Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.

BACKGROUND AND PURPOSE: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region. METHODS: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation. RESULTS: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds. CONCLUSIONS: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.

Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2.

PURPOSE: Spinocerebellar ataxia SCA1 and SCA2 are adult-onset hereditary disorders, due to triplet CAG expansion in their respective causative genes. The pathophysiology of SCA1 and SCA2 suggests alterations of cerebello-thalamo-cortical pathway and its connections to the basal ganglia. In this framework, thalamic integrity is crucial for shaping efficient whole-brain dynamics and functions. The aims of the study are to identify structural changes in thalamic nuclei in presymptomatic and symptomatic SCA1 and SCA2 patients and to assess disease progression within a 1-year interval. MATERIAL AND METHODS: A prospective 1-year clinical and MRI assessment was conducted in 27 presymptomatic and 23 clinically manifest mutation carriers for SCA1 and SCA2 expansions. Cross-sectional and longitudinal changes of thalamic nuclei volume were investigated in SCA1 and SCA2 individuals and in healthy participants (n = 20). RESULTS: Both SCA1 and SCA2 patients had significant atrophy in the majority of thalamic nuclei, except for the posterior and partly medial nuclei. The 1-year longitudinal evaluation showed a specific pattern of atrophy in ventral and posterior thalamus, detectable even at the presymptomatic stage of the disease. CONCLUSION: For the first time in vivo, our exploratory study has shown that different thalamic nuclei are involved at different stages of the degenerative process in both SCA1 and SCA2. It is therefore possible that thalamic alterations might significantly contribute to the progression of the disease years before overt clinical manifestations occur.

A multimodal imaging approach to foreign accent syndrome. A case report.

This article describes a case of Foreign accent syndrome (FAS) in an Italian woman who developed a Canadian-like foreign accent without brain damage (functional FAS). The patient underwent an in-depth neuroimaging and (neuro)psychological evaluation. Language networks in the frontotemporal-parietal areas were typically activated bilaterally through fMRI and MEG assessments based on task-based data. Resting-state fMRI showed preserved connectivity between language areas. An obsessive-compulsive personality profile and mild anxiety were found, suggesting psychological and psychiatric factors may be relevant. Accordingly with our findings, multimodal imaging is beneficial to understand FAS neurological and functional etiologies.

Brain structural alterations are distributed following functional, anatomic and genetic connectivity.

The pathological brain is characterized by distributed morphological or structural alterations in the grey matter, which tend to follow identifiable network-like patterns. We analysed the patterns formed by these alterations (increased and decreased grey matter values detected with the voxel-based morphometry technique) conducting an extensive transdiagnostic search of voxel-based morphometry studies in a large variety of brain disorders. We devised an innovative method to construct the networks formed by the structurally co-altered brain areas, which can be considered as pathological structural co-alteration patterns, and to compare these patterns with three associated types of connectivity profiles (functional, anatomical, and genetic). Our study provides transdiagnostical evidence that structural co-alterations are influenced by connectivity constraints rather than being randomly distributed. Analyses show that although all the three types of connectivity taken together can account for and predict with good statistical accuracy, the shape and temporal development of the co-alteration patterns, functional connectivity offers the better account of the structural co-alteration, followed by anatomic and genetic connectivity. These results shed new light on the possible mechanisms at the root of neuropathological processes and open exciting prospects in the quest for a better understanding of brain disorders.

The morphometric co-atrophy networking of schizophrenia, autistic and obsessive spectrum disorders.

By means of a novel methodology that can statistically derive patterns of co-alterations distribution from voxel-based morphological data, this study analyzes the patterns of brain alterations of three important psychiatric spectra-that is, schizophrenia spectrum disorder (SCZD), autistic spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD). Our analysis provides five important results. First, in SCZD, ASD, and OCSD brain alterations do not distribute randomly but, rather, follow network-like patterns of co-alteration. Second, the clusters of co-altered areas form a net of alterations that can be defined as morphometric co-alteration network or co-atrophy network (in the case of gray matter decreases). Third, within this network certain cerebral areas can be identified as pathoconnectivity hubs, the alteration of which is supposed to enhance the development of neuronal abnormalities. Fourth, within the morphometric co-atrophy network of SCZD, ASD, and OCSD, a subnetwork composed of eleven highly connected nodes can be distinguished. This subnetwork encompasses the anterior insulae, inferior frontal areas, left superior temporal areas, left parahippocampal regions, left thalamus and right precentral gyri. Fifth, the co-altered areas also exhibit a normal structural covariance pattern which overlaps, for some of these areas (like the insulae), the co-alteration pattern. These findings reveal that, similarly to neurodegenerative diseases, psychiatric disorders are characterized by anatomical alterations that distribute according to connectivity constraints so as to form identifiable morphometric co-atrophy patterns.

Neuropsychological correlates of instrumental activities of daily living in neurocognitive disorders: a possible role for executive dysfunction and mood changes.

ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreover, considering i-ADL scores, we observed an involvement of mood changes and a reduced awareness of deficits in terms of Hamilton Depression Rating Scale (p = 0.02) and Awareness of Deficit Questionnaire - Dementia scale (p < 0.0001), respectively.Our results suggest the importance of considering the association between a reduction in i-ADL and executive dysfunction in patients who have AD etiopathology, for which the ability to inhibit a response, self-monitoring, set-shifting and mood deflection play a key role. Besides, no straightforward associations between i-ADL scores and global cognition, memory, language comprehension, attention, and perspective taking abilities were found.

Lessons Learned From Nocebo Effects in Clinical Trials for Pain Conditions and Neurodegenerative Disorders.

It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments.

Pain anticipation: an activation likelihood estimation meta-analysis of brain imaging studies.

The anticipation of pain has been investigated in a variety of brain imaging studies. Importantly, today there is no clear overall picture of the areas that are involved in different studies and the exact role of these regions in pain expectation remains especially unexploited. To address this issue, we used activation likelihood estimation meta-analysis to analyze pain anticipation in several neuroimaging studies. A total of 19 functional magnetic resonance imaging were included in the analysis to search for the cortical areas involved in pain anticipation in human experimental models. During anticipation, activated foci were found in the dorsolateral prefrontal, midcingulate and anterior insula cortices, medial and inferior frontal gyri, inferior parietal lobule, middle and superior temporal gyrus, thalamus, and caudate. Deactivated foci were found in the anterior cingulate, superior frontal gyrus, parahippocampal gyrus and in the claustrum. The results of the meta-analytic connectivity analysis provide an overall view of the brain responses triggered by the anticipation of a noxious stimulus. Such a highly distributed perceptual set of self-regulation may prime brain regions to process information where emotion, action and perception as well as their related subcategories play a central role. Not only do these findings provide important information on the neural events when anticipating pain, but also they may give a perspective into nocebo responses, whereby negative expectations may lead to pain worsening.

Concordance of white matter and gray matter abnormalities in autism spectrum disorders: a voxel-based meta-analysis study.

There are at least two fundamental unanswered questions in the literature on autism spectrum disorders (ASD): Are abnormalities in white (WM) and gray matter (GM) consistent with one another? Are WM morphometric alterations consistent with alterations in the GM of regions connected by these abnormal WM bundles and vice versa? The aim of this work is to bridge this gap. After selecting voxel-based morphometry and diffusion tensor imaging studies comparing autistic and normally developing groups of subjects, we conducted an activation likelihood estimation (ALE) meta-analysis to estimate consistent brain alterations in ASD. Multidimensional scaling was used to test the similarity of the results. The ALE results were then analyzed to identify the regions of concordance between GM and WM areas. We found statistically significant topological relationships between GM and WM abnormalities in ASD. The most numerous were negative concordances, found bilaterally but with a higher prevalence in the right hemisphere. Positive concordances were found in the left hemisphere. Discordances reflected the spatial distribution of negative concordances. Thus, a different hemispheric contribution emerged, possibly related to pathogenetic factors affecting the right hemisphere during early developmental stages. Besides, WM fiber tracts linking the brain structures involved in social cognition showed abnormalities, and most of them had a negative concordance with the connected GM regions. We interpreted the results in terms of altered brain networks and their role in the pervasive symptoms dramatically impairing communication and social skills in ASD patients.

Self-unawareness of levodopa induced dyskinesias in patients with Parkinson's disease.

The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry. Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p=.04), monitoring resolution (p=.04) and control sensitivity (p=.04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task. We did not find any association with executive functions using the hypo-bradykinesia rating scale. Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.

Resting-state fMRI functional connectome of C9orf72 mutation status.

OBJECTIVE: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status. METHODS: Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables. RESULTS: When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole-connectome showed greater node degree (P < 0.001), while sensorimotor cortices resulted isolated in C9orf72+. INTERPRETATION: Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention.

Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain.

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia.

Impaired awareness of deficits in Alzheimer's disease: the role of everyday executive dysfunction.

The present study analyzed the awareness of deficits in 117 mild Alzheimer's disease participants. Since few studies have examined the cognitive and behavioral domains of reduced awareness in detail, we performed a domain-specific assessment using the Awareness of deficit Questionnaire - Dementia scale with the novel aim of describing the relationship with everyday executive dysfunction. Through the use of the subtests of the Behavioral Assessment of the Dysexecutive Syndrome, we hypothesized that executive cognitive functions may play an important role in the reduced awareness of deficits. We also considered other variables of interest to provide a novel comprehensive explanation of this phenomenon. Our first approach to the study was a factor analysis considering the role of these variables in the awareness of deficits; subsequently, regression analysis models were used to define which variables were associated with a reduction of awareness in cognitive and behavioral domains. In particular, the factors retained from the factor analysis, in terms of inhibition, self-monitoring, set-shifting, and mood orientation changes, appear to be important skills for awareness of instrumental activities of daily living (R(2) = .32). We also found hypo manic mood orientation and a tendency through apathy to be prominent indications of reduced behavioral awareness (R(2) = .13).

Implicit Selective Attention: The Role of the Mesencephalic-basal Ganglia System.

The ability of the brain to recognize and orient attention to relevant stimuli appearing in the visual field is highlighted by a tuning process, which involves modulating the early visual system by both cortical and subcortical brain areas. Selective attention is coordinated not only by the output of stimulus-based saliency maps but is also influenced by top-down cognitive factors, such as internal states, goals, or previous experiences. The basal ganglia system plays a key role in implicitly modulating the underlying mechanisms of selective attention, favouring the formation and maintenance of implicit sensory-motor memories that are capable of automatically modifying the output of priority maps in sensory-motor structures of the midbrain, such as the superior colliculus. The article presents an overview of the recent literature outlining the crucial contribution of several subcortical structures to the processing of different sources of salient stimuli. In detail, we will focus on how the mesencephalic-basal ganglia closed loops contribute to implicitly addressing and modulating selective attention to prioritized stimuli. We conclude by discussing implicit behavioural responses observed in clinical populations in which awareness is compromised at some level. Implicit (emergent) awareness in clinical conditions that can be accompanied by manifest anosognosic symptomatology (i.e., hemiplegia) or involving abnormal conscious processing of visual information (i.e., unilateral spatial neglect and blind sight) represents interesting neurocognitive "test cases" for inferences about mesencephalic-basal ganglia closed-loops involvement in the formation of implicit sensory-motor memories.

Sensory processing sensitivity and social pain: a hypothesis and theory.

Sensory-processing sensitivity (SPS) defined, as a personality trait, seems to be characterized by emotional sensitivity, and stronger reactivity to both external and internal stimuli. SPS can represent a risk factor for developing clinical conditions during childhood and adolescence. This personality trait is not to be considered a pathological clinical condition, however, can expose to greater environmental vulnerability. In particular, the recent studies about SPS can be contextualized to social situations that evoke traumatic and stressful emotional responses such as social exclusion. We hypothesize that highly sensitive people (HSP) are more vulnerable to social exclusion and social pain. This hypothesis could help structure new educational and intervention models designed to improve coping strategies and promote HSP's psychophysical and social well-being.

Parkinson's Disease, SARS-CoV-2, and Frailty: Is There a Vicious Cycle Related to Hypovitaminosis D?

The literature has long established the association between aging and frailty, with emerging evidence pointing to a relationship between frailty and SARS-CoV-2 contagion. The possible neurological consequences of SARS-CoV-2 infection, associated with physical and cognitive frailty, could lead to a worsening of Parkinson's disease (PD) in infected patients or-more rarely-to an increase in the Parkinsonian symptomatology. A possible link between those clinical pictures could be identified in vitamin D deficiency, while the whole process would appear to be associated with alterations in the microbiota-intestine-brain axis that fall within the α-Synuclein Origin site and Connectome (SOC) model, and allow for the identification of a body-first PD and a brain-first PD. The model of care for this condition must consider intrinsic and extrinsic variables so that care by a multidisciplinary team can be successfully predicted. A multidimensional screening protocol specifically designed to identify people at risk or in the early stages of the disease should begin with the investigation of indices of frailty and microbiota-intestine-brain axis alterations, with a new focus on cases of hypovitaminosis D.

Brain Correlates of Eating Disorders in Response to Food Visual Stimuli: A Systematic Narrative Review of FMRI Studies.

This article summarizes the results of studies in which functional magnetic resonance imaging (fMRI) was performed to investigate the neurofunctional activations involved in processing visual stimuli from food in individuals with anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED). A systematic review approach based on the PRISMA guidelines was used. Three databases-Scopus, PubMed and Web of Science (WoS)-were searched for brain correlates of each eating disorder. From an original pool of 688 articles, 30 articles were included and discussed. The selected studies did not always overlap in terms of research design and observed outcomes, but it was possible to identify some regularities that characterized each eating disorder. As if there were two complementary regulatory strategies, AN seems to be associated with general hyperactivity in brain regions involved in top-down control and emotional areas, such as the amygdala, insula and hypothalamus. The insula and striatum are hyperactive in BN patients and likely involved in abnormalities of impulsivity and emotion regulation. Finally, the temporal cortex and striatum appear to be involved in the neural correlates of BED, linking this condition to use of dissociative strategies and addictive aspects. Although further studies are needed, this review shows that there are specific activation pathways. Therefore, it is necessary to pay special attention to triggers, targets and maintenance processes in order to plan effective therapeutic interventions. Clinical implications are discussed.

Disorder of consciousness: Structural integrity of brain networks for the clinical assessment.

AIM: When studying brain networks in patients with Disorders of Consciousness (DoC), it is important to evaluate the structural integrity of networks in addition to their functional activity. Here, we investigated whether structural MRI, together with clinical variables, can be useful for diagnostic purposes and whether a quantitative analysis is feasible in a group of chronic DoC patients. METHODS: We studied 109 chronic patients with DoC and emerged from DoC with structural MRI: 65 in vegetative state/unresponsive wakefulness state (VS/UWS), 34 in minimally conscious state (MCS), and 10 with severe disability. MRI data were analyzed through qualitative and quantitative approaches. RESULTS: The qualitative MRI analysis outperformed the quantitative one, which resulted to be hardly feasible in chronic DoC patients. The results of the qualitative approach showed that the structural integrity of HighOrder networks, altogether, had better diagnostic accuracy than LowOrder networks, particularly when the model included clinical variables (AUC = 0.83). Diagnostic differences between VS/UWS and MCS were stronger in anoxic etiology than vascular and traumatic etiology. MRI data of all LowOrder and HighOrder networks correlated with the clinical score. The integrity of the left hemisphere was associated with a better clinical status. CONCLUSIONS: Structural integrity of brain networks is sensitive to clinical severity. When patients are chronic, the qualitative analysis of MRI data is indicated.

Cervical spinal cord atrophy in amyotrophic lateral sclerosis across disease stages.

OBJECTIVE: Spinal cord degeneration is a hallmark of amyotrophic lateral sclerosis. The assessment of gray matter and white matter cervical spinal cord atrophy across clinical stages defined using the King's staging system could advance the understanding of amyotrophic lateral sclerosis progression. METHODS: We assessed the in vivo spatial pattern of gray and white matter atrophy along cervical spinal cord (C2 to C6 segments) using 2D phase-sensitive inversion recovery imaging in a cohort of 44 amyotrophic lateral sclerosis patients, evaluating its change across the King's stages and the correlation with disability scored by the amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) and disease duration. A mathematical model inferring the potential onset of cervical gray matter atrophy was developed. RESULTS: In amyotrophic lateral sclerosis patients at King's stage 1, significant cervical spinal cord alterations were mainly identified in gray matter, whereas they involved both gray and white matter in patients at King's stage ≥ 2. Gray and white matter areas correlated with clinical disability at all cervical segments. C3-C4 level was the segment showing early gray matter atrophy starting about 7 to 20 months before symptom onset according to our model. INTERPRETATION: Our findings suggest that cervical spinal cord atrophy spreads from gray to white matter across King's stages in amyotrophic lateral sclerosis, making spinal cord magnetic resonance imaging an in vivo assessment tool to measure the progression of the disease.

C9orf72 ALS mutation carriers show extensive cortical and subcortical damage compared to matched wild-type ALS patients.

OBJECTIVE: C9orf72 mutation carriers with different neurological phenotypes show cortical and subcortical atrophy in multiple different brain regions, even in pre-symptomatic phases. Despite there is a substantial amount of knowledge, small sample sizes, clinical heterogeneity, as well as different choices of image analysis may hide anatomical abnormalities that are unique to amyotrophic lateral sclerosis (ALS) patients with this genotype or that are indicative of the C9orf72-specific trait overlain in fronto-temporal dementia patients. METHODS: Brain structural and resting state functional magnetic imaging was obtained in 24 C9orf72 positive (ALSC9+) ALS patients paired for burden disease with 24 C9orf72 negative (ALSC9-) ALS patients. A comprehensive structural evaluation of cortical thickness and subcortical volumes between ALSC9+ and ALSC9- patients was performed while a region of interest (ROI)-ROI analysis of functional connectivity was implemented to assess functional alterations among abnormal cortical and subcortical regions. Results were corrected for multiple comparisons. RESULTS: Compared to ALSC9- patients, ALSC9+ patients exhibited extensive disease-specific patterns of thalamo-cortico-striatal atrophy, supported by functional alterations of the identified abnormal regions. Cortical thinning was most pronounced in posterior areas and extended to frontal regions. Bilateral atrophy of the mediodorsal and pulvinar nuclei was observed, emphasizing a focal rather than global thalamus atrophy. Volume loss in a large portion of bilateral caudate and left putamen was reported. The marked reduction of functional connectivity observed between the left posterior thalamus and almost all the atrophic cortical regions support the central role of the thalamus in the pathogenic mechanism of C9orf72-mediated disease. CONCLUSIONS: These findings constitute a coherent and robust picture of ALS patients with C9orf72-mediated disease, unveiling a specific structural and functional characterization of thalamo-cortico-striatal circuit alteration. Our study introduces new evidence in the characterization of the pathogenic mechanisms of C9orf72 mutation.