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Neurologic evidence, including MRI, PET, and EEG, has been introduced in more than 2,800 criminal cases in the past decade, including 12% of all murder trials and 25% of death penalty trials, to argue whether neurologic diseases are present, contribute to criminal behavior, and ultimately whether the defendant is less criminally responsible, competent to stand trial, or should receive a reduced punishment for his or her crime. Unfortunately, neurologists are often not involved in these criminal cases despite being the medical specialty with the most relevant training and expertise to address these issues for the court. Reasons for the absence of neurologists in criminal cases include a lack of awareness from lawyers, judges, and other expert witnesses on the value of including neurologists in forensic evaluations, and the lack of experience, training, and willingness of neurologists to work as expert witnesses in criminal cases. Here, we discuss forensic neurology, a field bridging the gap between neurology, neuroscience, and the law. We discuss the process of performing forensic evaluations, including answering 3 fundamental questions: the neurologic diagnostic question, the behavioral neurology/neuropsychiatry question, and the forensic neurology question. We discuss practical aspects of performing forensic expert witness work and important ethical differences between the neurologist's role in treatment vs forensic settings. Finally, we discuss the currently available pathways for interested neurologists to receive additional training in forensic assessments.
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Medicina Legal , Neurología , Humanos , Neurología/educación , Medicina Legal/educación , Testimonio de Experto , NeurólogosRESUMEN
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.
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Demencia Frontotemporal , Teléfono Inteligente , Humanos , Femenino , Masculino , Persona de Mediana Edad , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/fisiopatología , Anciano , Índice de Severidad de la Enfermedad , Prueba de Estudio Conceptual , Adulto , Estudios Longitudinales , Pruebas Neuropsicológicas , Aplicaciones MóvilesRESUMEN
Forensic psychiatrists may be asked to opine on neurological evidence or neurological diseases outside the scope of their expertise. This article discusses the value of involving experts trained in behavioral neurology in such cases. First, we describe the field of behavioral neurology and neuropsychiatry, the subspecialty available to both neurologists and psychiatrists focused on the behavioral, cognitive, and neuropsychiatric manifestations of neurological diseases. Next, we discuss the added value of behavioral neurologists in forensic cases, including assisting in the diagnostic evaluation for complex neuropsychiatric diseases, using expertise in localization to provide a strong scientific basis for linking neurodiagnostic testing to relevant neuropsychiatric symptoms, and assisting in relating these symptoms to the relevant legal question in cases where such symptoms may be less familiar to forensic psychiatrists, such as frontal lobe syndromes. We discuss approaches to integrating behavioral neurology with forensic psychiatry, highlighting the need for collaboration and mentorship between disciplines. Finally, we discuss several forensic cases highlighting the additional value of experts trained in behavioral neurology. We conclude that forensic psychiatrists should involve behavioral neurology experts when encountering neurological evidence that falls outside their scope of expertise, and the need for further cross-disciplinary collaboration and training.
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Psiquiatría Forense , Neurólogos , Humanos , Neurología , Enfermedades del Sistema Nervioso/diagnóstico , Rol del Médico , Trastornos Mentales/diagnóstico , Masculino , Testimonio de ExpertoRESUMEN
Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Cohortes , Demencia Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/patología , Degeneración Lobar Frontotemporal/psicología , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados , Teléfono Inteligente , Ensayos Clínicos como AsuntoRESUMEN
Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
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OBJECTIVE: Patients with Alzheimer's disease (AD) have diffuse brain atrophy, but some regions, such as the anterior cingulate cortex (ACC), are spared and may even show increase in size compared to controls. The extent, clinical significance, and mechanisms associated with increased cortical thickness in AD remain unknown. Recent work suggested neural facilitation of regions anticorrelated to atrophied regions in frontotemporal dementia. Here, we aim to determine whether increased thickness occurs in sporadic AD, whether it relates to clinical symptoms, and whether it occur in brain regions functionally connected to-but anticorrelated with-locations of atrophy. METHODS: Cross-sectional clinical, neuropsychological, and neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed to investigate cortical thickness in AD subjects versus controls. Atrophy network mapping was used to identify brain regions functionally connected to locations of increased thickness and atrophy. RESULTS: AD patients showed increased thickness in the ACC in a region-of-interest analysis and the visual cortex in an exploratory analysis. Increased thickness in the left ACC was associated with preserved cognitive function, while increased thickness in the left visual cortex was associated with hallucinations. Finally, we found that locations of increased thickness were functionally connected to, but anticorrelated with, locations of brain atrophy (r = -0.81, p < 0.05). INTERPRETATION: Our results suggest that increased cortical thickness in Alzheimer's disease is relevant to AD symptoms and preferentially occur in brain regions functionally connected to, but anticorrelated with, areas of brain atrophy. Implications for models of compensatory neuroplasticity in response to neurodegeneration are discussed. ANN NEUROL 2024;95:929-940.
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Enfermedad de Alzheimer , Atrofia , Imagen por Resonancia Magnética , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Atrofia/patología , Estudios Transversales , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Anciano de 80 o más Años , Giro del Cíngulo/patología , Giro del Cíngulo/diagnóstico por imagen , Grosor de la Corteza Cerebral , Persona de Mediana EdadRESUMEN
Neurological evidence is increasingly used in criminal cases to argue that a defendant is less responsible for their behaviour, is not competent to stand trial or should receive a reduced punishment for the crime. Unfortunately, neurologists are rarely involved in such cases despite having the expertise to help to inform these decisions in court. In this Perspective, we advocate for the development of 'forensic neurology', a subspecialty of neurology focused on using neurological clinical and scientific expertise to address legal questions for the criminal justice system. We review literature suggesting that the incidence of criminal behaviour is higher in people with certain neurological disorders than the general public and that undiagnosed neurological abnormalities are common in people who commit crimes. We discuss the need for forensic neurologists in criminal cases to provide an opinion on what neurological diagnoses are present, the resulting symptoms and ultimately whether the symptoms affect legal determinations such as criminal responsibility or competency.
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Trastornos Mentales , Neurología , HumanosRESUMEN
Antisocial behavior may develop in otherwise normal persons as a result of neurological diseases, including patients with focal brain lesions, frontotemporal dementia, and Parkinson Disease patients taking dopamine agonist medications. Evidence from these neurological patients demonstrates that antisocial behaviors relate to dysfunction in several different brain regions that form a specific brain network, rather than any single location alone. This network associated with acquired antisocial behavior is involved in social decision-making (measured using moral decision-making tasks) and value-based decision-making (measured using neuroeconomic and reward-based tasks). Collectively, this work supports the hypothesis that antisocial behavior across different neurological diseases results from dysfunction within a common network of brain regions associated with social valuation and decision-making, providing insight into the neural mechanisms leading to acquired antisocial behavior. These findings have important implications, but also important limitations, for understanding criminal behavior in patients with psychopathy, for rehabilitation in criminals, for ethical discussions regarding moral and legal responsibility, and for forensic neurological evaluations in persons accused of crimes.
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Trastorno de Personalidad Antisocial , Demencia Frontotemporal , Humanos , Terapia Conductista , Encéfalo , DopaminaRESUMEN
OBJECTIVE: Antisocial behaviors are common and problematic among patients with behavioral variant frontotemporal dementia (bvFTD). In the present study, the investigators aimed to validate an informant-based questionnaire developed to measure the extent and severity of antisocial behaviors among patients with dementia. METHODS: The Social Behavior Questionnaire (SBQ) was developed to measure 26 antisocial behaviors on a scale from absent (0) to very severe (5). It was administered to 23 patients with bvFTD, 19 patients with Alzheimer's disease, and 14 patients with other frontotemporal lobar degeneration syndromes. Group-level differences in the presence and severity of antisocial behaviors were measured. Psychometric properties of the SBQ were assessed by using Cronbach's alpha, exploratory factor analysis, and comparisons with a psychopathy questionnaire. Cluster analysis was used to determine whether the SBQ identifies different subgroups of patients. RESULTS: Antisocial behaviors identified by using the SBQ were common and severe among patients with bvFTD, with at least one such behavior endorsed for 21 of 23 (91%) patients. Antisocial behaviors were more severe among patients with bvFTD, including the subsets of patients with milder cognitive impairment and milder disease severity, than among patients in the other groups. The SBQ was internally consistent (Cronbach's α=0.81). Exploratory factor analysis supported separate factors for aggressive and nonaggressive behaviors. Among the patients with bvFTD, the factor scores for aggressive behavior on the SBQ were correlated with those for antisocial behavior measured on the psychopathy scale, but the nonaggressive scores were not correlated with psychopathy scale measures. The k-means clustering analysis identified a subset of patients with severe antisocial behaviors. CONCLUSIONS: The SBQ is a useful tool to identify, characterize, and measure the severity of antisocial behaviors among patients with dementia.
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BACKGROUND: Anosognosia can manifest as an unawareness of neurobehavioral symptoms in individuals with Huntington disease (HD). Measurement of anosognosia is challenging, but the Anosognosia Scale (AS) represents a brief option with promising findings in small samples. OBJECTIVE: To replicate application of the AS in a larger HD sample than previous studies in order to assess psychometrics and demographic correlates and to investigate the genetic, motor, and neuropsychological correlates of the AS in individuals with HD. METHOD: We retrospectively reviewed the AS ratings of 74 genetically confirmed Huntington gene carriers, nearly all early motor manifest, who had been referred for clinical neuropsychological assessment. Concurrent clinical neurologic examination and neuropsychometric assessment data were compiled, where available (ns = 35-74). The severity of the anosognosia per AS ratings was characterized for the HD sample. RESULTS: The AS ratings did not correlate with demographic variables, genetic markers, or motor dysfunction severity. Correlation analyses revealed that higher AS ratings correlated with worse recognition-discrimination memory performance (r = 0.38, P < 0.05) but not cognitive control on executive functioning performance or on collateral-reported frontal-behavioral symptoms. Higher AS ratings also correlated with fewer patient-reported depressive symptoms (r = -0.38, P < 0.01) and diurnal hypersomnia symptoms (r = -0.44, P < 0.01). CONCLUSION: Anosognosia (per AS) is associated with recognition-discrimination deficits and fewer self-reported neuropsychiatric symptoms in individuals with pre-to-early manifest HD, though not with HD severity per genetic or motor markers, nor to executive dysfunction or collateral-reported frontal-behavioral symptoms.
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Agnosia , Disfunción Cognitiva , Enfermedad de Huntington , Agnosia/diagnóstico , Disfunción Cognitiva/complicaciones , Función Ejecutiva , Humanos , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/genética , Pruebas Neuropsicológicas , Estudios RetrospectivosRESUMEN
Unlawful behaviors have been reported in association with Huntington's disease (HD), although their overall prevalence and clinical significance remain unknown. Recognition of problematic behavior is limited by stigma and lack of routine clinical assessment, as well as the absence of validated screening measures. We performed a retrospective chart review of 289 patients treated for HD at Vanderbilt University Medical Center from 2006 to 2020 to assess the frequency of illegal activity in our HD population. We identified 31 patients with HD who have a documented history of unlawful behavior, comprising 11 percent of the charts reviewed. Physical violence was the most common behavior reported, followed by reckless driving, substance abuse, illegal financial activity, and inappropriate sexual behavior. Mean age at the time of the first offense was 37 years. Patients with criminal offenses were more likely to be male and in the early stages of disease with associated psychiatric symptoms. Our results emphasize that illegal activities are a significant clinical problem in individuals with HD, particularly young adult males with comorbid psychiatric symptoms. These findings highlight the need for improved screening measures to detect high-risk behaviors in individuals with HD, as well as evidence-based protocols to guide triage and management of patients engaging in potentially detrimental activities.
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Enfermedad de Huntington , Trastornos Relacionados con Sustancias , Comorbilidad , Femenino , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Masculino , Prevalencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Risky behaviors are common in Huntington's disease (HD) and can lead to significant adverse consequences. However, the prevalence and scope of these symptoms have not been studied systematically, and no empirically validated measures are available to screen for them. OBJECTIVE: To test a novel screening tool designed to assess risk-taking behaviors in HD. METHODS: We administered the Risk Behavior Questionnaire (RBQ-HD) to HD patients and caregivers at Vanderbilt University Medical Center between 2018-2019. Patients completed the questionnaire based on self-report; caregivers provided collateral reports. Clinical and demographic information were obtained from the electronic medical record. RESULTS: 60 patients and 60 caregivers completed the RBQ-HD. 80% of patients (nâ=â48) and 91.7% of caregivers (nâ=â60) reported at least one risky behavior. Adverse social behaviors, impulsive/compulsive behaviors, and reckless driving were the most common behavioral domains reported. Male patients were more likely to report risky behaviors than females (92.3% vs. 70.6%, pâ=â0.04). The number of risky behaviors reported by patients and caregivers was negatively correlated with patient age (râ=â-0.32, pâ=â0.01; râ=â-0.47, pâ=â0.0001, respectively). Patient and caregiver reports were highly correlated in matched pairs (nâ=â30; râ=â0.63, pâ=â0.0002). CONCLUSION: These findings emphasize that risky behaviors are highly prevalent in HD and can be effectively identified through the use of a novel screening measure. We hypothesize that early pathological involvement of frontostriatal and mesolimbic networks may be important factors in the development of these behaviors.
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Conducción de Automóvil , Conducta Compulsiva , Enfermedad de Huntington/psicología , Conducta Impulsiva , Asunción de Riesgos , Conducta Social , Trastornos Relacionados con Sustancias , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Conducción Agresiva , Cuidadores , Femenino , Humanos , Enfermedad de Huntington/fisiopatología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Autoinforme , Factores SexualesRESUMEN
There is both clinical and neuroanatomical variability at the single-subject level in Alzheimer's disease, complicating our understanding of brain-behaviour relationships and making it challenging to develop neuroimaging biomarkers to track disease severity, progression, and response to treatment. Prior work has shown that both group-level atrophy in clinical dementia syndromes and complex neurological symptoms in patients with focal brain lesions localize to brain networks. Here, we use a new technique termed 'atrophy network mapping' to test the hypothesis that single-subject atrophy maps in patients with a clinical diagnosis of Alzheimer's disease will also localize to syndrome-specific and symptom-specific brain networks. First, we defined single-subject atrophy maps by comparing cortical thickness in each Alzheimer's disease patient versus a group of age-matched, cognitively normal subjects across two independent datasets (total Alzheimer's disease patients = 330). No more than 42% of Alzheimer's disease patients had atrophy at any given location across these datasets. Next, we determined the network of brain regions functionally connected to each Alzheimer's disease patient's location of atrophy using seed-based functional connectivity in a large (n = 1000) normative connectome. Despite the heterogeneity of atrophied regions at the single-subject level, we found that 100% of patients with a clinical diagnosis of Alzheimer's disease had atrophy functionally connected to the same brain regions in the mesial temporal lobe, precuneus cortex, and angular gyrus. Results were specific versus control subjects and replicated across two independent datasets. Finally, we used atrophy network mapping to define symptom-specific networks for impaired memory and delusions, finding that our results matched symptom networks derived from patients with focal brain lesions. Our study supports atrophy network mapping as a method to localize clinical, cognitive, and neuropsychiatric symptoms to brain networks, providing insight into brain-behaviour relationships in patients with dementia.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Conectoma/métodos , Anciano , Anciano de 80 o más Años , Atrofia/diagnóstico por imagen , Atrofia/patología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma-specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole-brain voxel-wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.
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Tronco Encefálico/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/lesiones , Traumatismos Penetrantes de la Cabeza/diagnóstico por imagen , Traumatismos Penetrantes de la Cabeza/fisiopatología , Inconsciencia/diagnóstico por imagen , Adulto , Anciano , Mapeo Encefálico , Corteza Cerebral/fisiopatología , Claustro/diagnóstico por imagen , Claustro/fisiopatología , Coma , Conectoma , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Valor Predictivo de las Pruebas , Inconsciencia/fisiopatología , Veteranos , Guerra de VietnamRESUMEN
BACKGROUND: Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results. METHODS: Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression. RESULTS: Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression. CONCLUSIONS: Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.
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Encéfalo/patología , Trastorno Depresivo/fisiopatología , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Adulto , Anciano , Encéfalo/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Conectoma , Depresión , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Human memory is thought to depend on a circuit of connected brain regions, but this hypothesis has not been directly tested. We derive a human memory circuit using 53 case reports of strokes causing amnesia and a map of the human connectome (n = 1000). This circuit is reproducible across discovery (n = 27) and replication (n = 26) cohorts and specific to lesions causing amnesia. Its hub is at the junction of the presubiculum and retrosplenial cortex. Connectivity with this single location defines a human brain circuit that incorporates > 95% of lesions causing amnesia. Lesion intersection with this circuit predicts memory scores in two independent datasets (N1 = 97, N2 = 176). This network aligns with neuroimaging correlates of episodic memory, abnormalities in Alzheimer's disease, and brain stimulation sites reported to enhance memory in humans.
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Amnesia/patología , Encéfalo/patología , Conectoma , Memoria/fisiología , Red Nerviosa/patología , Adulto , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Amnesia/diagnóstico por imagen , Amnesia/etiología , Encéfalo/diagnóstico por imagen , Conjuntos de Datos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patologíaRESUMEN
Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.
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Encéfalo/patología , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Tortícolis/fisiopatología , Adulto , Anciano , Ganglios Basales/fisiopatología , Encéfalo/fisiopatología , Cerebelo/fisiopatología , Estudios de Cohortes , Conectoma/métodos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
In response to Dr. Corlett's paper regarding the two factor theory of delusional misidentifications, I discuss further evidence that VMPFC damaged patients do not have an isolated factor 1 defect. I then discuss more broadly the limitations in the modular view of brain function that leads to the 2-factor theory. Finally, I propose a connectionist based interpretation of delusional misidentifications that better fits with the clinical data from patients with focal brain lesions showing how these lesion locations relate to complex brain networks.
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Deluciones , Lóbulo Frontal , Encéfalo , Humanos , Reconocimiento en PsicologíaRESUMEN
BACKGROUND: Psychosis is common in Parkinson's disease-related disorders and is associated with significant morbidity. Pimavanserin is a newly approved treatment for Parkinson's disease psychosis, but real-world experience with pimavanserin has been limited by small sample sizes and limited assessment of longitudinal outcomes. OBJECTIVE: The aim was to summarize the clinical experience with pimavanserin in a large cohort of patients with Parkinson's disease-related psychosis. METHODS: We conducted a retrospective chart review of patients who were prescribed pimavanserin at Vanderbilt University Medical Center in the southeast United States between May 2016 and July 2018. We used Chi-squared analyses to compare efficacy and tolerability of pimavanserin, considering patient diagnosis, presence of dementia or delusions, use of deep brain stimulation, and prior antipsychotic failure. Additionally, we compared the clinical characteristics of patients who started treatment and those who did not, to evaluate safety outcomes. RESULTS: We identified 107 patients prescribed pimavanserin, and 91 began treatment. Clinical improvement in psychosis was documented in 76% of patients (69/91) and did not differ based on diagnosis, presence of dementia, delusions, use of deep brain stimulation, or prior antipsychotic failure. Adverse effects were reported in 20 patients (22%), the most common of which was worsening gait instability (5/91, 5%). Side effects led to cessation of therapy in 11 of the 91 patients (12%). At current follow-up, 50 (65%) of 77 living patients remain on treatment, with a mean treatment duration of 14.6 months. Although most of these patients are on pimavanserin monotherapy (33/50, 66%), 17 patients (34%) are on a dual-antipsychotic regimen. The living patients no longer on treatment stopped pimavanserin primarily because of a lack of perceived benefit (11/77, 14%), side effects (9/77, 12%), or both (1/77, 1%), though six patients (8%) stopped for reasons unrelated to medication effects, including the desire to reduce overall medication burden and negative media reporting on pimavanserin. CONCLUSIONS: Study results emphasize long-term efficacy and tolerability of pimavanserin for psychosis in Parkinson's disease-related disorders, including patients with dementia, delusions, deep brain stimulation use, or prior antipsychotic failure.