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Background: Actual challenge in surgical treatment of intra-axial gliomas involving eloquent areas is maximal safe resection. Mapping and monitoring of cortical and subcortical motor functions are important tools to avoid postoperative deficits. In the present study, we present our experience with a continuous dynamic motor mapping technique pairing a traditional monopolar stimulator with a Cavitron ultrasonic surgical aspirator (CUSA) to perform a continuous stimulation of the white matter avoiding removal interruption., Methods: We describe a single center retrospective analysis of 1-year consecutive patients with intraxial tumors located adjacent to corticospinal tract and treated with surgical resection adopting "continuous dynamic mapping technique." With the support of a reconstruction software (3D Slicer), we classified the extent of resection (EOR) as gross total resection (GTR) (>98%), sub-total resection (STR) (from 90% to 97%), and partial resection (<90%). Medical Research Council (MRC) grading was adopted to evaluate neurological outcomes (from 0 to 5), assessed on first postoperative day, at 1 week, 1 month and 3 months., Results: From July 2017 to July 2018, 29 patients underwent to surgical removal of intraxial tumor adjacent to motor areas, using continuous dynamic subcortical mapping. Median age was 54 years old (range 12-75 years). At preoperative MRI tractography reconstruction, mean distance between tumor and corticospinal tract was 4.4 mm (range At 1 week postoperative assessment, motor deficits were still present in 12 patients (41%). At 1 month, 10 patients (35%) had persisting deficits, which required admission to rehabilitation department. At 3 months, 4 patients (14%) had persistent motor impairment and overall 28 patients (98%) were able to walk by themselves., Conclusions: Our early experience showed that a combination of dynamic subcortical mapping with transcranial and cortical strip MEP (motor evoked potentials) monitoring is useful in tumors close to motor eloquent areas to extend surgical resection avoiding permanent consequences. However, we need for further experience to consolidate and improve this technique.

For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD., (© 2021. Springer Nature Limited.)

It is critical for hearing that the descending cochlear efferent system provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma. NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

Fluency-shaping enhances the speech fluency of persons who stutter, yet underlying conditions and neuroplasticity-related mechanisms are largely unknown. While speech production-related brain activity in stuttering is well studied, it is unclear whether therapy repairs networks of altered sensorimotor integration, imprecise neural timing and sequencing, faulty error monitoring, or insufficient speech planning. Here, we tested the impact of one-year fluency-shaping therapy on resting-state fMRI connectivity within sets of brain regions subserving these speech functions. We analyzed resting-state data of 22 patients who participated in a fluency-shaping program, 18 patients not participating in therapy, and 28 fluent control participants, measured one year apart. Improved fluency was accompanied by an increased connectivity within the sensorimotor integration network. Specifically, two connections were strengthened; the left inferior frontal gyrus showed increased connectivity with the precentral gyrus at the representation of the left laryngeal motor cortex, and the left inferior frontal gyrus showed increased connectivity with the right superior temporal gyrus. Thus, therapy-associated neural remediation was based on a strengthened integration of the command-to-execution pathway together with an increased auditory-to-motor coupling. Since we investigated task-free brain activity, we assume that our findings are not biased to network activity involved in compensation but represent long-term focal neuroplasticity effects., Competing Interests: Declaration of Competing Interest The author(s) declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To record crossed acoustic reflex thresholds (xART's) postoperatively from patients after surgical repair of unilateral congenital aural atresia (CAA). To seek explanations for when xARTs can and cannot be recorded. We hope to understand the implications for this central auditory reflex despite early afferent deprivation., Methods: Patients who underwent surgery to correct unilateral CAA at a tertiary academic medical were prospectively enrolled to evaluate for the presence of xART. Preoperative ARTs in the normal (non-atretic) ear, and postoperative ipsilateral ARTs (stimulus in the normal ear) and contralateral ARTs (stimulus in the newly reconstructed atretic ear; record in the normal ear) were measured at 500, 1000, and 2000 Hz., Results: Four of 11 patients with normal ipsilateral reflex thresholds preoperatively demonstrated crossed acoustic reflexes postoperatively (stimulus in reconstructed ear; record from normal ear). Four other patients demonstrated normal ipsilateral thresholds preoperatively but did not have crossed reflexes postoperatively. No reflexes (pre- or postoperatively) could be recorded in 3 patients. Crossed reflex threshold is significantly correlated with the postoperative audiometric threshold. There was no correlation between ipsilateral and contralateral reflex thresholds., Conclusion: Crossed acoustic reflexes can be recorded from some but not all postoperative atresia patients, and the thresholds for those reflexes correlate with the postoperative pure tone threshold. The presence of acoustic reflexes implies an intact CN VIII-to-opposite CN VII central reflex arc despite early unilateral sound deprivation.

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 β 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, β 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 β rhythms during movements compared with healthy controls in the core motor areas. Our findings of low frequency- and β-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., (Copyright © 2021. Published by Elsevier Inc.)

It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Minfei Qian et al.)

Stroke-related damage to the crossed lateral corticospinal tract causes motor deficits in the contralateral (paretic) limb. To restore functional movement in the paretic limb, the nervous system may increase its reliance on ipsilaterally descending motor pathways, including the uncrossed lateral corticospinal tract, the reticulospinal tract, the rubrospinal tract, and the vestibulospinal tract. Our knowledge about the role of these pathways for upper limb motor recovery is incomplete, and even less is known about the role of these pathways for lower limb motor recovery. Understanding the role of ipsilateral motor pathways to paretic lower limb movement and recovery after stroke may help improve our rehabilitative efforts and provide alternate solutions to address stroke-related impairments. These advances are important because walking and mobility impairments are major contributors to long-term disability after stroke, and improving walking is a high priority for individuals with stroke. This perspective highlights evidence regarding the contributions of ipsilateral motor pathways from the contralesional hemisphere and spinal interneuronal pathways for paretic lower limb movement and recovery. This perspective also identifies opportunities for future research to expand our knowledge about ipsilateral motor pathways and provides insights into how this information may be used to guide rehabilitation., (© 2021 Wiley Periodicals LLC.)

From molecular mechanisms to global brain networks, atypical fluctuations are the hallmark of neurodegeneration. Yet, traditional fMRI research on resting-state networks (RSNs) has favored static and average connectivity methods, which by overlooking the fluctuation dynamics triggered by neurodegeneration, have yielded inconsistent results. The present multicenter study introduces a data-driven machine learning pipeline based on dynamic connectivity fluctuation analysis (DCFA) on RS-fMRI data from 300 participants belonging to three groups: behavioral variant frontotemporal dementia (bvFTD) patients, Alzheimer's disease (AD) patients, and healthy controls. We considered non-linear oscillatory patterns across combined and individual resting-state networks (RSNs), namely: the salience network (SN), mostly affected in bvFTD; the default mode network (DMN), mostly affected in AD; the executive network (EN), partially compromised in both conditions; the motor network (MN); and the visual network (VN). These RSNs were entered as features for dementia classification using a recent robust machine learning approach (a Bayesian hyperparameter tuned Gradient Boosting Machines (GBM) algorithm), across four independent datasets with different MR scanners and recording parameters. The machine learning classification accuracy analysis revealed a systematic and unique tailored architecture of RSN disruption. The classification accuracy ranking showed that the most affected networks for bvFTD were the SN + EN network pair (mean accuracy = 86.43%, AUC = 0.91, sensitivity = 86.45%, specificity = 87.54%); for AD, the DMN + EN network pair (mean accuracy = 86.63%, AUC = 0.89, sensitivity = 88.37%, specificity = 84.62%); and for the bvFTD vs. AD classification, the DMN + SN network pair (mean accuracy = 82.67%, AUC = 0.86, sensitivity = 81.27%, specificity = 83.01%). Moreover, the DFCA classification systematically outperformed canonical connectivity approaches (including both static and linear dynamic connectivity). Our findings suggest that non-linear dynamical fluctuations surpass two traditional seed-based functional connectivity approaches and provide a pathophysiological characterization of global brain networks in neurodegenerative conditions (AD and bvFTD) across multicenter data., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

A systematic review of the literature was conducted comparing neurophysiological outcomes in persons with multiple sclerosis (PwMS) to healthy controls (HC), in studies of the central nervous system (CNS) function comprising motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) and in studies of the peripheral nervous system (PNS) function comprising electroneuronography (ENG) outcomes elicited by peripheral nerve stimulation. Studies comparing neuromuscular function, assessed during maximal voluntary contraction (MVC) of muscle, were included if they reported muscle strength along with muscle activation by use of electromyography (EMG) and/or interpolated twitch technique (ITT). Studies investigating CNS function showed prolonged central motor conduction times, asymmetry of nerve conduction motor pathways, and prolonged latencies in PwMS when compared to HC. Resting motor threshold, amplitude, and cortical silent periods showed conflicting results. CNS findings generally correlated with disabilities. Studies of PNS function showed near significant prolongation in motor latency of the median nerve, reduced nerve conduction velocities in the tibial and peroneal nerves, and decreased compound muscle action potential amplitudes of the tibial nerve in PwMS. ENG findings did not correlate with clinical severity of disabilities. Studies of neuromuscular function showed lower voluntary muscle activation and increased central fatigue in PwMS, whereas EMG showed divergent muscle activation (ie, EMG amplitude) during MVC. When comparing the existing literature on neurophysiological motor examinations in PwMS and HC, consistent and substantial impairments of CNS function were seen in PwMS, whereas impairments of the PNS were less pronounced and inconsistent. In addition, impairments in muscle activation were observed in PwMS., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We have previously demonstrated that pediatric-onset multiple sclerosis (POMS) negatively impacts the visual pathway as well as motor processing speed. Relationships between MS-related diffuse structural damage of gray and white matter (WM) tissue and cortical responses to visual and motor stimuli remain poorly understood. We used magnetoencephalography in 14 POMS patients and 15 age- and sex-matched healthy controls to assess visual gamma (30-80 Hz), motor gamma (60-90 Hz), and motor beta (15-30 Hz) cortical oscillatory responses to a visual-motor task. Then, 3T MRI was used to: (a) calculate fractional anisotropy (FA) of the posterior visual and corticospinal motor WM pathways and (b) quantify volume and thickness of the cuneus and primary motor cortex. Visual gamma band power was reduced in POMS and was associated with reduced FA of the optic radiations but not with loss of cuneus volume or thickness. Activity in the primary motor cortex, as measured by postmovement beta rebound amplitude associated with peak latency, was decreased in POMS, although this reduction was not predicted by structural metrics. Our findings implicate loss of WM integrity as a contributor to reduced electrical responses in the visual cortex in POMS. Future work in larger cohorts will inform on the cognitive implications of this finding in terms of visual processing function and will determine whether the progressive loss of brain volume known to occur in POMS ultimately contributes to both progressive dysfunction in such tasks as well as progressive reduction in cortical electrical responses in the visual cortex., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Pain has an inhibitory effect on the corticospinal excitability that has been interpreted as an evolutionary mechanism, directed to down-regulate cortical activity in order to facilitate rapid protective spinal reflexes. Here, we focused on the link between defensive mechanisms and motor system and we asked whether voluntary actions can modulate the corticospinal excitability during painful stimulations. To this aim, we manipulated the volition-related aspects of our paradigm by comparing conditions in which either the participant (self-generated action) or the experimenter (other-generated action) pressed the button to deliver painful high-intensity transcutaneous electric shocks to the right digit V. MEPs to TMS were recorded from the FDI and APB muscles of the stimulated hand. A compelling agent-dependent modulation of the corticospinal excitability was found, showing, in self-generated compared to other-generated actions, a significantly lower inhibitory effect, as measured by greater MEP amplitude. This finding suggests a top-down modulation of volitional actions on defensive mechanisms, promoting the view that predictive information from the motor system attenuates the responses to the foreseeable adverse events generated by one's own actions as compared to unpredictable events generated by someone else's actions., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Gait disturbance due to injuries of the descending motor pathway, including corticospinal tract (CST), corticoreticular pathway (CRP), and medial and lateral vestibulospinal tracts (VSTs), are commonly encountered disabling sequelae of pontine hemorrhage. We investigated relations between changes in the CST, CRP, and medial and lateral VST and corresponding changes in gait function in patients with pontine hemorrhage., Method: Nine consecutive stroke patients with pontine hemorrhage, and 6 age-matched normal subjects were recruited. Four patients were allocated to group A (can't walk independently) and 5 to group B (can walk independently). Diffusion tensor imaging (DTI) data were acquired twice at acute to subacute stage and chronic stage after stroke onset. Diffusion tensor tractography (DTT) was used to reconstruct CST, CRP, medial and lateral VST., Result: The CRP shows a significantly different between groups A and B in both initial and follow up DTT (p > 0.05). In contrast, CST, medial VST and lateral VST did not show a significant difference (p > 0.05). Regarding DTI parameters of CRPs in group A, percentages of patients with fractional anisotropy (FA) and mean diffusivity (MD) values more than two standard deviation from normal were higher by follow up DTI than by initial DTI, however, the CRPs in group B only showed increased abnormal range of MD., Conclusions: The CST does not play an essential role in recovery of independent walking and vestibulospinal tracts may not crucially affect recovery of independent walking in patients with pontine hemorrhage. In contrast, and intact CRP or changes of the CRP integrity appear to be related to the recovery of gait function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Nerve transfer has been developed to restore partial function after serious nerve injuries, for example, restoring bladder control after spinal cord injury (SCI). Our aim here was to establish a preclinical proof-of-concept model using nerve transfer for restoring anorectal function after SCI., Setting: We used laminectomy to model SCI, and bilateral spinal ventral and dorsal nerve root anastomosis to re-establish connectivity to the anorectal musculature., Methods: Multidisciplinary methods were used to assess the anatomical and functional integrity of the alternative spinal-to-anorectal nerve circuit. Adult rats were used to establish the model. Bilateral anterior and posterior L5 nerve roots were surgically matched with anterior and posterior of S1 nerve roots by microscopic anastomosis to establish an artificial rectal reflex arc with complete sensory and motor pathways. Twelve weeks later, we used retrograde nerve tracing and neurohistomorphological analysis to assess anatomical integrity of the new artificial rectal reflex arc. Anorectal manometry was used to assess the function of the new nerve circuit., Results: Retrograde tracing with recombinant attenuated pseudo rabies virus indicated that the new neural pathway was successfully established to the anorectal musculature after experimental SCI. Toluidine blue-stained sections of the anastomosis site revealed normal-appearing nerve fiber morphology and regeneration, and transmission electron microscopy revealed myelinated axons. Anorectal manometry revealed significant anorectal functional recovery., Conclusion: These results suggest that our model is a feasible first step in developing an alternative reflex pathway after laminectomy at L4 to S2 and shows promise for effective restoration of anorectal function.

Oropharyngeal dysphagia (OD) is a common post-stroke complication and is associated with respiratory infections. The aim was to assess the biomechanical impairments in swallow function and the afferent and efferent swallowing pathways impairing swallow safety in chronic post-stroke patients. We studied 30 patients with unilateral stroke and chronic OD (> 3 months from stroke onset) with impaired safety of swallow (Penetration-Aspiration Scale [PAS] ≥ 2). We evaluated the efficacy, safety, and kinematics of the swallow response (residue, PAS, laryngeal vestibule closure time [LVCT]) with videofluoroscopy, sensory evoked potentials to pharyngeal electrical stimulation (pSEP), and pharyngeal motor evoked potentials (pMEP) to transcranial magnetic stimulation of both hemispheres. Mean age of patients was 70.1 ± 10.9 years (7 women). Stroke severity at onset was moderate (NIHSS median 10 [IQ range 3-11.5]), and modified Rankin Scale 2.8 ± 1.3. Mean PAS was 5.1 ± 1.9; prevalence of delayed LVCT was 86.7% and 30% presented aspirations. Pharyngeal hypoesthesia was present in 46.7% of patients and 92.3% showed abnormally asymmetrical pSEPs when comparing the ipsilesional with the contralesional hemisphere. Increased duration of swallow was associated with lower pSEP amplitude (P1-N2) in the contralesional hemisphere (p = 0.033). Patients with right hemispheric strokes showed greater reduction of pSEPs amplitude (N1-P1, p = 0.049). In contrast, pharyngeal resting motor threshold and pMEPs were symmetric in 73.3% patients without the physiologic hemispheric dominance. Mild-to-moderate disabled chronic post-stroke patients with OD presented severe impaired biomechanics of swallow response and high prevalence of aspirations. Initial results from the neurophysiological evaluation demonstrated prevalent impairments with disrupted integration of pharyngeal sensory inputs and reduced cortical excitability of efferent pathways. Patients with right hemispheric strokes showed poorer neurophysiological responses.

Aim: To investigate whether type 1 diabetes mellitus (T1DM) could affect the efferent auditory system by analyzing the relationship between the activation of the medial olivocochlear reflex with disease duration, metabolic control and age at time of diagnosis., Method: A total of 101 children and adolescents were evaluated. They were divided into two groups: 50 with T1DM and 51 without the disease. The participants answered a structured questionnaire containing questions about auditory complaints and were evaluated for tonal audiometry, tympanometry, acoustic reflex, otoacoustic emission by distortion product to evaluate the inhibitory effect of medial olivocochlear reflex (MOC)., Results: The participants with T1DM presented changed AR (increased or absent) at all the frequencies in both ears (p < 0.05) when compared with the group without the disease. No differences were found between the DPOAE amplitudes of the individuals with and without T1DM, in both ears at all the frequencies. There were significant differences in the activation of the MOC reflex between the groups with and without T1DM, the participants with T1DM presented the absence of the inhibitory effect of the DPOAE in the right and left ears, in the frequencies of 4000 Hz (p = 0.035/0.002respectively) and 6000 Hz (p = 0.033/0.031 respectively) and 8000 Hz (p = 0.007/0.001 respectively) when compared to the healthy group. Significant differences were also observed between the groups with and without T1DM (p < 0.05) for self-reported complaints of tinitus, difficulties with the perception of speech when there was noise and distraction with noise. No association was found between the hearing complaints and the audiological measurements obtained and disease time, metabolic control and age at the time of diagnosis., Conclusion: The findings suggest the presence of early auditory dysfunction of the efferent pathway in patients with T1DM., (Copyright © 2019 Elsevier B.V. All rights reserved.)

One of the major causes of nocturia is overactive bladder (OAB). Somatic afferent nerve stimuli are used for treating OAB. However, clinical evidence for the efficacy of this treatment is insufficient due to the lack of appropriate control stimuli. Studies on anesthetized animals, which eliminate emotional factors and placebo effects, have demonstrated an influence of somatic stimuli on urinary bladder functions and elucidated the underlying mechanisms. In general, the effects of somatic stimuli are dependent on the modality, location, and physical characteristics of the stimulus. Recently we showed that gentle stimuli applied to the perineal skin using a soft elastomer roller inhibited micturition contractions to a greater extent than a roller with a hard surface. Studies aiming to elucidate the neural mechanisms of gentle stimulation-induced inhibition reported that 1-10 Hz discharges of low-threshold cutaneous mechanoreceptive Aβ, Aδ, and C fibers evoked during stimulation with an elastomer roller inhibited the micturition reflex by activating the spinal cord opioid system, thereby reducing both ascending and descending transmission between bladder and pontine micturition center. The present review will provide a brief summary of (1) the effect of somatic electrical stimulation on the micturition reflex, (2) the effect of gentle mechanical skin stimulation on the micturition reflex, (3) the afferent, efferent, and central mechanisms underlying the effects of gentle stimulation, and (4) a translational clinical study demonstrating the efficacy of gentle skin stimuli for treating nocturia in the elderly with OAB by using the two roller types inducing distinct effects on rat micturition contractions. Anat Rec, 302:1824-1836, 2019. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

Speech-in-noise (SIN) comprehension deficits in older adults have been linked to changes in both subcortical and cortical auditory evoked responses. However, older adults' difficulty understanding SIN may also be related to an imbalance in signal transmission (i.e., functional connectivity) between brainstem and auditory cortices. By modeling high-density scalp recordings of speech-evoked responses with sources in brainstem (BS) and bilateral primary auditory cortices (PAC), we show that beyond attenuating neural activity, hearing loss in older adults compromises the transmission of speech information between subcortical and early cortical hubs of the speech network. We found that the strength of afferent BS→PAC neural signaling (but not the reverse efferent flow; PAC→BS) varied with mild declines in hearing acuity and this "bottom-up" functional connectivity robustly predicted older adults' performance in a SIN identification task. Connectivity was also a better predictor of SIN processing than unitary subcortical or cortical responses alone. Our neuroimaging findings suggest that in older adults (i) mild hearing loss differentially reduces neural output at several stages of auditory processing (PAC > BS), (ii) subcortical-cortical connectivity is more sensitive to peripheral hearing loss than top-down (cortical-subcortical) control, and (iii) reduced functional connectivity in afferent auditory pathways plays a significant role in SIN comprehension problems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

After spinal cord injury (SCI), the motor-related cortical areas can be a potential substrate for functional recovery in addition to the spinal cord. However, a dynamic description of how motor cortical circuits reorganize after SCI is lacking. Here, we captured the comprehensive dynamics of motor networks across SCI in a nonhuman primate model. Using electrocorticography over the sensorimotor areas in monkeys, we collected broadband neuronal signals during a reaching-and-grasping task at different stages of recovery of dexterous finger movements after a partial SCI at the cervical levels. We identified two distinct network dynamics: grasping-related intrahemispheric interactions from the contralesional premotor cortex (PM) to the contralesional primary motor cortex (M1) in the high-γ band (>70 Hz), and motor-preparation-related interhemispheric interactions from the contralesional to ipsilesional PM in the α and low-β bands (10-15 Hz). The strengths of these networks correlated to the time course of behavioral recovery. The grasping-related network showed enhanced activation immediately after the injury, but gradually returned to normal while the strength of the motor-preparation-related network gradually increased. Our findings suggest a cortical compensatory mechanism after SCI, where two interdependent motor networks redirect activity from the contralesional hemisphere to the other hemisphere to facilitate functional recovery., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Spasticity is one of the most common symptoms manifested in humans with spinal cord injury (SCI). The neural mechanisms contributing to its development are not yet understood. Using neurophysiological and imaging techniques, we examined the influence of residual descending motor pathways on spasticity in humans with SCI., Methods: We measured spasticity in 33 individuals with motor complete SCI (determined by clinical examination) without preservation of voluntary motor output in the quadriceps femoris muscle. To examine residual descending motor pathways, we used magnetic and electrical stimulation over the leg motor cortex to elicit motor evoked potentials (MEPs) in the quadriceps femoris muscle and structural magnetic resonance imaging to measure spinal cord atrophy., Results: We found that 60% of participants showed symptoms of spasticity, whereas the other 40% showed no spasticity, demonstrating the presence of 2 clear subgroups of humans with motor complete SCI. MEPs were only present in individuals who had spasticity, and MEP size correlated with the severity of spasticity. Spinal cord atrophy was greater in nonspastic compared with spastic subjects. Notably, the degree of spared tissue in the lateral regions of the spinal cord was positively correlated with the severity of spasticity, indicating preservation of white matter related to motor tracts when spasticity was present., Interpretation: These results support the hypothesis that preservation of descending motor pathways influences spasticity in humans with motor complete SCI; this knowledge might help the rehabilitation and assessment of people with SCI. ANN NEUROL 2019., (© 2019 American Neurological Association.)

Objective: The objectives were to investigate the function of central auditory pathways and of the medial efferent olivocochlear system (MOCS)., Design: Event-related potentials (ERP) were recorded following the delivery of the stimulus /da/ in quiet and in ipsilateral, contralateral, and binaural noise conditions and correlated to the results of the auditory processing disorders (APD) diagnostic test battery. MOCS function was investigated by adding ipsilateral, contralateral, and binaural noise to transient evoked otoacoustic emission recordings. Auditory brainstem responses and pure tone audiogram were also evaluated., Study Sample: Nineteen children (7 to 12 years old) with APD were compared with 24 age-matched controls., Results: Otoacoustic emissions and ABR characteristics did not differ between groups, whereas ERP latencies were significantly longer and of higher amplitudes in APD children than in controls, in both quiet and noise conditions. The MOCS suppression was higher in APD children., Conclusions: Findings indicate that children with APD present with neural deficiencies in both challenging and nonchallenging environments with an increase in the timing of several central auditory processes correlated to their behavioural performances. Meanwhile, their modulation of the auditory periphery under noisy conditions differs from control children with higher suppression.

We investigated the influence of lesion location on cerebral blood flow (CBF) in chronic subcortical stroke patients. Three-dimensional pseudocontinuous arterial spin labeling was employed to obtain CBF images in normal controls (NC) and patients with left hemisphere subcortical infarctions involving motor pathways. Stroke patients were divided into two subgroups based on the infarction location (basal ganglia (BS) or pontine (PS). We mapped CBF alterations in a voxel-wise manner and compared them to detect differences among groups with height-level false discovery rate correction. Regions with significant group differences were extracted to perform post hoc analyses among the BS, PS and NC groups using a general linear model with age, gender, years of education, and interval after stroke as covariates. The BS group displayed significantly increased CBF in the contralesional putamen relative to NC and significantly decreased CBF in the ipsilesional sensorimotor cortex, ipsilesional thalamus and contralesional cerebellum. The PS group displayed significantly increased CBF in the contralesional inferior frontal gyrus relative to both the NC and BS groups. Nevertheless, the PS group showed significantly decreased CBF mainly in the cerebellum. Our results suggest different alteration patterns of CBF in chronic stroke patients with different infarct locations within subcortical motor pathways, potentially providing important information for the initiation of individualized rehabilitation strategies for subcortical stroke patients involving different infarct types., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To determine whether children aged 7 to 12 years with listening difficulties show objective evidence for efferent auditory function based on measurements of medial olivo-cochlear and middle ear muscle reflexes., Design: Click-evoked otoacoustic emissions recorded with and without contralateral broadband noise and ipsilateral and contralateral tonal (1000, 2000 Hz) middle ear muscle reflex thresholds were examined., Study Sample: 29 children diagnosed with suspected auditory processing disorder (APD) and a control group of 34 typically developing children participated in this study., Results: Children with suspected APD had poorer performance on auditory processing tests than the control group. Middle ear muscle reflex thresholds were significantly higher at 2000 Hz in the suspected APD group for contralateral stimulation. MOC inhibition effects did not differ between APD and control groups., Conclusions: This research supports earlier studies showing altered acoustic reflexes in children with APD. No group differences were found for the MOC reflex measures, consistent with some earlier studies in children with APD.

Purpose: Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. Although brain involvement is well recognized, the relationship between cortical motor control and voluntary movement has not been sufficiently explored. This study aims at assessing magnetoencephalographic (MEG) rhythms at oscillatory and connectivity levels to map central motor control., Methods: Magnetoencephalographic data were acquired from healthy subjects and five myotonic dystrophy type 1 subjects during resting state and foot movement. Resting state EEG band power, event-related desynchronization/synchronization, functional connectivity, and network features (node strength and betweenness centrality) were estimated. A statistical comparison of these indexes between the two groups was run; a linear correlation between event-related desynchronization and motor performance was obtained., Results: Myotonic dystrophy type 1 subjects showed higher theta power over central motor regions and lower beta power over frontal areas, with a decrease of beta node strength over the dominant hemisphere and an increase of betweenness centrality over the vertex. Foot movement in the most impaired myotonic dystrophy type 1 subjects was inefficient in evoking event-related desynchronization. In less severely impaired participants, dominant foot movement was related to a bilateral sensorimotor event-related desynchronization., Conclusions: Results provide proof of a central dysfunction of movement. Identification of neurophysiological motor patterns in myotonic dystrophy type 1 could provide a guide for tailored therapy.

The dorsal periaqueductal grey matter (dPAG) and the deep layers of the superior colliculus (dlSC) have been implicated in the organisation of innate fear-related defensive behaviours. Furthermore, GABAergic neurons from the substantia nigra pars reticulata (SNpr) connected to the dlSC and dPAG receive convergent disinhibitory inputs from the caudate-putamen (CPu), comprising the neostriatum, and modulate defence responses elicited by midbrain tectum stimulation. The purpose of this work was to study the effect of either excitatory cortico-neostriatal input blockade or neostriato-nigral GABAergic disinhibitory output activation on the responsivity of GABAergic nigro-collicular tonic inhibitory pathways during the elicitation of panic attack-like defensive responses produced by bicuculline administration into the dlSC. Thus, we investigated the effects of microinjection of either the synaptic activity blocker cobalt chloride (CoCl 2 ) or the NMDA receptor agonist N-methyl-D-aspartic acid in the CPu on the elaboration of the defensive behaviour elicited by the selective blockade of GABA A receptors in the dlSC. Our findings showed that pretreatment of the neostriatum with CoCl 2 caused clear anxiolytic and panicolytic-like effects, reducing the incidence and duration of alertness and diminishing defensive immobility and explosive escape responses. On the other hand, pretreatment of the neostriatum with NMDA (40 nmol) caused a pro-aversive effect, enhancing running and jumping responses elicited by GABAergic disinhibition in the dlSC. We conclude from the data that the neostriato-nigral disinhibitory and nigro-collicular inhibitory GABAergic pathways modulate innate fear and panic attack-like responses organised by dlSC neurons., (Copyright © 2018. Published by Elsevier Inc.)

Following injury, functional improvement can result from central nervous system plasticity. Use-dependent plasticity of motor systems is evident, for example, in recovery of function resulting from rehabilitative interventions. Here, we present a single patient who underwent bilateral microelectrode-guided stereotactic implantation of deep brain stimulating leads for the treatment of essential tremor 52 yr following bilateral arm amputations. The tremor affected his upper extremities and had rendered him unable to perform fine motor tasks with his prostheses, significantly reducing his independence. We found a large territory of neurons in the ventral intermediate nucleus of his thalamus that responded to shoulder protraction, the movement that he used to control fine motor movements of his terminal hook prostheses. We propose that reorganization of this motor nucleus may have occurred secondary to a use-dependent gain of function in neurons that were previously involved in hand movement. NEW & NOTEWORTHY We had a unique opportunity to record neurons in the ventrointermediate (Vim) motor nucleus of thalamus in a patient with essential tremor, decades following bilateral forearm amputations. We demonstrate that a large region of Vim is active during shoulder protraction-the movement used to operate the patient's mechanical prostheses. We suggest that this provides evidence of human motor thalamic plasticity.

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; Chrna9 KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI; Chrna9L9 ' T KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In Chrna9 KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the Chrna9L9 ' T KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium. SIGNIFICANCE STATEMENT Noise overexposure is a major cause of a variety of perceptual disabilities, including speech-in-noise difficulties, tinnitus, and hyperacusis. Here we show that exposure to noise levels that do not cause permanent threshold elevations or hair cell death can produce a loss of cochlear nerve synapses to inner hair cells as well as degeneration of medial olivocochlear (MOC) terminals contacting the outer hair cells. Enhancement of the MOC reflex can prevent both types of neuropathy, highlighting the potential use of drugs that increase α9α10 nicotinic cholinergic receptor activity as a pharmacotherapeutic strategy to avoid hidden hearing loss., (Copyright © 2018 the authors 0270-6474/18/387440-12$15.00/0.)

Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against myocardial ischemia/reperfusion (I/R) injury. However, whether the cardioprotection of VNS is mainly due to direct activation through its ipsilateral efferent fibers (motor) rather than indirect effects mediated by the afferent fibers (sensory) have not been clearly understood. We hypothesized that VNS exerts cardioprotection predominantly through its efferent vagal fibers. Thirty swine (30-35 kg) were randomized into five groups: I/R no VNS (I/R), and left mid-cervical VNS with both vagal trunks intact (LC-VNS), with left vagus nerve transection (LtVNX), with right vagus nerve transection (RtVNX) and with atropine pretreatment (Atropine), respectively. VNS was applied at the onset of ischemia (60 min) and continued until the end of reperfusion (120 min). Cardiac function, infarct size, arrhythmia score, myocardial connexin43 expression, apoptotic markers, oxidative stress markers, inflammatory markers (TNF-α and IL-10) and cardiac mitochondrial function, dynamics and fatty acid oxidation (MFN2, OPA1, DRP1, PGC1α and CPT1) were determined. LC-VNS exerted cardioprotection against myocardial I/R injury via improvement of mitochondrial function and dynamics and shifted cardiac fatty acid metabolism toward beta oxidation. However, LC-VNS and LtVNX, both efferent vagal fibers are intact, produced more profound cardioprotection, particularly infarct size reduction, decreased arrhythmia score, oxidative stress and apoptosis and attenuated mitochondrial dysfunction compared to RtVNX. These beneficial effects of VNS were abolished by atropine. Our findings suggest that selective efferent VNS may potentially be effective in attenuating myocardial I/R injury. Moreover, VNS required the contralateral efferent vagal activities to fully provide its cardioprotection.

Background: Neurogenic abnormalities characterize overt diabetic state. However, how early is their appearance in the clinical course of the disease is unclear., Methods: In 26 normotensive and normoweight prediabetic patients, aged 45.2 ± 3.2 years (mean ± SEM), we assessed efferent postganglionic muscle sympathetic nerve traffic (MSNA, microneurography), spontaneous baroreflex sensitivity, and a number of hemodynamic and metabolic variables, including homeostatic model assessment (HOMA) index. Measurements were compared with those obtained in a group of 30 healthy controls of similar age., Results: For similar clinic and ambulatory blood pressure and BMI values, prediabetic patients displayed significantly greater MSNA values than controls, both when expressed as bursts incidence over time (33.3 ± 2.0 vs. 25.6 ± 1.2 bursts/min, P < 0.01) and when corrected for heart rate values (49.6 ± 1.9 vs. 36.7 ± 1.4 bursts/100 heart beats, P < 0.01). This neurogenic abnormality was associated with a reduced spontaneous baroreflex MSNA sensitivity (-3.20 ± 0.2 vs. -4.72 ± 0.2 a.u., P < 0.01) and significantly greater HOMA index values (3.73 ± 0.1 vs. 1.65 ± 0.1 a.u., P < 0.01). In the multivariate analysis, performed in prediabetic patients, MSNA values were directly and significantly related to HOMA index and inversely and significantly to baroreflex-MSNA sensitivity., Conclusion: These data provide evidence that sympathetic and reflex abnormalities are of early appearance in the clinical course of the diabetic disease. The adrenergic overdrive and the baroreflex impairment may thus participate at the disease progression, favoring the development of the hypertensive state and adversely affecting the disease prognosis.

Afferent fibers expressing the vanilloid receptor 1 (VR1) channel have been implicated in cardiac nociception; however, their role in modulating reflex responses to cardiac stress is not well understood. We evaluated this role in Yorkshire pigs by percutaneous epicardial application of resiniferatoxin (RTX), a toxic activator of the VR1 channel, resulting in the depletion of cardiac VR1-expressing afferents. Hemodynamics, epicardial activation recovery intervals, and in vivo activity of stellate ganglion neurons (SGNs) were recorded in control and RTX-treated animals. Stressors included inferior vena cava or aortic occlusion and rapid right ventricular pacing (RVP) to induce dyssynchrony and ischemia. In the epicardium, stellate ganglia, and dorsal root ganglia, immunostaining for the VR1 channel, calcitonin gene-related peptide, and substance P was significantly diminished by RTX. RTX-treated animals exhibited higher basal systolic blood pressures and contractility than control animals. Reflex responses to epicardial bradykinin and capsaicin were mitigated by RTX. Cardiovascular reflex function, as assessed by inferior vena cava or aortic occlusion, was similar in RTX-treated versus control animals. RTX-treated animals exhibited resistance to hemodynamic collapse induced by RVP. Activation recovery interval shortening during RVP, a marker of cardiac sympathetic outflow, was greater in RTX-treated animals and exhibited significant delay in returning to baseline values after cessation of RVP. The basal firing rate of SGNs and firing rates in response to RVP were also greater in RTX-treated animals, as was the SGN network activity in response to cardiac stressors. These data suggest that elimination of cardiac nociceptive afferents reorganizes the central-peripheral nervous system interaction to enhance cardiac sympathetic outflow. NEW & NOTEWORTHY Our work demonstrates a role for cardiac vanilloid receptor-1-expressing afferents in reflex processing of cardiovascular stress. Current understanding suggests that elimination of vanilloid receptor-1 afferents would decrease reflex cardiac sympathetic outflow. We found, paradoxically, that sympathetic outflow to the heart is instead enhanced at baseline and during cardiac stress.

Background and Objectives: Cognition in ESRD may be improved by kidney transplantation, but mechanisms are unclear. We explored patterns of resting-state networks with resting-state functional magnetic resonance imaging among patients with ESRD before and after kidney transplantation., Design, Setting, Participants, & Measurements: Thirty-seven patients with ESRD scheduled for kidney transplantation and 22 age-, sex-, and education-matched healthy subjects underwent resting-state functional magnetic resonance imaging. Patients were imaged before and 1 and 6 months after kidney transplantation. Functional connectivity of seven resting-state subnetworks was evaluated: default mode network, dorsal attention network, central executive network, self-referential network, sensorimotor network, visual network, and auditory network. Mixed effects models tested associations of ESRD, kidney transplantation, and neuropsychological measurements with functional connectivity., Results: Compared with controls, pretransplant patients showed abnormal functional connectivity in six subnetworks. Compared with pretransplant patients, increased functional connectivity was observed in the default mode network, the dorsal attention network, the central executive network, the sensorimotor network, the auditory network, and the visual network 1 and 6 months after kidney transplantation ( P =0.01). Six months after kidney transplantation, no significant difference in functional connectivity was observed for the dorsal attention network, the central executive network, the auditory network, or the visual network between patients and controls. Default mode network and sensorimotor network remained significantly different from those in controls when assessed 6 months after kidney transplantation. A relationship between functional connectivity and neuropsychological measurements was found in specific brain regions of some brain networks., Conclusions: The recovery patterns of resting-state subnetworks vary after kidney transplantation. The dorsal attention network, the central executive network, the auditory network, and the visual network recovered to normal levels, whereas the default mode network and the sensorimotor network did not recover completely 6 months after kidney transplantation. Neural resting-state functional connectivity was lower among patients with ESRD compared with control subjects, but it significantly improved with kidney transplantation. Resting-state subnetworks exhibited variable recovery, in some cases to levels that were no longer significantly different from those of normal controls., (Copyright © 2018 by the American Society of Nephrology.)

Autism spectrum disorder (ASD) is a developmental disability that is poorly understood. ASD can influence communication, social interaction, and behavior. Children with ASD often have sensory hypersensitivities, including auditory hypersensitivity (hyperacusis). In adults with hyperacusis who are otherwise neurotypical, the medial olivocochlear (MOC) efferent reflex is stronger than usual. In children with ASD, the MOC reflex has been measured, but without also assessing hyperacusis. We assessed the MOC reflex in children with ASD by measuring the strength of MOC-induced inhibition of transient-evoked otoacoustic emissions (TEOAEs), a noninvasive physiological measure that reflects cochlear amplification. MOC activity was evoked by contralateral noise. Hyperacusis was assessed subjectively on the basis of the children's symptoms. We found a significant correlation between hyperacusis scores and MOC strength in children with ASD. When children were divided into ASD-with-severe-hyperacusis (ASDs), ASD-with-not-severe-hyperacusis (ASDns), and neurotypical (NT) groups, the last two groups had similar hyperacusis and MOC reflexes, whereas the ASDs group, on average, had hyperacusis and MOC reflexes that were approximately twice as strong. The MOC inhibition of TEOAEs averaged larger at all frequencies in the ASDs compared with ASDns and NT groups. The results suggest that the MOC reflex can be used to estimate hyperacusis in children with ASD and might be used to validate future questionnaires to assess hyperacusis. Our results also provide evidence that strong MOC reflexes in children with ASD are associated with hyperacusis and that hyperacusis is a comorbid condition and is not a necessary, integral part of the abnormal neural processing associated with ASD. NEW & NOTEWORTHY Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms., (Copyright © 2017 the American Physiological Society.)

Motor control is a ubiquitous aspect of human function, and from its earliest origins, abnormal motor control has been proposed as being central to schizophrenia. The neurobiological architecture of the motor system is well understood in primates and involves cortical and sub-cortical components including the primary motor cortex, supplementary motor area, dorsal anterior cingulate cortex, the prefrontal cortex, the basal ganglia, and cerebellum. Notably all of these regions are associated in some manner to the pathophysiology of schizophrenia. At the molecular scale, both dopamine and γ-Aminobutyric Acid (GABA) abnormalities have been associated with working memory dysfunction, but particularly relating to the basal ganglia and the prefrontal cortex respectively. As evidence from multiple scales (behavioral, regional and molecular) converges, here we provide a synthesis of the bio-behavioral relevance of motor dysfunction in schizophrenia, and its consistency across scales. We believe that the selective compendium we provide can supplement calls arguing for renewed interest in studying the motor system in schizophrenia. We believe that in addition to being a highly relevant target for the study of schizophrenia related pathways in the brain, such focus provides tractable behavioral probes for in vivo imaging studies in the illness. Our assessment is that the motor system is a highly valuable research domain for the study of schizophrenia., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: The recent introduction of incision-less lesional neurosurgery using Gamma Knife and MRI-guided focused ultrasound has revived interest in lesional treatment options for tremor disorders. Preliminary literature researches reveal that the consistency of treatment effects after lesional neurosurgery for tremor has not formally been assessed yet. Similarly, the efficacy of different targets for lesional treatment and incidence of persistent side effects of lesional neurosurgical interventions has not been comprehensively assessed. This work therefore aims to describe a suitable process how to review the existing literature on efficacy and persistent side effects of lesional neurosurgical treatment for tremor due to Parkinson's disease, essential tremor, multiple sclerosis and midbrain/rubral tremor., Methods and Analysis: We will search electronic databases (Medline, Cochrane) and reference lists of included articles for studies reporting lesional interventions for tremor in cohorts homogeneous for tremor aetiology and intervention (technique and target). We will include cohorts with a minimum number of five subjects and follow-up of 2 months. One investigator will perform the initial literature search and two investigators then independently decide which references to include for final efficacy and safety analysis. After settling of disagreement, data will be extracted from articles using a standardised template. We will perform a random-effect meta-analysis calculating standardised mean differences (Hedge's g) for comparison in Forest plots and subgroup analysis after assessment of heterogeneity using I 2 statistics., Ethics and Dissemination: This study will summarise the available evidence on the efficacy of lesional interventions for the most frequent tremor disorders, as well as for the incidence rate of persisting side effects after unilateral lesional treatment. This data will be useful to guide future work on incision-less lesional interventions for tremor., Systematic Review Registration: This study has been registered with the PROSPERO database (no. CRD42016048049)., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Structural and functional changes attributable to the neurodegenerative process in Huntington's disease (HD) may be evident in HTT CAG repeat expansion carriers before the clinical manifestations of HD. It remains unclear, though, how far from motor onset a consistent signature of the neurodegenerative process in HD can be detected. Twelve far from onset preHD and 22 age-matched healthy control participants underwent volumetric structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting-state functional MRI (11 preHD, 22 controls) as well as electrophysiological measurements (12 preHD, 13 controls). There were no significant differences in white matter macro- and microstructure between far from onset preHD participants and controls. Functional connectivity in a basal ganglia-thalamic and motor networks, all measures of the motor efferent and sensory afferent pathways as well as sensory-motor integration were also similar in far from onset preHD and controls. With the methods used in far from onset preHD sensory-motor neural macro- or micro-structure and brain function were similar to healthy controls. This suggests that any observable structural and functional change in preHD nearer to onset, or in manifest HD, at least using comparable techniques such as in this study, most likely reflects an ongoing neurodegenerative process.

In 2002, the International Continence Society defined the term overactive bladder (OAB) as a symptom syndrome that is accompanied by urgency with or without urge incontinence, frequency and nocturia. A proven urinary tract infection or other obvious pathologies must be excluded.The pathophysiology of OAB has not been clarified in detail and is the subject of ongoing research, so partially overlapping hypotheses exist. The urothelium-based hypothesis suggests functional changes of urothelial receptors as well as functional changes regarding the sensitivity and coupling of the suburothelial myofibroblasts, which ultimately lead to increasing activity of afferent signals and urgency. The myogenic hypothesis is based on the assumption that unstable detrusor contractions may be triggered by changes in their excitability and coupling with other myocytes or myofibroblasts. Unstable detrusor contractions generate increased afferent activity followed by symptoms of overactive bladder. The hypothesis of abnormal processing of afferent signals assumes that damage to central inhibitory pathways and/or sensitisation of afferent nerves lead to the activation of the micturition reflex, which, in turn, induces unstable detrusor contractions. In addition, hormonal and psychological influences are discussed., (© Georg Thieme Verlag KG Stuttgart · New York.)

OBJECTIVE Warning criteria for monitoring of motor evoked potentials (MEP) after direct cortical stimulation during surgery for supratentorial tumors have been well described. However, little is known about the value of MEP after transcranial electrical stimulation (TES) in predicting postoperative motor deficit when monitoring threshold level. The authors aimed to evaluate the feasibility and value of this method in glioma surgery by using a new approach for interpreting changes in threshold level involving contra- and ipsilateral MEP. METHODS Between November 2013 and December 2014, 93 patients underwent TES-MEP monitoring during resection of gliomas located close to central motor pathways but not involving the primary motor cortex. The MEP were elicited by transcranial repetitive anodal train stimulation. Bilateral MEP were continuously evaluated to assess percentage increase of threshold level (minimum voltage needed to evoke a stable motor response from each of the muscles being monitored) from the baseline set before dural opening. An increase in threshold level on the contralateral side (facial, arm, or leg muscles contralateral to the affected hemisphere) of more than 20% beyond the percentage increase on the ipsilateral side (facial, arm, or leg muscles ipsilateral to the affected hemisphere) was considered a significant alteration. Recorded alterations were subsequently correlated with postoperative neurological deterioration and MRI findings. RESULTS TES-MEP could be elicited in all patients, including those with recurrent glioma (31 patients) and preoperative paresis (20 patients). Five of 73 patients without preoperative paresis showed a significant increase in threshold level, and all of them developed new paresis postoperatively (transient in 4 patients and permanent in 1 patient). Eight of 20 patients with preoperative paresis showed a significant increase in threshold level, and all of them developed postoperative neurological deterioration (transient in 4 patients and permanent in 4 patients). In 80 patients no significant change in threshold level was detected, and none of them showed postoperative neurological deterioration. The specificity and sensitivity in this series were estimated at 100%. Postoperative MRI revealed gross-total tumor resection in 56 of 82 patients (68%) in whom complete tumor resection was attainable; territorial ischemia was detected in 4 patients. CONCLUSIONS The novel threshold criterion has made TES-MEP a useful method for predicting postoperative motor deficit in patients who undergo glioma surgery, and has been feasible in patients with preoperative paresis as well as in patients with recurrent glioma. Including contra- and ipsilateral changes in threshold level has led to a high sensitivity and specificity.

In response to acute physiological stress, the sympathetic nervous system modifies neural outflow through increased firing frequency of lower-threshold axons, recruitment of latent subpopulations of higher-threshold axons, and/or acute modifications of synaptic delays. Aging and coronary artery disease (CAD) often modify efferent muscle sympathetic nerve activity (MSNA). Therefore, we investigated whether CAD (n = 14; 61 ± 10 yr) and/or healthy aging without CAD (OH; n = 14; 59 ± 9 yr) modified these recruitment strategies that normally are observed in young healthy (YH; n = 14; 25 ± 3 yr) individuals. MSNA (microneurography) was measured at baseline and during maximal voluntary end-inspiratory (EI) and end-expiratory (EE) apneas. Action potential (AP) patterns were studied using a novel AP analysis technique. AP frequency increased in all groups during both EI- and EE-apnea (all P < 0.05). The mean AP content per integrated burst increased during EI- and EE-apnea in YH (EI: Δ6 ± 4 APs/burst; EE: Δ10 ± 6 APs/burst; both P < 0.01) and OH (EI: Δ3 ± 3 APs/burst; EE: Δ4 ± 5 APs/burst; both P < 0.01), but not in CAD (EI: Δ1 ± 3 APs/burst; EE: Δ2 ± 3 APs/burst; both P = NS). When APs were binned into "clusters" according to peak-to-peak amplitude, total clusters increased during EI- and EE-apnea in YH (EI: Δ5 ± 2; EE: Δ6 ± 4; both P < 0.01), during EI-apnea only in OH (EI: Δ1 ± 2; P < 0.01; EE: Δ1 ± 2; P = NS), and neither apnea in CAD (EI: Δ -2 ± 2; EE: Δ -1 ± 2; both P = NS). In all groups, the AP cluster size-latency profile was shifted downwards for every corresponding cluster during EI- and EE-apnea (all P < 0.01). As such, inherent dysregulation exists within the central features of apnea-related sympathetic outflow in aging and CAD., (Copyright © 2016 the American Physiological Society.)

Objective: Motor overflow is a common and frustrating symptom of dystonia, manifested as unintentional muscle contraction that occurs during an intended voluntary movement. Although it is suspected that motor overflow is due to cortical disorganization in some types of dystonia (e.g. focal hand dystonia), it remains elusive which mechanisms could initiate and, more importantly, perpetuate motor overflow. We hypothesize that distinct motor elements have low risk of motor overflow if their sensory inputs remain statistically independent. But when provided with correlated sensory inputs, pre-existing crosstalk among sensory projections will grow under spike-timing-dependent-plasticity (STDP) and eventually produce irreversible motor overflow., Approach: We emulated a simplified neuromuscular system comprising two anatomically distinct digital muscles innervated by two layers of spiking neurons with STDP. The synaptic connections between layers included crosstalk connections. The input neurons received either independent or correlated sensory drive during 4 days of continuous excitation. The emulation is critically enabled and accelerated by our neuromorphic hardware created in previous work., Main Results: When driven by correlated sensory inputs, the crosstalk synapses gained weight and produced prominent motor overflow; the growth of crosstalk synapses resulted in enlarged sensory representation reflecting cortical reorganization. The overflow failed to recede when the inputs resumed their original uncorrelated statistics. In the control group, no motor overflow was observed., Significance: Although our model is a highly simplified and limited representation of the human sensorimotor system, it allows us to explain how correlated sensory input to anatomically distinct muscles is by itself sufficient to cause persistent and irreversible motor overflow. Further studies are needed to locate the source of correlation in sensory input.

Objective: To use a combination of electrophysiological techniques to determine the extent of preserved muscle activity below the clinically-defined level of motor-complete spinal cord injury., Methods: Transcranial magnetic stimulation and vestibular-evoked myogenic potentials were used to investigate whether there was any preserved muscle activity in trunk, hip and leg muscles of 16 individuals with motor-complete spinal cord injury (C4-T12) and 16 able-bodied matched controls., Results: Most individuals (14/16) with motor-complete spinal cord injury were found to have transcranial magnetic stimulation evoked, and/or voluntary evoked muscle activity in muscles innervated below the clinically classified lesion level. In most cases voluntary muscle activation was accompanied by a present transcranial magnetic stimulation response. Furthermore, motor-evoked potentials to transcranial magnetic stimulation could be observed in muscles that could not be voluntarily activated. Vestibular-evoked myogenic potentials responses were also observed in a small number of subjects, indicating the potential preservation of other descending pathways., Conclusion: These results highlight the importance of using multiple electrophysiological techniques to assist in determining the potential preservation of muscle activity below the clinically-defined level of injury in individuals with a motor-complete spinal cord injury. These techniques may provide clinicians with more accurate information about the state of various motor pathways, and could offer a method to more accurately target rehabilitation.

Neurons have a limited capacity to regenerate in the adult central nervous system (CNS). The inability of damaged axons to re-establish original circuits results in permanent functional impairment after spinal cord injury (SCI). Despite abortive regeneration of axotomized CNS neurons, limited spontaneous recovery of motor function emerges after partial SCI in humans and experimental rodent models of SCI. It is hypothesized that this spontaneous functional recovery is the result of the reorganization of descending motor pathways spared by the injury, suggesting that plasticity of intact circuits is a potent alternative conduit to enhance functional recovery after SCI. In support of this hypothesis, several studies have shown that after unilateral corticospinal tract (CST) lesion (unilateral pyramidotomy), the intact CST functionally sprouts into the denervated side of the spinal cord. Furthermore, pharmacologic and genetic methods that enhance the intrinsic growth capacity of adult neurons or block extracellular growth inhibitors are effective at significantly enhancing intact CST reorganization and recovery of motor function. Owing to its importance in controlling fine motor behavior in primates, the CST is the most widely studied descending motor pathway; however, additional studies in rodents have shown that plasticity within other spared descending motor pathways, including the rubrospinal tract, raphespinal tract, and reticulospinal tract, can also result in restoration of function after incomplete SCI. Identifying the molecular mechanisms that drive plasticity within intact circuits is crucial in developing novel, potent, and specific therapeutics to restore function after SCI. In this review we discuss the evidence supporting a focus on exploring the capacity of intact motor circuits to functionally repair the damaged CNS after SCI.

Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼ 140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼ 170 mmHg. RDNX reduced MAP ∼ 10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves., (Copyright © 2016 the American Physiological Society.)

Background: Amygdala dysfunction is hypothesized to underlie the social deficits observed in autism spectrum disorders (ASD). However, the neurobiological basis of this hypothesis is underspecified because it is unknown whether ASD relates to abnormalities of the amygdaloid input or output nuclei. Here, we investigated the functional connectivity of the amygdaloid social-perceptual input nuclei and emotion-regulation output nuclei in ASD versus controls., Methods: We collected resting state functional magnetic resonance imaging (fMRI) data, tailored to provide optimal sensitivity in the amygdala as well as the neocortex, in 20 adolescents and young adults with ASD and 25 matched controls. We performed a regular correlation analysis between the entire amygdala (EA) and the whole brain and used a partial correlation analysis to investigate whole-brain functional connectivity uniquely related to each of the amygdaloid subregions., Results: Between-group comparison of regular EA correlations showed significantly reduced connectivity in visuospatial and superior parietal areas in ASD compared to controls. Partial correlation analysis revealed that this effect was driven by the left superficial and right laterobasal input subregions, but not the centromedial output nuclei., Conclusions: These results indicate reduced connectivity of specifically the amygdaloid sensory input channels in ASD, suggesting that abnormal amygdalo-cortical connectivity can be traced down to the socio-perceptual pathways.

After injury, electrical stimulation of the nervous system can augment plasticity of spared or latent circuits through focal modulation. Pairing stimulation of two parts of a spared circuit can target modulation more specifically to the intended circuit. We discuss 3 kinds of paired stimulation in the context of the corticospinal system, because of its importance in clinical neurorehabilitation. The first uses principles of Hebbian plasticity: by altering the stimulation timing of presynaptic neurons and their postsynaptic targets, synapse function can be modulated up or down. The second form uses synchronized presynaptic inputs onto a common synaptic target. We dub this a "convergent" mechanism, because stimuli have to converge on a common target with coordinated timing. The third form induces focal modulation by tonic excitation of one region (e.g., the spinal cord) during phasic stimulation of another (e.g., motor cortex). Additionally, endogenous neural activity may be paired with exogenous electrical stimulation. This review addresses what is known about paired stimulation of the corticospinal system of both humans and animal models, emphasizes how it qualitatively differs from single-site stimulation, and discusses the gaps in knowledge that must be addressed to maximize its use and efficacy in neurorehabilitation.

Background: Studies have recognized that the damage in the subcortical and supratentorial regions may affect voluntary and involuntary aspects of the swallowing function. The current study attempted to explore the dysphagia characteristics in patients with subcortical and supratentorial stroke., Methods: Twelve post first or second subcortical and supratentorial stroke patients were included in the study. The location of the stroke was ascertained by computed tomography and magnetic resonance imaging. The characteristics of swallowing disorder were assessed by video fluoroscopic swallowing assessment/fiberoptic endoscopic evaluation of swallowing. The following main parameters were analyzed: oral transit time, pharyngeal delay time, presence of cricopharyngeal muscle achalasia (CMA), distance of laryngeal elevation, the amounts of vallecular residue and pyriform sinus residue (PSR), and the extent of pharyngeal contraction., Results: Eighty-three percent of the 12 patients were found suffering from pharyngeal dysphagia, with 50% having 50%-100% PSRs, 50% having pharyngeal delay, and 41.6% cases demonstrating CMA. Simple regression analysis showed PSRs were most strongly associated with CMA. Pharyngeal delay in the study can be caused by infarcts of basal ganglia/thalamus, infarcts of sensory tract, infarcts of swallowing motor pathways in the centrum semiovale, or a combination of the three., Conclusion: Subcortical and supratentorial stroke may result in pharyngeal dysphagia such as PSR and pharyngeal delay. PSR was mainly caused by CMA., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The aim of our study was to evaluate validity of transcranial magnetic stimulation as evaluation tool of motor pathways condition dynamics in patients with gliomas and meningitis. There were included 91 patients: 40 children with aseptic meningitis, 26 matching age controls, 10 adults with gliomas and 16 matching controls. All patients underwent transcranial magnetic stimulation (TMS) before and after the treatment. TMS showed good tolerability in all groups. Significant improvement of central motor pathways conductivity (MEPs amplitudes) was seen in both groups. In meningitis group significant rising of functional state of motoneurons was seen as well. We propose that TMS proved to be effective evaluation tool of motor pathways condition dynamic in patients with gliomas and meningitis.

Purpose: Abnormal structure or function in the central nervous system (CNS) can also affect obstructive sleep apnea (OSA). Because human afferent and motor pathways that regulate apnea are still poorly understood, it is not possible to modify the behavior of motor neurons to control airway function. The purpose of this article is to clear the central control mechanism of genioglossus (GG) and to discuss how altered activity in the limbic system and its related structures might affect OSA development, in order to provide help for the treatment of this disease., Methods: Functional magnetic resonance imaging (fMRI) data from previous studies on OSA-related brain damage in human beings plus the data from clinical and animal experiments are summarized. These articles are overviewed to discuss the roles of the limbic system-the insular cortex (Ic), the habenula (Hb), and CNS-in the pathogenesis and mechanisms of OSA., Results: The Ic, which relays signals through the Hb, may play a role in OSA because activating the Ic causes the Hb to suppress activity of the raphe nucleus (RN), resulting in lower levels of 5-hydroxytryptamine (5-HT) that decreases the muscle tone of the GG. This leads to airway collapse., Conclusions: The Ic may be an important region in the development of OSA. Altered activity in the limbic system and its related structures could also be associated with OSA.

Objective: For most patients, resolution of upper limb impairment during the first 6 months poststroke is 70% of the maximum possible. We sought to identify candidate mechanisms of this proportional recovery. We hypothesized that proportional resolution of upper limb impairment depends on ipsilesional corticomotor pathway function, is mirrored by proportional recovery of excitability in this pathway, and is unaffected by upper limb therapy dose., Methods: Upper limb impairment was measured in 93 patients at 2, 6, 12, and 26 weeks after first-ever ischemic stroke. Motor evoked potentials (MEPs) and motor threshold were recorded from extensor carpi radialis using transcranial magnetic stimulation, and fractional anisotropy (FA) in the posterior limbs of the internal capsules was determined with diffusion-weighted magnetic resonance imaging., Results: Initial impairment score, presence of MEPs and FA asymmetry were the only predictors of impairment resolution, indicating a key role for corticomotor tract function. By 12 weeks, upper limb impairment resolved by 70% in patients with MEPs regardless of their initial impairment, and ipsilesional rest motor threshold also resolved by 70%. Resolution of impairment was insensitive to upper limb therapy dose., Interpretation: These findings indicate that upper limb impairment resolves by 70% of the maximum possible, regardless of initial impairment, but only for patients with intact corticomotor function. Impairment resolution seems to reflect spontaneous neurobiological processes that involve the ipsilesional corticomotor pathway. A better understanding of these mechanisms could lead to interventions that increase resolution of impairment above 70%., (© 2015 American Neurological Association.)