Search

Objective: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects., Methods: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested., Results: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task., Interpretation: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252., (© 2021 American Neurological Association.)

Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications., (© 2021. The Author(s).)

Transcranial static magnetic field stimulation (tSMS) has inhibitory neuromodulatory effects on the human brain. Most of the studies on static magnetic fields have been performed in vitro. To further understand the biological mechanisms of tSMS, we investigated the effects of in vivo tSMS on motor behavior in normal awake rats. The skull of a male Wistar rat was exposed and a polyethylene tube was attached to the skull using dental cement at the center of the motor cortex (n = 7) or the other cortex (n = 6). By attaching a cylindrical NdFeB neodymium magnet into the tube, in vivo tSMS (REAL) was performed. For SHAM, we applied a similar size non-magnetic stainless-steel cylinder. All rats received twice each SHAM and REAL stimulation every two days using a crossover design, and motor function was measured during the stimulation. Activity level and asymmetry of forelimb use were not affected, but less accurate movements in the horizontal ladder test were found in REAL stimulation of the motor cortex. This study shows that in vivo tSMS has inhibitory neuromodulatory effects on motor behavior depending on the stimulated region on the rat cortex., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Non-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability., Methods: Sixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition., Results: tDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity., Conclusions: Simultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect., Significance: The simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

During voluntary contractions, corticomuscular coherence (CMC) is thought to reflect a mutual interaction between cortical and muscle oscillatory activities, respectively measured by electroencephalography (EEG) and electromyography (EMG). However, it remains unclear whether CMC modulation would depend on the contribution of neural mechanisms acting at the spinal level. To this purpose, modulations of CMC were compared during submaximal isometric, shortening and lengthening contractions of the soleus (SOL) and the medial gastrocnemius (MG) with a concurrent analysis of changes in spinal excitability that may be reduced during lengthening contractions. Submaximal contractions intensity was set at 50% of the maximal SOL EMG activity. CMC was computed in the time-frequency domain between the Cz EEG electrode signal and the unrectified SOL or MG EMG signal. Spinal excitability was quantified through normalized Hoffmann (H) reflex amplitude. The results indicate that beta-band CMC and normalized H-reflex were significantly lower in SOL during lengthening compared with isometric contractions, but were similar in MG for all three muscle contraction types. Collectively, these results highlight an effect of contraction type on beta-band CMC, although it may differ between agonist synergist muscles. These novel findings also provide new evidence that beta-band CMC modulation may involve spinal regulatory mechanisms.

Non-invasive brain stimulation techniques including repetitive transcranial magnetic stimulation (rTMS), continuous theta-burst stimulation (cTBS), paired associative stimulation (PAS), and transcranial direct current stimulation (tDCS) have been applied over the cerebellum to induce plasticity and gain insights into the interaction of the cerebellum with neo-cortical structures including the motor cortex. We compared the effects of 1 Hz rTMS, cTBS, PAS and tDCS given over the cerebellum on motor cortical excitability and interactions between the cerebellum and dorsal premotor cortex / primary motor cortex in two within subject designs in healthy controls. In experiment 1, rTMS, cTBS, PAS, and tDCS were applied over the cerebellum in 20 healthy subjects. In experiment 2, rTMS and PAS were compared to sham conditions in another group of 20 healthy subjects. In experiment 1, PAS reduced cortical excitability determined by motor evoked potentials (MEP) amplitudes, whereas rTMS increased motor thresholds and facilitated dorsal premotor-motor and cerebellum-motor cortex interactions. TDCS and cTBS had no significant effects. In experiment 2, MEP amplitudes increased after rTMS and motor thresholds following PAS. Analysis of all participants who received rTMS and PAS showed that MEP amplitudes were reduced after PAS and increased following rTMS. rTMS also caused facilitation of dorsal premotor-motor cortex and cerebellum-motor cortex interactions. In summary, cerebellar 1 Hz rTMS and PAS can effectively induce plasticity in cerebello-(premotor)-motor pathways provided larger samples are studied.

Recently, modulatory effects of static magnetic field stimulation (tSMS) on excitability of the motor cortex have been reported. In our previous study we failed to replicate these results. It was suggested that the lack of modulatory effects was due to the use of an auditory oddball task in our study. Thus, we aimed to evaluate the role of an oddball task on the effects of tSMS on motor cortex excitability. In a within-subject-design we compared 10 minutes tSMS with and without oddball task. In one of the two sessions subjects had to solve an auditory oddball task during the exposure to the magnet, whereas there was no task during exposure in the other session. Motor cortex excitability was measured before and after tSMS. No modulation was observed in any condition. However, when data were pooled regarding the order of the sessions, a trend for an increase of excitability was observed in the first session compared to the second session. We now can rule out that the auditory oddball task destroys tSMS effects, as postulated. Our results rather suggest that fluctuations in the amplitudes of single pulse motor evoked potentials may possibly mask weak modulatory effects but may also lead to false positive results if the number of subjects in a study is too low. In addition, there might be a habituation effect to the whole procedure, resulting in less variability when subjects underwent the same experiment twice., Competing Interests: The authors have declared that no competing interests exist.

Purpose: This study is aimed at investigating the effect of low-intensity electrical stimulation on the voluntary activation level (VA) and the cortical facilitation/inhibition of quadriceps in people with chronic anterior cruciate ligament lesion., Methods: Twenty former athletes with unilateral ACL deficiencies (ACL group) and 20 healthy subjects (healthy control group) participated in the study. The quadriceps VA level, motor-evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) elicited by transcranial magnetic stimulation were tested before and after 30 minutes of low-intensity electrical stimulation (ES)., Results: Before ES, the quadriceps VA in the ACL lesion legs of the ACL group was lower compared to the legs of the healthy control group ( P < 0.05). The MEP sizes in the ACL lesion legs and the healthy control were not significantly different. The ACL lesion legs showed lower SICI and higher ICF compared to the healthy control group ( P < 0.05). After ES, the quadriceps VA level increased and the SICI-ICF was modulated only in the ACL lesion legs ( P < 0.05) but not in the healthy controls., Conclusions: Low-intensity ES can normalize the modulation of intracortical inhibition and facilitation, thereby ameliorating the activation failure in individuals with ACL lesion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wen-Tzu Tang et al.)

Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients., Materials and Methods: Eleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes' Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2)., Results: rTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed., Conclusion: This is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To understand striatal function, it is essential to know the functional organization of the numerous inputs targeting the diverse population of striatal neurons. Using optogenetics, we activated terminals from ipsi- or contralateral primary somatosensory cortex (S1) or primary motor cortex (M1), or thalamus while obtaining simultaneous whole-cell recordings from pairs or triplets of striatal medium spiny neurons (MSNs) and adjacent interneurons. Ipsilateral corticostriatal projections provided stronger excitation to fast-spiking interneurons (FSIs) than to MSNs and only sparse and weak excitation to low threshold-spiking interneurons (LTSIs) and cholinergic interneurons (ChINs). Projections from contralateral M1 evoked the strongest responses in LTSIs but none in ChINs, whereas thalamus provided the strongest excitation to ChINs but none to LTSIs. In addition, inputs varied in their glutamate receptor composition and their short-term plasticity. Our data revealed a highly selective organization of excitatory striatal afferents, which is determined by both pre- and postsynaptic neuronal identity., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults., Competing Interests: The authors have declared that no competing interests exist.

Neuropathic pain can be generated by chronic compression of dorsal root ganglion (CCD). Stimulation of primary motor cortex can disrupt the nociceptive sensory signal at dorsal root ganglion level and reduce pain behaviors. But the mechanism behind it is still implicit. Protein kinase C gamma is known as an essential enzyme for the development of neuropathic pain, and specific inhibitor of protein kinase C gamma can disrupt the sensory signal and reduce pain behaviors. Optogenetic stimulation has been emerged as a new and promising conducive method for refractory neuropathic pain. The aim of this study was to provide evidence whether optical stimulation of primary motor cortex can modulate chronic neuropathic pain in CCD rat model. Animals were randomly divided into CCD group, sham group, and control group. Dorsal root ganglion-compressed neuropathic pain model was established in animals, and knocking down of protein kinase C gamma was also accomplished. Pain behavioral scores were significantly improved in the short hairpin Protein Kinase C gamma knockdown CCD animals during optic stimulation. Ventral posterolateral thalamic firing inhibition was also observed during light stimulation on motor cortex in CCD animal. We assessed alteration of pain behaviors in pre-light off, stimulation-light on, and post-light off state. In vivo extracellular recording of the ventral posterolateral thalamus, viral expression in the primary motor cortex, and protein kinase C gamma expression in dorsal root ganglion were investigated. So, optical cortico-thalamic inhibition by motor cortex stimulation can improve neuropathic pain behaviors in CCD animal, and knocking down of protein kinase C gamma plays a conducive role in the process. This study provides feasibility for in vivo optogenetic stimulation on primary motor cortex of dorsal root ganglion-initiated neuropathic pain.

Objective: Although low-intensity transcranial ultrasound stimulation (TUS) enhances/suppresses neural oscillations and causes electroencephalography changes in the motor cortex, researchers have not clearly determined the manner in which the relative power and entropy of neural oscillations in the motor cortex vary with ultrasonic parameters, such as ultrasound intensity, stimulation duration (SD), and duty cycle., Methods: In this paper, we use the transcranial ultrasound of different parameters to stimulate the mouse motor cortex, cause tail muscle contraction and movement, and simultaneously record local field potentials (LFPs) in the mouse motor cortex. The relative power and entropy of the LFPs under different ultrasonic parameters are analyzed., Results: The relative power of the theta [4-8 Hz] frequency bands decreases with an increase in spatial-peak and pulse-average intensity (I sppa ) at 0-0.5 s and 0.5-1 s; the relative power of the gamma [30-45 Hz] frequency bands increases with an increase in I sppa at 0-0.5 s and 0.5-1 s; the relative power each of the gamma [30-45 Hz] and high gamma [55-100 Hz] frequency bands increases with an increase in the SD at 0-0.5 s and 0.5-1 s; the entropy values decrease with increases in I sppa and SD at 0-0.5 s., Conclusion: The relative power and entropy of neural oscillations in the motor cortex can be modulated by TUS with different parameters, namely, ultrasound intensity and stimulation duration.

Background and Objectives: Respiratory muscles dysfunction has been reported in COPD. Transcranial magnetic stimulation (TMS) has been used for assessing the respiratory corticospinal pathways particularly of diaphragm. We aimed to study the cortico-diaphragmatic motor system changes in COPD using TMS and to correlate the findings with the pulmonary function., Methods: A case control study recruited 30 stable COPD from the out-patient respiratory clinic of Main Alexandria University hospital- Egypt and 17 healthy control subjects who were subjected to spirometry. Cortical conduction of the diaphragm was performed by TMS to all participants followed by cervical magnetic stimulation of the phrenic nerve roots. Diaphragmatic resting motor threshold (DRMT), cortical motor evoked potential latency (CMEPL), CMEP amplitude (CMEPA), peripheral motor evoked potential latency (PMEPL), PMEP amplitude (PMEPA) and central motor conduction time (CMCT) were measured., Results: 66.7% of COPD patients had severe and very severe COPD with median age of 59 (55-63) years. There was statistically significant bilateral decrease in DRMT, CMEPA and PMEPA in COPD group versus healthy subjects and significant increase in CMEPL and PMEPL (p <0.01). Left CMCT was significantly prolonged in COPD group versus healthy subjects (p <0.0001) but not right CMCT. Further, there was significant increase in CMEPL and CMCT of left versus right diaphragm in COPD group (p = 0.003 and 0.001 respectively) that inversely correlated with FEV1% and FVC% predicted. Right and left DRMT were insignificantly different in COPD group (p >0.05) but positively correlated with FEV1/FVC, FEV1% and FVC% predicted., Conclusion: Central cortico-diaphragmatic motor system is affected in COPD patients with heterogeneity of both sides that is correlated with pulmonary function., Significance: Coticospinal pathway affection could be a factor for development of diaphragmatic dysfunction in COPD patients accordingly its evaluation could help in personalization of COPD management especially pulmonary rehabilitation programs., Competing Interests: The authors have declared that no competing interests exist.

Objective: Low-frequency low-intensity pulsed ultrasound (LIPUS) has emerged as a non-invasive neuromodulation tool. The aim of this study is to examine whether LIPUS stimulation of the motor cortex can improve parkinsonian motor deficit in a mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)., Methods: Acute Parkinson's disease (PD) mouse model is built by injection of MPTP (20 mg/kg) every 4 h in a total of four doses in one day. Mice are randomized into control, MPTP, sham-LIPUS+MPTP, and LIPUS+MPTP group. For LIPUS+MPTP group, 7 days of LIPUS (800 kHz, 10% duty cycle, 100-Hz pulse repetition frequency, 40 min/day) is delivered to the motor cortex. An open field test (OFT) is conducted on day 4 and a pole test on day 5, respectively. Striatal total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) are measured on day 8. The safety of LIPUS is verified using Hematoxylin and esosin (HE) staining and Nissl staining., Results: LIPUS treatment improves rearing number in the OFT on day 4 (n = 8, p = 0.037) and locomotor activity in the pole test on day 5 (n = 8, p = 0.007) compared with the sham-LIPUS+MPTP group. Moreover, LIPUS increases T-SOD (n = 7, p = 0.006) and GSH-PX (n = 7, p = 0.030) compared with the sham-LIPUS+MPTP group. In addition, HE and Nissl staining shows no brain tissue injury induced by LIPUS., Conclusion: These findings demonstrate that LIPUS may have neuromodulation effects in PD mice., Significance: LIPUS may provide a novel neuromodulation tool for PD treatment.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability for minutes to hours after the end of intervention. However, it has not been precisely determined to what extent cortical plasticity prevails spatially in the cortex. Recent studies have shown that rTMS induces changes in "interhemispheric" functional connectivity, the resting-state functional connectivity between the stimulated region and the symmetrically corresponding region in the contralateral hemisphere. In the present study, quadripulse stimulation (QPS) was applied to the index finger representation in the left primary motor cortex (M1), while the position of the stimulation coil was constantly monitored by an online navigator. After QPS application, resting-state functional magnetic resonance imaging was performed, and the interhemispheric functional connectivity was compared with that before QPS. A cluster of connectivity changes was observed in the stimulated region in the central sulcus. The cluster was spatially extended approximately 10 mm from the center [half width at half maximum (HWHM): approximately 3 mm] and was extended approximately 20 mm long in depth (HWHM: approximately 7 mm). A localizer scan of the index finger motion confirmed that the cluster of interhemispheric connectivity changes overlapped spatially with the activation related to the index finger motion. These results indicate that cortical plasticity in M1 induced by rTMS was relatively restricted in space and suggest that rTMS can reveal functional dissociation associated with adjacent small areas by inducing neural plasticity in restricted cortical regions., Competing Interests: The authors have declared that no competing interests exist.

Transcranial ultrasound stimulation (tUS) is a promising noninvasive approach to modulate brain circuits. While low-intensity tUS is putatively safe and has already been used for human participants, pre-clinical studies that aim to determine the effects of tUS on the brain still need to be carried out. Conventional tUS stimulation, however, requires the use of the anesthetized or immobilized animal model, which can place considerable restrictions on behavior. Thus, this work presents a portable, low cost, wireless system to achieve ultrasound brain stimulation in freely behaving animals. The tUS system was developed based on a commercial 16 MHz microcontroller and amplifier circuit. The acoustic wave with a central frequency of 450 kHz was generated from a 5mm PZT with a peak pressure of 426 kPa. The wireless tUS with a total weight of 20 g was placed on the back of the rat allowing the animal a full range of unimpeded motion. The mobile ultrasound system was able to induce a robust ear movement as a response to stimulation of the motor cortex. The outcome demonstrates the ability of wireless tUS to modulate the brain circuit of a freely behaving rat. The portability of the whole system provides a more natural environment for investigating the effect of tUS on behavior and chronic studies.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that may modulate cortical excitability, metabolite concentration, and human behaviour. The supplementary motor area (SMA) has been largely ignored as a potential target for tDCS neurorehabilitation but is an important region in motor compensation after brain injury with strong efferent connections to the primary motor cortex (M1). The objective of this work was to measure tissue metabolite changes in the human motor cortex immediately following tDCS. We hypothesized that bihemispheric tDCS would change levels of metabolites involved in neuromodulation including N-acetylaspartate (NAA), glutamate (Glu), and creatine (tCr). In this single-blind, randomized, cross-over study, fifteen healthy adults aged 21-60 participated in two 7T MRI sessions, to identify changes in metabolite concentrations by magnetic resonance spectroscopy. Immediately after 20 minutes of tDCS, there were no significant changes in metabolite levels or metabolite ratios comparing tDCS to sham. However there was a trend toward increased NAA/tCr concentration (p = 0.08) in M1 under the stimulating cathode. There was a strong, positive correlation between the change in the absolute concentration of NAA and the change in the absolute concentration of tCr (p<0.001) suggesting an effect of tDCS. Both NAA and creatine are important markers of neurometabolism. Our findings provide novel insight into the modulation of neural metabolites in the motor cortex immediately following application of bihemispheric tDCS., Competing Interests: The authors have declared that no competing interests exist.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neuropsychiatric conditions. However, the mechanisms underlying its mode of action are still unclear. This is the first rodent study using resting-state functional MRI (rs-fMRI) to examine low-intensity (LI) rTMS effects, in an effort to provide a direct means of comparison between rodent and human studies. Using anaesthetised Sprague-Dawley rats, rs-fMRI data were acquired before and after control or LI-rTMS at 1 Hz, 10 Hz, continuous theta burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS). Independent component analysis revealed LI-rTMS-induced changes in the resting-state networks (RSN): (i) in the somatosensory cortex, the synchrony of resting activity decreased ipsilaterally following 10 Hz and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS; (ii) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, a contralateral decrease in synchrony following BHFS, and an ipsilateral increase following cTBS; and (iii) hippocampal synchrony decreased ipsilaterally following 10 Hz, and bilaterally following 1 Hz stimulation and BHFS. The present findings demonstrate that LI-rTMS modulates functional links within the rat RSN with frequency-specific outcomes, and the observed changes are similar to those described in humans following rTMS.

Objective: Repetitive transcranial magnetic stimulation (rTMS) has been widely used to modulate the excitability of the cortical control of limbs muscles, but rarely in the cortical control of human masseter muscles. This study aims to investigate the effects of rTMS on masseter motor-neuron pool excitability in humans., Materials and Methods: A total of 20 healthy participants were selected and received a total of three rTMS sessions involving stimulation of the right masseter-motor complex: one session of 10-Hz rTMS, one session of 1-Hz rTMS and one session of sham rTMS at an intensity of 80% of the active motor threshold (AMT). The masseter AMT, motor-evoked potentials (MEPs), cortical-silent period (CSP), and short-interval intracortical inhibition (SICI) were measured before and after each rTMS session., Results: The masseter SICI was significantly decreased following 10-Hz rTMS, with no significant changes in AMT, MEPs or CSP. No significant differences in masseter AMT, MEPs, CSP or SICI were observed in either the 1-Hz, or sham rTMS groups., Conclusions: The present findings demonstrate that high-frequency rTMS increases masseter motor-neuron pool excitability., (Copyright © 2016. Published by Elsevier Ltd.)

Neural activity maintains representations that bridge past and future events, often over many seconds. Network models can produce persistent and ramping activity, but the positive feedback that is critical for these slow dynamics can cause sensitivity to perturbations. Here we use electrophysiology and optogenetic perturbations in the mouse premotor cortex to probe the robustness of persistent neural representations during motor planning. We show that preparatory activity is remarkably robust to large-scale unilateral silencing: detailed neural dynamics that drive specific future movements were quickly and selectively restored by the network. Selectivity did not recover after bilateral silencing of the premotor cortex. Perturbations to one hemisphere are thus corrected by information from the other hemisphere. Corpus callosum bisections demonstrated that premotor cortex hemispheres can maintain preparatory activity independently. Redundancy across selectively coupled modules, as we observed in the premotor cortex, is a hallmark of robust control systems. Network models incorporating these principles show robustness that is consistent with data.

Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble.

Low-intensity focused ultrasound induces neuronal activation via mechanisms that remain to be elucidated. We recorded local field potential fluctuations in the motor cortex in response to ultrasound stimulation of the somatosensory barrel cortex, comparing them to those recorded in response to optogenetic stimulation of interneurons and pyramidal neurons of the somatosensory cortex in the same animals. Comparison of the waveform produced by ultrasound stimulation to those produced by optogenetic stimulation revealed similarities between ultrasound-induced responses and optogenetically-induced responses to pyramidal cell stimulation, but not interneuron stimulation, which may indicate that ultrasound stimulation is mediated by excitation of cerebral cortical pyramidal neurons. Comparison of post mortem evoked responses to responses in living tissue confirmed the necessity for excitable tissue in the evoked response. Collectively, these experiments demonstrate an excitation-dependent response to low-frequency transdural ultrasound stimulation of cerebral cortical neuronal activity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation., Approach: Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject's cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E-field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET., Main Results: This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E-field vectors in the outward normal direction suggesting inhibitory responses., Significance: These results provide critical new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality.

Background: The main objective of this study was to evaluate the efficacy of integrating the blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) and diffusion tensor imaging (DTI) data into radiation treatment planning for high-grade gliomas located near the primary motor cortexes (PMCs) and corticospinal tracts (CSTs)., Methods: A total of 20 patients with high-grade gliomas adjacent to PMCs and CSTs between 2012 and 2014 were recruited. The bilateral PMCs and CSTs were located in the normal regions without any overlapping with target volume of the lesions. BOLD-fMRI, DTI and conventional MRI were performed on patients (Karnofsky performance score ≥ 70) before radical radiotherapy treatment. Four different imaging studies were conducted in each patient: a planning computed tomography (CT), an anatomical MRI, a DTI and a BOLD-fMRI. For each case, three treatment plans (3DCRT, IMRT and IMRT&#95;PMC&CST) were developed by 3 different physicists using the Pinnacle planning system., Results: Our study has shown that there was no significant difference between the 3DCRT and IMRT plans in terms of dose homogeneity, but IMRT displayed better planning target volume (PTV) dose conformity. In addition, we have found that the Dmax and Dmean to the ipsilateral and contralateral PMC and CST regions were considerably decreased in IMRT&#95;PMC&CST group (p < 0.001)., Conclusions: In conclusion, integration of BOLD-fMRI and DTI into radiation treatment planning is feasible and beneficial. With the assistance of the above-described techniques, the bilateral PMCs and CSTs adjacent to the target volume could be clearly marked as OARs and spared during treatment.

Transcranial direct current stimulation (tDCS) has been used as a useful interventional brain stimulation technique to improve unilateral upper-limb motor function in healthy humans, as well as in stroke patients. Although tDCS applications are supposed to modify the interhemispheric balance between the motor cortices, the tDCS after-effects on interhemispheric interactions are still poorly understood. To address this issue, we investigated the tDCS after-effects on interhemispheric inhibition (IHI) between the primary motor cortices (M1) in healthy humans. Three types of tDCS electrode montage were tested on separate days; anodal tDCS over the right M1, cathodal tDCS over the left M1, bilateral tDCS with anode over the right M1 and cathode over the left M1. Single-pulse and paired-pulse transcranial magnetic stimulations were given to the left M1 and right M1 before and after tDCS to assess the bilateral corticospinal excitabilities and mutual direction of IHI. Regardless of the electrode montages, corticospinal excitability was increased on the same side of anodal stimulation and decreased on the same side of cathodal stimulation. However, neither unilateral tDCS changed the corticospinal excitability at the unstimulated side. Unilateral anodal tDCS increased IHI from the facilitated side M1 to the unchanged side M1, but it did not change IHI in the other direction. Unilateral cathodal tDCS suppressed IHI both from the inhibited side M1 to the unchanged side M1 and from the unchanged side M1 to the inhibited side M1. Bilateral tDCS increased IHI from the facilitated side M1 to the inhibited side M1 and attenuated IHI in the opposite direction. Sham-tDCS affected neither corticospinal excitability nor IHI. These findings indicate that tDCS produced polarity-specific after-effects on the interhemispheric interactions between M1 and that those after-effects on interhemispheric interactions were mainly dependent on whether tDCS resulted in the facilitation or inhibition of the M1 sending interhemispheric volleys.