S‐Nitrosylation of Dexras1 Controls Post‐Stroke Recovery via Regulation of Neuronal Excitability and Dendritic Remodeling

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

ABSTRACT Aims Stroke is a major public health concern leading to high rates of death and disability worldwide, unfortunately with no effective treatment available for stroke recovery during the repair phase. Methods Photothrombotic was induced in mice. Adeno‐associated viruses (AAV) were microinjected into peri‐infarct cortex immediately after photothrombotic stroke. Grid‐walking task cylinder used assess motor function. Western blotting, Golgi staining, electrophysiology recordings performed uncover mechanisms. Results The ternary complex neuronal nitric oxide synthase (nNOS), carboxy‐terminal PDZ ligand nNOS (CAPON) dexamethasone‐induced ras protein 1 (Dexras1) structurally beneficial S‐nitrosylation Dexras1 (SNO‐Dexras1). In our previous study, uncoupling nNOS‐CAPON interaction by Tat‐CAPON‐12C promoted functional Here, we show that ischemia elevated levels nNOS‐Dexras1 SNO‐Dexras1 days 4–10 induction, as excepted, Tat‐CAPON‐12C, peptide disrupting interaction, significantly reversed these changes. above information implies repressed may mediate functional‐promoting effects could be vital molecular substrate post‐stroke phage. Inhibiting ischemia‐induced AAV vector‐mediated knockdown or over‐expression dominant negative (Dexras1‐C11S) produced sustained function from contrast, up‐regulation over‐expressing worsened outcome. Using recordings, also observed silence increased spike number miniature excitatory postsynaptic currents (mEPSCs) frequency, suggesting enhancement excitability. addition, dendritic complexity cultured neuron more importantly enhanced spine density cortex, implying remodeling. Conclusion Thus, inhibition positively regulates via excitability Our results identify serve novel target promoting restoration delayed phase, shedding light on treatment.

Language: Английский

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Sleep-like cortical dynamics during wakefulness and their network effects following brain injury

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 22, 2024

By connecting old and recent notions, different spatial scales, research domains, we introduce a novel framework on the consequences of brain injury focusing key role slow waves. We argue that long-standing finding EEG waves after reflects intrusion sleep-like cortical dynamics during wakefulness; illustrate how these are generated they can lead to functional network disruption behavioral impairment. Finally, outline scenario whereby post-injury be modulated reawaken parts have fallen asleep optimize rehabilitation strategies promote recovery. In this Perspective, authors propose result in slowing wakefulness. The generation their effects networks behavior discussed, as well future directions for neuromodulation.

Language: Английский

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Translational Connectomics: overview of machine learning in macroscale Connectomics for clinical insights

BMC Neurology, Journal Year: 2024, Volume and Issue: 24(1)

Published: Sept. 28, 2024

Language: Английский

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Multifractal dynamic changes of spontaneous brain activity in psychiatric disorders: Adult attention deficit-hyperactivity disorder, bipolar disorder, and schizophrenia

Journal of Affective Disorders, Journal Year: 2025, Volume and Issue: 373, P. 291 - 305

Published: Jan. 5, 2025

Language: Английский

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The physiology of stroke neurorehabilitation

The Journal of Physiology, Journal Year: 2025, Volume and Issue: 603(3), P. 611 - 615

Published: Jan. 21, 2025

The Cochrane network, in its definition of rehabilitation, refers to "interventions targeting a person's" capacity (by addressing body structures, functions, and activities/participation) … with the goal "optimizing" "functioning" "persons health conditions currently experiencing disability or likely experience …" (Negrini et al., 2022). In respect significance accorded 'capacity' 'functioning', rehabilitation lies squarely within purview physiology, emphasis on integration molecular, cellular, systems whole-body function. Neurorehabilitation (a.k.a. neurological rehabilitation) deals more specifically (e.g. National Institute for Health & Care Excellence, 2021) impairments that arise from injury brain, spine peripheral nerves, caused by disease, trauma, tumours, infections, metabolic insults disorders blood supply – such as stroke. terms ramifications, stroke ranks second highest cause death (Roth 2018), follows only neonatal ischaemic heart disease an agent long-term (Kyu 2018). Most notably, has impact severity, greater than any other chronic Adamson 2004). It is estimated approximately 15 million strokes occur worldwide every year (World Organization, 2024). Of those who survive, half will be left demands neurorehabilitation. With lethality falling, incidence rising especially low-income middle-income countries (Prust 2024), there renewed imperative direct research towards life after stroke, particularly since targets neurorehabilitation feature prominently among priorities identified survivors their carers (Pollock 2012). seems self-evident physiological knowledge should inform neurorehabilitation, when aspiration increase efficacy efficiency delivery. this context, might extend mechanisms mediate adaptation to, recovery from, brain damage. may also encompass means through which technique exerts effect. Writing collection, Carson Hayward (2025) point out these strands are integrated less frequently one suppose. addition, unlike many areas clinical science, relevant physiology sought (if at all) following concoction novel therapy, rather precursor. Perhaps due lack appreciation existing corpus directly This special issue Journal Physiology been devised aim highlighting recent empirical contributions corpus, along key theoretical concepts information can parsed. Many features responses observed tissue (and beyond) haemorrhagic have deeply characterised cellular levels, primarily using animal models. Especially salient context relationships exist between specific sequelae acute effects functions human nervous system. describing pathophysiology post-stroke dysphagia (PSD), Sasegbon al. emphasise understand PSD, it first necessary comprehend neurophysiology swallowing humans. complex involve dynamic interplay control centres defined level brainstem, well higher cerebellum cerebral cortices. Damage element distributed network result discoordination oropharyngeal oesophageal muscles otherwise engaged precise sequence safely convey ingested material oral cavity stomach. Yet, highlight, our interactions give rise requisite muscle synergies remains incomplete. Consequentially, not yet possible determine whether subcortical lesions arises damage centres, alterations connectivity cortical centres. gap understanding reflects general tension long-standing view functional deficits grey matter 'hub regions' (i.e. loci), increasingly influential conception 'circuitopathy' (Cassidy 2022), whereby magnitude white determines severity capacity. regard, Urbin draws attention observation macro-level typically lower threshold infarction matter. highlight findings integrity structural (brain) connectome preeminent factor determining extent motor function occurs weeks Structural disconnection seen exert causal influence (on capacity) disruption circuits tracts afford. support position, they review observations 'cross-road' regions comprising several expressed span multiple domains memory spatial memory, attention, motor, language). upper limb, long recognised (constituting 'projectome') efferent commands spinal neurons profound degree movement preserved Much contemporary discourse has, however, exclusive focus fibres corticospinal tract. exhaustive review, rich detailed analysis neuroanatomy, reminds us neural impulses goal-directed conveyed single Rather, keeping notion 'volitional set' Gottlieb, 1996), corticospinal-mediated changes excitability motoneurons shaped descending segmental pathways. Neuroanatomy further dictates rarely affects tract, heterogeneity distribution sustained across accounting least some variation impairment loss exhibited individuals (Urbin, 2025). nature imposes especial challenges forecast outcomes individual patients. Undertaken subacute stage, presence absence motor-evoked potentials (MEPs) contralateral delivery transcranial magnetic stimulation (TMS) scalp locations overlying primary cortex, offers promise biomarker limb Due various pathways (other tract) post-synaptic state motoneurons, MEPs cannot simply interpreted indicative tract integrity. does not, diminish potential utility MEPS, provide broadly encompassing measure corticomotor access final common pathway preserved. issue, Shanks Byblow argue binary MEP outcome (present absent) hitherto used biomarker, fail fully exploit prognostic power potentials. because criterion applied present arbitrary amplitude value 50 µV). As out, sub-threshold contain appraisal impairment, recovery. extension refinement approach, advocate use TMS-evoked obtained simultaneously wide range intensities. Three classes response designated: (1) meet conventional deemed 'present'; (2) below ordinarily (in scheme) marked 'absent'; (3) instances which, given muscle, intensity fails elicit MEP. resulting 'threshold matrix', subject compositional data analysis, represented ternary plot. Beyond providing granular status, phase during attenuated absent, hypothesise sub-regions plot differentiate phenotypes. A challenge determination optimal basis upon phenotypes recovery) defined. wide-ranging fatigue, Kuppuswamy argues presently unknown derived class variable perceptual/behavioural/neuronal), composite types. Although evidently broad significance, question relation fatigue. Divination answer is, hampered multidimensional fatigue symptomology, transcends paradigms assessment. Arguing that, fundamentally, 'fatigue' perceptual experience, makes case systematisation phenotyping precursor, firstly, enhanced pathophysiology, secondly, development effective treatments. While necessarily, multiplicity engenders manifestation models ground process beginning emerge. Analysing merits models, 'sensory attenuation model' dysfunction, provides promising account diverse phenomenology particular mediating altered attentional processes. model complementary conceptions apathy (described Hayward, 2025) diffuse cerebrovascular pathology impairs large-scale networks underpin control, reinforcement learning reward-based decision-making. theme emerge again, concept 'neuroplasticity' underpins much conducted domain fired popular imagination, works Brain That Changes Itself (Doidge, 2007). supposition instilled most vivid portrayals neuroplasticity, 'endless adaptability' (Sacks, An allied conjecture 'reorganisation' idea take new (for critical discussion see Makin Krakauer, 2023). inspirational studies notwithstanding, considerations evidence indicate, instead, neuroplastic adaptations already 'representational computational capacity' compromised. 'structural blueprint' system strong constraints realisable (Makin notes even cases severe paresis tends preservation brainstem origin course carry neuron pools. Rehabilitating therefore involves certain reintegration supraspinal circuits, vascular insult restricted former. Focussing neuraxis transmission tracts, study transneuronal degeneration regeneration) cord 'poor cousin' concerns itself infarcts circuits. 'Downstream' 'upstream' can, levels These include segregation into origins frontal parietal areas, funiculi terminations lumbar cervical segments, pools ventral horn Importantly, remain viable responsive excitation regardless identity fibre considerable period cells deprived usual trophic inputs. remarks, 'restoring about forming extensively circuitry altering substrate remains'. comprehensive focussing experience-driven competition reorganisation Jones emphasises under consideration, fundamental assumption regenerative reactions activity-dependent. practice tenet equivalent status behavioural interventions activity patterns manner promotes reactions. resides principles guide design interventions. Drawing work undertaken rodent seeks delineate permit identified, generalise populations. consistent experimentally induced cortex rodents de novo skill performed non-paretic forelimb interfere rehabilitative training engender improvements paretic paw. implication new-experience dependent performance paw disruptive (Jones, At glance, appear run counter impaired (discussed Kitchen 2025 (through 'cross education' effect) bring limb. detrimental consequences arising counteracted bimanual training, interleaving limbs. To echo raised (2025), determined whether, patients, schedule alternating engagement delineating molecular processes remodelling overstated, (which occupies bulk (Ebbesen Brecht, 2017)) very rare humans (van Assche 2021). interest additional yield convergent role both hemispheres promoting presumption endogenous CNS augmented neurons. employed engendering non-invasively (see 2025), current (tDCS) variants repetitive TMS (rTMS). balance available Ahmed 2023) protocols designed ipsilesional hemisphere efficacy, whereas intention decreasing contralesional limited meta-analysis (Ahmed indicated positive transcutaneous vagus nerve (VNS) exceeded physical alone outranked all forms non-invasive stimulation, measures activities daily living. contribution Schambra Hays survey foundational VNS therapy. They optimally mechanistic acts network. underlined probably different ascribed tDCS rTMS. large 'paired therapy' lends weight assertion. Applied non-invasively, administered ('open loop') (usually limb). paired VNS, bursts electrical delivered via implanted electrodes, intervals relative movements made 'closed loop' arrangement. Detailed profiling form supports triggers widespread release neuromodulatory neurotransmitters (including noradrenaline, serotonin acetylcholine), alters synapses generation movement) activated recently. Timing critical. Delivered 2 s event, experimental indices gains. If, hand, delay 10 s, no (Schambra Hays, There observation. When preclinical employed, traces synaptic differ depending spared injury. instrumental drive practical delivering electrode specificity suggests accommodate life-threatening event requiring urgent medical assistance care hospital, public education campaigns rightly urge vigilance manifestations. example, Service UK includes cardinal sign: 'weakness numbness down 1 side your body'. Medical textbooks too Torbey Selim, 2013), put unilateral expression symptoms. vein also, scientific literature replete articles draw contrast 'impaired limb' 'non-impaired limb'. tendency thus conceive body. Surveying garnered over decades, sometimes subtle, but definitively systematic, arm follow hemispheric specialisation selective demonstrated arms contingent injured. Expressed language dominance hypothesis (Sainburg, 2002, 2005), right-handed individuals) contains 'tuned' facilitate dynamics. Whereas right adapted regulation impedance. corollary while differentiation revealed clearly (the characteristics of) arm, local each play ipsilateral (Kitchen Consistent model, show early reaching misspecification initial direction), often achieving accurate position contrast, suffered commonly exhibit abnormalities decelerative accentuated errors positioning What more, appears closely related New strategies paresis) advanced remediate hemisphere-specific reader note convergence outworking approaches driven cross-education. Remaining way generated tests therapeutic phenomenon cross-education (Calvert Carson, 2022; lateralisation became functionally adaptive, i.e. phylogenetic sense, presumably evolved neuroanatomical structures capable supporting two hemispheres. Integration counterpart (hemispheric) specialisation. Accordingly, appraised callosum largest connecting hemispheres, significant bearing scope subsequent 2020). important future disconnectome modelling delineated scan referred either atlas structural/functional database healthy brains (dis)connectivity (Carson survivor, programme tailored 'recovery connectome' (Latifi Carmichael. papers collected illustrate concerning level, antecedent efficacious Such interruptions brain. lingua franca demanded match 2024) constituted processes, Please note: publisher responsible content functionality supplied authors. Any queries missing content) directed corresponding author article. No competing interests declared. Sole author. funding.

Language: Английский

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Transcranial direct current stimulation and lesions hierarchically reorganize brain network dynamics with biological annotations

Fundamental Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Alterations of static and dynamic changes in intrinsic brain activity and its relation to behavioral outcomes in subcortical ischemic stroke after one-month intervention

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 8, 2025

Ischemic stroke is a prominent contributor to cognitive dysfunction and disability. Gaining comprehensive understanding of the neuronal activity longitudinal changes underlying crucial for designing effective rehabilitative strategies. However, neural mechanisms responsible reorganization following remain unclear. The objective this study was comprehensively investigate potential abnormalities in brain among patients before after one month intervention (antiplatelet therapy, as well intravenous citicoline). To achieve goal, we combined static dynamic functional imaging indicators analysis. Twenty ischemic at subacute stage seventeen age-matched healthy controls were included final analysis from center. Additionally, resting-state magnetic scans conducted on all twice with one-month interval between scans. Four intrinsic (static amplitude low-frequency fluctuation (sALFF), fractional (sfALFF), regional homogeneity (sReHo), degree centrality (sDC)), along their corresponding indicators, calculated detect alterations onset. Correlation analyses also performed these within areas exhibiting group differences clinical scale scores disease duration. Significant variations image observed stroke. There substantial overlap abnormal regions detected, primarily including decreased sALFF/sfALFF/dALFF bilateral central precuneus, increased sfALFF/sReHo/sDC/dReHo left superior sALFF/sReHo/dfALFF inferior temporal gyrus, sReHo/sDC anterior cingulate cortex, sReHo/dfALFF right parietal lobe, sfALFF/sDC fusiform sALFF/dALFF angular gyrus. Furthermore, disrupted some exhibited only partial recovery second time point. percentage (sfALFF sDC dALFF precuneus) two points positively correlated (FMA MBI). In combination, demonstrates that its can be achieved by integrating methods. Regions showing significant different consistent image-behavior relationships may have values predicting outcomes.

Language: Английский

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Using mechanistic knowledge to appraise contemporary approaches to the rehabilitation of upper limb function following stroke

The Journal of Physiology, Journal Year: 2024, Volume and Issue: 603(3), P. 635 - 650

Published: Aug. 11, 2024

It is a paradox of neurological rehabilitation that, in an era which preclinical models have produced significant advances our mechanistic understanding neural plasticity, there inadequate support for many therapies recommended use clinical practice. When the goal to estimate probability that specific form therapy will positive effect, integration knowledge (concerning 'the structure or way working parts natural system') may improve quality inference. This illustrated by analysis three contemporary approaches lateralized dysfunction affecting people living with stroke: constraint-induced movement therapy; mental practice; and mirror therapy. Damage 'cross-road' regions structural (white matter) brain connectome generates deficits span multiple domains (motor, language, attention verbal/spatial memory). The integrity these determines not only initial functional status, but also response As disconnection constrains recovery capability, 'disconnectome' modelling provides basis personalized prognosis precision rehabilitation. now feasible refer lesion delineated using standard scan (dis)connectivity atlas derived from brains other stroke survivors. individual pattern thus obtained suggests most likely be compromised, therapeutic regimen can tailored accordingly. Stroke complex disorder burdens individuals distinct constellations damage. Mechanistic indispensable when seeking ameliorate behavioural impairments such damage gives rise.

Language: Английский

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Impaired brain ability of older adults to transit and persist to latent states with well-organized structures at wakeful rest

GeroScience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Language: Английский

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Mechanisms underlying the spontaneous reorganization of depression network after stroke

NeuroImage Clinical, Journal Year: 2024, Volume and Issue: 45, P. 103723 - 103723

Published: Dec. 11, 2024

Exploring the causal relationship between focal brain lesions and post-stroke depression (PSD) can provide therapeutic insights. However, a gap exists information. repair processes could bridge this gap. We defined network using normative connectome investigated predictive capacity of lesion-induced damage on depressive symptoms in discovery cohort 96 patients, at baseline six months post-stroke. Stepwise functional connectivity (SFC) was used to examine topological changes over time identify patterns reorganization. The value reorganization information evaluated for follow-up validation 1 (22 worsening PSD patients) as well treatment responsiveness 2 (23 antidepressant-treated patients). consistency significant areas with neuromodulation targets. Spatial correlations gene expression neurotransmitter maps were analyzed. power diminished compared (Δadjusted R

Language: Английский

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