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Objectives: Absence seizures impair psychosocial function, yet their detailed neuronal basis remains unknown. Recent work in a rat model suggests that cortical arousal state changes prior to seizures and that single neurons show diverse firing patterns during seizures. Our aim was to extend these investigations to a mouse model with studies of neuronal activity and arousal state to facilitate future fundamental investigations of absence epilepsy., Methods: We performed in vivo extracellular single unit recordings on awake head-fixed C3H/HeJ mice. Mice were implanted with tripolar electrodes for cortical electroencephalography (EEG). Extracellular single unit recordings were obtained with glass micropipettes in the somatosensory barrel cortex, while animals ambulated freely on a running wheel. Signals were digitized and analyzed during seizures and at baseline., Results: Neuronal activity was recorded from 36 cortical neurons in 19 mice while EEG showed characteristic 7-8 Hz spike-wave discharges. Different single neurons showed distinct firing patterns during seizures, but the overall mean population neuronal firing rate during seizures was no different from pre-seizure baseline. However, the rhythmicity of neuronal firing during seizures was significantly increased (p < 0.001). In addition, beginning 10s prior to seizure initiation, we observed a progressive decrease in cortical high frequency (>40 Hz) EEG and an increase in lower frequency (1-39 Hz) activity suggesting decreased arousal state., Significance: We found that the awake head-fixed C3H/HeJ mouse model demonstrated rhythmic neuronal firing during seizures, and a decreased cortical arousal state prior to seizure onset. Unlike the rat model we did not observe an overall decrease in neuronal firing during seizures. Similarities and differences across species strengthen the ability to investigate fundamental key mechanisms. Future work in the mouse model will identify the molecular basis of neurons with different firing patterns, their role in seizure initiation and behavioral deficits, with ultimate translation to human absence epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Movement constraints in stroke survivors are often accompanied by additional impairments in related somatosensory perception. A complex interplay between the primary somatosensory and motor cortices is essential for adequate and precise movements. This necessitates investigating the role of the primary somatosensory cortex in movement deficits of stroke survivors. The first step towards this goal could be a fast and reliable functional Magnetic Resonance Imaging (fMRI)-based mapping of the somatosensory cortex applicable for clinical settings. Here, we compare two 3 T fMRI-based somatosensory digit mapping techniques adapted for clinical usage in seven neurotypical volunteers and two sessions, to assess their validity and retest-reliability. Both, the traveling wave and the blocked design approach resulted in complete digit maps in both sessions of all participants, showing the expected layout. Similarly, no evidence for differences in the volume of activation, nor the activation overlap between neighboring activations could be detected, indicating the general feasibility of the clinical adaptation and their validity. Retest-reliability, indicated by the Dice coefficient, exhibited reasonable values for the spatial correspondence of single digit activations across sessions, but low values for the spatial correspondence of the area of overlap between neighboring digits across sessions. Parameters describing the location of the single digit activations exhibited very high correlations across sessions, while activation volume and overlap only exhibited medium to low correlations. The feasibility and high retest-reliabilities for the parameters describing the location of the single digit activations are promising concerning the implementation into a clinical context to supplement diagnosis and treatment stratification in upper limb stroke patients., (© 2024. The Author(s).)

This study describes cortical recordings in a large animal nerve injury model. We investigated differences in primary somatosensory cortex (S1) hyperexcitability when stimulating injured and uninjured nerves and how different cortical layers contribute to S1 hyperexcitability after spared ulnar nerve injury. We used a multielectrode array to record single-neuron activity in the S1 of ten female Danish landrace pigs. Electrical stimulation of the injured and uninjured nerve evoked brain activity up to 3 h after injury. The peak amplitude and latency of early and late peristimulus time histogram responses were extracted for statistical analysis. Histological investigations determined the layer of the cortex in which each electrode contact was placed. Nerve injury increased the early peak amplitude compared with that of the control group. This difference was significant immediately after nerve injury when the uninjured nerve was stimulated, while it was delayed for the injured nerve. The amplitude of the early peak was increased in layers III-VI after nerve injury compared with the control. In layer III, S1 excitability was also increased compared with preinjury for the early peak. Furthermore, the late peak was significantly larger in layer III than in the other layers in the intervention and control group before and after injury. Thus, the most prominent increase in excitability occurred in layer III, which is responsible for the gain modulation of cortical output through layer V. Therefore, layer III neurons seem to have an important role in altered brain excitability after nerve injury., (© 2024. The Author(s).)

Background: Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function., Methods: Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered., Results: Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41)., Conclusion: This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype., Significance Statement: Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks., (© 2024. The Author(s).)

Abstract: There is an urgent and unmet clinical need to develop nonpharmacological interventions for chronic pain management because of the critical side effects of opioids. Low-intensity transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly focused 128-element ultrasound transducer to specifically target small mouse brains using dynamic focus steering. We demonstrate that tFUS stimulation at pain-processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (eg, insula) and multisession focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitivity-related and chronic hyperalgesia-associated neural signals after focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting interexperiment intervals, and investigating effects on age, sex, and genotype in a head-fixed awake model. Importantly, tFUS was found to be safe, causing no adverse effects on motor function or the brain's neuropathology. In conclusion, the validated proof-of-principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Brain network hubs are highly connected brain regions serving as important relay stations for information integration. Recent studies have linked mental disorders to impaired hub function. Provincial hubs mainly integrate information within their own brain network, while connector hubs share information between different brain networks. This study used a novel time-varying analysis to investigate whether hubs aberrantly follow the trajectory of other brain networks than their own. The aim was to characterize brain hub functioning in clinically remitted bipolar patients. We analyzed resting-state functional magnetic resonance imaging data from 96 euthymic individuals with bipolar disorder and 61 healthy control individuals. We characterized different hub qualities within the somatomotor network. We found that the somatomotor network comprised mainly provincial hubs in healthy controls. Conversely, in bipolar disorder patients, hubs in the primary somatosensory cortex displayed weaker provincial and stronger connector hub function. Furthermore, hubs in bipolar disorder showed weaker allegiances with their own brain network and followed the trajectories of the limbic, salience, dorsal attention, and frontoparietal network. We suggest that these hub aberrancies contribute to previously shown functional connectivity alterations in bipolar disorder and may thus constitute the neural substrate to persistently impaired sensory integration despite clinical remission., (© The Author(s) 2024. Published by Oxford University Press.)

Altered functional connectivity has been demonstrated in key brain regions involved in pain processing in painful diabetic peripheral neuropathy. However, the impact of neuropathic pain treatment on functional connectivity does not appear to have been investigated. Sixteen participants underwent resting state functional MRI when optimally treated for neuropathic pain during their involvement in the Optimal Pathway for Treating Neuropathic Pain in Diabetes Mellitus trial and 1 week following withdrawal of treatment. On discontinuation of pain treatment, there was an increase in functional connectivity between the left thalamus and primary somatosensory cortex (S1) and the left thalamus and insular cortex, key brain regions that are involved in cerebral processing of pain. The changes in functional connectivity between scans also correlated with measures of pain (baseline pain severity and Neuropathic Pain Symptom Inventory). Moreover, when participants were stratified into higher- and lower-than-average baseline pain subgroups, the change in thalamic-S1 cortical functional connectivity between scans was significantly greater in those with high baseline pain compared with the lower-baseline-pain group. This study shows that thalamo-cortical functional connectivity has the potential to act as an objective biomarker for neuropathic pain in diabetes for use in clinical pain trials., (© 2024 by the American Diabetes Association.)

Classic attachment theory emphasizes the sensitivity of the parent to perceive and appropriately respond to the infant's cues. However, parent-child attachment is a dyadic interaction that is also dependent upon the sensitivity of the child to the early caregiving environment. Individual differences in infant sensitivity to parental cues is likely shaped by both the early caregiving environment as well as the infant's neurobiology, such as perceptual sensitivity to social stimuli. Here, we investigated associations between maternal postpartum depression and infant neurological sensitivity to affective touch using brain signal entropy - a metric of the brain's moment-to-moment variability related to signal processing. We recruited two independent samples of infants aged 0-5 months. In Sample 1 (n = 79), we found increased levels of maternal postpartum depression were associated with diminished perceptual sensitivity - i.e. lower entropy - to affective tactile stimulation specifically within the primary somatosensory cortex. In Sample 2 (n = 36), we replicated this finding and showed that this effect was not related to characteristics of the touch administered during the experiment. These results suggest that decreased affective touch early in life - a common consequence of postpartum depression - likely impacts the infant's perceptual sensitivity to affective touch and ultimately the formation of experience-dependent neural networks that support the successful formation of attachment relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice., Methods: Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca 2+ imaging. CCI-induced changes in responses were analyzed., Results: Before CCI, whisker stimulation induced a greater Ca 2+ response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca 2+ response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca 2+ response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca 2+ response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels., Conclusion: These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words)., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine., Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain., Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed., Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification., Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed., (© 2024 American Headache Society.)

Background: Motor impairments and sensory processing abnormalities are prevalent in autism spectrum disorder (ASD), closely related to the core functions of the primary motor cortex (M1) and the primary somatosensory cortex (S1). Currently, there is limited knowledge about potential therapeutic targets in the subregions of M1 and S1 in ASD patients. This study aims to map clinically significant functional subregions of M1 and S1., Methods: Resting-state functional magnetic resonance imaging data (NTD = 266) from Autism Brain Imaging Data Exchange (ABIDE) were used for subregion modeling. We proposed a distance-weighted sparse representation algorithm to construct brain functional networks. Functional subregions of M1 and S1 were identified through consensus clustering at the group level. Differences in the characteristics of functional subregions were analyzed, along with their correlation with clinical scores., Results: We observed symmetrical and continuous subregion organization from dorsal to ventral aspects in M1 and S1, with M1 subregions conforming to the functional pattern of the motor homunculus. Significant intergroup differences and clinical correlations were found in the dorsal and ventral aspects of M1 (p < 0.05/3, Bonferroni correction) and the ventromedial BA3 of S1 (p < 0.05/5). These functional characteristics were positively correlated with autism severity. All subregions showed significant results in the ROI-to-ROI intergroup differential analysis (p < 0.05/80)., Limitations: The generalizability of the segmentation model requires further evaluation., Conclusions: This study highlights the significance of M1 and S1 in ASD treatment and may provide new insights into brain parcellation and the identification of therapeutic targets for ASD., Competing Interests: Declaration of competing interest This is an original manuscript and no parts of this manuscript are being considered for publication elsewhere. All authors have approved this manuscript. The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction/aims: While amyotrophic lateral sclerosis (ALS) is primarily characterized as a motor system disorder, there is a growing body of evidence indicating sensory involvement. This study aimed to examine the hypothesis that somatosensory processing is impaired in ALS., Methods: Study participants were ALS patients followed at the Neuromuscular Outpatient Unit, as well as healthy volunteers, from March 2021 to July 2023. The Medical Research Council (MRC) sum score was calculated for nine muscle groups bilaterally. The clinical status of patients was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Penn Upper Motor Neuron core. Somatosensory temporal discrimination thresholds (STDTs) were recorded on the medial and lateral parts of both hands. Somatosensory cortex excitability was investigated with the paired somatosensory evoked potentials (SEP) paradigm in a subgroup., Results: Increased STD values were detected in ALS patients compared to controls in both medial (107.66 ± 35 ms vs. 82.7 ± 32.5 ms, p = .001) and lateral (106.5 ± 34.5 ms vs. 82.9 ± 31.3 ms, p = .002) hands. There were no significant differences in STDTs among ALS patients across four regions (medial and lateral parts of the right and left hands). Amplitude ratios obtained from the paired-pulse SEP paradigm were approximately 1 for all interstimulus intervals (ISIs). STDTs did not show any correlations with motor findings or scales., Discussion: Somatosensory processing appears to be compromised among ALS patients. The lack of correlation between impaired STDT and motor findings implies that it is a purely sensory deficit in ALS., (© 2024 Wiley Periodicals LLC.)

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe (TL) seizures induced by penicillin injection in the hippocampus (HPC) of two nonhuman primates. The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then compared the 3-second segments recorded in pre-ictal, onset, offset and post-ictal periods based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This study constitutes the first demonstration of TL seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the onset and offset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests:Robert E. Gross serves as a consultant to Medtronic, which manufactures products related to the research described in this manuscript and receives compensation for these services. He also receives support for unrelated research. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policiesThis does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Connolly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Atypical sensory processing is common in autism, but how neural coding is disrupted in sensory cortex is unclear. We evaluate whisker touch coding in L2/3 of somatosensory cortex (S1) in Cntnap2 -/- mice, which have reduced inhibition. This classically predicts excess pyramidal cell spiking, but this remains controversial, and other deficits may dominate. We find that c-fos expression is elevated in S1 of Cntnap2 -/- mice under spontaneous activity conditions but is comparable to that of control mice after whisker stimulation, suggesting normal sensory-evoked spike rates. GCaMP8m imaging from L2/3 pyramidal cells shows no excess whisker responsiveness, but it does show multiple signs of degraded somatotopic coding. This includes broadened whisker-tuning curves, a blurred whisker map, and blunted whisker point representations. These disruptions are greater in noisy than in sparse sensory conditions. Tuning instability across days is also substantially elevated in Cntnap2 -/- . Thus, Cntnap2 -/- mice show no excess sensory-evoked activity, but a degraded and unstable tactile code in S1., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Central post-stroke pain (CPSP) is a chronic pain resulting from a lesion in somatosensory pathways. Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) that target the primary motor cortex (M1), have shown promise for the treatment of CPSP. High-frequency (Hf) rTMS exhibits analgesic effects compared to low-frequency (Lf) rTMS; however, its analgesic mechanism is unknown. We aimed to elucidate the mechanism of rTMS-induced analgesia by evaluating alterations of tactile functional magnetic resonance imaging (fMRI) due to Hf- and Lf-rTMS in a CPSP monkey model. Consistent with the patient findings, the monkeys showed an increase in pain threshold after Hf-rTMS, which indicated an analgesic effect. However, no change after Lf-rTMS was observed. Compared to Lf-rTMS, Hf-rTMS produced enhanced tactile-evoked fMRI signals not only in M1 but also in somatosensory processing regions, such as the primary somatosensory and midcingulate cortices. However, the secondary somatosensory cortex (S2) was less active after Hf-rTMS than after Lf-rTMS, suggesting that activation of this region was involved in CPSP. Previous studies showed pharmacological inhibition of S2 reduces CPSP-related behaviors, and the present results emphasize the involvement of an S2 inhibitory system in rTMS-induced analgesia. Verification using the monkey model is important to elucidate the inhibition system., (© 2024. The Author(s).)

Objective: Infant hypersensitivity affects daily challenges and parental stress. Although the crucial role of tactile sensation in infants' brain function has been highlighted, hypersensitive infants and their families lack support. Electroencephalography may be useful for understanding hypersensitivity traits. We investigated the relationship between infant perceptual hypersensitivity and parental stress, somatosensory-evoked potential (SEP), and magnitude-squared coherence (MSC) in the general population., Methods: Infants aged 8 months (n = 63) were evaluated for hypersensitivity and parental stress using a questionnaire and for cortical activity using electroencephalography. Vibration stimuli were applied to the infant's left foot. SEP components that peaked around 150 ms (N2) and at 200 ms (P2) after stimulus onset were evaluated by amplitude and latency at the midline electrode (Cz) and MSC between the midline electrodes (C3-C4)., Results: Parental stress was associated with infant hypersensitivity. The latency of Cz was delayed, and C3-C4 delta MSC was high in infants with hypersensitivity., Conclusions: Increasing inter-hemispheric MSC synchrony in the stimulated condition in infants with hypersensitivity suggested atypical somatosensory cortical function., Significance: These findings contribute to identifying, understanding the mechanisms of, and developing effective coping strategies for early-stage hypersensitivity., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Pain perception mechanisms in cerebral palsy remain largely unclear., Aims: This study investigates brain activity in adults with cerebral palsy during painful and non-painful stretching to elucidate their pain processing characteristics., Methods and Procedures: Twenty adults with cerebral palsy and 20 controls underwent EEG in three conditions: rest, non-painful stretching, and painful stretching. Time-frequency power density of theta, alpha, and beta waves in somatosensory and frontal cortices was analyzed, alongside baseline pressure pain thresholds., Outcomes and Results: Cerebral palsy individuals exhibited higher theta, alpha, and beta power density in both cortices during painful stretching compared to rest, and lower during non-painful stretching. Controls showed higher power density during non-painful stretching but lower during painful stretching. Cerebral palsy individuals had higher pain sensitivity, with those more sensitive experiencing greater alpha power density., Conclusions and Implications: These findings confirm alterations in the cerebral processing of pain in individuals with cerebral palsy. This knowledge could enhance future approaches to the diagnosis and treatment of pain in this vulnerable population., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Touch is an essential form of mother-child interaction, instigating better social bonding and emotional stability., Methods: We used diffuse optical tomography to explore the relationship between total haemoglobin (HbT) responses to affective touch in the child's brain at two years of age and maternal self-reported prenatal depressive symptoms (EPDS). Affective touch was implemented via slow brushing of the child's right forearm at 3 cm/s and non-affective touch via fast brushing at 30 cm/s and HbT responses were recorded on the left hemisphere., Results: We discovered a cluster in the postcentral gyrus exhibiting a negative correlation (Pearson's r = -0.84, p = 0.015 corrected for multiple comparisons) between child HbT response to affective touch and EPDS at gestational week 34. Based on region of interest (ROI) analysis, we found negative correlations between child responses to affective touch and maternal prenatal EPDS at gestational week 14 in the precentral gyrus, Rolandic operculum and secondary somatosensory cortex. The responses to non-affective touch did not correlate with EPDS in these regions., Limitations: The number of mother-child dyads was 16. However, by utilising high-density optode arrangements, individualised anatomical models, and video and accelerometry to monitor movement, we were able to minimize methodological sources of variability in the data., Conclusions: The results show that maternal depressive symptoms during pregnancy may be associated with reduced child responses to affective touch in the temporoparietal cortex. Responses to affective touch may be considered as potential biomarkers for psychosocial development in children. Early identification of and intervention in maternal depression may be important already during early pregnancy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

An epidemic of sleep loss currently affects modern societies worldwide and is implicated in numerous physiological disorders, including pain sensitization, although few studies have explored the brain pathways affected by active sleep deprivation (ASD; e.g., due to recreation). Here, we describe a neural circuit responsible for pain sensitization in mice treated with 9-h non-stress ASD. Using a combination of advanced neuroscience methods, we found that ASD stimulates noradrenergic inputs from locus coeruleus (LC NA ) to glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HL Glu ). Moreover, artificial inhibition of this LC NA →S1HL Glu pathway alleviates ASD-induced pain sensitization in mice, while chemogenetic activation of this pathway recapitulates the pain sensitization observed following ASD. Our study thus implicates activation of the LC NA →S1HL Glu pathway in ASD-induced pain sensitization, expanding our fundamental understanding of the multisystem interplay involved in pain processing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Speech brain-machine interfaces (BMIs) translate brain signals into words or audio outputs, enabling communication for people having lost their speech abilities due to diseases or injury. While important advances in vocalized, attempted and mimed speech decoding have been achieved, results for internal speech decoding are sparse and have yet to achieve high functionality. Notably, it is still unclear from which brain areas internal speech can be decoded. Here two participants with tetraplegia with implanted microelectrode arrays located in the supramarginal gyrus (SMG) and primary somatosensory cortex (S1) performed internal and vocalized speech of six words and two pseudowords. In both participants, we found significant neural representation of internal and vocalized speech, at the single neuron and population level in the SMG. From recorded population activity in the SMG, the internally spoken and vocalized words were significantly decodable. In an offline analysis, we achieved average decoding accuracies of 55% and 24% for each participant, respectively (chance level 12.5%), and during an online internal speech BMI task, we averaged 79% and 23% accuracy, respectively. Evidence of shared neural representations between internal speech, word reading and vocalized speech processes was found in participant 1. SMG represented words as well as pseudowords, providing evidence for phonetic encoding. Furthermore, our decoder achieved high classification with multiple internal speech strategies (auditory imagination/visual imagination). Activity in S1 was modulated by vocalized but not internal speech in both participants, suggesting no articulator movements of the vocal tract occurred during internal speech production. This work represents a proof-of-concept for a high-performance internal speech BMI., (© 2024. The Author(s).)

Purpose: Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation., Methods: Micro-electrode arrays containing 16 (animal 1) or 32 electrodes (animal 2-7) were implanted in the primary somatosensory cortex of seven female pigs, and continuous electrical stimulation was applied at 0.2 Hz to a cuff electrode implanted on the ulnar nerve. Ischemic stroke was induced after 30 min of baseline recording by injection of endothelin-1 onto the cortex adjacent to the micro-electrode array. Evoked responses were extracted over a moving window of 180 s and averaged across channels as a measure of cortical excitability., Results: Across the animals, the cortical excitability was significantly reduced in all seven 30 min segments following endothelin-1 injection, as compared to the 30 min preceding this intervention. This difference was not explained by changes in the anesthesia, ventilation, end-tidal CO 2 , mean blood pressure, heart rate, blood oxygenation, or core temperature, which all remained stable throughout the experiment., Conclusions: The animal model may assist in maturing neuroprotective approaches by testing them in an accessible model of resemblance to human neural and cardiovascular physiology and body size. This would constitute an intermediate step for translating positive results from rodent studies into human application, by more efficiently enabling effective optimization prior to chronic pre-clinical studies in large animals.

Facial palsy can result in a serious complication known as facial synkinesis, causing both physical and psychological harm to the patients. There is growing evidence that patients with facial synkinesis have brain abnormalities, but the brain mechanisms and underlying imaging biomarkers remain unclear. Here, we employed functional magnetic resonance imaging (fMRI) to investigate brain function in 31 unilateral post facial palsy synkinesis patients and 25 healthy controls during different facial expression movements and at rest. Combining surface-based mass-univariate analysis and multivariate pattern analysis, we identified diffused activation and intrinsic connection patterns in the primary motor cortex and the somatosensory cortex on the patient's affected side. Further, we classified post facial palsy synkinesis patients from healthy subjects with favorable accuracy using the support vector machine based on both task-related and resting-state functional magnetic resonance imaging data. Together, these findings indicate the potential of the identified functional reorganizations to serve as neuroimaging biomarkers for facial synkinesis diagnosis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Central sulcus localization is undertaken intraoperatively with subdural electrodes through a phase reversal technique using somatosensory evoked potentials from sensorimotor cortices. Extraoperative central sulcus localization using stereoelectroencephalography has not been described previously., Methods: Six pediatric patients (aged 12-18 years, 50% females) were investigated with stereoelectroencephalography. Peripheral median and posterior tibial nerve stimulation were performed while recording somatosensory evoked potentials from stereoelectroencephalography electrodes., Results: Central sulcus was successfully localized by this novel method, and this was further supplemented by cortical stimulation data., Conclusions: This is the first report of somatosensory evoked potentials gained using stereoelectroencephalography in primary motor and sensory cortices. This can further supplement other data for safe surgical resection in the eloquent cortex., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Despite substantial progress in mapping the trajectory of network plasticity resulting from focal ischemic stroke, the extent and nature of changes in neuronal excitability and activity within the peri-infarct cortex of mice remains poorly defined. Most of the available data have been acquired from anesthetized animals, acute tissue slices, or infer changes in excitability from immunoassays on extracted tissue, and thus may not reflect cortical activity dynamics in the intact cortex of an awake animal. Here, in vivo two-photon calcium imaging in awake, behaving mice was used to longitudinally track cortical activity, network functional connectivity, and neural assembly architecture for 2 months following photothrombotic stroke targeting the forelimb somatosensory cortex. Sensorimotor recovery was tracked over the weeks following stroke, allowing us to relate network changes to behavior. Our data revealed spatially restricted but long-lasting alterations in somatosensory neural network function and connectivity. Specifically, we demonstrate significant and long-lasting disruptions in neural assembly architecture concurrent with a deficit in functional connectivity between individual neurons. Reductions in neuronal spiking in peri-infarct cortex were transient but predictive of impairment in skilled locomotion measured in the tapered beam task. Notably, altered neural networks were highly localized, with assembly architecture and neural connectivity relatively unaltered a short distance from the peri-infarct cortex, even in regions within 'remapped' forelimb functional representations identified using mesoscale imaging with anaesthetized preparations 8 weeks after stroke. Thus, using longitudinal two-photon microscopy in awake animals, these data show a complex spatiotemporal relationship between peri-infarct neuronal network function and behavioral recovery. Moreover, the data highlight an apparent disconnect between dramatic functional remapping identified using strong sensory stimulation in anaesthetized mice compared to more subtle and spatially restricted changes in individual neuron and local network function in awake mice during stroke recovery., Competing Interests: MB, IW No competing interests declared, (© 2023, Bandet and Winship.)

This study examined how gait adaptation during predictable and non-predictable obstacle avoidance affects the sensorimotor network in both healthy controls (HC) and persons with multiple sclerosis (pwMS). We utilized fNIRS measurements of HbO2 and HHb to estimate cortical activations and connectivity networks, which were then analyzed using power spectral density (PSD) and partial directed coherence (PDC). The findings revealed distinct patterns of cortical activation and connectivity for each task condition in both groups. Healthy individuals displayed lower cortical activations in the bilateral motor cortex (MC) during non-predictable obstacle avoidance, indicating efficient neural processing. On the other hand, pwMS exhibited lower cortical activations across most brain areas during non-predictable tasks, suggesting potential limitations in neural resource allocation. When tasks were combined, pwMS demonstrated higher cortical activation across all recorded brain areas compared to HC, indicating a compensatory mechanism to maintain gait stability. Functional connectivity analysis revealed that pwMS recruited higher bilateral somatosensory association cortex (SAC) than HC, whereas healthy individuals engaged more bilateral premotor cortices (PMC). These findings suggest alterations in sensorimotor integration and motor planning in pwMS. Four machine learning models (KNN, SVM, DT, and DA) achieved high classification accuracies (92-99%) in differentiating between task conditions within each group. These results highlight the potential of integrating fNIRS-based cortical activation and connectivity measures with machine learning as biomarkers for MS-related impairments in cognitive-motor interaction. Such biomarkers could aid in predicting future mobility decline, fall risk, and disease progression.

Determining the mechanistic causes of complex biopsychosocial health conditions such as low back pain (LBP) is challenging, and research is scarce. Cross-sectional studies demonstrate altered excitability and organization of the somatosensory and motor cortex in people with acute and chronic LBP, however, no study has explored these mechanisms longitudinally or attempted to draw causal inferences. Using sensory evoked potential area measurements and transcranial magnetic stimulation derived map volume we analyzed somatosensory and motor cortex excitability in 120 adults experiencing acute LBP. Following multivariable regression modelling with adjustment for confounding, we identified lower primary (OR = 2.08, 95% CI = 1.22-3.57) and secondary (OR = 2.56, 95% CI = 1.37-4.76) somatosensory cortex excitability significantly increased the odds of developing chronic pain at 6-month follow-up. Corticomotor excitability in the acute stage of LBP was associated with higher pain intensity at 6-month follow-up (B = -0.15, 95% CI: -0.28 to -0.02) but this association did not remain after confounder adjustment. These data provide evidence that low somatosensory cortex excitability in the acute stage of LBP is a cause of chronic pain. PERSPECTIVE: This prospective longitudinal cohort study design identified low sensorimotor cortex excitability during the acute stage of LBP in people who developed chronic pain. Interventions that target this proposed mechanism may be relevant to the prevention of chronic pain., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Stroke individuals' daily function has been demonstrated to be influenced by their somatosensory capability, cognitive capability, and upper extremity (UE) motor abilities. However, the structural relationships among these abilities on stroke individuals' independence in daily function remain unclear. We analyzed the pretest measures of 153 stroke individuals in outpatient rehabilitation settings by structural equation modeling to determine the structural relationship among somatosensory capability, UE muscle strength, UE motor function, and cognitive capability that influences independence in daily function. The standardized results indicated somatosensory capability negatively influenced UE muscle strength, but positively influenced UE muscle strength mediated by UE motor function. UE muscle strength, then, positively influenced individuals' independence in daily function. On the other hand, somatosensory capability positively influenced cognitive capability, which marginally and positively affected the performance of independence in daily function. To the best of our knowledge, this is the first study to demonstrate the influence of somatosensory capability on the daily function is mediated mainly by motor functions and marginally by cognitive capability. This structural model may allow future clinical therapists to design more effective task-related training protocols to promote the independence in daily function for stroke individuals., (© 2022. The Author(s).)

Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms., (© 2022. The Author(s).)

The primary somatosensory cortex (S1) plays a critical role in processing multiple somatosensations, but the mechanism underlying the representation of different submodalities of somatosensation in S1 remains unclear. Using in vivo two-photon calcium imaging that simultaneously monitors hundreds of layer 2/3 pyramidal S1 neurons of awake male mice, we examined neuronal responses triggered by mechanical, thermal, or pruritic stimuli. We found that mechanical, thermal, and pruritic stimuli activated largely overlapping neuronal populations in the same somatotopic S1 subregion. Population decoding analysis revealed that the local neuronal population in S1 encoded sufficient information to distinguish different somatosensory submodalities. Although multimodal S1 neurons responding to multiple types of stimuli exhibited no spatial clustering, S1 neurons preferring mechanical and thermal stimuli tended to show local clustering. These findings demonstrated the coding scheme of different submodalities of somatosensation in S1, paving the way for a deeper understanding of the processing and integration of multimodal somatosensory information in the cortex. SIGNIFICANCE STATEMENT Cortical processing of somatosensory information is one of the most fundamental aspects in cognitive neuroscience. Previous studies mainly focused on mechanical sensory processing within the rodent whisking system, but mechanisms underlying the coding of multiple somatosensations remain largely unknown. In this study, we examined the representation of mechanical, thermal, and pruritic stimuli in S1 by in vivo two-photon calcium imaging of awake mice. We revealed a multiplexed representation for multiple somatosensory stimuli in S1 and demonstrated that the activity of a small population of S1 neurons is capable of decoding different somatosensory submodalities. Our results elucidate the coding mechanism for multiple somatosensations in S1 and provide new insights that improve the present understanding of how the brain processes multimodal sensory information., (Copyright © 2021 the authors.)

Because the presence of pain impedes motor recovery in individuals with spinal cord injury (SCI), it is necessary to understand their supraspinal substrates in translational animal models. Using functional magnetic resonance imaging (fMRI) in a rat model of hemicontusion cervical SCI, supraspinal changes were mapped and correlated with sensorimotor behavioral outcomes. Female adult rats underwent sham or SCI using a 2.5 mm impactor and 150 kdyn force. SCI permanently impaired motor activity in only the ipsilesional forelimb along with thermal hyperalgesia at 5 and 6 weeks. Spinal MRI at 8 weeks after SCI showed ipsilateral T1 and T2 lesions with no discernable lesions across shams. fMRI mapping during electrical forepaw stimulation indicated SCI-induced sensorimotor reorganization with an expansion of the contralesional forelimb representation. Resting state fMRI-based functional connectivity density (FCD), a marker of regional neuronal hubs, increased or decreased across brain regions involved in nociception. FCD increases after SCI were in the primary and secondary somatosensory cortices (S1 and S2), anterior cingulate cortex (ACC), insula, and the pre-frontal cortex (PFC), and decreases were across the hippocampus, thalamus, hypothalamus, and amygdala in SCI. Resting state functional connectivity (RSFC) assessments from the FCD altered regions of interest indicated cortico-cortical RSFC increases and cortico-insular, cortico-thalamic, and cortico-hypothalamic RSFC decreases after SCI. Hippocampus, amygdala, and thalamus showed decreased RSFC with most cortical regions and between themselves except the hippocampus-amygdala network, which showed increased RSFC after SCI. Whereas select nociceptive region's intrinsic activity associated strongly with evoked pain behaviors after SCI (e.g., PFC, ACC, hippocampus, thalamus, hypothalamus, M1, and S1 BF ) other nociceptive regions had weaker associations (e.g., amygdala, insula, auditory cortex, S1 FL , S1 HL , S2, and M2), but differed significantly in their intrinsic activities between sham and SCI. The weaker associated nociceptive regions may possibly encode both the evoked and affective components of pain.

Aim: To synthetize studies assessing somatosensory deficits and alterations in cerebral responses evoked by somatosensory stimulation in individuals with cerebral palsy (CP) compared to typically developing individuals., Method: A scoping review of the literature was performed in the MEDLINE, Embase, PsycInfo, CINAHL, Evidence-Based Medicine Reviews, and Web of Science databases (last search carried out on 6th and 7th August 2020) with a combination of keywords related to CP and somatosensory functions. Somatosensory deficits were measured with clinical tests and alterations in cerebral responses were measured with functional magnetic resonance imaging, electroencephalography, and magnetoencephalography., Results: Forty-eight articles were included. Overall, 1463 participants with CP (mean [SD] age 13y 1mo [4y 11mo], range 1-55y; 416 males, 319 females, sex not identified for the remaining participants) and 1478 controls (mean [SD] age 13y 1mo [5y 8mo], range 1-42y; 362 males, 334 females, sex not identified for the remaining participants) were included in the scoping review. For tactile function, most studies reported registration (8 out of 13) or perception (21 out of 21) deficits in participants with CP. For proprioception, most studies also reported registration (6 out of 8) or perception (10 out of 15) deficits. Pain function has not been studied as much, but most studies reported registration (2 out of 3) or perception (3 out of 3) alterations. Neuroimaging findings (18 studies) showed alterations in the somatotopy, morphology, latency, or amplitude of cortical responses evoked by somatosensory stimuli., Interpretation: Despite the heterogeneity in the methods employed, most studies reported somatosensory deficits. The focus has been mainly on tactile and proprioceptive function, whereas pain has received little attention. Future research should rigorously define the methods employed and include a sample that is more representative of the population with CP. What this paper adds Most of the papers reviewed found tactile registration and perception deficits in the upper limbs. Proprioceptive deficits were generally observed in cerebral palsy but results were heterogeneous. Pain has received little attention compared to tactile and proprioceptive functions. Neuroimaging studies supported behavioral observations. Alterations were observed for both the most and least affected limb., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception., (© 2021. The Author(s).)

Background: Alzheimer's disease (AD) is generally thought to spare primary sensory function; however, such interpretations have drawn from a literature that has rarely taken into account the variable cognitive declines seen in patients with AD. As these cognitive domains are now known to modulate cortical somatosensory processing, it remains possible that abnormalities in somatosensory function in patients with AD have been suppressed by neuropsychological variability in previous research., Methods: In this study, we combine magnetoencephalographic (MEG) brain imaging during a paired-pulse somatosensory gating task with an extensive battery of neuropsychological tests to investigate the influence of cognitive variability on estimated differences in somatosensory function between biomarker-confirmed patients on the AD spectrum and cognitively-normal older adults., Findings: We show that patients on the AD spectrum exhibit largely non-significant differences in somatosensory function when cognitive variability is not considered (p-value range: .020-.842). However, once attention and processing speed abilities are considered, robust differences in gamma-frequency somatosensory response amplitude (p < .001) and gating (p = .004) emerge, accompanied by significant statistical suppression effects., Interpretation: These findings suggest that patients with AD exhibit insults to functional somatosensory processing in primary sensory cortices, but these effects are masked by variability in cognitive decline across individuals., Funding: National Institutes of Health, USA; Fremont Area Alzheimer's Fund, USA., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest. Dr. Murman reported receiving grants from Green Valley Pharmaceuticals, Functional Neuromodulation, Roche, and Eli Lilly and Co. and serving on an advisory board for Biogen. Dr. Wilson reported serving as a board member for the American Clinical Magnetoencephalography Society and the International Society for the Advancement of Clinical Magnetoencephalography., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Altered brain activity and functional reorganization patterns during self-initiated movements have been reported in early pre-motor and motor stages of Parkinson's disease. The aim of this study was to investigate whether similar alterations can be observed in patients with idiopathic REM-sleep behavior disorder (RBD)., Methods: 13 polysomnography-confirmed male and right-handed RBD patients and 13 healthy controls underwent a bilateral hand-movement fMRI task including internally selected (INT) and externally-guided (EXT) movement conditions for each hand. We examined functional activity and connectivity differences between groups and task-conditions, structural differences using voxel-based morphometry, as well as associations between functional activity and clinical variables., Results: No group differences were observed in fMRI-task performance or in voxel-based morphometry. Both groups showed faster reaction times and exhibited greater neural activation when movements were internally selected compared to externally-guided tasks. Compared to controls, RBD patients displayed stronger activation in the dorsolateral prefrontal cortex and primary somatosensory cortex during INT-tasks, and in the right fronto-insular cortex during EXT-tasks performed with the non-dominant hand. Stronger activation in RBD patients was associated with cognitive and olfactory impairment. Connectivity analysis demonstrated overall less interregional coupling in patients compared to controls. In particular, patients showed reduced temporo-cerebellar, occipito-cerebellar and intra-cerebellar connectivity, but stronger connectivity in fronto-cerebellar and fronto-occipital pathways., Conclusion: The observed stronger activation during hand-movement tasks and connectivity changes in RBD may reflect early compensatory and reorganization patterns in order to preserve motor functioning. Our findings may contribute to a better understanding and prognosis of prodromal stages of α-synucleinopathies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Children with hemiplegic cerebral palsy (HCP) often show disturbances of somatosensation. Despite extensive evidence of somatosensory deficits, neurophysiological alterations associated with somatosensory deficits in children with HCP have not been elucidated. Here, we aim to assess phase synchrony within and between contralateral primary (S1) and secondary (S2) somatosensory areas in children with HCP. Intra-regional and inter-regional phase synchronizations within and between S1 and S2 were estimated from somatosensory evoked fields (SEFs) in response to passive pneumatic stimulation of contralateral upper extremities and recorded with pediatric magnetoencephalography (MEG) in children with HCP and typically developing (TD) children. We found aberrant phase synchronizations within S1 and between S1 and S2 in both hemispheres in children with HCP. Specifically, the less-affected (LA) hemisphere demonstrated diminished phase synchronizations after the stimulus onset up to ~120 ms compared to the more-affected (MA) hemisphere and the dominant hemisphere of TD children, while the MA hemisphere showed enhanced phase synchronizations after ~100 ms compared to the LA hemisphere and the TD dominant hemisphere. Our findings indicate abnormal somatosensory functional connectivity in both hemispheres of children with HCP., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The effects of spinal cord injury (SCI) on sensorimotor cortex plasticity have not been well studied. Therefore, to explore the reorganization after SCI, we dynamically monitored postsynaptic dendritic spines of pyramidal neurons in vivo., Methods: Thy1-YFP transgenic mice were randomly divided into two groups: the control and SCI group. We then opened the spinal vertebral plates of all mice and sectioned one-half of the spinal cord in SCI group. The relevant areas were imaged bilaterally at 0, 3, 14 and 28 days post-SCI. The rates of elimination, formation and stable spines were evaluated., Results: At the early stage, the rate of stable and elimination spines experienced a similar change trend. But the rate of formation spines in the contralateral sensory cortex was significantly increased after SCI compared with those in the control group. At the late stage, spines of three types remodeled very differently between the sensory and motor cortex. Compared with those in the control group, spines in the bilateral sensory cortex demonstrated obvious differences in the rate of stable and elimination spines but not formation spines, while spines in the motor cortex, especially in the contralateral cortex increased significantly in the rate of formation after SCI. As for survival rate, differences mainly appeared in time frame instead of cortex type or region., Conclusions: The dendritic spines in hindlimb representation area of the sensorimotor cortex experienced bilaterally remodeling after SCI. And those spines in the sensory and motor cortex experienced great but different change trends after SCI., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cervical dystonia (CD) is the most common form of focal dystonia with involuntary movements and postures of the head. The pathogenesis and neural mechanisms underlying CD have not been fully elucidated., Methods: Twenty-seven newly drug-naïve patients with CD and 21 healthy controls (HCs) were recruited with clinical assessment and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Severity of CD was measured by Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scores. Whole-brain voxel-wise intrinsic connectivity (IC) and seed-based functional connectivity (FC) analyses were performed for detection of changes in the CD group relative to HCs, controlling for age, gender, and global time series correlation, followed by correlation analyses of IC, seed-based FC and clinically relevant features, respectively., Results: In comparison with HCs, CD patients showed significantly increased IC measurement in the anterior part of the left supramarginal gyrus and extended to the inferior left postcentral gyrus (AL-SMG/IL-PCG). With this cluster as a seed, decreased FC was found in the right precentral and postcentral gyrus. Moreover, the regional IC value in the AL-SMG/IL-PCG was significantly positively correlated with TWSTRS-1 (severity) score, and significantly negatively correlated with the associated seed-based FC strength., Conclusions: Our results showed signs of both hyper- and hypo-connectivity in bilateral regions of the sensorimotor network related to CD. The imbalance of functional connectivity (both hyper- and hypo-) may hint both overloading and disrupted somatosensory or sensorimotor integration dysfunction within the sensorimotor network underlying the pathophysiology of CD, thus providing a network target for future therapies., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: A large N20 and P25 of the median nerve somatosensory evoked potential (SEP) predicts short survival in amyotrophic lateral sclerosis (ALS). We investigated whether high frequency oscillations (HFOs) over N20 are enlarged and associated with survival in ALS., Methods: A total of 145 patients with ALS and 57 healthy subjects were studied. We recorded the median nerve SEP and measured the onset-to-peak amplitude of N20 (N20o-p), and peak-to-peak amplitude between N20 and P25 (N20p-P25p). We obtained early and late HFO potentials by filtering SEP between 500 and 1 kHz, and measured the peak-to-peak amplitude. We followed up patients until endpoints (death or tracheostomy) and analyzed the relationship between SEP or HFO amplitudes and survival using a Cox analysis., Results: Patients showed larger N20o-p, N20p-P25p, and early and late HFO amplitudes than the control values. N20p-P25p was associated with survival periods (p = 0.0004), while early and late HFO amplitudes showed no significant association with survival (p = 0.4307, and p = 0.6858, respectively)., Conclusions: The HFO amplitude in ALS is increased, but does not predict survival., Significance: The enlarged HFOs in ALS might be a compensatory phenomenon to the hyperexcitability of the sensory cortex pyramidal neurons., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Musician's dystonia is a type of focal task-specific dystonia (FTSD) characterized by abnormal muscle hypercontraction and loss of fine motor control specifically during instrument playing. Although the neuropathophysiology of musician's dystonia remains unclear, it has been suggested that maladaptive functional abnormalities in subcortical and cortical regions may be involved. Here, we hypothesized that aberrant effective connectivity between the cerebellum (subcortical) and motor/somatosensory cortex may underlie the neuropathophysiology of musician's dystonia. Using functional magnetic resonance imaging, we measured the brain activity of 30 pianists with or without FTSD as they played a magnetic resonance imaging-compatible piano-like keyboard, which elicited dystonic symptoms in many but not all pianists with FTSD. Pianists with FTSD showed greater activation of the right cerebellum during the task than healthy pianists. Furthermore, patients who reported dystonic symptoms during the task demonstrated greater cerebellar activation than those who did not, establishing a link between cerebellar activity and overt dystonic symptoms. Using multivoxel pattern analysis, moreover, we found that dystonic and healthy pianists differed in the task-related effective connectivity between the right cerebellum and left premotor/somatosensory cortex. The present study indicates that abnormal cerebellar activity and cerebello-cortical connectivity may underlie the pathophysiology of FTSD in musicians., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In a series of previous studies, we demonstrated that damage to the dorsal column in the cervical spinal cord deactivates the contralateral somatosensory hand cortex and impairs hand use in a reach-to-grasp task in squirrel monkeys. Nevertheless, considerable cortical reactivation and behavioral recovery occurs over the following weeks to months after lesion. This timeframe may also be a window for targeted therapies to promote cortical reactivation and functional reorganization, aiding in the recovery process. Here we asked if and how task specific training of an impaired hand would improve behavioral recovery and cortical reorganization in predictable ways, and if recovery related cortical changes would be detectable using noninvasive functional magnetic resonance imaging (fMRI). We further asked if invasive neurophysiological mapping reflected fMRI results. A reach-to-grasp task was used to test impairment and recovery of hand use before and after dorsal column lesions (DC-lesion). The activation and organization of the affected primary somatosensory cortex (area 3b) was evaluated with two types of fMRI - either blood oxygenation level dependent (BOLD) or cerebral blood volume (CBV) with a contrast agent of monocrystalline iron oxide nanocolloid (MION) - before and after DC-lesion. At the end of the behavioral and fMRI studies, microelectrode recordings in the somatosensory areas 3a, 3b and 1 were used to characterize neuronal responses and verify the somatotopy of cortical reactivations. Our results indicate that even after nearly complete DC lesions, monkeys had both considerable post-lesion behavioral recovery, as well as cortical reactivation assessed with fMRI followed by extracellular recordings. Generalized linear regression analyses indicate that lesion extent is correlated with the behavioral outcome, as well as with the difference in the percent signal change from pre-lesion peak activation in fMRI. Monkeys showed behavioral recovery and nearly complete cortical reactivation by 9-12 weeks post-lesion (particularly when the DC-lesion was incomplete). Importantly, the specific training group revealed trends for earlier behavioral recovery and had higher magnitude of fMRI responses to digit stimulation by 5-8 weeks post-lesion. Specific kinematic measures of hand movements in the selected retrieval task predicted recovery time and related to lesion characteristics better than overall task performance success. For measures of cortical reactivation, we found that CBV scans provided stronger signals to vibrotactile digit stimulation as compared to BOLD scans, and thereby may be the preferred non-invasive way to study the cortical reactivation process after sensory deprivations from digits. When the reactivation of cortex for each of the digits was considered, the reactivation by digit 2 stimulation as measured with microelectrode maps and fMRI maps was best correlated with overall behavioral recovery., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this paper, we investigate the forelimbs somatosensory evoked potential (SSEP) signals, which are representative of the integrity of ascending sensory pathways and their stability as well as function, recorded from corresponding cortices, post thoracic spinal cord injury (SCI). We designed a series of distinctive transection SCI to investigate whether forelimbs SSEPs change after right T10 hemi-transection, T8 and T10 double hemi-transection and T8 complete transection in rat model of SCI. We used electrical stimuli to stimulate median nerves and recorded SSEPs from left and right somatosensory areas of both cortices. We monitored pre-injury baseline and verified changes in forelimbs SSEP signals on Days 4, 7, 14, and 21 post-injury. We previously characterized hindlimb SSEP changes for the abovementioned transection injuries. The focus of this article is to investigate the quality and quantity of changes that may occur in the forelimb somatosensory pathways post-thoracic transection SCI. It is important to test the stability of forelimb SSEPs following thoracic SCI because of their potential utility as a proxy baseline for the traumatic SCIs in clinical cases wherein there is no opportunity to gather baseline of the lower extremities. We observed that the forelimb SSEP amplitudes increased following thoracic SCI but gradually returned to the baseline. Despite changes found in the raw signals, statistical analysis found forelimb SSEP signals become stable relatively soon. In summary, though there are changes in value (with p >  0.05), they are not statistically significant. Therefore, the null hypothesis that the mean of the forelimb SSEP signals are the same across multiple days after injury onset cannot be rejected during the acute phase., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks' hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons' susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism., Competing Interests: The authors have declared that no competing interests exist.

Epidemiological data suggest that elevated homocysteine is associated with migraine with aura. However, how homocysteine contributes to migraine is still unclear. Here, we tested whether hyperhomocysteinemia (hHCY) promotes cortical spreading depression (CSD), a phenomenon underlying migraine with aura, and whether hHCY contributes to pain behavior. hHCY was induced by dietary methionine in female rats while the testing was performed on their 6-8week-old offspring. CSD and multiple unit activity (MUA) induced by KCl were recorded from the primary somatosensory cortex, S1, using multichannel electrodes. In hHCY rats, compared to control, we found: i) higher probability of CSD occurrence; ii) induction of CSD by lower concentrations of KCl; iii) faster horizontal propagation of CSD; iv) smaller CSD with longer duration; v) higher frequency of MUA at CSD onset along with slower reappearance. Rats with hHCY demonstrated high level of locomotor activity and grooming while spent less time in the central area of the open field, indicating anxiety. These animals showed light sensitivity and facial mechanical allodinia. Thus, hHCY acquired at birth promotes multiple features of migraine such as higher cortical excitability, mechanical allodynia, photophobia, and anxiety. Our results provide the first experimental explanation for the higher occurrence of migraine with aura in patients with hHCY., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.

Objective: We assessed in extremely preterm born (EPB) children whether secondary somatosensory cortex (SII) responses recorded with magnetoencephalography (MEG) at term-equivalent age (TEA) correlate with neurodevelopmental outcome at age 6 years. Secondly, we assessed whether SII responses differ between 6-year-old EPB and term-born (TB) children., Methods: 39 EPB children underwent MEG with tactile stimulation at TEA. At age 6 years, 32 EPB and 26 TB children underwent MEG including a sensorimotor task requiring attention and motor inhibition. SII responses to tactile stimulation were modeled with equivalent current dipoles. Neurological outcome, motor competence, and general cognitive ability were prospectively evaluated at age 6 years., Results: Unilaterally absent SII response at TEA was associated with abnormal motor competence in 6-year-old EPB children (p = 0.03). At age 6 years, SII responses were bilaterally detectable in most EPB (88%) and TB (92%) children (group comparison, p = 0.69). Motor inhibition was associated with decreased SII peak latencies in TB children, but EPB children lacked this effect (p = 0.02)., Conclusions: Unilateral absence of an SII response at TEA predicted poorer motor outcome in EPB children., Significance: Neurophysiological methods may provide new means for outcome prognostication in EPB children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Abstract: In dystonic and spastic movement disorders, abnormalities of motor control and somatosensory processing as well as cortical modulations associated with clinical improvement after botulinum toxin A (BoNT-A) treatment have been reported, but electrophysiological evidence remains controversial. In the present observational study, we aimed to uncover central correlates of post-stroke spasticity (PSS) and BoNT-A-related changes in the sensorimotor cortex by investigating the cortical components of somatosensory evoked potentials (SEPs). Thirty-one chronic stroke patients with PSS of the upper limb were treated with BoNT-A application into the affected muscles and physiotherapy. Clinical and electrophysiological evaluations were performed just before BoNT-A application (W0), then 4 weeks (W4) and 11 weeks (W11) later. PSS was evaluated with the modified Ashworth scale (MAS). Median nerve SEPs were examined in both upper limbs with subsequent statistical analysis of the peak-to-peak amplitudes of precentral P22/N30 and postcentral N20/P23 components. At baseline (W0), postcentral SEPs were significantly lower over the affected cortex. At follow up, cortical SEPs did not show any significant changes attributable to BoNT-A and/or physiotherapy, despite clear clinical improvement. Our results imply that conventional SEPs are of limited value in evaluating cortical changes after BoNT-A treatment and further studies are needed to elucidate its central actions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Recovery after stroke is thought to be mediated by adaptive circuit plasticity, whereby surviving neurons assume the roles of those that died. However, definitive longitudinal evidence of neurons changing their response selectivity after stroke is lacking. We sought to directly test whether such functional "remapping" occurs within mouse primary somatosensory cortex after a stroke that destroys the C1 barrel. Using in vivo calcium imaging to longitudinally record sensory-evoked activity under light anesthesia, we did not find any increase in the number of C1 whisker-responsive neurons in the adjacent, spared D3 barrel after stroke. To promote plasticity after stroke, we also plucked all whiskers except C1 (forced use therapy). This led to an increase in the reliability of sensory-evoked responses in C1 whisker-responsive neurons but did not increase the number of C1 whisker-responsive neurons in spared surround barrels over baseline levels. Our results argue against remapping of functionality after barrel cortex stroke, but support a circuit-based mechanism for how rehabilitation may improve recovery.

Lower resting-state functional connectivity (RSFC) between 'visual' and non-'visual' neural circuits has been reported as a hallmark of congenital blindness. In sighted individuals, RSFC between visual and non-visual brain regions has been shown to increase during rest with eyes closed relative to rest with eyes open. To determine the role of visual experience on the modulation of RSFC by resting state condition-as well as to evaluate the effect of resting state condition on group differences in RSFC-, we compared RSFC between visual and somatosensory/auditory regions in congenitally blind individuals (n = 9) and sighted participants (n = 9) during eyes open and eyes closed conditions. In the sighted group, we replicated the increase of RSFC between visual and non-visual areas during rest with eyes closed relative to rest with eyes open. This was not the case in the congenitally blind group, resulting in a lower RSFC between 'visual' and non-'visual' circuits relative to sighted controls only in the eyes closed condition. These results indicate that visual experience is necessary for the modulation of RSFC by resting state condition and highlight the importance of considering whether sighted controls should be tested with eyes open or closed in studies of functional brain reorganization as a consequence of blindness.