Spinocerebellar ataxia type 3(SCA3)is an autosomal dominant neurodegenerative disease,with core clinical symptoms including motor disorders and cognitive impairment.Since there is currently no effective radical treatment,the development of targeted diagnostic strategies and intervention measures to delay disease progression is particularly urgent.In recent years,neuromodulation technique has attracted widespread attention as an emerging therapeutic strategy for neurological diseases;they achieve therapeutic goals by precisely adjusting stimulation parameters to act on specific brain regions.This article aims to systematically discuss the existing efficacy studies of three neuromodulation techniques,including non-invasive techniques such as repetitive transcranial magnetic stimulation(rTMS),transcranial electrical stimulation(TES),and invasive technique such as deep brain stimulation(DBS),in the clinical application of SCA3,and explore the application potential of neuromodulation technique such as transcranial focused ultrasound stimulation(tFUS)and optogenetics in the field of SCA3 treatment.It is expected to provide new ideas and references for the in-depth research and clinical transformation of neuromodulation technique in SCA3.

Background Migraine affects nearly one billion people worldwide and remains a major global health burden with inadequate treatment options. In this study, transcranial low-intensity focused ultrasound (LIFU) targeting the medial prefrontal cortex (mPFC) was assessed as a novel, non-invasive neuromodulatory strategy for migraine abortive treatment. The therapeutic potential and safety of LIFU were evaluated in animal models to support its future clinical translation.Methods Male C57BL/6 mice were administered intraperitoneally with nitroglycerin (NTG) to induce an acute migraine model, whereas control animals received vehicle (VEH). Following model induction, mice were subjected to either mPFC-targeted LIFU or sham stimulation, which underwent an identical protocol without ultrasonic output. A series of behavioral, histological, and molecular assays was performed to evaluate the therapeutic effects and neuromodulatory mechanisms of LIFU. Mechanical allodynia was assessed using the von Frey test; anxiety-like behavior was evaluated in the elevated plus maze. Neuronal activation was examined via c-Fos immunofluorescence and GABA/glutamate co-staining. Tissue safety was assessed by HE staining and TUNEL assay. All quantitative analyses were conducted under blinded conditions.Results NTG injection induced significant allodynia and anxiety-like behaviors. LIFU stimulation significantly attenuated cephalic and plantar allodynia and ameliorated anxiety-like behaviors compared to the sham group. The NTG-induced migraine model exhibited significant mPFC c-Fos hyperactivation, which LIFU stimulation effectively suppressed. NTG injection significantly increased the proportion of activated glutamatergic neurons (GLU-N) and decreased activated GABAergic neurons (GABA-Ns) among total c-Fos-positive cells in the mPFC. This imbalance was reversed by LIFU, i.e., it was characterized by a decrease in activated GLU-Ns and an increase in activated GABA-Ns. No significant histopathological damage or apoptosis was detected following LIFU exposure.Conclusions Aberrant activation and excitatory and inhibitory (E/I) imbalance of neurons in mPFC were involved in acute NTG-induced episodes. The LIFU targeting mPFC could alleviate NTG-induced mechanical allodynia and anxiety-like behavior by restoring E/I balance. LIFU is a novel, safe, non-invasive neuromodulatory strategy offering a potential migraine treatment.

Recent years have witnessed significant advances in neuromodulation techniques for stroke rehabilitation, especially in ameliorating motor deficits, positioning them as a key focus in both research and clinical practice. The selection of stimulation targets is crucial, as different sites engage distinct neural mechanisms and yield varied therapeutic outcomes. This review systematically synthesizes evidence from neuromodulation studies that target key regions, including the cerebral hemispheres, sensorimotor cortex, cerebellum, and vagus nerve. By analyzing the stimulation protocols, therapeutic effects, and optimal parameters associated with each target, we aim to provide a theoretical foundation and practical guidance for refining neuromodulation strategies in stroke rehabilitation.

IntroductionCerebral small vessel disease (CSVD) is a chronic systemic degenerative disease affecting small blood vessels in the brain, leading to cognitive impairments. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that applies low electrical currents to the scalp, shows promise in treating cognitive and movement disorders. However, further clinical evaluation is required to assess the long-term effects of tDCS on neuroplasticity and gait in patients with CSVD. We investigated the effects of long-term, repeated tDCS on local brain perfusion, network connectivity, cognition, and gait in patients with CSVD and gait disorders (CSVD-GD).MethodsThis prospective, single-blind, multicenter, randomized controlled study enrolled 66 patients with CSVD-GD, categorized into the tDCS and Sham groups. Imaging and gait characteristic data were collected over three periods using magnetic resonance imaging and a gait analyzer, along with neuropsychological assessments.ResultsAmong 156 volunteers with CSVD-GD, 66 participated in this study, with 60 completing the entire process. Compared to the Sham group, the tDCS group exhibited a more pronounced increase in the cerebral blood flow to the dural cerebrospinal fluid ratio in regions such as the orbitofrontal cortex and cingulate gyrus (P < 0.05, FDR corrected), along with significantly greater improvements in gait speed and stride length. Tolerance to tDCS was good, with no difference in adverse reactions between the groups, except for a scalp burning sensation reported during the 1st week (24.24% and 6.06% in the tDCS and Sham groups, respectively; P = 0.003).DiscussionLong-term tDCS is effective and safe for improving neuroplasticity and gait cognition in patients with CSVD.

Low-intensity focused ultrasound stimulation (LIFUS) has garnered attention for its potential in vascular dementia (VD) treatment. However, the lack of sufficient data supporting its efficacy and elucidating its mechanisms of action limits its further clinical translation and application. Considerable researches support the idea that LIFUS can improve the disturbance of neural oscillation modes caused by a variety of neurological diseases. However, the effect of LIFUS on neural oscillation modes in VD remains unclear. Therefore, this study aims to investigate the therapeutic effects of LIFUS on neural oscillation modes in VD. To achieve this purpose, the VD model was established via the bilateral common carotid artery occlusion, followed by two weeks of LIFUS treatment targeting the bilateral hippocampus. The therapeutic effects of LIFUS were evaluated by behavioral tests and cerebral blood flow measurement. Electrophysiological signals were recorded from the hippocampal CA1 and CA3 and medial prefrontal cortex (mPFC). The results indicated LIFUS could effectively improve cognitive dysfunction in VD rats. The underlying electrophysiological mechanisms involved the restoration of phase-amplitude coupling (PAC) of theta-gamma oscillations within both the CA3-CA1 local circuit and the hippocampus-mPFC cross-brain circuit. Classification results based on PAC characteristics suggested that PAC metrics are effective for evaluating the efficacy of LIFUS in treating VD, with optimal recognition performance observed in the hippocampus-mPFC cross-brain circuit. Our findings provide neuroelectrophysiological insights into the mechanisms of LIFUS in VD treatment and propose a promising diagnostic biomarker for evaluating LIFUS efficacy in future applications.

Emotional state is a critical indicator of astronaut performance during long-duration space missions, significantly impacting both mission efficiency and post-mission adaptation to life on Earth. In this context, transcranial magnetic stimulation (TMS) may serve as a valuable tool for studying the psychological changes induced by the space environment. By combining whole-brain imaging, finite element model, cerebral blood flow imaging, genomics, and molecular validation, we tried to identify potential regulatory targets and their cofactors involved in rTMS-mediated improvement of emotional abnormalities under simulated spaceflight conditions. We identified the activation patterns of brain-wide neurons in simulated space composite environment (SSCE), particularly the reduced neuronal activity in the prefrontal cortex (PFC). The rTMS could activate PFC neurons and, on a macro scale, alleviate abnormal cortical hemodynamics. Importantly, synapsin III (Syn III) is a key candidate for rTMS-mediated improvement of emotional abnormalities under SSCE, working together with proteins such as MAPK, PSD95, and NR2B. Our work not only advances the understanding of spaceflight-associated neuropsychiatric risks but also establishes a molecular framework for developing targeted neuromodulation strategies in stress-related psychiatric disorders.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides and a progressive decline in cognitive function. Hippocampus as a crucial brain area for learning and memory, is also adversely affected by AD's pathology. The accumulation of Aβ is often associated with the loss of dendritic spines of the hippocampus. However, the dynamic alterations in dendritic spines throughout AD progression are not fully understood. To investigate it, we conducted in-vivo imaging in two mouse models representing the early and late stages of AD pathology: young mice injected with Aβ1-42 oligomers and APP/PS1 transgenic mice. In the early-stage AD model, imaging was conducted at third- and fifth- weeks post-injection. In the late-stage AD model, a four-month imaging began at 14 months old. The imaging results showed spine elimination in both models. Notably, acute Aβ exposure was linked to heightened spine loss on secondary dendrites, while in the late stage the primary effect was on tertiary dendrites. Concurrently, with the metabolism of Aβ, cognition recovered to some extent by five weeks post Aβ1-42 exposure. These findings suggested that dendritic spine plasticity was impaired during the development of AD, as evidenced by increasing spine loss at different levels. However, the cognitive recovery observed in early-stage AD model mice may indicate a compensatory structural reorganization, highlighting the potential of early intervention to mitigate disease progression. Our results provide novel insights into the neurotoxic effects of Aβ1-42 and may contribute to the development of therapeutic strategies for AD.

Background:Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising non-invasive intervention for Alzheimer's disease (AD), yet therapeutic outcomes remain inconsistent across studies. This meta-analysis aimed to evaluate the cognitive benefits of rTMS in AD patients, with a specific focus on stimulation targets and protocols variations. Methods:A systematic literature search was conducted in PubMed, Web of Science, Embase, and Cochrane Library for relevant English-language studies published up to 31 May 2024. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-Cog). Data were pooled using a random-effects model, with standardized mean difference (SMD) or mean differences (MD) and 95% confidence intervals (CI) calculated. Subgroup analyses were performed to examine the effects of stimulation targets, protocol variations and population demographics on rTMS efficacy. Results:Twenty-two studies involving 874 participants were included in this meta-analysis. Overall, rTMS significantly improved cognitive function (SMD = 0.27; 95% CI = 0.14-0.41; p < 0.0001), showing that the efficacy of rTMS varied by stimulation target and protocol. Stimulation of the dorsolateral prefrontal cortex (DLPFC) led to significant cognitive improvement (SMD = 0.49, 95% CI = -0.26 to 0.73; p < 0.0001), whereas bilateral DLPFC stimulation showed no significant improvement (SMD = 0.13; 95% CI = -0.40 to 0.66; p = 0.62). Stimulating the parietal lobe or associated regions produced moderate cognitive benefits (SMD = 0.29; 95% CI = 0.03-0.55; p = 0.03). Notably, multi-target stimulation over the bilateral DLPFC, parietal lobes, Wernicke's area, and Broca's area also showed substantial cognitive improvement (MD = 2.85; 95% CI = 1.69-4.00; p < 0.00001). Additionally, subgroup analysis based on geographical background revealed greater effects in studies conducted in Asia (SMD = 0.40, 95% CI = 0.14-0.65; p < 0.003). Conclusion:rTMS is an effective intervention for cognitive enhancement in AD, with its efficacy significantly influenced by stimulation target and protocol. Notably, the greater cognitive benefits observed in Asian populations suggest a potential role of genetic and demographic factors that warrant further investigation. These findings contribute to the development of optimized, personalized rTMS protocols for AD treatment. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/recorddashboard, CRD42023434084.

Long-duration space exploration, including missions to the Moon and Mars, demands strategies to preserve astronauts' emotional well-being for optimal performance. This study combines behavioral phenotyping, multimodal MRI, in vivo calcium imaging, and brain-wide genomics to bridge macroscopic brain function with mesoscopic neural activity and microscopic genetic processes, providing a dynamic characterization of the mouse connectome under simulated spaceflight conditions. We observed a reduction in gray matter volume, particularly in the prefrontal cortex, with prolonged exposure. Simulated space composite environment (SSCE) disrupted multi-scale functional connectivity and altered the macro-organizational functional gradient, reversing the relationship between brain function and emotional behaviors. Neural activity in the medial prefrontal cortex demonstrated exposure-time-dependent changes across emotional tasks, while genetic analyses linked SSCE-induced alterations in functional profiles to synaptic function and ion channel activity. Our findings reveal how extreme environments impact emotional behaviors, brain networks, and neural activity, offering insights for interventions to maintain brain integrity during extended space missions.

Depression is the most prevalent psychiatric illness, and its pathogenesis is associated with neuroinflammation. Follistatinlike protein 1 (FSTL1), a novel inflammatory protein, participates in the pathogenesis of diseases related to neuroinflammation. Therefore, we aimed to investigate the effect of FSTL1 in the pathogenesis of depression mediated using neuroinflammation-mediated models. Our results showed that lipopolysaccharide (LPS) administration could induce despair-like behavior and increase proinflammatory cytokine levels in both male and female mice. Then, a significant positive correlation between hippocampal Fstl1 mRNA expression, microglial activation and despair-like behaviors was observed in male mice. Moreover, knockdown FSTL1 significantly reduced microglial activation and the expression of proinflammatory cytokines, while overexpression of Fstl1 in hippocampus could exacerbate the activation of microglial under the LPS-induced condition in male mice. Mechanically, knockdown Fstl1 inhibited LPS-induced activation of BV2 microglia and reduced the production of proinflammatory cytokines, thereby protecting the survival of HT22 neurons. In conclusion, our results implied that Fstl1 may modulate despair-like behaviors through regulation of microglial activation and neuronal viability, which would lay the experimental and theoretical foundation for the neuroinflammatory mechanisms underlying depression.

The experience-dependent spatial cognitive process requires sequential organization of hippocampal neural activities by theta rhythm, which develops to represent highly compressed information for rapid learning. However, how the theta sequences were developed in a finer timescale within theta cycles remains unclear. In this study, we found in rats that sweep-ahead structure of theta sequences developing with exploration was predominantly dependent on a relatively large proportion of FG-cells, that is a subset of place cells dominantly phase-locked to fast gamma rhythms. These ensembles integrated compressed spatial information by cells consistently firing at precessing slow gamma phases within the theta cycle. Accordingly, the sweep-ahead structure of FG-cell sequences was positively correlated with the intensity of slow gamma phase precession, in particular during early development of theta sequences. These findings highlight the dynamic network modulation by fast and slow gamma in the development of theta sequences which may further facilitate memory encoding and retrieval.

Alzheimer’s disease (AD) patients exhibited episodic memory impairments including location-object recognition in a spatial environment, which was also presented in animal models with amyloid-β (Aβ) accumulation. A potential cellular mechanism was the unstable representation of spatial information and lack of discrimination ability of novel stimulus in the hippocampal place cells. However, how the firing characteristics of different hippocampal subsets responding to diverse spatial information were interrupted by Aβ accumulation remains unclear. In this study, we observed impaired novel object-location recognition in Aβ-treated Long-Evans rats, with larger receptive fields of place cells in hippocampal CA1, compared with those in the saline-treated group. We identified two subsets of place cells coding object information (ObjCell) and global environment (EnvCell) during the task, with firing heterogeneity in response to introduced novel information. ObjCells displayed a dynamic representation responding to the introduction of novel information, while EnvCells exhibited a stable representation to support the recognition of the familiar environment. However, the dynamic firing patterns of these two subsets of cells were disrupted to present attenuated heterogeneity under Aβ accumulation. The impaired spatial representation novelty information could be due to the disturbed gamma modulation of neural activities. Taken together, these findings provide new evidence for novelty recognition impairments of AD rats with spatial representation dysfunctions of hippocampal subsets.

Exploring new effective treatments for depression holds important social significance and clinical value. Low-intensity focused ultrasound stimulation (LIFUS) has been proven to have significant neuroprotective effects on depression. However, the specific genes regulated by LIFUS in depressive mice remain unclear. We established a depression mice model using chronic restraint stress (CRS) and applied LIFUS to the medial prefrontal cortex (mPFC) following CRS. We explored the impact of modeling and treatment on gene expression changes through transcriptomics, revealing that the therapeutic effect of LIFUS may be associated with the improvement of the activity of calcium signaling pathway and synaptic plasticity. The study provides preclinical evidence and a theoretical basis for applying LIFUS for depression treatment.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disease in the world. Motor dysfunctions related to the motor cortex, are the most common clinical manifestation of PD. In previous studies, it has been proved that Low-intensity focused ultrasound stimulation (LIFUS) is an effective therapy for PD and the primary motor cortex (M1) is considered to be the central hub responsible for action planning and execution of movement. It remains unknown whether LIFUS targeted on M1 could improve motor deficit, and which motor symptoms can be improved. In addition, we evaluated the long-term effects of 14 consecutive days of LIFUS in the treatment of PD. The open field test results showed slowness of movement recovered with an increase in walking distance and a decrease in resting time. The gait test revealed that gait function (eg., freezing of gait and postural instability) has a significant improvement after LIFUS. The rotarod test suggests that the coordination ability of PD rats undergoing LIFUS was significantly better. We further found that this effect lasted for at least 7 days. Our study evaluates the therapeutic efficacy of LIFUS and provides a new target and a therapeutic strategy therapeutic strategy for further clinical application of LIFUS in PD.