Identifying the anatomy of circuits causal of psychosis could inform treatment targets for schizophrenia. We identified 155 published case reports of brain lesions that caused new-onset psychosis. We mapped connectivity of these lesions using a normative human fMRI connectome. Lesions causing psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus. This circuit was consistent both across individual symptoms of psychosis (delusions, hallucinations, and thought disorders), and when excluding lesions that touched the hippocampus. In an independent observational study (n=181), lesions connected to this circuit were preferentially associated with psychotic symptoms. A location in the rostromedial prefrontal cortex with high connectivity to this psychosis circuit was identified as a potential target for transcranial magnetic stimulation. Based on these results, we conclude that lesions that cause psychosis have common functional connections to the posterior subiculum of the hippocampus.

Importance Identifying anatomy causally involved in psychosis could inform therapeutic neuromodulation targets for schizophrenia. Objective To assess whether lesions that cause secondary psychosis have functional connections to a common brain circuit. Design, Setting, and Participants This case-control study mapped functional connections of published cases of lesions causing secondary psychosis compared with control lesions unassociated with psychosis. Published cases of lesion-induced psychosis were analyzed in a computational laboratory. Participants had documented brain lesions associated with new-onset psychotic symptoms without a history of psychosis. Control cases included 1156 patients with lesions not associated with psychosis. Generalizability across lesional datasets was assessed using an independent cohort of 181 patients with brain lesions who subsequently underwent neurobehavioral testing. Data were analyzed from June 2022 to April 2024. Exposures Lesions causing secondary psychosis. Main Outcomes and Measures Psychosis or no psychosis. Results A total of 153 lesions from published cases were determined to be causal of psychosis, 42 of which were described as schizophrenia or schizophrenia-like (71 [46%] patients were male, 82 [54%] female; mean [SD] age, 50.0 [20.8] years). Lesions that caused secondary psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus (84% functional overlap, family-wise error [FWE] rate corrected P < 5 x 10(-5)). At a lower statistical threshold (>75% overlap, FWE-corrected P < 5 x 10(-4)), this circuit included the ventral tegmental area, retrosplenial cortex, lobule IX and dentate nucleus of the cerebellum, and the mediodorsal and midline nuclei of the thalamus. This circuit was consistent when derived from schizophrenia-like cases (spatial r = 0.98). We repeated these analyses after excluding lesions intersecting the hippocampus (n = 47) and found a consistent functional connectivity profile (spatial r = 0.98) with the posterior subiculum remaining the center of connectivity (>75% overlap, FWE-corrected P < 5 x 10(-5)), demonstrating a circuit-level effect. In an independent observational cohort of patients with penetrating head trauma (n = 181), lesions associated with symptoms of psychosis exhibited significantly similar connectivity profiles to the lesion-derived psychosis circuit (suspiciousness, P = .03; unusual thought content, P = .046). Voxels in the rostromedial prefrontal cortex are highly correlated with this psychosis circuit (spatial r = 0.82), suggesting the rostromedial prefrontal cortex as a promising transcranial magnetic stimulation target for psychosis. Conclusions and Relevance Lesions that cause secondary psychosis affect a common brain circuit in the hippocampus. These results can help inform therapeutic neuromodulation targeting.

INTRODUCTION: Paper-based screening examinations are well-validated but minimally scalable. If a DCA replicate paper-based screening, it would improve scalability while benefiting from their extensive validation. METHODS: We developed and evaluated the Rapid Online Cognitive Assessment (RoCA) against gold-standard paper-based tests in patients with a range of cognitive integrity (n = 46). Patient perception of the RoCA was also evaluated with post-examination survey. RESULTS: The RoCA classifies patients similarly to gold standard paper-based tests, with a receiver operating characteristic area under the curve of 0.81 (95%CI 0.67-0.91, p < 0.001). It achieves a sensitivity of 0.94 (95%CI 0.80-1.0, p < 0.001). This was robust to multiple control analyses. 83% of patient respondents reported the RoCA as highly intuitive, with 95% perceiving it as adding value to their care. DISCUSSION: The RoCA may act as a simple and highly scalable cognitive screen ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by MITACS. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been conducted in accordance with the ethical standards. This study was conducted in accordance with ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Approval was achieved by the Research Ethics Board of the Bannatyne Campus, University of Manitoba (#HS25666). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available upon reasonable request.

To develop a scalable solution for dementia testing.

Background In Lewis Carroll’s 1865 novel “Alice’s Adventures in Wonderland”, the protagonist experiences distortions in the size of her body and those of others. This fiction becomes reality in neurological patients with Alice in Wonderland Syndrome (AIWS). Brain lesions causing AIWS may offer unique insights into the syndrome’s elusive neuroanatomy. Methods A systematic literature search identified 37 cases of lesion-induced AIWS. Lesion locations were mapped onto a brain atlas and functional connectivity between each lesion location and other brain regions was estimated using resting-state fMRI data from 1000 healthy subjects. Connections common to AIWS lesions were identified and compared to connections from 1073 lesions associated with 25 other neuropsychiatric disorders. Alignment between this lesion-derived AIWS network and neuroimaging findings from patients with AIWS due to other etiologies was assessed. Results Although AIWS lesions occurred in many different brain locations, these lesions fell within a specific, functionally connected brain network. This network was defined by connectivity to the right extrastriate body area, a brain region selectively activated by viewing body parts, and the inferior parietal cortex, a brain region involved in processing of size and scale. This connectivity pattern was specific to AIWS when compared to lesions causing other neuropsychiatric disorders and aligned with neuroimaging findings in patients with AIWS from other etiologies. Conclusion Lesions causing AIWS fall within a specific brain network defined by connectivity to two distinct brain regions, one region involved in body perception and another in processing of size and scale. ### Competing Interest Statement MDF owns patents on using brain connectivity to guide brain stimulation, and has received investigator-initiated research funding from Neuronetics Inc, which is unrelated to the present work. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This retrospective study is based on 37 cases from the medical literature. The table is included in the manuscript. Case IDAIWS\_TypeDOI / Pubmed identifier (PMID)Foundational search AIWS\_01A10.1186/s12883-020-01970-3Y AIWS\_02B10.21203/rs.3.rs-2090631/v1N AIWS\_03B10.21203/rs.3.rs-2090631/v1N AIWS\_04A10.1007/s00415-012-6827-5Y AIWS\_05B10.1371/journal.pone.0079938Y AIWS\_06A10.1016/j.neuropsychologia.2011.11.018N AIWS\_07B10.1007/s00415-007-0671-zN AIWS\_08A10.1097/WNN.0b013e31826b70deY AIWS\_09A10.1097/WNN.0b013e31826b70deY AIWS\_10B10.1590/0004-282X20190094Y AIWS\_11C10.1080/13554794.2019.1656751Y AIWS\_12B10.1080/13554794.2018.1562079Y AIWS\_13B10.5692/clinicalneurol.cn-001081Y AIWS\_14B10.1016/j.nrl.2016.10.011Y AIWS\_15B10.4103/jnrp.jnrp\_449\_17Y AIWS\_16B10.1007/978-981-10-7668-8\_52Y AIWS\_17B10.1007/s11682-015-9355-yY AIWS\_18B10.1155/2014/272084Y AIWS\_19B10.1016/j.nrl.2014.09.009Y AIWS\_20B10.1016/j.nrl.2014.09.009Y AIWS\_21B10.1016/j.ajem.2012.10.029Y AIWS\_22B10.1016/j.nrl.2010.07.029Y AIWS\_23B10.1016/j.jns.2010.05.015Y AIWS\_24B10.1016/j.jns.2010.05.015Y AIWS\_25B10.1136/jnnp.2006.100842Y AIWS\_26B10.1016/s0028-3932(99)00041-xY AIWS\_27B10.1093/brain/122.2.339Y AIWS\_28B10.1016/S0010-9452(08)70742-1NY AIWS\_29B10.1136/jnnp.57.1.73Y AIWS\_30B10.1136/jnnp.57.1.73Y AIWS\_31CKim YD, Ryu SY, Kim JS, Lee KS. Alice in Wonderland Syndrome in a Case with Infarct in the Right Medial Temporal Lobe. J Korean Neurol Assoc. 2006;24(4):364-366.Y AIWS\_32BPMID: 26111290Y AIWS\_33B10.1136/jnnp.54.1.68N AIWS\_34B10.2169/internalmedicine.8295-16N AIWS\_35B10.1136/jnnp.61.4.420-aN AIWS\_36B10.1016/j.cortex.2020.02.012N AIWS_37A10.1093/brain/awz179N I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Lesion masks in MNI space are available upon request to the corresponding author. The code for lesion connectivity analysis is freely distributed via the Lead-DBS toolbox ([www.lead-dbs.org][1]). The fully preprocessed version of the human resting-state fMRI-derived connectome is publicly available on Harvard Dataverse ( doi:10.7910/DVN/ILXIKS and . [1]: http://www.lead-dbs.org

Structured AbstractINTRODUCTIONThe rising prevalence of dementia necessitates a scalable solution to cognitive screening and diagnosis. Digital cognitive assessments offer a solution but lack the extensive validation of older paper-based tests. Creating a digital cognitive assessment which recreates a paper-based assessment could have the strengths of both tests.METHODSWe developed the Autonomous Cognitive Examination (ACoE), a fully remote and automated digital cognitive assessment which recreates the assessments of paper-based tests. We assessed its ability to reproduce entire cognitive screens in a comparison cohort (n = 35), and the ability to reproduce overall diagnoses with an additional validation cohort (n = 11).RESULTSThe ACoE reproduced overall cognitive assessments with excellent agreement (intraclass correlation coefficient = 0.89) and reproduced overall diagnoses with excellent fidelity (area under the curve = 0.96).DISCUSSIONThe ACoE may reliably reproduce the evaluations of the ACE-3, which may help in accessible evaluation of patient cognition. Assessment in larger population of patients with specific diseases will be necessary to determine usefulness.

OBJECTIVE:To create an open source, web-based platform for aggregating, viewing, and analyzing published case reports of brain lesions. BACKGROUND:Given the recent surge of methodological innovation using human brain lesion data, our objective is to create an open source, web-based platform for aggregating, viewing, and analyzing published case reports containing both brain imaging and clinical evaluation of the patient. DESIGN/METHODS:LesionBank.org provides a user-friendly platform for curated brain lesion reports, allowing search, visualization, and retrieval of lesion images and metadata. The application leverages the Django web-framework and a Postgres database to process user requests and handle the user interface. The application is deployed on a DigitalOcean droplet, and imaging data is stored in an S3-compatible DigitalOcean object space. Currently, the collection includes 163 lesion ROIs and associated lesion network maps that were found from previous published case reports. RESULTS:LesionBank.org has been launched with a viewer and search capabilities based on both textual search of case reports and image-based search of published brain lesion images. To date, the LesionBank.org platform has been used to successfully reproduce primary findings from an already-published study on amnesia (Ferguson, 2019). Additionally, LesionBank.org has been used to support training of several dozen undergraduate research assistants to identify brain lesion case reports of interest, create digital lesion tracings from published, catalog metadata, and relate brain lesions to their underlying functional connectivity. CONCLUSIONS:Science: LesionBank, an open source platform for brain lesion case reports, is able to reproduce brain lesion mapping results from published literature. Education: LesionBank is able to power an asynchronous undergraduate semester research course on clinical neuroscience. Disclosure: Mr. Turner has nothing to disclose. Mr. Suvarna has nothing to disclose. Ms. Chen has nothing to disclose. Mr. Baughan has nothing to disclose. Ms. Bunnell has nothing to disclose. Dr. Howard has received intellectual property interests from a discovery or technology relating to health care. Dr. Howard has a non-compensated relationship as a Founder with KiTH Solutions that is relevant to AAN interests or activities. Dr. Schaper has nothing to disclose. Dr. Ferguson has nothing to disclose. Prof. Nielsen has nothing to disclose.

OBJECTIVE:Alice in Wonderland syndrome (AIWS) profoundly affects human perception of size and scale, particularly regarding one's own body and the environment. Its neuroanatomical basis has remained elusive, partly because brain lesions causing AIWS can occur in different brain regions. Here, we aimed to determine if brain lesions causing AIWS map to a distributed brain network. METHODS:A retrospective case-control study analyzing 37 cases of lesion-induced AIWS identified through systematic literature review was conducted. Using resting-state functional connectome data from 1,000 healthy individuals, the whole-brain connections of each lesion were estimated and contrasted with those from a control dataset comprising 1,073 lesions associated with 25 other neuropsychiatric syndromes. Additionally, connectivity findings from lesion-induced AIWS cases were compared with functional neuroimaging results from 5 non-lesional AIWS cases. RESULTS:AIWS-associated lesions were located in various brain regions with minimal overlap (≤33%). However, the majority of lesions (≥85%) demonstrated shared connectivity to the right extrastriate body area, known to be selectively activated by viewing body part images, and the inferior parietal cortex, involved in size and scale judgements. This pattern was uniquely characteristic of AIWS when compared with other neuropsychiatric disorders (family-wise error-corrected p < 0.05) and consistent with functional neuroimaging observations in AIWS due to nonlesional causes (median correlation r = 0.56, interquartile range 0.24). INTERPRETATION:AIWS-related perceptual distortions map to one common brain network, encompassing regions critical for body representation and size-scale processing. These findings lend insight into the neuroanatomical localization of higher-order perceptual functions, and may inform future therapeutic strategies for perceptual disorders. ANN NEUROL 2024;96:662-674.

The Vietnam Head Injury Study has been curated by Dr Jordan Grafman since the 1980s in an effort to study patients with penetrating traumatic brain injuries suffered during the Vietnam War. Unlike many datasets of ischemic stroke lesions, the VHIS collected extraordinarily deep phenotyping and was able to sample lesion locations that are not constrained to typical vascular territories. For decades, this dataset has helped researchers draw causal links between neuroanatomical regions and neuropsychiatric symptoms. The value of the VHIS has only increased over time as techniques for analyzing the dataset have developed and evolved. Tools such as voxel lesion symptom mapping allowed one to relate symptoms to individual brain voxels. With the advent of the human connectome, tools such as lesion network mapping allow one to relate symptoms to connected brain networks by combining lesion datasets with new atlases of human brain connectivity. In a series of recent studies, lesion network mapping has been combined with the Vietnam Head Injury dataset to identify brain networks associated with spirituality, religiosity, consciousness, memory, emotion regulation, addiction, depression, and even transdiagnostic mental illness. These findings are enhancing our ability to make diagnoses, identify potential treatment targets for focal brain stimulation, and understand the human brain generally. Our techniques for studying brain lesions will continue to improve, as will our tools for modulating brain circuits. As these advances occur, the value of well characterized lesion datasets such as the Vietnam Head Injury Study will continue to grow. This study aims to review the history of the Vietnam Head Injury Study and contextualize its role in modern-day localization of neurological symptoms.

With the burgeoning population of patients with cognitive disorders such as dementia, healthcare is already having significant difficulty in caring for this new population of patients. However, with the last decade's advances in neural networks, it is possible to begin creating software which may aid in healthcare for these patients. Specifically, it may aid in diagnosis, such as in expediting cognitive examinations. Within this paper, we describe a custom neural network utilizing a SqueezeNet which is used to classify a custom dataset of hand-drawn images commonly used in cognitive examinations. We demonstrate that our model has 97% accuracy. Specifically, this enables the development of entire automated and accurate cognitive examinations. The work presented here demonstrates neural networks may assist with healthcare for patients with cognitive disorders, having impact upon the fields of neurology, psychiatry, and family medicine. Importantly, within the context of the COVID-19 pandemic restricting in-person visits and promoting telemedicine, this provides the foundations to transition cognitive examinations to a telemedicine modality.

Brain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS-induced effects. We studied 53 amnesia-causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1-year post-DBS activation scores. Connectivity between AD patients' DBS sites and a subiculum region derived from amnesia-causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham-first (Spearman’s rho = 0.33, p = 0.027) and stimulation-first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole-brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p<0.00001). Both maps showed data-driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data-driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value. Our findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix-targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.

With the burgeoning population of patients with cognitive disorders such as dementia, healthcare is already having significant difficulty in caring for this new population of patients. However, with the last decade’s advances in neural networks, it is possible to begin creating software which may aid in healthcare for these patients. Specifically, it may aid in diagnosis, such as in expediting cognitive examinations. Within this paper, we describe a custom neural network utilizing a SqueezeNet which is used to classify a custom dataset of hand-drawn images commonly used in cognitive examinations. We demonstrate that our model has 97% accuracy. Specifically, this enables the development of entire automated and accurate cognitive examinations. The work presented here demonstrates neural networks may assist with healthcare for patients with cognitive disorders, having impact upon the fields of neurology, psychiatry, and family medicine. Importantly, within the context of the COVID-19 pandemic restricting in-person visits and promoting telemedicine, this provides the foundations to transition cognitive examinations to a telemedicine modality.

The objectives of this study is to create the foundation for an automated computerized cognitive examination. Further, the second objective was to train subcomponents of the cognitive examination to be graded by deep-learning methods.

Noisy stimuli may hold the key for optimal electrical stimulation of the nervous system. Possible mechanisms of noise's impact upon neuronal function are discussed, including intracellular, extracellular, and systems-level mechanisms. Specifically, channel resonance, stochastic resonance, high conductance states, and network binding are investigated. These mechanisms are examined and possible directions of growth for the field are discussed, with examples of applications provided from the fields of deep brain stimulation or spinal cord injury. Together, this review highlights the theoretical basis and evidence base for the use of noise to enhance current stimulation paradigms of the nervous system.

The Canadian healthcare system serves as an example of equity and federal service to citizens across the world. However, it is not without its challenges. Prosthetic coverage across Canada is highly variable and largely unable to provide equal coverage for Canadian persons living with amputation. Many persons with limb loss are forced to rely upon personal resources, fundraising, or the charity of non-governmental organizations in order to meet this basic healthcare need. This disparity in the Canadian healthcare system is unusual and largely undescribed in the literature. We thus explore the nature of Canadian healthcare prosthetic coverage across Canada, investigating the variability in coverage, presence of prosthetic coverage policies, clarity of policy, eligibility criteria, and interval of prosthetic replacement. Our findings highlight potential areas for improvement within current Canadian healthcare policy.