Longitudinal neurofunctional changes in medication overuse headache patients after mindfulness practice in a randomized controlled trial (the MIND-CM study).

BACKGROUND: Mindfulness practice has gained interest in the management of Chronic Migraine associated with Medication Overuse Headache (CM-MOH). Mindfulness is characterized by present-moment self-awareness and relies on attention control and emotion regulation, improving headache-related pain management. Mindfulness modulates the Default Mode Network (DMN), Salience Network (SN), and Fronto-Parietal Network (FPN) functional connectivity. However, the neural mechanisms underlying headache-related pain management with mindfulness are still unclear. In this study, we tested neurofunctional changes after mindfulness practice added to pharmacological treatment as usual in CM-MOH patients. METHODS: The present study is a longitudinal phase-III single-blind Randomized Controlled Trial (MIND-CM study; NCT03671681). Patients had a diagnosis of CM-MOH, no history of neurological and severe psychiatric comorbidities, and were attending our specialty headache centre. Patients were divided in Treatment as Usual (TaU) and mindfulness added to TaU (TaU + MIND) groups. Patients underwent a neuroimaging and clinical assessment before the treatment and after one year. Longitudinal comparisons of DMN, SN, and FPN connectivity were performed between groups and correlated with clinical changes. Vertex-wise analysis was performed to assess cortical thickness changes. RESULTS: 177 CM-MOH patients were randomized to either TaU group or TaU + MIND group. Thirty-four patients, divided in 17 TaU and 17 TaU + MIND, completed the neuroimaging follow-up. At the follow-up, both groups showed an improvement in most clinical variables, whereas only TaU + MIND patients showed a significant headache frequency reduction (p = 0.028). After one year, TaU + MIND patients showed greater SN functional connectivity with the left posterior insula (p-FWE = 0.007) and sensorimotor cortex (p-FWE = 0.026). In TaU + MIND patients only, greater SN-insular connectivity was associated with improved depression scores (r = -0.51, p = 0.038). A longitudinal increase in cortical thickness was observed in the insular cluster in these patients (p = 0.015). Increased anterior cingulate cortex thickness was also reported in TaU + MIND group (p-FWE = 0.02). CONCLUSIONS: Increased SN-insular connectivity might modulate chronic pain perception and the management of negative emotions. Enhanced SN-sensorimotor connectivity could reflect improved body-awareness of painful sensations. Expanded cingulate cortex thickness might sustain improved cognitive processing of nociceptive information. Our findings unveil the therapeutic potential of mindfulness and the underlying neural mechanisms in CM-MOH patients. TRIAL REGISTRATION: Name of Registry; MIND-CM study; Registration Number ClinicalTrials.gov identifier: NCT0367168; Registration Date: 14/09/2018.

Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

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.

Epilepsy Care in Latin America and the Caribbean: Overcoming Challenges and Embracing Opportunities.

The burden of epilepsy in the Latin America and the Caribbean (LAC) region causes a profound regional impact on the health care system and significantly contributes to the global epilepsy burden. As in many other resource-limited settings worldwide, health care professionals and patients with epilepsy in LAC countries face profound challenges due to a combination of factors, including high disease prevalence, stigmatization of epilepsy, disparities in access to care, limited resources, substantial treatment gaps, insufficient training opportunities for health care providers, and a diverse patient population with varying needs. This article presents an overview of the epidemiology of epilepsy and discusses the principal obstacles to epilepsy care and key contributors to the epilepsy diagnosis and treatment gap in the LAC region. We conclude by highlighting various initiatives across different LAC countries to improve epilepsy care in marginalized communities, listing strategies to mitigate treatment gaps and facilitate better health care access for patients with epilepsy by enhancing the epilepsy workforce.

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.

[Concordance between essential medicines lists and diabetes guidelines in Latin America and the CaribbeanConcordância entre as listas de medicamentos essenciais e diretrizes para diabetes na América Latina e no Caribe]. / Concordancia entre las listas de medicamentos esenciales y las guías para diabetes en América Latina y el Caribe.

Objective: Conduct an analysis to determine the existence and updating of national essential medicines lists (EMLs) and clinical practice guidelines (CPGs) for the treatment of diabetes in Latin America and the Caribbean (LAC); and compare the medicines included in each country's list and guidelines both with each other and with those of the World Health Organization (WHO). Methods: Cross-sectional study. EMLs and CPGs for diabetes were found on the websites of the Pan American Health Organization and national health authorities. Medicines were noted and analyzed according to pharmacological group, based on the fourth level of nomenclature of the Anatomical Therapeutic Chemical (ATC) classification system. F1 scoring was used to assess the proximity of EMLs to the WHO Model List of Essential Medicines (MLEM). Results: Of the total number of countries, 87.2% have EMLs, and 91% have CPGs (78% and 45% updated in the last five years, respectively). Compared to the six hypoglycemic groups of the MLEM, the EMLs had a median (range) of 6 (4-13) and an F1 score of 0.80; This indicates proper alignment. CPGs had a median (range) of 12 (1-12) hypoglycemic drugs compared to eight in the WHO guidelines. CPGs had a median of 15 more drugs than their respective EMLs. Conclusions: While most LAC countries have EMLs and CPGs for diabetes, the lack of concordance among them limits their effectiveness. It is necessary to align the processes and criteria for the development of these two tools for policymaking on medicines.

Objetivos: Analisar a existência e a atualização das listas nacionais de medicamentos (LNMs) e guias de prática clínica (GPCs) para o tratamento do diabetes na América Latina e no Caribe (ALC). Comparar os medicamentos incluídos nas listas e nas diretrizes de cada país entre si e com as da Organização Mundial da Saúde (OMS). Métodos: Estudo transversal. Foram identificadas LMNs e GPCs para o diabetes nos sites da Organização Pan-Americana da Saúde e das autoridades sanitárias nacionais. Os medicamentos foram pesquisados e analisados por grupo farmacológico de acordo com o quarto nível da classificação ATC. A pontuação F1 foi utilizada para avaliar o grau de proximidade das LMNs com a lista-modelo de medicamentos essenciais (LMME) da OMS. Resultados: Do total de países, 87,2% dispõem de uma LNM e 91%, de GPCs (78% e 45%, respectivamente, atualizadas nos últimos 5 anos). Em comparação com os seis grupos de agentes hipoglicemiantes da LMME, as LMNs tinham uma mediana (intervalo) de 6 (4 a 13) e uma pontuação F1 de 0,80, o que indica uma conformidade adequada. As GPCs tinham uma mediana (intervalo) de 12 (1 a 12) agentes hipoglicemiantes, em comparação com 8 nos guias da OMS. As GPCs tinham uma mediana de 15 medicamentos a mais do que as respectivas LNMs. Conclusões: Embora a maioria dos países da América Latina e do Caribe disponha de LNMs e GPCs para o diabetes, a falta de concordância entre elas limita sua eficácia. É necessário alinhar os processos e os critérios de desenvolvimento dessas duas ferramentas da política de medicamentos.

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.

The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal. OBJECTIVES: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET. METHODS: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response. RESULTS: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events. CONCLUSIONS: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT.

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.

Concordancia entre las listas de medicamentos esenciales y las guías para diabetes en América Latina y el Caribe / Concordance between essential medicines lists and diabetes guidelines in Latin America and the Caribbean / Concordância entre as listas de medicamentos essenciais e diretrizes para diabetes na América Latina e no Caribe

RESUMEN Objetivo. Analizar la existencia y actualización de las listas de medicamentos nacionales (LMN) y guías de práctica clínica (GPC) para el tratamiento de la diabetes en América Latina y el Caribe (ALC). Comparar los fármacos incluidos en las listas y guías de cada país, entre sí y con los de la Organización Mundial de la Salud (OMS). Métodos. Estudio de corte transversal. Se identificaron las LMN y GPC para diabetes en los sitios web de la Organización Panamericana de la Salud y de las autoridades sanitarias nacionales. Se relevaron los fármacos y se analizaron por grupo farmacológico según el cuarto nivel de la nomenclatura ATC. Se utilizó el puntaje F1 para evaluar la proximidad de las LMN con la lista modelo de medicamentos esenciales (LMME) de la OMS. Resultados. Del total de países, 87,2% cuentan con LMN, y 91% con GPC (78% y 45% actualizadas en los últimos 5 años, respectivamente). En comparación con los 6 grupos de hipoglucemiantes de la LMME, las LMN tenían una mediana (rango) de 6 (4-13) y un puntaje F1 de 0,80; esto indica una consonancia adecuada. Las GPC tenían una mediana (rango) de 12 (1-12) hipoglucemiantes frente a los 8 de las guías de la OMS. Las GPC tuvieron una mediana de 15 fármacos más que las respectivas LMN. Conclusiones. Si bien la mayoría de los países de ALC cuentan con LMN y GPC para diabetes, la falta de concordancia entre ellas limita su eficacia. Es necesario alinear los procesos y criterios de elaboración de estas dos herramientas de la política de medicamentos.

ABSTRACT Objective. Conduct an analysis to determine the existence and updating of national essential medicines lists (EMLs) and clinical practice guidelines (CPGs) for the treatment of diabetes in Latin America and the Caribbean (LAC); and compare the medicines included in each country's list and guidelines both with each other and with those of the World Health Organization (WHO). Methods. Cross-sectional study. EMLs and CPGs for diabetes were found on the websites of the Pan American Health Organization and national health authorities. Medicines were noted and analyzed according to pharmacological group, based on the fourth level of nomenclature of the Anatomical Therapeutic Chemical (ATC) classification system. F1 scoring was used to assess the proximity of EMLs to the WHO Model List of Essential Medicines (MLEM). Results. Of the total number of countries, 87.2% have EMLs, and 91% have CPGs (78% and 45% updated in the last five years, respectively). Compared to the six hypoglycemic groups of the MLEM, the EMLs had a median (range) of 6 (4-13) and an F1 score of 0.80; This indicates proper alignment. CPGs had a median (range) of 12 (1-12) hypoglycemic drugs compared to eight in the WHO guidelines. CPGs had a median of 15 more drugs than their respective EMLs. Conclusions. While most LAC countries have EMLs and CPGs for diabetes, the lack of concordance among them limits their effectiveness. It is necessary to align the processes and criteria for the development of these two tools for policymaking on medicines.

RESUMO Objetivos. Analisar a existência e a atualização das listas nacionais de medicamentos (LNMs) e guias de prática clínica (GPCs) para o tratamento do diabetes na América Latina e no Caribe (ALC). Comparar os medicamentos incluídos nas listas e nas diretrizes de cada país entre si e com as da Organização Mundial da Saúde (OMS). Métodos. Estudo transversal. Foram identificadas LMNs e GPCs para o diabetes nos sites da Organização Pan-Americana da Saúde e das autoridades sanitárias nacionais. Os medicamentos foram pesquisados e analisados por grupo farmacológico de acordo com o quarto nível da classificação ATC. A pontuação F1 foi utilizada para avaliar o grau de proximidade das LMNs com a lista-modelo de medicamentos essenciais (LMME) da OMS. Resultados. Do total de países, 87,2% dispõem de uma LNM e 91%, de GPCs (78% e 45%, respectivamente, atualizadas nos últimos 5 anos). Em comparação com os seis grupos de agentes hipoglicemiantes da LMME, as LMNs tinham uma mediana (intervalo) de 6 (4 a 13) e uma pontuação F1 de 0,80, o que indica uma conformidade adequada. As GPCs tinham uma mediana (intervalo) de 12 (1 a 12) agentes hipoglicemiantes, em comparação com 8 nos guias da OMS. As GPCs tinham uma mediana de 15 medicamentos a mais do que as respectivas LNMs. Conclusões. Embora a maioria dos países da América Latina e do Caribe disponha de LNMs e GPCs para o diabetes, a falta de concordância entre elas limita sua eficácia. É necessário alinhar os processos e os critérios de desenvolvimento dessas duas ferramentas da política de medicamentos.

Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF). Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat. Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences. Trial registration numbers: NCT05287503, EudraCT 2021-004565-13.

Structural and connectivity parameters reveal spared connectivity in young patients with non-progressive compared to slow-progressive cerebellar ataxia.

Introduction: Within Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of compensatory strategies of the intact areas in NonP brain network. Methods: Eleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate whether eventual spared connectivity between basal ganglia and cerebellum explains the different postural motor behavior of NonP and SlowP patients. Results: Cerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. Discussion: This work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the possible compensatory role of basal ganglia in patients with stable cerebellar malformation.

Differential diagnosis of neurodegenerative dementias with the explainable MRI based machine learning algorithm MUQUBIA.

Biomarker-based differential diagnosis of the most common forms of dementia is becoming increasingly important. Machine learning (ML) may be able to address this challenge. The aim of this study was to develop and interpret a ML algorithm capable of differentiating Alzheimer's dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal control subjects based on sociodemographic, clinical, and magnetic resonance imaging (MRI) variables. 506 subjects from 5 databases were included. MRI images were processed with FreeSurfer, LPA, and TRACULA to obtain brain volumes and thicknesses, white matter lesions and diffusion metrics. MRI metrics were used in conjunction with clinical and demographic data to perform differential diagnosis based on a Support Vector Machine model called MUQUBIA (Multimodal Quantification of Brain whIte matter biomArkers). Age, gender, Clinical Dementia Rating (CDR) Dementia Staging Instrument, and 19 imaging features formed the best set of discriminative features. The predictive model performed with an overall Area Under the Curve of 98%, high overall precision (88%), recall (88%), and F1 scores (88%) in the test group, and good Label Ranking Average Precision score (0.95) in a subset of neuropathologically assessed patients. The results of MUQUBIA were explained by the SHapley Additive exPlanations (SHAP) method. The MUQUBIA algorithm successfully classified various dementias with good performance using cost-effective clinical and MRI information, and with independent validation, has the potential to assist physicians in their clinical diagnosis.

Electroencephalography as a Biomarker of Prognosis in Acute Brain Injury.

Electroencephalography (EEG) is a noninvasive tool that allows the monitoring of cerebral brain function in critically ill patients, aiding with diagnosis, management, and prognostication. Specific EEG features have shown utility in the prediction of outcomes in critically ill patients with status epilepticus, acute brain injury (ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, and traumatic brain injury), anoxic brain injury, and toxic-metabolic encephalopathy. Studies have also found an association between particular EEG patterns and long-term functional and cognitive outcomes as well as prediction of recovery of consciousness following acute brain injury. This review summarizes these findings and demonstrates the value of utilizing EEG findings in the determination of prognosis.

Normative values of the topological metrics of the structural connectome: A multi-site reproducibility study across the Italian Neuroscience network.

PURPOSE: The use of topological metrics to derive quantitative descriptors from structural connectomes is receiving increasing attention but deserves specific studies to investigate their reproducibility and variability in the clinical context. This work exploits the harmonization of diffusion-weighted acquisition for neuroimaging data performed by the Italian Neuroscience and Neurorehabilitation Network initiative to obtain normative values of topological metrics and to investigate their reproducibility and variability across centers. METHODS: Different topological metrics, at global and local level, were calculated on multishell diffusion-weighted data acquired at high-field (e.g. 3 T) Magnetic Resonance Imaging scanners in 13 different centers, following the harmonization of the acquisition protocol, on young and healthy adults. A "traveling brains" dataset acquired on a subgroup of subjects at 3 different centers was also analyzed as reference data. All data were processed following a common processing pipeline that includes data pre-processing, tractography, generation of structural connectomes and calculation of graph-based metrics. The results were evaluated both with statistical analysis of variability and consistency among sites with the traveling brains range. In addition, inter-site reproducibility was assessed in terms of intra-class correlation variability. RESULTS: The results show an inter-center and inter-subject variability of <10%, except for "clustering coefficient" (variability of 30%). Statistical analysis identifies significant differences among sites, as expected given the wide range of scanners' hardware. CONCLUSIONS: The results show low variability of connectivity topological metrics across sites running a harmonised protocol.

Utilization of the ketogenic diet for adults with status epilepticus.

BACKGROUND: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with therapeutic potential in refractory seizures, both in outpatient and inpatient settings. Successful implementation of KD involves a multifaceted, interdisciplinary approach to address anticipated challenges. We sought to characterize the utilization of KD among healthcare providers caring for adults with status epilepticus (SE). METHODS: We distributed a web-based survey through professional societies, including the American Academy of Neurology (AAN), Neurocritical Care Society (NCS), American Epilepsy Society (AES), Neuro Anesthesia and Critical Care Society (NACCS), and the Academy of Nutrition and Dietetics (AND), and via research contacts. We asked respondents about practice experience and experience using KD as a treatment for SE. Descriptive statistics and Chi-square tests were used to analyze the results. RESULTS: Of 156 respondents, 80% of physicians and 18% of non-physicians reported experience with KD for SE. Anticipated difficulty in achieving ketosis (36.3%), lack of expertise (24.2%), and lack of resources (20.9%) were identified as the most important barriers limiting the utilization of KD. The absence of dietitians (37.1%) or pharmacists (25.7%) support was the most important missing resource. Reasons for stopping KD included perceived ineffectiveness (29.1%), difficulty achieving ketosis (24.6%), and side effects (17.3%). Academic centers had more experience with the use of KD and greater EEG monitoring availability and fewer barriers to its implementation. The need for randomized clinical trials supporting efficacy (36.5%) and better practice guidelines for implementation and maintenance of KD (29.6%) were cited most frequently as factors to increase utilization of KD. CONCLUSION: This study identifies important barriers to the utilization of KD as a treatment for SE despite evidence supporting its efficacy in the appropriate clinical context, namely lack of resources and interdisciplinary support, and lack of established practice guidelines. Our results highlight the need for future research to improve understanding of the efficacy and safety of KD along with better interdisciplinary collaborations to increase its utilization.

Quality assessment, variability and reproducibility of anatomical measurements derived from T1-weighted brain imaging: The RIN-Neuroimaging Network case study.

Initiatives for the collection of harmonized MRI datasets are growing continuously, opening questions on the reliability of results obtained in multi-site contexts. Here we present the assessment of the brain anatomical variability of MRI-derived measurements obtained from T1-weighted images, acquired according to the Standard Operating Procedures, promoted by the RIN-Neuroimaging Network. A multicentric dataset composed of 77 brain T1w acquisitions of young healthy volunteers (mean age = 29.7 ± 5.0 years), collected in 15 sites with MRI scanners of three different vendors, was considered. Parallelly, a dataset of 7 "traveling" subjects, each undergoing three acquisitions with scanners from different vendors, was also used. Intra-site, intra-vendor, and inter-site variabilities were evaluated in terms of the percentage standard deviation of volumetric and cortical thickness measures. Image quality metrics such as contrast-to-noise and signal-to-noise ratio in gray and white matter were also assessed for all sites and vendors. The results showed a measured global variability that ranges from 11% to 19% for subcortical volumes and from 3% to 10% for cortical thicknesses. Univariate distributions of the normalized volumes of subcortical regions, as well as the distributions of the thickness of cortical parcels appeared to be significantly different among sites in 8 subcortical (out of 17) and 21 cortical (out of 68) regions of i nterest in the multicentric study. The Bland-Altman analysis on "traveling" brain measurements did not detect systematic scanner biases even though a multivariate classification approach was able to classify the scanner vendor from brain measures with an accuracy of 0.60 ± 0.14 (chance level 0.33).

Craniovertebral Junction Instability after Oncological Resection: A Narrative Review.

The craniovertebral junction (CVJ) is a complex transition area between the skull and cervical spine. Pathologies such as chordoma, chondrosarcoma and aneurysmal bone cysts may be encountered in this anatomical area and may predispose individuals to joint instability. An adequate clinical and radiological assessment is mandatory to predict any postoperative instability and the need for fixation. There is no common consensus on the need for, timing and setting of craniovertebral fixation techniques after a craniovertebral oncological surgery. The aim of the present review is to summarize the anatomy, biomechanics and pathology of the craniovertebral junction and to describe the available surgical approaches to and considerations of joint instability after craniovertebral tumor resections. Although a one-size-fits-all approach cannot encompass the extremely challenging pathologies encountered in the CVJ area, including the possible mechanical instability that is a consequence of oncological resections, the optimal surgical strategy (anterior vs posterior vs posterolateral) tailored to the patient's needs can be assessed preoperatively in many instances. Preserving the intrinsic and extrinsic ligaments, principally the transverse ligament, and the bony structures, namely the C1 anterior arch and occipital condyle, ensures spinal stability in most of the cases. Conversely, in situations that require the removal of those structures, or in cases where they are disrupted by the tumor, a thorough clinical and radiological assessment is needed to timely detect any instability and to plan a surgical stabilization procedure. We hope that this review will help shed light on the current evidence and pave the way for future studies on this topic.