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Background: Pseudobulbar affect (PBA), referring to exaggerated or inappropriate episodes of laughing and/or crying without an apparent motivating stimulus, has been mainly attributed to bilateral degeneration of corticobulbar tracts. We aimed at exploring brain functional connectivity (FC) correlates of PBA in patients with amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, frequently associated with PBA.Methods: Resting state functional MRI (RS-fMRI) independent component (ICA) and seed-based analyses and voxel-based morphometry (VBM) whole-brain analysis were performed on 27 ALS patients (13 with PBA; 14 without PBA) and 26 healthy controls (HC), for investigating functional and structural abnormalities in ALS patients compared to HC and in patients with PBA compared to patients without PBA.Results: Between-patient analysis revealed different FC patterns, especially regarding decreased FC in several areas of cognitive (default mode, frontoparietal, salience) and sensory-motor networks in patients with PBA compared to those without PBA. However, no significant differences were found in gray matter atrophy. Seed-based analysis showed increased FC between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA. Conclusions: Our findings suggest that some alterations of fronto-tempo-parietal-cerebellar circuits could be related to PBA in ALS. In particular, the abnormal FC between cerebellum and posterior cingulate cortex and left middle frontal gyrus in patients with PBA compared to patients without PBA highlights a crucial role of the cerebellum in regulating emotion expression in patients with ALS.

The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS.

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p

Objective: Advanced neuroimaging techniques may offer the potential to monitor disease spreading in amyotrophic lateral sclerosis (ALS). We aim to investigate brain functional and structural magnetic resonance imaging (MRI) changes in a cohort of ALS patients, examined at diagnosis and clinically monitored over 18 months, in order to early discriminate fast progressors (FPs) from slow progressors (SPs). Methods: Resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses were performed at baseline in 54 patients with ALS and 22 HCs. ALS patients were classified a posteriori into FPs (n = 25) and SPs (n = 29) based on changes in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score from baseline to the 18-month assessment (ΔALSFRS-R), applying a k-means clustering algorithm. Results: At diagnosis, when compared to HCs, ALS patients showed reduced functional connectivity in both motor and extra-motor networks. When compared to SPs, at baseline, FPs showed decreased function connectivity in paracentral lobule (sensorimotor network), precuneus (in the default mode network), middle frontal gyri (frontoparietal networks) and increased functional connectivity in insular cortices (salience network). Structural analyses did not reveal significant differences in gray and white matter damage by comparing FPs to SPs. Receiver operating characteristic (ROC) curve analysis showed that functional connectivity increase in the left insula at baseline best discriminated FPs and SPs (area under the curve 78%). Conclusions: Impairment of extra-motor networks may appear early in ALS patients with faster disease progression, suggesting that a more widespread functional connectivity damage may be an indicator of poorer prognosis.

Family caregivers of people with amyotrophic lateral sclerosis (ALS), a severely disabling neurodegenerative disease due to the degeneration of both upper and lower motor neurons, have a very demanding role in managing their relatives, thereby often experiencing heavy care burden. Previous literature has widely highlighted that this situation reduces caregivers’ quality of life and increases their psychological distress and risk of health problems, but there are relatively few studies that focus on psychological interventions for these situations. Family support is more—not less—important during crisis. However, during the COVID-19 pandemic, maintaining public safety has required restricting the physical presence of families for hospitalized patients. Caregivers of ALS patients felt increased sense of loneliness and experienced greater difficulties in the access to both hospital and home assistance. In response, health systems rapidly adapted family-centric procedures and tools to circumvent restrictions on physical presence. In this regard, internet-based and telehealth solutions have been adopted to facilitate the routine, predictable, and structured communication, crucial to family-centered care. This narrative review aims at addressing more current matters on support needs and interventions for improving wellbeing of caregivers of ALS patients. In particular, we aimed at highlighting several gaps related to the complex needs of caregivers of ALS patients, to the interventions carried out in order to respond to these needs, and to the changes that COVID-19 pandemic caused from 2020 to nowadays in clinical managing of ALS patients. Finally, we report ongoing experiences of psychological support for family caregivers of ALS patients through telehealth solutions, which have been reinforced in case of needing of physical distancing during the COVID-19 pandemic.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.