Connectivity Of Frontoparietal Network Research Articles

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

The role of stimulant washout status in functional connectivity of default mode and fronto-parietal networks in children with neurodevelopmental conditions

BackgroundStimulant medication is the primary pharmacological treatment for attention dysregulation and is commonly prescribed for children with Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism. Neuroimaging studies of these groups commonly use a 24–48-hour washout period to mediate the effects of stimulant medication on functional connectivity (FC) metrics. However, the impact of washout on functional connectivity has received limited study. MethodsWe used fMRI data from participants with diagnosis of Autism and ADHD (and an off stimulant control) from the Adolescent Brain and Cognitive Development (ABCD) and Autism Brain Imaging Data Exchange (ABIDE) databases to explore the effect of simulant washout on FC. Connectivity within and between the default mode (DMN) and fronto-parietal networks (FPN) was examined, as these networks have previously been implicated in attention dysregulation and associated with stimulant medication usage. For each diagnostic group, we assessed effects in interconnectivity between DMN and FPN, intraconnectivity within DMN, and intraconnectivity within FPN. ResultsWe found no significant effect of medication status in intra- and inter-connectivity of the DMN and the FPN in either diagnostic group. ImplicationsOur findings suggest that more information is needed about the effect of stimulant medication, and washout, on the FC of attention networks in clinical populations.

Data-driven connectivity profiles relate to smoking cessation outcomes.

At a group level, nicotine dependence is linked to differences in resting-state functional connectivity (rs-FC) within and between three large-scale brain networks: the salience network (SN), default mode network (DMN), and frontoparietal network (FPN). Yet, individuals may display distinct patterns of rs-FC that impact treatment outcomes. This study used a data-driven approach, Group Iterative Multiple Model Estimation (GIMME), to characterize shared and person-specific rs-FC features linked with clinically-relevant treatment outcomes. 49 nicotine-dependent adults completed a resting-state fMRI scan prior to a two-week smoking cessation attempt. We used GIMME to identify group, subgroup, and individual-level networks of SN, DMN, and FPN connectivity. Regression models assessed whether within- and between-network connectivity of individual rs-FC models was associated with baseline cue-induced craving, and craving and use of regular cigarettes (i.e., "slips") during cessation. As a group, participants displayed shared patterns of connectivity within all three networks, and connectivity between the SN-FPN and DMN-SN. However, there was substantial heterogeneity across individuals. Individuals with greater within-network SN connectivity experienced more slips during treatment, while individuals with greater DMN-FPN connectivity experienced fewer slips. Individuals with more anticorrelated DMN-SN connectivity reported lower craving during treatment, while SN-FPN connectivity was linked to higher craving. In conclusion, in nicotine-dependent adults, GIMME identified substantial heterogeneity within and between the large-scale brain networks. Individuals with greater SN connectivity may be at increased risk for relapse during treatment, while a greater positive DMN-FPN and negative DMN-SN connectivity may be protective for individuals during smoking cessation treatment.

Concurrent and prospective associations between infant frontoparietal and default mode network connectivity and negative affectivity

Emotion dysregulation is linked to differences in frontoparietal (FPN) and default mode (DMN) brain network functioning. These differences may be identifiable early in development. Temperamental negative affectivity has been identified as a precursor to later emotion dysregulation, though the underlying neurodevelopmental mechanism is unknown. The present study explores concurrent and prospective associations between FPN and DMN connectivity in infants and measures of negative affectivity. 72 infants underwent 5.03–13.28 min of resting state fMRI during natural sleep (M±SD age=4.90 ± 0.84 weeks; 54% male; usable data=9.92 ± 2.15 min). FPN and DMN intra- and internetwork connectivity were computed using adult network assignments. Crying was obtained from both parent-report and day-long audio recordings. Temperamental negative affectivity was obtained from a parent-report questionnaire. In this preregistered study, based on analyses conducted with a subset of this data (N = 32), we hypothesized that greater functional connectivity within and between FPN and DMN would be associated with greater negative affectivity. In the full sample we did not find support for these hypotheses. Instead, greater DMN intranetwork connectivity at age one month was associated with lower concurrent parent-reported crying and temperamental negative affectivity at age six months (ßs>−0.35, ps<.025), but not crying at age six months. DMN intranetwork connectivity was also negatively associated with internalizing symptoms at age eighteen-months (ß=−0.58, p = .012). FPN intra- and internetwork connectivity was not associated with negative affectivity measures after accounting for covariates. This work furthers a neurodevelopmental model of emotion dysregulation by suggesting that infant functional connectivity at rest is associated with later emotional functioning.

6 Adjunctive Transcranial Direct Current Stimulation and Cognitive Training Alters Default Mode and Frontoparietal Control Network Connectivity in Older Adults

Objective:Aging is associated with disruptions in functional connectivity within the default mode (DMN), frontoparietal control (FPCN), and cingulo-opercular (CON) resting-state networks. Greater within-network connectivity predicts better cognitive performance in older adults. Therefore, strengthening network connectivity, through targeted intervention strategies, may help prevent age-related cognitive decline or progression to dementia. Small studies have demonstrated synergistic effects of combining transcranial direct current stimulation (tDCS) and cognitive training (CT) on strengthening network connectivity; however, this association has yet to be rigorously tested on a large scale. The current study leverages longitudinal data from the first-ever Phase III clinical trial for tDCS to examine the efficacy of an adjunctive tDCS and CT intervention on modulating network connectivity in older adults.Participants and Methods:This sample included 209 older adults (mean age = 71.6) from the Augmenting Cognitive Training in Older Adults multisite trial. Participants completed 40 hours of CT over 12 weeks, which included 8 attention, processing speed, and working memory tasks. Participants were randomized into active or sham stimulation groups, and tDCS was administered during CT daily for two weeks then weekly for 10 weeks. For both stimulation groups, two electrodes in saline-soaked 5x7 cm2 sponges were placed at F3 (cathode) and F4 (anode) using the 10-20 measurement system. The active group received 2mA of current for 20 minutes. The sham group received 2mA for 30 seconds, then no current for the remaining 20 minutes.Participants underwent resting-state fMRI at baseline and post-intervention. CONN toolbox was used to preprocess imaging data and conduct region of interest (ROI-ROI) connectivity analyses. The Artifact Detection Toolbox, using intermediate settings, identified outlier volumes. Two participants were excluded for having greater than 50% of volumes flagged as outliers. ROI-ROI analyses modeled the interaction between tDCS group (active versus sham) and occasion (baseline connectivity versus postintervention connectivity) for the DMN, FPCN, and CON controlling for age, sex, education, site, and adherence.Results:Compared to sham, the active group demonstrated ROI-ROI increases in functional connectivity within the DMN following intervention (left temporal to right temporal [T(202) = 2.78, pFDR &lt; 0.05] and left temporal to right dorsal medial prefrontal cortex [T(202) = 2.74, pFDR &lt; 0.05]. In contrast, compared to sham, the active group demonstrated ROI-ROI decreases in functional connectivity within the FPCN following intervention (left dorsal prefrontal cortex to left temporal [T(202) = -2.96, pFDR &lt; 0.05] and left dorsal prefrontal cortex to left lateral prefrontal cortex [T(202) = -2.77, pFDR &lt; 0.05]). There were no significant interactions detected for CON regions.Conclusions:These findings (a) demonstrate the feasibility of modulating network connectivity using tDCS and CT and (b) provide important information regarding the pattern of connectivity changes occurring at these intervention parameters in older adults. Importantly, the active stimulation group showed increases in connectivity within the DMN (a network particularly vulnerable to aging and implicated in Alzheimer’s disease) but decreases in connectivity between left frontal and temporal FPCN regions. Future analyses from this trial will evaluate the association between these changes in connectivity and cognitive performance post-intervention and at a one-year timepoint.

1 Subjective Cognitive Concerns, Neuropsychological Test Performances, and Frontoparietal Thickness and Connectivity in High-Functioning Older Adults

Objective:Neuropsychologists have difficulty detecting cognitive decline in high-functioning older adults, in whom substantially greater neurological change may need to occur before performance on cognitive tests are low enough to indicate cognitive impairment. For high-functioning older adults, subjective cognitive concerns (SCC) may indicate decline that is not detected by the presence of low cognitive test scores but may be related to the absence of high scores and the presence of latent neurological changes. We hypothesized that high-functioning older adults with SCC would have fewer high scores than those without concerns, but a comparable number of low scores. These findings would indicate that objective decline has occurred but would not be detected by a traditional focus on low scores. We also hypothesized that SCC would be associated with lower frontoparietal network volume, thickness, and connectivity, indicating latent neurological change underlying subjective cognitive concerns.Participants and Methods:Participants from an imaging sub-study of an ongoing longitudinal aging study were selected if they had high estimated premorbid functioning, defined as either (a) estimated intelligence &gt;75th percentile on the North American Adult Reading Test (n=48) or (b) having a college degree (n=62). This resulted in 68 participants subdivided based on SCC, defined as one or more self-reported SCC on the Medical Outcomes Study Cognitive Functioning Scale (MOS-Cog). Participants with SCC (n=35; 73.9 years-old, SD=9.6, range: 60-95; 62.9% female; 94.3% White) and without SCC (n=33; 71.0 years-old, SD=7.2, range: 61-85, 75.8% female; 100% White) completed a neuropsychological test battery of memory and executive functions, including the Rey Auditory Verbal Learning Test, Trail Making Test Parts A and B, Controlled Oral Word Association Test, Digit Span, and Letter-Number Sequencing, and underwent structural MRI. MR images were analyzed for frontoparietal network volume, thickness, and connectivity.Results:Participants with and without SCC were compared on the number of low test scores (i.e., at or below the 16th percentile) and high test scores (i.e., at or above the 75th percentile), finding a comparable number of low scores, t=1.66, p=.103, d=.40, but a lower number of high scores among participants with SCC, t=2.95, p=.004, d=.71. Participants with SCC had lower bilateral mean frontoparietal network volumes (left: t=2.98, p=.004, d=.74; right: t=2.63, p=.011, d=.66) and cortical thickness (left: t=2.65, p=.010, d=.66; right: t=2.18, p=.033, d=.54), but did not differ from those without SCC in terms of network connectivity.Conclusions:SCC have been reported as a potential risk factor for dementia in older adults. High-functioning older adults with SCC presented with fewer high scores than those without SCC but had a comparable number of low scores. Among high-functioning older adults, subjective cognitive decline may correspond with objective cognitive change not detected by the traditional emphasis on low scores, but rather the absence of high scores. SCC were also related to underlying changes in the volume and thickness of the frontoparietal network, but not connectivity. In high-functioning older adults, subjective cognitive decline may correspond with a reduction from high average functioning in some domains and underlying neurological changes.

B - 86 Association of Fronto-Parietal Network White Matter Tract Connectivity with Executive Functioning and Working Memory in a Diverse Sample.

We evaluated whether Fronto-Parietal Network (FPN) connectivity is associated with cognitive performance within an ethnically diverse sample. Linear regression modeling of 50 FPN white matter tract connectivity measures (volume, anisotropy, diffusivity) predicted executive functioning (EF) and working memory (WM) data including Trails Making Test parts A and B (TMTA/TMTB), Digit Span (DSF/DSB/DST), and Digit Symbol Substitution (DSS) in an ethnically diverse sample (n = 2715, African American = 515, Non-Hispanic White = 1096, Mexican American = 1104). Maximum Likelihood Factoring (MLF) controlled for collinearity within connectivity measures. The best predictors of cognitive performance were thickness of the right caudal anterior cingulate (CAC) (p < 0.001 with DSF, DST, DSS) and mean diffusivity of the right superior longitudinal fasciculus (rSLF) (p < 0.001 with DSF, DST, TB). Within cognitive tests, DSF had the greatest number of significant relationships with connectivity measures (mean diffusivity of the superior longitudinal fasciculus, thickness of the right caudal anterior cingulate, and thickness of the right rostral anterior cingulate, each at p < 0.001). Three factors emerged from MLF which each had multiple significant relationships with cognitive task variables. However, variance accounted for was minimal (R2< 0.01). Relationships between FPN white matter tract connectivity with EF and WM scores are replicable in ethnically heterogeneous samples. Both the CAC and rSLF have previously been shown to be implicated in frontoparietal working memory functionality, however the lateralization of the functional relationship shown above appears to be unique to this sample. Further ethnically heterogenous neuroimaging studies are necessary to determine the uniqueness of these findings.

Detecting cognitive decline in high-functioning older adults: The relationship between subjective cognitive concerns, frequency of high neuropsychological test scores, and the frontoparietal control network.

Neuropsychologists have difficulty detecting cognitive decline in high-functioning older adults because greater neurological change must occur before cognitive performances are low enough to indicate decline or impairment. For high-functioning older adults, early neurological changes may correspond with subjective cognitive concerns and an absence of high scores. This study compared high-functioning older adults with and without subjective cognitive concerns, hypothesizing those with cognitive concerns would have fewer high scores on neuropsychological testing and lower frontoparietal network volume, thickness, and connectivity. Participants had high estimated premorbid functioning (e.g., estimated intelligence ≥75th percentile or college-educated) and were divided based on subjective cognitive concerns. Participants with cognitive concerns (n = 35; 74.0 ± 9.6 years old, 62.9% female, 94.3% White) and without cognitive concerns (n = 33; 71.2 ± 7.1 years old, 75.8% female, 100% White) completed a neuropsychological battery of memory and executive function tests and underwent structural and resting-state magnetic resonance imaging, calculating frontoparietal network volume, thickness, and connectivity. Participants with and without cognitive concerns had comparable numbers of low test scores (≤16th percentile), p = .103, d = .40. Participants with cognitive concerns had fewer high scores (≥75th percentile), p = .004, d = .71, and lower mean frontoparietal network volumes (left: p = .004, d = .74; right: p = .011, d = .66) and cortical thickness (left: p = .010, d = .66; right: p = .033, d = .54), but did not differ in network connectivity. Among high-functioning older adults, subjective cognitive decline may correspond with an absence of high scores on neuropsychological testing and underlying changes in the frontoparietal network that would not be detected by a traditional focus on low cognitive test scores.

Resting-state functional connectivity is modulated by cognitive reserve in early Parkinson's disease.

Fronto-striatal disconnection is thought to be at the basis of dysexecutive symptoms in patients with Parkinson's disease (PD). Multiple reserve-related processes may offer resilience against functional decline. Among these, cognitive reserve (CR) refers to the adaptability of cognitive processes. To test the hypothesis that functional connectivity of pathways associated with executive dysfunction in PD is modulated by CR. Twenty-six PD patients and 24 controls underwent resting-state functional magnetic resonance imaging. Functional connectivity was explored with independent component analysis and seed-based approaches. The following networks were selected from the outcome of the independent component analysis: default-mode (DMN), left and right fronto-parietal (l/rFPN), salience (SalN), sensorimotor (SMN), and occipital visual (OVN). Seed regions were selected in the substantia nigra and in the dorsolateral and ventromedial prefrontal cortex for the assessment of seed-based functional connectivity maps. Educational and occupational attainments were used as CR proxies. Compared with their counterparts with high CR, PD individuals with low CR had reduced posterior DMN functional connectivity in the anterior cingulate and basal ganglia, and bilaterally reduced connectivity in fronto-parietal regions within the networks defined by the dorsolateral and ventrolateral prefrontal seeds. Hyper-connectivity was detected within medial prefrontal regions when comparing low-CR PD with low-CR controls. CR may exert a modulatory effect on functional connectivity in basal ganglia and executive-attentional fronto-parietal networks. In PD patients with low CR, attentional control networks seem to be downregulated, whereas higher recruitment of medial frontal regions suggests compensation via an upregulation mechanism. This upregulation might contribute to maintaining efficient cognitive functioning when posterior cortical function is progressively reduced.

Preliminary evidence for changes in frontoparietal network connectivity in the early abstinence period in alcohol use disorder: a longitudinal resting-state functional magnetic resonance imaging study.

The early abstinence period is a crucial phase in alcohol use disorder (AUD) in which patients have to find a new equilibrium and may start recovery, or conversely, relapse. However, the changes in brain functions during this key period are still largely unknown. We set out to study longitudinal changes in large-scale brain networks during the early abstinence period using resting-state scans. We scanned AUD patients twice in a well-controlled inpatient setting, with the first scan taking place shortly after admission and the second scan 4 weeks (±9 days) later near the end of the treatment period. We studied 37 AUD patients (22 males) and 27 healthy controls (16 males). We focused on three networks that are affected in AUD and underly core symptom dimensions in this disorder: the frontoparietal networks (left and right FPN) and default mode network (DMN). Both the whole brain and within network connectivity of these networks were studied using dual regression. Finally, we explored correlations between these brain networks and various neuropsychological and behavioral measures. In contrast to the controls (Z = -1.081, p = 0.280), the AUD patients showed a decrease in within left FPN connectivity (Z = -2.029, p = 0.042). However, these results did not survive a strict Bonferroni correction. The decrease in left FPN connectivity during the early abstinence period in AUD may reflect an initially upregulated FPN, which recovers to a lower resting-state connectivity level during subsequent weeks of abstinence. The AUD patients showed a trend for a positive association between the change in left FPN connectivity and trait anxiety (rs = 0.303, p = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (rs = -0.283, p = 0.089) (uncorrected for multiple comparisons). This suggests that the FPN might be involved in top-down control of impulsivity and anxiety, which are important risk factors for relapse. Although there were no statistically significant results (after multiple comparison correction), our preliminary findings encourage further research into the dynamic neuroadaptations during the clinically crucial early abstinence period and could inform future study designs.

Functional Connectivity and Microstructural Network Correlates of Interindividual Variability in Distinct Executive Functions of Healthy Older Adults

Executive functions, essential for daily life, are known to be impaired in older age. Some executive functions, including working memory updating and value-based decision-making, are specifically sensitive to age-related deterioration. While their neural correlates in young adults are well-described, a comprehensive delineation of the underlying brain substrates in older populations, relevant to identify targets for modulation against cognitive decline, is missing. Here, we assessed letter updating and Markov decision-making task performance to operationalize these trainable functions in 48 older adults. Resting-state functional magnetic resonance imaging was acquired to quantify functional connectivity (FC) in task-relevant frontoparietal and default mode networks. Microstructure in white matter pathways mediating executive functions was assessed with diffusion tensor imaging and quantified by tract-based fractional anisotropy (FA). Superior letter updating performance correlated with higher FC between dorsolateral prefrontal cortex and left frontoparietal and hippocampal areas, while superior Markov decision-making performance correlated with decreased FC between basal ganglia and right angular gyrus. Furthermore, better working memory updating performance was related to higher FA in the cingulum bundle and the superior longitudinal fasciculus. Stepwise linear regression showed that cingulum bundle FA added significant incremental contribution to the variance explained by fronto-angular FC alone. Our findings provide a characterization of distinct functional and structural connectivity correlates associated with performance of specific executive functions. Thereby, this study contributes to the understanding of the neural correlates of updating and decision-making functions in older adults, paving the way for targeted modulation of specific networks by modulatory techniques such as behavioral interventions and non-invasive brain stimulation.

Altered functional connectivity of the default mode and frontal control networks in patients with insomnia.

The purpose of this study was to investigate the association between spontaneous regional activity and brain functional connectivity, which maybe can distinguish insomnia while being responsive to repetitive transcranial magnetic stimulation (rTMS) treatment effects in insomnia patients. Using resting-state functional magnetic resonance imaging data from 38 chronic insomnia patients and 36 healthy volunteers, we compared the amplitude of low-frequency fluctuations (ALFF) between the two groups. Of all the patients with insomnia, 20 received rTMS for 4 weeks, while 18 patients received a 4-week pseudo-stimulation intervention. Seed-based resting-state functional connectivity (RSFC) analysis was conducted from regions with significantly different ALFF values, and the association between RSFC value and Pittsburgh Sleep Quality Index score was determined. Our results revealed that insomnia patients presented a significantly higher ALFF value in the posterior cingulate cortex (PCC), whereas a significantly lower ALFF value was observed in the superior parietal lobule (SPL). Moreover, significantly reduced RSFC was detected from both PCC to prefrontal cortex connections, as well as from left SPL to frontal pole connections. In addition, RSFC from frontal pole to left SPL negatively predicted sleep quality (PSQI) and treatment response in patients' group. Our findings suggest that disrupted frontoparietal network connectivity may be a biomarker for insomnia in middle-aged adults, reinforcing the potential of rTMS targeting the frontal lobes. Monitoring pretreatment RSFC could offer greater insight into how rTMS treatments are responded to by insomniacs.

Improvement of cognition across a decade after stroke correlates with the integrity of functional brain networks

Background and objectiveWe recently reported improvements of working memory across 10 years post stroke among middle-aged individuals. However, the mechanisms underlying working-memory recovery are largely unknown. This study investigated the associations between long-term improvement of working memory and resting-state functional connectivity in two frontoparietal networks: the frontoparietal network and the dorsal attention network. MethodsWorking memory was repeatedly assessed by the Digit Span Backwards task in 21 persons, within 1 year after stroke onset and again 10 years post stroke onset. Brain functional connectivity was examined by resting state functional magnetic resonance imaging at the 10-year follow-up. ResultsA significant improvement of working memory was found among 21 persons after stroke (median age = 64) at the 10-year follow-up compared to the within-one-year assessment. The magnitude of performance improvement on the Digit Span Backwards task was significantly positively correlated with stronger brain connectivity in the frontoparietal network (r = 0.51, p = 0.018) measured at the 10-year follow-up only. A similar association was observed in the dorsal attention network (r = 0.43, p = 0.052) but not in a visual network (r = -0.17, p = 0.46) that served as a control network. The association between functional connectivity within the above-mentioned networks and Digit Span Backwards scores at 10-year after stroke was in the same direction but did not reach significance. ConclusionsThe present work relate stronger long-term performance improvement on the Digit Span Backwards task with higher integrity of frontoparietal network connectivity.

Functional reconfiguration of task-active frontoparietal control network facilitates abstract reasoning.

While the brain's functional network architecture is largely conserved between resting and task states, small but significant changes in functional connectivity support complex cognition. In this study, we used a modified Raven's Progressive Matrices Task to examine symbolic and perceptual reasoning in human participants undergoing fMRI scanning. Previously, studies have focused predominantly on discrete symbolic versions of matrix reasoning, even though the first few trials of the Raven's Advanced Progressive Matrices task consist of continuous perceptual stimuli. Our analysis examined the activation patterns and functional reconfiguration of brain networks associated with resting state and both symbolic and perceptual reasoning. We found that frontoparietal networks, including the cognitive control and dorsal attention networks, were significantly activated during abstract reasoning. We determined that these same task-active regions exhibited flexibly-reconfigured functional connectivity when transitioning from resting state to the abstract reasoning task. Conversely, we showed that a stable network core of regions in default and somatomotor networks was maintained across both resting and task states. We propose that these regionally-specific changes in the functional connectivity of frontoparietal networks puts the brain in a "task-ready" state, facilitating efficient task-based activation.

Multimodal visual system analysis as a biomarker of visual hallucinations in Parkinson's disease.

Visual hallucinations (VH) are present in up to 75% of Parkinson's disease (PD) patients. However, their neural bases and participation of the visual system in VH are not well-understood in PD. Seventy-four participants, 12 PD with VH (PDVH), 35 PD without VH (PDnoVH) and 27 controls underwent a battery of primary visual function and visual cognition tests, retinal optical coherence tomography and structural and resting-state functional brain MRI. We quantified cortical thickness with Freesurfer and functional connectivity (FC) of Visual (VIS), Fronto-Parietal (FP), Ventral Attention (VAN) and Dorsal Attention (DAN) networks with CONN toolbox. Group comparisons were performed with MANCOVA. Area Under the Curve (AUC) was computed to assess the ability of visual variables to differentiate PDVH and PDnoVH. There were no significant PDVH vs PDnoVH differences in disease duration, motor manifestations, general cognition or dopamine agonist therapy (DA) use. Compared to PDnoVH and HC, and regardless of DA use, PDVH showed significantly reduced contrast sensitivity, visuoperceptive and visuospatial abilities, increased retina photoreceptor layer thickness, reduced cortical thickness mostly in right visual associative areas, decreased between-network VIS-VAN and VAN-DAN connectivity and increased within-network DAN connectivity. The combination of clinical and imaging variables that best discriminated PDVH and PDnoVH (highest AUC), where within-network DAN FC, photoreceptor layer thickness and cube analysis test from Visual Object and Space Perception Battery (accuracy of 81.8%). Compared to PDnoVH, PDVH have specific functional and structural abnormalities within the visual system, which can be quantified non-invasively and could potentially constitute biomarkers for VH in PD.

Sensorimotor and Frontoparietal Network Connectivity Are Associated With Subsequent Maintenance of Gait Speed and Episodic Memory in Older Adults.

Slow gait is predictive of functional impairments in older adults, while concomitant slow gait and cognitive complaints are associated with a greater risk for cognitive decline and dementia. However, functional neural correlates for gait speed maintenance are unclear. As the sensorimotor network (SMN) and frontoparietal network (FPN) are integral components of these functions, this study investigated differences in SMN and FPN in older adults with/without gait speed decline over 24 months; and whether these networks were associated with the maintenance of cognitive function. We included 42 community-dwelling older adults aged >70 years from the MOBILIZE Boston Study. Resting-state fMRI was performed at the study baseline. Participant characteristics, gait speed, Mini-Mental State Examination, and Hopkins Verbal Learning Test (HVLT) were assessed at baseline and at 24-month follow-up. Decliners were identified as individuals with >0.05 meters/second decline in gait speed from baseline to 24 months. Of the 26 decliners and 16 maintainers, decliners exhibited a significant decline in delayed-recall performance on the HVLT over 24 months. Controlling for baseline age and multiple comparisons, contrary to initial hypothesis, maintainers exhibited lower baseline primary motor and premotor connectivity (p = .01) within the SMN, and greater baseline ventral visual-supramarginal gyrus connectivity within the FPN (p = .02) compared to decliners. Lower primary motor-premotor connectivity was correlated with maintenance of delayed-recall performance on the HVLT (p = .04). These findings demonstrated a potential compensatory mechanism involved in the link between the decline in gait speed and episodic memory, whereby baseline connectivity of the SMN and FPN may underlie subsequent maintenance of gait speed and cognitive function in old age.

P01.10.B The relation between executive functioning and MEG multilayer network centrality in glioma patients

Abstract Background Many patients with glioma suffer from deficits in executive functioning (EF), regardless of tumor location and size. While some patients experience improving EF after tumor resection, others deteriorate over time. This variability in cognitive trajectories is still poorly understood, but neuroscientific approaches that view the brain as a network may bear correlative and predictive value in this respect. Particularly integrative network connectivity of the fronto-parietal network are crucial for EF, but studies so far have only investigated isolated neural frequency bands of interest. Here, we synergize fronto-parietal network connectivity across frequency bands and test its explanatory power for EF at diagnosis and 1 year after tumor resection. Material and Methods Patients with diffuse glioma (n=37) underwent neuropsychological assessments, including three tests for EF, and resting-state magnetoencephalography (MEG) at both time points. Patients’ EF performance was standardized to z-scores using validated norm scores, adjusting for age, sex and education. MEG was source-reconstructed using patients’ MRI in combination with a beamformer approach and time series were filtered into six classical frequency bands. Band-specific functional connectivity between 78 cortical regions was estimated, after which an interconnected multilayer, multi-frequency network was created per patient. Multilayer centrality was then calculated as a measure of integrative network connectivity per region, and averaged over all fronto-parietal network regions to yield a single value reflecting integrative, multi-frequency network connectivity per patient at each time point. Results At diagnosis, eight patients had z-scores &amp;lt;-1.5, indicating clinically relevant cognitive deficits. Preoperatively, poorer performance on the Concept Shifting Task was associated with lower multilayer centrality (p=.017), while improving performance on this task from diagnosis to 1 year after resection was associated with an increase in multilayer centrality (p=.022). Multilayer centrality at diagnosis did not significantly predict EF at follow-up. Conclusion Our results establish a significant relationship between poorer and decreasing EF with lower and decreasing multilayer, multi-frequency integrative connectivity of the fronto-parietal network in glioma patients. Studies with larger and more homogeneous samples may further explore the relevance of this multilayer approach in understanding and particularly predicting postoperative decline in EF in these patients, as our sample was characterized by large heterogeneity in cognitively relevant patient and tumor characteristics.

Lifespan differences in background functional connectivity of core cognitive large-scale brain networks

Large-scale brain networks undergo functional reorganization over the course of the lifespan, with concurrent implications for cognition. Characterizing network connectivity during a task may provide complementary insight into cognitive development and aging, to that provided by resting-state. We assessed network background connectivity, which refers to connectivity that remains after task effects have been regressed out, during a visual memory-encoding task in a lifespan sample. More specifically we assessed the within- and between-network background connectivity of the default mode, salience, and frontoparietal networks. Within-network background connectivity of salience and frontoparietal networks differed between age groups, with late-life adults showing lower connectivity. We did not find an effect of age group in default mode network background connectivity, contrary to previous findings using resting-state. However, default mode between-network background connectivity with salience and frontoparietal networks was greater in mid-life and late-life adults than in younger age groups. Overall, our findings in a lifespan sample are in line with previous observations of age-related network de-differentiation. However, the lack of age effect in default mode network background connectivity suggests that background connectivity indeed represents a complementary measure to resting-state connectivity, providing a differential glance of network connectivity during a particular state.

Three Dimensions of Association Link Migraine Symptoms and Functional Connectivity.

Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Because of previous analytic shortcomings, variance in migraine symptoms has been inconsistently related to brain function. In the current analysis, we used data from two sites (n = 143, male and female humans), and performed canonical correlation analysis, relating resting-state functional connectivity (RSFC) with a broad range of migraine symptoms, ranging from headache characteristics to sleep abnormalities. This identified three dimensions of covariance between symptoms and RSFC. The first dimension related to headache intensity, headache frequency, pain catastrophizing, affect, sleep disturbances, and somatic abnormalities, and was associated with frontoparietal and dorsal attention network connectivity, both of which are major cognitive networks. Additionally, RSFC scores from this dimension, both the baseline value and the change from baseline to postintervention, were associated with responsiveness to mind-body therapy. The second dimension was related to an inverse association between pain and anxiety, and to default mode network connectivity. The final dimension was related to pain catastrophizing, and salience, sensorimotor, and default mode network connectivity. In addition to performing canonical correlation analysis, we evaluated the current clustering of migraine patients into episodic and chronic subtypes, and found no evidence to support this clustering. However, when using RSFC scores from the three significant dimensions, we identified a novel clustering of migraine patients into four biotypes with unique functional connectivity patterns. These findings provide new insight into individual variability in migraine, and could serve as the foundation for novel therapies that take advantage of migraine heterogeneity.SIGNIFICANCE STATEMENT Using a large multisite dataset of migraine patients, we identified three dimensions of multivariate association between symptoms and functional connectivity. This analysis revealed neural networks that relate to all measured symptoms, but also to specific symptom ensembles, such as patient propensity to catastrophize painful events. Using these three dimensions, we found four biotypes of migraine informed by clinical and neural variation together. Such findings pave the way for precision medicine therapy for migraine.

BDNF and KIBRA Polymorphisms Are Related to Altered Resting State Network Connectivity in Middle Age.

Disease-modifying treatments for Alzheimer's disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF, COMT, and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF, COMT, and KIBRA and functional connectivity within networks related to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (ps < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (ps < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p < 0.05). There were no COMT-related differences in functional connectivity of any of the three networks investigated (ps > 0.05). Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers.