Brain Hubs Research Articles

Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n=41) and ESZ (n=70) relative to healthy controls (HC; n=74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps<.024) relative to HC and CHR-P, with this reduction specific to the rich-club even after accounting for other connections in ESZ relative to HC (ps<.048). There was also cortical thinning of rich-club regions in ESZ (ps<.013). In contrast, there was no strong evidence of global network organization differences among the three groups. Although connectome abnormalities were not present in CHR-P overall, CHR-P converters to psychosis (n=9) had fewer connections among rich-club regions (ps<.037) and greater modularity (ps<.037) compared to CHR-P non-converters (n=19). Lastly, symptom severity and antipsychotic dosage were not significantly associated with connectome metrics (ps<.012). Findings suggest that rich-club and connectome organization abnormalities are present early in schizophrenia and in CHR-P individuals who subsequently transition to psychosis.

Ascending neurons convey behavioral state to integrative sensory and action selection brain regions

Knowing one’s own behavioral state has long been theorized as critical for contextualizing dynamic sensory cues and identifying appropriate future behaviors. Ascending neurons (ANs) in the motor system that project to the brain are well positioned to provide such behavioral state signals. However, what ANs encode and where they convey these signals remains largely unknown. Here, through large-scale functional imaging in behaving animals and morphological quantification, we report the behavioral encoding and brain targeting of hundreds of genetically identifiable ANs in the adult fly, Drosophila melanogaster. We reveal that ANs encode behavioral states, specifically conveying self-motion to the anterior ventrolateral protocerebrum, an integrative sensory hub, as well as discrete actions to the gnathal ganglia, a locus for action selection. Additionally, AN projection patterns within the motor system are predictive of their encoding. Thus, ascending populations are well poised to inform distinct brain hubs of self-motion and ongoing behaviors and may provide an important substrate for computations that are required for adaptive behavior.

Altered Functional Connectivity Strength in Distinct Brain Networks of Children With Early-Onset Schizophrenia.

Schizophrenia is regarded as a brain network or connectome disorder that is associated with neurodevelopment. Children with early-onset schizophrenia (EOS) provide an opportunity to evaluate the neuropathology of schizophrenia at a very early stage without potential confounding factors. But dysfunction in brain networks of schizophrenia is inconsistent. To identify abnormal functional connectivity (FC) in EOS patients and relationships with clinical symptoms, we aimed to reveal neuroimaging phenotypes of EOS. Prospective, cross-sectional. Twenty-six female/22 male patients (age:14.3 ± 3.45 years) with first-episode EOS, 27 female/22 male age- and gender-matched healthy controls (HC) (age:14.1 ± 4.32). 3-T, resting-state (rs) gradient-echo echo-planar imaging and three-dimensional magnetization-prepared rapid gradient-echo imaging. Intelligence quotient (IQ) was measured by the Wechsler Intelligence Scale-Fourth edition for Children (WISC-IV). The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). FC strength (FCS) from rs functional MRI (rsfMRI) was used to investigate functional integrity of global brain regions. In addition, associations between regionally altered FCS and clinical symptoms in EOS patients were examined. Two-sample t-test controlling for sample size, diagnostic method, brain volume algorithm, and age of the subjects, Bonferroni correction, Pearson's correlation analysis. A P-value <0.05 with a minimum cluster size of 50 voxels was considered statistically significant. Compared with HC, EOS patients had significantly lower total IQ scores (IQ:91.5 ± 16.1), increased FCS in the bilateral precuneus, left dorsolateral prefrontal cortex, left thalamus, and left parahippocampus (paraHIP), and decreased FCS in the right cerebellum posterior lobe and right superior temporal gyrus. The PANSS total score of EOS patients (PANSS total score:74.30 ± 7.23) was found to be positively correlated to FCS in the left paraHIP (r=0.45). Our study revealed that disrupted FC of brain hubs illustrate multiple abnormalities in brain networks in EOS patients. 1 TECHNICAL EFFICACY STAGE: 2.

Inducible CRISPR Epigenome Systems Mimic Cocaine Induced Bidirectional Regulation of Nab2 and Egr3.

Substance use disorder is a chronic disease and a leading cause of disability around the world. The NAc is a major brain hub mediating reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. We previously reported repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, and reduced it in D2-MSNs. Here, we report our findings of repeated cocaine exposure in male mice inducing MSN subtype-specific bidirectional expression of the Egr3 corepressor NGFI-A-binding protein 2 (Nab2). Using CRISPR activation and interference (CRISPRa and CRISPRi) tools combined with Nab2 or Egr3-targeted sgRNAs, we mimicked these bidirectional changes in Neuro2a cells. Furthermore, we investigated D1-MSN- and D2-MSN-specific expressional changes of histone lysine demethylases Kdm1a, Kdm6a, and Kdm5c in NAc after repeated cocaine exposure in male mice. Since Kdm1a showed bidirectional expression patterns in D1-MSNs and D2-MSNs, like Egr3, we developed a light-inducible Opto-CRISPR-KDM1a system. We were able to downregulate Egr3 and Nab2 transcripts in Neuro2A cells and cause similar bidirectional expression changes we observed in D1-MSNs and D2-MSNs of mouse repeated cocaine exposure model. Contrastingly, our Opto-CRISPR-p300 activation system induced the Egr3 and Nab2 transcripts and caused opposite bidirectional transcription regulations. Our study sheds light on the expression patterns of Nab2 and Egr3 in specific NAc MSNs in cocaine action and uses CRISPR tools to further mimic these expression patterns.SIGNIFICANCE STATEMENT Substance use disorder is a major societal issue. The lack of medication to treat cocaine addiction desperately calls for a treatment development based on precise understanding of molecular mechanisms underlying cocaine addiction. In this study, we show that Egr3 and Nab2 are bidirectionally regulated in mouse NAc D1-MSNs and D2-MSNs after repeated exposure to cocaine. Furthermore, histone lysine demethylations enzymes with putative EGR3 binding sites showed bidirectional regulation in D1- and D2-MSNs after repeated exposure to cocaine. Using Cre- and light-inducible CRISPR tools, we show that we can mimic this bidirectional regulation of Egr3 and Nab2 in Neuro2a cells.

Local synchronicity in dopamine-rich caudate nucleus influences Huntington's disease motor phenotype.

Structural grey and white matter changes precede the manifestation of clinical signs of Huntington's disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure-function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington's disease close to onset and very early manifest Huntington's disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington's disease phase despite clear evidence of brain atrophy. In manifest Huntington's disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington's disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington's disease or motor manifest Huntington's disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington's disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable.

Nutritional supplement induced modulations in the functional connectivity of a porcine brain

ABSTRACT Background Functional connectivity (FC) measures statistical dependence between cortical brain regions. Studies of FC facilitate understanding of the brain’s function and architecture that underpin normal cognition, behavior, and changes associated with various factors (e.g. nutritional supplements) at a large scale. Objective We aimed to identify modifications in FC patterns and targeted brain anatomies in piglets following perinatal intake of different nutritional diets using a graph theory based approach. Methods Forty-four piglets from four groups of pregnant sows, who were treated with nutritional supplements, including control diet, docosahexaenoic acid (DHA), egg yolk (EGG), and DHA + EGG, went through resting-state functional magnetic resonance imaging (rs-fMRI). We introduced the use of differential degree test (DDT) to identify differentially connected edges (DCEs). Simulation studies were first conducted to compare the DDT with permutation test, using three network structures at different noise levels. DDT was then applied to rs-fMRI data acquired from piglets. Results In simulations, the DDT showed a greater accuracy in detecting DCEs when compared with the permutation test. For empirical data, we found that the strength of internodal connectivity is significantly increased for more than 6% of edges in the EGG group and more than 8% of edges in the DHA and DHA + EGG groups, all compared to the control group. Moreover, differential wiring diagrams between group comparisons provided means to pinpoint brain hubs affected by nutritional supplements. Conclusion DDT showed a greater accuracy of detection of DCEs and demonstrated EGG, DHA, and DHA + EGG supplemented diets lead to an improved internodal connectivity in the developing piglet brain.

Prolonged microgravity induces reversible and persistent changes on human cerebral connectivity

The prospect of continued manned space missions warrants an in-depth understanding of how prolonged microgravity affects the human brain. Functional magnetic resonance imaging (fMRI) can pinpoint changes reflecting adaptive neuroplasticity across time. We acquired resting-state fMRI data of cosmonauts before, shortly after, and eight months after spaceflight as a follow-up to assess global connectivity changes over time. Our results show persisting connectivity decreases in posterior cingulate cortex and thalamus and persisting increases in the right angular gyrus. Connectivity in the bilateral insular cortex decreased after spaceflight, which reversed at follow-up. No significant connectivity changes across eight months were found in a matched control group. Overall, we show that altered gravitational environments influence functional connectivity longitudinally in multimodal brain hubs, reflecting adaptations to unfamiliar and conflicting sensory input in microgravity. These results provide insights into brain functional modifications occurring during spaceflight, and their further development when back on Earth.

Genetic and environmental influence on resting state networks in young male and female adults: a cartographer mapping study.

We propose a unique, minimal assumption, approach based on variance analyses (compared with standard approaches) to investigate genetic influence on individual differences on the functional connectivity of the brain using 65 monozygotic and 65 dizygotic healthy young adult twin pairs' low-frequency oscillation resting state functional Magnetic Resonance Imaging (fMRI) data from the Human Connectome Project. Overall, we found high number of genetically-influenced functional (GIF) connections involving posterior to posterior brain regions (occipital/temporal/parietal) implicated in low-level processes such as vision, perception, motion, categorization, dorsal/ventral stream visuospatial, and long-term memory processes, as well as high number across midline brain regions (cingulate) implicated in attentional processes, and emotional responses to pain. We found low number of GIF connections involving anterior to anterior/posterior brain regions (frontofrontal > frontoparietal, frontotemporal, frontooccipital) implicated in high-level processes such as working memory, reasoning, emotional judgment, language, and action planning. We found very low number of GIF connections involving subcortical/noncortical networks such as basal ganglia, thalamus, brainstem, and cerebellum. In terms of sex-specific individual differences, individual differences in males were more genetically influenced while individual differences in females were more environmentally influenced in terms of the interplay of interactions of Task positive networks (brain regions involved in various task-oriented processes and attending to and interacting with environment), extended Default Mode Network (a central brain hub for various processes such as internal monitoring, rumination, and evaluation of self and others), primary sensorimotor systems (vision, audition, somatosensory, and motor systems), and subcortical/noncortical networks. There were >8.5-19.1 times more GIF connections in males than females. These preliminary (young adult cohort-specific) findings suggest that individual differences in the resting state brain may be more genetically influenced in males and more environmentally influenced in females; furthermore, standard approaches may suggest that it is more substantially nonadditive genetics, rather than additive genetics, which contribute to the differences in sex-specific individual differences based on this young adult (male and female) specific cohort. Finally, considering the preliminary cohort-specific results, based on standard approaches, environmental influences on individual differences may be substantially greater than that of genetics, for either sex, frontally and brain-wide. [Correction added on 10 May 2023, after first online publication: added: functional Magnetic Resonance Imaging. Added: individual differences in, twice. Added statement between furthermore … based on standard approaches.].

Secondary thalamic atrophy related to brain infarction may contribute to post-stroke cognitive impairment

Background and purposeThe thalamus is a key brain hub that is globally connected to many cortical regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or cognitive correlates. This study investigates associations between thalamic volumes and post-stroke cognitive function. MethodsParticipants with non-thalamic brain infarcts (3-42 months) underwent MRI and cognitive testing. Focal infarcts and thalami were traced manually. In cases with bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics were extracted using a standardized and previously validated neuroimaging pipeline. Age and gender-matched healthy controls provided normal comparative thalamic volumes. Thalamic atrophy was considered when the volume exceeded 2 standard deviations greater than the controls. ResultsThalamic volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.5 cc, p < 0.001) and right (4.4 ± 1.4 vs. 5.5 ± 0.6 cc, p < 0.001) thalamic volumes in the controls. After controlling for head-size and global brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume (β= -0.069, p=0.024). Left thalamic atrophy correlated significantly with poorer cognitive performance (β = 4.177, p = 0.008), after controlling for demographics and infarct volumes. ConclusionsOur results suggest that the remote effect of infarction on ipsilateral thalamic volume is associated with global post-stroke cognitive impairment

Axonal degeneration in the anterior insular cortex is associated with Alzheimer’s co-pathology in Parkinson’s disease and dementia with Lewy bodies

BackgroundAxons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB.Methodsα-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.ResultsCompared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit.ConclusionsOur results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.

Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading

AbstractBackgroundIn Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD.MethodWe included two independent samples with longitudinal Flortaucipir tau‐PET covering the AD spectrum (ADNI: n(controls/AD‐preclinical/AD‐symptomatic)=93/60/89, BioFINDER, n(controls/AD‐preclinical/AD‐symptomatic)=16/16/25). In addition, we included resting‐state fMRI from human connectome project participants (n=1000), applying a 200‐ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A‐D). Applying the same atlas to tau‐PET we transformed SUVRs to tau positivities using a pre‐established gaussian‐mixture modeling approach (Fig.1E‐F). By mapping tau‐PET positivities to the fMRI‐derived global connectivity map (Fig.1G‐L), we assessed the degree to which subject specific tau‐PET patterns were shifted towards globally connected hubs or non‐hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation.ResultIn symptomatic AD patients, younger age was associated with a stronger shift of tau‐PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&amp;B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]&lt;0.001/0.001, Fig.2C&amp;D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau‐PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau‐PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046).ConclusionYounger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.

Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading

AbstractBackgroundIn Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD.MethodWe included two independent samples with longitudinal Flortaucipir tau‐PET covering the AD spectrum (ADNI: n(controls/AD‐preclinical/AD‐symptomatic)=93/60/89, BioFINDER, n(controls/AD‐preclinical/AD‐symptomatic)=16/16/25). In addition, we included resting‐state fMRI from human connectome project participants (n=1000), applying a 200‐ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A‐D). Applying the same atlas to tau‐PET we transformed SUVRs to tau positivities using a pre‐established gaussian‐mixture modeling approach (Fig.1E‐F). By mapping tau‐PET positivities to the fMRI‐derived global connectivity map (Fig.1G‐L), we assessed the degree to which subject specific tau‐PET patterns were shifted towards globally connected hubs or non‐hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation.ResultIn symptomatic AD patients, younger age was associated with a stronger shift of tau‐PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&amp;B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]&lt;0.001/0.001, Fig.2C&amp;D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau‐PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau‐PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046).ConclusionYounger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.

Reorganized Hubs of Brain Functional Networks after Acute Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI)-associated damage to hub regions can lead to disrupted modular structures of functional brain networks and may result in widespread cognitive and behavioral deficits. The spatial layout of brain connections and modules is essential for understanding the reorganization of brain networks to trauma. We investigated the roles of hubs in inter-subnetwork information coordination and integration using participation coefficients (PCs) in 74 patients with acute mTBI and 51 matched healthy controls. In some brain networks, such as default mode network (DMN) and frontoparietal network (FPN), mild TBI patients had decreased PC levels, while this measure was saliently increased in patients in other networks, such as the visual network. The hub disruption index was defined as the gradient of a straight line fitted to scatterplots of individual mTBI in participation coefficient versus mean participation coefficient of healthy groups. There was a trend of radical reorganization of some efficient "hub" nodes in patients (κ = -0.15), compared with controls (κ close to 0). The PC of brain hubs can also differentiate mTBI patients from controls with an 88% accuracy, and decreased PC levels in FPN can predict patient' s worse cognitive information processing speed (r = 0.36, p < 0.002) and working memory performance (r = 0.35, p < 0.002). Reduced PC within the DMN was associated with patients' complaints of post-concussion symptoms (r = -0.35, p < 0.002). This evidence suggests a trend of spatial transition of hub profiles in acute mTBI, and graph metrics of PC measures can be used as potential diagnostic biomarkers.

Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading

In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.

Linking Plasma Amyloid Beta and Neurofilament Light Chain to Intracortical Myelin Content in Cognitively Normal Older Adults

Evidence suggests that lightly myelinated cortical regions are vulnerable to aging and Alzheimer’s disease (AD). However, it remains unknown whether plasma markers of amyloid and neurodegeneration are related to deficits in intracortical myelin content, and whether this relationship, in turn, is associated with altered patterns of resting-state functional connectivity (rs-FC). To shed light into these questions, plasma levels of amyloid-β fragment 1–42 (Aβ1–42) and neurofilament light chain (NfL) were measured using ultra-sensitive single-molecule array (Simoa) assays, and the intracortical myelin content was estimated with the ratio T1-weigthed/T2-weighted (T1w/T2w) in 133 cognitively normal older adults. We assessed: (i) whether plasma Aβ1–42 and/or NfL levels were associated with intracortical myelin content at different cortical depths and (ii) whether cortical regions showing myelin reductions also exhibited altered rs-FC patterns. Surface-based multiple regression analyses revealed that lower plasma Aβ1–42 and higher plasma NfL were associated with lower myelin content in temporo-parietal-occipital regions and the insular cortex, respectively. Whereas the association with Aβ1–42 decreased with depth, the NfL-myelin relationship was most evident in the innermost layer. Older individuals with higher plasma NfL levels also exhibited altered rs-FC between the insula and medial orbitofrontal cortex. Together, these findings establish a link between plasma markers of amyloid/neurodegeneration and intracortical myelin content in cognitively normal older adults, and support the role of plasma NfL in boosting aberrant FC patterns of the insular cortex, a central brain hub highly vulnerable to aging and neurodegeneration.

Multiscale fractality in partial phase synchronisation on simplicial complexes around brain hubs

Brain hubs are best connected central nodes in the human connectome that play a critical role in integrated brain dynamics. How the hubs perform their function vs different dynamical processes and the role of their higher-order connections involving different brain regions remains elusive. Here we simulate the phase synchronisation processes on the human connectome core network consisting of the eight brain hubs and all attached simplexes of different sizes. The leading pairwise interactions among neighbouring nodes are assumed, taking into account the natural weights of edges. Our results reveal that increasing the positive pairwise couplings promotes a continuous synchronisation while a weak partial synchronisation occurs for a wide range of negative couplings. The weights of edges stabilise the synchronisation process supporting the absence of hysteresis. Furthermore, the time evolution of the order parameter shows cyclic fluctuations induced by the concurrent evolution of phases associated with different groups of nodes. We show that these oscillations exhibit long-range temporal correlations and multifractality. The asymmetrical singularity spectra are determined, which vary with the time scale and depend on the weights of edges. These findings suggest a possible way that the brain functional geometry maintains a desirable low-level synchrony through complex patterns of phase fluctuations.

Differential Effects of N-methyl-D-aspartate Receptors Activation in the Insular Cortex during Memory Formation and Updating of a Motivational Conflict Task

Recognizing and weighing the value of stimuli is necessary for survival, as it allows living things to respond quickly and adequately to new experiences by comparing them with previous ones. Recent evidence shows that context change could affect flavor learning, suggesting a more intricate scenario during complex associations of stimuli with opposite or different valence in a motivational conflict task. Furthermore, linked to the ability to weigh the value of stimuli is the ability to predict the consequences associated with them from previous experiences. The insular cortex (IC) is a brain hub connecting and integrating different sensory, emotional, motivational, and cognitive processing systems. In this regard, previous evidence indicates that glutamatergic activity in this area, mediated by N-methyl-D-aspartate receptors (NMDARs), could be important during positive or negative valence encoding. Hence, the present study examines the involvement of NMDARs in the IC during a complex association of stimuli with opposite valence through the modified inhibitory avoidance (MIA) task and memory updating of a previously learned appetitive context during latent inhibition of the MIA process. This study demonstrates that during a motivational conflict-learning task with stimuli of opposite valences, avoidance memory formation will prevail. NMDARs activation in the IC decreases avoidance memory formation during a complex task (MIA) but not memory formation for an appetitive context. Furthermore, NMDARs activation does not affect the transition from appetitive to aversive learning. Overall, our results propose a different IC-NMDARs function during novel learning and memory updating.

Multiplex Connectome Changes across the Alzheimer's Disease Spectrum Using Gray Matter and Amyloid Data.

The organization of the Alzheimer’s disease (AD) connectome has been studied using graph theory using single neuroimaging modalities such as positron emission tomography (PET) or structural magnetic resonance imaging (MRI). Although these modalities measure distinct pathological processes that occur in different stages in AD, there is evidence that they are not independent from each other. Therefore, to capture their interaction, in this study we integrated amyloid PET and gray matter MRI data into a multiplex connectome and assessed the changes across different AD stages. We included 135 cognitively normal (CN) individuals without amyloid-β pathology (Aβ−) in addition to 67 CN, 179 patients with mild cognitive impairment (MCI) and 132 patients with AD dementia who all had Aβ pathology (Aβ+) from the Alzheimer’s Disease Neuroimaging Initiative. We found widespread changes in the overlapping connectivity strength and the overlapping connections across Aβ-positive groups. Moreover, there was a reorganization of the multiplex communities in MCI Aβ + patients and changes in multiplex brain hubs in both MCI Aβ + and AD Aβ + groups. These findings offer a new insight into the interplay between amyloid-β pathology and brain atrophy over the course of AD that moves beyond traditional graph theory analyses based on single brain networks.

Binocular Integrated Visual Field Deficits Are Associated With Changes in Local Network Function in Primary Open-Angle Glaucoma: A Resting-State fMRI Study.

In glaucoma participants, both structural and functional brain changes have been observed, but we still have insufficient understanding of how these changes also affect the integrity of cortical functional networks, and how these changes relate to visual function. This is relevant, as functional network integrity may affect the applicability of future treatments, as well as the options for rehabilitation or training. Here, we compare global and local functional connectivity in local and global brain networks between glaucoma and control participants. Moreover, we study the relationship between functional connectivity and visual field (VF) loss. For our study, 20 subjects with primary open-angle glaucoma (POAG) and 24 age-similar healthy participants were recruited to undergo an ophthalmic assessment followed by two resting-state (RS) (f)MRI scans. For each scan and for each group, the ROIs with eigenvector centrality (EC) values higher than the 95th percentile were considered the most central brain regions (“hubs”). Hubs for which we found a significant difference in EC in both scans between glaucoma and healthy participants were considered to provide evidence for network changes. In addition, we tested the notion that a brain region's hub function in POAG might relate to the severity of a participant's VF defect, irrespective of which eye contributed mostly to this. To determine this, for each participant, eye-independent scores were derived for: (1) sensitivity of the worse eye – indicating disease severity, (2) sensitivity of both eyes combined – with one eye potentially compensating for loss in the other, or (3) difference in eye sensitivity – potentially requiring additional network interactions. By correlating each of these VF scores and the EC values, we assessed whether VF defects could be associated with centrality alterations in POAG. Our results show that no functional connectivity disruptions were found at the global brain level in POAG participants. This indicates that in glaucoma global brain network communication is preserved. Furthermore, for the Lingual Gyrus, identified as a brain hub, we found a positive correlation between the EC value and the VF sensitivity of both eyes combined. The fact that reduced local network functioning is associated with reduced binocular VF sensitivity suggests the presence of local brain reorganization that has a bearing on functional visual abilities.

Altered brain network topology in children with auditory processing disorder: A resting-state multi-echo fMRI study

Children with auditory processing disorder (APD) experience hearing difficulties, particularly in the presence of competing sounds, despite having normal audiograms. There is considerable debate on whether APD symptoms originate from bottom-up (e.g., auditory sensory processing) and/or top-down processing (e.g., cognitive, language, memory). A related issue is that little is known about whether functional brain network topology is altered in APD. Therefore, we used resting-state functional magnetic resonance imaging data to investigate the functional brain network organization of 57 children from 8 to 14 years old, diagnosed with APD (n = 28) and without hearing difficulties (healthy control, HC; n = 29). We applied complex network analysis using graph theory to assess the whole-brain integration and segregation of functional networks and brain hub architecture. Our results showed children with APD and HC have similar global network properties –i.e., an average of all brain regions– and modular organization. Still, the APD group showed different hub architecture in default mode-ventral attention, somatomotor and frontoparietal-dorsal attention modules. At the nodal level –i.e., single-brain regions–, we observed decreased participation coefficient (PC – a measure quantifying the diversity of between-network connectivity) in auditory cortical regions in APD, including bilateral superior temporal gyrus and left middle temporal gyrus. Beyond auditory regions, PC was also decreased in APD in bilateral posterior temporo-occipital cortices, left intraparietal sulcus, and right posterior insular cortex. Correlation analysis suggested a positive association between PC in the left parahippocampal gyrus and the listening-in-spatialized-noise -sentences task where APD children were engaged in auditory perception. In conclusion, our findings provide evidence of altered brain network organization in children with APD, specific to auditory networks, and shed new light on the neural systems underlying children's listening difficulties.