Contralateral Primary Motor Cortex Research Articles

Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain

L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson’s disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu2/3) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu2/3 activation, we performed autoradiographic binding with [3H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [3H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [3H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu2/3 receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia.

3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.

Aging alters functional connectivity of motor theta networks during sensorimotor reactions

ObjectiveBoth cognitive and primary motor networks alter with advancing age in humans. The networks activated in response to external environmental stimuli supported by theta oscillations remain less well explored. The present study aimed to characterize the effects of aging on the functional connectivity of response-related theta networks during sensorimotor tasks. MethodsElectroencephalographic signals were recorded in young and middle-to-older age adults during three tasks performed in two modalities, auditory and visual: a simple reaction task, a Go-NoGo task, and a choice-reaction task. Response-related theta oscillations were computed. The phase-locking value (PLV) was used to analyze the spatial synchronization of primary motor and motor control theta networks. ResultsPerformance was overall preserved in older adults. Independently of the task, aging was associated with reorganized connectivity of the contra-lateral primary motor cortex. In younger adults, it was synchronized with motor control regions (intra-hemispheric premotor/frontal and medial frontal). In older adults, it was only synchronized with intra-hemispheric sensorimotor regions. ConclusionsMotor theta networks of older adults manifest a functional decoupling between the response-generating motor cortex and motor control regions, which was not modulated by task variables. The overall preserved performance in older adults suggests that the increased connectivity within the sensorimotor network is associated with an excessive reliance on sensorimotor feedback during movement execution compensating for a deficient cognitive regulation of motor regions during sensorimotor reactions. SignificanceNew evidence is provided for the reorganization of motor networks during sensorimotor reactions already at the transition from middle to old age.

The Role of Perineuronal Nets in the Contralateral Hemisphere in the Electroacupuncture-Mediated Rehabilitation of Poststroke Dysphagia Mice.

Acupuncture at Lianquan (CV23) acupoint has been shown to improve swallowing function in poststroke dysphagia (PSD). This improvement is supposed to be associated with the regulation of neuronal activity in the contralateral primary motor cortex (M1), while the underlying mechanism still needs to be elucidated. Perineuronal nets (PNNs) are well-known to be involved in the regulation of neuronal activity. Thus, we here aimed to detect the role of PNNs in the contralateral M1 hemisphere in the electroacupuncture (EA)-mediated effect in male mice. The results were obtained from a combination of methods, including in vitro slice electrophysiological recording, in vivo electrophysiological recording, and immunofluorescent staining in male mice. These results showed a decrease of the excitatory postsynaptic currents (sEPSCs) and no alteration of the inhibitory postsynaptic currents (sIPSCs) in the GABAergic neurons and the tonic inhibition in the excitatory neurons in the contralateral M1 after stroke induction, and EA recovered the impaired sEPSCs in the GABAergic neurons. We further found that the effect of EA-induced increase of c-Fos expression, enhancement of spike firing, potentiation of sEPSCs in the excitatory neurons, and improvement of swallowing function were all blocked by the removal of PNNs in the contralateral M1. In conclusion, the PNNs in the contralateral M1 was suggested to be participated in stroke pathogenesis and might be associated with the EA-mediated swallowing function rehabilitation of PSD in male mice. Our study provides insight into how PNNs might be involved in the mechanism of EA treatment for stroke rehabilitation.

Regular cannabis use alters the neural dynamics serving complex motor control.

Cannabis is the most widely used recreational drug in the United States and regular use has been linked to deficits in attention and memory. However, the effects of regular use on motor control are less understood, with some studies showing deficits and others indicating normal performance. Eighteen users and 23 nonusers performed a motor sequencing task during high-density magnetoencephalography (MEG). The MEG data was transformed into the time-frequency domain and beta responses (16-24 Hz) during motor planning and execution phases were imaged separately using a beamformer approach. Whole-brain maps were examined for group (cannabis user/nonuser) and time window (planning/execution) effects. As expected, there were no group differences in task performance (e.g., reaction time, accuracy, etc.). Regular cannabis users exhibited stronger beta oscillations in the contralateral primary motor cortex compared to nonusers during the execution phase of the motor sequences, but not during the motor planning phase. Similar group-by-time window interactions were observed in the left superior parietal, right inferior frontal cortices, right posterior insular cortex, and the bilateral motor cortex. We observed differences in the neural dynamics serving motor control in regular cannabis users compared to nonusers, suggesting regular users may employ compensatory processing in both primary motor and higher-order motor cortices to maintain adequate task performance. Future studies will need to examine more complex motor control tasks to ascertain whether this putative compensatory activity eventually becomes exhausted and behavioral differences emerge.

Efficacy of Repetitive Transcranial Magnetic Stimulation on spasticity in Egyptian Multiple Sclerosis Patients

Background; One of the most common neurologic disorders is multiple sclerosis. To improve quality of life, many tools have been employed. Repetitive transcranial magnetic stimulation (rTMS) is a new established technique to treat spasticity and improve the outcome of rehabilitation program in various neurologic conditions. Aim and objectives; To assess the effect of high frequency rTMS on improving spasticity in a sample of Egyptian MS patients. Patients and methods; 40 patients were recruited from the MS unit at Al-Azhar University hospitals with established diagnosis of MS and spasticity. Recruitment started from beginning of Jan, 2022 for 6 months. Patients were then randomly allocated into two groups: Study Group: 20 patients received 12 sessions of high frequency (HF) rTMS over the period of 3 weeks, followed by physical therapy (PT) for 30 minutes. rTMS protocol: Contralateral primary motor cortex (M1) was the site of stimulation. 1500 pulses (50 pulses per train with total 30 trains) per session with an intensity of 90% of the resting motor threshold at a frequency of 10 Hz were received. Each train had duration of 30 sec with inter- train delay of 25 seconds. Control Group: 20 patients received only physical therapy (PT) of 30 minutes over the period of 3 weeks). Results: The both groups received their medical treatment and physiotherapy. Compared with the control group, the study group had a statistically significant improvement. Conclusion: High frequency r-TMS could be beneficial in reducing spasticity and enhancing motor recovery in Egyptian MS patients.

No Polarity-specific Modulation of Prefrontal-to-M1 Interhemispheric Inhibition by Transcranial Direct Current Stimulation Over the Lateral Prefrontal Cortex

The lateral prefrontal cortex (PFC) plays a variety of crucial roles in higher-order cognitive functions. Previous works have attempted to modulate lateral PFC function by applying non-invasive transcranial direct current stimulation (tDCS) and demonstrated positive effects on performance of tasks involving cognitive processes. The neurophysiological underpinning of the stimulation effects, however, remain poorly understood. Here, we explored the neurophysiological after-effects of tDCS over the lateral PFC by assessing changes in the magnitude of interhemispheric inhibition from the lateral PFC to the contralateral primary motor cortex (PFC-M1 IHI). Using a dual-site transcranial magnetic stimulation paradigm, we assessed PFC-M1 IHI before and after the application of tDCS over the right lateral PFC. We conducted a double-blinded, crossover, and counterbalanced design where 15 healthy volunteers participated in three sessions during which they received either anodal, cathodal, and sham tDCS. In order to determine whether PFC-M1 IHI could be modulated at all, we completed the same assessment on a separate group of 15 participants as they performed visuo-motor reaction tasks that likely engage the lateral PFC. The results showed that tDCS over the right lateral PFC did not modulate the magnitude of PFC-M1 IHI, whereas connectivity changed when Go/NoGo decisions were implemented in reactions during the motor tasks. Although PFC-M1 IHI is sensitive enough to be modulated by behavioral manipulations, tDCS over the lateral PFC does not have substantial modulatory effects on PFC to M1 functional connectivity, or at least not to the degree that can be detected with this measure.

Cortical Contributions to Imagined Power Grip Task: An EEG-Triggered TMS Study.

Previous studies have demonstrated that motor imagery leads to desynchronization in the alpha rhythm within the contralateral primary motor cortex. However, the underlying electrophysiological mechanisms responsible for this desynchronization during motor imagery remain unclear. To examine this question, we conducted an investigation using EEG in combination with noninvasive transcranial magnetic stimulation (TMS) during index finger abduction (ABD) and power grip imaginations. The TMS was administered employing diverse coil orientations to selectively stimulate corticospinal axons, aiming to target both early and late synaptic inputs to corticospinal neurons. TMS was triggered based on the alpha power levels, categorized in 20th percentile bins, derived from the individual alpha power distribution during the imagined tasks of ABD and power grip. Our analysis revealed negative correlations between alpha power and motor evoked potential (MEP) amplitude, as well as positive correlations with MEP latency across all coil orientations for each imagined task. Furthermore, we conducted functional network analysis in the alpha band to explore network connectivity during imagined index finger abduction and power grip tasks. Our findings indicate that network connections were denser in the fronto-parietal area during imagined ABD compared to power grip conditions. Moreover, the functional network properties demonstrated potential for effectively classifying between these two imagined tasks. These results provide functional evidence supporting the hypothesis that alpha oscillations may play a role in suppressing MEP amplitude and latency during imagined power grip. We propose that imagined ABD and power grip tasks may activate different populations and densities of axons at the cortical level.

Ischemic stroke rehabilitation through optogenetic modulation of parvalbumin neurons in the contralateral motor cortex

BackgroundBased on the theory of interhemispheric inhibition and the bimodal balance–recovery model in stroke, we explored the effects of excitation/inhibition (E/I) of parvalbumin (PV) neurons in the contralateral primary motor cortex (cM1) connecting the ipsilateral M1 (iM1) via the corpus callosum (cM1-CC-iM1) of ischemic stroke rats by optogenetic stimulation. MethodsWe tested this by injecting anterograde and retrograde virus in rats with middle cerebral artery occlusion (MCAO), and evaluated the neurological scores, motor behavior, volume of cerebral infarction and the E/I balance of the bilateral M1 two weeks after employing optogenetic treatment. ResultsWe found that concentrations of Glu and GABA decreased and increased, respectively, in the iM1 of MCAO rats, and that the former increased in the cM1, suggesting E/I imbalance in bilateral M1 after ischemic stroke. Interestingly, optogenetic stimulation improved M1 E/I imbalance, as illustrated by the increase of Glu in the iM1 and the decrease of GABA in both iM1 and cM1, which were accompanied by an improvement in neurological deficit and motor dysfunction. In addition, we observed a reduced infarct volume, an increase in the expression of the NMDAR and AMPAR, and a decrease in GAD67 in the iM1 after intervention. ConclusionsOptogenetic modulation of PV neurons of the iM1-CC-cM1 improve E/I balance, leading to reduced neurological deficit and improved motor dysfunction following ischemic stroke in rats.

Bilateral motor cortex functional differences in left-handed approaching-avoiding behavior.

Automatic action tendencies occur at behavioral and neurophysiological levels during task performance with the dominant right hand, with shorter reaction times (RTs) and higher excitability of the contralateral primary motor cortex (M1) during automatic vs. regulated behavior. However, effects associated with the non-dominant left-hand in approaching-avoiding behavior remain unclear. Here, we used transcranial magnetic stimulation during the performance by 18 participants of an approaching-avoiding task using the non-dominant left hand. Single-pulse transcranial magnetic stimulation was applied over left or right M1 at 150 and 300 ms after the onset of an emotional stimulus. RTs and motor-evoked potentials (MEPs) were recorded. Significant automatic action tendencies were observed at the behavioral level. Higher MEP amplitudes were detected 150 ms after stimulus onset from the right hand (non-task hand, corresponding to left M1) during regulated behavior compared with during automatic behavior. However, no significant modulation was found for MEP amplitudes from the left hand (task hand, corresponding to right M1). These findings suggested that left M1 may play a principal role in the early phase of mediating left-handed movement toward an emotional stimulus.

Effects of short-term arm immobilization on motor skill acquisition.

Learning to sequence movements is necessary for skillful interaction with the environment. Neuroplasticity, particularly long-term potentiation (LTP), within sensorimotor networks underlies the acquisition of motor skill. Short-term immobilization of the arm, even less than 12 hours, can reduce corticospinal excitability and increase the capacity for LTP-like plasticity within the contralateral primary motor cortex. However, it is still unclear whether short-term immobilization influences motor skill acquisition. The current study aimed to evaluate the effect of short-term arm immobilization on implicit, sequence-specific motor skill acquisition using a modified Serial Reaction Time Task (SRTT). Twenty young, neurotypical adults underwent a single SRTT training session after six hours of immobilization of the non-dominant arm or an equivalent period of no immobilization. Our results demonstrated that participants improved SRTT performance overall after training, but there was no evidence of an effect of immobilization prior to task training on performance improvement. Further, improvements on the SRTT were not sequence-specific. Taken together, motor skill acquisition for sequential, individuated finger movements improved following training but the effect of six hours of immobilization was difficult to discern.

Shouting strengthens voluntary force during sustained maximal effort through enhancement of motor system state via motor commands

Previous research indicates that shouting during momentary maximal exertion effort potentiates the maximal voluntary force through the potentiation of motor cortical excitability. However, the muscular force-enhancing effects of shouting on sustained maximal force production remain unclear. We investigated the effect of shouting on the motor system state by examining motor evoked potentials in response to transcranial magnetic stimulation applied over the hand area of the contralateral primary motor cortex (M1) during sustained maximal voluntary contraction, and by assessing handgrip maximal voluntary force. We observed that shouting significantly increased handgrip maximal voluntary force and reduced the silent period. Our results indicate that shouting increased handgrip voluntary force during sustained maximal exertion effort through the reduced silent period. This is the first objective evidence that the muscular force of shouting during maximal force exertion is associated with the potentiation of motor system activity produced by the additional drive of shouting operating on the motor system (i.e., shouting-induced excitatory input to M1).

Transcranial Direct Current Stimulation Targeting the Entire Motor Network Does Not Increase Corticospinal Excitability.

Transcranial direct current stimulation (tDCS) over the contralateral primary motor cortex of the target muscle (conventional tDCS) has been described to enhance corticospinal excitability, as measured with transcranial magnetic stimulation. Recently, tDCS targeting the brain regions functionally connected to the contralateral primary motor cortex (motor network tDCS) was reported to enhance corticospinal excitability more than conventional tDCS. We compared the effects of motor network tDCS, 2 mA conventional tDCS, and sham tDCS on corticospinal excitability in 21 healthy participants in a randomized, single-blind within-subject study design. We applied tDCS for 12 min and measured corticospinal excitability with TMS before tDCS and at 0, 15, 30, 45, and 60 min after tDCS. Statistical analysis showed that neither motor network tDCS nor conventional tDCS significantly increased corticospinal excitability relative to sham stimulation. Furthermore, the results did not provide evidence for superiority of motor network tDCS over conventional tDCS. Motor network tDCS seems equally susceptible to the sources of intersubject and intrasubject variability previously observed in response to conventional tDCS.

Origin of Multisynaptic Corticospinal Pathway to Forelimb Segments in Macaques and Its Reorganization After Spinal Cord Injury.

Removal of the monosynaptic corticospinal pathway (CSP) terminating within the forelimb segments severely impairs manual dexterity. Functional recovery from the monosynaptic CSP lesion can be achieved through the remaining multisynaptic CSP toward the forelimb segments. In the present study, we applied retrograde transsynaptic labeling with rabies virus to a monkey model of spinal cord injury. By injecting the virus into the spinal forelimb segments immediately after the monosynaptic CSP lesion, we showed that the contralateral primary motor cortex (M1), especially its caudal and bank region (so-called “new” M1), was the principal origin of the CSP linking the motor cortex to the spinal forelimb segments disynaptically (disynaptic CSP). This forms a striking contrast to the architecture of the monosynaptic CSP that involves extensively other motor-related areas, together with M1. Next, the rabies injections were made at the recovery period of 3 months after the monosynaptic CSP lesion. The second-order labeled neurons were located in the ipsilateral as well as in the contralateral “new” M1. This indicates that the disynaptic CSP input from the ipsilateral “new” M1 is recruited during the motor recovery from the monosynaptic CSP lesion. Our results suggest that the disynaptic CSP is reorganized to connect the ipsilateral “new” M1 to the forelimb motoneurons for functional compensation after the monosynaptic CSP lesion.

Cerebellar noninvasive neuromodulation influences the reactivity of the contralateral primary motor cortex and surrounding areas: a TMS-EMG-EEG study.

Understanding cerebellar-cortical physiological interactions is of fundamental importance to advance the efficacy of neurorehabilitation strategies for patients with cerebellar damage. Previous works have aimed to modulate this pathway by applying transcranial electrical or magnetic stimulation (TMS) over the cerebellum and probing the resulting changes in the primary motor cortex (M1) excitability with motor-evoked potentials (MEPs). While these protocols produce changes in cerebellar excitability, their ability to modulate MEPs has produced inconsistent results, mainly due to the MEP being a highly variable outcome measure that is susceptible to fluctuations in the excitability of M1 neurons and spinal interneurons. To overcome this limitation, we combined TMS with electroencephalography (EEG) to directly record TMS-evoked potentials (TEPs) and oscillations from the scalp. In three sessions, we applied intermittent theta-burst stimulation (iTBS), cathodal direct current stimulation (c-DC) or sham stimulation to modulate cerebellar activity. To assess the effects on M1 and nearby cortex, we recorded TMS-EEG and MEPs before, immediately after (T1) and 15min (T2) following cerebellar neuromodulation. We found that cerebellar iTBS immediately increased TMS-induced alpha oscillations and produced lasting facilitatory effects on TEPs, whereas c-DC immediately decreased TMS-induced alpha oscillations and reduced TEPs. We also found increased MEP following iTBS but not after c-DC. All of the TMS-EEG measures showed high test-retest repeatability. Overall, this work importantly shows that cerebellar neuromodulation influences both cortical and corticospinal physiological measures; however, they are more pronounced and detailed when utilizing TMS-EEG outcome measures. These findings highlight the advantage of using TMS-EEG over MEPs when assessing the effects of neuromodulation.

Motor planning brings human primary somatosensory cortex into action-specific preparatory states.

Motor planning plays a critical role in producing fast and accurate movement. Yet, the neural processes that occur in human primary motor and somatosensory cortex during planning, and how they relate to those during movement execution, remain poorly understood. Here, we used 7T functional magnetic resonance imaging and a delayed movement paradigm to study single finger movement planning and execution. The inclusion of no-go trials and variable delays allowed us to separate what are typically overlapping planning and execution brain responses. Although our univariate results show widespread deactivation during finger planning, multivariate pattern analysis revealed finger-specific activity patterns in contralateral primary somatosensory cortex (S1), which predicted the planned finger action. Surprisingly, these activity patterns were as informative as those found in contralateral primary motor cortex (M1). Control analyses ruled out the possibility that the detected information was an artifact of subthreshold movements during the preparatory delay. Furthermore, we observed that finger-specific activity patterns during planning were highly correlated to those during execution. These findings reveal that motor planning activates the specific S1 and M1 circuits that are engaged during the execution of a finger press, while activity in both regions is overall suppressed. We propose that preparatory states in S1 may improve movement control through changes in sensory processing or via direct influence of spinal motor neurons.

Longitudinal evaluations of somatosensory-motor inhibition in Dopa-responsive dystonia

IntroductionGCH1 mutations have been linked to decreased striatal dopamine and development of dopa-responsive dystonia (DRD) and Parkinsonism. Sensory and sensorimotor integration impairments have been documented in various forms of dystonia.DRD patients with confirmed GCH1 mutations have demonstrated normal short-latency afferent inhibition (SAI), a measure of sensorimotor inhibition, under chronic dopaminergic replacement therapy (DRT), but reduced inhibition after a single l-dopa dose following 24 h withdrawal. Studies have revealed normal SAI in other forms of dystonia but reductions with DRT in Parkinson's disease. Longitudinal changes in sensorimotor inhibition are unknown. MethodsWe analyzed sensorimotor inhibition using two different measures: SAI and somatosensory-motor inhibition using dual-site transcranial magnetic stimulation (ds-TMS). SAI was measured using digit stimulation 25 ms prior to contralateral primary motor cortex (M1) TMS. DS-TMS was measured using TMS over the somatosensory cortex 1 or 2.5 ms prior to ipsilateral M1 stimulation.A total of 20 GCH1 mutation carriers and 20 age-matched controls were included in the study. SAI and ds-TMS were evaluated in GCH1 mutation carriers both OFF and ON DRT compared to controls. Furthermore, longitudinal changes of SAI were examined in a subset of the same individuals that were measured ∼five years earlier. ResultsNeither SAI nor ds-TMS were significantly different in GCH1 mutation carriers relative to controls. No effects of DRT on SAI or ds-TMS were seen but SAI decreased over time in mutation carriers OFF DRT. ConclusionOur longitudinal results suggest changes in SAI that could be associated with plasticity changes in sensorimotor networks.

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning.In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27).We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power.These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.

Somatosensory inputs modulate the excitability of cerebellar-cortical interaction

ObjectiveTranscranial magnetic stimulation (TMS) delivered over the cerebellum 5–7 ms prior to a stimulus over the contralateral primary motor cortex (M1) reduces the excitability of M1 output, a phenomenon termed cerebellar brain inhibition (CBI). The cerebellum receives sensory information for adaptive motor coordination and motor planning. Here, we explored through TMS whether a peripheral electrical stimulus modulates CBI. MethodsWe studied the effect of right median nerve electrical stimulation (ES) on CBI from right cerebellum (conditioning stimulus, CS) to left M1 (test stimulus, TS) in 12 healthy subjects. The following ES-CS inter-stimulus intervals (ISIs) were tested: 25, 30 and 35 ms. CS-TS ISI was set at 5 ms. ResultsWe found significantly weaker CBI when the ES was delivered 25 ms (p < 0.001) and 35 ms (p < 0.001) earlier the CS over the ipsilateral cerebellum and a trend for 30 ms ES-CS ISI (p = 0.07). ConclusionsWe hypothesize that the activation of cerebellar interneurons together with intrinsic properties of Purkinje cells may be responsible of the decreased CBI when the peripheral stimulation preceded the cerebellar stimulation of 25 and 35 ms. SignificanceTo test the interaction between somatosensory inputs and cerebello-cortical pathway may be important in a variety of motor tasks and neuropsychiatric disorders.

Shouting strengthens maximal voluntary force and is associated with augmented pupillary dilation

Previous research has demonstrated that human maximal voluntary force is generally limited by neural inhibition. Producing a shout during maximal exertion effort enhances the force levels of maximal voluntary contraction. However, the mechanisms underlying this enhancement effect on force production remain unclear. We investigated the influence of producing a shout on the pupil-linked neuromodulatory system state by examining pupil size. We also examined its effects on the motor system state by examining motor evoked potentials in response to transcranial magnetic stimulation applied over the contralateral primary motor cortex, and by evaluating handgrip maximal voluntary force. Analysis revealed that producing a shout significantly increased handgrip maximal voluntary force, followed by an increase in pupil size and a reduction of the cortical silent period. Our results indicate that producing a shout increased handgrip maximal voluntary force through the enhancement of motor cortical excitability, possibly via the enhancement of noradrenergic system activity. This study provides evidence that the muscular force-enhancing effect of shouting during maximal force exertion is related to both the motor system state and the pupil-linked neuromodulatory system state.