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Frontiers in Neurology 2024To investigate whether changes occur in the dynamic functional connectivity (dFC) of motor cerebellum with cerebral cortex in juvenile myoclonic epilepsy (JME).
OBJECTIVE
To investigate whether changes occur in the dynamic functional connectivity (dFC) of motor cerebellum with cerebral cortex in juvenile myoclonic epilepsy (JME).
METHODS
We adopted resting-state electroencephalography-functional magnetic resonance imaging (EEG-fMRI) and a sliding-window approach to explore the dFC of motor cerebellum with cortex in 36 JME patients compared with 30 and age-matched health controls (HCs). The motor cerebellum was divided into five lobules (I-V, VI, VIIb, VIIIa, and VIIIb). Additionally, correlation analyses were conducted between the variability of dFC and clinical variables in the Juvenile Myoclonic Epilepsy (JME) group, such as disease duration, age at disease onset, and frequency score of myoclonic seizures.
RESULTS
Compared to HCs, the JME group presented increased dFC between the motor cerebellum with SMN and DMN. Specifically, connectivity between lobule VIIb and left precentral gyrus and right inferior parietal lobule (IPL); between lobule VIIIa and right inferior frontal gyrus (IFG) and left IPL; and between lobule VIIIb and left middle frontal gyrus (MFG), bilateral superior parietal gyrus (SPG), and left precuneus. In addition, within the JME group, the strength of dFC between lobule VIIIb and left precuneus was negatively ( = -0.424, = 0.025, Bonferroni correction) related with the frequency score of myoclonic seizures.
CONCLUSION
In patients with JME, there is a functional dysregulation between the motor cerebellum with DMN and SMN, and the variability of dynamic functional connectivity may be closely associated with the occurrence of motor symptoms in JME.
PubMed: 38903166
DOI: 10.3389/fneur.2024.1373125 -
BioRxiv : the Preprint Server For... May 2024Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These...
BACKGROUND
Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet.
METHODS
Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9.
RESULTS
Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling.
CONCLUSIONS
There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.
PubMed: 38903110
DOI: 10.1101/2024.05.24.595755 -
MedRxiv : the Preprint Server For... May 2024Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of...
Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted. Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations ( = 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described 'action-mode' network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei. These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.
PubMed: 38903109
DOI: 10.1101/2024.05.24.24307896 -
Social Cognitive and Affective... Jun 2024Friendships increase mental wellbeing and resilient functioning in young people with childhood adversity (CA). However, the mechanisms of this relationship are unknown....
Early adolescent perceived friendship quality aids affective and neural responses to social inclusion and exclusion in young adults with and without adverse childhood experiences.
Friendships increase mental wellbeing and resilient functioning in young people with childhood adversity (CA). However, the mechanisms of this relationship are unknown. We examined the relationship between perceived friendship quality at age 14 after the experience of CA and reduced affective and neural responses to social exclusion at age 24. Resilient functioning was quantified as psychosocial functioning relative to the degree of CA severity in 310 participants at age 24. From this cohort, 62 young people with and without CA underwent functional Magnetic Resonance Imaging to assess brain responses to social inclusion and exclusion. We observed that good friendship quality was significantly associated with better resilient functioning. Both friendship quality and resilient functioning were related to increased affective responses to social inclusion. We also found that friendship quality, but not resilient functioning, was associated with increased dorsomedial prefrontal cortex responses to peer exclusion. Our findings suggest that friendship quality in early adolescence may contribute to the evaluation of social inclusion by increasing affective sensitivity to positive social experiences and increased brain activity in regions involved in emotion regulation to negative social experiences. Future research is needed to clarify this relationship with resilient functioning in early adulthood.
PubMed: 38902943
DOI: 10.1093/scan/nsae044 -
Molecular Brain Jun 2024Alternative splicing (AS) contributes to the biological heterogeneity between species, sexes, tissues, and cell types. Many diseases are either caused by alterations in...
Alternative splicing (AS) contributes to the biological heterogeneity between species, sexes, tissues, and cell types. Many diseases are either caused by alterations in AS or by alterations to AS. Therefore, measuring AS accurately and efficiently is critical for assessing molecular phenotypes, including those associated with disease. Long-read sequencing enables more accurate quantification of differentially spliced isoform expression than short-read sequencing approaches, and third-generation platforms facilitate high-throughput experiments. To assess differences in AS across the cerebellum, cortex, hippocampus, and striatum by sex, we generated and analyzed Oxford Nanopore Technologies (ONT) long-read RNA sequencing (lrRNA-Seq) C57BL/6J mouse brain cDNA libraries. From > 85 million reads that passed quality control metrics, we calculated differential gene expression (DGE), differential transcript expression (DTE), and differential transcript usage (DTU) across brain regions and by sex. We found significant DGE, DTE, and DTU across brain regions and that the cerebellum had the most differences compared to the other three regions. Additionally, we found region-specific differential splicing between sexes, with the most sex differences in DTU in the cortex and no DTU in the hippocampus. We also report on two distinct patterns of sex DTU we observed, sex-divergent and sex-specific, that could potentially help explain sex differences in the prevalence and prognosis of various neurological and psychiatric disorders in future studies. Finally, we built a Shiny web application for researchers to explore the data further. Our study provides a resource for the community; it underscores the importance of AS in biological heterogeneity and the utility of long-read sequencing to better understand AS in the brain.
Topics: Animals; Mice, Inbred C57BL; Male; Brain; Female; Sequence Analysis, RNA; RNA, Messenger; Sex Characteristics; Alternative Splicing; RNA Isoforms; Organ Specificity; Mice; Gene Expression Profiling
PubMed: 38902764
DOI: 10.1186/s13041-024-01112-7 -
Translational Psychiatry Jun 2024Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying...
Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T) and iron concentration (proxied by transverse relaxation time T*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.
Topics: Humans; Depressive Disorder, Major; Magnetic Resonance Imaging; Female; Male; Adult; Prefrontal Cortex; Gyrus Cinguli; Myelin Sheath; Middle Aged; Iron; Case-Control Studies
PubMed: 38902245
DOI: 10.1038/s41398-024-02976-y -
Nature Communications Jun 2024The ability to establish associations between environmental stimuli is fundamental for higher-order brain functions like state inference and generalization. Both the...
The ability to establish associations between environmental stimuli is fundamental for higher-order brain functions like state inference and generalization. Both the hippocampus and orbitofrontal cortex (OFC) play pivotal roles in this, demonstrating complex neural activity changes after associative learning. However, how precisely they contribute to representing learned associations remains unclear. Here, we train head-restrained mice to learn four 'odor-outcome' sequence pairs composed of several task variables-the past and current odor cues, sequence structure of 'cue-outcome' arrangement, and the expected outcome; and perform calcium imaging from these mice throughout learning. Sequence-splitting signals that distinguish between paired sequences are detected in both brain regions, reflecting associative memory formation. Critically, we uncover differential contents in represented associations by examining, in each area, how these task variables affect splitting signal generalization between sequence pairs. Specifically, the hippocampal splitting signals are influenced by the combination of past and current cues that define a particular sensory experience. In contrast, the OFC splitting signals are similar between sequence pairs that share the same sequence structure and expected outcome. These findings suggest that the hippocampus and OFC uniquely and complementarily organize the acquired associative structure.
Topics: Animals; Hippocampus; Prefrontal Cortex; Neurons; Mice; Male; Mice, Inbred C57BL; Association Learning; Cues; Odorants; Memory
PubMed: 38902232
DOI: 10.1038/s41467-024-49652-9 -
Acta Medica Okayama Jun 2024Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was...
Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.
Topics: Animals; Zolpidem; Lipopolysaccharides; Mice; Pyridines; Male; Receptors, GABA-A; Symporters; Reflex, Righting; Hippocampus; K Cl- Cotransporters; Hypnotics and Sedatives; Inflammation; Frontal Lobe
PubMed: 38902210
DOI: 10.18926/AMO/67197 -
ENeuro Jun 2024Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated...
Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated G-protein coupled receptor (GPCR) signaling has been shown to affect memory processing, but little is known about the role of cortical astrocytic G-GPCR signaling in remote memory acquisition and the functioning of cortical engram neurons. We assessed this by chemogenetic manipulation of astrocytes in the medial prefrontal cortex (mPFC) of male mice, during either encoding or consolidation of a contextual fear memory, while simultaneously labeling cortical engram neurons. We found that stimulation of astrocytic G signaling during memory encoding and consolidation did not alter remote memory expression. In line with this, the size of the mPFC engram population and the recall-induced reactivation of these neurons was unaffected. Hence, our data indicate that activation of G-GPCR signaling in cortical astrocytes is not sufficient to alter memory performance and functioning of cortical engram neurons.
Topics: Animals; Astrocytes; Male; Prefrontal Cortex; Signal Transduction; Neurons; Fear; Mice, Inbred C57BL; GTP-Binding Protein alpha Subunits, Gs; Mice; Memory; Memory, Long-Term
PubMed: 38902023
DOI: 10.1523/ENEURO.0056-24.2024 -
Brain Stimulation Jun 2024Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial...
BACKGROUND
Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) is unclear.
METHODS
In this single-center retrospective chart review, 208 TRD patients completed the Stanford Expectation of Treatment Scale (SETS) before starting open-label rTMS treatment. Patients were offered two excitatory rTMS protocols (deep TMS or intermittent theta-burst stimulation), which stimulated the left dorsolateral prefrontal cortex. A minimum of 20 once daily treatments were provided, delivered over 4-6 weeks. Primary outcomes were 1) remission, measured by a post-treatment score of <8 on the Hamilton Depression Rating Scale (HAMD-17), and 2) premature discontinuation. The change in HAMD-17 scores over time was used as a secondary outcome. Physicians were blinded to SETS scores. Logistic and linear regression, adjusting for covariates, assessed SETS and HAMD-17 relationships.
RESULTS
Of 208 patients, 177 had baseline and covariate data available. The mean positivity bias score (positive expectancy minus negative expectancy subscale averages) was 0.48 ± 2.21, indicating the cohort was neutral regarding the expectations of their treatment on average. Higher positive expectancy scores were significantly associated with greater odds of remission (OR = 1.90, p = 0.003) and greater reduction in HAMD-17 scores (β = 1.30, p = 0.005) at the end of acute treatment, after adjusting for covariates. Negative expectancy was not associated with decreased odds of remission (p = 0.2) or treatment discontinuation (p = 0.8).
CONCLUSIONS
Higher pre-treatment positive expectations were associated with greater remission rates with open-label rTMS in a naturalistic cohort of patients with TRD.
PubMed: 38901565
DOI: 10.1016/j.brs.2024.06.006