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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 -
ELife Jun 2024A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1), while another...
A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1), while another arises from the deep cerebellar nuclei (Cb). M1 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi), and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1 in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1 through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1. Separately, we also demonstrate that, perhaps unexpectedly, GABAergic GPi and SNr inputs converge with those from the Cb. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1 and Cb information to cortex.
Topics: Animals; Motor Cortex; Mice; Basal Ganglia; Thalamus; Male; Female; Cerebellum; Neural Pathways; Optogenetics; GABAergic Neurons; Mice, Inbred C57BL
PubMed: 38856045
DOI: 10.7554/eLife.97489 -
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 -
CNS Neuroscience & Therapeutics Jun 2024To investigate dynamic functional connectivity (dFC) within the cerebellar-whole brain network and dynamic topological properties of the cerebellar network in...
PURPOSE
To investigate dynamic functional connectivity (dFC) within the cerebellar-whole brain network and dynamic topological properties of the cerebellar network in obstructive sleep apnea (OSA) patients.
METHODS
Sixty male patients and 60 male healthy controls were included. The sliding window method examined the fluctuations in cerebellum-whole brain dFC and connection strength in OSA. Furthermore, graph theory metrics evaluated the dynamic topological properties of the cerebellar network. Additionally, hidden Markov modeling validated the robustness of the dFC. The correlations between the abovementioned measures and clinical assessments were assessed.
RESULTS
Two dynamic network states were characterized. State 2 exhibited a heightened frequency, longer fractional occupancy, and greater mean dwell time in OSA. The cerebellar networks and cerebrocerebellar dFC alterations were mainly located in the default mode network, frontoparietal network, somatomotor network, right cerebellar CrusI/II, and other networks. Global properties indicated aberrant cerebellar topology in OSA. Dynamic properties were correlated with clinical indicators primarily on emotion, cognition, and sleep.
CONCLUSION
Abnormal dFC in male OSA may indicate an imbalance between the integration and segregation of brain networks, concurrent with global topological alterations. Abnormal default mode network interactions with high-order and low-level cognitive networks, disrupting their coordination, may impair the regulation of cognitive, emotional, and sleep functions in OSA.
Topics: Humans; Male; Sleep Apnea, Obstructive; Cerebellum; Middle Aged; Adult; Nerve Net; Magnetic Resonance Imaging; Connectome; Neural Pathways; Default Mode Network
PubMed: 38828694
DOI: 10.1111/cns.14786 -
Alzheimer's Research & Therapy May 2024Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and...
BACKGROUND
Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology.
METHODS
142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates.
RESULTS
At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity.
CONCLUSIONS
Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.
Topics: Humans; Female; Male; Alzheimer Disease; Aged; Locus Coeruleus; Magnetic Resonance Imaging; Parietal Lobe; Aged, 80 and over; Attention; Frontal Lobe; Positron-Emission Tomography; Cross-Sectional Studies; Neural Pathways; Cognitive Dysfunction; Neuropsychological Tests
PubMed: 38822365
DOI: 10.1186/s13195-024-01485-w -
Nature Communications May 2024Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic...
Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation or plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either synaptic or intrinsic plasticity. Spatial analysis of calcium signals demonstrated that intrinsic, but not synaptic plasticity, enhances the spread of dendritic parallel fiber response potentiation. Simultaneous dendrite and axon initial segment recordings confirm these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of long-term potentiation on neuronal responsiveness.
Topics: Animals; Purkinje Cells; Mice; Neuronal Plasticity; Cerebellum; Long-Term Potentiation; Dendrites; Synapses; Calcium; Male; Axons; Mice, Inbred C57BL; Electric Stimulation; Female
PubMed: 38821918
DOI: 10.1038/s41467-024-48373-3