Memory consolidation affects the interplay of place and response navigation.

Navigation through space is based on memory representations of landmarks ('place') or movement sequences ('response'). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation.

Neuropsychiatric symptoms and metamemory across the life span: psychometric properties of the German Multifactorial Memory Questionnaire (MMQ).

OBJECTIVE: We assessed the psychometric properties, established normative data for the German Multifactorial Memory Questionnaire (MMQ), and analyzed its association with neuropsychiatric factors across the life span to provide a validated metamemory assessment for a German-speaking population. METHODS: The three MMQ scales (memory satisfaction, self-rated ability, and strategy application) were translated into German, considering cultural, linguistic, and conceptual aspects. To validate the MMQ and assess associations with neuropsychiatric factors, the Complainer Profile Identification, Geriatric Depression Scale, Beck Anxiety Inventory, Pittsburgh Sleep Quality Index, and Short-Form-Health Survey were applied in an online study in 336 healthy participants with follow-up after 8 months. RESULTS: Psychometric evaluation of the German MMQ showed normal distribution of all scales and good to excellent validity, internal consistency, and retest reliability. We provide percentiles and normative data for z-score conversion. Importantly, even subclinically elevated scores in depressiveness and anxiety were associated with decreased memory satisfaction and self-rated ability. Furthermore, although the influence of age on the German MMQ scales was minimal, effects of neuropsychiatric factors such as sleep quality, anxiety, and depressiveness on MMQ Satisfaction and Ability varied across the life span. CONCLUSIONS: Our study provides a validated German translation of the MMQ with normative data and reliability measures, including reliable change scores. We show the impact of neuropsychiatric factors on the MMQ scales across the life span and emphasize the relevance of a multifactorial approach to metamemory as a measure of individualized everyday functionality and the importance of including neuropsychiatric factors into both research and clinical assessments of metamemory.

Definition of the Post-COVID syndrome using a symptom-based Post-COVID score in a prospective, multi-center, cross-sectoral cohort of the German National Pandemic Cohort Network (NAPKON).

PURPOSE: The objective examination of the Post-COVID syndrome (PCS) remains difficult due to heterogeneous definitions and clinical phenotypes. The aim of the study was to verify the functionality and correlates of a recently developed PCS score. METHODS: The PCS score was applied to the prospective, multi-center cross-sectoral cohort (in- and outpatients with SARS-CoV-2 infection) of the "National Pandemic Cohort Network (NAPKON, Germany)". Symptom assessment and patient-reported outcome measure questionnaires were analyzed at 3 and 12 months (3/12MFU) after diagnosis. Scores indicative of PCS severity were compared and correlated to demographic and clinical characteristics as well as quality of life (QoL, EQ-5D-5L). RESULTS: Six hundred three patients (mean 54.0 years, 60.6% male, 82.0% hospitalized) were included. Among those, 35.7% (215) had no and 64.3% (388) had mild, moderate, or severe PCS. PCS severity groups differed considering sex and pre-existing respiratory diseases. 3MFU PCS worsened with clinical severity of acute infection (p = .011), and number of comorbidities (p = .004). PCS severity was associated with poor QoL at the 3MFU and 12MFU (p < .001). CONCLUSION: The PCS score correlated with patients' QoL and demonstrated to be instructive for clinical characterization and stratification across health care settings. Further studies should critically address the high prevalence, clinical relevance, and the role of comorbidities. TRAIL REGISTRATION NUMBER: The cohort is registered at www. CLINICALTRIALS: gov under NCT04768998.

Cognitive decline in post-COVID-19 syndrome does not correspond with persisting neuronal or astrocytic damage.

Cognitive impairment is the most frequent symptom reported in post-COVID-19 syndrome (PCS). Aetiology of cognitive impairment in PCS is still to be determined. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are increased in acute COVID-19. Their role as biomarkers in other neurological disorders is under debate. We analysed serum levels of NfL and GFAP as markers for neuronal and astrocytic damage in 53 patients presenting to a PCS Neurology outpatient clinic. Only individuals with self-reported cognitive complaints were included. In these individuals, cognitive complaints were further assessed by comprehensive neuropsychological assessment (NPA). Patients were categorized into subgroups of subjective cognitive decline, single domain impairment, or multi-domain impairment. Serum NfL was in normal range, however an increase of serum GFAP was detected in 4% of patients. Serum NfL and GFAP levels correlated with each other, even when adjusting for patient age (r = 0.347, p = 0.012). NPA showed deficits in 70%; 40% showing impairment in several tested domains. No significant differences were found between serum NfL- and GFAP-levels comparing patients with subjective cognitive decline, single domain impairment, or multi-domain impairment. Persistent neuronal or astrocytic damage did not correlate with cognitive impairment in PCS.

Fractal Dimension Analysis in Neurological Disorders: An Overview.

Fractal analysis has emerged as a powerful tool for characterizing irregular and complex patterns found in the nervous system. This characterization is typically applied by estimating the fractal dimension (FD), a scalar index that describes the topological complexity of the irregular components of the nervous system, both at the macroscopic and microscopic levels, that may be viewed as geometric fractals. Moreover, temporal properties of neurophysiological signals can also be interpreted as dynamic fractals. Given its sensitivity for detecting changes in brain morphology, FD has been explored as a clinically relevant marker of brain damage in several neuropsychiatric conditions as well as in normal and pathological cerebral aging. In this sense, evidence is accumulating for decreases in FD in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and many other neurological disorders. In addition, it is becoming increasingly clear that fractal analysis in the field of clinical neurology opens the possibility of detecting structural alterations in the early stages of the disease, which highlights FD as a potential diagnostic and prognostic tool in clinical practice.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Dataset for: Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune-related adverse events.

The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study.

Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery. Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584). Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges' g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits. Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention. Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

Characteristic functional connectome related to Post-COVID-19 syndrome.

Post-COVID-19 syndrome is a serious complication following SARS-CoV-2 infection, characterized primarily by fatigue and cognitive complaints. Although first metabolic and structural imaging alterations in Post-COVID-19 syndrome have been identified, their functional consequences remain unknown. Thus, we explored the impact of Post-COVID-19 syndrome on the functional connectome of the brain providing a deeper understanding of pathophysiological mechanisms. In a cross-sectional observational study, resting-state functional magnetic resonance imaging data of 66 patients with Post-COVID-19 syndrome after mild infection (mean age 42.3 years, 57 female) and 57 healthy controls (mean age 42.1 years, 38 female) with a mean time of seven months after acute COVID-19 were analysed using a graph theoretical approach. Network features were quantified using measures including mean distance, nodal degree, betweenness and Katz centrality, and compared between both groups. Graph measures were correlated with clinical measures quantifying fatigue, cognitive function, affective symptoms and sleep disturbances. Alterations were mainly found in the brainstem, olfactory cortex, cingulate cortex, thalamus and cerebellum on average seven months after SARS-CoV-2 infection. Additionally, strong correlations between fatigue severity, cognitive functioning and daytime sleepiness from clinical scales and graph measures were observed. Our study confirms functional relevance of brain imaging changes in Post-COVID-19 syndrome as mediating factors for persistent symptoms and improves our pathophysiological understanding.

Superficial white matter integrity in neuromyelitis optica spectrum disorder and multiple sclerosis.

Background: Superficial white matter (SWM) is a particularly vulnerable area of white matter adjacent to cerebral cortex that was shown to be a sensitive marker of disease severity in several neurological and psychiatric disorders, including multiple sclerosis (MS), but has not been studied in neuromyelitis optica spectrum disorder (NMOSD). Objective: To compare the integrity of SWM between MS patients, NMOSD patients and healthy controls, and explore the correlation of SWM integrity with cognitive performance and overall disability. Methods: Forty NMOSD patients, 48 MS patients and 52 healthy controls were included in the study. Mean diffusivity (MD) values obtained by diffusion tensor imaging were used as a measure of SWM integrity. Cognitive performance and overall disability were assessed with standardized tests. Results: Superficial white matter MD was increased in MS patients compared to healthy controls. Higher MD was associated with poorer spatial memory (most prominently in right temporal and right limbic lobe) and poorer information processing speed in MS patients. After adjusting for age, no significant differences of SWM MD were observed between NMOSD patients and healthy controls. Conclusion: Integrity of SWM is compromised in MS, but not in NMOSD, and can serve as a sensitive marker of disease severity.

Translating spatial navigation evaluation from experimental to clinical settings: The virtual environments navigation assessment (VIENNA).

Spatial navigation abilities are frequently impaired in neurological disorders and they also decline with normal aging. Researchers and clinicians therefore need valid and easy-to-use spatial navigation assessment tools to study the impact of different neuropathologies and prevent relevant cognitive impairments from going undetected. However, current experimental paradigms rarely address which cognitive processes they recruit, often have resource-intensive setups, and usually require active navigation, e.g., using a joystick or keyboard, thus confounding cognitive performance with fine motor skills. Yet, for clinical feasibility, time-efficient paradigms are needed that are informative and easy to administer in participants with limited technical experience and diverging impairments. Here, we introduce the virtual environments navigation assessment (VIENNA), a virtual adaptation of a brief, standardized, and intuitive spatial navigation paradigm ( https://osf.io/kp4c5/ ). VIENNA is designed to assess spatial navigation without episodic memory demands, requires no interface device, and takes about 16 min to complete. We evaluated VIENNA in 79 healthy middle-aged to older participants (50-85 years) and provide evidence for its feasibility and construct validity. Tests of visuospatial and executive functions, but not episodic memory or selective attention, were identified as cognitive correlates of VIENNA, even when controlling for participant age and overall cognitive performance. Furthermore, VIENNA scores correlated with subjective navigation ability and age, but not with depressiveness, cognitive complaints, or education. The straightforward administration of VIENNA allows for its integration into routine neuropsychological assessments and enables differentiated evaluation of spatial navigation performance in patients with motor impairments and episodic memory deficits.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment. METHODS: T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted. RESULTS: Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51). CONCLUSIONS: The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.

The Patient Perspective in Encephalitis Research.

Research on autoimmune and infectious encephalitis has made substantial progress in recent years in revealing the pathophysiology of these diseases, establishing robust diagnostic criteria, and developing promising treatment options, with a range of clinical trials currently underway. Outcome measures in studies on autoimmune and infectious encephalitis mainly relied on established and widely used tools such as the modified Rankin Scale (mRS). However, the mRS was developed to assess stroke outcome and has a strong focus on motor symptoms and the degree of dependence in daily activities. For example, approximately 80% of patients with anti-NMDA receptor encephalitis (i.e., the most common autoimmune encephalitis variant) achieve a good outcome 2 years after disease onset when evaluated using the mRS.1 In contrast to these findings, recent studies show that a majority of patients with anti-NMDA receptor encephalitis suffer from relevant and persistent cognitive impairment, despite mRS scores indicating good or very good recovery.2,3 This shows that the mRS fails to detect clinically relevant long-term symptoms in these patients. Indeed, persisting cognitive deficits with their detrimental effect on quality of life are specifically important in the frequently very young patients with encephalitis. More recently, encephalitis-specific scores have been developed, e.g., the CASE score for the clinical assessment of patients with autoimmune encephalitis.4 While this score is tailored to symptoms in autoimmune encephalitis, it has a strong focus on acute disease symptoms and is less well suited to capture long-term sequalae.

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

OBJECTIVES: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation. METHODS: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics. RESULTS: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes. DISCUSSION: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

Neuropsychological Testing in Autoimmune Encephalitis: A Scoping Review.

BACKGROUND AND OBJECTIVES: Identifying optimal methods for evaluation and monitoring of cognitive outcomes in AE is important for clinical care and research. This scoping review aimed to evaluate neuropsychological tests (NPT) that are most frequently impaired in AE cohorts to provide recommendations for a standardized NPT battery for AE outcome. METHODS: PubMed search for studies examining NPT in patients with AE was conducted on June 9, 2023. Studies were screened for inclusion/exclusion criteria as follows: at least 1 NPT, individual NPT test scores with comparison with healthy controls or normative data and neural-IgG status, total sample size ≥5, and English manuscript available. RESULTS: The search yielded 5,393 studies, of which 3,359 were screened, 107 were full text reviewed, and 32 met inclusion/exclusion criteria, anti-NMDA-R (k = 18), anti-LGI1 (k = 10), anti-GABAB-R (k = 2), anti-GAD-65 (k = 4), and anti-CASPR2 (k = 3). The cognitive domains most frequently impaired were visual and verbal episodic memory, attention/working memory, processing speed, and aspects of executive functions. DISCUSSION: Given the dearth of literature examining NPT in AE in combination with small sample sizes and methodological differences, more research in this area is needed. However, we provide recommendations for a test battery to be used in future studies, with the aim of standardizing research in this area. Based on the available literature, we recommend the use of comprehensive NPT batteries, spanning all cognitive domains. The highest yield measures may include the tests of (1) visual and verbal learning/memory, (2) basic and sustained attention, (3) processing speed, and (4) executive functions.

Multisensory input modulates memory-guided spatial navigation in humans.

Efficient navigation is supported by a cognitive map of space. The hippocampus plays a key role for this map by linking multimodal sensory information with spatial memory representations. However, in human navigation studies, the full range of sensory information is often unavailable due to the stationarity of experimental setups. We investigated the contribution of multisensory information to memory-guided spatial navigation by presenting a virtual version of the Morris water maze on a screen and in an immersive mobile virtual reality setup. Patients with hippocampal lesions and matched controls navigated to memorized object locations in relation to surrounding landmarks. Our results show that availability of multisensory input improves memory-guided spatial navigation in both groups. It has distinct effects on navigational behaviour, with greater improvement in spatial memory performance in patients. We conclude that congruent multisensory information shifts computations to extrahippocampal areas that support spatial navigation and compensates for spatial navigation deficits.

Impaired functional connectivity of the hippocampus in translational murine models of NMDA-receptor antibody associated neuropsychiatric pathology.

Decreased hippocampal connectivity and disruption of functional networks are established resting-state functional MRI (rs-fMRI) features that are associated with neuropsychiatric symptom severity in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, the underlying pathophysiology of NMDAR encephalitis remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 (GluN1) subunit of the NMDAR now allows for the translational investigation of functional connectivity in experimental murine NMDAR antibody disease models with neurodevelopmental disorders. Using rs-fMRI, we studied functional connectivity alterations in (1) adult C57BL/6 J mice that were intrathecally injected with a recombinant human NR1 antibody over 14 days (n = 10) and in (2) a newly established mouse model with in utero exposure to a human recombinant NR1 antibody (NR1-offspring) at the age of (2a) 8 weeks (n = 15) and (2b) 10 months (n = 14). Adult NR1-antibody injected mice showed impaired functional connectivity within the left hippocampus compared to controls, resembling impaired connectivity patterns observed in human NMDAR encephalitis patients. Similarly, NR1-offspring showed significantly reduced functional connectivity in the hippocampus after 8 weeks, and impaired connectivity in the hippocampus was likewise observed in NR1-offspring at the age of 10 months. We successfully reproduced functional connectivity changes within the hippocampus in different experimental murine systems that were previously observed in human NMDAR encephalitis patients. Translational application of this method within a combined imaging and histopathological framework will allow future experimental studies to identify the underlying biological mechanisms and may eventually facilitate non-invasive monitoring of disease activity and treatment responses in autoimmune encephalitis.

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité Fatigue Center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.