Transcranial alternating current stimulation does not modulate corticospinal activity in humans

Transcranial alternating current stimulation (TACS) is commonly used to synchronise the output of a cortical area to other parts of the nervous system, but evidence for this based on brain recordings in humans is challenging. The brain transmits beta oscillations (~21Hz) to tonically contracted limb muscles linearly and through the fastest corticospinal pathways. Therefore, muscle activity may be used as a proxy measure for the level of beta entrainment in the corticospinal tract due to TACS over motor cortex. Here, we assessed if TACS is able to modulate the neural inputs to muscles, which would provide an indirect evidence for TACS-driven neural entrainment. In the first part of this study, we ran a series of simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results indicated that MNs should be highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N=10) in which TACS (at 1mA) was delivered over the motor cortex at 21Hz (beta stimulation), or at 7Hz or 40Hz (control conditions) while the abductor digiti minimi (ADM) or the tibialis anterior muscle (TA) were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the spiking activity of pools of motor units innervating the studied muscles. By analysing motor unit pool activity, we observed that none of the tested TACS conditions could consistently alter the spectral characteristics of the common neural inputs received by the muscles. These results suggest that 1mA-TACS over motor cortex given at frequencies in the beta band does not affect corticospinal beta entrainment.

Automatic Radiotherapy Planning for Glioblastoma Radiotherapy With Sparing of the Hippocampus and nTMS-Defined Motor Cortex

BackgroundNavigated transcranial magnetic stimulation (nTMS) of the motor cortex has been successfully implemented into radiotherapy planning by a number of studies. Furthermore, the hippocampus has been identified as a radiation-sensitive structure meriting particular sparing in radiotherapy. This study assesses the joint protection of these two eloquent brain regions for the treatment of glioblastoma (GBM), with particular emphasis on the use of automatic planning.Patients and MethodsPatients with motor-eloquent brain glioblastoma who underwent surgical resection after nTMS mapping of the motor cortex and adjuvant radiotherapy were retrospectively evaluated. The radiotherapy treatment plans were retrieved, and the nTMS-defined motor cortex and hippocampus contours were added. Four additional treatment plans were created for each patient: two manual plans aimed to reduce the dose to the motor cortex and hippocampus by manual inverse planning. The second pair of re-optimized plans was created by the Auto-Planning algorithm. The optimized plans were compared with the “Original” plan regarding plan quality, planning target volume (PTV) coverage, and sparing of organs at risk (OAR).ResultsA total of 50 plans were analyzed. All plans were clinically acceptable with no differences in the PTV coverage and plan quality metrics. The OARs were preserved in all plans; however, overall the sparing was significantly improved by Auto-Planning. Motor cortex protection was feasible and significant, amounting to a reduction in the mean dose by >6 Gy. The dose to the motor cortex outside the PTV was reduced by >12 Gy (mean dose) and >5 Gy (maximum dose). The hippocampi were significantly improved (reduction in mean dose: ipsilateral >6 Gy, contralateral >4.6 Gy; reduction in maximum dose: ipsilateral >5 Gy, contralateral >5 Gy). While the dose reduction using Auto-Planning was generally better than by manual optimization, the radiated total monitor units were significantly increased.ConclusionConsiderable dose sparing of the nTMS-motor cortex and hippocampus could be achieved with no disadvantages in plan quality. Auto-Planning could further contribute to better protection of OAR. Whether the improved dosimetric protection of functional areas can translate into improved quality of life and motor or cognitive performance of the patients can only be decided by future studies.

The Excitability of Ipsilateral Motor Evoked Potentials Is Not Task-specific and Spatially Distinct From the Contralateral Motor Hotspot

ObjectiveThe role of ipsilateral descending motor pathways in voluntary movement of humans is still a matter of debate. Few studies have examined the task dependent modulation of ipsilateral motor evoked potentials (iMEPs). Here, we determined the location of upper limb biceps brachii (BB) representation within the ipsilateral primary motor cortex. MethodsMR-navigated transcranial magnetic stimulation mapping of the dominant hemisphere was undertaken with twenty healthy participants who made tonic unilateral, bilateral homologous or bilateral antagonistic elbow flexion-extension voluntary contractions. Map center of gravity (CoG) and area for each BB were obtained. ResultsThe map CoG of the ipsilateral BB was located more anterior-laterally than those of the contralateral BB within the primary motor cortex. However different tasks had no effect on either the iMEP CoG location or the size. ConclusionOur data suggests that ipsilateral and contralateral MEP might originate in distinct adjacent neural populations in the primary motor cortex, independent of task dependence.

Impact of interhemispheric inhibition on bimanual movement control in young and old

Interhemispheric interactions demonstrate a crucial role for directing bimanual movement control. In humans, a well-established paired-pulse transcranial magnetic stimulation paradigm enables to assess these interactions by means of interhemispheric inhibition (IHI). Previous studies have examined changes in IHI from the active to the resting primary motor cortex during unilateral muscle contractions; however, behavioral relevance of such changes is still inconclusive. In the present study, we evaluated two bimanual tasks, i.e., mirror activity and bimanual anti-phase tapping, to examine behavioral relevance of IHI for bimanual movement control within this behavioral framework. Two age groups (young and older) were evaluated as bimanual movement control demonstrates evident behavioral decline in older adults. Two types of IHI with differential underlying mechanisms were measured; IHI was tested at rest and during a motor task from the active to the resting primary motor cortex. Results demonstrate an association between behavior and short-latency IHI in the young group: larger short-latency IHI correlated with better bimanual movement control (i.e., less mirror activity and better bimanual anti-phase tapping). These results support the view that short-latency IHI represents a neurophysiological marker for the ability to suppress activity of the contralateral side, likely contributing to efficient bimanual movement control. This association was not observed in the older group, suggesting age-related functional changes of IHI. To determine underlying mechanisms of impaired bimanual movement control due to neurological disorders, it is crucial to have an in-depth understanding of age-related mechanisms to disentangle disorder-related mechanisms of impaired bimanual movement control from age-related ones.

Shaping the Sensory–Motor Network by Short-Term Unresolvable Sensory–Motor Mismatch

Learning from errors as the main mechanism for motor adaptation has two fundamental prerequisites: a mismatch between the intended and performed movement and the ability to adapt motor actions. Many neurological patients are limited in their ability to transfer an altered motor representation into motor action due to a compromised motor pathway. Studies that have investigated the effects of a sustained and unresolvable mismatch over multiple days found changes in brain processing that seem to optimize the potential for motor learning (increased drive for motor adaptation and a weakening of the current implementation of motor programs). However, it remains unclear whether the observed effects can be induced experimentally and more important after shorter periods. Here, we used task-based and resting-state fMRI to investigate whether the known pattern of cortical adaptations due to a sustained mismatch can be induced experimentally by a short (20 min), but unresolvable, sensory–motor mismatch by impaired facial movements in healthy participants by transient facial tapping. Similar to long-term mismatch, we found plastic changes in a network that includes the striatal, cerebellar and somatosensory brain areas. However, in contrast to long-term mismatch, we did not find the involvement of the cerebral motor cortex. The lack of the involvement of the motor cortex can be interpreted both as an effect of time and also as an effect of the lack of a reduction in the motor error. The similar effects of long-term and short-term mismatch on other parts of the sensory–motor network suggest that the brain-state caused by long-term mismatch can be (at least partly) induced by short-term mismatch. Further studies should investigate whether short-term mismatch interventions can be used as therapeutic strategy to induce an altered brain-state that increase the potential for motor learning.

Aging-Related Changes in Cortical Sources of Sleep Oscillatory Neural Activity Following Motor Learning Reflect Contributions of Cortical Thickness and Pre-sleep Functional Activity

Oscillatory neural activity during sleep, such as that in the delta and sigma bands, is important for motor learning consolidation. This activity is reduced with typical aging, and this reduction may contribute to aging-related declines in motor learning consolidation. Evidence suggests that brain regions involved in motor learning contribute to oscillatory neural activity during subsequent sleep. However, aging-related differences in regional contributions to sleep oscillatory activity following motor learning are unclear. To characterize these differences, we estimated the cortical sources of consolidation-related oscillatory activity using individual anatomical information in young and older adults during non-rapid eye movement sleep after motor learning and analyzed them in light of cortical thickness and pre-sleep functional brain activation. High-density electroencephalogram was recorded from young and older adults during a midday nap, following completion of a functional magnetic resonance imaged serial reaction time task as part of a larger experimental protocol. Sleep delta activity was reduced with age in a left-weighted motor cortical network, including premotor cortex, primary motor cortex, supplementary motor area, and pre-supplementary motor area, as well as non-motor regions in parietal, temporal, occipital, and cingulate cortices. Sleep theta activity was reduced with age in a similar left-weighted motor network, and in non-motor prefrontal and middle cingulate regions. Sleep sigma activity was reduced with age in left primary motor cortex, in a non-motor right-weighted prefrontal-temporal network, and in cingulate regions. Cortical thinning mediated aging-related sigma reductions in lateral orbitofrontal cortex and frontal pole, and partially mediated delta reductions in parahippocampal, fusiform, and lingual gyri. Putamen, caudate, and inferior parietal cortex activation prior to sleep predicted frontal and motor cortical contributions to sleep delta and theta activity in an age-moderated fashion, reflecting negative relationships in young adults and positive or absent relationships in older adults. Overall, these results support the local sleep hypothesis that brain regions active during learning contribute to consolidation-related neural activity during subsequent sleep and demonstrate that sleep oscillatory activity in these regions is reduced with aging.

Mercury is present in neurons and oligodendrocytes in regions of the brain affected by Parkinson’s disease and co-localises with Lewy bodies

Objective Environmental toxicants are suspected to play a part in the pathogenesis of idiopathic Parkinson’s disease (PD) and may underlie its increasing incidence. Mercury exposure in humans is common and is increasing due to accelerating levels of atmospheric mercury, and mercury damages cells via oxidative stress, cell membrane damage, and autoimmunity, mechanisms suspected in the pathogenesis of PD. We therefore compared the cellular distribution of mercury in the tissues of people with and without PD who had evidence of previous mercury exposure by mercury being present in their locus ceruleus neurons. Materials and methods Paraffin sections from the brain and general organs of two people with PD, two people without PD with a history of mercury exposure, and ten people without PD or known mercury exposure, were stained for inorganic mercury using autometallography, combined with immunostaining for a-synuclein and glial cells. All had mercury-containing neurons in locus ceruleus neurons. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to confirm the presence of mercury and to look for other potentially toxic elements. Autometallography-stained locus ceruleus paraffin sections were examined to compare the frequency of previous mercury exposure between 20 PD and 40 non-PD individuals. Results In PD brains, autometallography-detected mercury was seen in neurons affected by the disease, such as those in the substantia nigra, motor cortex, striatum, thalamus, and cerebellum. Mercury was seen in oligodendrocytes in white and grey matter. Mercury often co-localised with Lewy bodies and neurites. A more restricted distribution of brain mercury was seen in people without PD (both with or without known mercury exposure), with no mercury present in the substantia nigra, striatum, or thalamus. The presence of autometallography-detected mercury in PD was confirmed with LA-ICP-MS, which demonstrated other potentially toxic metals in the locus ceruleus and high iron levels in white matter. Autometallography-detected mercury was found in locus ceruleus neurons in a similar proportion of PD (65%) and non-PD (63%) individuals. Conclusions In people with PD, mercury was found in neurons and oligodendrocytes in regions of the brain that are affected by the disease, and often co-localised with aggregated a-synuclein. Mercury in the motor cortex, thalamus and striatum could result in bradykinesia and rigidity, and mercury in the cerebellum could cause tremor. People without PD had a restricted uptake of mercury into the brain. The similar frequency of mercury in the locus ceruleus of people with and without PD suggests these two groups have had comparable previous mercury exposures but that PD brains have a greater predisposition to take up circulating mercury. While this post mortem study does not provide a direct link between mercury and idiopathic PD, it adds to the body of evidence that metal toxicants such as mercury play a role in the disease. A precautionary approach would be to reduce rising mercury levels in the atmosphere by limiting the burning of fossil fuels, which may be contributing to the increasing incidence of PD.