European Journal of Neuroscience

Emotions often occur within social interactions where affective cues are accessible or inferable by others. This raises questions regarding how and to which degree social context modulates subjective, physiological and behavioural affective responses, as well as their coherence, questions which remain points of tension in emotion research. To investigate this, we measured subjective affective ratings, autonomic sympathetic and parasympathetic activity, and facial behaviour while participants completed an emotion-induction task. In the social-context condition (but not control), participants believed that their video feed was accessible to a potential future interaction partner. Results show that even such "minimal social context" selectively and differentially modulated affective response modalities, characterised by both intensification of autonomic responses and dampening of overt facial and subjective affect. Multivariate dimensionality analysis further identified a cross-modal affective dimension Interestingly, social context reduced participants coupling with this shared affective response structure, indicating weaker cross-modal coherence. These findings suggest that emotional responding relies on a flexible, rather than rigid, configuration of affective features, likely recruited to meet the socioemotional demands of a given context. This has important implications for understanding the structure and function of emotion, as well as typical and atypical socioemotional responding.

Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood. The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT). Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation. Our findings indicate that regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit during both anticipatory and outcome phases of reward processing, accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) greater VTA activation during outcome of successful monetary win and loss avoidance and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) impaired behavioural performance, reflected in lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling. Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of cannabis use.

Research in cognitive neuroscience has relied on simple, highly controlled stimuli due to the difficulty in developing standardized, ecologically valid stimulus sets. However, there is a consensus that using ecologically valid stimuli is imperative to generalize results beyond controlled laboratory settings. The current study introduces a naturalistic audio stimulus database, consisting of short, recognizable, and emotionally rated stimuli. To create such a database, the current study collected 291 audio files from a wide range of sources. 361 participants rated the audio clips on emotionality, arousal, and recognizability, and subsequently freely described the audios by typing what they believed the sound to be. The text responses of the participants were embedded and clustered using an unsupervised machine-learning algorithm to derive a participant-grounded organization of auditory object categories. The results indicate audio clips were easily recognizable, while emotionality and arousal ratings showed broad variability, making the database suitable for diverse experimental needs. Furthermore, the final database comprises 10 distinct semantic categories, providing a diverse set of auditory stimuli.

Individuals with autism spectrum disorder (ASD) often exhibit atypical auditory processing, yet it remains unclear whether and how the integration of simple acoustic features and contextual information is impacted in ASD. One real-world example of this integration is the auditory looming bias, the prioritized processing and perception of approaching auditory stimuli. We designed a paradigm that presents intensity-rising (looming) and intensity-falling (receding) auditory stimuli to 3-4-year-old children with ASD (n = 21), children with sensory processing concerns who do not have ASD (SPC; n = 16) and children with typical development (TD; n = 30). We recorded neural responses using electroencephalography (EEG) and found evidence of looming bias in the SPC and TD groups, as indexed by greater P1 peak amplitude during the looming than receding stimuli (TD: t(64) = 6.87, p < .001; SPC: t(64) = 4.07, p < .001). But this finding was not present in the ASD group (p = .194). Additionally, the ASD group showed reduced differentiation between looming and receding stimuli, as indicated by significantly lower Rise-Fall Difference Score (RFDS) in comparison to the TD group (Z = -3.00, padj = .008). These findings suggested altered context-dependent modulation of sensory input in ASD.

BackgroundPersistent automatic approach tendencies toward alcohol cues that resist goal-directed control are a key feature of harmful alcohol use, yet the causal neural mechanisms underlying this imbalance remain poorly understood. Converging evidence implicates the frontoparietal network (FPN) in actively regulating alcohol approach-avoidance behavior, but whether its constituent nodes make dissociable causal contributions has not been established. MethodsIn a within-subject, active-sham counterbalanced design, inhibitory continuous theta burst stimulation (cTBS) was applied to right dorsolateral prefrontal cortex (rDLPFC) and right posterior parietal cortex (rPPC) in separate groups of non-clinical alcohol users (rDLPFC: n = 29; rPPC: n = 28), followed by an Alcohol Approach-Avoidance Task. ResultsActive rDLPFC cTBS selectively slowed down alcohol push responses, whereas rPPC suppression produced a bidirectional action-specific shift in response to alcohol cues, where pull responses accelerated, and push slowed simultaneously. Suppression of either node shifted automatic tendencies toward greater alcohol approach through mechanistically distinct routes. ConclusionThese dissociable profiles indicate that rDLPFC is causally necessary for effortful top-down avoidance control, while rPPC supports the priority-based selection of alcohol cue-driven actions. These findings provide the first node-specific causal evidence for functional specialization within the FPN in the context of automatic tendencies towards alcohol. Alcohol avoidance emerges as an active, prefrontal-dependent process, whereas priority-based regulation emerges as a parietal-dependent process, together indicating rDLPFC and rPPC as mechanistically independent targets for intervention in maladaptive alcohol approach behavior.

Chronotype reflects individual circadian preference for timing of sleep, wakefulness, and peak performance and has been linked to variability in prefrontal cognitive function across the day. Whether chronotype independently relates to dual-task gait cost (DTC) and whether this relationship differs by cognitive task domain is unclear. Sixty-nine healthy young adults (37 female; mean age 21.3 years) completed the Morningness-Eveningness Questionnaire (MEQ). Spatiotemporal gait parameters were recorded with three-dimensional motion capture during single-task walking and three dual-task conditions: backward word spelling (5LWB; phonological), serial subtraction by seven (SS7; arithmetic), and reverse month recitation (RMR; sequential). DTC was calculated for eight gait parameters. Condition differences were assessed with nonparametric tests and post-hoc comparisons. Multiple linear regression, adjusting for age, sex, BMI, and baseline gait velocity, tested the independent association between MEQ score and mean velocity DTC; exploratory Spearman correlations examined other parameters. SS7 produced the largest mean velocity DTC (-12.76%), significantly greater than 5LWB (-7.95%; p = 0.002) and RMR (-9.57%; p = 0.021). MEQ score independently predicted mean velocity DTC in 5LWB ({beta} = -0.51, p < 0.001, R{superscript 2} = 0.269) and RMR ({beta} = -0.55, p = 0.004, R{superscript 2} = 0.222), indicating greater morningness associated with better gait-speed preservation under cognitive load; the SS7 association was not significant ({beta} = -0.33, p = 0.071). Exploratory correlations showed MEQ-DTC associations across 7/8 parameters in 5LWB, 4/8 in RMR, and 3/8 in SS7. Chronotype is independently associated with dual-task gait cost in a task-domain-specific manner, with stronger effects for phonological and sequential tasks than for arithmetic processing. The SS7 condition yielded the largest interference but weakest chronotype modulation, suggesting arithmetic dual-task disruption may be less sensitive to circadian arousal. Fixed testing time and cross-sectional design warrant within-subject, multi-timepoint studies to confirm chronotype effects separate from time-of-day confounds.

Objectives: Non-suicidal self-injury (NSSI) and self-harming sexual behaviours share functional and behavioural overlaps. However, the relationship between NSSI and problematic sexual behaviour (PSB) remains underexplored. This study aimed to investigate the association between NSSI and PSB in two cohorts - a non-clinical university cohort and a clinical PSB patient cohort. Methods: Data were collected from 2,189 university participants and 477 clinical PSB patients. NSSI was assessed via self-report, and PSB was measured with the Sexual Addiction Screening Test-Revised (SAST-R) Core. The four core addictive dimensions of PSB: relationship disturbance, loss of control, preoccupation, and affect disturbance, were also evaluated. Logistic regression analyses were conducted to examine the association between PSB (presence/absence and severity) and NSSI, looking at effects of gender and contributions of addictive dimensions of PSB. Results: Rates of NSSI were similar in the university (7.1%) and patient (5.7%) cohorts; stratified by gender, a higher proportion of women PSB patients had NSSI compared to in the university cohort (29.3% vs 9.3%). In the university group, who had milder PSB than patients, PSB was associated with NSSI (OR=2.11, p<0.001); a significant gender by PSB interaction was found showing that women with PSB were over four times more likely to have NSSI than men without PSB (OR=4.44, p=0.037). In contrast, PSB severity was not associated with NSSI in PSB patients (OR=1.10, p=0.25). Associations of the addictive dimensions of PSB with NSSI were observed only in the subgroup of university women, in the 'preoccupation' dimension (p<0.001). Conclusions: Our findings highlight gender-specific patterns in the association between PSB and NSSI, suggesting the need for further research and possibly targeted prevention and intervention strategies in women.

Disability worsening is the critical long-term outcome in multiple sclerosis, yet the Expanded Disability Status Scale incompletely captures neurological deterioration and has limited sensitivity in the short time windows of clinical trials. Composite endpoints incorporating functional measures have been proposed to address these limitations, but whether they reliably improve detection of treatment effects has not been established across trials. We conducted a post-hoc analysis of individual patient data from ten phase III randomised controlled trials (ASCEND, BRAVO, CONFIRM, DEFINE, EXPAND, INFORMS, OLYMPUS, OPERA I/II, and ORATORIO; n = 9,369), spanning relapsing-remitting and progressive multiple sclerosis. Confirmed disability worsening was defined using harmonised criteria with the msprog package and confirmed at 24 weeks. Treatment effects were estimated using Cox proportional hazards models and combined across trials in a one-stage individual patient data framework. Composite endpoints were constructed from the Expanded Disability Status Scale, the timed 25-foot walk test, and the nine-hole peg test using logical unions (OR-type), intersections (AND-type), and majority-vote structures. Sensitivity to treatment effect was quantified using Z-scores (the ratio of the pooled log-hazard ratio to its standard error) and compared to the Expanded Disability Status Scale reference using interaction tests. Event rates varied across components: the timed walk test generated the highest rates (up to 46.8%) while the nine-hole peg test generated the lowest (as low as 2.1%). OR-type composite endpoints showed weaker treatment effects than the Expanded Disability Status Scale alone, with the largest reductions in sensitivity observed for endpoints incorporating the timed walk test ({Delta}Z up to +2.26; interaction p = 0.004). These findings were confirmed across disease subtypes and were pronounced in relapsing-remitting trials, where no composite endpoint outperformed the Expanded Disability Status Scale. In progressive multiple sclerosis, the combination of the Expanded Disability Status Scale and the nine-hole peg test showed numerically stronger treatment effects ({Delta}Z = -1.65), though interaction tests did not reach statistical significance (p = 0.051). Composite endpoints do not systematically improve treatment effect detection in multiple sclerosis trials. Increased event capture driven by the timed walk test introduces noise that dilutes the treatment signal rather than amplifying it, highlighting that event rate and endpoint quality are not interchangeable. Upper limb function assessed by the nine-hole peg test provides complementary and specific information, particularly in progressive disease. The combination of global disability and upper limb measures represents a promising direction for future endpoint development in progressive multiple sclerosis trials, warranting validation.

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

The replicability of experimental results is considered a cornerstone of empirical research. However, the reproducibility of results from groups that have not undergone experimental manipulation -- the standard against which comparisons in an experiment are made -- has been almost entirely neglected in animal research. Our aim is to address this gap by exemplarily determining within-laboratory replicability using research in pigs, an increasingly popular large animal model species. Drawing on data from twelve independent porcine holeboard studies conducted in our laboratory, we examine the replicability of groups that were not subjected to experimental manipulation (typically the control group), eventually including groups on which the experimental treatments had no effect. These analyses were also performed on all eight studies involving the Terra x Finnish Landrace x Duroc pig breed, with all other breeds excluded to increase genetic uniformity. The holeboard is a complex spatial discrimination task in which an animal must learn to find food at four of sixteen possible locations (holes) arranged in a 4 x 4 matrix. The main variables measured are spatial working memory (WM), reference memory (RM) and the inter-visit interval (IVI), which serves as an index of motivation. All studies showed predominantly linear improvements in WM and learning rates across successive trial blocks. IVI showed greater variation across trialblocks, but this did not affect WM and RM learning, which are robust and replicable indices of spatial learning in pigs. Assessing replicability provides relevant information, such as whether behavioural and physiological traits in a model species are stably expressed and robust across studies. Including replicability research and publishing its results can stimulate the development and use of more replicable methods and workflows, thereby increasing scientific rigour. Provided the data are available and accessible, the next step should be to expand replicability studies to include those conducted in different laboratories.

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim light conditions at six predefined time points around habitual sleep onset (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.

Recent studies describe Eye Movement-related Eardrum Oscillations (EMREOs), low-frequency signals recorded in the ear canal that arise from the tympanic membrane and are triggered by saccadic eye movements. Because EMREOs are thought to arise from motor elements in the peripheral auditory system, we examined how two known modulators of these elements affect the EMREO time course. First, the activity of outer hair cells (OHC) can be suppressed by the medial olivocochlear reflex (MOCR). If OHCs contribute to the generation of EMREOs, activation of this reflex should reduce EMREO amplitude. To test this, we compared EMREO amplitudes elicited by saccades performed in silence and in the presence of contralateral noise. Second, gravitational cues linked to head orientation may influence EMREOs via oculomotor control circuits that possibly modulate middle ear muscles. To test this, we recorded EMREOs while participants made saccades with their head upright (0{degrees} azimuth) and with their head tilted 30{degrees} in either direction. Across both experiments our data reveal no clear modulation of the EMREO time course by these experimental manipulations. Together with other recent studies these findings advocate for a stability of the EMREO time course towards multiple experimental modulations and fuel speculations that the signal may serve as a temporal reference frame when combining signals across the senses.

Age- and disease-related vestibular decline can cause dizziness and postural instability, motivating interventions such as noisy galvanic vestibular stimulation (nGVS). nGVS is commonly delivered at "subsensory" amplitudes and explained by stochastic resonance, yet because galvanic stimulation directly modulates vestibular afferents, even imperceptible currents may also exert deterministic effects on balance. This study examined whether low-amplitude nGVS (<1 mA), as typically used in stochastic resonance paradigms, directly influences postural behavior through stimulus-response coupling. Twenty healthy young adults stood on a force plate with feet together and eyes closed on either a rigid surface or 10-cm foam. In randomized order, they completed 300-second trials with band-limited (0-30 Hz), zero-mean nGVS at {+/-}0, 0.1, 0.2, 0.3, 0.5, and 0.7 mA. Coupling between the stimulation waveform and mediolateral ground-reaction force was assessed using coherence and time-cumulant density. Mean coherence was significant mainly at higher amplitudes (0.5-0.7 mA) on both surfaces, whereas time-cumulant density identified significant time-locked vestibular-evoked response components at much lower amplitudes, down to 0.1 mA. These included an early response around 135-155 ms and a later, prominent response around 360-410 ms. Individually, significant coherence was common at 0.5-0.7 mA (15-19 of 20 participants), while cumulant-based responses appeared in some participants even at 0.1 mA. Responses were clearer on foam, consistent with greater vestibular reliance when somatosensory input is less reliable. Overall, low-amplitude nGVS can entrain postural output, suggesting that balance changes during "subsensory" stimulation may reflect both stochastic-resonance-like effects and deterministic vestibular drive, underscoring the need to quantify coupling alongside performance outcomes.

Qualitative models of Alzheimers pathology often posit that amyloid accumulation follows a sigmoid curve, indicating that the rate of deposition wanes over time. Longitudinal PET data now allow us to investigate amyloid accumulation trajectories with greater detail and over longer follow-up periods. We combine inferences from simulated amyloid trajectories, empirical PET data from the Alzheimers Disease Neuroimaging Initiative (ADNI), and the sampled iterative local approximation algorithm (SILA) to assess whether amyloid accumulation reaches a physiologic ceiling. We find that SILA reliably detects a ceiling, when present, across a range of simulated scenarios that impose a sigmoid shape. When fit to empirical data from ADNI, however, SILA does not appear to indicate the presence of a ceiling. Thus, we conclude that amyloid trajectories may not reach a physiologic ceiling during the stages of Alzheimers disease typically observed while patients remain under follow-up in cohort studies. Fits using SILA indicate that illustrative models of biomarker cascades, while useful tools for conceptualizing and interrogating pathologic processes, may not represent the shapes of amyloid trajectories accurately. Summary for General PublicAmyloid, a protein implicated in Alzheimers disease, is thought to reach a plateau in the brain, but methods that estimate how amyloid changes over time suggest it grows unabated. Gantenberg et al. use one such method and simulations to argue that amyloid does not reach a plateau during the typical course of Alzheimers.

The striatum is a major cortical input site of the basal ganglia and plays a critical role in the control of orofacial movements such as licking. However, how striatal activity relates to the spatial features of licking behavior remains unclear. In this study, we examined whether neural activity in the striatal matrix and striosomal compartments is associated with the spatial position of a licking target during an operant task. Head-fixed mice performed a licking task in which the target positions were varied across three spatial dimensions. Using fiber photometry in Calb1-IRES-Cre and Pdyn-IRES-Cre mice, we recorded calcium signals from matrix and striosomal neurons. Associations between neural activity, target position, and behavioral variables were quantified using linear mixed-effects modeling with cross-validation. Matrix activity prior to licking onset was primarily associated with the dorsal-ventral target position and reaction time. During licking, matrix activity was modulated by anterior-posterior and medial-lateral positions, independent of reaction time and lick count. In contrast, striosomal activity during licking was predominantly associated with the dorsal-ventral position. These findings demonstrate that neural matrix activity is systematically associated with spatial features of licking behavior, with distinct contributions before and during movement. Our results suggest that striatal matrix circuits provide task-relevant spatial signals for the control of orofacial actions. Significant StatementWe show that neural activity in the striatal matrix is associated with the three-dimensional position of a licking target during an operant task. Activity prior to licking onset reflects dorsal-ventral position, whereas activity during licking is modulated by the anterior-posterior and medial-lateral positions. These findings indicate that matrix activity represents spatial aspects of licking behavior, supporting a role for the striatum in integrating motor execution with task-specific spatial information and pointing to the matrix compartment as a substrate for transforming spatial coordinates into action-specific motor commands.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

Biological sex is a key determinant in the onset and progression of multiple diseases. In multiple sclerosis (MS), females exhibit higher disease prevalence, earlier onset, and more pronounced inflammatory activity, whereas males tend to experience a more severe neurodegenerative course, characterized by accelerated central nervous system damage and increased brain atrophy. The gut microbiome has emerged as a critical factor in MS, as its composition can either ameliorate or exacerbate disease progression. In this study, we aimed to identify reproducible sex-associated differences in gut microbial composition across independent cohorts of MS patients. Through a systematic search we identified six independent studies based on 16S rRNA gene sequencing, comprising a total of 337 samples. Despite substantial inter-study variability, sex-associated differences were more pronounced in MS patients than in healthy controls. We identified 11 microbial taxa showing significant sex-associated differences in MS, nine enriched in females and two in males. Notably, the female-enriched taxa Eggerthella and Eisenbergiella were associated with specific MS subtypes and higher disability. To facilitate the use of our findings by the scientific community, we developed a freely accessible web-based tool that provides full access to our results. Thus, in this work we identified consistent and reproducible sex differences in the gut microbiota of MS patients, highlighting the importance of incorporating sex as a critical variable in microbiome research, with potential implications for understanding disease heterogeneity in MS. IMPORTANCEMultiple sclerosis (MS) affects females and males differently, but the biological reasons behind these differences are not fully understood. One potential factor is the gut microbiome (i.e., the community of microorganisms living in our intestines) which can influence immune function and disease progression. In this study, we analyzed data from multiple independent cohorts and found consistent differences in gut microbial composition between female and male MS patients. Notably, certain bacteria were more abundant in females and were linked to more severe disease features. We also developed a freely accessible web tool where researchers can explore the complete findings in detail. Our results highlight the importance of considering sex as a key factor in microbiome research and may help guide more personalized approaches to understanding and treating MS.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

There is a dearth of information on how different cocktails sweetened with different sugars impact brain activity. Glucose enters the brain faster and in greater concentration than fructose and directly affects neuronal activity of melanin-concentrating hormone (MCH) neurons. MCH signaling promotes both glucose drinking and alcohol intake by integrating central and sensory inputs, but it is currently unknown how MCH neuronal activity relates to sweetened cocktail drinking. This study sought to investigate the relationship between MCH activity and sugar-sweetened alcoholic cocktail drinking. We also sought to compare MCH neuronal responses to the sugar solutions without alcohol as well as their response to sensory stimuli. In female and male rats, we used fiber photometry to monitor MCH neurons in response to sensory stimuli and during drinking of 10% glucose, 10% fructose, and glucose or fructose cocktails with 1.25% or 10% alcohol. We found that MCH activity rises in response to a variety of sensory stimuli and peaks before the start of drinking for all cocktails, before returning to baseline near the start of drinking. The cocktail type impacted the dynamics of MCH activity, where increased alcohol concentration resulted in earlier MCH activity for fructose but not glucose cocktails. Finally, we found that peak MCH activity during drinking is correlated with approach behavior for all sugar and cocktail types. These findings suggest that glucose and alcohol may interact to directly influence MCH activity. Further, MCH neurons may regulate cocktail drinking in response to sugar type and alcohol concentration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/719280v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@b992c3org.highwire.dtl.DTLVardef@1526895org.highwire.dtl.DTLVardef@1504c6dorg.highwire.dtl.DTLVardef@c990fc_HPS_FORMAT_FIGEXP M_FIG C_FIG New and noteworthyFiber photometry was used to monitor lateral hypothalamic melanin-concentrating hormone (MCH) neurons in male and female rats during sensory stimuli and drinking of glucose, fructose, or glucose- or fructose-sweetened alcoholic cocktails. Subsecond-scale changes in MCH activity occurred after stimuli. Peak MCH activity during drinking was correlated with approach behavior. Alcohol concentration only impacted MCH activity with fructose cocktails. We discuss the implications of MCH dynamics towards brain function, associative learning, and alcohol use disorder.

Background and PurposePathogenic aggregation and propagation of seed-competent TAU assemblies drive tauopathies. MAPT P301 mutations accelerate aggregation and enhance seed competence, yet pharmacological strategies selectively targeting these pathogenic species remain limited. We investigated whether the clinically approved catechol-O-methyltransferase inhibitors tolcapone (TOL) and entacapone (ENT) preferentially modulate mutant TAU aggregation and seeding. Experimental ApproachTOL and ENT effects on TAU aggregation were evaluated via cell-free assays, surface plasmon resonance (SPR), and in silico docking. Functional consequences of compound-modified fibrils were assessed in mutant TAU-expressing SH-SY5Y cells. Translational relevance was examined in human induced pluripotent stem cell (hiPSC)-derived neurons exposed to pathogenic K18 fibrils, followed by post-seeding compound treatment. Key ResultsBoth compounds dose-dependently inhibited TAU aggregation, exhibiting greater potency, stronger SPR binding affinities, and more favorable computed interaction energies for P301S mutant versus wild-type TAU. Fibrils formed with TOL or ENT induced less downstream TAU oligomerization and phosphorylation in SH-SY5Y cells, with TOL showing superior protection. In hiPSC-derived neurons, post-seeding treatment with either compound decreased fibril-induced, sarkosyl-insoluble TAU aggregation and phosphorylation without overt cytotoxicity. Conclusion and ImplicationsTOL and ENT preferentially inhibit the aggregation and seeding of pathogenic P301 mutant TAU. This supports mutation-focused pharmacological strategies and highlights catechol scaffolds as viable starting points for the development of disease-modifying therapeutics. Future research must determine the precise interaction mechanisms with aggregation intermediates and evaluate in vivo efficacy in animal models.