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Nature Communications May 2024Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the...
Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the vestibular system, sensory input that is the consequence of active self-motion is canceled early at the first central stage of processing to ensure postural and perceptual stability. However, the source of the required cancellation signal was unknown. Here, we show that the cerebellum combines sensory and motor-related information to predict the sensory consequences of active self-motion. Recordings during attempted but unrealized head movements in two male rhesus monkeys, revealed that the motor-related signals encoded by anterior vermis Purkinje cells explain their altered sensitivity to active versus passive self-motion. Further, a model combining responses from ~40 Purkinje cells accounted for the cancellation observed in early vestibular pathways. These findings establish how cerebellar Purkinje cells predict sensory outcomes of self-movements, resolving a long-standing issue of sensory signal suppression during self-motion.
Topics: Animals; Purkinje Cells; Male; Macaca mulatta; Head Movements; Cerebellum; Vestibule, Labyrinth; Motion Perception
PubMed: 38734715
DOI: 10.1038/s41467-024-48376-0 -
Journal of Parkinson's Disease 2024Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share...
BACKGROUND
Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share common sleep disorders, such as poor quality of sleep (QoS). LC pathology is a feature of both diseases. A question arises regarding the contribution of LC degeneration to the occurrence of poor QoS.
OBJECTIVE
To evaluate the association between LC impairment and sleep disorders in ET and PD patients.
METHODS
A total of 83 patients with ET, 124 with PD, and 83 healthy individuals were recruited and divided into ET/PD with/without poor QoS (Sle/NorET and Sle/NorPD) subgroups according to individual Pittsburgh Sleep Quality Index (PSQI) score. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and free-water imaging derived from diffusion MRI were performed. Subsequently, we evaluated the association between contrast-to-noise ratio of LC (CNRLC) and free-water value of LC (FWLC) with PSQI scores in ET and PD groups.
RESULTS
CNRLC was significantly lower in ET (p = 0.047) and PD (p = 0.018) than in healthy individuals, whereas no significant difference was found in FWLC among the groups. No significant differences were observed in CNR/FWLC between patients with/without sleep disorders after multiple comparison correction. No correlation was identified between CNR/FWLC and PSQI in ET and PD patients.
CONCLUSIONS
LC degeneration was observed in both ET and PD patients, implicating its involvement in the pathophysiology of both diseases. Additionally, no significant association was observed between LC integrity and PSQI, suggesting that LC impairment might not directly relate to overall QoS.
Topics: Humans; Essential Tremor; Locus Coeruleus; Female; Male; Parkinson Disease; Aged; Middle Aged; Sleep Wake Disorders; Magnetic Resonance Imaging; Nerve Degeneration; Sleep Quality; Melanins
PubMed: 38728202
DOI: 10.3233/JPD-240001 -
Scientific Reports May 2024Homeostatic plasticity, the ability of neurons to maintain their averaged activity constant around a set point value, is thought to account for the central hyperactivity...
Homeostatic plasticity, the ability of neurons to maintain their averaged activity constant around a set point value, is thought to account for the central hyperactivity after hearing loss. Here, we investigated the putative role of GABAergic neurotransmission in this mechanism after a noise-induced hearing loss larger than 50 dB in high frequencies in guinea pigs. The effect of GABAergic inhibition is linked to the normal functioning of K + -Cl- co-transporter isoform 2 (KCC2) which maintains a low intracellular concentration of chloride. The expression of membrane KCC2 were investigated before and after noise trauma in the ventral and dorsal cochlear nucleus (VCN and DCN, respectively) and in the inferior colliculus (IC). Moreover, the effect of gabazine (GBZ), a GABA antagonist, was also studied on the neural activity in IC. We show that KCC2 is downregulated in VCN, DCN and IC 3 days after noise trauma, and in DCN and IC 30 days after the trauma. As expected, GBZ application in the IC of control animals resulted in an increase of spontaneous and stimulus-evoked activity. In the noise exposed animals, on the other hand, GBZ application decreased the stimulus-evoked activity in IC neurons. The functional implications of these central changes are discussed.
Topics: Animals; Symporters; Guinea Pigs; K Cl- Cotransporters; Hearing Loss, Noise-Induced; gamma-Aminobutyric Acid; Male; Cochlear Nucleus; Pyridazines; Neurons
PubMed: 38724641
DOI: 10.1038/s41598-024-60858-1 -
Annals of Clinical and Translational... Jun 2024Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral...
OBJECTIVE
Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum.
METHODS
We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls.
RESULTS
Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity.
INTERPRETATION
Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.
Topics: Humans; Fragile X Syndrome; Tremor; Extracellular Vesicles; Ataxia; Male; Aged; Female; Fragile X Mental Retardation Protein; Middle Aged; Mitochondria; Cerebellum; Aged, 80 and over; Brain; Frontal Lobe
PubMed: 38717724
DOI: 10.1002/acn3.52040 -
Developmental Cognitive Neuroscience Jun 2024The human cerebellum emerges as a posterior brain structure integrating neural networks for sensorimotor, cognitive, and emotional processing across the lifespan....
INTRODUCTION
The human cerebellum emerges as a posterior brain structure integrating neural networks for sensorimotor, cognitive, and emotional processing across the lifespan. Developmental studies of the cerebellar anatomy and function are scant. We examine age-dependent MRI morphometry of the anterior cerebellar vermis, lobules I-V and posterior neocortical lobules VI-VII and their relationship to sensorimotor and cognitive functions.
METHODS
Typically developing children (TDC; n=38; age 9-15) and healthy adults (HAC; n=31; 18-40) participated in high-resolution MRI. Rigorous anatomically informed morphometry of the vermis lobules I-V and VI-VII and total brain volume (TBV) employed manual segmentation computer-assisted FreeSurfer Image Analysis Program [http://surfer.nmr.mgh.harvard.edu]. The neuropsychological scores (WASI-II) were normalized and related to volumes of anterior, posterior vermis, and TBV.
RESULTS
TBVs were age independent. Volumes of I-V and VI-VII were significantly reduced in TDC. The ratio of VI-VII to I-V (∼60%) was stable across age-groups; I-V correlated with visual-spatial-motor skills; VI-VII with verbal, visual-abstract and FSIQ.
CONCLUSIONS
In TDC neither anterior I-V nor posterior VI-VII vermis attained adult volumes. The "inverted U" developmental trajectory of gray matter peaking in adolescence does not explain this finding. The hypothesis of protracted development of oligodendrocyte/myelination is suggested as a contributor to TDC's lower cerebellar vermis volumes.
Topics: Humans; Adolescent; Child; Female; Male; Magnetic Resonance Imaging; Cognition; Adult; Young Adult; Cerebellar Vermis; Cerebellum
PubMed: 38713999
DOI: 10.1016/j.dcn.2024.101385 -
Alzheimer's Research & Therapy May 2024The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in...
BACKGROUND
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
METHODS
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
RESULTS
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
CONCLUSIONS
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
Topics: Humans; Frontotemporal Dementia; Male; Locus Coeruleus; Alzheimer Disease; Female; Aged; Magnetic Resonance Imaging; Basal Nucleus of Meynert; Middle Aged; Neuropsychological Tests; Amnesia; Positron-Emission Tomography
PubMed: 38702802
DOI: 10.1186/s13195-024-01466-z -
Communications Biology May 2024An organism's ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions....
An organism's ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions. Notably, the sensorimotor expectations produced when touching one's own body attenuate such sensations, making them feel weaker and less ticklish and rendering them easily distinguishable from potentially harmful touches of external origin. How the brain learns and keeps these action-related sensory expectations updated is unclear. Here we employ psychophysics and functional magnetic resonance imaging to pinpoint the behavioral and neural substrates of dynamic recalibration of expected temporal delays in self-touch. Our psychophysical results reveal that self-touches are less attenuated after systematic exposure to delayed self-generated touches, while responses in the contralateral somatosensory cortex that normally distinguish between delayed and nondelayed self-generated touches become indistinguishable. During the exposure, the ipsilateral anterior cerebellum shows increased activity, supporting its proposed role in recalibrating sensorimotor predictions. Moreover, responses in the cingulate areas gradually increase, suggesting that as delay adaptation progresses, the nondelayed self-touches trigger activity related to cognitive conflict. Together, our results show that sensorimotor predictions in the simplest act of touching one's own body are upheld by a sophisticated and flexible neural mechanism that maintains them accurate in time.
Topics: Humans; Somatosensory Cortex; Male; Magnetic Resonance Imaging; Cerebellum; Female; Adult; Young Adult; Touch Perception; Touch
PubMed: 38702520
DOI: 10.1038/s42003-024-06188-4 -
Annals of Medicine Dec 2024
Topics: Humans; Motor Cortex; Transcranial Direct Current Stimulation; Cerebellum; Stroke; Stroke Rehabilitation; Randomized Controlled Trials as Topic
PubMed: 38686845
DOI: 10.1080/07853890.2024.2348052 -
BMC Neurology Apr 2024Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has...
BACKGROUND
Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders.
METHODS
Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS.
DISCUSSION
Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06122675, first registered November 7, 2023.
Topics: Humans; Cerebral Palsy; Deep Brain Stimulation; Child; Adolescent; Young Adult; Movement Disorders; Cerebellum; Male; Female; Adult
PubMed: 38684956
DOI: 10.1186/s12883-024-03633-z -
Transgenic Research Jun 2024Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior...
Golli-myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli-myelin basic protein is necessary for myelination and neuronal maturation during central nervous system development. In this study, we established Golli-myelin basic protein-floxed mice to elucidate the cell-type-specific effects of Golli-myelin basic protein knockout through the generation of conditional knockout mice (Golli-myelin basic proteins; E3CreN), in which Golli-myelin basic proteins were specifically deleted in cerebellar granule neurons, where Golli-myelin basic proteins are expressed abundantly in wild-type mice. To investigate the role of Golli-myelin basic proteins in cerebellar granule neurons, we further performed histopathological analyses of these mice, with results indicating no morphological changes or degeneration of the major cellular components of the cerebellum. Furthermore, behavioral analysis showed that Golli-myelin basic proteins; E3CreN mice were healthy and did not display any abnormal behavior. These results suggest that the loss of Golli-myelin basic proteins in cerebellar granule neurons does not lead to cerebellar perturbations or behavioral abnormalities. This mouse model could therefore be employed to analyze the effect of Golli-myelin basic protein deletion in specific cell types of the central nervous system, such as other neuronal cells and oligodendrocytes, or in lymphocytes of the immune system.
Topics: Animals; Neurons; Mice, Knockout; Mice; Cerebellum; Myelin Basic Protein
PubMed: 38684589
DOI: 10.1007/s11248-024-00382-0