Neurotherapeutics最新文献

Tinnitus disorder can have a significant negative impact on quality of life, especially when refractory to standard care. Deep brain stimulation (DBS) of the medial geniculate body (MGB) attenuates pathological neuronal activity in the central auditory pathway and is a potential treatment for severe tinnitus. The aim of this pilot study was to assess the safety and feasibility of bilateral MGB DBS in patients with refractory tinnitus disorder. This randomised double-blind 2 ​× ​2 cross-over study was conducted at Maastricht University Medical Centre, Maastricht, the Netherlands. The included patients had treatment refractory, severe, and chronic tinnitus without an anatomical substrate. Patients with bilateral MGB DBS were randomised to an ON-OFF or OFF-ON stimulation order for two cross-over phases. Primary outcomes consisted of safety and feasibility. Secondary outcomes on tinnitus severity, psychiatric and cognitive functioning and quality of life were assessed at screening, after both cross-over phases and at one-year follow-up. Four patients were included. No irreversible stimulation-induced side effects were observed. Surgical-related side effects were transient and resolved within two weeks. All patients experienced DBS as an acceptable treatment. Three of four patients showed improvement of tinnitus complaints based on the Tinnitus Functional Index. In the non-responder, electrodes had the largest distance from the centre of the MGB. To conclude, this study shows that bilateral MGB DBS is safe and feasible for patients with refractory tinnitus. Findings suggest the potential for clinically meaningful reduction in tinnitus burden through DBS. Effectiveness needs to be further evaluated in a follow-up study.

Pathogenic DNA variants in chromatin-related genes constitute an important minority of neurodevelopmental disorders (NDDs). Epigenetic mechanisms, including chromatin regulation driven by genetic or environmental factors, are increasingly recognised as key contributors to pathogenesis of diverse NDDs. We hypothesise that therapeutic strategies targeting chromatin dysregulation, such as histone deacetylase inhibition with butyrate, may be a potential disease modifying therapy for NDDs. We first performed peripheral blood bulk RNA sequencing (RNA-seq) to explore baseline gene regulation in children with chromatin-related NDDs (Kabuki syndrome (KMT2D, n ​= ​4), CHARGE syndrome (CHD7, n ​= ​2), and Rett syndrome (MECP2, n ​= ​5), and children with NDDs but without a monogenic diagnosis (non-monogenic, n ​= ​8), compared with sex-matched healthy controls (total n ​= ​21). Next, to explore the effects of butyrate, single-cell RNA sequencing (scRNA-seq) was performed on 101,539 peripheral immune cells from four selected patients (one per condition) and two controls, before and after butyrate treatment. At baseline, dysregulation of ribosomal and immune pathways was seen in all four NDD cohorts (KMT2D, CHD7, MECP2, non-monogenic) compared to controls. Butyrate largely reversed these pathways, normalising ribosomal and immune pathways in patient and control cells. Butyrate induced up-regulation of ribosome, GTPase, cytoskeletal, mitochondrial pathways, and down-regulation of epigenetic and immune pathways. In conclusion, we identified a common ribosomal-immune RNA signature in chromatin-related NDDs, and a similar signature in non-monogenic NDDs. We showed that butyrate modulates epigenetic and immune gene networks in monogenic and non-monogenic NDDs, positioning butyrate as a promising therapeutic modulator across diverse NDDs.

Functional connectivity (FC) is crucial for the execution of functional activities and the progression of diseases. From a functional perspective, changes in subthalamic nucleus (STN)-based FC and network properties across lifespan and their effectiveness in predicting age require further investigation. The STN-based atlas was constructed using neuroimaging data from 1060 healthy participants. Based on this atlas, the FC and brain network properties were quantified subsequently. Both linear and non-linear changes in FC and network properties with aging, and relationships across brain regions were analyzed with generalized additive model (GAM). Connectome-based predictive modeling (CPM) was used to evaluate the performance of FC in predicting age, while computational lesion analysis was utilized to identify the FC with significant contributions to model performance. The STN-based atlas mainly involved bilateral sensory, motor, and sensory-motor integration cortices, subcortical nuclei, and cerebellar crus I and II. Global network properties were declined with aging (all P ​< ​0.05). Significant non-linear age-related changes were identified in regional network properties of bilateral M1 and right STN (all P ​< ​0.05). There were non-linear negative relationships between bilateral M1, and between right M1 and right STN (all P ​< ​0.05). The FC within motor cortex, and between limbic areas and subcortical nuclei, significantly contributed to the performance of CPM. Therefore, from a functional perspective, dynamic changes in FC and network properties across the lifespan were highlighted, particularly within motor-related circuits. This provides valuable insights into neural mechanisms underlying motor dysfunction during aging and informs circuit-based neuromodulation strategies.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2-5 years of symptom onset. Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1^A4V or SOD1^G85R mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.

Traumatic brain injury (TBI) constitutes a major global public health concern associated with substantial mortality and long-term disability, while its diagnostic approaches and underlying pathophysiological mechanisms remain to be fully elucidated. In this study, we conducted longitudinal metabolomic profiling of cerebrospinal fluid (CSF) from 23 TBI patients (9 mild, 14 severe) and 5 uninjured controls using high-resolution mass spectrometry. Comprehensive quantification of metabolites was performed at three critical post-injury time points (days 1, 3, and 7), revealing distinct temporal metabolic patterns. Our results demonstrated significant alterations in the CSF metabolome following TBI. Early-phase changes (day 1) predominantly involved energy-related metabolites, including sphingosine, glucose, and dl-lactate. More pronounced metabolic shifts were observed by day 3, characterized by marked variations in amino acids (l-glutamine, l-histidine) and medium-chain fatty acids (caprylic acid, octanoic acid), suggesting the transition from primary to secondary injury mechanisms. The day 7 profile revealed accumulation of repair-associated metabolites such as 2'-deoxyuridine 5'-monophosphate and 1,2-dihexadecanoyl-sn-glycerol, potentially indicative of processes occurring in the chronic phase, which may include both reparative mechanisms and ongoing pathology. Notably, we identified significant alterations in established biomarkers (trimethylamine N-oxide) and novel small peptides (e.g., Gly-His-Lys), with distinct metabolic signatures differentiating mild versus severe TBI cases. These findings delineate temporally dynamic and severity-dependent metabolic reprogramming in TBI, providing mechanistic insights into the progression from acute injury through secondary pathogenesis to chronic recovery phases. The identified metabolic signatures may serve as potential biomarkers for injury staging and therapeutic monitoring.

Ketamine exhibits superior efficacy compared to conventional antidepressants, yet its clinical application remains limited by dose-dependent side effects. Ascorbic acid (AA) augments ketamine's antidepressant-like effects, suggesting that AA co-administration with subtherapeutic ketamine doses may achieve optimal efficacy while improving safety. Since AA itself lacks independently clinical antidepressant efficacy, its enhancement on the efficacy of ketamine raises a mechanistic question. This study investigated the antidepressant-like effects of AA combined with esketamine (ketamine's S-enantiomer) and elucidated the role of hippocampal TARP-γ8-containing AMPA receptors (AMPARs) in this enhancement. We employed a chronic restraint stress-induced mouse model of depression to evaluate depressive-like behaviors, hippocampal synaptic markers, and neural plasticity. The effects of AA, esketamine, and their combination were examined, along with pharmacological modulation of hippocampal TARP-γ8-containing AMPARs. Our findings demonstrated that AA enhanced the action of a subeffective dose of esketamine, fully reversing both behavioral and synaptic deficits in depressed mice to levels comparable with healthy controls. This combinatorial effect was equivalent to that achieved by an effective dose of esketamine alone. Selective pharmacological blockade of hippocampal TARP-γ8-containing AMPARs completely abolished the antidepressant-like efficacy of the subeffective-dosed AA-esketamine combination. However, the same blockade did not affect baseline depressive-like phenotypes in depressed mice or the inactivity of either agent at subeffective dose alone. These results indicate that AA's enhancement of esketamine's antidepressant-like effects requires the dependent mediation of hippocampal TARP-γ8-containing AMPARs for synaptic modulation, providing both mechanistic insight and potential clinical implications for optimizing ketamine-based strategies of therapeutics for depression.

Pain and sleep disturbances are primary reasons for medicinal cannabis use. Cannabis influences both pain and sleep through its modulation of the endocannabinoid system, which regulates pain and sleep signaling. Despite their interconnected roles, the effects of cannabis and chronic pain on sleep architecture have been studied mainly in isolation. An integrated understanding is needed to guide use and minimize risks in this population. Our primary aim was to examine the potential interactive effect of regular cannabis use on chronic pain and sleep. A total of 339 nights (2273.43 ​h) of in-home sleep electroencephalogram (EEG) recordings were collected from 60 adults (50 ​% male; 32 ​% chronic pain; 47 ​% cannabis use; M_age ​= ​25.25; SE ​= ​1.05) over seven consecutive nights per participant. A mixed-model repeated-measures ANCOVA tested the main effects and interactions of chronic pain and regular cannabis use on total sleep time (TST), total slow-wave sleep (SWS%), total rapid-eye-movement (REM%), sleep onset latency (SOL), and number of awakenings. There was a significant main effect of cannabis use on SWS, TST, SOL, and REM. There was a significant main effect of chronic pain on TST. Significant interactions emerged between cannabis use and chronic pain on SWS and REM. These findings may reflect a dysregulated sleep response in individuals using cannabis to manage chronic pain, highlighting the need to consider both beneficial and detrimental effects of cannabis on specific sleep stages.

Racemic (R,S)-ketamine exerts rapid antidepressant effects, and growing evidence suggests its R-isomer may offer sustained efficacy with fewer side effects. However, the neurobiological mechanisms underlying (R)-ketamine's action in the human brain are largely unknown. To address this, we acquired resting-state fMRI data from 32 healthy volunteers 24 ​h before and after intranasal administration of (R)-ketamine (n ​= ​24) or placebo (n ​= ​8). We primarily assessed changes in long-range functional synchrony using degree centrality (DC) and elucidated the sources of these changes with functional connectivity (FC) analysis. (R)-ketamine significantly decreased DC in a key cognitive-motor integration hub: the supplementary motor area/middle cingulate cortex (SMA/MCC, cluster-corrected P ​< ​0.05). Critically, the reduction of DC was absent under the placebo condition, yielding a significant group-by-time interaction (P ​= ​0.01). The reduction in long-range synchrony of the SMA/MCC was primarily driven by attenuated FC with both the dorsal medial prefrontal cortex/dorsal anterior cingulate cortex (dMPFC/dACC) and the cerebellum, and was spatially correlated with serotonin, norepinephrine, and acetylcholine neurotransmitter profiles. More importantly, the clinical relevance of the neuroimaging phenotypes was established in an independent Major Depressive Disorder (MDD) cohort, where FC between the SMA/MCC and dMPFC/dACC significantly correlated with depressive symptom severity (HAMD score, P ​= ​0.019). This study provides novel, system-level evidence that intranasal (R)-ketamine modulates specific human brain networks by attenuating long-range synchrony in the SMA/MCC. The link between the neuroimaging phenotype, depression-relevant neurotransmitter profiles, and clinical symptom severity may offer a plausible therapeutic mechanism of (R)-ketamine.

Neuropsychiatric symptoms (NPS) are among the most distressing and functionally disruptive features of Alzheimer's disease (AD), affecting the vast majority of individuals across the disease continuum. These symptoms, ranging from apathy and depression to agitation and psychosis, not only worsen quality of life but also predict faster decline, earlier institutionalization, and heightened caregiver burden. Yet, despite their clinical significance, NPS remain under-recognized and undertreated. This review synthesizes current understanding of the biological underpinnings of NPS in AD, highlighting network-level dysfunction, neurotransmitter imbalances, neuroinflammation, and emerging roles for tau pathology and circadian disruption. We critically examine current treatment paradigms, noting that pharmacologic interventions offer benefit but often carry significant risks. In contrast, non-pharmacological approaches, particularly those that integrate caregiver training, environmental design, and sensory engagement, hold promise but are inconsistently applied in routine care. Emerging innovations, including neuromodulation, repurposed agents (e.g., beta-blockers, cannabinoids), and digital therapeutics such as virtual reality and AI-enabled monitoring tools, offer new therapeutic avenues. We call for a paradigm shift toward person-centered, mechanistically-informed care that aligns intervention strategies with biological drivers of NPS. Future progress hinges on inclusive clinical trials, implementation of first-line behavioral strategies, and development of biomarker-guided, precision approaches to symptom management. Effective care for NPS in AD demands integration, not substitution, of pharmacologic and non-pharmacologic strategies, grounded in a deeper understanding of both disease biology and lived patient experience.

Ischemic retinal damage is the most common cause of severe vision impairment and blindness. Anti-vascular endothelial growth factor (anti-VEGF) agents have transformed the treatment of retinal ischemic disorders and have become the cornerstone therapy for these conditions. Nonetheless, the risk for systemic and ocular adverse effects necessitates careful consideration. Meanwhile, the therapeutic potential of natural compounds for ischemic retinal injury is increasingly attracting attention. In this study, piperine (PIP), a natural compound derived from pepper, was found to reduce apoptosis by reducing the severity of retinal and optic nerve ischemic damage. However, the precise pharmacological mechanisms of PIP are yet to be fully elucidated. Molecular docking (MD) studies, MD simulations, and surface plasmon resonance experiments were conducted to determine the molecular targets of PIP. Our data revealed that PIP can bind to apurinic/apyrimidinic endonuclease 1 (APE1), thereby inhibiting apoptosis by decreasing the expression of caspase-9 and caspase-3 and regulating the mitochondrial pathway. In summary, PIP may directly targets the APE1 protein and further regulates the caspase-9/caspase-3 axis to provide neuroprotection against ischemic retinal injury.