Brain activation during processing of mouth actions in patients with disorders of consciousness.

In the past 2 decades, several attempts have been made to promote a correct diagnosis and possible restorative interventions in patients suffering from disorders of consciousness. Sensory stimulation has been proved to be useful in sustaining the level of arousal/awareness and to improve behavioural responsiveness with a significant effect on oro-motor functions. Recently, action observation has been proposed as a stimulation strategy in patients with disorders of consciousness, based on neurophysiological evidence that the motor cortex can be activated not only during action execution but also when actions are merely observed in the absence of motor output, or during listening to action sounds and speech. This mechanism is provided by the activity of mirror neurons. In the present study, a group of patients with disorders of consciousness (11 males, 4 females; median age: 55 years; age range: 19-74 years) underwent task-based functional MRI in which they had, in one condition, to observe and listen to the sound of mouth actions, and in another condition, to listen to verbs with motor or abstract content. In order to verify the presence of residual activation of the mirror neuron system, the brain activations of patients were compared with that of a group of healthy individuals (seven males, eight females; median age: 33.4 years; age range: 24-65 years) performing the same tasks. The results show that brain activations were lower in patients with disorders of consciousness compared with controls, except for primary auditory areas. During the audiovisual task, 5 out of 15 patients with disorders of consciousness showed only residual activation of low-level visual and auditory areas. Activation of high-level parieto-premotor areas was present in six patients. During the listening task, three patients showed only low-level activations, and six patients activated also high-level areas. Interestingly, in both tasks, one patient with a clinical diagnosis of vegetative state showed activations of high-level areas. Region of interest analysis on blood oxygen level dependent signal change in temporal, parietal and premotor cortex revealed a significant linear relation with the level of clinical functioning, assessed with coma recovery scale-revised. We propose a classification of the patient's response based on the presence of low-level and high-level activations, combined with the patient's functional level. These findings support the use of action observation and listening as possible stimulation strategies in patients with disorders of consciousness and highlight the relevance of combined methods based on functional assessment and brain imaging to provide more detailed neuroanatomical specificity about residual activated areas at both cortical and subcortical levels.

Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.

OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

Involvement of the ipsilateral-to-the-pain anterior-superior hypothalamic subunit in chronic cluster headache.

BACKGROUND: Despite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition. METHODS: We used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models. Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients. RESULTS: Patients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior-superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found. CONCLUSIONS: We identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.

Efficacy of mindfulness added to treatment as usual in patients with chronic migraine and medication overuse headache: a phase-III single-blind randomized-controlled trial (the MIND-CM study).

BACKGROUND: Mindfulness gained considerable attention for migraine management, but RCTs are lacking. We aimed to assess the efficacy of a six-sessions mindfulness-based treatment added to treatment as usual (TaU) in patients with Chronic Migraine (CM) and Medication Overuse Headache (MOH) on headache frequency, medication intake, quality of life, disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. METHODS: In this Phase-III single-blind RCT carried out in a specialty Italian headache center, 177 patients with CM and MOH were randomized 1:1 to either TaU (withdrawal from overused drugs, education on proper medication use and lifestyle issues, and tailored prophylaxis) or mindfulness-based intervention added to TaU (TaU + MIND). The mindfulness-based intervention consisted of six group session of mindfulness practice and 7-10 min daily self-practice. The primary endpoint was the achievement of ≥ 50% headache frequency reduction at 12 months compared to baseline, and was analyzed on an intention-to-treat principle using Pearson's Chi-Squared test. Secondary endpoints included medication intake, quality of life (QoL), disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. The secondary endpoints were analyzed using per-protocol linear mixed models. RESULTS: Out of the 177 participants 89 were randomized to TaU and 88 to TaU + MIND. Patients in the TaU + MIND group outperformed those in TaU for the primary endpoint (78.4% vs. 48.3%; p < 0.0001), and showed superior improvement in headache frequency, QoL and disability, headache impact, loss of productive time, medication intake, and in total, indirect and direct healthcare costs. CONCLUSIONS: A mindfulness-based treatment composed of six-week session and 7-10 min daily self-practice added on to TaU is superior to TaU alone for the treatment of patients with CM and MOH. TRIAL REGISTRATION: MIND-CM was registered on clinicaltrials.gov (NCT03671681) on14/09/2018.

Case report: Multiple brain intravascular papillary endothelial hyperplasia: incidence, diagnostic challenges, and management approach.

Multiple hemorrhagic brain lesions are mainly diagnosed based on clinico-radiological features integrated with histological data. Intravascular papillary endothelial hyperplasia (IPEH), or Masson's tumor, is a very rare entity, particularly when localized in the brain. In this study, we describe a case of multiple recurrent brain IPEHs and provide details on the diagnostic phase, therapeutic approaches, and related challenges. A 55-year-old woman presented with a relapsing neurological deficit. Brain magnetic resonance imaging (MRI) revealed a hemorrhagic right frontal-parietal lesion. When new neurological symptoms occurred, subsequent MRI scans detected more bleeding cerebral lesions. She underwent a series of single hemorrhagic lesion debulking. For any samples that underwent histopathological examination, the first results were not informative; the second and the third results revealed hemangioendothelioma (HE); and the fourth results led to the IPEH diagnosis. Interferon alpha (IFN-α) and subsequently sirolimus were prescribed. Both were well tolerated. Clinical and radiological features remained stable 43 months after starting sirolimus therapy and 132 months after the first diagnosis. To date, 45 cases of intracranial IPEH have been reported, mostly as single lesions without parenchymal location. They are usually treated by surgery and sometimes by radiotherapy upon recurrence. Our case is notable for two main reasons: because of the consecutive recurrent multifocal exclusively cerebral lesions and the therapeutic approach we used. Based on multifocal brain recurrence and good performance, we propose pharmacological therapy, including IFN-α and sirolimus, to stabilize IPEH.

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.

The central autonomic system revisited - Convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses.

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (that differ in empirical assumptions), we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 758 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). Applying an unbiased approach, we were able to identify a single condition-independent functional circuit that supports CAN activity. Partially overlapping with the salience network this functional circuit includes the bilateral insular cortex and midcingulate cortex as well as the bilateral inferior parietal lobules. Remarkably, the critical regions of the CAN observed in this meta-analysis overlapped with the salience network as well as regions commonly reported across different cognitive and affective neuroimaging paradigms and regions being dysregulated across different mental and neurological disorders.

Neurophysiology-Guided Laser Interstitial Thermal Therapy: A Synergistic Approach For Motor Function Preservation. Technical Note.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive ablative technique with specific indications for neuro-oncology, especially in the case of lesions in eloquent areas. Even being performed through a small catheter under stereotactic conditions, the risk of damaging vital structures such as white matter tracts or cortical eloquent areas is not negligible. The mechanism of damage can be related to catheter insertion or to excessive laser ablation. An accurate preoperative workup, aimed at locating the eloquent structures, can be combined with a real-time intraoperative neurophysiologic monitoring to reduce surgical morbidity while maximizing the efficacy of LITT. METHODS: We developed a synergistic approach for neurophysiology-guided LITT based on state-of-the-art technologies, namely, magnetoencephalography, diffusion tensor imaging, and intraoperative neurophysiologic monitoring. RESULTS: As a result, we improved the planning phase thanks to a more precise representation of functional structures that allows the simulation of different trajectories and the identification of the most suitable trajectory to treat the lesion while respecting the functional boundaries. Catheter insertion is conducted under continuous neurophysiologic feedback and the ablation phase is modeled on the functional boundaries identified by stimulation, allowing it to be extremely accurate. CONCLUSIONS: An integrated approached guided by neurophysiology is able to reduce the surgical morbidity even in a relatively accurate technique such as LITT. To the best of our knowledge, this represents the first report on this synergistic approach which could really impact the treatment of tumors in eloquent areas. Future studies are needed in the effort to implement this approach in functional or epilepsy neurosurgery as well.

Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN-Neuroimaging Network.

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.

Mesocorticolimbic system abnormalities in chronic cluster headache patients: A neural signature?

BACKGROUND: Converging evidence suggests that anatomical and functional mesocorticolimbic abnormalities support the chronicization of pain disorders. METHODS: We mapped structural and functional alterations of the mesocorticolimbic system in a sample of chronic cluster headache patients (n = 28) in comparison to age and sex-matched healthy individuals (n = 28) employing structural MRI and resting-state functional MRI. RESULTS: Univariate logistic regression models showed that several of the examined structures/areas (i.e., the bilateral nucleus accumbens, ventral diencephalon, hippocampus, and frontal pole, and the right amygdala) differentiated chronic cluster headache patients from healthy individuals (p < 0.05, uncorrected). Specifically, all the significant structures/areas had increased volumes in chronic cluster headache patients compared to healthy individuals. The examination of the groups suffering from left and right-sided cranial attacks showed a lateralization effect: ipsilateral to the pain ventral diencephalic regions and contralateral to the pain nucleus accumbens discriminated chronic cluster headache patients from healthy individuals. The resting-state functional MRI data analyses showed that chronic cluster headache patients compared to CTRL individuals present robust reduced functional connectivity in the right frontal pole-right amygdala pathway (p < 0.05, FDR-corrected). CONCLUSION: Our results showed that chronic cluster headache patients present anatomical and functional maladaptation of the mesocorticolimbic system, with functional data indicating a possible prefrontal areas' failure to modulate the mesolimbic structures. These results were opposite to what we hypothesized based on the previous literature on chronic pain conditions.Future studies should assess whether the observed mesocorticolimbic abnormalities are due to the neuroprotective effects of the assumed medications, or to the frequent comorbidity of CH with neuropsychiatric disorders or if they are a genuine neural signature of CH and/or chronic cluster headache condition.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta-analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Chronic cluster headache: A study of the telencephalic and cerebellar cortical thickness.

PURPOSE: Previous studies on brain morphological alterations in chronic cluster headache revealed inconsistent findings. METHOD: The present cross-sectional explorative study determined telencephalic and cerebellar cortex thickness alterations in a relatively wide sample of chronic cluster headache patients (n = 28) comparing them to matched healthy individuals. RESULTS: The combination of two highly robust state-of-the-art approaches for thickness estimation (Freesurfer, CERES), strengthened by functional characterization of the identified abnormal regions, revealed four main results: chronic cluster headache patients show 1) cortical thinning in the right middle cingulate cortex, left posterior insula, and anterior cerebellar lobe, regions involved in nociception's sensory and sensory-motor aspects and possibly in autonomic functions; 2) cortical thinning in the left anterior superior temporal sulcus and the left collateral/lingual sulcus, suggesting neuroplastic maladaptation in areas possibly involved in social cognition, which may promote psychiatric comorbidity; 3) abnormal functional connectivity among some of these identified telencephalic areas; 4) the identified telencephalic areas of cortical thinning present robust interaction, as indicated by the functional connectivity results, with the left posterior insula possibly playing a pivotal role. CONCLUSION: The reported results constitute a coherent and robust picture of the chronic cluster headache brain. Our study paves the way for hypothesis-driven studies that might impact our understanding of the pathophysiology of this condition.

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.

Corrigendum: Preservation of Language Processing and Auditory Performance in Patients With Disorders of Consciousness: A Multimodal Assessment.

[This corrects the article DOI: 10.3389/fneur.2020.526465.].

The Frontal Aslant Tract: A Systematic Review for Neurosurgical Applications.

The frontal aslant tract (FAT) is a recently identified white matter tract connecting the supplementary motor complex and lateral superior frontal gyrus to the inferior frontal gyrus. Advancements in neuroimaging and refinements to anatomical dissection techniques of the human brain white matter contributed to the recent description of the FAT anatomical and functional connectivity and its role in the pathogenesis of several neurological, psychiatric, and neurosurgical disorders. Through the application of diffusion tractography and intraoperative electrical brain stimulation, the FAT was shown to have a role in speech and language functions (verbal fluency, initiation and inhibition of speech, sentence production, and lexical decision), working memory, visual-motor activities, orofacial movements, social community tasks, attention, and music processing. Microstructural alterations of the FAT have also been associated with neurological disorders, such as primary progressive aphasia, post-stroke aphasia, stuttering, Foix-Chavany-Marie syndrome, social communication deficit in autism spectrum disorders, and attention-deficit hyperactivity disorder. We provide a systematic review of the current literature about the FAT anatomical connectivity and functional roles. Specifically, the aim of the present study relies on providing an overview for practical neurosurgical applications for the pre-operative, intra-operative, and post-operative assessment of patients with brain tumors located around and within the FAT. Moreover, some useful tests are suggested for the neurosurgical evaluation of FAT integrity to plan a safer surgery and to reduce post-operative deficits.

Resting State Functional Connectivity Signatures of MRgFUS Vim Thalamotomy in Parkinson's Disease: A Preliminary Study.

Magnetic Resonance-guided high-intensity Focused Ultrasound (MRgFUS) of the thalamic ventral intermediate nucleus (Vim) for tremor has increasingly gained interest as a new non-invasive alternative to standard neurosurgery. Resting state functional connectivity (rs-FC) correlates of MRgFUS have not been extensively investigated yet. A region of interest (ROI)-to-ROI rs-FC MRI "connectomic" analysis focusing on brain regions relevant for tremor was conducted on 15 tremor-dominant patients with Parkinson's disease who underwent MRgFUS. We tested whether rs-FC between tremor-related areas was modulated by MRgFUS at 1 and 3 months post-operatively, and whether such changes correlated with individual clinical outcomes assessed by the MDS-UPDRS-III sub items for tremor. Significant increase in FC was detected within bilateral primary motor (M1) cortices, as well as between bilateral M1 and crossed primary somatosensory cortices, and also between pallidum and the dentate nucleus of the untreated hemisphere. Correlation between disease duration and FC increase at 3 months was found between the putamen of both cerebral hemispheres and the Lobe VI of both cerebellar hemispheres, as well as between the Lobe VI of untreated cerebellar hemisphere with bilateral supplementary motor area (SMA). Drop-points value of MDS-UPDRS at 3 months correlated with post-treatment decrease in FC, between the anterior cingulate cortex and bilateral SMA, as well as between the Lobe VI of treated cerebellar hemisphere and the interpositus nucleus of untreated cerebellum. Tremor improvement at 3 months, expressed as percentage of intra-subject MDS-UPDRS changes, correlated with FC decrease between bilateral occipital fusiform gyrus and crossed Lobe VI and Vermis VI. Good responders (≥50% of baseline tremor improvement) showed reduced FC between bilateral SMA, between the interpositus nucleus of untreated cerebellum and the Lobe VI of treated cerebellum, as well as between the untreated SMA and the contralateral putamen. Good responders were characterized at baseline by crossed hypoconnectivity between bilateral putamen and M1, as well as between the putamen of the treated hemisphere and the contralateral SMA. We conclude that MRgFUS can effectively modulate brain FC within the tremor network. Such changes are associated with clinical outcome. The shifting mode of integration among the constituents of this network is, therefore, susceptible to external redirection despite the chronic nature of PD.

Understanding Cluster Headache Using Magnetic Resonance Imaging.

Cluster headache is an excruciating pain syndrome characterized by unilateral head pain attacks, lasting between 15 and 180 min, accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. Despite important insights provided by neuroimaging studies and deep brain stimulation findings, the pathophysiology of cluster headache and its pathways of chronicization are still elusive. In this mini-review, we will provide an overview of the functional and structural neuroimaging studies in episodic and chronic cluster headache conditions conducted to clarify the underlying pathophysiology.

Preservation of Language Processing and Auditory Performance in Patients With Disorders of Consciousness: A Multimodal Assessment.

The impact of language impairment on the clinical assessment of patients suffering from disorders of consciousness (DOC) is unknown or underestimated and may mask the presence of conscious behavior. In a group of DOC patients (n = 11; time post-injury range: 5-252 months), we investigated the main neural functional and structural underpinnings of linguistic processing, and their relationship with the behavioral measures of the auditory function using the Coma Recovery Scale-Revised (CRS-R). We assessed the integrity of the brainstem auditory pathways, of the left superior temporal gyrus and arcuate fasciculus, the neural activity elicited by passive listening of an auditory language task, and the mean hemispheric glucose metabolism. Our results support the hypothesis of a relationship between the level of preservation of the investigated structures/functions and the CRS-R auditory subscale scores. Moreover, our findings indicate that patients in minimally conscious state minus (MCS-): (1) when presenting the auditory startle (at the CRS-R auditory subscale) might be aphasic in the receptive domain, being severely impaired in the core language structures/functions; (2) when presenting the localization to sound might retain language processing, being almost intact or intact in the core language structures/functions. Despite the small group of investigated patients, our findings provide a grounding of the clinical measures of the CRS-R auditory subscale in the integrity of the underlying auditory structures/functions. Future studies are needed to confirm our results that might have important consequences for the clinical practice.

Cognitive Syndromes and C9orf72 Mutation Are Not Related to Cerebellar Degeneration in Amyotrophic Lateral Sclerosis.

OBJECTIVE: The notion that cerebellar pathology may contribute to cognitive impairment in ALS, especially in patients with C9orf72 repeated expansion, has been inconsistently reported. This study aimed exploring the relationship between cerebellar involvement, cognitive impairment and C9orf72 repeated expansion of patients with ALS. METHODS: Quantitative in vivo assessment of cerebellar lobules has been investigated in 66 non-demented patients with ALS and 28 healthy controls (HCs). Pathologic C9orf72 repeated expansion was found in 13 patients. Mild cognitive and/or behavioral impairment was diagnosed in 22 C9orf72 negative ALS patients. Measures of cortical volume (CV) and cortical thickness (CT) of cerebellar lobules of all participants were used for Principal Component Analysis (PCA) to identify clusters of lobular measures highly correlated with each other. PCA outcomes were used for between group comparisons and correlation analyses with neuropsychological and clinical features. RESULTS: Disease severity measured with ALS functional rating scale and index of disease progression rate significantly correlated with CV reduction of the second PCA cluster loading CV measures of anterior lobules. In all patients, cognitive impairment, measured with verbal fluency, was related to CV reduction of the third cluster comprising posterior lobules. No specific cortical thinning or volume reduction of cerebellar clustering patterns could be detected in ALS subgroups. CONCLUSION: Our data show that specific patterns of subregional cerebellar involvement are associated with physical disability or cognitive impairment in ALS, in line with the topographic organization of the cerebellum. However, there was no specific correlation between cerebellar degeneration and cognitive syndromes or C9orf72 mutations.

Cluster headache: insights from resting-state functional magnetic resonance imaging.

The comprehension of cluster headache (CH) has greatly benefited from the tremendous progress of the neuroimaging techniques over the last 20 years. Since the pioneering study of May et al. (1998), the neuroimaging results have indeed revolutionized the conception of this disease, now considered as a dysfunction of the central nervous system. Clinical, neuroendocrinological, and neuroimaging studies strongly suggested the involvement of the hypothalamus as the generator of cluster headache attacks. However, the latency of the improvement and the inefficacy of the hypothalamic deep brain stimulation (DBS) in the acute phase suggested that the hypothalamus might play a modulating role, pointing to the presence of some dysfunctional brain networks, normalized or modulated by the DBS. Despite the great importance of possible dysfunctional hypothalamic networks in cluster headache pathophysiology, only quite recently the scientific community has begun to explore the functional connectivity of these circuits using resting-state functional magnetic resonance imaging. This is a neuroimaging technique extensively employed to investigate the functional connectivity among separated regions of the brain at rest in the low-frequency domain (< 0.1 Hz). Here, we present a review of the few resting-state functional magnetic resonance imaging studies investigating the hypothalamic network contributing to a deeper comprehension of this neurological disorder. These studies seem to demonstrate that both the hypothalamus and the diencephalic-mesencephalic junction regions might play an important role in the pathophysiology of CH. However, future studies are needed to confirm the results and to clarify if the observed dysfunctional networks are a specific neural fingerprint of the CH pathophysiology or an effect of the severe acute pain. It will be also crucial to clarify the neural pathways of the chronicization of this disorder.