Brain Integrity Research Articles

Association of balance control mechanisms with brain structural integrity in older adults with mild cognitive impairment

BackgroundOlder adults with mild cognitive impairment (OAwMCI) exhibit subtle balance control and gait deficits which are predominantly associated with structural brain pathologies such as impaired white matter integrity and reduced gray matter volume. However, the relationship between balance recovery mechanisms and neural substrates in OAwMCI remains unknown. This study thus aimed to explore the associations of volitional (self-initiated) and reactive balance (in response to an external perturbation) control with structural brain integrity. MethodsTen OAwMCI (MoCA 18-25/30; greater than 55 years) were examined on the limits of stability test (volitional balance via Equitest), stance perturbation test (reactive balance via ActiveStep treadmill) and underwent magnetic resonance imaging. Forward movement (frequently performed functional activity of daily living) was quantified by maximum excursion (maximum ability to shift one’s center of gravity toward the theoretical limit [MXE-%])and directional control (amount of movement exhibited towards the target proportional to the movement away from the target [DCL-%]) on the limits of stability test. Slip-like (prevalent type of accidental falls) perturbations were quantified by postural stability (shortest distance of the COM motion state, i.e., its position and velocity, to the theoretical boundary) on the ActiveStep treadmill. White matter integrity was quantified by fractional anisotropy (FA, movement of water molecules directionality) and gray matter volume measured in mm3. ResultsFor volitional balance control, reduced forward MXE was significantly (p < 0.05) associated with lower FA in left (R2 = 0.56) and right (R2 = 0.60) corticospinal tract, left (R2 = 0.49) and right (R2 = 0.51) corticothalamic tract, left (R2 = 0.70) and right (R2 = 0.57) frontopontine tract, right (R2 = 0.67) cingulum, anterior commissure (R2 = 0.82), and corpus callosum (R2 = 0.62). Reduced forward DCL was significantly (p < 0.05) associated with reduced gray matter volume in the left (R2 = 0.75) and right (R2 = 0.81) cerebellum, brainstem (R2 = 0.64), right (R2 = 0.49) thalamus. For reactive balance control, reduced postural stability (p < 0.05) was significantly associated with reduced FA in the left (R2 = 0.75) and right (R2 = 0.64) corticospinal tract, left (R2 = 0.67) and right (R2 = 0.65) frontopontine tract. Reduced postural stability was significantly (p < 0.05) associated with reduced gray matter volume in the brainstem (R2 = 0.72) and right cerebellum (R2 = 0.70). ConclusionOur results indicate that structural brain integrity influences stability control in OAwMCI for both volitional and reactive balance tasks, which may share some common cortico-subcortical motor pathways and relay centers. Results also show that the integrity of descending pathways from cortical attentional centers could influence stability control for both tasks.

129 Network controllability and regional gene expression explain visual hallucinations in Parkinson’s

Visual hallucinations are common in Parkinson’s (PD) and associated with poorer prognosis. Imaging studies have shown white matter and functional changes in PD-hallucinations1 2but the biological factors underlying selective vulnerability of brain regions are unknown.We performed diffusion-weighted imaging in 100 PD patients (81 without hallucinations [PD-non-VH], 19 with hallucinations [PD-VH]) and 34 controls. We used network-based statistics to identify structural con- nectivity changes in PD-VH and performed an analysis of controllability, an emerging technique that allows quantification of influence across the rest of the network. We used the Allen brain atlas to identify regional gene expression patterns associated with affected areas of the network.We identified a subnetwork of reduced connectivity in PD-VH. Within this network, PD-VH showed reduced controllability (influence over other brain regions), than PD-non-VH (U=526, p=0.014) and controls (U=176.5, p=0.003). This subnetwork appears to be critical for brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork (U=572.5, p&lt;0.001). Gene expression analysis revealed downregulated genes related to mRNA metabolism and upregulated genes related to membrane localisation.Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions.ReferenceShine,et al. The role of dysfunctional attentional control networks in visual misperceptions in Parkinson’s disease. HumBrainMapp;2014.a.zarkali@ucl.ac.uk

Culture and gender modulate dlPFC integration in the emotional brain: evidence from dynamic causal modeling.

Past research has recognized culture and gender variation in the experience of emotion, yet this has not been examined on a level of effective connectivity. To determine culture and gender differences in effective connectivity during emotional experiences, we applied dynamic causal modeling (DCM) to electroencephalography (EEG) measures of brain activity obtained from Chinese and American participants while they watched emotion-evoking images. Relative to US participants, Chinese participants favored a model bearing a more integrated dorsolateral prefrontal cortex (dlPFC) during fear v. neutral experiences. Meanwhile, relative to males, females favored a model bearing a less integrated dlPFC during fear v. neutral experiences. A culture-gender interaction for winning models was also observed; only US participants showed an effect of gender, with US females favoring a model bearing a less integrated dlPFC compared to the other groups. These findings suggest that emotion and its neural correlates depend in part on the cultural background and gender of an individual. To our knowledge, this is also the first study to apply both DCM and EEG measures in examining culture-gender interaction and emotion.

Assessment of Executive Function in Infants and Toddlers: A Potential Role of the Bayley-4.

The development of executive function (EF) in infants and toddlers has received increased interest by clinicians and researchers. Higher rates of deficits in EF have been reported in at-risk groups of infants such as those born extremely preterm. These deficits play an important role in the etiology of early neurodevelopmental problems and are predictive of subsequent nonoptimal educational outcomes. In this study, the Bayley-4 is used to follow the developmental course of EF and to determine whether EF is a unitary concept or can be parsed into discrete components over the first 42 months. All 81 cognitive items from the Bayley-4 normative sample of 1700 infants and toddlers were classified a priori into 6 EFs, and then, 5 age groups derived from Bayley-4 start points were factor analyzed to determine at what age EFs emerge and to address the controversy of whether the factor structure of the cognitive items for each of 5 age groups reflect a single factor or multiple factors. Bayley-4 items form 1 to 5 EF factors for each age group, accounting for 59% to 74% of the variance. There is a developmental progression in EF as well. The results indicate EF constructs can be identified early. Executive function tasks in infants and toddlers are interrelated with task content either remaining the same or changing with advancing age (i.e., content that is homotypic or heterotypic, respectively). EFs measured by Bayley-4 items are useful clinically and become more complex with increasing age, corresponding to more advanced brain development and integration. The findings have the potential of providing additional information in the assessment of infants at risk such as those born preterm.

Change in Latent Gray-Matter Structural Integrity Is Associated With Change in Cardiovascular Fitness in Older Adults Who Engage in At-Home Aerobic Exercise.

In aging humans, aerobic exercise interventions have been found to be associated with more positive or less negative changes in frontal and temporal brain areas, such as the anterior cingulate cortex (ACC) and hippocampus, relative to no-exercise control conditions. However, individual measures such as gray-matter (GM) probability may afford less reliable and valid conclusions about maintenance or losses in structural brain integrity than a latent construct based on multiple indicators. Here, we established a latent factor of GM structural integrity based on GM probability assessed by voxel-based morphometry, magnetization transfer saturation, and mean diffusivity. Based on this latent factor, we investigated changes in structural brain integrity during a six-month exercise intervention in brain regions previously reported in studies using volumetric approaches. Seventy-five healthy, previously sedentary older adults aged 63–76 years completed an at-home intervention study in either an exercise group (EG; n = 40) or in an active control group (ACG; n = 35). Measures of peak oxygen uptake (VO2peak) taken before and after the intervention revealed a time-by-group interaction, with positive average change in the EG and no reliable mean change in the ACG. Significant group differences in structural brain integrity changes were observed in the right and left ACC, right posterior cingulate cortex (PCC), and left juxtapositional lobule cortex (JLC). In all instances, average changes in the EG did not differ reliably from zero, whereas average changes in the ACG were negative, pointing to maintenance of structural brain integrity in the EG, and to losses in the ACG. Significant individual differences in change were observed for right ACC and left JLC. Following up on these differences, we found that exercising participants with greater fitness gains also showed more positive changes in structural integrity. We discuss the benefits and limitations of a latent-factor approach to changes in structural brain integrity, and conclude that aerobic fitness interventions are likely to contribute to brain maintenance in old age.

Effects of Framingham 10-Year Cardiovascular Risk Score and Viral Load on Brain Integrity in Persons With HIV.

Combination antiretroviral therapy (cART) has allowed for viral load (VL) suppression and increased life expectancy for persons with HIV (PWH). Altered brain integrity, measured by neuropsychological (NP) performance and neuroimaging, is still prevalent among virally suppressed PWH. Age-related conditions such as cardiovascular disease may also affect brain integrity. This study investigated the effects of cardiovascular risk, VL, and HIV serostatus on cerebral blood flow (CBF), brain volumetrics, and cognitive function in PWH and persons without HIV (PWoH). Ten-year cardiovascular risk, using the Framingham Heart Study criteria, was calculated in PWH (n = 164) on cART with undetectable (≤20 copies/mL; n = 134) or detectable (>20 copies/mL; n = 30) VL and PWoH (n = 66). The effects of cardiovascular risk on brain integrity (CBF, volume, and cognition) were compared for PWH (undetectable and detectable VL) and PWoH. PWH had smaller brain volumes and worse NP scores than PWoH. PWH with detectable and undetectable VL had similar brain integrity measures. Higher cardiovascular risk was associated with smaller volumes and lower CBF in multiple brain regions for PWH and PWoH. Significant interactions between HIV serostatus and cardiovascular risk on brain volumes were observed in frontal, orbitofrontal, and motor regions. Cardiovascular risk was not associated with cognition for PWH or PWoH. Neuroimaging, but not cognitive measures, was associated with elevated cardiovascular risk. HIV serostatus was associated with diminished brain volumes and worse cognition while CBF remained unchanged, reflecting potential protective effects of cART. Neuroimaging measures of structure (volume) and function (CBF) may identify contributions of comorbidities, but future longitudinal studies are needed.

Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression.

Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR.

Categorizing Visual Information in Subpopulations of Honeybee Mushroom Body Output Neurons.

Multisensory integration plays a central role in perception, as all behaviors usually require the input of different sensory signals. For instance, for a foraging honeybee the association of a food source includes the combination of olfactory and visual cues to be categorized as a flower. Moreover, homing after successful foraging using celestial cues and the panoramic scenery may be dominated by visual cues. Hence, dependent on the context, one modality might be leading and influence the processing of other modalities. To unravel the complex neural mechanisms behind this process we studied honeybee mushroom body output neurons (MBON). MBONs represent the first processing level after olfactory-visual convergence in the honeybee brain. This was physiologically confirmed in our previous study by characterizing a subpopulation of multisensory MBONs. These neurons categorize incoming sensory inputs into olfactory, visual, and olfactory-visual information. However, in addition to multisensory units a prominent population of MBONs was sensitive to visual cues only. Therefore, we asked which visual features might be represented at this high-order integration level. Using extracellular, multi-unit recordings in combination with visual and olfactory stimulation, we separated MBONs with multisensory responses from purely visually driven MBONs. Further analysis revealed, for the first time, that visually driven MBONs of both groups encode detailed aspects within this individual modality, such as light intensity and light identity. Moreover, we show that these features are separated by different MBON subpopulations, for example by extracting information about brightness and wavelength. Most interestingly, the latter MBON population was tuned to separate UV-light from other light stimuli, which were only poorly differentiated from each other. A third MBON subpopulation was neither tuned to brightness nor to wavelength and encoded the general presence of light. Taken together, our results support the view that the mushroom body, a high-order sensory integration, learning and memory center in the insect brain, categorizes sensory information by separating different behaviorally relevant aspects of the multisensory scenery and that these categories are channeled into distinct MBON subpopulations.

Cardiorespiratory Fitness Is Associated With Better White Matter Integrity in Persons Living With HIV.

Despite improved survival rates, neurocognitive impairment persists in persons living with HIV (PLWH). An active lifestyle is linked to improved cognition among PLWH, yet the neural substrates remain unclear. Diffusion tensor imaging and diffusion basis spectrum imaging measure HIV-related changes in brain white matter integrity. We used these measures of structural brain integrity to assess white matter changes, physical fitness, and cognition in a cross-sectional study of PLWH. Forty-four virologically well-controlled PLWH were recruited (average age of 56 years, a median recent CD4+ count of 682 cells/mm3). Diffusion tensor imaging -derived fractional anisotropy (FA) and diffusion basis spectrum imaging-derived axonal density were calculated. Cardiorespiratory fitness [maximal volume of oxygen consumption (VO2 max)] was measured by performing indirect calorimetry during exercise to volitional exhaustion. Cardiovascular risk was assessed by the Framingham risk score. Neuropsychological performance (NP) testing evaluated learning, memory, psychomotor/processing speed, and executive function. Partial correlations assessed the relationships among cardiorespiratory fitness, neuroimaging, NP, and HIV clinical metrics (CD4+ count and time since diagnosis). Higher VO2 max was associated with higher FA and higher axonal density in multiple white matter tracts, including the corticospinal tract and superior longitudinal fasciculus. Better NP in the motor/psychomotor domain was positively associated with FA and axonal density in diverse tracts including those associated with motor and visuospatial processing. However, higher VO2 max was not associated with NP or HIV clinical metrics. An active lifestyle promoting cardiorespiratory fitness may lead to better white matter integrity and decreased susceptibility to cognitive decline in virologically well-controlled PLWH.

Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.

Role of Cardiovascular Risk Factors on the Association Between Physical Activity and Brain Integrity Markers in Older Adults.

Background and ObjectivesPhysical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults.MethodsAt baseline, participants from the Age-Well study completed a physical activity questionnaire and underwent cardiovascular risk factors collection (systolic blood pressure, body mass index [BMI], current smoker status, and high-density lipoprotein cholesterol, total cholesterol, and insulin levels) and multimodal neuroimaging (structural MRI, diffusion MRI, FDG-PET, and florbetapir PET). Multiple regressions were conducted to assess the association among physical activity, cardiovascular risk factors, and neuroimaging. Mediation analyses were performed to test whether cardiovascular risk factors mediated the associations between physical activity and neuroimaging.ResultsA total of 134 cognitively unimpaired older adults (≥65 years) were included. Higher physical activity was associated with higher gray matter (GM) volume (β = 0.174, p = 0.030) and cerebral glucose metabolism (β = 0.247, p = 0.019) but not with amyloid deposition or white matter integrity. Higher physical activity was associated with lower insulin level and BMI but not with the other cardiovascular risk factors. Lower insulin level and BMI were related to higher GM volume but not to cerebral glucose metabolism. When controlling for insulin level and BMI, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with GM volume was lost. When insulin level and BMI were entered in the same model, only BMI remained a significant predictor of GM volume. Mediation analyses confirmed that insulin level and BMI mediated the association between physical activity and GM volume. Analyses were replicated within Alzheimer disease–sensitive regions and results remained overall similar.DiscussionThe association between physical activity and GM volume is mediated by changes in insulin level and BMI. In contrast, the association with cerebral glucose metabolism seems to be independent from cardiovascular risk factors. Older adults engaging in physical activity experience cardiovascular benefits through the maintenance of a lower BMI and insulin level, resulting in greater structural brain integrity. This study has implications for understanding how physical activity affects brain health and may help in developing strategies to prevent or delay age-related decline.Trial Registration InformationEudraCT: 2016-002,441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

Graph analysis of nonlinear fMRI connectivity dynamics reveals distinct brain network configurations for integrative and segregated information processing

The human brain is organized into functional networks, whose spatial layout can be described with functional magnetic resonance imaging (fMRI). Interactions among these networks are highly dynamic and nonlinear, and evidence suggests that distinct functional network configurations interact on different levels of complexity. To gain new insights into topological properties of constellations interacting on different levels of complexity, we analyze a resting state fMRI dataset from the human connectome project. We first measure the complexity of correlational time series among resting state networks, obtained from sliding window analysis, by calculating their sample entropy. We then use graph analysis to create two functional representations of the network: A ‘high complexity network’ (HCN), whose inter-node interactions display irregular fast changes, and a ‘low complexity network’ (LCN), whose interactions are more self-similar and change more slowly in time. Graph analysis shows that the HCNs structure is significantly more globally efficient, compared to the LCNs, indicative of an architecture that allows for more integrative information processing. The LCNs layout displays significantly higher modularity than the HCNs, indicative of an architecture lending itself to segregated information processing. In the HCN, subcortical thalamic and basal ganglia networks display global hub properties, whereas cortical networks act as connector hubs in the LCN. These results can be replicated in a split sample dataset. Our findings show that investigating nonlinear properties of resting state dynamics offers new insights regarding the relative importance of specific brain regions to the two fundamental requirements for healthy brain functioning, that is, integration and segregation.

Functional and Structural Brain Connectivity in Children With Bilateral Cerebral Palsy Compared to Age-Related Controls and in Response to Intensive Rapid-Reciprocal Leg Training.

BackgroundCompared to unilateral cerebral palsy (CP), less is known about brain reorganization and plasticity in bilateral CP especially in relation or response to motor training. The few trials that reported brain imaging results alongside functional outcomes include a handful of studies in unilateral CP, and one pilot trial of three children with bilateral CP. This study is the first locomotor training randomized controlled trial (RCT) in bilateral CP to our knowledge reporting brain imaging outcomes.MethodsObjective was to compare MRI brain volumes, resting state connectivity and white matter integrity using DTI in children with bilateral CP with PVL and preterm birth history (<34 weeks), to age-related controls, and from an RCT of intensive 12 week rapid-reciprocal locomotor training using an elliptical or motor-assisted cycle. We hypothesized that connectivity in CP compared to controls would be greater across sensorimotor-related brain regions and that functional (resting state) and structural (fractional anisotropy) connectivity would improve post intervention. We further anticipated that baseline and post-intervention imaging and functional measures would correlate.ResultsImages were acquired with a 3T MRI scanner for 16/27 children with CP in the trial, and 18 controls. No conclusive evidence of training-induced neuroplastic effects were seen. However, analysis of shared variance revealed that greater increases in precentral gyrus connectivity with the thalamus and pons may be associated with larger improvements in the trained device speed. Exploratory analyses also revealed interesting potential relationships between brain integrity and multiple functional outcomes in CP, with functional connectivity between the motor cortex and midbrain showing the strongest potential relationship with mobility. Decreased posterior white matter, corpus callosum and thalamic volumes, and FA in the posterior thalamic radiation were the most prominent group differences with corticospinal tract differences notably not found.ConclusionsResults reinforce the involvement of sensory-related brain areas in bilateral CP. Given the wide individual variability in imaging results and clinical responses to training, a greater focus on neural and other mechanisms related to better or worse outcomes is recommended to enhance rehabilitation results on a patient vs. group level.

395 Vascular Cognitive Impairment: Novel Endothelial Mechanisms and the Impact of Dietary PUFAs

OBJECTIVES/GOALS: Vascular cognitive impairment (VCI) is the leading cause of dementia behind Alzheimers Disease (AD) and is often the result of brain hypoxia. Diets rich in polyunsaturated fatty acids (PUFAs) can lower cognitive decline and AD incidence in human patients. Therefore, our goal is to determine the mechanisms that PUFAs influence in a mouse model of VCI. METHODS/STUDY POPULATION: We hypothesize that hypoxia promotes endothelial P-tau accumulation and vasotrophic uncoupling, impairing endothelial integrity. Additionally, we believe that a preventative PUFA-enriched diet blocks this uncoupling and subsequently prevents/delays neurovascular dysfunction and cognitive decline. Male and female mice will be administered a control or novel PUFA-enriched dietary intervention 1 month prior to hypoxic injury using the bilateral carotid artery stenosis model. Mice will continue their diet and be assessed for cerebral blood flow, cognitive function, and motor function at 1- &amp; 3-month time points. Following euthanasia, tissue samples from deep cortical regions and microvasculature will be examined for endothelial- &amp; neuronal-specific P-tau accumulation, inflammation, and cell death. RESULTS/ANTICIPATED RESULTS: Preliminary data in our lab indicates that hypoxia leads to a two-fold increase in endothelial P-tau accumulation and lowered mature BDNF (mBDNF) in brain microvascular endothelial cells (BMECs) compared to controls. Further, BMECs cultured in media with the PUFA docasahexaenoic acid (DHA) had lowered P-tau and increased mBDNF after hypoxia compared to controls. Based on this data and past research, we anticipate that mice on the PUFA-enriched diet will have enhanced cognitive and motor function alongside improved cerebral blood flow compared to controls. Also, we expect that mice on our PUFA-enriched diet will have lowered tau pathology, cell death, and neuroinflammation alongside increased blood brain barrier integrity and altered fatty acid composition in brain and vascular tissue samples. DISCUSSION/SIGNIFICANCE: An AHA Presidential Advisory identified cognitive function as modifiable through the management of cardiovascular risk factors, like diet. However, the mechanisms underlying the benefits of PUFA-enriched diets are unknown. Successful completion of these studies will provide insight into the vaso-neuronal protective effects of PUFAs in VCI.

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition.

We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice (N = 23; baseline age: 8 months) and AppNL–G–F mice (N = 37; baseline age: 5 months) using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aβ-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.

Sense of Coherence Mediates the Relationship Between Cognitive Reserve and Cognition in Middle-Aged Adults.

In recent years, supported by new scientific evidence, the conceptualization of cognitive reserve (CR) has been progressively enriched and now encompasses not only cognitive stimulating activities or educational level, but also lifestyle activities, such as leisure physical activity and socialization. In this context, there is increasing interest in understanding the role of psychological factors in brain health and cognitive functioning. In a previous study, we have found that these factors mediated the relationship between CR and self-reported cognitive functioning. In this study, we have confirmed an association between two important constructs included in the psychological wellbeing and salutogenic models, “purpose in life” and “sense of coherence,” CR, as assessed using a questionnaire, and cognitive functioning, as evaluated using a comprehensive neuropsychological battery. Results from 888 middle-aged healthy participants from the Barcelona Brain Health Initiative indicate that both sense of coherence (SoC) and CR were positively associated with verbal memory, reasoning and attention, working memory, and global cognition. Moreover, the relation between CR and cognitive functioning in the different domains is partially mediated by SoC. When we controlled for brain integrity, introducing into the model neurofilament light chain measures, the mediator role of SoC was confirmed for reasoning and attention and global cognition. However, purpose in life was not associated with cognitive functioning. These results reveal the central role of the SoC construct, which mediates the association between classic CR estimates and cognitive functions, potentially representing a modifiable target for interventions that aim to promote brain health.

Topological Alteration Is Associated with Non-dependent Alcohol Use in Bipolar Disorder.

Introduction: Structural alterations in cortical thickness and the microstructural organization of white matter are independently associated with non-dependent alcohol consumption and bipolar disorder (BD). Identifying their interactive and network-level effects on brain topology may identify the impact of alcohol on reward and emotion circuitry, and its contribution to relapse in BD. Materials and Methods: Thirty-four BD-I (DSM-IV-TR) and 38 healthy controls (HC) underwent T1 and diffusion-weighted magnetic resonance imaging scanning, and the Alcohol Use Disorders Identification Test-Consumption to assess alcohol use. Connectomes comprising 34 cortical and 9 subcortical nodes bilaterally (Freesurfer v5.3) connected by fractional anisotropy-weighted edges derived from non-tensor based deterministic constrained spherical deconvolution tractography (ExploreDTI v4.8.6) underwent permutation-based topological analysis (NBS v1.2) and were examined for the effects of alcohol use and diagnosis-by-alcohol use accounting for age, sex, and diagnosis. Results: Alcohol was significantly related to a subnetwork, encompassing connections between fronto-limbic, basal ganglia, and temporal nodes (Frange = 5-8.4, p = 0.031) and it was not detected to have an effect on global brain integration or segregation. A portion of this network (18%), involving cortico-limbic and basal ganglia connections, was differentially impacted by alcohol in the BD relative to the control group (Frange = 5-8.8, p = 0.033), despite the groups' consuming similar amounts of alcohol (BD: mean ± standard deviation 4.95 ± 3.0; HC 3.62 ± 3.0, T = 1.88, p = 0.06). Discussion: Non-dependent alcohol use impacts brain architectural organization and connectivity within salience, reward, and affective circuitry. The relationship between alcohol use and topology of the network in BD suggests an interactive effect between specific biological vulnerability and alcohol use, which may explain the susceptibility to an increased risk of relapse in the disorder. Impact statement The association between non-dependent alcohol use and neural architecture in bipolar disorder (BD) is unknown, despite the poor clinical trajectory and increased likelihood of relapse associated with alcohol use in BD. We demonstrate that together alcohol and a diagnosis of BD is associated with a subnetwork involving nodes of the cortico-limbic and reward networks. This subnetwork, demonstrated in BD and absent in controls, differentially involves nodes that are specific to reward and emotion processes. This suggests a diagnosis-specific biological vulnerability for alcohol use and may be consistent with known mood lability and thus relapse associated with alcohol use in BD.

Enhancing cortical network-level participation coefficient as a potential mechanism for transfer in cognitive training in aMCI

Effective cognitive training must improve cognition beyond the trained domain (show a transfer effect) and be applicable to dementia-risk populations, e.g., amnesic mild cognitive impairment (aMCI). Theories suggest training should target processes that 1) show robust engagement, 2) are domain-general, and 3) reflect long-lasting changes in brain organization. Brain regions that connect to many different networks (i.e., show high participation coefficient; PC) are known to support integration. This capacity is 1) relatively preserved in aMCI, 2) required across a wide range of cognitive domains, and 3) trait-like. In 49 individuals with aMCI that completed a 6-week visual speed of processing training (VSOP) and 28 active controls, enhancement in PC was significantly more related to transfer to working memory at global and network levels in VSOP compared to controls, particularly in networks with many high-PC nodes. This suggests that enhancing brain integration may provide a target for developing effective cognitive training.

Mind the gap: Performance metric evaluation in brain-age prediction.

Estimating age based on neuroimaging‐derived data has become a popular approach to developing markers for brain integrity and health. While a variety of machine‐learning algorithms can provide accurate predictions of age based on brain characteristics, there is significant variation in model accuracy reported across studies. We predicted age in two population‐based datasets, and assessed the effects of age range, sample size and age‐bias correction on the model performance metrics Pearson's correlation coefficient (r), the coefficient of determination (R 2), Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE). The results showed that these metrics vary considerably depending on cohort age range; r and R 2 values are lower when measured in samples with a narrower age range. RMSE and MAE are also lower in samples with a narrower age range due to smaller errors/brain age delta values when predictions are closer to the mean age of the group. Across subsets with different age ranges, performance metrics improve with increasing sample size. Performance metrics further vary depending on prediction variance as well as mean age difference between training and test sets, and age‐bias corrected metrics indicate high accuracy—also for models showing poor initial performance. In conclusion, performance metrics used for evaluating age prediction models depend on cohort and study‐specific data characteristics, and cannot be directly compared across different studies. Since age‐bias corrected metrics generally indicate high accuracy, even for poorly performing models, inspection of uncorrected model results provides important information about underlying model attributes such as prediction variance.

Individual differences in beta frequency correlate with the audio-visual fusion illusion.

Presenting one flash with two beeps induces a perception of two flashes (audio-visual [AV] fission illusion), while presenting two flashes with one beep induces a perception of one flash (fusion illusion). Although previous studies showed a relationship between the frequency of the alpha rhythm (alpha cycle) and one's susceptibility to the fission illusion, the relationship between neural oscillations and the fusion illusion is unknown. Using electroencephalography, here I investigated the frequency of oscillatory signals in the pre-stimulus period and found a significant correlation between the beta rhythm and the fusion illusion; specifically, participants with a lower beta frequency showed a larger fusion illusion. These data indicate two separate time windows of AV integration in the human brain, one defined by the alpha cycle (fission) and another defined by the beta cycle (fusion).