IntroductionEvidence suggests that dissociation may play a role in the manifestation of functional neurological disorder (FND). Dissociative experiences are frequently reported in FND, yet their dynamic associations with affective and physiological states remain underexplored. This pilot study aimed to examine dissociative symptoms in daily life in FND, to identify predictors of dissociation using ecological momentary assessment (EMA) combined with wearable heart-rate monitoring.MethodsSeventeen individuals with FND (functional seizures/motor symptoms) and seventeen age- and gender-matched healthy controls completed EMA via pseudorandom smartphone prompts eight times daily for one week. This was a secondary analysis of data from a pilot case-control intensive longitudinal observation study. Dissociation (depersonalisation, derealisation, amnesia), negative affect, and subjective arousal were assessed using items modified from validated scales, while heart-rate was continuously recorded via Fitbit devices. Multilevel modelling was conducted to examine between-group differences, and momentary associations between predictors (negative affect, subjective arousal, heart-rate) and dissociative symptoms within the FND group. Time-lagged analyses explored temporal relationships between the predictors and dissociative symptoms.ResultsThe FND group reported significantly higher dissociative symptoms across the week compared to controls; amnesia (F(1,34)=13.09, p <.001), depersonalisation (F(1, 34)=7.35, p = .010), and derealisation (F(1, 34)=8.31, p = .007), these differences withstood correction for anxiety, but not for depression. Negative affect (p-values=<0.001, β=0.094-0.111), subjective arousal (p-values=<0.001, β=0.102-0.124), and higher heart-rate (p-values = 0.01-0.006, β= 0.078-0.091) were each significant concurrent predictors of all three dissociative symptom types. In combined models, negative affect and subjective arousal remained robust predictors across all symptom domains, whereas heart-rate lost significance. Time-lagged analyses did not yield significant associations.ConclusionIndividuals with FND self-reported elevated dissociative symptoms in daily life compared to healthy controls; however, these significant differences did not remain when controlling for depression. Dissociation was consistently associated with subjective arousal and negative affect, but not heart-rate, underscoring the importance of subjective emotional states over physiological influences on self-reported dissociative symptom variability. The absence of temporal effects highlights the transient nature of dissociation in FND. These findings support the possibility of conceptualising FND through a dissociative lens and emphasise the need for larger longitudinal studies to clarify underlying mechanisms.
Prostate Cancer Therapy Targets Disordered Region of Androgen Receptor
In a new study published in Nature Signal Transduction and Targeted Therapy titled, “Drugging the intrinsically disordered transactivation domain of androgen receptor,” researchers from the University of British Columbia and BC Cancer present a new approach for designing drugs that bind more strongly to intrinsically disordered proteins. These proteins play a central role in a wide range of diseases, including cancer, neurodegenerative disorders, heart disease and autoimmune conditions, and are extremely difficult to target due to their flexible nature.
Transactivation domains (TADs) of transcription factors are enriched in intrinsically disordered regions (IDRs) that lack a stable three-dimensional structure. The plasticity of an IDR permits dynamic conformations that regulate cellular and biological functions.
The new study developed inhibitors that bound to the TADs of the androgen receptor, a therapeutic target for prostate cancer. While therapeutic interventions often target its folded ligand-binding domain (LBD), resistance ultimately develops due to reactivation of androgen receptor signaling.
Inhibitors stabilized the protein in the inactive state to prevent the activation of genes that drive cancer growth. In animal studies, several compounds slowed prostate cancer growth more effectively than a commonly used prostate cancer treatment. Notably, several antigen receptor TAD inhibitors displayed strong binding affinities higher than, or were comparable to the LBD-inhibitor enzalutamide, with dissociation constants in the picomolar to low-nanomolar range
“Most drug discovery is like designing a key for a very specific lock,” said Marianne Sadar, PhD, professor of pathology and laboratory medicine at the UBC faculty of medicine, distinguished scientist at BC Cancer, and co-corresponding author of the study. “But disordered proteins don’t behave like locks at all, they’re more like moving strands of spaghetti.”
“This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy,” she continued. “The findings could have profound implications for the treatment of cancer and other diseases, providing a roadmap for the development of new treatments.”
“What surprised us was how effectively these molecules could attach to a protein that doesn’t have a fixed structure,” said Raymond Andersen, PhD, professor in UBC’s department of chemistry and co-corresponding author of the study. “We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working.”
The researchers now aim to advance the most promising candidates toward clinical trials, with the goal of developing prostate cancer drugs for early intervention and with fewer side-effects.
“If the approach continues to prove successful, it could dramatically expand the number of proteins that scientists can target with medicines—turning what was once considered a dead end into a promising new frontier for drug discovery,” said Sadar.
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The prefrontal cortex controls memory organization in the hippocampus
Nature Neuroscience, Published online: 28 April 2026; doi:10.1038/s41593-026-02231-1
Related memories are sometimes encoded in overlapping neurons. The authors show that the prefrontal cortex controls this type of memory organization in the hippocampus through direct projections to the medial entorhinal cortex.
Lithuanian children’s trauma characteristics and correlates: comparison of clinical and non-clinical samples
IntroductionPrevious studies have shown that children’s exposure to potentially traumatic events and their trauma−related symptoms may not always be consistently identified. This study aims to examine differences in trauma exposure and related psychological outcomes between clinical and non−clinical Lithuanian children.MethodsThis cross-sectional study included 10–17−year−old children and adolescents recruited from a clinical inpatient setting (Vilnius University Hospital Santaros Klinikos) and general−education schools in Vilnius and nearby districts. After parental consent and child assent, participants completed a secure mobile assessment covering exposure to potentially traumatic events (CATS), dissociation (A−DES), mood and feeling (SMFQ), post−traumatic cognitions (CPTCI), PTSD symptoms (CATS; PCL−5 for convergent validation), and perceived social support (CASSS). Data were collected in 2023–2024. Group differences were examined using Welch’s t−tests (with Mann–Whitney U as robustness checks), and associations were assessed using Pearson correlations.ResultsIn the clinical sample over 40% of children experienced physical violence, while in the non−clinical sample 82.9% children reported exposure to multiple traumatic events. The clinical sample showed significantly higher dissociation, negative mood, and PTSD symptoms compared to the non−clinical sample. However, among children exposed to more than one traumatic event, differences in dissociation, PTSD symptoms, and close−friend support were not significant. Across both samples, exposure to potentially traumatic events was strongly associated with PTSD symptoms, dissociation, and post−traumatic cognitions, and moderately associated with mood symptoms. In the non−clinical sample, parental support showed moderate negative associations with dissociation, mood symptoms, post−traumatic cognitions, and PTSD symptoms.DiscussionThis study identified between−sample differences in exposure to potentially traumatic events and trauma−related psychological outcomes among Lithuanian children in inpatient and community settings, highlighting the need for trauma−informed assessment and attention to social support within child mental health and welfare services.
Effect of low-intensity focused ultrasound on hippocampus of alcohol addicted mice: a preliminary study
Alcohol addiction is a chronic relapsing brain disorder characterized by significant neurobiological changes, particularly within the hippocampus, which mediates emotional regulation and reward-seeking behavior. Previous studies have shown that alcohol-induced neuronal injury contributes to withdrawal-associated anxiety and persistent alcohol preference. This study investigated the therapeutic effects of low-intensity focused ultrasound (LIFU) on the hippocampus in a mouse model of alcohol addiction. Twenty-six male C57BL/6 mice were allocated to an alcohol-exposed group (n = 20) and a control group (n = 6). Following a 28-day modeling period, the alcohol group was randomly subdivided into a therapy group and a sham group. The therapy group received LIFU treatment, while the sham group underwent an identical procedure with the ultrasound transducer powered off. After seven days of treatment, the therapy group exhibited less severe anxiety symptoms upon alcohol withdrawal and a reduced preference for alcohol compared to the sham group. The brain-derived neurotrophic factor (BDNF) concentration was significantly lower in the therapy group than in the sham group, but did not differ significantly from the control group. Hippocampal HE staining revealed more pronounced degeneration and apoptosis of granule cells in the dentate gyrus (DG) region in the sham group relative to the therapy group. These preliminary findings suggest that LIFU may modulate alcohol addiction by mitigating hippocampal neuronal injury.
Role of TRPC1 in the pathogenesis of depression induced by traumatic brain injury
BackgroundTraumatic brain injury (TBI) is one of the leading causes of mortality and disability, with many patients developing long-term sequelae. Depression is among the most common psychiatric complications following TBI, yet its underlying mechanisms remain unclear. Transient receptor potential canonical 1 (TRPC1) has been implicated in neurological disorders, but its role in post-TBI depression is not well understood.MethodsA controlled cortical impact (CCI) model was used to induce moderate TBI in mice. At 4 weeks post-injury, depressive-like behaviors were assessed using the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). Subsequently, reactive astrocytes and microglia were quantified, along with the expression of inflammatory cytokines, in the ipsilateral hippocampus. Synaptic function was also evaluated.ResultsBehavioral tests revealed that TBI mice exhibited significant depressive- and anxiety-like behaviors at 4 weeks post-injury. Concurrently, TRPC1 expression was downregulated in the ipsilateral hippocampus, accompanied by reduced levels of synaptic-associated proteins, elevated pro-inflammatory cytokines, and increased reactive astrocytes and microglia. Further experiments demonstrated that TRPC1 overexpression attenuated neuroinflammation, restored synaptic function, and ameliorated depressive-like behaviors in TBI mice.ConclusionThis study suggests that TBI may trigger depression by downregulating TRPC1, thereby promoting neuroinflammation and synaptic dysfunction. Conversely, TRPC1 overexpression mitigates these effects, highlighting its potential as a therapeutic target for post-TBI depression.
Diffusion tensor imaging-functional MRI fusion reveals disrupted white matter structure–function coupling in HIV-associated asymptomatic neurocognitive impairment
ObjectiveConventionally, blood oxygen level-dependent (BOLD) signals derived from resting-state functional magnetic resonance imaging (rs-fMRI) are attributed to gray matter, but recent evidence confirms stable low-frequency oscillations within white matter. While structure–function coupling is pivotal in neuropsychiatry, it remains underexplored in HIV-associated neurocognitive disorders (HAND). Focusing on Asymptomatic Neurocognitive Impairment (ANI), the earliest stage of HAND, this study establishes a white matter skeleton-based fusion framework integrating diffusion tensor imaging (DTI) and rs-fMRI to investigate underlying mechanisms.MethodsWe enrolled 47 patients with ANI and 48 matched healthy controls. Fractional anisotropy (FA) images from DTI and BOLD signals derived from rs-fMRI were projected onto a unified white matter skeleton to achieve structure–function spatial alignment. FA, skeleton-based white matter amplitude of low-frequency fluctuations (SWALFF), and its dynamic variability (dSWALFF) were calculated. Group differences in white matter structure and function were assessed, with structure–function coupling examined in regions showing overlapping FA-SWALFF and FA-dSWALFF alterations. Additionally, a novel White Matter Dys-coupling Index (WDI) was proposed to quantify the deviation between structural integrity and functional activity and evaluate its clinical relevance.ResultsCompared to controls, ANI patients exhibited widespread FA reductions and increased mean diffusivity (MD) and radial diffusivity (RD), indicating diffuse demyelination. Functionally, a spatial dissociation emerged: SWALFF was reduced in posterior occipital pathways (left vertical occipital fasciculus, forceps major), whereas SWALFF and dSWALFF were elevated in prefrontal pathways (forceps minor). Overlapping regions revealed complex coupling patterns, ranging from concordant decline to compensatory upregulation and decoupling. The interaction between FA and dSWALFF further highlighted instability in dynamic regulation. The WDI was significantly correlated with infection duration, immune status, and cognitive domain scores.ConclusionThis study identifies a characteristic “coupling imbalance” in the white matter of ANI patients, defined by the coexistence of structural degeneration and functional reorganization. We propose the WDI as a quantitative metric for this deviation. Its significant associations with clinical and cognitive metrics suggest its potential as a neuroimaging biomarker for the early identification and mechanistic understanding of HAND.
Aberrant local and global neural activation patterns in pediatric Prader–Willi syndrome
PurposeAlthough cognitive disorders in children with Prader–Willi syndrome (PWS) are linked to abnormalities in spontaneous neural activation and functional connectivity (FC), the specific neural activation patterns remain uncertain, especially in young children with PWS.MethodsThe current study set out to explore specific local and global neural activation in pediatric PWS using the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and seed-based whole brain FC. Information was gathered from 35 pediatric PWS patients and 33 healthy controls (HC). Both groups’ ALFF and ReHo values were computed, and FC were constructed on the basis of altered ALFF and ReHo regions. The relationships between altered ALFF, ReHo, and FC and the Griffiths Developmental Scales (GDS) of the PWS group were analyzed using partial correlation analysis.ResultsBoth ALFF and ReHo exhibited decreases in occipital lobe, temporal lobe, and cingulate gyrus, and altered ReHo was present in parietal lobe, frontal lobe, and basal ganglia areas. Moreover, ALFF and ReHo also exhibited increases in occipital and temporal lobes. Decreased FC was detected in the visual network (VN), sensorimotor network (SMN), salience network (SAN), and default mode network (DMN). The SMN-, cingulate-, and occipital lobe-related neural activation patterns were significantly positively correlated with the GDS score.ConclusionThe PWS group was characterized mainly by decreased neuronal physiological function and the ReHo was similar to ALFF but more extensive. The decreased local and global brain neural activation patterns may serve as early physiological indicators of cognitive abnormalities.
A novel phase-difference transcranial alternating current stimulation system enables precise dual-site neuromodulation
Precise modulation of large-scale brain networks requires neuromodulation technologies capable of delivering frequency-locked stimulation with accurate and stable inter-regional phase control. However, conventional transcranial alternating current stimulation (tACS) systems generally lack robust dual-channel phase regulation and are rarely validated under realistic biological impedance conditions. Here, we present a novel phase-difference tACS system (PD-stim) designed to deliver programmable, high-precision phase offsets between stimulation targets. We performed a comprehensive engineering and in vivo validation of PD-stim, assessing biological impedance stability, waveform fidelity, amplitude stability, and phase-delivery accuracy. Impedance measurements obtained from the medial prefrontal cortex and hippocampus of rats demonstrated stable frequency-dependent profiles during stimulation. Benchmark comparisons against a clinically approved tACS device revealed comparable waveform fidelity and amplitude stability under both a standardised resistive load and in vivo recording conditions. Using simultaneous dual-channel oscilloscope recordings, PD-stim consistently generated stable sinusoidal waveforms with high phase-delivery accuracy across theta (8 Hz), beta (20 Hz), and gamma (40 Hz) frequency bands, under both biological and resistive conditions. Together, these results establish PD-stim as a precise, stable, and biologically robust dual-site neuromodulation platform that overcomes key technical limitations of existing tACS systems. This work provides a rigorously validated engineering framework for future mechanistic investigations of phase-specific modulation in distributed brain networks, while not addressing functional or therapeutic outcomes.
Prefrontal and hippocampal microstructural gray matter following cognitive training under moderate hypoxia in mood disorders: a randomized controlled trial
BackgroundCognitive impairment persists during partial or full remission in 50–70% of individuals with mood disorders and impacts daily functioning and clinical prognosis. Preclinical evidence suggests that extended exposure to moderate hypoxia, combined with motor-cognitive learning, may elevate neuroplasticity and improve cognition. In these individuals with remitted mood disorders, we found that cognitive training under repeated moderate normobaric hypoxia improved executive function, and here investigate neurobiological mechanisms.MethodsParticipants with major depressive disorder (MDD) or bipolar disorder (BD) in partial or full remission were randomized to 3 weeks of 3.5-h daily normobaric hypoxia (12% O2) combined with cognitive training five to 6 days per week or treatment-as-usual (TAU). Participants were assessed with cognitive tests and diffusion-weighted MRI at baseline and 1 month after treatment completion (week 8) as part of the ALTIBRAIN trial (ClinicalTrials.gov: NCT06121206). Prefrontal and hippocampal gray matter microstructure were modelled with Neurite Orientation Dispersion and Density Imaging (NODDI).ResultsFifty-seven participants (mean age 39 years, SD: 13, 70% female) with baseline MRI data were included. No significant effects of hypoxia-cognition training vs. TAU on neurite density index (NDI) or orientation dispersion index (ODI) were observed in either the prefrontal cortex or hippocampus (all p-FDR ≥ 0.832). No significant associations were observed between microstructural changes and changes in cognitive function in either region (all p-FDR ≥ 0.721). At baseline, microstructure in both regions was not associated with executive function or global cognition (all p > 0.40).ConclusionThe absence of detectable microstructural changes, despite selective improvements in executive function, indicates that NODDI-derived metrics did not capture structural correlates of the cognitive response to hypoxia-cognition training. Whether this reflects functional neural mechanisms, measurement insensitivity, or the timing of the single follow-up assessment remains to be determined. Future studies should incorporate multiple imaging time points to capture the dynamic trajectories of putative microstructural brain changes.