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.

Cognitive Function Remains Associated With Functional Impairment in Profound Dementia: Alzheimer Disease and Dementia With Lewy Bodies.

Background and Objectives: The Baylor Profound Mental Status Examination (BPMSE) was developed to assess cognitive function in the profound stage of dementia. The Clinical Dementia Rating (CDR) scale has been widely used in measuring functional performance in dementia. We aimed to determine whether cognitive function is related to overall functional impairment in profound dementia. Methods: We selected 864 patients with probable Alzheimer disease (AD) and 25 patients with possible dementia with Lewy Bodies (DLB) cases with profound dementia by Mini-Mental Status Examination or/and clinical global impression. We used BPMSE to measure cognitive function and the CDR sum-of-boxes (CDR-SB) score to determine overall functional status. We used Spearman rank order correlation to examine the univariate association between CDR-SB and BPMSE in the 2 diagnostic groups separately and multivariable regression analysis to investigate whether BPMSE remained associated with functional status after adjustment for age, sex, education, and APOE ε4 genotype. We expected to see an inverse correlation between BPMSE and CDR-SB scores based on the directionality of the rating scale scoring. Results: In both AD and DLB, total BPMSE scores had a significant inverse correlation with CDR-SB scores (AD: r = -0.453, p < 0.001; DLB: r = -0.489, p = 0.013). It is of interest that in DLB, the "attention" domain of BPMSE had the strongest association with CDR-SB (r = -0.700, p < 0.001) compared with other domains. The multivariable regression models showed that higher BPMSE scores (i.e., better cognitive function) remained significantly correlated with lower CDR-SB scores (i.e., better global function) in AD (CDR-SB: ß = -0.340, p < 0.001), but the regression coefficient for BPMSE did not reach significance in the DLB model (CDR-SB: ß = -0.298, p = 0.174). Discussion: In patients with AD and DLB who enter the profound dementia stage, cognitive function is associated with the severity of functional impairment. The lack of significance for DLB in multivariable regression could be due to small sample size because the correlation magnitude is similar to that in AD.

Fatigue Impacts Quality of Life in People with Spinocerebellar Ataxias.

BACKGROUND: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. OBJECTIVES: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. METHODS: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. RESULTS: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. CONCLUSIONS: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

Cognitive, Emotional, and Other Non-motor Symptoms of Spinocerebellar Ataxias.

PURPOSE OF REVIEW: Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive and behavioral symptoms of SCAs in the context of recent knowledge of the role of the cerebellum in higher intellectual function. RECENT FINDINGS: Recent studies suggest that patients with spinocerebellar ataxia can display cognitive deficits even early in the disease. These have been given the term cerebellar cognitive affective syndrome (CCAS). CCAS can be tracked using newly developed rating scales. In addition, patients with spinocerebellar ataxia also display impulsive and compulsive behavior, depression, anxiety, fatigue, and sleep disturbances. This review stresses the importance of recognizing non-motor symptoms in SCAs. There is a pressing need for novel therapeutic interventions to address these symptoms given their deleterious impact on patients' quality of life.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

The Role of the Cerebellum in Learning to Predict Reward: Evidence from Cerebellar Ataxia.

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward.

Ataxias: Hereditary, Acquired, and Reversible Etiologies.

A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.

Gambling associated risk-taking decision in cerebellar ataxia.

INTRODUCTION: People with cerebellar ataxia (CA) can develop impulsive and compulsive behaviors that significantly affect their and their family's quality of life. To further assess the decision-making process associated with these behaviors, we used the Iowa Gambling Task (IGT) to study people with CA. METHODS: Sixty individuals with CA and thirty age-matched controls were enrolled in the study to complete the IGT. No participants had a prior or comorbid neurologic or psychiatric disorder associated with impulsivity. IGT performance in each of the five 20-trial blocks was compared between groups and the progression of participants' performance was assessed with simple linear regression models. Subgroup analyses were performed with genetic and non-genetic CA cases. RESULTS: CA cases obtained significantly lower IGT total scores than controls (-5.30 ± 37.53 vs. 21.30 ± 37.37, p = 0.004). In addition, those with CA made riskier decisions throughout the task compared to controls. Although both CA and controls learned to make decisions with more favorable outcomes over the course of completing the IGT, CA participants never matched the controls' performance. IGT performance did not correlate with ataxia severity or depressive symptoms. CONCLUSION: The IGT may capture a unique behavioral symptom of CA. Future studies may help elucidate the mechanisms underlying impaired decision-making in CA and further the understanding of a broader spectrum of cerebellar cognitive affective syndrome.

Cerebellar impulsivity-compulsivity assessment scale.

OBJECTIVE: The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively measure ICBs in cerebellar disorders, we aim to develop and validate a new scale, Cerebellar Impulsivity-Compulsivity Assessment (CIA). METHODS: We recruited 62 cerebellar ataxia cases, categorized into those with ICBs and those without. We developed a preliminary version of CIA, containing 17 questions. We studied the internal consistency, test-retest reliability, and inter-rater reliability to formulate the final version of CIA, which constitutes only 10 questions. The receiver operating characteristic curve (ROC) was generated to assess the sensitivity and specificity of CIA. RESULTS: Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test-retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity. INTERPRETATION: CIA is a novel tool to assess ICBs in cerebellar ataxia and broaden our understanding of the cerebellum-related cognitive and behavioral symptoms.

Clinicopathological correlates of pyramidal signs in multiple system atrophy.

OBJECTIVE: Pyramidal signs are common but often under-recognized in multiple system atrophy (MSA). The clinicopathological correlates of pyramidal signs in MSA are not well characterized. The present study aims to understand the role of pyramidal signs in MSA. METHODS: We examined 40 autopsy-confirmed MSA cases in New York Brain Bank. The pyramidal signs were quantified by an established rating scale, summarized as the pyramidal score. We assessed whether pyramidal scores are associated with autonomic, parkinsonism, and cerebellar features and survival. We also examined whether the density of glial cytoplasmic inclusions (GCIs) in the motor cortex and its underlying white matter is associated with the pyramidal score. RESULTS: MSA parkinsonian type cases have higher pyramidal scores compared to cerebellar type cases (p = 0.017). MSA cases with high pyramidal scores are more likely to have laryngeal stridor (OR = 4.89, p = 0.022), but less likely to have orthostatic hypotension (OR = 0.11, p = 0.006) and erectile dysfunction (OR = 0.05, p = 0.018). MSA cases with high pyramidal scores do not differ from those with low pyramidal scores in terms of bowel dysfunction, dry eyes and mouth, and survival. Finally, MSA cases with more GCIs in the motor cortex have higher pyramidal scores compared to those with few GCIs (p = 0.017). INTERPRETATION: Pyramidal signs in MSA are associated with the parkinsonian subtype, laryngeal stridor, and certain autonomic dysfunction.

Impulsivity Trait Profiles in Patients With Cerebellar Ataxia and Parkinson Disease.

BACKGROUND AND OBJECTIVES: Individuals with cerebellar ataxia (CA) can develop impulsive behavioral symptoms, often resulting in negative interpersonal consequences, detrimentally affecting their quality of life. Limited evidence exists concerning impulsivity in CA and its associated behavioral changes. We assessed impulsive traits in CA using the Barratt Impulsivity Scale (BIS-11) and compared them with those of Parkinson disease (PD) to investigate the differences in the impulsive trait profiles between CA and PD. METHODS: We conducted a dual-center cross-sectional study with individuals with CA and PD enrolled through consecutive sampling from movement disorders clinics at Columbia University Medical Center and Vanderbilt University Medical Center, respectively. Age-matched controls were recruited at the respective institutions. Participants were excluded if they had prior or comorbid neurologic and psychiatric diseases known to be associated with impulsivity. All participants completed the BIS-11 questionnaire as a measure of impulsive traits. We used a general linear model and a least absolute shrinkage and selection operation regression to compare the total, subscale, and individual items of the BIS-11 scores between groups. Subgroup analyses were performed to isolate cerebellar contributions to impulsivity from potential effects of extracerebellar pathology and dopaminergic dysfunction or medications. RESULTS: A total of 190 participants-90 age-matched controls, 50 participants with CA, and 50 with PD-completed the assessments. Persons with CA reported 9.7% higher BIS-11 scores than controls (p < 0.001), while persons with PD reported 24.9% higher scores than controls (p < 0.001). In CA, the most affected domain of impulsivity was nonplanning. In contrast, persons with PD noted greater impulsivity across the nonplanning, attentional, and motor domains. DISCUSSION: Impulsivity in CA is uniquely driven by the nonplanning trait, unlike in PD. This suggests that the cerebellum and basal ganglia may differentially govern impulsive behaviors with the cerebellum contributing to the brain circuitry of impulsivity in a domain-specific manner.

The Impact of Compulsivity and Impulsivity in Cerebellar Ataxia: A Case Series.

Background: The cerebellum has recently been identified to have a key role in reward processing, and individuals with ataxia have been found to be more impulsive and compulsive as part of cerebellum-related cognitive and behavioral disturbances. Case Report: We reported five individuals with cerebellar ataxia who demonstrate impulsive and compulsive behaviors, including hobbyism, gambling, and compulsive medication use, to illustrate that these symptoms can be highly disabling. Discussion: These five cases provide examples of behavioral symptoms in cerebellar ataxia. Further investigations of the pathomechanism of these symptoms will advance our understanding of the cerebellum in cognition and behavior.