Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Session-level effects of cognitive processing therapy and prolonged exposure on individual symptoms of posttraumatic stress disorder among U.S. veterans.

OBJECTIVE: To compare the course of change in individual posttraumatic stress disorder (PTSD) symptoms during prolonged exposure therapy (PE) and cognitive processing therapy (CPT). METHOD: We analyzed data from a previously published randomized clinical trial comparing PE and CPT among male and female U.S. military veterans with PTSD (Schnurr et al., 2022). Using data from a self-rated PTSD symptom measure administered before each therapy session, we evaluated individual symptom change from pretreatment to final therapy session (N = 802). Then, using network intervention analysis, we modeled session-by-session PTSD symptom networks that included treatment allocation (CPT vs. PE) as a node in the networks, allowing us to compare individual symptom change following each session in each treatment. RESULTS: Relative to CPT, PE was associated with greater reduction in 10 PTSD symptoms from first to final session of therapy. Numerous treatment-specific effects on individual symptoms emerged during the treatment period; these session-level effects occurred only in symptoms relatively specific to the diagnosis of PTSD (e.g., avoidance, hypervigilance). PE was associated with greater reduction in avoidance following the introduction and early weeks of imaginal exposure. The treatments yielded comparable effects on trauma-related blame and negative beliefs from pretreatment to final therapy session. However, there were differences in session-level change in these symptoms that may reflect differential timing of interventions that reduce distorted cognitions within each treatment. CONCLUSIONS: Findings may facilitate the shared decision-making process for patients choosing between CPT and PE. Session-level results provide direction for future research on the specific intervention components of CPT and PE. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.

Background: CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS). Methods: RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N = 45) were randomised 1:1 to receive 30 mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively. Findings: In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI: -11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: -56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI: -12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio = 0.408 (95% Wald CI: 0.166 to 1.001, log-rank p = 0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed. Interpretation: CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS. Funding: The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.

Comparing the Prevalence of Probable DSM-IV and DSM-5 Posttraumatic Stress Disorder in a Sample of U.S. Military Veterans Using the PTSD Checklist.

Posttraumatic stress disorder (PTSD) changed substantially when Diagnostic and Statistical Manual of Mental Disorders transitioned from fourth (DSM-IV) to fifth (DSM-5) edition. Hoge et al. found that although diagnostic prevalence remained consistent across nomenclatures, diagnostic concordance was low (55%). Study goals were to examine both the generalizability of these findings and whether either diagnosis systematically excluded patients. U.S. veterans (N = 1,171) who completed the PTSD Checklist for DSM-IV (PCL-S) and DSM-5 (PCL-5) were classified as: probable PTSD on both measures; probable PTSD on PCL-S only; probable PTSD on PCL-5 only; or no PTSD on either measure. Diagnostic prevalence was equivalent. Unlike Hoge et al.'s findings, diagnostic concordance was high (91.3%). Furthermore, observed demographic and severity differences were driven by disparities between veterans in the no PTSD versus the probable PTSD groups, not diagnostic changes. Findings suggest translatability across measures and that diagnostic changes do not systematically exclude patients.

The moderating roles of emotion regulation and coping self-efficacy on the association between PTSD symptom severity and drug use among female sexual assault survivors.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and substance use disorders are a significant comorbid concern among sexual assault survivors. Thus, underlying risk and protective factors are critical to investigate in understanding how to prevent this comorbidity. METHOD: The current study assessed potential moderating effects of coping self-efficacy (CSE) and emotion dysregulation on the association between sexual assault-related PTSD symptom severity and drug use severity in a sample of college women. In this study, 518 female undergraduate students completed self-report measures of nonconsensual sexual experiences, PTSD symptoms, CSE, emotion dysregulation, and drug use severity. RESULTS: Of these participants, 287 women reported at least 1 incident of attempted or completed rape. We found evidence of a significant moderation effect, suggesting that high levels of CSE and low levels of emotion dysregulation reduce the likelihood of drug use issues for female sexual assault survivors. CONCLUSIONS: These findings suggest that assessment tools, interventions, and trauma-related policies should target CSE and emotion dysregulation in attenuating the risk of drug use for women with assault-related PTSD symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ongoing traumatic stress during a global pandemic.

OBJECTIVE: The COVID-19 pandemic has been conceptualized as a potentially traumatic event, although heterogeneity in experience (e.g., isolation) and in type and severity of traumatic stress response (e.g., hygiene hypervigilance) query the applicability of the posttraumatic stress disorder (PTSD) diagnostic construct. Parallels may be drawn to chronic illness and continuous traumatic situations (CTS) literature, which suggests unique symptom presentations that may occur during cumulative, ongoing traumas. METHOD: Eighty-four adults completed the PTSD Checklist with appended questions evaluating pandemic index events, temporality of intrusive symptoms, self-appraised abnormality, and context dependence of symptoms. Using exploratory latent profile analysis, we modeled the latent structure of traumatic stress response to COVID-19 in order to evaluate possible nuanced patterns of symptoms differentiating PTSD from a transient ongoing trauma response. RESULTS: Two profiles broadly delineated by severity across all variables emerged, suggesting the framework of PTSD is apt when applied to COVID-19. However, secondary analyses revealed subtle signals supporting chronic illness and CTS frameworks. Specifically, some participants who met criteria for PTSD did not endorse index events meeting Criterion A, most endorsed intrusive symptoms related to a present or future threat (versus a past trauma), and 30% reported their symptoms to be context dependent. CONCLUSION: Results highlight a need for improved assessment and opportunities for treatment modification. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review.

Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes; clinico-pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP-43) pathology (12), non-TDP-43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.

A laboratory examination of risky sexual behavior among female sexual trauma survivors.

Sexual violence against women is highly prevalent on college campuses. Survivors of sexual violence often engage in coping strategies such as risky sexual behavior. The present study used a behavioral task to measure sexual risk-taking following experiences of positive or negative affect and an emotion suppression experimental manipulation. Sexually active adult female undergraduates (N = 175) completed measures of sexual traumatization and affective experiences as well as an autobiographical recall task and a delay discounting task for hypothetical sexual outcomes. Half of the participants (n = 87) were asked to suppress their emotional response to the autobiographical recall task. The findings indicate that sexual traumatization had a significant effect on risky sexual decision-making, F(1, 167) = 23.27, p < .001, ηp 2 = .12, but affective condition, F(1, 167) = .57, p = .451, and emotion suppression, F(1, 167) = .69, p = .412, exhibited no significant associations with sexual risk-taking. These findings suggest other factors may underlie the association between sexual trauma and risky sexual behavior, but further research is warranted.

Introduction to the special section on women's health and trauma.

This is an introduction to the special section "Women's Health and Trauma." This special section aims to provide compelling and clinically relevant findings from eight rigorous studies with diverse samples of women. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Longing for sleep after violence: The impact of PTSD symptoms, avoidance, and pain on insomnia among female veterans.

Women survivors of intimate partner violence often struggle with mental and physical problems that arise from incidents of violence. Beyond posttraumatic stress disorder (PTSD), the most common outcome, women also may suffer from debilitating chronic pain due to physical injuries sustained during particularly violent physical and/or sexual encounters. This may be a key interaction to explore as PTSD can lead to avoidance of distressing experiences, including chronic pain, resulting in enduring medical problems such as extreme sleep difficulties. This study aimed to identify if posttraumatic stress disorder (PTSD) symptoms from intimate partner violence (IPV) experiences had a conditional indirect effect on insomnia via chronic pain severity moderated by experiential avoidance among women. Female Veterans of at least 18 years of age completed online surveys at three timepoints (T1-T3) between 2014 and 2017 that included measures of PTSD, chronic pain, experiential avoidance, and insomnia. A total of 411 women participated in the initial survey at T1; 208 had a lifetime history of IPV experiences. The conditional indirect effect of PTSD symptoms (T1) on insomnia (T3) via chronic pain (T2) contingent upon experiential avoidance (T2) was also significant, demonstrating a significant moderated mediation model. This model was not significant for women without a history of IPV at T1. The findings indicate that women with IPV-related PTSD symptoms who are highly avoidant are more likely to experience chronic pain, leading to worse insomnia. Women without IPV experiences did not exhibit this same pattern. Findings have implications for improving trauma-focused treatment, approach coping strategies, pain management, and sleep interventions to address these deleterious psychological and medical issues.

Real-time associations between discrimination, cannabis use, and mood among sexual and gender minority individuals.

OBJECTIVE: Sexual and gender minority (SGM) individuals experience high rates of discrimination, which is associated with increased cannabis use. Studies have also linked daily SGM discrimination to event-based mood states, but none have examined the degree to which cannabis buffers or potentially exacerbates mood in response to discrimination in real time. METHOD: Fifty SGM individuals participated in a 2-week ecological momentary assessment study. Participants completed a baseline assessment and then received six daily prompts assessing SGM discrimination, cannabis use, and current mood. We investigated the immediate associations between SGM discrimination and mood, and how cannabis use differentially moderated these associations. RESULTS: SGM discrimination was associated with increased negative mood and decreased positive mood. Among those who experienced discrimination, individuals who used cannabis reported feeling less anxious and depressed, and happier and more relaxed, in the 2 hr following an SGM discrimination experience compared to those that did not use cannabis. CONCLUSIONS: These findings uncover some of the acute within-day effects of both daily SGM discrimination and cannabis use on mood. These findings build on the current understanding of minority stress, in real time, and suggest avenues for prevention, and intervention efforts to offset risk for psychological distress and cannabis use among SGM individuals who experience minority stress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A prospective examination of health care costs associated with posttraumatic stress disorder diagnostic status and symptom severity among veterans.

Posttraumatic stress disorder (PTSD) is associated with increased health care costs; however, most studies exploring this association use PTSD diagnostic data in administrative records, which can contain inaccurate diagnostic information and be confounded by the quantity of service use. We used a diagnostic interview to determine PTSD diagnostic status and examined associations between PTSD symptom severity and health care costs and utilization, extracted from Veteran Health Administration (VHA) administrative databases. Using a nationwide longitudinal sample of U.S. veterans with and without PTSD (N = 1,377) enrolled in VHA health care, we determined the costs and utilization of mental health and non-mental health outpatient, pharmacy, and inpatient services for 1 year following cohort enrollment. Relative to veterans without PTSD, those with PTSD had higher total health care, B = 0.47; mental health clinic care, B = 0.72; non-mental health clinic care, B = 0.30; and pharmacy costs, B = 0.72, ps < .001. More severe PTSD symptoms were associated with mental health clinic care costs, B = 0.12; non-mental health clinic care costs, B = 0.27; and higher odds of inpatient, B = 0.63, and emergency service use, B = 0.39, p < .001-p = .012. These findings indicate that veterans' PTSD status, determined by a clinician-administered semistructured diagnostic interview, was associated with higher health care costs and increased use of mental health and non-mental health clinic services. The findings also suggest that more severe PTSD is associated with increased costs and utilization, including costly emergency and inpatient utilization.

The role of PTSD symptom clusters and criterion in predicting future high-risk drug and alcohol use among returning veteran men and women.

The prevalence of co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD) remains exceptionally high among returning veterans, with numerous studies linking PTSD, but not specific PTSD symptoms, to future SUD risk. Further explication of PTSD symptom effects on future SUD risk will likely promote intervention development and refinement while offsetting SUD risk. Accordingly, In this study we explored the prospective associations between PTSD symptom clusters, symptoms, and future SUD risk and use of specific drug classes. Returning veterans (N = 1,295; Mage = 42.3, SD = 9.89; 51% female; 66.8% White) completed structured diagnostic interviews to assess PTSD symptoms and self-report measures of substance use 14-36 months later (M = 24.59, SD = 2.97). Hyperarousal and reckless/self-destructive symptoms specifically predicted future high-risk drug use and binge drinking behavior, and avoidance of internal stimuli (i.e., of trauma memories, thoughts, and feelings) differentiated individuals classified as high-risk for alcohol use based on their AUDIT total score. Further, negative alterations in cognition and mood predicted future opioid (i.e., nightmares) and stimulant use (i.e., flashbacks), whereas concentration difficulties were inversely associated with future binge drinking. This longitudinal study identified prospective and enduring associations between specific PTSD symptom clusters, symptoms, and future high-risk substance use patterns among returning veterans. Accordingly, careful assessment of specific PTSD criteria and differential motivations for substance use is warranted, along with tailored interventions to offset risk for opioid, stimulant, and alcohol use among returning veterans. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Longitudinal course of mental health symptoms among veterans with and without cannabis use disorder.

OBJECTIVE: Cannabis use disorder (CUD) is the most common non-alcohol related substance use disorder (SUD) in the United States and is especially prevalent among returning veterans. The long-term mental health correlates of CUD remain unknown, which is significant given the rise in legalization and also recreational and medicinal cannabis use nationally. METHOD: Using a gender-balanced, national sample of 1,649 veterans (n = 115 with CUD; 75.2% White; M age = 37.49, SD = 9.88), we used latent growth curve modeling to examine posttraumatic stress disorder (PTSD) symptom severity, depressive symptoms, generalized anxiety, alcohol use, and psychosocial functioning between veterans with versus without a prior diagnosis of CUD over five time points, spanning an average of 7 years. RESULTS: Returning veterans with CUD compared to those without reported higher alcohol use, depression, anxiety, PTSD symptom severity, and worse psychosocial functioning at baseline. We observed nonlinear change across each outcome. We also found that CUD moderated change in alcohol use (quadratic: b = -.129, p < .001) and PTSD symptoms (quadratic: b = -.280, p = .019), such that individuals with CUD evidenced decelerated change and worse outcomes relative to veterans without a previously documented CUD diagnosis. Trajectories of depression, anxiety, and psychosocial functioning were similar across individuals with versus without CUD. CONCLUSIONS: In the first long-term and longitudinal evaluation of mental health and alcohol use course among returning veterans, CUD was associated with worse and more persistent alcohol use and PTSD symptom severity over time. These data have implications for clinical assessment, case conceptualization, and treatment of veterans and may inform efforts to offset risk for hazardous drinking and PTSD following a diagnosis of CUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Factors That Influence Non-Motor Impairment Across the ALS-FTD Spectrum: Impact of Phenotype, Sex, Age, Onset and Disease Stage.

Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients. Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity. Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments. Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.

Recovering From Intimate Partner Violence Through Strengths and Empowerment: Findings From a Randomized Clinical Trial.

Objective: Recovering from Intimate Partner Violence through Strengths and Empowerment (RISE) is a brief, variable-length (1-6 sessions), modular, individualized psychosocial counseling intervention for women experiencing intimate partner violence (IPV). Pilot findings demonstrated the potential helpfulness, acceptability, and feasibility of RISE; however, a randomized clinical trial (RCT) is needed to support program effectiveness.Methods: This RCT enrolled 60 women who experienced IPV within the prior year. Participants were recruited from an urban Veterans Health Administration hospital (October 2018 to September 2020). Participants completed a pretreatment assessment that included measures of relevant outcomes (primary: empowerment, self-efficacy, patient activation, and valued living; secondary: depression symptoms, IPV, and satisfaction with the intervention) and were randomly assigned to RISE or an enhanced care as usual (ECAU) condition. RISE participants received 1 to 6 sessions. ECAU participants received a single session consisting of psychoeducation, safety planning, resources, and referrals. Participants were reassessed 10 and 14 weeks after enrollment.Results: Intent-to-treat analyses using unconditional growth models revealed significant time-by-condition effects: RISE participants demonstrated higher increases in empowerment (d = 3.46) and self-efficacy (d = 1.09). RISE participants also experienced significant improvements in valued living (d = 0.53), depression symptoms (d = 0.49), and IPV reduction (d = 1.07) over time; however, the lack of a significant difference by condition suggested similar effectiveness of the interventions on these outcomes. Satisfaction was significantly higher for RISE than ECAU (d = 1.23).Conclusions: Results indicate the effectiveness of RISE in enhancing psychosocial well-being, especially empowerment and self-efficacy, among women experiencing IPV, for whom accessible health care-based interventions are needed.Trial Registration: ClinicalTrials.gov identifier: NCT03261700.

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS.

Pseudobulbar affect is a disorder of emotional expression commonly observed in amyotrophic lateral sclerosis (ALS), presenting as episodes of involuntary laughter, or crying. The objective of the current study was to determine the association between frequency of pathological laughter and crying (PLC) episodes with clinical features, cognitive impairment, and brainstem pathology. Thirty-five sporadic ALS patients underwent neuropsychological assessment, with a subset also undergoing brain imaging. The Center for Neurological Study Lability Scale (CNS-LS) was used to screen for presence and severity of pseudobulbar affect (CNS-LS ≥ 13) and frequency of PLC episodes. Presence of pseudobulbar affect was significantly higher in bulbar onset ALS (p = 0.02). Frequency of PLC episodes was differentially associated with cognitive performance and brainstem integrity. Notably pathological laughter frequency, but not crying, showed a significant positive association with executive dysfunction on the Trail Making Test B-A (R 2 = 0.14, p = 0.04). Similarly, only pathological laughter frequency demonstrated a significant negative correlation with gray matter volume of the brainstem (R 2 = 0.46, p < 0.01), and mean fractional anisotropy of the superior cerebellar peduncles (left: R 2 = 0.44, p < 0.01; right: R 2 = 0.44, p < 0.01). Hierarchical regression indicated brainstem imaging in combination with site of symptom onset explained 73% of the variance in pathological laughter frequency in ALS. The current findings suggest emotional lability is underpinned by degeneration across distinct neural circuits, with brainstem integrity critical in the emergence of pathological laughter.

Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.