Relationship between brain structural network integrity and emotional symptoms in youth with perinatally-acquired HIV

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

NREM sleep stages specifically alter dynamical integration of large-scale brain networks.

Determine whether subjects with chronic nausea and orthostatic intolerance share common alterations in key brain networks associated with central autonomic control: default mode, salience, and central executive networks, and the insula, a key component of the salience network. Ten subjects (ages 12-18years; 8 females, 2 males) with nausea predominant dyspepsia, orthostatic intolerance, and abnormal head-upright tilt test were consecutively recruited from pediatric gastroenterology clinic. These subjects were compared with healthy controls (n=8) without GI symptoms or orthostatic intolerance. Resting-state fMRI and brain network modularity analyses were performed. Differences in the default mode, salience, and central executive networks, and insular connectivity were measured. The community structure of the default mode network and salience network was significantly different between tilt-abnormal children and controls (p=0.034 and 0.012, respectively), whereas, no group difference was observed in the central executive network (p=0.48). The default mode network was more consistently "intact," and the consistency of the community structure in the salience network was reduced in tilt-abnormal children, especially in the insula. Children with chronic nausea and orthostatic intolerance have altered connectivity in the default mode network and salience network/insula, which supports over-monitoring of their body and altered processing of bodily states resulting in interoceptive hyper self-awareness. The connectivity of the salience network would not support optimal regulation of appropriate attention to internal and external stimuli, and the hyper-connected default mode network may result in a persistent self-referential state with feelings of emotion, pain, and anxiety.

ABSTRACTAutism spectrum disorder (ASD) is a prevalent and highly heterogeneous neurodevelopmental disorder. Previous studies have attempted to identify ASD subgroups by analyzing isolated cortical structural features. However, these studies have not considered the relationship between multiple structural features, which provide information on the structural organization of the brain. Morphometric similarity network (MSN), a structural brain network contributed by multiple anatomical features (gray matter volume, mean cortical thickness, surface area, mean curvature, Gaussian curvature, curvature index, and fold index), strongly relates to cytoarchitectonic and genomic measures of histological similarity between cortical areas. We applied K-means clustering on MSN from 236 individuals with ASD and identified three subtypes. Subtype-1 showed relatively similar MSN values with typically developmental individuals (TD). Subtype-2 showed higher morphometric similarities in the lateral frontal and temporal cortical regions and lower in anterior prefrontal and occipital regions compared to TD. These patterns were the opposite in subtype-3. Behaviorally, subtype-3 had more severe verbal and social deficits compared to subtype-2. The weaker resting-state functional connectivity (rs-FC) between the language and salience networks was observed between subtype-2 and TD. Subtype-3 had stronger rs-FC between salience and default mode networks (DMN), between frontoparietal and visual networks, and between language and dorsal attention networks, while weaker rs-FC within DMN, within sensorimotor, and within salience networks. In addition, genes with expression patterns associated with regional MS changes in ASD subtypes were functionally enriched in neuron-specific biological processes related to nervous system development, synaptic signaling and chromatin organization. These genes were particularly enriched in GABAergic neurons, glutamatergic neurons, astrocytes and microglia. Taken together, our findings suggest the existence of different neuroanatomical subtypes based on multiple anatomical features in ASD with distinct transcriptomic signatures and functional connectome patterns.

Neuroimaging studies have just begun to explore the acute effects of psychedelics on large-scale brain networks' functional organization. Even less is known about the neural correlates of subacute effects taking place days after the psychedelic experience. This study explores the subacute changes of primary sensory brain networks and networks supporting higher-order affective and self-referential functions 24 hours after a single session with the psychedelic ayahuasca. We leveraged task-free functional magnetic resonance imaging data 1 day before and 1 day after a randomized placebo-controlled trial exploring the effects of ayahuasca in naïve healthy participants (21 placebo/22 ayahuasca). We derived intra- and inter-network functional connectivity of the salience, default mode, visual, and sensorimotor networks, and assessed post-session connectivity changes between the ayahuasca and placebo groups. Connectivity changes were associated with Hallucinogen Rating Scale scores assessed during the acute effects. Our findings revealed increased anterior cingulate cortex connectivity within the salience network, decreased posterior cingulate cortex connectivity within the default mode network, and increased connectivity between the salience and default mode networks 1 day after the session in the ayahuasca group compared to placebo. Connectivity of primary sensory networks did not differ between groups. Salience network connectivity increases correlated with altered somesthesia scores, decreased default mode network connectivity correlated with altered volition scores, and increased salience default mode network connectivity correlated with altered affect scores. These findings provide preliminary evidence for subacute functional changes induced by the psychedelic ayahuasca on higher-order cognitive brain networks that support interoceptive, affective, and self-referential functions.

It is poorly understood why patients with mesial temporal lobe epilepsy (TLE) have cognitive deficits and brain network changes that extend beyond the temporal lobe, including altered extratemporal intrinsic connectivity networks (ICNs). However, subcortical arousal structures project broadly to the neocortex, are affected by TLE, and thus may contribute to these widespread network effects. The authors' objective was to examine functional connectivity (FC) patterns between subcortical arousal structures and neocortical ICNs, possible neurocognitive relationships, and FC changes after epilepsy surgery. The authors obtained resting-state functional magnetic resonance imaging (fMRI) in 50 adults with TLE and 50 controls. They compared nondirected FC (correlation) and directed FC (Granger causality laterality index) within the salience network, default mode network, and central executive network, as well as between subcortical arousal structures; these 3 ICNs were also compared between patients and controls. They also used an fMRI-based vigilance index to relate alertness to arousal center FC. Finally, fMRI was repeated in 29 patients > 12 months after temporal lobe resection. Nondirected FC within the salience (p = 0.042) and default mode (p = 0.0008) networks, but not the central executive network (p = 0.79), was decreased in patients in comparison with controls (t-tests, corrected). Nondirected FC between the salience network and subcortical arousal structures (nucleus basalis of Meynert, thalamic centromedian nucleus, and brainstem pedunculopontine nucleus) was reduced in patients in comparison with controls (p = 0.0028-0.015, t-tests, corrected), and some of these connectivity abnormalities were associated with lower processing speed index, verbal comprehension, and full-scale IQ. Interestingly, directed connectivity measures suggested a loss of top-down influence from the salience network to the arousal nuclei in patients. After resection, certain FC patterns between the arousal nuclei and salience network moved toward control values in the patients, suggesting that some postoperative recovery may be possible. Although an fMRI-based vigilance measure suggested that patients exhibited reduced alertness over time, FC abnormalities between the salience network and arousal structures were not influenced by the alertness levels during the scans. FC abnormalities between subcortical arousal structures and ICNs, such as the salience network, may be related to certain neurocognitive deficits in TLE patients. Although TLE patients demonstrated vigilance abnormalities, baseline FC perturbations between the arousal and salience networks are unlikely to be driven solely by alertness level, and some may improve after surgery. Examination of the arousal network and ICN disturbances may improve our understanding of the downstream clinical effects of TLE.

Cognitive impairment is common in Parkinson's disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson's disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson's disease.

BackgroundAgitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods.MethodParticipants comprised 600 subjects from 3 existing databases: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University. Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not. Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent. We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q.ResultFor the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction. For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction.ConclusionAcross different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis.

We investigated sex differences in the association between a measure of physical health, cardiorespiratory fitness (CRF), and brain function using resting-state functional connectivity fMRI. We examined these sex differences in the default, frontoparietal control, and cingulo-opercular networks, assemblies of functionally connected brain regions known to be impacted by both age and fitness level. Healthy older adults ( n = 49; 29 women) were scanned to obtain measures of intrinsic connectivity within and across these 3 networks. We calculated global efficiency (a measure of network integration) and local efficiency (a measure of network specialization) using graph theoretical methods. Across all three networks combined, local efficiency was positively associated with CRF, and this was more robust in male versus female older adults. Furthermore, global efficiency was negatively associated with CRF, but only in males. Our findings suggest that in older adults, associations between brain network integrity and physical health are sex-dependent. These results underscore the importance of considering sex differences when examining associations between fitness and brain function in older adulthood. NEW & NOTEWORTHY We examined the association between cardiorespiratory fitness and resting state functional connectivity in several brain networks known to be impacted by age and fitness level. We found significant associations between fitness and measures of network integration and network specialization, but in a sex-dependent manner, highlighting the interplay between sex differences, fitness, and aging brain health. Our findings underscore the importance of considering sex differences when examining associations between fitness and brain function in older adulthood.

Decline in cognitive skills, especially in memory, is often viewed as part of "normal" aging. Yet some individuals "age better" than others. Building on prior research showing that cortical thickness in one brain region, the anterior midcingulate cortex, is preserved in older adults with memory performance abilities equal to or better than those of people 20-30 years younger (i.e., "superagers"), we examined the structural integrity of two large-scale intrinsic brain networks in superaging: the default mode network, typically engaged during memory encoding and retrieval tasks, and the salience network, typically engaged during attention, motivation, and executive function tasks. We predicted that superagers would have preserved cortical thickness in critical nodes in these networks. We defined superagers (60-80 years old) based on their performance compared to young adults (18-32 years old) on the California Verbal Learning Test Long Delay Free Recall test. We found regions within the networks of interest where the cerebral cortex of superagers was thicker than that of typical older adults, and where superagers were anatomically indistinguishable from young adults; hippocampal volume was also preserved in superagers. Within the full group of older adults, thickness of a number of regions, including the anterior temporal cortex, rostral medial prefrontal cortex, and anterior midcingulate cortex, correlated with memory performance, as did the volume of the hippocampus. These results indicate older adults with youthful memory abilities have youthful brain regions in key paralimbic and limbic nodes of the default mode and salience networks that support attentional, executive, and mnemonic processes subserving memory function. Memory performance typically declines with age, as does cortical structural integrity, yet some older adults maintain youthful memory. We tested the hypothesis that superagers (older individuals with youthful memory performance) would exhibit preserved neuroanatomy in key brain networks subserving memory. We found that superagers not only perform similarly to young adults on memory testing, they also do not show the typical patterns of brain atrophy in certain regions. These regions are contained largely within two major intrinsic brain networks: the default mode network, implicated in memory encoding, storage, and retrieval, and the salience network, associated with attention and executive processes involved in encoding and retrieval. Preserved neuroanatomical integrity in these networks is associated with better memory performance among older adults.

Multi-modality connectome-based predictive modeling of individualized compulsions in obsessive-compulsive disorder

It is now widely accepted that cognitive control depends on the integrated operation of large-scale distributed brain networks. Recent methodological advances allow both structural and functional connectivity (FC) within these networks to be studied non- invasively in vivo. These approaches hold the promise of dramatically extending our understanding of the impact of traumatic brain injury (TBI) on cognitive control, which has the potential to help determine strategic targets for the rehabilitation of individuals with TBI. In the current thesis, structural and functional magnetic resonance imaging is combined to test the general hypothesis that cognitive deficits after TBI arise from functional disconnection within brain networks that mediate cognitive functions. Of particular interest are the interactions between two brain networks known as the Salience Network (SN) and the Default Mode Network (DMN). These networks are thought to be important for cognitive control however, how these networks interact during cognitive control is limited. This thesis largely investigates the effect of TBI on network interactions that accompany changing motor control. Functional MRI of the Stop Signal Task (SST) is initially used to study response inhibition. In healthy subjects, FC between the right anterior insula (rAI), a key node of the SN, and the DMN transiently increased during stopping. This change in FC was not seen in a group of TBI patients with impaired cognitive control. Furthermore, the amount of damage to the underlying white matter tract negatively correlated with the strength of FC between the networks. These findings are confirmed in a second group of TBI patients. In the second group, switching rather than inhibiting a motor response: (1) was accompanied by a similar increase in network FC in healthy controls; (2) was not seen in TBI patients; and (3) tract damage after TBI again correlated with FC breakdown. I also replicate this pattern of structure-function in a group of elderly participants who demonstrate similar cognitive control impairments as the TBI group. The findings show that FC between the rAI and DMN increases with cognitive control, and that the ability to efficiently regulate the FC between the rAI and DMN can be predicted by the structural integrity within a remote brain network previously proposed to be involved in switching between internally and externally directed attention. This work provides evidence for a model of cognitive control where the SN is involved in the attentional capture of salient external stimuli and signals the DMN to reduce its activity when attention is externally focused. It also identifies DMN dysfunction as underlying various cognitive deficits after TBI, and confirms the relevance of white matter damage in the development of brain dysfunctions after TBI.

The two major brain networks, i.e. the default mode network (DMN) and the task positive network, typically reveal negative and variable connectivity in resting-state. In the present study, we examined whether the connectivity between the DMN and different components of the task positive network were modulated by other brain regions by using physiophysiological interaction (PPI) on resting-state functional magnetic resonance imaging data. Spatial independent component analysis was first conducted to identify components that represented networks of interest, including the anterior and posterior DMNs, salience, dorsal attention, left and right executive networks. PPI analysis was conducted between pairs of these networks to identify networks or regions that showed modulatory interactions with the two networks. Both network-wise and voxel-wise analyses revealed reciprocal positive modulatory interactions between the DMN, salience, and executive networks. Together with the anatomical properties of the salience network regions, the results suggest that the salience network may modulate the relationship between the DMN and executive networks. In addition, voxel-wise analysis demonstrated that the basal ganglia and thalamus positively interacted with the salience network and the dorsal attention network, and negatively interacted with the salience network and the DMN. The results demonstrated complex modulatory interactions among the DMNs and task positive networks in resting-state, and suggested that communications between these networks may be modulated by some critical brain structures such as the salience network, basal ganglia, and thalamus.

The two major brain networks, i.e., the default mode network (DMN) and the task positive network, typically reveal negative and variable connectivity in resting-state. In the present study, we examined whether the connectivity between the DMN and different components of the task positive network were modulated by other brain regions by using physiophysiological interaction (PPI) on resting-state functional magnetic resonance imaging data. Spatial independent component analysis was first conducted to identify components that represented networks of interest, including the anterior and posterior DMNs, salience, dorsal attention, left and right executive networks. PPI analysis was conducted between pairs of these networks to identify networks or regions that showed modulatory interactions with the two networks. Both network-wise and voxel-wise analyses revealed reciprocal positive modulatory interactions between the DMN, salience, and executive networks. Together with the anatomical properties of the salience network regions, the results suggest that the salience network may modulate the relationship between the DMN and executive networks. In addition, voxel-wise analysis demonstrated that the basal ganglia and thalamus positively interacted with the salience network and the dorsal attention network, and negatively interacted with the salience network and the DMN. The results demonstrated complex modulatory interactions among the DMNs and task positive networks in resting-state, and suggested that communications between these networks may be modulated by some critical brain structures such as the salience network, basal ganglia, and thalamus.

Older age is associated with alterations in executive functioning (EF). Age-related alterations in the integrity of structural brain networks may contribute to EF decline, with potential consequences for independent living. Graph theory provides powerful metrics to examine the brain's structural connectome, but few studies have investigated the relationship of EF and structural brain networks, as described by graph-theoretical measures, in older adults. We aimed to investigate the mediatory role of network characteristics for the relationship between age and EF in older adults. Eighty-four older adults completed a battery of EF tasks to allow for the extraction of a latent Common-EF factor. White-matter tractograms were generated from diffusion neuroimaging using anatomically-constrained tractography (ACT) and spherical-deconvolution informed filtering of tractograms (SIFT2). From the resulting networks, global efficiency (reflecting integration) as well as local efficiency (reflecting segregation) were calculated. Older age was associated with worse EF and decreased global and local efficiency. Both global and local efficiency were positively correlated with EF. Local efficiency mediated the negative correlation of age and EF, whereas no such relationship was found for global efficiency. Further regional efficiency analyses identified the nodes that contributed to the mediation effect of local efficiency. These results shed light on the shared variability among the integrity of structural brain networks and EF at older age. A causal role of a reduced segregation in structural brain networks to support EF in older adults remains to be determined but would bear promising potential for preserving EF during aging.