A neural circuit for spatial orientation derived from brain lesions.

There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal, and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions.

Network Localization of Awareness in Visual and Motor Anosognosia.

OBJECTIVE: Unawareness of a deficit, anosognosia, can occur for visual or motor deficits and lends insight into awareness itself; however, lesions associated with anosognosia occur in many different brain locations. METHODS: We analyzed 267 lesion locations associated with either vision loss (with and without awareness) or weakness (with and without awareness). The network of brain regions connected to each lesion location was computed using resting-state functional connectivity from 1,000 healthy subjects. Both domain specific and cross-modal associations with awareness were identified. RESULTS: The domain-specific network for visual anosognosia demonstrated connectivity to visual association cortex and posterior cingulate while motor anosognosia was defined by insula, supplementary motor area, and anterior cingulate connectivity. A cross-modal anosognosia network was defined by connectivity to the hippocampus and precuneus (false discovery rate p < 0.05). INTERPRETATION: Our results identify distinct network connections associated with visual and motor anosognosia and a shared, cross-modal network for awareness of deficits centered on memory-related brain structures. ANN NEUROL 2023;94:434-441.

Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

Morality and the Brain: The Right Hemisphere and Doing Right.

Morality, the set of shared attitudes and practices that regulate individual behavior to facilitate cohesion and well-being, is a function of the brain, yet its localization is uncertain. Neuroscientific study of morality has been conducted by examining departures from moral conduct after neurologic insult and by functional neuroimaging of moral decision-making in cognitively intact individuals. These investigations have yielded conflicting results: Acquired sociopathy, a syndromic surrogate for acquired immorality, has been reported predominantly after right frontotemporal lesions, whereas functional neuroimaging during moral decision-making has demonstrated bilateral activation. Although morality is bilaterally represented, the right hemisphere is clinically more critical in light of focal lesion data suggesting that moral behavior is subserved by a network of right frontotemporal structures and their subcortical connections. Evolution may have endowed the brain with bilaterally represented but unilaterally right-dominant morality. The unilateral dominance of morality permits concentration of an essential social cognitive function to support the perceptual and executive operations of moral behavior within a single hemisphere; the bilateral representation of morality allows activation of reserve tissue in the contralateral hemisphere in the event of an acquired hemispheric injury. The observed preponderance of right hemisphere lesions in individuals with acquired immorality offers a plausible hypothesis that can be tested in clinical settings. Advances in the neuroscience of morality promise to yield potentially transformative clinical and societal benefits. A deeper understanding of morality would help clinicians address disordered conduct after acquired neurologic insults and guide society in bolstering public health efforts to prevent brain disease.

Multiple sclerosis lesions that impair memory map to a connected memory circuit.

BACKGROUND: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. METHODS: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. RESULTS: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. CONCLUSIONS: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

Gender disparity and abuse in functional movement disorders: a multi-center case-control study.

BACKGROUND: To determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history. METHODS: We performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence. RESULTS: Higher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval 2.31-9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval 1.53-5.12; p = 0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05-0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites. CONCLUSIONS: Our study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider.

Psychiatric Comorbidities in Functional Movement Disorders: A Retrospective Cohort Study.

BACKGROUND: Functional movement disorders (FMD) are characterized by abnormal movements and motor symptoms incongruent with a known structural neurologic cause. While psychological stressors have long been considered an important risk factor for developing FMD, little is known about the impact of psychiatric comorbidities on disease manifestations or complexity. OBJECTIVES: To compare characteristics of FMD patients with co-occurring mood and trauma-related psychiatric conditions to FMD patients without psychiatric conditions. METHODS: We performed a retrospective cohort study of patients seen in the University of Colorado Health system between January 1, 2015 and December 31, 2019. Patients were included if they had a diagnosis of FMD, determined by ICD-10 coding and ≥1 phenomenology-related diagnostic code (tremor, gait disturbances, ataxia, spasms, and weakness), and at least one encounter with a neurology specialist. Fisher's exact and unpaired t-tests were used to compare demographics, healthcare utilization, and phenomenologies of patients with psychiatric conditions to those with none. RESULTS: Our review identified 551 patients with a diagnosis of FMD who met inclusion criteria. Patients with psychiatric conditions (N = 417, 75.7%) had increased five-year healthcare utilization (mean emergency room encounters 9.9 vs. 3.5, P = 0.0001) and more prevalent non-epileptic seizures (18.2% vs. 7.5%, P = 0.001). Suicidal ideation (8.4%) and self-harm (4.1%) were only observed amongst patients with comorbid psychiatric conditions. CONCLUSIONS: Patients with FMD and comorbid psychiatric conditions require more healthcare resources and have greater disease complexity than patients without psychiatric illness. This may have implications for treatment of patients without comorbid psychiatric conditions who may benefit from targeted physiotherapy alone.

Skin-brain axis signaling mediates behavioral changes after skin wounding.

Patients with chronic wounds often have associated cognitive dysfunction and depression with an as yet unknown mechanism for this association. To address the possible causality of skin wounding inducing these changes, behavior and cognitive functions of female C57BL/6 mice with an excisional skin wound were compared to unwounded animals. At six days post wounding, animals exhibited anxiety-like behaviors, impaired recognition memory, and impaired coping behavior. Wounded animals also had concomitant increased hippocampal expression of Tnfa, the pattern recognition receptor (PRR) Nod2, the glucocorticoid receptors GR/Nr3c1 and Nr3c2. Prefrontal cortex serotonin and dopamine turnover were increased on day six post-wounding. In contrast to the central nervous system (CNS) findings, day six post -wounding serum catecholamines did not differ between wounded and unwounded animals, nor did levels of the stress hormone corticosterone, TNFα, or TGFß. Serum IL6 levels were, however elevated in the wounded animals. These findings provide evidence of skin-to-brain signaling, mediated either by elevated serum IL6 or a direct neuronal signaling from the periphery to the CNS, independent of systemic mediators. Wounding in the periphery is associated with an altered expression of inflammatory mediators and PRR genes in the hippocampus, which may be responsible for the observed behavioral deficits.

Gender as a Risk Factor for Functional Movement Disorders: The Role of Sexual Abuse.

BACKGROUND: The prevalence of functional movement disorders is 2 to 3 times higher in women than in men. Trauma and adverse life events are important risk factors for developing functional movement disorders. On a population level, rates of sexual abuse against women are higher when compared with the rates against men. OBJECTIVES: To determine gender differences in rates of sexual abuse in functional movement disorders compared with other neurologic disorders and evaluate if the gender prevalence is influenced by higher rates of sexual abuse against women. METHODS: We performed a case-control series including 199 patients with functional movement disorders (149 women) and 95 controls (60 women). We employed chi-squared test to assess gender and sexual abuse associations and Bayes formula to condition on sexual abuse. RESULTS: Our analysis showed an association between sexual abuse and functional movement disorders in women (odds ratio, 4.821; 95% confidence interval, 2.089-12.070; P < 0.0001), but not men. Bayesian analysis found the functional movement disorder prevalence ratio between women and men conditional on sexual abuse to be 4.87 times the unconditioned ratio. CONCLUSIONS: There is a statistically significant association between sexual abuse and functional movement disorders in women and a greater likelihood that women who are sexually abused will develop functional movement disorders than men who are sexually abused. Our findings suggest that the increased prevalence of functional movement disorders in women is associated, at least in part, with sexual abuse and its sequelae; however, further research is needed to explore the role of other traumatic and nontraumatic factors.

Subjective cognitive concern in multiple sclerosis is associated with reduced thalamic and cortical gray matter volumes.

OBJECTIVE: Brain atrophy has been correlated with objective cognitive dysfunction in multiple sclerosis but few studies have explored self-reported subjective cognitive concerns and their relationship to brain volume changes. This study explores the relationship between subjective cognitive concerns in multiple sclerosis and reduced brain volume in regions of interest implicated in cognitive dysfunction. METHODS: A total of 158 patients with multiple sclerosis completed the Quality of Life in Neurologic Disorders Measures (Neuro-QoL) short forms to assess subjective cognitive concerns and underwent brain magnetic resonance imaging. Regional brain volumes from regions of interest implicated in cognitive dysfunction were measured using NeuroQuant automated volumetric quantitation. Linear regression was used to analyze the relationship between subjective cognitive concerns and brain volume. RESULTS: Controlling for age, disease duration, gender, depression and fatigue, increased subjective cognitive concerns were associated with reduced thalamic volume (standardized ß = 0.223, t150 =2.406, P = 0.017) and reduced cortical gray matter volume (standardized ß = 0.240, t150 = 2.777, P = 0.006). Increased subjective cognitive concerns were not associated with any other regions of interest that were analyzed. CONCLUSIONS: Subjective cognitive concern in MS is associated with reduced thalamic and cortical gray matter volumes, areas of the brain that have been implicated in objective cognitive impairment. These findings may lend neuroanatomical significance to subjective cognitive concerns and patient-reported outcomes as measured by Neuro-QoL.