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Neurology(R) Neuroimmunology &... Sep 2024To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
BACKGROUND AND OBJECTIVES
To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
METHODS
CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs.
RESULTS
The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN ( < 0.001), CXCL13 ( = 0.001), and sTNFR1 ( = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN ( = 0.002) and IL19 ( = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], = 0.004) at the multivariate logistic regression model.
DISCUSSION
These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.
Topics: Humans; Osteopontin; Female; Male; Adult; Multiple Sclerosis, Relapsing-Remitting; Atrophy; Middle Aged; Cerebral Cortex; Magnetic Resonance Imaging; Biomarkers; Follow-Up Studies; Young Adult; Disease Progression
PubMed: 38917380
DOI: 10.1212/NXI.0000000000200265 -
PLoS Biology Jun 2024Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field...
Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field potentials (LFPs) during pre-cued reaching behavior in macaques. They contained a low beta band (<20 Hz) dominant in primary motor cortex and a high beta band (>20 Hz) dominant in dorsal premotor cortex (PMd). Low beta correlated positively with reaction time (RT) from visual cue onset and negatively with uninstructed hand postural micro-movements throughout the trial. High beta reflected temporal task prediction, with selective modulations before and during cues, which were enhanced in moments of increased focal attention when the gaze was on the work area. This double-dissociation in sources and behavioral correlates of motor cortical low and high beta, with respect to both task-instructed and spontaneous behavior, reconciles the largely disparate roles proposed for the beta rhythm, by suggesting band-specific roles in both movement control and spatiotemporal attention.
Topics: Animals; Motor Cortex; Attention; Beta Rhythm; Movement; Reaction Time; Macaca mulatta; Male; Cues; Psychomotor Performance
PubMed: 38917200
DOI: 10.1371/journal.pbio.3002670 -
PloS One 2024Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and...
Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and cognitive deficits all involve aberrant immune signaling. Microglia are the primary neuroimmune cells and regulate brain development. Microglia are particularly sensitive to early life insults, which can program their responses to future challenges. ELA in the form of maternal separation (MS) in rats alters later-life microglial morphology and the inflammatory profile of the prefrontal cortex, a region important for cognition. However, the role of microglial responses during MS in the development of later cognition is not known. Therefore, here we aimed to determine whether the presence of microglia during MS mediates long-term impacts on adult working memory. Clodronate liposomes were used to transiently deplete microglia from the brain, while empty liposomes were used as a control. We hypothesized that if microglia mediate the long-term impacts of ELA on working memory in adulthood, then depleting microglia during MS would prevent these deficits. Importantly, microglial function shifts throughout the neonatal period, so an exploratory investigation assessed whether depletion during the early versus late neonatal period had different effects on adult working memory. Surprisingly, empty liposome treatment during the early, but not late, postnatal period induced microglial activity changes that compounded with MS to impair working memory in females. In contrast, microglial depletion later in infancy impaired later life working memory in females, suggesting that microglial function during late infancy plays an important role in the development of cognitive function. Together, these findings suggest that microglia shift their sensitivity to early life insults across development. Our findings also highlight the potential for MS to impact some developmental processes only when compounded with additional neuroimmune challenges in a sex-dependent manner.
Topics: Animals; Microglia; Female; Maternal Deprivation; Rats; Male; Cognition; Memory, Short-Term; Animals, Newborn; Prefrontal Cortex; Rats, Sprague-Dawley; Age Factors
PubMed: 38917075
DOI: 10.1371/journal.pone.0306022 -
ELife Jun 2024Adaptive motor behavior depends on the coordinated activity of multiple neural systems distributed across the brain. While the role of sensorimotor cortex in motor...
Adaptive motor behavior depends on the coordinated activity of multiple neural systems distributed across the brain. While the role of sensorimotor cortex in motor learning has been well established, how higher-order brain systems interact with sensorimotor cortex to guide learning is less well understood. Using functional MRI, we examined human brain activity during a reward-based motor task where subjects learned to shape their hand trajectories through reinforcement feedback. We projected patterns of cortical and striatal functional connectivity onto a low-dimensional manifold space and examined how regions expanded and contracted along the manifold during learning. During early learning, we found that several sensorimotor areas in the dorsal attention network exhibited increased covariance with areas of the salience/ventral attention network and reduced covariance with areas of the default mode network (DMN). During late learning, these effects reversed, with sensorimotor areas now exhibiting increased covariance with DMN areas. However, areas in posteromedial cortex showed the opposite pattern across learning phases, with its connectivity suggesting a role in coordinating activity across different networks over time. Our results establish the neural changes that support reward-based motor learning and identify distinct transitions in the functional coupling of sensorimotor to transmodal cortex when adapting behavior.
Topics: Humans; Magnetic Resonance Imaging; Reward; Male; Learning; Female; Adult; Young Adult; Sensorimotor Cortex; Brain Mapping; Motor Activity; Cerebral Cortex
PubMed: 38916598
DOI: 10.7554/eLife.91928 -
Frontiers in Endocrinology 2024Spexin (SPX, NPQ) is a 14-amino acid neuroactive peptide identified using bioinformatics. This amino acid sequence of the mature spexin peptide has been highly conserved... (Review)
Review
Spexin (SPX, NPQ) is a 14-amino acid neuroactive peptide identified using bioinformatics. This amino acid sequence of the mature spexin peptide has been highly conserved during species evolution and is widely distributed in the central nervous system and peripheral tissues and organs. Therefore, spexin may play a role in various biological functions. Spexin, the cognate ligand for GALR2/3, acting as a neuromodulator or endocrine signaling factor, can inhibit reproductive performance. However, controversies and gaps in knowledge persist regarding spexin-mediated regulation of animal reproductive functions. This review focuses on the hypothalamic-pituitary-gonadal axis and provides a comprehensive overview of the impact of spexin on reproduction. Through this review, we aim to enhance understanding and obtain in-depth insights into the regulation of reproduction by spexin peptides, thereby providing a scientific basis for future investigations into the molecular mechanisms underlying the influence of spexin on reproductive function. Such investigations hold potential benefits for optimizing farming practices in livestock, poultry, and fish industries.
Topics: Animals; Reproduction; Peptide Hormones; Vertebrates; Humans; Hypothalamo-Hypophyseal System
PubMed: 38915898
DOI: 10.3389/fendo.2024.1422711 -
Journal of Neuroengineering and... Jun 2024Repeated transcranial magnetic stimulation (rTMS) could induce alterations in cortical excitability and promote neuroplasticity. To precisely quantify these effects,... (Meta-Analysis)
Meta-Analysis Review
Impact of repetitive transcranial magnetic stimulation on cortical activity: a systematic review and meta-analysis utilizing functional near-infrared spectroscopy evaluation.
BACKGROUND
Repeated transcranial magnetic stimulation (rTMS) could induce alterations in cortical excitability and promote neuroplasticity. To precisely quantify these effects, functional near-infrared spectroscopy (fNIRS), an optical neuroimaging modality adept at detecting changes in cortical hemodynamic responses, has been employed concurrently alongside rTMS to measure and tailor the impact of diverse rTMS protocols on the brain cortex.
OBJECTIVE
This systematic review and meta-analysis aimed to elucidate the effects of rTMS on cortical hemodynamic responses over the primary motor cortex (M1) as detected by fNIRS.
METHODS
Original articles that utilized rTMS to stimulate the M1 cortex in combination with fNIRS for the assessment of cortical activity were systematically searched across the PubMed, Embase, and Scopus databases. The search encompassed records from the inception of these databases up until April, 2024. The assessment for risk of bias was also conducted. A meta-analysis was also conducted in studies with extractable raw data.
RESULTS
Among 312 studies, 14 articles were eligible for qualitative review. 7 studies were eligible for meta-analysis. A variety of rTMS protocols was employed on M1 cortex. In inhibitory rTMS, multiple studies observed a reduction in the concentration of oxygenated hemoglobin [HbO] at the ipsilateral M1, contrasted by an elevation at the contralateral M1. Meta-analysis also corroborated this consistent trend. Nevertheless, certain investigations unveiled diminished [HbO] in bilateral M1. Several studies also depicted intricate inhibitory or excitatory interplay among distinct cortical regions.
CONCLUSION
Diverse rTMS protocols led to varied patterns of cortical activity detected by fNIRS. Meta-analysis revealed a trend of increasing [HbO] in the contralateral cortices and decreasing [HbO] in the ipsilateral cortices following low frequency inhibitory rTMS. However, due to the heterogeneity between studies, further research is necessary to comprehensively understand rTMS-induced alterations in brain activity.
Topics: Transcranial Magnetic Stimulation; Spectroscopy, Near-Infrared; Humans; Motor Cortex
PubMed: 38915003
DOI: 10.1186/s12984-024-01407-9 -
Scientific Reports Jun 2024Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the...
Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C-C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.
Topics: Animals; Chemokine CCL2; Rats; Disease Models, Animal; Spinal Cord Stimulation; Male; Seizures; Epilepsy; Kainic Acid; Hippocampus; Neuroglia; Rats, Sprague-Dawley; Electroencephalography
PubMed: 38914629
DOI: 10.1038/s41598-024-64972-y -
Nature Communications Jun 2024Idling brain activity has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the idling brain can...
Idling brain activity has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the idling brain can create novel ideas. Here, we show that cortical offline activity is both necessary and sufficient for building unlearned inferential knowledge from previously acquired information. In a transitive inference paradigm, male C57BL/6J mice gained the inference 1 day after, but not shortly after, complete training. Inhibiting the neuronal computations in the anterior cingulate cortex (ACC) during post-learning either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep, but not wakefulness, disrupted the inference without affecting the learned knowledge. In vivo Ca imaging suggests that NREM sleep organizes the scattered learned knowledge in a complete hierarchy, while REM sleep computes the inferential information from the organized hierarchy. Furthermore, after insufficient learning, artificial activation of medial entorhinal cortex-ACC dialog during only REM sleep created inferential knowledge. Collectively, our study provides a mechanistic insight on NREM and REM coordination in weaving inferential knowledge, thus highlighting the power of idling brain in cognitive flexibility.
Topics: Animals; Sleep, REM; Male; Mice, Inbred C57BL; Prefrontal Cortex; Learning; Mice; Gyrus Cinguli; Wakefulness; Sleep, Slow-Wave; Knowledge; Entorhinal Cortex; Neurons
PubMed: 38914541
DOI: 10.1038/s41467-024-48816-x -
ELife Jun 2024Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is...
Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive transcranial magnetic stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial anterior PFC (aPFC, encompassing the Brodmann area 10) on threat memory and generalization. Here we showed that rTMS over the aPFC applied before threat memory retrieval immediately decreases implicit reactions to learned and novel stimuli in humans. These effects enduringly persisted 1 week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, rTMS over the aPFC resulted in a more pronounced reduction of defensive responses compared to rTMS targeting the dorsolateral PFC. These findings reveal a previously unexplored prefrontal region, the modulation of which can efficiently and durably inhibit implicit reactions to learned threats. This represents a significant advancement toward the long-term deactivation of exaggerated responses to threats.
Topics: Humans; Fear; Prefrontal Cortex; Transcranial Magnetic Stimulation; Male; Young Adult; Female; Adult; Extinction, Psychological
PubMed: 38913410
DOI: 10.7554/eLife.85951 -
International Journal of Nanomedicine 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a...
BACKGROUND
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR TItpr3/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.
METHODS
Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.
RESULTS
Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX and SOX2/GFAP cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.
CONCLUSION
In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.
Topics: Animals; Mice, Inbred C57BL; Mice; Fullerenes; Autism Spectrum Disorder; Cognitive Dysfunction; Disease Models, Animal; Male; Doublecortin Protein; Social Behavior; Behavior, Animal; Hippocampus; Vascular Endothelial Growth Factor A; Neuroprotective Agents; Neurogenesis; Autistic Disorder
PubMed: 38911505
DOI: 10.2147/IJN.S459511