A Compartmental Model for the Iron Trafficking Across the Blood-Brain Barriers in Neurodegenerative Diseases.

Iron accumulation in the brain is supposed to play a central role in the induction of oxidative stress and consequently in neurodegeneration. The sensitive balance of iron in the brain is maintained by the brain barriers system, i.e., the blood-brain barrier between the blood and brain interstitial fluid and the blood-cerebrospinal fluid barrier between the blood and cerebrospinal fluid (CSF). In this work, we proposed a three-compartmental mathematical model simulating iron trafficking between blood, CSF, and cerebral space, describing the direction of fluxes based on the structural and functional characteristics of the brain barriers system. Different techniques of sensitivity analysis were used to evaluate the most important parameters, providing an indication for the most relevant biological functions that potentially affect the physiological transport of iron across brain barriers.

A mathematical model for the evaluation of iron transport across the blood-cerebrospinal fluid barrier in neurodegenerative diseases.

Iron plays important roles in healthy brain but altered homeostasis and concentration have been correlated to aging and neurodegenerative diseases. Iron enters the central nervous system by crossing the brain barrier systems: the Blood- Brain Barrier separating blood and brain and the Blood-Cerebrospinal Fluid Barrier (BCSFB) between blood and CSF, which is in contact with the brain by far less selective barriers. Herein, we develop a two-compartmental model for the BCSFB, based on first-order ordinary differential equations, performing numerical simulations and sensitivity analysis. Furthermore, as input parameters of the model, experimental data from patients affected by Alzheimer's disease, frontotemporal dementia, mild cognitive impairment and matched neurological controls were used, with the aim of investigating the differences between physiological and pathological conditions in the regulation of iron passage between blood and CSF which can be possibly targeted by therapy.

A novel neurocognitive approach for placebo analgesia in neurocognitive disorders.

Neural correlates of placebo analgesia (PA) in patients with neurocognitive disorders have not yet been elucidated. The present study aimed to evaluate how and to what extent executive (dys)functions of the medial prefrontal cortex (MPFC) may be related to PA. To this end, twenty-three subjects complaining of different cognitive deficits (from mild cognitive impairment likely due to Alzheimer's disease to mild AD) were recruited. PA was investigated by a well-known experimental venipuncture pain paradigm (open versus hidden [O-H] application of lidocaine). Patients also underwent a comprehensive neuropsychological evaluation and a functional magnetic resonance imaging (fMRI) GO/No-GO task for eliciting selective activation of the MPFC. Selected neuropsychological variables were correlated to the OH-PA paradigm. The association between the fMRI response on the "No-GO" versus "GO" contrast and PA was investigated over the whole-brain by regression analysis. We showed the existence of a relationship between a lower PA and MPFC dysfunctions through the neuropsychological and fMRI assessment. A separate voxel-based morphometry (VBM) analysis controlled for possible influence of grey matter (GM) volume reduction on both fMRI results and PA. fMRI results were not directly affected by, and therefore independent of, disease-specific GM atrophy, which was indeed located more anteriorly within the rostral anterior cingulate and inversely correlated with PA. Our findings shed new light on the underestimated contribution of executive (dys)functions mediated by the MPFC (response-inhibition, self-monitoring and set-shifting abilities) in PA pathogenesis, with a special purely (i.e. independently from brain structural alterations) functional role played by the MCC. Results are discussed in terms of possible clinical relevance in the management of patients with neurocognitive disorders.

Recent advances in the molecular genetics of frontotemporal lobar degeneration.

The term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes. Genetic variants in three genes, MAPT, GRN and C9orf72, account for about half of familial FTLD cases. In addition, rare defects in the CHMP2B, VCP, TARDBP, SQSTM1, FUS, UBQLN, OPTN, TREM2, CHCHD10 and TBK1 genes have been described. Additional genes are expected to be found in near future. The purpose of this review is to describe recent advances in the molecular genetics of the FTLD spectrum and to discuss implications for genetic counseling.

Consensus Paper: Cerebellum and Emotion.

Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing.

Chemotherapy-Induced Neurotoxicity: Evidence of a Protective Role of CC Homozygosis in the Interleukin-1ß Gene-511 C>T Polymorphism.

We hypothesized that the IL-1ß-511 C>T polymorphism could be associated with the development of neurotoxicity and that it could be a possible biomarker to rate the risk of occurrence of neurotoxicity in cancer patients. Genomic DNA was extracted from 85 cancer patients: 49 received systemic chemotherapeutic treatment (CHT) and 36 patients did not receive it (No-CHT). All subjects were genotyped for the functionally active polymorphisms of IL-1ß-511 C>T. We estimated neurotoxicity with the evaluation of neurological deficits. CHT patients showed erythrocytopenia, neurological deficit and a slight lowering of cognitive performance. The subgroup of patients carrying the CC genotype of the IL-1ß-511 C>T gene showed lesser neurological deficits. In the context of cancer treatment, we suggested the potential value of IL-1ß-511 C>T as genetic biomarkers to identify patients with higher risk to develop neurological deficits.

Cerebellar Clustering and Functional Connectivity During Pain Processing.

The cerebellum has been traditionally considered a sensory-motor structure, but more recently has been related to other cognitive and affective functions. Previous research and meta-analytic studies suggested that it could be involved in pain processing. Our aim was to distinguish the functional networks subserved by the cerebellum during pain processing. We used functional magnetic resonance imaging (fMRI) on 12 subjects undergoing mechanical pain stimulation and resting state acquisition. For the analysis of data, we used fuzzy c-mean to cluster cerebellar activity of each participant during nociception. The mean time courses of the clusters were used as regressors in a general linear model (GLM) analysis to explore brain functional connectivity (FC) of the cerebellar clusters. We compared our results with the resting state FC of the same cluster and explored with meta-analysis the behavior profile of the FC networks. We identified three significant clusters: cluster V, involving the culmen and quadrangular lobules (vermis IV-V, hemispheres IV-V-VI); cluster VI, involving the posterior quadrangular lobule and superior semilunar lobule (hemisphere VI, crus 1, crus 2), and cluster VII, involving the inferior semilunar lobule (VIIb, crus1, crus 2). Cluster V was more connected during pain with sensory-motor areas, cluster VI with cognitive areas, and cluster VII with emotional areas. Our results indicate that during the application of mechanical punctate stimuli, the cerebellum is not only involved in sensory functions but also with areas typically associated with cognitive and affective functions. Cerebellum seems to be involved in various aspects of nociception, reflecting the multidimensionality of pain perception.

Identifying neuroanatomical signatures of anorexia nervosa: a multivariate machine learning approach.

BACKGROUND: There are currently no neuroanatomical biomarkers of anorexia nervosa (AN) available to make clinical inferences at an individual subject level. We present results of a multivariate machine learning (ML) approach utilizing structural neuroanatomical scan data to differentiate AN patients from matched healthy controls at an individual subject level. METHOD: Structural neuroimaging scans were acquired from 15 female patients with AN (age = 20, s.d. = 4 years) and 15 demographically matched female controls (age = 22, s.d. = 3 years). Neuroanatomical volumes were extracted using the FreeSurfer software and input into the Least Absolute Shrinkage and Selection Operator (LASSO) multivariate ML algorithm. LASSO was 'trained' to identify 'novel' individual subjects as either AN patients or healthy controls. Furthermore, the model estimated the probability that an individual subject belonged to the AN group based on an individual scan. RESULTS: The model correctly predicted 25 out of 30 subjects, translating into 83.3% accuracy (sensitivity 86.7%, specificity 80.0%) (p < 0.001; χ 2 test). Six neuroanatomical regions (cerebellum white matter, choroid plexus, putamen, accumbens, the diencephalon and the third ventricle) were found to be relevant in distinguishing individual AN patients from healthy controls. The predicted probabilities showed a linear relationship with drive for thinness clinical scores (r = 0.52, p < 0.005) and with body mass index (BMI) (r = -0.45, p = 0.01). CONCLUSIONS: The model achieved a good predictive accuracy and drive for thinness showed a strong neuroanatomical signature. These results indicate that neuroimaging scans coupled with ML techniques have the potential to provide information at an individual subject level that might be relevant to clinical outcomes.

The Neurobiological Basis of the Distress Thermometer: A PET Study in Cancer Patients.

The objective of this study was to investigate the possible associations between the Distress Thermometer (DT) scores and the brain metabolism of structures involved in stress response. Twenty-one cancer patients were assessed using the DT, Problem Checklist and Hospital Anxiety and Depression Scale (HADS). The psychological measures were correlated with [18 F]PET-FDG brain glucose metabolism. Multiple and linear regression and binary logistic regression were run to analyse data. The DT and HADS scores illustrated that 48% of patients were distressed, 19% were depressed and 48% were anxious. Results showed that some subcortical areas activity, such as part of midbrain and of hypothalamus, was correlated with the DT scores. The Problem Checklist scores correlated with the activity of the same areas and included more regions in the limbic forebrain and brainstem. Compared with the DT and Problem Checklist, HADS-Depression scores showed a more extensive pattern of correlation with brain activity, including limbic and cortical areas. The results highlighted that the DT scores correlated with the activity of brain areas typically involved in stress response. Indeed, hypothalamus metabolism was found to be the best predictor of distressed patients.

Impairment of emotional facial expression and prosody discrimination due to ischemic cerebellar lesions.

A growing literature points to a specific role of the cerebellum in affect processing. However, understanding of affect processing disturbances following discrete cerebellar lesions is limited. We administered the Tübingen Affect Battery to assess recognition of emotional facial expression and emotional prosody in 15 patients with a cerebellar infarction and 10 age-matched controls. On emotional facial expression tasks, patients compared to controls showed impaired selection and matching of facial affect. On prosody tasks, patients showed marked impairments in naming affect and discriminating incongruencies. These deficits were more pronounced for negative affects. Our results confirm a significant role of the cerebellum in processing emotional recognition, a component of social cognition.

Intrinsic connectivity networks within cerebellum and beyond in eating disorders.

Cerebellum seems to have a role both in feeding behavior and emotion regulation; therefore, it is a region that warrants further neuroimaging studies in eating disorders, severe conditions that determine a significant impairment in the physical and psychological domain. The aim of this study was to examine the cerebellum intrinsic connectivity during functional magnetic resonance imaging resting state in anorexia nervosa (AN), bulimia nervosa (BN), and healthy controls (CN). Resting state brain activity was decomposed into intrinsic connectivity networks (ICNs) using group spatial independent component analysis on the resting blood oxygenation level dependent time courses of 12 AN, 12 BN, and 10 CN. We extracted the cerebellar ICN and compared it between groups. Intrinsic connectivity within the cerebellar network showed some common alterations in eating disordered compared to healthy subjects (e.g., a greater connectivity with insulae, vermis, and paravermis and a lesser connectivity with parietal lobe); AN and BN patients were characterized by some peculiar alterations in connectivity patterns (e.g., greater connectivity with the insulae in AN compared to BN, greater connectivity with anterior cingulate cortex in BN compared to AN). Our data are consistent with the presence of different alterations in the cerebellar network in AN and BN patients that could be related to psychopathologic dimensions of eating disorders.

The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients.

AIM: A growing number of neuropsychological studies reported that chemotherapy may impair brain functions, inducing persistent cognitive changes in a subset of cancer survivors. The aim of this paper was to investigate the neural basis of the chemotherapy induced neurobehavioral changes by means of metabolic imaging and neuropsychological testing. METHODS: We studied the resting brain [¹8F]FDG-PET/CT images of 50 adult cancer patients with diagnosis of lymphoma: 18 patients were studied prior and 32 after to chemotherapy. All patients underwent to a neuropsychological examination assessing cognitive impairment (tests for shifting attention, verbal memory, phonemic fluency), depression, anxiety and distress. RESULTS: Compared to no chemotherapy patients, the treated group showed significant bilateral lower rate of glucose metabolism in prefrontal cortices, cerebellum, medial cortices and limbic brain areas. The metabolism of these regions negatively correlated with number of cycles and positively with post-chemotherapy time. The treated group showed a poorer performance in many frontal functions, but similar level of depression, anxiety and distress. CONCLUSIONS: Chemotherapy induced significant long-term changes in metabolism of multiple regions with a prevailing involvement of the prefrontal cortex. The observed cognitive dysfunctions could be explained by these changes. The recovery from chemotherapy is probably affected by treatment duration and by the time elapsed after its end. We speculated that the mechanism could be an accelerating ageing / oxidative stress that, in some patients at risk, could result in an early and persistent cognitive impairment.

Virtual navigation for memory rehabilitation in a traumatic brain injured patient.

The use of 3D video games in memory rehabilitation has been explored very little. A virtual navigation task allows participants to encode the spatial layout of the virtual environment and activate areas involved in memory processing. We describe the rehabilitation of a 24-year-old man with traumatic brain injury presenting memory deficits, and evaluate the efficacy of a navigational training program measuring neuropsychological changes and fMRI modification cerebral activations. Memory improvement appears to be present both after navigational training and in follow-up testing. Furthermore, fMRI data suggest that this training may increase activation of the hippocampal and parahippocampal brain regions. The results suggest that intensive training in virtual navigational tasks may result in an enhancement of memory function in brain-damaged adults.

Altered resting state attentional networks in diabetic neuropathic pain.

BACKGROUND: Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. METHODS: The authors sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. RESULTS: NP patients showed a widespread reduction in connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. The authors also found a generalised reduction in the length of functional connections in the NP group: in all the examined networks, the Euclidean distance between connected voxels was significantly shorter in patients than in controls. CONCLUSION: In diabetic NP, a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self-monitoring, pain processing and salience detection.

Disrupted intrinsic functional connectivity in the vegetative state.

It is debatable as to whether the spontaneous blood-oxygen-level dependent fluctuations that are observed in the resting brain in turn reflect consciously directed mental activity or, alternatively, constitute an intrinsic property of functional brain organisation persisting in the absence of consciousness. This report shows for the first time, in three patients, that the persistent vegetative state (PVS) is marked by a dysfunctional default mode network, with decreased connectivity in several brain regions, including the dorsolateral prefrontal cortex and anterior cingulated cortex, especially in the right hemisphere. This finding supports the view that the resting state is involved in self-consciousness, and that the right-hemisphere default state may play a major role in conscious processes. It is speculated that the default state may act as a surrogate marker of PVS with awareness contents and, therefore, could replace a more complex activation paradigm.

The effect of gender on planning: An fMRI study using the Tower of London task.

Since the introduction of brain mapping, evidences of functional gender differences have been corroborating previous behavioral and neuropsychological results showing a sex-specific brain organization. We investigated gender differences in brain activation during the performance of the Tower of London (TOL) task which is a standardized test to assess executive functions. Eighteen healthy subjects (9 females and 9 males) underwent fMRI scanning while solving a series of TOL problems with different levels of difficulty. Data were analyzed by modeling both genders and difficulty task load. Task-elicited brain activations comprised a bilateral fronto-parietal network, common to both genders; within this network, females activated more than males in dorsolateral prefrontal cortex (DLPFC) and right parietal cortex, whereas males showed higher activity in precuneus. A prominent parietal activity was found at low level of difficulty while, with heavier task demand, several frontal regions and subcortical structures were recruited. Our results suggest peculiar gender strategies, with males relying more on visuospatial abilities and females on executive processing.