring of information between the two hemispheres. In congenital agenesis of the corpus callosum (ACC), an alternative functional connection might exist between the hemispheres; however, this has yet to be demonstrated. The present study evaluated a 27-year-old man with ACC but no detectable motor function deficits using diffusion tensor imaging (DTI), movement-related cortical potential (MRCP), and interhemispheric inhibition (IHI). The MRCP was analyzed at the electrodes of C3, FCZ, and C4. IHI was measured using paired transcranial magnetic stimulation over the hand area of the primary motor cortex at both hemispheres. Data of the patient were compared with those of an age-matched healthy control group (n = 8, mean age: 27.6 ± 2.5 years). DTI showed absence of the callosal fibers and the presence of enhanced transcommissural fibers in the ACC patient. The mean fractional anisotropy of the transcommissural fibers revealed a significant difference between the patient and the control group (0.62 vs. 0.43, p < 0.01). The MRCP and IHI, supposed to be highly relevant to the transcallosal pathway, were present in the patient though they occurred to a relatively low degree compared to the control group. Findings suggest that in the ACC patient, the abnormal transcommissural fibers might be functional and serve as an alternative pathway connecting the bilateral hemispheres.

Stepwise Dual-Target Magnetic Resonance-Guided Focused Ultrasound in Tremor-Dominant Parkinson Disease: A Feasibility Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) has been applied successfully in treating refractory tremors in Parkinson disease (PD). It generates a precise thermal ablation in a specific nucleus or tract, such as ventral intermediate nucleus (VIM) or pallidothalamic tract (PTT). Despite a single lesion improving parts of the PD symptoms, the feasibility and efficacy of a stepwise dual-lesion in VIM and PTT are yet to be explored. METHODS: Three patients with tremor-dominant PD (aged 60.7 ± 6.0 years) received dual-target MRgFUS treatment with a series of primary and secondary outcome measures. The VIM and PTT were navigated based on individual magnetic resonance imaging planning of the brain. The primary outcome measures were the off-status Clinical Rating Scale for Tremor and Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The secondary outcome measures included UPDRS I, II, IV, Hohen and Yahr score, Neuropsychiatry Inventory, Quality of life in PD Rating Scale, Non-Motor Symptoms Scale, and Clinical Global Impression. The baseline data were compared with those acquired 1 day and 1 month following the treatment. RESULTS: The severity of tremor and motor deficits represented by Clinical Rating Scale for Tremor-part B and UPDRS III were significantly improved (P < 0.05 by nonparametric Mann-Whitney U tests) after dual-target ablations. The nonmotor symptoms investigated by UPDRS II and Non-Motor Symptoms Scale also showed significant improvement at the 1-day and 1-month follow-up. There was no adverse effect except temporary procedure-related headache and dizziness during the treatment. CONCLUSIONS: Stepwise dual-lesion targeting VIM and PTT is a safe and effective MRgFUS therapeutic strategy for patients with PD.

The Rehabilitative Effect of Archery Exercise Intervention in Patients with Parkinson's Disease.

Background: Archery exercise exerts a rehabilitative effect on patients with paraplegia and might potentially serve as complementary physiotherapy for patients with Parkinson's disease. Objective: This study aimed to examine the rehabilitative effects of an archery intervention. Methods: A randomized controlled trial of a 12-week intervention was performed in patients with idiopathic Parkinson's disease. Thirty-one of the 39 eligible patients recruited from a medical center in Taiwan participated in the trial, of whom 16 were in the experimental group practicing archery exercises and 15 were in the control group at the beginning; twenty-nine completed the whole process. The Purdue pegboard test (PPT), the Unified Parkinson's Disease Rating Scale I to III (UPDRS I to III), physical fitness test, and timed up and go test (TUG) were used to assess the intervention effects of archery exercise. Results: Compared to the control group, the outcome differences between the posthoc and baseline tests in PPT, UPDRS I to III, lower extremity muscular strength, and TUG in the experimental group (between-group difference in difference's mean: 2.07, 1.59, 1.36, -2.25, -3.81, -9.10, 3.57, and -1.51, respectively) did show positive changes and their effect sizes examined from Mann-Whitney U tests (η: 0.631, 0.544, 0.555, 0.372, 0.411, 0.470, 0.601, and 0.381, respectively; Ps < 0.05) were medium to large, indicating that the archery intervention exerted promising effects on improving hand flexibility and finger dexterity, activity functions in motor movement, lower extremity muscular strength, and gait and balance ability. Conclusions: Traditional archery exercise was suggested to have a rehabilitative effect for mild to moderate Parkinson's disease and could be a form of physiotherapy. Nevertheless, studies with larger sample sizes and extended intervention periods are needed to ascertain the long-term effects of archery exercise.

State-dependent and timing-dependent bidirectional associative plasticity in the human SMA-M1 network.

The supplementary motor area (SMA-proper) plays a key role in the preparation and execution of voluntary movements. Anatomically, SMA-proper is densely reciprocally connected to primary motor cortex (M1), but neuronal coordination within the SMA-M1 network and its modification by external perturbation are not well understood. Here we modulated the SMA-M1 network using MR-navigated multicoil associative transcranial magnetic stimulation in healthy subjects. Changes in corticospinal excitability were assessed by recording motor evoked potential (MEP) amplitude bilaterally in a hand muscle. We found timing-dependent bidirectional Hebbian-like MEP changes during and for at least 30 min after paired associative SMA-M1 stimulation. MEP amplitude increased if SMA stimulation preceded M1 stimulation by 6 ms, but decreased if SMA stimulation lagged M1 stimulation by 15 ms. This associative plasticity in the SMA-M1 network was highly topographically specific because paired associative stimulation of pre-SMA and M1 did not result in any significant MEP change. Furthermore, associative plasticity in the SMA-M1 network was strongly state-dependent because it required priming by near-simultaneous M1 stimulation to occur. We conclude that timing-dependent bidirectional associative plasticity is demonstrated for the first time at the systems level of a human corticocortical neuronal network. The properties of this form of plasticity are fully compatible with spike-timing-dependent plasticity as defined at the cellular level. The necessity of priming may reflect the strong interhemispheric connectivity of the SMA-M1 network. Findings are relevant for better understanding reorganization and potentially therapeutic modification of neuronal coordination in the SMA-M1 network after cerebral lesions such as stroke.

Homeostatic metaplasticity of corticospinal excitatory and intracortical inhibitory neural circuits in human motor cortex.

Homeostatic metaplasticity, a fundamental principle for maintaining overall synaptic weight in the physiological range in neuronal networks, was demonstrated at the cellular and systems level predominantly for excitatory synaptic neurotransmission. Although inhibitory networks are crucial for regulating excitability, it is largely unknown to what extent homeostatic metaplasticity of inhibition also exists. Here, we employed intermittent and continuous transcranial magnetic theta burst stimulation (iTBS, cTBS) of the primary motor cortex in healthy subjects for induction of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity. We studied metaplasticity by testing the interactions of priming TBS with LTP/LTD-like plasticity induced by subsequent test TBS. Changes in excitatory neurotransmission were measured by the input-output curve of motor-evoked potentials (IO-MEP), and changes in GABA(A)ergic inhibitory neurotransmission by the IO of short-interval intracortical inhibition (IO-SICI, four conditioning stimulus intensities of 70-100% active motor threshold, interstimulus interval 2.0 ms). Non-primed iTBS increased IO-MEP, while non-primed cTBS decreased IO-MEP. Pairing of identical protocols (iTBSiTBS, cTBScTBS) resulted in suppression of the non-primed TBS effects on IO-MEP, and pairing of different protocols (cTBSiTBS, iTBScTBS) enhanced the test TBS effects on IO-MEP. While non-primed TBS did not result in significant changes of IO-SICI, iTBSiTBS resulted in IO-SICI decrease, and cTBScTBS in IO-SICI increase compared with the non-primed conditions. The changes in SICI induced by priming TBS correlated with the changes in MEP induced by subsequent test TBS. Findings demonstrate that plasticity in both excitatory and inhibitory circuits in the human motor cortex are regulated by homeostatic metaplasticity, and that priming effects on inhibition contribute to the homeostatic regulation of metaplasticity in excitatory circuits.

Movement related cortical potentials of cued versus self-initiated movements: double dissociated modulation by dorsal premotor cortex versus supplementary motor area rTMS.

The dorsal premotor cortex (PMd) is thought to play a significant role in movement preparation cued by sensory information rather than in self-initiated movements. The evidence in humans for this contention is still circumstantial. Here we explored the effects of modulation of PMd by excitability decreasing 1 Hz repetitive transcranial magnetic stimulation (rTMS) versus excitability increasing 5 Hz rTMS on two forms of movement related cortical potentials: contingent negative variation (CNV) versus Bereitschaftspotential (BP) reflecting externally cued versus self-triggered movement preparation. Ten healthy right-handed subjects performed visually cued or self-triggered simple sequential finger movements with their right hand. CNV and BP were recorded by 25 EEG electrodes covering the fronto-centro-parietal cortex and divided into an early (1500-500 ms before a go-signal or movement onset) and a late potential (500-0 ms). MRI-navigated 1 Hz rTMS of the left PMd resulted in significant increase of the late CNV over the left central region predominantly contralateral to the prepared right hand movement, while 5 Hz rTMS had no effect on CNV. In contrast, 1 and 5 Hz rTMS did not modify BP. Control experiments of 1 Hz rTMS of the supplementary motor area (SMA) and of low-intensity 1 Hz rTMS of the left primary motor cortex did not change CNV, but 1 Hz SMA-rTMS increased late BP. This double dissociation of effects of PMd-rTMS versus SMA-rTMS on CNV versus BP provides direct evidence that the left PMd in humans is more involved in preparatory processes of externally cued rather than self-initiated movements, contrasting with an opposite role of the SMA.

Effective connectivity between human supplementary motor area and primary motor cortex: a paired-coil TMS study.

The supplementary motor area (SMA) is important for preparation and execution of voluntary movements and densely anatomically connected with the hand area of primary motor cortex (M1). However, little is known about the effective connectivity between SMA and ipsilateral M1 (SMA â†’ M1). Here, we used paired-coil transcranial magnetic stimulation (pcTMS) to study the SMA â†’ M1 effective connectivity in healthy human subjects. In Experiment 1, we tested the effects of different induced current directions in the SMA and M1, and different intensities of conditioning SMA stimulation. Coil placement over the SMA-proper was verified by MRI-navigation. We found a SMA â†’ M1 facilitatory effect on motor evoked potential (MEP) amplitude that occurred very specifically only with an induced conditioning current directed from the midline towards the targeted SMA, an induced test current in M1 directed antero-medially and sufficient intensity of conditioning SMA stimulation. In Experiment 2, we selected these effective parameters to explore the effects of SMA â†’ M1 on the active MEP amplitude, cortical silent period (CSP) duration, and using a triple-pulse protocol, on short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). None of these measures was affected by conditioning SMA stimulation. Our findings demonstrate that pcTMS identifies predominantly facilitatory connections from SMA-proper to the hand area of the ipsilateral M1. The successful activation of this connection depends on effective SMA-proper stimulation, is state dependent and likely mediated via excitatory interneurons in M1.

The neuromuscular responses in patients with Parkinson's disease under different conditions during whole-body vibration training.

BACKGROUND: Whole-body vibration (WBV) training can provoke reactive muscle response and thus exert beneficial effects in various neurological patients. This study aimed to investigate the muscles activation and acceleration transmissibility of the lower extremity to try to understand the neuromuscular control in the Parkinson's disease (PD) patients under different conditions of the WBV training, including position and frequency. METHODS: Sixteen PD patients and sixteen controls were enrolled. Each of them would receive two WBV training sessions with 3 and 20 Hz mechanical vibration in separated days. In each session, they were asked to stand on the WBV machine with straight and then bended knee joint positions, while the vibration stimulation was delivered or not. The electromyographic (EMG) signals and the segmental acceleration from the lower extremity were recorded and processed. The amplitude, co-contraction indexes (CCI), and normalized median frequency slope (NMFS) from the EMG signals, and the acceleration transmissibility were calculated. RESULTS: The results showed larger rectus femoris (RF) amplitudes under 3 Hz vibration than those in 20 Hz and no vibration conditions; larger tibialis anterior (TA) in 20 Hz than in no vibration; larger gastrocnemius (GAS) in 20 Hz than in 3 Hz and no vibration. These results indicated that different vibration frequencies mainly induced reactive responses in different muscles, by showing higher activation of the knee extensors in 3 Hz and of the lower leg muscles in 20 Hz condition, respectively. Comparing between groups, the PD patients reacted to the WBV stimulation by showing larger muscle activations in hamstring (HAM), TA and GAS, and smaller CCI in thigh than those in the controls. In bended knee, it demonstrated a higher RF amplitude and a steeper NMFS but smaller HAM activations than in straight knee position. The higher acceleration transmissibility was found in the control group, in the straight knee position and in the 3 Hz vibration conditions. CONCLUSION: The PD patients demonstrated altered neuromuscular control compared with the controls in responding to the WBV stimulations, with generally higher EMG amplitude of lower extremity muscles. For designing WBV strengthening protocol in the PD population, the 3 Hz with straight or flexed knee protocol was recommended to recruit more thigh muscles; the bended knee position with 20 Hz vibration was for the shank muscles.

Modulation of excitability in human primary somatosensory and motor cortex by paired associative stimulation targeting the primary somatosensory cortex.

Input from primary somatosensory cortex (S1) to primary motor cortex (M1) is important for high-level motor performance, motor skill learning and motor recovery after brain lesion. This study tested the effects of manipulating S1 excitability with paired associative transcranial stimulation (S1-PAS) on M1 excitability. Given the important role of S1 in sensorimotor integration, we hypothesized that changes in S1 excitability would be directly paralleled by changes in M1 excitability. We applied two established protocols (S1-PAS(LTP) and S1-PAS(LTD) ) to the left S1 to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like plasticity. S1 excitability was assessed by the early cortical components (N20-P25) of the median nerve somatosensory-evoked potential. M1 excitability was assessed by motor-evoked potential amplitude and short-interval intracortical inhibition. Effects of S1-PAS(LTP) were compared with those of a PAS(LTP) protocol targeting the left M1 (M1-PAS(LTP) ). S1-PAS(LTP) and S1-PAS(LTD) did not result in significant modifications of S1 or M1 excitability at the group level due to substantial interindividual variability. The individual S1-PAS-induced changes in S1 and M1 excitability showed no correlation. Furthermore, the individual changes in S1 and M1 excitability induced by S1-PAS(LTP) did not correlate with changes in M1 excitability induced by M1-PAS(LTP) . This demonstrates that the effects of S1-PAS in S1 are variable across individuals and, within a given individual, unrelated to those induced by S1-PAS or M1-PAS in M1. Potentially, this extends the opportunities of therapeutic PAS applications because M1-PAS 'non-responders' may well respond to S1-PAS.

Bereitschaftspotential in Multiple System Atrophy.

Objective: Multiple system atrophy (MSA) is a neurodegenerative disorder manifesting as parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is categorized into MSA with predominant parkinsonism (MSA-P) and into MSA with predominant cerebellar ataxia (MSA-C). The pathophysiology of motor control circuitry involvement in MSA subtype is unclear. Bereitschaftspotential (BP) is a feasible clinical tool to measure electroencephalographic activity prior to volitional motions. We recorded BP in patients with MSA-P and MSA-C to investigate their motor cortical preparation and activation for volitional movement. Methods: We included eight patients with MSA-P, eight patients with MSA-C, and eight age-matched healthy controls. BP was recorded during self-paced rapid wrist extension movements. The electroencephalographic epochs were time-locked to the electromyography onset of the voluntary wrist movements. The three groups were compared with respect to the mean amplitudes of early (1,500-500 ms before movement onset) and late (500-0 ms before movement onset) BP. Results: Mean early BP amplitude was non-significantly different between the three groups. Mean late BP amplitude in the two patient groups was significantly reduced in the parietal area contralateral to the movement side compared with that in the healthy control group. In addition, the late BP of the MSA-C group but not the MSA-P group was significantly reduced at the central parietal area compared with that of the healthy control group. Conclusions: Our findings suggest that patients with MSA exhibit motor cortical dysfunction in voluntary movement preparation and activation. The dysfunction can be practicably evaluated using late BP, which represents the cerebello-dentato-thalamo-cortical pathway.

Transient receptor potential V1 modulates neuroinflammation in Parkinson's disease dementia: Molecular implications for electroacupuncture and rivastigmine.

OBJECTIVES: Parkinson's disease (PD) is a common progressive neurodegeneration disease. Its incidence increases with age and affects about 1% of people over 60. Incidentally, transient receptor potential V1 (TRPV1) and its relation with neuroinflammation in mouse brain has been widely reported. MATERIALS AND METHODS: We used 6-hydroxydopamine (6-OHDA) to induce PDD in mice. We then used the Morris water maze and Bio-Plex to test learning and inflammatory mediators in mouse plasma. Western blotting and immunostaining were used to examine TRPV1 pathway in the hippocampus and medial prefrontal cortex (mPFC). RESULTS: On acquisition days 3 (Control = 4.40 ± 0.8 sec, PDD = 9.82 ± 1.52 sec, EA = 5.04 ± 0.58 sec, Riva = 4.75 ± 0.87 sec; P=0.001) and 4, reversal learning days 1, 2, 3 (Control = 2.86 ± 0.46 sec, PDD = 9.80 ± 1.83 sec, EA = 4.6 ± 0.82 sec, Riva = 4.6 ± 1.03 sec; P=0.001) and 4, PDD mice showed significantly longer escape latency than the other three groups. Results showed that several cytokines were up-regulated in PDD mice and reversed by EA and rivastigmine. TRPV1 and downstream molecules were up-regulated in PDD mice and further reversed by EA and rivastigmine. Interestingly, α7 nicotinic receptors and parvalbumin levels in both the hippocampus and prefrontal cortex increased in EA-treated mice, but not in rivastigmine-treated mice. CONCLUSION: Our results showed that TRPV1 played a role in the modulation of neuroinflammation of PDD, and could potentially be a new target for treatment.

Gait-Related Brain Activation During Motor Imagery of Complex and Simple Ambulation in Parkinson's Disease With Freezing of Gait.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is a devastating clinical phenomenon that has a detrimental impact on patients. It tends to be triggered more often during turning (complex) than during forwarding straight (simple) walking. The neural mechanism underlying this phenomenon remains unclear and requires further elucidation. Objective: To investigate the differences in cerebral functional magnetic resonance imaging responses between PD patients with and without FOG during explicitly video-guided motor imagery (MI) of various complex (normal, freezing) and simple (normal, freezing) walking conditions. Methods: We recruited 34 PD patients, namely, 20 with FOG and 14 without FOG, and 15 normal controls. Participants underwent video-guided MI of turning and straight walking, with and without freezing, while their brain blood oxygen level-dependent (BOLD) activities were measured. Gait analysis was performed. Results: While comparing FOG turning with FOG straight walking, freezers showed higher activation of the superior occipital gyrus, left precentral gyrus, and right postcentral gyrus compared with non-freezers. Normal controls also manifest similar findings compared with non-freezers, except no difference was noted in occipital gyrus activity between the two groups. Freezers also displayed a higher effect size in the locomotor regions than non-freezers during imagery of normal turning. Conclusions: Our findings suggest that freezers require a higher drive of cortical and locomotion regions to overcome the overinhibition of the pathways in freezers than in non-freezers. Compared with simple walking, increased dorsal visual pathway and deep locomotion region activities might play pivotal roles in tackling FOG in freezers during complex walking.

Personalization of Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder According to the Existing Psychiatric Comorbidity.

Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) are evidenced-based treatments for patients with major depressive disorder (MDD) who fail to respond to standard first-line therapies. However, although various TMS protocols have been proven to be clinically effective, the response rate varies across clinical applications due to the heterogeneity of real-world psychiatric comorbidities, such as generalized anxiety disorder, posttraumatic stress disorder, panic disorder, or substance use disorder, which are often observed in patients with MDD. Therefore, individualized treatment approaches are important to increase treatment response by assigning a given patient to the most optimal TMS treatment protocol based on his or her individual profile. This literature review summarizes different rTMS or TBS protocols that have been applied in researches investigating MDD patients with certain psychiatric comorbidities and discusses biomarkers that may be used to predict rTMS treatment response. Furthermore, we highlight the need for the validation of neuroimaging and electrophysiological biomarkers associated with rTMS treatment responses. Finally, we discuss on which directions future efforts should focus for developing the personalization of the treatment of depression with rTMS or iTBS.