Antibody-mediated encephalitides are a rapidly evolving class of disorders in which autoantibodies against neuronal surface proteins disrupt synaptic function, neural circuits and cognition. This article summarizes the presentations and discussions from a symposium at the 2025 meeting of the Spanish Society of Neuroscience (SENC). Rather than providing a comprehensive review of autoimmune encephalitis, we highlight selected advances that illustrate how antibody-mediated mechanisms contribute to neurological dysfunction, using anti-NMDAR encephalitis as a paradigmatic example. Specifically, we contrast experimental approaches that have shaped current understanding of disease pathogenesis, including in vitro systems, passive-transfer mouse models and active immunization paradigms that capture B-cell responses, intrathecal immunity, microglial engagement and relapse biology. We also examine emerging evidence that antibody Fc features, including subclass and glycosylation, contribute to innate immune activation and clinical heterogeneity, with examples linking proinflammatory Fc signatures to poorer outcomes. Finally, we review selected studies addressing behavioural and cognitive consequences in animal models and patients, particularly long-lasting deficits in working memory, and discuss therapeutic implications ranging from synapse-stabilizing strategies and NMDAR positive allosteric modulators to B-cell-targeting treatments and approaches aimed at modulating Fc-dependent pathways. Together, these findings suggest that integrating molecular immunoprofiling with systems neuroscience may improve prognostic accuracy and inform therapies that restore immune homeostasis and functional circuit recovery.

The ability to successfully retain and manipulate information in working memory (WM) requires that objects' individual features are bound into cohesive representations; yet, the mechanisms supporting feature binding remain unclear. Binding (or swap) errors, where memorized features are erroneously associated with the wrong object, can provide a window into the intrinsic limits in capacity of WM that represent a key bottleneck in our cognitive ability. We tested the hypothesis that binding in WM is accomplished via neural phase synchrony and that swap errors result from perturbations in this synchrony. Using magnetoencephalography data collected from human subjects in a task designed to induce swap errors, we showed that swaps are characterized by reduced phase-locked oscillatory activity during memory retention, as predicted by an attractor model of spiking neural networks. Further, we found that this reduction arises from increased phase-coding variability in the alpha-band over a distributed network of sensorimotor areas. Our findings demonstrate that feature binding in WM is accomplished through phase-coding dynamics that emerge from the competition between different memories.

Serial dependence, a behavioral phenomenon where information from previous trials biases current trial reports, is pervasive in working memory tasks. There is growing interest in its mechanisms, and recent work has shown that individuals with schizophrenia and anti-NMDA receptor (NMDAR) encephalitis exhibit reduced serial dependence in simple delayed-response tasks. Modeling and experimental evidence suggest that serial dependence stems from the interplay between persistent neural activity and short-term synaptic plasticity in cortical circuits, with neural reactivations in between trials increasing serial dependence. A computational model that implements this hypothesis showed that a reduction in short-term plasticity, potentially due to NMDAR dysfunction, can replicate the observed reduction of serial dependence in patients with anti-NMDAR encephalitis and schizophrenia, compared with healthy subjects. Yet, its neurophysiological predictions remain untested. Here, we used electroencephalography (EEG) to test if these patient groups have reduced neural reactivations, as the model predicts. Our findings confirm the absence of memory reactivations in schizophrenia and anti-NMDAR encephalitis. We show that this result does not depend on motor-related activity. Further, while memory codes are specifically impaired in these patients, the perceptual component of the code is as robust as in healthy participants. Overall, we report empirical evidence supporting a mechanistic model of serial dependence, which links reduced neural reactivations with diminished serial dependence in neuropsychiatric disorders.

Abstract The prefrontal hemispheres must coordinate dynamically to maintain a unified representation of visual space. Recently, two opposing theories using distinct storage strategies have been proposed: A high-capacity specialized architecture, where each hemisphere governs contralateral behavior, and a fail-safe redundant one, where both hemispheres jointly guide behavior across the visual space. Here, we analyzed simultaneous bilateral prefrontal cortex recordings from three male macaque monkeys performing a visuo-spatial working memory task. Both hemispheres equally predicted behavioral imprecision, decoding errors were weakly correlated between hemispheres, and serial dependence remained local within hemispheres, suggesting a redundant, weakly coupled organization. Attractor network simulations showed that redundancy improved precision when task demands were below memory capacity, while weak interhemispheric coupling increased capacity in more demanding tasks by allowing hemispheric specialization. These predicted patterns were validated in human and monkey data, reconciling previous findings and revealing a versatile interhemispheric architecture that adapts to varying cognitive demands.

BACKGROUND:In vivo assessment of glutamatergic metabolites in patients with anti-NMDA receptor (anti-NMDAR) encephalitis compared with schizophrenia may help increase understanding of the pathophysiology of both conditions. METHODS:This 24-month prospective case-control study included participants ages 12 to 60 years with anti-NMDAR encephalitis during the post-acute stage and age- and sex-matched individuals with schizophrenia and healthy control participants (HCs). Single-voxel magnetic resonance spectroscopy was used to estimate brain concentrations of glutamatergic metabolites, myo-inositol, and N-acetylaspartate+N-acetylaspartylglutamate (tNAA) in the left dorsomedial prefrontal region (dmPF) and medial temporal lobe. The effect of group and time on metabolite levels and the relationship between metabolite levels and psychiatric and cognitive features were tested with multilevel linear mixed models. RESULTS:Thirty-two participants with anti-NMDAR encephalitis (84% women), 27 participants with schizophrenia (63% women), and 36 HCs (72% women) were included. In the dmPF, levels of glutamate and glutamate+glutamine were significantly lower in patients with anti-NMDAR encephalitis than in participants with schizophrenia (Cohen's d = -0.87 and d = -0.80, respectively) and HCs (d = -0.73 and d = -0.71). Myo-inositol levels were significantly higher in both participants with anti-NMDAR encephalitis (d = 0.91) and patients with schizophrenia (d = 1.07) than in HCs. Group differences remained stable over time. Metabolite levels were not associated with psychiatric or cognitive symptoms. CONCLUSIONS:This is the first report of hypoglutamatergia in the left dmPF in anti-NMDAR encephalitis and of increased levels of myo-inositol in both anti-NMDAR encephalitis and schizophrenia. The findings suggest persistent alterations in glutamatergic neurotransmission during the post-acute stage of anti-NMDAR encephalitis and overlapping neuroinflammatory processes between anti-NMDAR encephalitis and schizophrenia.

The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the nucleus basalis (NB) of Meynert have been recently examined in two male monkeys (Qi et al., 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in the PFC.

ABSTRACT Short-term memory (STM) is prone to failure, especially during prolonged memory maintenance or under limited cognitive control. Despite predictive mechanistic frameworks based on persistent neural activity and attractor states, a direct assessment of network dynamics during multifactorial STM failure is still missing. We addressed this in a delayed-response task where mice maintained a prospective response during a long variable delay. Mice behavior episodically switched between a task-engaged state described by an attractor model, and a task-disengaged state purely determined by previous choices. During task engagement, the anterolateral motor cortex (ALM) showed delay persistent activity stably encoding correct choices, whereas the encoding reversed during the delay in error trials. In contrast, in task-disengaged phases ALM showed no clear traces of attractor dynamics and instead exhibited enhanced synchrony at ∼ 4-5Hz. Thus, ALM switches between distinct error-generating dynamics: in control-capable trials, transitions between memory attractors cause forgetting errors, whereas non-memory errors are caused by the dissociation of ALM during the mnemonic period reflecting the lack of cognitive control.

BACKGROUND:Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy. METHODS:For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions-the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry. FINDINGS:Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67-155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5-10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2-4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1-106·4; p=0·038). INTERPRETATION:Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome. FUNDING:Fundació La Caixa.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Background Anti-NMDA receptor (NMDAR) encephalitis is associated with a post-acute stage that is not well known. We aimed to describe the clinical features of this stage, similarities with schizophrenia spectrum disorders, and the factors that predict cognitive-psychiatric outcomes and could serve as prognostic biomarkers. Methods In this prospective cohort study, participants (aged 12-60 years) with anti-NMDAR encephalitis during the post-acute stage visited Hospital Clinic de Barcelona (Barcelona, Spain) on three occasions (at study entry [V1], at 6 months [V2], and at 12 months [V3]) and underwent comprehensive neuropsychiatric evaluations. Similar evaluations were done in a group of age-matched participants with schizophrenia spectrum disorders and a group of age-matched and sex-matched healthy participants also recruited from Hospital Clinic de Barcelona. We analysed differences between and within groups in the longitudinal follow-up using multilevel linear mixed-effect models, adjusting for group, age, sex, and socioeconomic status to control for possible confounding. Findings Between Jan 1, 2017, and Sept 30, 2020, 82 participants were recruited, 28 (34%) with anti-NMDAR encephalitis, 27 (33%) with schizophrenia spectrum disorders, and 27 (33%) healthy participants. Although, by V1 (median 4 months [IQR 3-7] from disease onset), many acute-stage symptoms in participants with anti-NMDAR encephalitis had resolved (acute stage median modified Rankin Scale [mRS] score 5 [IQR 4-5] vs V1 mRS score 2 [1-2]; p < 0middot0001), 25 (89%) participants showed deficits in at least one cognitive domain. In this group, 15 (68%) of 22 cognitive domain variables were impaired at V1, whereas only eight (36%) were altered at V3 (p=0.016). In participants with schizophrenia spectrum disorders, 11 (50%) of 22 variables (all shared with participants with anti-NMDAR encephalitis) were impaired at V1, without changes at V3. Two acute-stage features of anti-NMDAR encephalitis (ie, decreased consciousness and no improvement within the first 4 weeks of treatment) predicted cognitive domain outcomes, and a visuospatial task (ie, serial biases) at V1 showed potential in predicting learning and memory outcomes. At V1, all psychiatric symptom clusters were similarly altered in participants with anti-NMDAR encephalitis and in those with schizophrenia spectrum disorders, but only those in individuals with anti-NMDAR encephalitis subsequently improved (p=0.031). The greatest cognitive-psychiatric improvement in participants with anti-NMDAR encephalitis occurred between V1 and V2. During this interval, four (14%) participants with anti-NMDAR encephalitis would have met the diagnostic criteria of schizophrenia if CSF antibody findings had not been investigated. Interpretation The cognitive-psychiatric symptoms of anti-NMDAR encephalitis in the post-acute stage resembled those of stabilised schizophrenia, but only those in participants with anti-NMDAR encephalitis progressively improved, predominantly during V1-V2. These findings are important for clinical trials on anti-NMDAR encephalitis and suggest that prompt cognitive-psychosocial rehabilitation might be a valuable intervention. Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved.