Functional Integrity Of Brain Research Articles

Copper homeostasis and the ubiquitin proteasome system.

Copper is involved in many physiological pathways and important biological processes as a cofactor of several copper-dependent enzymes. Given the requirement for copper and its potential toxicity, intracellular copper levels are tightly controlled. Disturbances of human copper homeostasis are characterized by disorders of copper overload (Wilson's disease) or copper deficiency (Menkes disease). The maintenance of cellular copper levels involves numerous copper transporters and copper chaperones. Recently, accumulating evidence has revealed that components of the ubiquitin proteasome system (UPS) participate in the posttranslational regulation of these proteins, suggesting that they might play a role in maintaining copper homeostasis. Cellular copper levels could also affect the activity of the UPS, indicating that copper homeostasis and the UPS are interdependent. Copper homeostasis and the UPS are essential to the integrity of normal brain function and while separate links between neurodegenerative diseases and UPS inhibition/copper dyshomeostasis have been extensively reported, there is growing evidence that these two networks might contribute synergistically to the occurrence of neurodegenerative diseases. Here, we review the role of copper and the UPS in the development of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and discuss the genetic interactions between copper transporters/chaperones and components of the UPS.

Cognitive and neuroimaging outcomes in individuals with benign and low-grade brain tumours receiving radiotherapy: a protocol for a prospective cohort study

IntroductionRadiation-induced cognitive decline (RICD) occurs in 50%–90% of adult patients 6 months post-treatment. In patients with low-grade and benign tumours with long expected survival, this is of paramount importance. Despite...

A neuroergonomic approach to assessing motor performance in stroke patients using fNIRS and behavioral data

Stroke is characterized by high morbidity and disability, and proposing effective methods for assessing and designing rehabilitation products is an attractive topic in current research. In this study, a hand function rehabilitation aid was developed for stroke patients. Ten stroke patients and 20 healthy older people as a control group were recruited to perform a 600 s task after a 600 s resting by gripping a stick while clicking on a flashing light in an electronic insert in sequence according to a pattern. The functional near-infrared spectroscopy (fNIRS) and behavioral data were collected during their rehabilitation training. Brain function was analyzed using three indicators, namely brain area activation, functional connectivity and effective connectivity, while behavioral performance was analyzed using ten indicators, such as velocity and acceleration, and correlations were made between both. Followed by proposing a quantitative assessment method based on the fusion of multiple data sources. The results showed that the developed rehabilitation tool could effectively stimulate the patient's brain and help recover their cognitive and behavioral capacities. The scientific validity of the proposed assessment approach was further confirmed by contrasting the data results of the stroke group with those of the healthy elderly group. This study has integrated brain function and behavioral data, providing a practical quantitative evaluation method of product ergonomics and data-driven product design concepts for stroke patients.

DUAL-TASK TRAINING FOR IMPROVING COGNITIVE-MOTOR INTERFERENCE

Abstract Dr. Bhatt will discuss the differences in types of cognitive motor interference patterns experienced for different tasks (gaitand volitional versus reactive balance) in cognitively intact versus people with mild cognitive impairment. She will discuss the effectiveness of dual-task training and exergaming on gait, volitional and reactive balance control in older adults with mild cognitive impairment. After 4 weeks of such training, the results showed beneficial effects on improving volitional based performance when performed with a cognitive task (i.e., spatial memory and executive function) and had significant improvement in NIH toolbox (cognitive- increased working memory, episodic memory and executive function, and motor-increased gait speed). However, its positive effects on dual task reactive balance control were limited. Additionally, the speaker will go on to discuss the associations of balance control deficits in mild cognitive impairment with neural correlates (structural and functional brain integrity) to understand the attributing factors to increased fall risk in people with mild cognitive impairment.

C‐reactive protein (CRP) blood concentrations associate with reduced global system segregation in middle‐aged individuals

AbstractBackgroundHigh concentrations of circulating C‐reactive protein (CRP) have been related to poorer cognition in adults (Lewis et al. Age Ageing. 2021;50:2199). Within the Lifebrain consortium (Walhovd et al. Eur Psychiatry. 2018;50:47), we recently reported overall lifespan associations between increased CRP and smaller hippocampal (HPC) volumes, albeit these could not be observed in one subsample of middle‐aged individuals (Wang et al. Brain Behav Immun. 2022;100:243). Here we hypothesized that functional brain integrity measures would be sensitive to predict CRP levels in this group. We focused on global system segregation (SyS) a graph theory‐based metric which quantifies the extent to which major functional networks are segregated from each other.MethodWe included 336 volunteers (mean age 53.8; SD: 7.1; 47.9% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018;10:321). High‐sensitive CRP (hsCRP) concentrations were determined through dry blood samples and log10 transformed (Wang et al. Brain Behav Immun. 2022;100:243). Adjusted HPC volumes were estimated from T1‐wheigthed 3T MRI acquisitions (Raz et al. Cereb Cortex 2005;15:1676). SyS values were calculated (Ewers et al. Brain. 2021;144:2176) from 100 nodes defined by the Schaefer‐Yeo atlas (Fig 1a). Multiple linear regression investigated the associations between age, gender, cognitive function (MMSE and episodic memory), HPC volumes, APOE status and SyS as predictor variables and hs‐CRP as the dependent measure.ResultIn the adjusted model only SyS (β= ‐0.56, p<0.05) and APOE (β= ‐0.21, p=0.003) predicted hsCRP concentrations. Global SyS was negatively related to hsCRP (Fig 1b). As in Wang et al (2022), APOE E4 carriers (N=71; mean:‐0.43; SD=0.62) exhibited lower CRP circulating levels than non‐E4 bearers (N=265; mean: ‐0.20; SD=0.51; t=3.23, p<0.001), however there were no differences in SyS according to APOE genotypes (t=0.95, p=0.34).Conclusionhs‐CRP blood concentrations were predicted by global segregation of functional networks in absence of HPC volume or cognitive status effects. As such, blood derived hsCRP levels may represent an early indicator of middle‐age individual variations in a measure recently reported to predict future cognitive decline (Chan et al. Nat Aging 2021;1:1053) and represent a cognitive resilience mechanism in the face of AD pathology (Ewers et al. Brain. 2021;144:2176).

Ginkgolides and bilobalide for treatment of Alzheimer's disease and COVID-19: potential mechanisms of action.

Alzheimer's disease (AD) is an irreversible degenerative illness of the central nervous system with characteristic histological alterations, known as amyloid plaques and neurofibrillary tangles (NFT). Aggregation of plaques and tangles in the brain induces neurotoxicity and synaptic dysfunction, eventually contributing to neuronal cell death and neurodegeneration. Recent studies have revealed that COVID-19 has a great impact on the development of AD, directly or indirectly, by facilitating the accumulation of amyloid plaques, causing altered functional brain integrity or increasing the phosphorylation rate of tau protein. As two important bioactive components of Ginkgo biloba extract (GbE), ginkgolides and bilobalide (BB) have been reported to show neuroprotective effects in AD via multiple mechanisms such as anti-excitotoxicity, anti-inflammatory and anti-oxidative activities. Intriguingly, ginkgolides and BB also seem to demonstrate antiviral properties against COVID-19 by inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. Herein, we review studies on the neuroprotective and antiviral mechanisms of ginkgolides and bilobalide, as well as their therapeutic potential against AD and COVID-19.

Neural efficiency and proficiency adaptation of effective connectivity corresponding to early and advanced skill levels in athletes of racket sports.

This study explored how the neural efficiency and proficiency worked in athletes with different skill levels from the perspective of effective connectivity brain network in resting state. The deconvolved conditioned Granger causality (GC) analysis was applied to functional magnetic resonance imaging (fMRI) data of 35 elite athletes (EAs) and 42 student-athletes (SAs) of racket sports as well as 39 normal controls (NCs), to obtain the voxel-wised hemodynamic response function (HRF) parameters representing the functional segregation and effective connectivity representing the functional integration. The results showed decreased time-to-peak of HRF in the visual attention brain regions in the two athlete groups compared with NC and decreased response height in the advanced motor control brain regions in EA comparing to the nonelite groups, suggesting the neural efficiency represented by the regional HRF was different in early and advanced skill levels. GC analysis demonstrated that the GC values within the middle occipital gyrus had a linear trend from negative to positive, suggesting a stepwise "neural proficiency" of the effective connectivity from NC to SA then to EA. The GC values of the inter-lobe circuits in EA had the trend to regress to NC levels, in agreement with the neural efficiency of these circuits in EA. Further feature selection approach suggested the important role of the cerebral-brainstem GC circuit for discriminating EA. Our findings gave new insight into the complementary neural mechanisms in brain functional segregation and integration, which was associated with early and advanced skill levels in athletes of racket sports.

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person’s risk for Alzheimer’s disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from −0.08 to −0.11), tested cognitive deficits (β's from −0.36 to −0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from −0.18 to −0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Interindividual variability in functional connectivity discovers differential development of cognition and transdiagnostic dimensions of psychopathology in youth

Cognitive and psychological development during adolescence is different from one another, which is rooted in individual differences in maturational changes in the adolescent brain. This study employed multi-modal MRI data and characterized interindividual variability in functional connectivity (IVFC) and its associations with cognition and psychopathology using the Philadelphia Neurodevelopmental Cohort (PNC) of 755 youth. We employed resting state functional MRI (rs-fMRI) and diffusion weighted images (DWIs) to estimate brain structural and functional networks. We computed the IVFC of individuals and examined its relation with structural and functional organizations. We further employed sparse partial least squares (sparse-PLS) and meta-analysis to examine the developmental associations of the IVFC with cognition and transdiagnostic dimensions of psychopathology in early, middle, and late adolescence. Our results revealed that the IVFC spatial topography reflects the brain functional integration and structure-function decoupling. Age effects on the IVFC of association networks were mediated by the FC among the triple networks, including frontoparietal, salience, and default mode networks (DMN), while those of primary and cerebellar networks were mediated by the cerebello-cortical FC. The IVFC of the triple and cerebellar networks explained the variance of executive functions and externalizing behaviors in early adolescence and then the variance of emotion and internalizing and psychosis in middle and late adolescence. We further evaluated this finding via meta-analysis on task-based studies on cognition and psychopathology. These findings implicate the emerging importance of the IVFC of the triple and cerebellar networks in cognitive, emotional, and psychopathological development during adolescence.

Research progress and application of transfer entropy algorithm

In recent years, exploring the physiological and pathological mechanisms of brain functional integration from the neural network level has become one of the focuses of neuroscience research. Due to the non-stationary and nonlinear characteristics of neural signals, its linear characteristics are not sufficient to fully explain the potential neurophysiological activity mechanism in the implementation of complex brain functions. In order to overcome the limitation that the linear algorithm cannot effectively analyze the nonlinear characteristics of signals, researchers proposed the transfer entropy (TE) algorithm. In recent years, with the introduction of the concept of brain functional network, TE has been continuously optimized as a powerful tool for nonlinear time series multivariate analysis. This paper first introduces the principle of TE algorithm and the research progress of related improved algorithms, discusses and compares their respective characteristics, and then summarizes the application of TE algorithm in the field of electrophysiological signal analysis. Finally, combined with the research progress in recent years, the existing problems of TE are discussed, and the future development direction is prospected.

Electrophysiological resting-state hyperconnectivity and poorer behavioural regulation as predisposing profiles of adolescent binge drinking.

Adolescent Binge Drinking (BD) has become an increasing health and social concern, with detrimental consequences for brain development and functional integrity. However, research on neurophysiological and neuropsychological traits predisposing to BD are limited at this time. In this work, we conducted a 2‐year longitudinal magnetoencephalography (MEG) study over a cohort of initially alcohol‐naïve adolescents with the purpose of exploring anomalies in resting‐state electrophysiological networks, impulsivity, sensation‐seeking, and dysexecutive behaviour able to predict future BD patterns. In a sample of 67 alcohol‐naïve adolescents (age = 14.5 ± 0.9), we measured resting‐state activity using MEG. Additionally, we evaluated their neuropsychological traits using self‐report ecological scales (BIS‐11, SSS‐V, BDEFS, BRIEF‐SR and DEX). In a second evaluation, 2 years later, we measured participant's alcohol consumption, sub‐dividing the original sample in two groups: future binge drinkers (22 individuals, age 14.6 ± 0.8; eight females) and future light/no drinkers (17 individuals, age 14.5 ± 0.8; eight females). Then, we searched for differences predating alcohol BD intake. We found abnormalities in MEG resting state, in a form of gamma band hyperconnectivity, in those adolescents who transitioned into BD years later. Furthermore, they showed higher impulsivity, dysexecutive behaviours and sensation seeking, positively correlated with functional connectivity (FC). Sensation seeking and impulsivity mainly predicted BD severity in the future, while the relationship between dysexecutive trait and FC with future BD was mediated by sensation seeking. These findings shed light to electrophysiological and neuropsychological traits of vulnerability towards alcohol consumption. We hypothesise that these differences may rely on divergent neurobiological development of inhibitory neurotransmission pathways and executive prefrontal circuits.

Neural Correlates of Non-ordinary States of Consciousness in Pranayama Practitioners: The Role of Slow Nasal Breathing.

The modulatory effect of nasal respiration on integrative brain functions and hence consciousness has recently been unambiguously demonstrated. This effect is sustained by the olfactory epithelium mechanical sensitivity complemented by the existence of massive projections between the olfactory bulb and the prefrontal cortex. However, studies on slow nasal breathing (SNB) in the context of contemplative practices have sustained the fundamental role of respiratory vagal stimulation, with little attention to the contribution of the olfactory epithelium mechanical stimulation. This study aims at disentangling the effects of olfactory epithelium stimulation (proper of nasal breathing) from those related to respiratory vagal stimulation (common to slow nasal and mouth breathing). We investigated the psychophysiological (cardio-respiratory and electroencephalographic parameters) and phenomenological (perceived state of consciousness) aftereffects of SNB (epithelium mechanical – 2.5 breaths/min) in 12 experienced meditators. We compared the nasal breathing aftereffects with those observed after a session of mouth breathing at the same respiratory rate and with those related to a resting state condition. SNB induced (1) slowing of electroencephalography (EEG) activities (delta-theta bands) in prefrontal regions, (2) a widespread increase of theta and high-beta connectivity complemented by an increase of phase-amplitude coupling between the two bands in prefrontal and posterior regions belonging to the Default Mode Network, (3) an increase of high-beta networks small-worldness. (4) a higher perception of being in a non-ordinary state of consciousness. The emerging scenario strongly suggests that the effects of SNB, beyond the relative contribution of vagal stimulation, are mainly ascribable to olfactory epithelium stimulation. In conclusion, slow Pranayama breathing modulates brain activity and hence subjective experience up to the point of inducing a non-ordinary state of consciousness.

Altered Spontaneous Brain Activity and Functional Integration in Hemodialysis Patients With End-Stage Renal Disease

PurposeUsing the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) algorithm to study the alteration of brain function in hemodialysis patients with end-stage renal disease (ESRD).Patients and MethodsWe recruited 20 patients with ESRD on regular hemodialysis and 17 healthy controls (HCs). All of the participants underwent resting-state fMRI (rs-fMRI), neuropsychological tests, and blood biochemical examination. The individual ALFF values between the two groups were tested by an independent sample t-test. Then, we set the altered ALFF brain areas as seed regions of interest (ROIs), and FC analysis was used to investigate the functional integration patterns between the seed ROI and the voxels within the whole brain.ResultsThe ALFF values of the right precuneus and angular gyrus (RAG) in the ESRD group were lower than those in the HC subjects, but the right precentral gyrus showed higher ALFF values in patients. Hemoglobin (Hb) was negatively correlated with the ALFF values of the right precentral gyrus, and the ALFF values of the right precuneus were negatively correlated with line-tracing test (LTT) scores in patients with ESRD. Patients with ESRD show decreased connectivity between the RAG and the left precuneus, right superior frontal gyrus (RSFG), and the connectivity within the RAG was weak. In addition, FC in the RAG-right cuneus, right precuneus-left supramarginal gyrus was enhanced in the patient group.ConclusionOur research suggested that, in hemodialysis patients with ESRD, the brain areas with abnormal spontaneous brain activity and FC are mainly located in the default mode network (DMN) regions. Hb and the LTT results were correlated with abnormal spontaneous brain activity. These findings provide additional evidence to understand the possible underlying neuropathological mechanisms in patients with ESRD.

Social support mediates the influence of cerebellum functional connectivity strength on postpartum depression and postpartum depression with anxiety

Post-Partum Depression (PPD) is the most common health issue impacting emotional well being in women and is often comorbid with anxiety (PPD-A). Previous studies have shown that adequate social support can protect against PPD and PPD-A. However, how the brain connectome is disrupted in PPD and PPD-A and the neural basis underlying the role of social support in PPD and PPD-A remains unclear. The present study aims to explore these issues in patients with PPD and PPD-A. Well-established questionnaires and resting-state functional Magnetic Resonance Imaging (rsfMRI) were performed in 45 PPD, 31 PDD-A patients and 62 Healthy Postnatal Women (HPW). Brain functional integration was measured by analysis of Functional Connectivity Strength (FCS). Association and mediation analyses were performed to investigate relationships between FCS, PPD and PPD-A symptoms and social support. PPD patients showed specifically higher FCS in right parahippocampus, whereas PPD-A patients showed specifically higher FCS in left ventrolateral prefrontal cortex. In all postpartum women, depression symptoms positively correlated with FCS in left paracentral lobule; depression and anxiety symptoms were negatively correlated with FCS in right cerebellem posterior lobe (CPL), a brain region implicated in supporting social cognition and regulation of emotion. Subsequent mediation analysis revealed that perceived social support mediated the association between right CPL FCS and PPD and PPD-A symptoms. Measurement of FCS in disorder-specific neural circuits offers a potential biomarker to study and measure the efficacy of social support for PPD and PPD-A.

Bidirectional Association Between Sleep and Brain Atrophy in Aging.

Human brain aging is characterized by the gradual deterioration of its function and structure, affected by the interplay of a multitude of causal factors. The sleep, a periodically repeating state of reversible unconsciousness characterized by distinct electrical brain activity, is crucial for maintaining brain homeostasis. Indeed, insufficient sleep was associated with accelerated brain atrophy and impaired brain functional connectivity. Concurrently, alteration of sleep-related transient electrical events in senescence was correlated with structural and functional deterioration of brain regions responsible for their generation, implying the interconnectedness of sleep and brain structure. This review discusses currently available data on the link between human brain aging and sleep derived from various neuroimaging and neurophysiological methods. We advocate the notion of a mutual relationship between the sleep structure and age-related alterations of functional and structural brain integrity, pointing out the position of high-quality sleep as a potent preventive factor of early brain aging and neurodegeneration. However, further studies are needed to reveal the causality of the relationship between sleep and brain aging.

Brain state instability as a biomarker of Alzheimer’s disease progression: A dynamic functional network connectivity study

AbstractBackgroundFinding a biomarker predicting the Alzheimer’s disease (AD) progression from a healthy stage to mild cognitive impairment (MCI), mild dementia (MD) and further to AD is an essential step toward early medical intervention. In recent years, dynamic functional network connectivity (dFNC) from resting state‐fMRI, which estimates brain states during the scan, revealed excellent knowledge about AD progression's underlying mechanism. The current study explored whether the AD brain produces similar and stable dFNC states across different scanning sessions and introduced dFNC state (or brain) instability as a potential biomarker of AD progression.MethodThe data from the longitudinal Open Access Series of Imaging Studies (OASIS)‐3 cohort were used in this study. The dataset contains two rs‐fMRI sessions on the same day of 1048 healthy controls or HC (clinical dementia rating sum of boxes or CDR‐SOB=0, age= 70.80± 8.57), 193 MCI (4.5=<CDR‐SOB<=9, age= 71.00±9.48), and 75 MD patients (with clinical dementia rating 4.5=<CDR‐SOB<=9, age=71.90±9.65). We did not observe a significant age and gender difference across groups (ttest p>0.2). We used Group‐independent component analysis to extract independent components of the whole‐brain for each subject. Next, we applied the sliding window with Pearson correlation to estimate dFNC of each individual in each session. Subsequently, k‐means clustering (k=3, L1‐norm as a distance metric, and 1000 iterations) separately was applied to put the dFNCs of each group and session in three distinct states. Pearson correlation between the cluster (state) centroid was used to assess the similarity of state across two sessions.ResultWe found that HC and MCI groups generate similar dFNC states in both sessions in which The correlation between inter‐session “matched” states for HCs and MCIs was more than 0.99 (p<0.0001). But, MD patients did not generate similar brain states across two sessions. This points to a degradation in the stability of functional brain integration among MD patients.ConclusionOur findings highlight brain instability as a potential biomarker of Alzheimer’s disease progression. Also, the instability of dFNC observed in mild dementia patients suggests a need for multiple scanning sessions to analyze rs‐fMRI data in this group of patients.

Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia.

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub‐second dynamics of resting‐state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA‐related changes in resting‐state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting‐state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12–51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median‐split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo‐parietal junctions (TPJ). FRDA patients with an ASO <11 years presented altered temporal dynamics of those two HMM states compared with FRDA patients with an ASO > 11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute‐long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub‐second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub‐second network activity and functional brain integration over long timescales.

Oxygen Sensing and Signaling in Alzheimer's Disease: A Breathtaking Story!

Oxygen sensing and homeostasis is indispensable for the maintenance of brain structural and functional integrity. Under low-oxygen tension, the non-diseased brain has the ability to cope with hypoxia by triggering a homeostatic response governed by the highly conserved hypoxia-inducible family (HIF) of transcription factors. With the advent of advanced neuroimaging tools, it is now recognized that cerebral hypoperfusion, and consequently hypoxia, is a consistent feature along the Alzheimer's disease (AD) continuum. Of note, the reduction in cerebral blood flow and tissue oxygenation detected during the prodromal phases of AD, drastically aggravates as disease progresses. Within this scenario a fundamental question arises: How HIF-driven homeostatic brain response to hypoxia "behaves" during the AD continuum? In this sense, the present review is aimed to critically discuss and summarize the current knowledge regarding the involvement of hypoxia and HIF signaling in the onset and progression of AD pathology. Importantly, the promises and challenges of non-pharmacological and pharmacological strategies aimed to target hypoxia will be discussed as a new "hope" to prevent and/or postpone the neurodegenerative events that occur in the AD brain.

Structural and functional brain changes in X-linked Charcot-Marie-Tooth disease: insights from a multimodal neuroimaging study.

Brain involvement in X-linked Charcot-Marie-Tooth disease (CMTX) has been previously reported. We studied the brain structural and functional integrity using a multimodal neuroimaging approach in patients with no current central nervous system (CNS) symptoms, in order to further delineate the disease's phenotype. Seventeen CMTX patients with no current CNS symptoms and 24 matched healthy controls underwent brain magnetic resonance imaging (MRI). Structural integrity was evaluated performing Gray matter analysis with voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI). Functional integrity was evaluated with resting-state functional MRI (rs-fMRI). Decreased gray matter density was detected in CMTX patients compared to healthy controls in bilateral hippocampus, left thalamus, left postcentral gyrus, left superior parietal lobule, left cerebellum crus I and II, and vermis VI. DTI analysis showed increased fractional anisotropy and radial diffusivity in the right anterior insula and increased axial diffusivity in right cerebellum crus I in CMTX patients. rs-fMRI revealed decreased spontaneous neural activity on left precentral gyrus in patients compared to healthy controls. Advanced magnetic resonance (MR) neuroimaging techniques in CMTX patients revealed structural and functional involvement of multiple motor and extra-motor brain areas. MR neuroimaging techniques have the potential to delineate the CNS phenotype of a peripheral neuropathy like CMTX.

The longitudinal relationship between BOLD signal variability changes and white matter maturation during early childhood

Intra-individual transient temporal fluctuations in brain signal, as measured by fMRI blood oxygenation level dependent (BOLD) variability, is increasingly considered an important signal rather than measurement noise. Evidence from computational and cognitive neuroscience suggests that signal variability is a good proxy-measure of brain functional integrity and information processing capacity. Here, we sought to explore across-participant and longitudinal relationships between BOLD variability, age, and white matter structure in early childhood. We measured standard deviation of BOLD signal, total white matter volume, global fractional anisotropy (FA) and mean diffusivity (MD) during passive movie viewing in a sample of healthy children (aged 2–8 years; N = 83). We investigated how age and white matter development related to changes in BOLD variability both across- and within-participants. Our across-participant analyses using behavioural partial least squares (bPLS) revealed that the influence of age and white matter maturation on BOLD variability was highly interrelated. BOLD variability increased in widespread frontal, temporal and parietal regions, and decreased in the hippocampus and parahippocampal gyrus with age and white matter development. Our longitudinal analyses using linear mixed effects modelling revealed significant associations between BOLD variability, age and white matter microstructure. Analyses using artificial neural networks demonstrated that BOLD variability and white matter micro and macro-structure at earlier ages were strong predictors of BOLD variability at later ages. By characterizing the across-participant and longitudinal features of the association between BOLD variability and white matter micro- and macrostructure in early childhood, our results provide a novel perspective to understand structure-function relationships in the developing brain.