This study applied multivariate ANOVA to investigate age-related microstructural changes in the brain tissues driven primarily by myelin, iron, and water content, as observed in MRI (semi-)quantitative R1, R2*, MTsat and PD maps. This is effectively a re-analysis of the data analyzed in a univariate way in a previous publication. Voxel-wise analyses were performed on gray matter (GM) and white matter (WM), in addition to region of interest (ROI) analyses. The multivariate approach identified brain regions showing coordinated alterations in multiple tissue properties and demonstrated bidirectional correlations between age and all examined modalities in various brain regions, including the caudate nucleus, putamen, insula, cerebellum, lingual gyri, hippocampus, and olfactory bulb. The multivariate model was more sensitive than univariate analyses, as evidenced by detecting a larger number of significant voxels within clusters in the supplementary motor area, frontal cortex, hippocampus, amygdala, occipital cortex, and cerebellum bilaterally. Though when cross validating the results by splitting the data into 2 subsets, sensitivity is strongly reduced, even more so for the multivariate approach. The examination of normalized, smoothed, and z-transformed maps within the ROIs revealed concurrent age-dependent alterations in myelin, iron, and water content. These findings contribute to our understanding of age-related brain differences and provide insights into the underlying mechanisms of aging. The study emphasizes the importance of multivariate analysis for detecting subtle microstructural changes associated with aging when dealing with multiple quantitative MRI parameter maps.
ASGCT 2026: Beverly Davidson Offers Vehicle and Route for Huntington’s Disease Gene Therapy
BOSTON – Geneticist Beverly Davidson, PhD, received the 2026 Outstanding Achievement Award from the American Society of Gene and Cell Therapy (ASGCT). Davidson is currently the chief scientific strategy officer at the Children’s Hospital of Philadelphia (CHOP) and a former president of ASGCT.
Some of the research Davidson presented was conducted at a new biotech company she co-founded called Latus Bio, which earlier this month announced it had raised $97 million in a Series A round. The company develops novel AAVs to specifically target central nervous system (CNS) disorders, with a lead program in Huntington’s disease (HD).
After thanking her mentors—Bill Kelly, MD, Michael Welsh, MD, and Kathy High, MD—Davidson turned her attention to presenting new advances in engineered gene therapies. Throughout her career, she has focused on improving adeno-associated viruses (AAVs) for CNS gene therapies, with a particular emphasis now on HD. Key elements include selecting the right cargo and developing the appropriate delivery vehicle. Her goal is to scale lab research in neurons, mouse models, and non-human primates (NHPs) to treat patients, including adults with HD.
Major hurdles to tackling genetic diseases of the brain include scalability and a lack of potency, Davidson said. The search for alternative AAV serotypes to AAV2 that could target neuronal cells began back in 2000. IV administration does not provide sufficient targeting to the brain. Even AAVs that have been engineered to enter the brain from the blood have high peripheral exposure and a high cost of goods per patient, which significantly lowers scalability and impact. (In one study, liver biodistribution of AAV was many orders of magnitude higher than in the CNS.)
Davidson focused on HD, the late-onset, dominantly inherited genetic disease. The identification of the gene harboring the HD mutation in the early 1990s by a consortium of researchers was one of the biggest success stories in human genetics. Even more remarkable was the underlying disease mechanism—the expansion in exon 1 of the gene of a triplet repeat sequence (CAG) producing an abnormally long string of glutamine residues in the huntingtin protein.
The right target
One of the major challenges in devising a gene therapy for HD is ensuring that the therapeutic reaches the right network—the deep brain and cortical areas. Therapies have to reach the right circuit, and the right cells in those circuits, Davidson said. Over the years, her group has tailored AAVs for delivery to the brain, inserting peptides into exposed loops of the virion to allow for targeting and unbiased diversity for blood-to-brain delivery. Nowadays, she said, machine learning approaches can be applied for further capsid improvements.
Davidson’s CHOP lab developed a method for screening AAVs with enhanced potency for CNS therapies. After generating huge libraries containing tens of millions of novel capsids, the group performed serial enrichments to identify the most attractive capsids. After screening pools of injected capsids into two species of monkeys, a winning capsid emerged: AAV-DB-3.
Davidson’s group infused AAV-DB-3 into NHPs, looking for targeting to the putamen (base of the forebrain) and caudate regions. Those results were published in Nature Communications in 2025. “AAV-DB-3 really stood out for its ability to transduce deep layer cortical neurons that are important” in HD, Davidson said. Moreover, the results were achieved with relatively low doses and only required a single infusion per hemisphere, outperforming the widely used AAV5.
Somatic instability
With a promising delivery vehicle identified, Davidson next addressed the therapeutic strategy, which takes aim at the somatic expansion of the CAG repeat. This codon grows longer over time in certain cells in the brain, sometimes expanding to hundreds of repeats.
MSH3 is a DNA repair protein that is required for CAG repeat expansions, as seen in mouse models of HD and other triplet repeat disorders, including myotonic dystrophy. Research led by Paul Ranum, PhD, who is a co-founder of Latus Bio, posted in a preprint on bioRxiv earlier this year, modeled the impact of lowering levels of MSH3 on somatic instability.
Ranum and colleagues used an artificial microRNA showed to lower MSH3 levels in NHPs by 48-94 percent. Computational modeling suggests that this would reduce somatic instability and delay onset of HD symptoms by many years. Early studies using a well-known HD mouse model, the Q111 mouse, to assess biodistribution, quantify knockdowns, and assess the impact on somatic CAG repeat expansion. AAV-DB-3 expression is highest in the striatum and cortex at 16 weeks, dropping MSH3 levels by 50%.
Davidson closed by emphasizing the need to ensure scalability for treatment beyond ultra-rare disorders. Latus hopes to file an Investigational New Drug application for its HD therapy, LTS-201, in the second half of 2026. At least two other biotech companies are also targeting MSH3 by other means.
The post ASGCT 2026: Beverly Davidson Offers Vehicle and Route for Huntington’s Disease Gene Therapy appeared first on GEN – Genetic Engineering and Biotechnology News.
Acupuncture Treament in Children With Tic Disorders
Conditions: Tic Disorder, Childhood
Interventions: Other: Acupuncture; Behavioral: Comprehensive Behavioral Intervention for Tics (CBIT)
Sponsors: Meizhou People’s Hospital
Not yet recruiting
Interventions: Other: Acupuncture; Behavioral: Comprehensive Behavioral Intervention for Tics (CBIT)
Sponsors: Meizhou People’s Hospital
Not yet recruiting
1H-MRS brain metabolites as biomarkers of high-altitude hypobaric hypoxia following mild traumatic brain injury in mice
Introduction and objectivePopulations at high altitude (HA) face a higher incidence and severity of traumatic brain injury (TBI). This pilot study utilized longitudinal 1H-MRS to identify neurochemical biomarkers of HA adaptation and the subsequent metabolic response to mild TBI (mTBI).MethodsMale C57BL/6J mice were exposed to simulated HA (5,000 m) or sea level (SL) for 12 weeks. Following adaptation, a unilateral mTBI was induced via closed head injury (CHI). Mice were then monitored for an additional 2 weeks at HA (total duration of 14 weeks). In vivo1H-MRS spectra (7 T) were collected from the frontal cortex, hippocampi, and cerebellum at weeks 0, 4, 12 to assess HA adaptation. Following the CHI, subsequent measurements were collected at week 12 (post-injury) and week 14 to monitor longitudinal neurochemical responses to the mTBI.ResultsChronic HA exposure induced significant reductions in myo-inositol (Ins) and total choline (tCho) in the hippocampus, establishing a baseline of metabolic fragility that sensitized the brain to subsequent traumatic insult. Post-mTBI, the HA group exhibited a profound “metabolic crisis,” characterized by significantly lower tCho and failed recovery of total N-acetylaspartate (tNAA) compared to SL controls. Total creatine (tCr) was the most acutely affected metabolite, underscoring a depletion of the bioenergetic reserve.ConclusionChronic hypobaric hypoxia fundamentally alters baseline brain metabolism and impairs the neurochemical recovery from mTBI. These findings suggest that standard recovery protocols may be insufficient for HA-adapted populations and highlight 1H-MRS as a critical tool for detecting “invisible” metabolic vulnerability in extreme environments.
Synchronous climbing fiber activity enables instructive signaling for cerebellar learning through modulation of disinhibitory circuits
Nature Neuroscience, Published online: 14 May 2026; doi:10.1038/s41593-026-02268-2
Combining connectomics, physiology and behavior, this study shows how the cerebellum decides when to learn. Synchronized climbing-fiber error signals lift an inhibitory signal gate on Purkinje cells, enabling synaptic plasticity and motor adaptation.
Targeted Ultrasound Could Offer Alternative to Chronic Pain Medication
A new study has shown that targeting ultrasound stimulation to brain regions involved in processing pain can induce long-lasting changes in brain activity, significantly reducing pain perception. Published in Nature Communications, these findings point at a novel non-invasive strategy to treat chronic pain.
“Our study represents an important first step in understanding how this technology can non-invasively stimulate deep brain regions involved in pain processing,” said Sam Hughes, PhD, senior lecturer in pain neuroscience at the University of Exeter. “We found that targeting a specific brain region involved in pain processing can alter how pain is perceived and change how this area communicates with other parts of the brain’s pain network. The next stage of our research will be to test whether this approach can help people living with chronic pain.”
Hughes and colleagues used transcranial ultrasound stimulation (TUS), a low-intensity neuromodulation technique, to target the dorsal anterior cingulate cortex (dACC), a brain region implicated in chronic pain. The study recruited a total of 32 healthy volunteers, who were treated either with TUS or a sham while putting their right hand in a cold gel to trigger pain due to the low temperature. All participants were asked to rate the severity of the pain they were feeling and underwent MRI and MRS scans to monitor the physiological changes caused by the treatment.
Results showed that, while TUS had no immediate effect on pain intensity, participants reported a significant reduction in pain from 28 to 55 minutes after the stimulation, suggesting it can trigger a delayed analgesic effect. At the physiological level, TUS was found to disrupt the relationship between temperature and pain intensity, increasing the connectivity between the dACC and other brain regions involved in pain modulation and changing the concentration of the GABA neurotransmitter within the dCC.
“The study aimed to characterize how transcranial ultrasound stimulation interacts with—and potentially also alters—the brain’s processing of pain,” said Sophie Clarke, PhD, postdoctoral research fellow at the University of Plymouth and lead author of the study. “Understanding these mechanisms will be very important to support the next steps in understanding whether the stimulation can be effective in helping patients with chronic pain.”
Previous research at the University of Plymouth had shown the potential benefits of TUS for psychiatric conditions including anxiety, depression, and addiction. This study shows these benefits could extend beyond neurological disorders and one day offer a non-invasive treatment option for those experiencing chronic pain due to conditions such as fibromyalgia, back pain, and arthritis, or recovering after cancer treatment.
“Having shown the use of ultrasound can yield positive results for people with a variety of neurological conditions, we wanted to explore what it could mean for those living with chronic pain,” said Elsa Fouragnan, PhD, director of the University of Plymouth’s Brain Research and Imaging Centre (BRIC) and Centre for Therapeutic Ultrasound (CENTUS). “Most of us know someone experiencing chronic pain, and there are very few treatments that deliver any form of long-term benefit. The findings of this new work are really promising, and we are already building on it to assess whether TUS could be a beneficial and non-invasive therapeutic treatment.”
The post Targeted Ultrasound Could Offer Alternative to Chronic Pain Medication appeared first on Inside Precision Medicine.
Direct modulation of human GABA-A α1β2γ2 receptors by the endocannabinoid 2-arachidonoylglycerol: implications for cannabinoid-related ligands and limitations for anxiolytic drug development
Anxiety disorders are associated with impaired inhibitory neurotransmission mediated by γ-aminobutyric acid type A (GABA-A) receptors. Although benzodiazepines remain effective anxiolytics, their clinical utility is limited by sedation, cognitive impairment, tolerance, and dependence, prompting the search for mechanistically distinct GABAergic modulators. Among cannabinoid-related molecules, the strongest evidence for direct GABA-A receptor modulation concerns the endocannabinoid 2-arachidonoylglycerol (2-AG), which potentiates recombinant human α1β2γ2 receptors through residues located in the M4 helix of the β2 subunit. Here, we review the structural architecture, biophysical properties, and pharmacological profile of the human GABA-A α1β2γ2 isoform as the relevant molecular framework for evaluating this mechanism, while discussing the broader relevance of cannabinoid-related ligands and selected phytocannabinoids without assuming mechanistic equivalence. We further assess the hypothesis that 2-AG reaches the β2-M4 site through a membrane-access route and identify five conceptual barriers that currently limit translation of this mechanism into anxiolytic drug development: supraphysiological effective concentrations, unresolved synaptic-versus-extrasynaptic actions, uncertain subtype selectivity, incomplete validation of lipid-environment effects, and lack of clinical evidence linking this mechanism to anxiolysis in humans. We conclude that direct modulation through β2-M4 defines a mechanistically intriguing allosteric pathway distinct from benzodiazepine action; however, its location on a shared β2 subunit and the micromolar concentrations required for modulation represent substantial obstacles to the rational design of anxioselective agents based on this mechanism.
Real-world use of brexpiprazole during inpatient treatment for schizophrenia: continuation, discontinuation, and concomitant psychotropics
IntroductionIn the treatment of schizophrenia, antipsychotics used during acute inpatient care must control acute symptoms while remaining sufficiently tolerable to support treatment beyond the acute phase. Brexpiprazole, a serotonin-dopamine activity modulator may be one such option; however, its real-world use and short-term continuation in acute inpatient settings remain insufficiently characterized.MethodsWe conducted a retrospective observational study of inpatients with DSM-5 schizophrenia treated with brexpiprazole at a university hospital in Japan between June 2018 and July 2024. The index date (week 0) was defined as the date of brexpiprazole initiation during the index hospitalization. The primary outcome was brexpiprazole continuation at week 8. We compared baseline demographic and treatment-related variables between the continuation and discontinuation groups and summarized reasons for discontinuation from electronic medical records. As a secondary exploratory analysis, we examined longitudinal changes in Clinical Global Impressions–Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRS) total scores (weeks 0/4/8) in the continuation group using a linear mixed-effects model including time, concomitant psychotropic medication status, and their interaction.ResultsSixty-seven patients were included. Baseline illness severity was substantial (median CGI-S 5.0 [IQR 5.0–6.0]; mean BPRS total 58.5 ± 9.6). Concomitant psychotropic medications were common. Thirty-six patients continued brexpiprazole to week 8 (53.7%). In unadjusted exploratory comparisons, continuation was associated with the female sex (p = 0.036), lower prior chlorpromazine-equivalent dose (p = 0.015), and shorter duration of untreated psychosis (p = 0.003), with a trend toward shorter duration since onset (p = 0.073). The most frequent reason for discontinuation was adverse events (n = 10, 32.3%), most commonly akathisia (n = 6), followed by insufficient efficacy (n = 9, 29.0%) and patient preference/refusal (n = 7, 22.6%). In exploratory mixed-effects analyses within the continuation group, CGI-S and BPRS total scores decreased over time, with significant group-by-time interactions by concomitant medication status. However, between-group differences should be interpreted cautiously.DiscussionThis study describes 8-week continuation and reasons for discontinuation of brexpiprazole in acute inpatient schizophrenia care. Given the retrospective single-center design and potential selection/information bias and unmeasured confounding, further studies are warranted to clarify its clinical positioning in real-world practice.
Analysis of risk factors for tic disorders in children in Hubei region based on liquid chromatography-tandem mass spectrometry
ObjectiveThis study aims to investigate the correlation between trace element concentrations, 25-hydroxyvitamin D [25(OH)D] levels, and the severity of tic disorders (TD) in children from the Hubei region. Additionally, it seeks to explore the interrelationships among these monitored indicators to provide a reference for the clinical diagnosis and treatment of pediatric TD.MethodsA retrospective review was conducted on the medical records of 237 children diagnosed with TD (TD group) and 137 healthy controls, admitted to the Department of Neurology at Hubei Maternal and Child Health Care Hospital. The TD group was further divided into mild and moderate-to-severe subgroups based on the Yale Global Tic Severity Scale scores. General clinical data were collected, and serum trace element levels were measured using inductively coupled plasma mass spectrometry (ICP-MS), while serum 25(OH)D levels were quantified via liquid chromatography–tandem mass spectrometry (LC–MS/MS). Group comparisons, Spearman correlation analysis, and univariate/multivariate logistic regression analyses were performed.ResultsThe findings indicated that serum 25(OH)D levels were significantly lower in children with TD compared to controls (p < 0.001). Logistic regression analysis demonstrated that 25(OH)D was an independent protective factor against tic disorders.(p < 0.001). Compared to the control group, children with TD exhibited significantly lower levels of calcium and copper (p < 0.001), along with higher levels of iron and cadmium (p < 0.01). These differences were more pronounced in the subgroup of children older than 6 years. An age-stratified subgroup analysis revealed no significant differences in any other indicators except for cadmium between the TD and control groups among children aged 6 years or younger (p > 0.05). Spearman correlation analysis demonstrated that within the TD group, 25(OH)D levels had the most significant correlations with calcium and copper (p < 0.001). No statistically significant differences were observed in the levels of the 10 trace elements or 25(OH)D between the mild and moderate-to-severe TD subgroups (p > 0.05).ConclusionChildren with Tic Disorders in Hubei Province demonstrate a distinctive alteration in their micronutrient profile, primarily characterized by a deficiency in 25(OH)D, alongside reduced levels of calcium and copper, and elevated levels of iron and cadmium. This association is particularly pronounced in male children over the age of six. While 25(OH)D deficiency is identified as an independent risk factor for TD, its concentration does not significantly correlate with the severity of the disorder.
Timing of exercise differentially modulates fear memory and hippocampal neurotransmitters in male rats
Exercise promotes neurogenesis and enhances memory consolidation while reducing the retention of aversive memories and anxiety-like behaviors. While our previous work found that acute exercise alters neurotransmitter concentrations, including dopamine and serotonin, in a time-of-day-dependent manner, the long-term effects of chronically timed exercise on neurotransmitter dynamics and behavioral phenotypes remain unclear. To examine whether the daily timing of a chronic exercise intervention modulates its impact on neurotransmitter profiles and fear responses, male rats were conditioned using a Pavlovian contextual fear approach, then assigned to a 4-week treadmill exercise intervention performed during the early (ZT14) or late (ZT22) active phase or a time-matched sham-exercise control group. One day after completing training, rats underwent a context retrieval test in the middle of active phase (ZT18), and hippocampal neurotransmitters were quantified using UPLC–MRM/MS. Rats subjected to sham-exercise at ZT22 exhibited higher freezing than sham-exercised rats at ZT14, whereas exercise interventions at ZT22 selectively attenuated freezing. Histamine, acetylcholine, and GABA exhibited significant exercise × time interactions. Direct neurotransmitter–freezing correlations were weak after false discovery rate control, consistent with a network-level reorganization rather than a single transmitter driver. These findings suggest that vulnerability to aversive memory expression can be buffered by exercise, if timed appropriately, and that exercise reshapes hippocampal neuromodulatory tone in a circadian–phase–dependent manner, supporting the potential of exercise timing as a chronotherapeutic strategy to enhance stress resilience and mental wellbeing.