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CNS Neuroscience & Therapeutics Jun 2024In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are urgently needed. Transcranial magnetic stimulation is a promising therapeutic option, but applicability is limited by lengthy duration of stimulation protocols.
METHODS
In this randomized sham controlled clinical trial, patients were assigned to verum (n = 15) or sham (n = 18) cerebellar transcranial magnetic stimulation. To yield best possible treatment effects, both intervention groups received intensified physiotherapy for the duration of the study.
RESULTS
Ataxia severity was reduced by 1.6 points on the Scale for assessment and Rating of Ataxia among patients in the verum group (p < 0.001). Clinical improvement was significantly larger in the verum group, compared to the sham group (p < 0.01). The treatment effect was mainly carried by improved appendicular coordination. Patients in the verum group also significantly improved in the 8 Meter Walk Test (p < 0.05) and PATA rate (p < 0.01).
CONCLUSIONS
Cerebellar rTMS ameliorates ataxia severity in patient with spinocerebellar ataxia. Condensing treatment duration to only 5 days without reduction of treatment effects facilitates applicability and therefore broadens availability to larger patient populations.
Topics: Humans; Spinocerebellar Ataxias; Male; Female; Transcranial Magnetic Stimulation; Middle Aged; Adult; Cerebellum; Physical Therapy Modalities; Treatment Outcome; Combined Modality Therapy; Aged; Severity of Illness Index
PubMed: 38887169
DOI: 10.1111/cns.14797 -
Alzheimer's Research & Therapy Jun 2024Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a...
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Topics: Humans; Locus Coeruleus; Female; Alzheimer Disease; Male; Aged; Magnetic Resonance Imaging; tau Proteins; Aged, 80 and over; Cohort Studies; Amyloid beta-Peptides; Positron-Emission Tomography; Cerebral Cortex; Carbolines; Thiazoles; Aniline Compounds; Brain Cortical Thickness
PubMed: 38886798
DOI: 10.1186/s13195-024-01500-0 -
BMC Neurology Jun 2024The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms. However, studies on the effect and safety of cerebellar TMS to improve balance capacity and activity of daily living (ADL) for stroke patients are limited. This systematic review and meta-analysis aimed to investigate the effect and safety of cerebellar TMS on balance capacity and ADL in stroke patients.
METHOD
A systematic search of seven electronic databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang and Chinese Scientific Journal) were conducted from their inception to October 20, 2023. The randomized controlled trials (RCTs) of cerebellar TMS on balance capacity and/or ADL in stroke patients were enrolled. The quality of included studies were assessed by Physiotherapy Evidence Database (PEDro) scale.
RESULTS
A total of 13 studies involving 542 participants were eligible. The pooled results from 8 studies with 357 participants showed that cerebellar TMS could significantly improve the post-intervention Berg balance scale (BBS) score (MD = 4.24, 95%CI = 2.19 to 6.29, P < 0.00001; heterogeneity, I = 74%, P = 0.0003). The pooled results from 4 studies with 173 participants showed that cerebellar TMS could significantly improve the post-intervention Time Up and Go (TUG) (MD=-1.51, 95%CI=-2.8 to -0.22, P = 0.02; heterogeneity, I = 0%, P = 0.41). The pooled results from 6 studies with 280 participants showed that cerebellar TMS could significantly improve the post-intervention ADL (MD = 7.75, 95%CI = 4.33 to 11.17, P < 0.00001; heterogeneity, I = 56%, P = 0.04). The subgroup analysis showed that cerebellar TMS could improve BBS post-intervention and ADL post-intervention for both subacute and chronic stage stroke patients. Cerebellar high frequency TMS could improve BBS post-intervention and ADL post-intervention. Cerebellar TMS could still improve BBS post-intervention and ADL post-intervention despite of different cerebellar TMS sessions (less and more than 10 TMS sessions), different total cerebellar TMS pulse per week (less and more than 4500 pulse/week), and different cerebellar TMS modes (repetitive TMS and Theta Burst Stimulation). None of the studies reported severe adverse events except mild side effects in three studies.
CONCLUSIONS
Cerebellar TMS is an effective and safe technique for improving balance capacity and ADL in stroke patients. Further larger-sample, higher-quality, and longer follow-up RCTs are needed to explore the more reliable evidence of cerebellar TMS in the balance capacity and ADL, and clarify potential mechanisms.
Topics: Humans; Transcranial Magnetic Stimulation; Activities of Daily Living; Postural Balance; Stroke Rehabilitation; Cerebellum; Stroke; Randomized Controlled Trials as Topic
PubMed: 38879485
DOI: 10.1186/s12883-024-03720-1 -
Mathematical Biosciences and... Apr 2024Attention deficit hyperactivity disorder (ADHD) is a common childhood developmental disorder. In recent years, pattern recognition methods have been increasingly applied...
Attention deficit hyperactivity disorder (ADHD) is a common childhood developmental disorder. In recent years, pattern recognition methods have been increasingly applied to neuroimaging studies of ADHD. However, these methods often suffer from limited accuracy and interpretability, impeding their contribution to the identification of ADHD-related biomarkers. To address these limitations, we applied the amplitude of low-frequency fluctuation (ALFF) results for the limbic system and cerebellar network as input data and conducted a binary hypothesis testing framework for ADHD biomarker detection. Our study on the ADHD-200 dataset at multiple sites resulted in an average classification accuracy of 93%, indicating strong discriminative power of the input brain regions between the ADHD and control groups. Moreover, our approach identified critical brain regions, including the thalamus, hippocampal gyrus, and cerebellum Crus 2, as biomarkers. Overall, this investigation uncovered potential ADHD biomarkers in the limbic system and cerebellar network through the use of ALFF realizing highly credible results, which can provide new insights for ADHD diagnosis and treatment.
Topics: Attention Deficit Disorder with Hyperactivity; Humans; Cerebellum; Limbic System; Biomarkers; Child; Male; Female; Magnetic Resonance Imaging; Brain Mapping; Neuroimaging; Adolescent; Algorithms; Hippocampus
PubMed: 38872559
DOI: 10.3934/mbe.2024256 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of...
OBJECTIVE
To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of mice.
METHODS
Thirty-two male ICR mice were randomly divided into sham operation group (=8) and rmTBI group (=24). The mice in the latter group were subjected to repeated mild impact injury of the parietal cortex by a free-falling object. The mice surviving the injuries were evaluated for neurological deficits using neurological severity scores (NSS), righting reflex test and forced swimming test, and pathological changes of the neuronal cells in the medulla oblongata were observed with HE and Nissl staining. Western blotting and immunofluorescence staining were used to detect the expressions of neuroligin 1(NLG-1) and postsynaptic density protein 95(PSD-95) in the medulla oblongata of the mice that either survived rmTBI or not.
RESULTS
None of the mice in the sham-operated group died, while the mortality rate was 41.67% in rmTBI group. The mice surviving rmTBI showed significantly reduced NSS, delayed recovery of righting reflex, increased immobility time in forced swimming test ( < 0.05), and loss of Nissl bodies; swelling and necrosis were observed in a large number of neurons in the medulla oblongata, where the expression levels of NLG-1 and PSD-95 were significantly downregulated ( < 0.05). The mice that did not survive rmTBI showed distorted and swelling nerve fibers and decreased density of neurons in the medulla oblongina with lowered expression levels of NLG-1 and PSD-95 compared with the mice surviving the injuries ( < 0.01).
CONCLUSION
The structural and functional anomalies of the synapses in the medulla oblongata may contribute to death and neurological impairment following rmTBI in mice.
Topics: Animals; Mice; Medulla Oblongata; Disks Large Homolog 4 Protein; Male; Mice, Inbred ICR; Parietal Lobe; Cell Adhesion Molecules, Neuronal; Neurons; Brain Injuries, Traumatic; Neuronal Plasticity
PubMed: 38862454
DOI: 10.12122/j.issn.1673-4254.2024.05.18 -
JCI Insight Jun 2024Human cytomegalovirus (HCMV) infection in infants infected in utero can lead to a variety of neurodevelopmental disorders. However, mechanisms underlying altered...
Human cytomegalovirus (HCMV) infection in infants infected in utero can lead to a variety of neurodevelopmental disorders. However, mechanisms underlying altered neurodevelopment in infected infants remain poorly understood. We have previously described a murine model of congenital HCMV infection in which murine CMV (MCMV) spreads hematogenously and establishes a focal infection in all regions of the brain of newborn mice, including the cerebellum. Infection resulted in disruption of cerebellar cortical development characterized by reduced cerebellar size and foliation. This disruption was associated with altered cell cycle progression of the granule cell precursors (GCPs), which are the progenitors that give rise to granule cells (GCs), the most abundant neurons in the cerebellum. In the current study, we have demonstrated that MCMV infection leads to prolonged GCP cell cycle, premature exit from the cell cycle, and reduced numbers of GCs resulting in cerebellar hypoplasia. Treatment with TNF-α neutralizing antibody partially normalized the cell cycle alterations of GCPs and altered cerebellar morphogenesis induced by MCMV infection. Collectively, our results argue that virus-induced inflammation altered the cell cycle of GCPs resulting in a reduced numbers of GCs and cerebellar cortical hypoplasia, thus providing a potential mechanism for altered neurodevelopment in fetuses infected with HCMV.
Topics: Animals; Cytomegalovirus Infections; Mice; Cerebellum; Cell Cycle; Disease Models, Animal; Female; Cytomegalovirus; Neural Stem Cells; Muromegalovirus; Animals, Newborn; Humans; Neurons; Tumor Necrosis Factor-alpha; Developmental Disabilities; Nervous System Malformations
PubMed: 38855871
DOI: 10.1172/jci.insight.175525 -
Scientific Reports Jun 2024Digital media (DM) takes an increasingly large part of children's time, yet the long-term effect on brain development remains unclear. We investigated how individual...
Digital media (DM) takes an increasingly large part of children's time, yet the long-term effect on brain development remains unclear. We investigated how individual effects of DM use (i.e., using social media, playing video games, or watching television/videos) on the development of the cortex (i.e., global cortical surface area), striatum, and cerebellum in children over 4 years, accounting for both socioeconomic status and genetic predisposition. We used a prospective, multicentre, longitudinal cohort of children from the Adolescent Brain and Cognitive Development Study, aged 9.9 years when entering the study, and who were followed for 4 years. Annually, children reported their DM usage through the Youth Screen Time Survey and underwent brain magnetic resonance imaging scans every 2 years. Quadratic-mixed effect modelling was used to investigate the relationship between individual DM usage and brain development. We found that individual DM usage did not alter the development of cortex or striatum volumes. However, high social media usage was associated with a statistically significant change in the developmental trajectory of cerebellum volumes, and the accumulated effect of high-vs-low social media users on cerebellum volumes over 4 years was only β = - 0.03, which was considered insignificant. Nevertheless, the developmental trend for heavy social media users was accelerated at later time points. This calls for further studies and longer follow-ups on the impact of social media on brain development.
Topics: Humans; Child; Male; Female; Brain; Magnetic Resonance Imaging; Longitudinal Studies; Video Games; Social Media; Prospective Studies; Child Development; Adolescent; Cerebellum
PubMed: 38844772
DOI: 10.1038/s41598-024-63566-y -
ENeuro Jun 2024Social behavior is important for our well-being, and its dysfunctions impact several pathological conditions. Although the involvement of glutamate is undeniable, the...
Social behavior is important for our well-being, and its dysfunctions impact several pathological conditions. Although the involvement of glutamate is undeniable, the relevance of vesicular glutamate transporter type 3 (VGluT3), a specific vesicular transporter, in the control of social behavior is not sufficiently explored. Since midbrain median raphe region (MRR) is implicated in social behavior and the nucleus contains high amount of VGluT3+ neurons, we compared the behavior of male VGluT3 knock-out (KO) and VGluT3-Cre mice, the latter after chemogenetic MRR-VGluT3 manipulation. Appropriate control groups were included. Behavioral test battery was used for social behavior (sociability, social discrimination, social interaction, resident intruder test) and possible confounding factors (open field, elevated plus maze, Y-maze tests). Neuronal activation was studied by c-Fos immunohistochemistry. Human relevance was confirmed by VGluT3 gene expression in relevant human brainstem areas. VGluT3 KO mice exhibited increased anxiety, social interest, but also aggressive behavior in anxiogenic environment and impaired social memory. For KO animals, social interaction induced lower cell activation in the anterior cingulate, infralimbic cortex, and medial septum. In turn, excitation of MRR-VGluT3+ neurons was anxiolytic. Inhibition increased social interest 24 h later but decreased mobility and social behavior in aggressive context. Chemogenetic activation increased the number of c-Fos+ neurons only in the MRR. We confirmed the increased anxiety-like behavior and impaired memory of VGluT3 KO strain and revealed increased, but inadequate, social behavior. MRR-VGluT3 neurons regulated mobility and social and anxiety-like behavior in a context-dependent manner. The presence of VGluT3 mRNA on corresponding human brain areas suggests clinical relevance.
Topics: Animals; Male; Social Behavior; Mice, Knockout; Humans; Anxiety; Raphe Nuclei; Mice; Neurons; Mice, Inbred C57BL; Behavior, Animal; Mice, Transgenic; Amino Acid Transport Systems, Acidic; Proto-Oncogene Proteins c-fos; Aggression
PubMed: 38839305
DOI: 10.1523/ENEURO.0332-23.2024 -
The International Journal of... Jun 2024The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior.
METHODS
We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes.
RESULTS
We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction.
CONCLUSION
The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.
Topics: Humans; Ketamine; Locus Coeruleus; Male; Adult; Magnetic Resonance Imaging; Cross-Over Studies; Young Adult; Attention; Excitatory Amino Acid Antagonists; Double-Blind Method; Antidepressive Agents
PubMed: 38833581
DOI: 10.1093/ijnp/pyae022 -
Neurologia Jun 2024Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex,...
Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias.
Topics: Animals; Purkinje Cells; Male; Rats, Sprague-Dawley; Rats; Cerebellum; Cerebellar Ataxia; Pyridines; Neuronal Plasticity
PubMed: 38830720
DOI: 10.1016/j.nrleng.2021.09.015