Cerebellar Research Articles

Cerebellar contribution to emotion regulation and its association with medial frontal GABA level.

Distancing involves changing perspectives to alter the psychological distance from stimuli that elicit emotional reactions as a tactic to regulate emotions. Using magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging, this study aimed to examine 1) whether the neural correlates of emotion upregulation via distancing differ across emotional valence (i.e., emotional responses toward positive and negative pictures), and 2) whether the gamma-aminobutyric acid (GABA) concentration in the medial prefrontal cortex (MPFC), one of the crucial areas of emotion regulation, is correlated with brain activity related to either negative or positive emotion upregulation. Thirty-four healthy Japanese adults participated in this study. Compared to the condition involving positive emotion upregulation, negative emotion upregulation induced increased activation in the MPFC, left temporoparietal junction, bilateral anterior insula, pre-supplementary motor area, and bilateral cerebellum. In contrast, when comparing positive emotion upregulation with negative emotion upregulation, no significant activation was found. Right cerebellar activity during negative emotion upregulation positively correlated with GABA concentration in the MPFC. These findings provide evidence of cerebellar involvement in the upregulation of negative emotion via distancing and its association with the prefrontal GABA concentration.

Neurprotective Role of Amaranthus Dubius on Penicillin Induced Experimental Epileptic Rat Model by Combating the Multineurotransmitter Deficiency

Objective: The study aims to clarify the protective effects of Amaranthus dubius (AD) in penicillin (PCN)-induced experimental epilepsy models in rats. Method: In this study, twenty-four adult male Wistar albino rats, each weighing between 200-250 grams, were utilized. The rats were allocated into four groups: a control group, an Amaranthus dubius (AD) treated control group, a PCN-induced experimental epileptic rat model group, and an AD pretreated PCN-induced experimental epileptic rat model group. All groups were administered a daily oral dosage of 400 mg/kg body weight of AD aqueous leaf extract for fourteen days via an orogastric cannula. For the experimental epileptic model, PCN was injected into designated areas of the somatosensory cortex. On the concluding fifteenth day, subsequently, the rats were humanely euthanized. Tissue specimens from the cerebral cortex (CC), cerebellum (CB), caudate nucleus (CN), pons and medulla (PM), and midbrain (MB) were extracted, measured, and homogenized to facilitate subsequent biochemical analyses. Result: Pretreatment with AD has demonstrated significant changes in the levels of antioxidants and neurotransmitters in the brain. Conclusion: Amaranthus Dubius aids in combating multi-neurotransmitter deficiencies and enhances the body's antioxidant capabilities.

Longitudinal Monitoring of Glutathione Stability in Different Microenvironments

Glutathione (GSH) is a master antioxidant which primarily protects cells from oxidative stress. Clinical studies have found significant depletion of GSH from the hippocampus in patients with mild cognitive impairment (MCI), a transitional stage before conversion to Alzheimer’s disease (AD). Significant depletion of GSH is considered an early diagnostic biomarker of AD. Postmortem studies have confirmed significant GSH depletion in hippocampal tissue in MCI patients. The stability of GSH in different microenvironments is essential to validate GSH as a reliable biomarker for AD. Accordingly, we have conducted longitudinal monitoring of GSH from various brain regions (frontal cortex (FC), parietal cortex (PC), occipital cortex (OC), and cerebellum (CER)) from healthy subjects using MEshcher-GArwood Point RESolved Spectroscopy (MEGA-PRESS) pulse sequence on a 3T scanner. Additionally, in vitro magnetic resonance spectroscopy (MRS) assessments were conducted longitudinally using the same study protocol involving GSH supplement in a physiologically relevant phosphate buffer solution (PBS). We report that GSH within the brain microenvironment of a healthy person remains stable over time. GSH, however, is susceptible to oxidation over time in a phosphate buffer environment. The stability of GSH in a longitudinal study in the brains of healthy individuals supports the consideration of GSH as a candidate for stable biomarker for AD.

Static and Dynamic Functional Network Connectivity inParkinson's Disease Patients With Postural Instability andGait Disorder.

The exact cause of the parkinsonism gait remains uncertain. We first focus on understanding the underlying neurological reasons for these symptoms through the examination of both static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC). We recruited 64 postural instability and gait disorder-dominated Parkinson's disease (PIGD-PD) patients, 31 non-PIGD-PD (nPIGD-PD) patients, and 54 healthy controls (HC) from Nanjing Brain Hospital. The GIFT software identified five distinct independent components: the basal ganglia (BG), cerebellum (CB), sensory networks (SMN), default mode network (DMN), and central executive network (CEN). We conducted a comparison between the SFNC and DFNC of the five networks and analyzed their correlations with postural instability and gait disorder (PIGD) symptoms. Compared with nPIGD-PD patients, the PIGD-PD patients demonstrated reduced connectivity between CEN and DMN while spending less mean dwell time (MDT) in state 4. This is characterized by strong connections. Compared with HC, PIGD-PD patients exhibited enhanced connectivity in the SFNC between CB and CEN, as well as the network between CB and DMN. Patients with PIGD-PD spent more MDT in state 1, which is characterized by few connections, and less MDT in state 4. In state 3, there was an increase in the functional connectivity between the CB and DMN in patients with PIGD-PD. The nPIGD patients showed increased SFNC connectivity between CB and DMN compared to HC. These patients spent more MDT in state 1 and less in state 4. The MDT and fractional windows of state 2 showed a positive link with PIGD scores. Patients with PIGD-PD exhibit a higher likelihood of experiencing reduced brain connectivity and impaired information processing. The enhanced connection between the cerebellum and DMN networks is considered a type of dynamic compensation.

Thalamic integration of basal ganglia and cerebellar circuits during motor learning.

The ability to control movement and learn new motor skills is one of the fundamental functions of the brain. The basal ganglia (BG) and the cerebellum (CB) are two key brain regions involved in controlling movement, and neuronal plasticity within these two regions is crucial for acquiring new motor skills. However, how these regions interact to produce a cohesive unified motor output remains elusive. Here, we discovered that a subset of neurons in the motor thalamus receive converging synaptic inputs from both BG and CB. By performing multi-site fiber photometry in mice learning motor tasks, we found that motor thalamus neurons integrate BG and CB signals and show distinct movement-related activity. Lastly, we found a critical role of these thalamic neurons and their BG and CB inputs in motor learning and control. These results identify the thalamic convergence of BG and CB and its crucial role in integrating movement signals.

Non-allometric expansion and enhanced compartmentalization of Purkinje cell dendrites in the human cerebellum.

Purkinje cell (PC) dendrites are optimized to integrate the vast cerebellar input array and drive the sole cortical output. PCs are classically seen as stereotypical computational units, yet mouse PCs are morphologically diverse and those with multi-branched structure can receive non-canonical climbing fiber (CF) multi-innervation that confers independent compartment-specific signaling. While otherwise uncharacterized, human PCs are universally multi-branched. Do they exceed allometry to achieve enhanced integrative capacities relative to mouse PCs? To answer this, we used several comparative histology techniques in adult human and mouse to analyze cellular morphology, parallel fiber (PF) and CF input arrangement, and regional PC demographics. Human PCs are substantially larger than previously described; they exceed allometric constraint by cortical thickness and are the largest neuron in the brain with 6-7cm total dendritic length. Unlike mouse, human PC dendrites ramify horizontally to form a multi-compartment motif that we show can receive multiple CFs. Human spines are denser (6.9 vs 4.9 spines/μm), larger (~0.36 vs 0.29μm), and include an unreported 'spine cluster' structure-features that may be congruent with enhanced PF association and amplification as human-specific adaptations. By extrapolation, human PCs may receive 500,000 to 1 million synaptic inputs compared with 30-40,000 in mouse. Collectively, human PC morphology and input arrangement is quantitatively and qualitatively distinct from rodent. Multi-branched PCs are more prevalent in posterior and lateral cerebellum, co-varying with functional boundaries, supporting the hypothesis that this morphological motif permits expanded input multiplexing and may subserve task-dependent needs for input association.

Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia.

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.

Increased cerebellar vermis volume following repetitive transcranial magnetic stimulation in drug-resistant epilepsy: a voxel-based morphometry study.

Voxel-based morphometry (VBM) was applied to explore structural changes induced by repetitive transcranial magnetic stimulation (rTMS) and the relationship with clinical outcomes. Moreover, the relationship between each segmented regional gray matter (GM) volume was investigated to identify circuits involved in the rTMS treatment process in patients with drug-resistant epilepsy (DRE). Nineteen patients with DRE were finally included in the analysis. A session of rTMS was applied for 5 consecutive days. Participants received either 1,000 or 3,000 pulses, at a frequency of 0.5 Hz and the intensity was set at 90% of the individual's resting motor threshold. VBM analysis was performed to explore regional GM volume changes 2 months after rTMS application. The regional volume change was correlated with seizure reduction rate. Relationships between changes in GM volume in each anatomically parcellated region were analyzed using a fully-automated segmentation pipeline. Compared to the baseline, seizure frequency was reduced, and quality of life was improved after rTMS treatment. Regional volume was increased in the cerebellar vermis 2 months after rTMS application. The increased cerebellar vermis volume correlated with the reduced seizure frequency. Regional volume changes in the cerebellar vermis were correlated with changes in the subcortical and cortical GM regions including the thalamus, caudate, and frontal cortex. These results indicate that rTMS treatment effectively reduced seizure frequency in patients with DRE. Increased volume in the cerebellar vermis and activations of the cerebello-thalamo-cortical circuit may be a crucial mechanism underlying the effectiveness of rTMS application in patients with DRE.

Reward-driven cerebellar climbing fiber activity influences both neural and behavioral learning.

The cerebellum plays a key role in motor coordination and learning. In contrast with classical supervised learning models, recent work has revealed that CFs can signal reward-predictive information in some behaviors. This raises the question of whether CFs may also operate according to principles similar to those described by reinforcement learning models. To test how CFs operate during reward-guided behavior, and evaluate the role of reward-related CF activity in learning, we have measured CF responses in Purkinje cells of the lateral cerebellum during a Pavlovian task using 2-photon calcium imaging. Specifically, we have performed multi-stimulus experiments to determine whether CF activity meets the requirements of a reward prediction error (rPE) signal for transfer from an unexpected reward to a reward-predictive cue. We find that once CF activity is transferred to a conditioned stimulus, and there is no longer a response to reward, CFs cannot generate learned responses to a second conditioned stimulus that carries the same reward prediction. In addition, by expressing the inhibitory opsin GtACR2 in neurons of the inferior olive, and optically inhibiting these neurons across behavioral training at the time of unexpected reward, we find that the transfer of CF signals to the conditioned stimulus is impaired. Moreover, this optogenetic inhibition also impairs learning, resulting in a deficit in anticipatory lick timing. Together, these results indicate that CF signals can exhibit several characteristics in common with rPEs during reinforcement learning, and that the cerebellum can harness these learning signals to generate accurately timed motor behavior.

Cerebellar activity predicts vocalization in fruit bats

Echolocating bats exhibit remarkable auditory behaviors, enabled by adaptations both within and outside their auditory system. Yet research on echolocating bats has focused mostly on brain areas that belong to the classic ascending auditory pathway. This study provides direct evidence linking the cerebellum, an evolutionarily ancient and non-classic auditory structure, to vocalization and hearing. We report that in the fruit-eating bat Carollia perspicillata, external sounds can evoke cerebellar responses with latencies below 20ms. Such fast responses are indicative of early inputs to the bat cerebellum. After establishing fruit-eating bats as a good model to study cerebellar auditory responses, we searched for a neural correlate of vocal production within the cerebellum. We investigated spike trains and field potentials occurring before and after vocalization and found that the type of sound produced (echolocation pulses or communication calls) can be decoded from pre-vocal and post-vocal neural signals, with prediction accuracies that reach above 85%. The latter provides a direct correlate of vocalization in an ancient motor-coordination structure that lies outside of the classic ascending auditory pathway. Taken together, our findings provide evidence of specializations for vocalization and hearing in the cerebellum of an auditory specialist.

Rehabilitation Response in Tremor- and Non-Tremor-Dominant Parkinson Disease: A Task-fMRI Study.

Tremor-dominant (TD) and nontremor-dominant (NTD) Parkinson's disease (PD) showed different responses to rehabilitation. However, the neural mechanism behind this remains unclear. This cohort study explores changes in motor function, brain activation, and functional connectivity following 2 weeks of rehabilitation in TD-PD and NTD-PD patients, respectively. A total of 11 TD-PD patients, 24 NTD-PD patients, and 21 age-matched healthy controls (HCs) were included. At baseline, all participants underwent functional magnetic resonance imaging (fMRI) while performing the foot tapping task. Motor symptoms, gait, balance, and task-based fMRI were then evaluated in patients before and after rehabilitation. Compared to HCs, TD-PD patients showed increased activity in the left inferior frontal gyrus and the right insula, and NTD-PD patients showed increased activations in the left postcentral gyrus and decreased within-cerebellar connectivity at baseline. Rehabilitation improved motor function in PD patients regardless of motor subtype. TD-PD patients showed increased recruitments of the sensorimotor cortex and the bilateral thalamus after rehabilitation, and NTD-PD patients showed increased cerebellar activation and within-cerebellar connectivity that was associated with better motor performance. This study demonstrated that rehabilitation-induced brain functional reorganization varied by motor subtypes in PD, which may have important implications for making individualized rehabilitation programs. ClinicalTrials.gov identifier: ChiCTR1900020771.

Functional activity, functional connectivity and complex network biomarkers of progressive hyposmia Parkinson's disease with no cognitive impairment: evidences from resting-state fMRI study.

Olfactory dysfunction stands as one of the most prevalent non-motor symptoms in the initial stage of Parkinson's disease (PD). Nevertheless, the intricate mechanisms underlying olfactory deficits in Parkinson's disease still remain elusive. This study collected rs-fMRI data from 30 PD patients [15 with severe hyposmia (PD-SH) and 15 with no/mild hyposmia (PD-N/MH)] and 15 healthy controls (HC). To investigate functional segregation, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were utilized. Functional connectivity (FC) analysis was performed to explore the functional integration across diverse brain regions. Additionally, the graph theory-based network analysis was employed to assess functional networks in PD patients. Furthermore, Pearson correlation analysis was conducted to delve deeper into the relationship between the severity of olfactory dysfunction and various functional metrics. We discovered pronounced variations in ALFF, ReHo, FC, and topological brain network attributes across the three groups, with several of these disparities exhibiting a correlation with olfactory scores. Using fMRI, our study analyzed brain function in PD-SH, PD-N/MH, and HC groups, revealing impaired segregation and integration in PD-SH and PD-N/MH. We hypothesize that changes in temporal, frontal, occipital, and cerebellar activities, along with aberrant cerebellum-insula connectivity and node degree and betweenness disparities, may be linked to olfactory dysfunction in PD patients.

Thymoquinone Abrogates Acrylamide-Induced Cerebellar Toxicity via Modulation of Nuclear Factor Erythroid 2-Related Factor 2/Nuclear Factor Kappa B Signaling, Oxidative Neuroinflammation, and Neuroapoptosis in Rats.

Acrylamide (ACR) is an obligate human neurotoxicant ubiquitously produced and found in foods processed at high temperature. There is an increasing public health concern regarding its probable carcinogenic potential. Its prevailing toxicity mechanism is oxidative inflammation and apoptosis. Herein, we explored whether thymoquinone (TQ), a bioactive quinone in Nigella sativa seed, could mitigate ACR-induced cerebellar toxicity in rats. Our study design featured four rat groups: control, TQ (5 mg/kg bw), ACR (50 mg/kg bw), and TQ + ACR (5 mg/kg + 50 mg/kg). After 14 days of respective treatments, cerebellar homogenate was used to estimate acetylcholinesterase activity (AchE) activity, antioxidant enzymes (catalase [CAT], superoxide dismutase [SOD], and glutathione peroxidase [GPx]), malondialdehyde (MDA), inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, IL-4, and IL-10), nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), caspase-3, and caspase-9. The level of DNA damage by fragmentation and histopathological lesions was also determined in the cerebellum. The rat exposure to ACR caused significant decreases in the cerebellar activities of AchE, CAT, SOD, and GPx, IL-4, IL-10, and expression of Nrf2, whereas the levels of MDA, IL-6, TNF-α, caspase-3, and caspase-9 were prominently increased compared with the control. ACR induced significant DNA fragments and cerebellar lesions when compared with the control. Contrarily, TQ treatment inhibited the depression of CAT, SOD, and GPx activities and reversed the MDA level and expression of Nrf2/NF-κB, cytokines, and caspases. These effects were confirmed by reduced DNA damage and cerebellar histopathological lesions in comparison with the ACR. TQ afforded neuroprotection via its antioxidant, anti-inflammatory, and antiapoptotic mechanisms in rats.

Cerebellar activity in hemi-parkinsonian rats during volitional gait and freezing.

Parkinson's disease is a neurodegenerative disease characterized by gait dysfunction in the advanced stages of the disease. The unilateral 6-hydroxydopamine toxin-induced model is the most studied animal model of Parkinson's disease, which reproduces gait dysfunction after >68% dopamine loss in the substantia nigra pars compacta. The extent to which the neural activity in hemi-parkinsonian rats correlates to gait dysfunction and dopaminergic cell loss is not clear. In this article, we report the effects of unilateral dopamine depletion on cerebellar vermis activity using micro-electrocorticography during walking and freezing on a runway. Gait and neural activity were measured in 6-hydroxydopamine- and sham-lesioned rats aged between 4 and 5 months at 14, 21 and 28 days after infusion of 6-hydroxydopamine or control vehicle into the medial forebrain bundle (n = 20). Gait deficits in 6-hydroxydopamine rats were different from sham rats at 14 days (P < 0.05). Gait deficits in 6-hydroxydopamine rats improved at 21 and 28 days except for run speed, which decreased at 28 days (P = 0.018). No differences in gait deficits were observed in sham-lesioned rats at any time points. Hemi-parkinsonian rats showed hyperactivity in the cerebellar vermis at 21 days (P < 0.05), but not at 14 and 28 days, and the activity was reduced during freezing epochs in Lobules VIa, VIb and VIc (P < 0.05). These results suggest that dopaminergic cell loss causes pathological cerebellar activity at 21 days post-lesion and suggest that compensatory mechanisms from the intact hemisphere contribute to normalized cerebellar activity at 28 days. The decrease in cerebellar oscillatory activity during freezing may be indicative of neurological changes during freezing of gait in patients with Parkinson's disease making this region a potential location for biomarker detection. Although the unilateral 6-hydroxydopamine model presents gait deficits that parallel clinical presentations of Parkinson's disease, further studies in animal models of bilateral dopamine loss are needed to understand the role of the cerebellar vermis in Parkinson's disease.

Cerebellar activity in PINK1 knockout rats during volitional gait.

Preclinical models of Parkinson's disease are imperative to gain insight into the neural circuits that contribute to gait dysfunction in advanced stages of the disease. A PTEN-induced putative kinase 1 knockout early-onset model of Parkinson's disease may be a useful rodent model to study the effects of neurotransmitter degeneration caused by a loss of PTEN-induced putative kinase 1 function on brain activity during volitional gait. The goal of this study was to measure changes in neural activity at the cerebellar vermis at 8 months of age. It was found that gait deficits, except run speed, were not significantly different from age-matched wild-type controls, as previously reported. PTEN-induced putative kinase 1 knockout (n = 4) and wild-type (n = 4) rats were implanted with a micro-electrocorticographic array placed over cerebellar vermis Lobules VI (a-c) and VII. Local field potential recordings were obtained during volitional gait across a runway. Power spectral analysis and coherence analysis were used to quantify network oscillatory activity in frequency bands of interest. Cerebellar vermis power was hypoactive in the beta (VIb, VIc and VII) and alpha (VII) bands at cerebellar vermis Lobules VIb, VIc and VII in PTEN-induced putative kinase 1 knockout rats compared with wild-type controls during gait (P < 0.05). These results suggest that gait improvement in PTEN-induced putative kinase 1 knockout rats at 8 months may be a compensatory mechanism attributed to movement corrections caused by a decreased inhibition of the alpha band of cerebellar vermis Lobule VII and beta band of Lobules VIb, VIc and VII. The PTEN-induced putative kinase 1 knockout model may be a valuable tool for understanding the circuit mechanisms underlying gait dysfunction in patients with early-onset Parkinson's disease with a functional loss of PTEN-induced putative kinase 1. Future studies investigating the cerebellar vermis as a potential biomarker and therapeutic target for the treatment of gait dysfunction in Parkinson's disease are warranted.

The Role of Vitamin C on ATPases Activities in Monosodium Glutamate-Induced Oxidative Stress in Rat Striatum and Cerebellum.

Monosodium glutamate (MSG) is a silent excitotoxin used as a flavour enhancer but exerts serious health hazards to consumers. MSG plays a role in neuronal function as the dominant excitatory neurotransmitter. It is transferred into the blood and ultimately increases brain glutamate levels, causing functional disruptions notably via oxidative stress. The study evaluated the toxic effect of high consumption of MSG and the modulatory role of vitamin C on ATPase activities in the striatum and cerebellum of male Wistar rats for five weeks. Rats were grouped into four (A-D): group A was fed with rat's show only; Group B was fed with diet containing 15% MSG; Group C was treated with vitamin C (200mg/kg b.wgt orally in 0.9% saline solution) only for 3weeks; and group D rats were fed with MSG and vitamin C. The findings show that MSG does not affect body and cerebellum weights but increases striatal weight. MSG increases the malondialdehyde (MDA) level and significantly decreases catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) levels. MSG significantly impaired striatal and cerebellar ATPases activities (Na+/K+-, Ca2+-, Mg2+- and total ATPases). Vitamin C treatment abolishes MSG-induced oxidative stress and improves ATPase activities. The findings show that vitamin C has beneficial effects in improving the functions of membrane-bound ATPases against MSG toxicity in rat's striatum and cerebellum.

Electroacupuncture Reduced Fibromyalgia-Pain-like Behavior through Inactivating Transient Receptor Potential V1 and Interleukin-17 in Intermittent Cold Stress Mice Model.

Fibromyalgia (FM) is a widespread musculoskeletal pain associated with psychological disturbances, the etiopathogenesis of which is still not clear. One hypothesis implicates inflammatory cytokines in increasing central and peripheral sensitization along with neuroinflammation, leading to an elevation in pro-inflammatory cytokines, e.g., interleukin-17A (IL-17A), enhanced in FM patients and animal models. The intermittent cold stress (ICS)-induced FM-like model in C57BL/6 mice has been developed since 2008 and proved to have features which mimic the clinical pattern in FM patients such as mechanical allodynia, hyperalgesia, and female predominance of pain. Electroacupuncture (EA) is an effective treatment for relieving pain in FM patients, but its mechanism is not totally clear. It was reported as attenuating pain-like behaviors in the ICS mice model through the transient receptor potential vanilloid 1 (TRPV1) pathway. Limited information indicates that TRPV1-positive neurons trigger IL-17A-mediated inflammation. Therefore, we hypothesized that the IL-17A would be inactivated by EA and TRPV1 deletion in the ICS-induced FM-like model in mice. We distributed mice into a control (CON) group, ICS-induced FM model (FM) group, FM model with EA treatment (EA) group, FM model with sham EA treatment (Sham) group, and TRPV1 gene deletion (Trpv1-/-) group. In the result, ICS-induced mechanical and thermal hyperalgesia increased pro-inflammatory cytokines including IL-6, IL-17, TNFα, and IFNγ in the plasma, as well as TRPV1, IL-17RA, pPI3K, pAkt, pERK, pp38, pJNK, and NF-κB in the somatosensory cortex (SSC) and cerebellum (CB) lobes V, VI, and VII. Moreover, EA and Trpv1-/- but not sham EA countered these effects significantly. The molecular mechanism may involve the pro-inflammatory cytokines, including IL-6, IL-17, TNFα, and IFNγ. IL-17A-IL-17RA play a crucial role in peripheral and central sensitization as well as neuroinflammation and cannot be activated without TRPV1 in the ICS mice model. EA alleviated FM-pain-like behaviors, possibly by abolishing the TRPV1- and IL-17A-related pathways. It suggests that EA is an effective and potential therapeutic strategy in FM.

Improving efficacy of repetitive transcranial magnetic stimulation for treatment of Parkinson disease gait disorders.

Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitive-motor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal ganglia-cortex-cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP.

Noninvasive quantification of [18F]SynVesT-1 binding using simplified reference tissue model 2.

[18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.

Differential neural mechanisms for movement adaptations following neuromuscular training in young female athletes with a history of sports-related concussion

Sports-related concussion (SRC) in adolescent athletes is associated with an increased risk of subsequent lower extremity injury. Neuromuscular training (NMT) has shown promise for reducing lower extremity injuries following SRC, however, neural adaptations in response to changes in lower extremity biomechanics following NMT in athletes with a history of SRC (HxSRC) remains poorly understood. Therefore, the purpose of this study was to identify changes in neural activity associated with lower extremity movement adaptations following a six-week NMT intervention in athletes with a HxSRC. Thirty-two right-hand/foot-dominant female adolescent athletes (16 with self-reported HxSRC, 16 age- and anthropometrically-matched controls) completed a bilateral leg press task with 3D motion analysis during functional magnetic resonance imaging (fMRI). Movement adaptations were defined as a change in frontal and sagittal plane range of motion (ROM) during the fMRI bilateral leg press task. Significant pre- to post-NMT reductions were observed in the non-dominant (left) mean frontal plane ROM. Whole-brain neural correlate analysis revealed that increased cerebellar activity was significantly associated with reduced mean left-knee frontal ROM for matched controls. Exploratory within group analyses identified neural correlates in the postcentral gyrus for the HxSRC group which was associated with reduced mean left-knee frontal plane ROM. These distinct longitudinal changes provide preliminary evidence of differential neural activity associated with NMT to support knee frontal plane control in athletes with and without a HxSRC.