Brain signal variability and executive functions across the life span.

Neural variability is thought to facilitate survival through flexible adaptation to changing environmental demands. In humans, such capacity for flexible adaptation may manifest as fluid reasoning, inhibition of automatic responses, and mental set-switching-skills falling under the broad domain of executive functions that fluctuate over the life span. Neural variability can be quantified via the BOLD signal in resting-state fMRI. Variability of large-scale brain networks is posited to underpin complex cognitive activities requiring interactions between multiple brain regions. Few studies have examined the extent to which network-level brain signal variability across the life span maps onto high-level processes under the umbrella of executive functions. The present study leveraged a large publicly available neuroimaging dataset to investigate the relationship between signal variability and executive functions across the life span. Associations between brain signal variability and executive functions shifted as a function of age. Limbic-specific variability was consistently associated with greater performance across subcomponents of executive functions. Associations between executive function subcomponents and network-level variability of the default mode and central executive networks, as well as whole-brain variability, varied across the life span. Findings suggest that brain signal variability may help to explain to age-related differences in executive functions across the life span.

Traditionally, regional variability in brain signals has been viewed as a source of noise in human neuroimaging research. Our study demonstrates that brain signal variability may contain meaningful information related to psychological processes. We demonstrate that brain signal variability, particularly whole-brain variability, may serve as a reliable indicator of cognitive functions across the life span. Global variability and network-level variability play differing roles in supporting executive functions. Findings suggest that brain signal variability serves as a meaningful indicator of development and cognitive aging.

Neutrophil to lymphocyte ratio is a transdiagnostic biomarker of depression and structural and functional brain alterations in older adults.

The neutrophil to lymphocyte ratio (N:L) is an emergent transdiagnostic biomarker shown to predict peripheral inflammation as well as neuropsychiatric impairment. The afferent signaling of inflammation to the central nervous system has been implicated in the pathophysiology of sickness behavior and depression. Here, the N:L was compared to structural and functional limbic alterations found concomitant with depression within a geriatric cohort. Venous blood was collected for a complete blood count, and magnetic resonance imaging as well as phenotypic data were collected from the 66 community-dwelling older adults (aged 65-86 years). The N:L was regressed on gray matter volume and resting-state functional connectivity (rsFC) of the subgenual anterior cingulate (sgACC). Thresholded parameter estimates were extracted from structural and functional brain scans and bivariate associations tested with scores on the geriatric depression scale. Greater N:L predicted lower volume of hypothalamus and rsFC of sgACC with ventromedial prefrontal cortex. Both parameters were correlated (p < 0.05) with greater symptomology in those reporting moderate to severe levels of depression. These findings support the N:L as a transdiagnostic biomarker of limbic alteration underpinning mood disturbance in non-treated older adults.

Brain Dynamics Underlying Cognitive Flexibility Across the Lifespan.

The neural mechanisms contributing to flexible cognition and behavior and how they change with development and aging are incompletely understood. The current study explored intrinsic brain dynamics across the lifespan using resting-state fMRI data (n = 601, 6-85 years) and examined the interactions between age and brain dynamics among three neurocognitive networks (midcingulo-insular network, M-CIN; medial frontoparietal network, M-FPN; and lateral frontoparietal network, L-FPN) in relation to behavioral measures of cognitive flexibility. Hierarchical multiple regression analysis revealed brain dynamics among a brain state characterized by co-activation of the L-FPN and M-FPN, and brain state transitions, moderated the relationship between quadratic effects of age and cognitive flexibility as measured by scores on the Delis-Kaplan Executive Function System (D-KEFS) test. Furthermore, simple slope analyses of significant interactions revealed children and older adults were more likely to exhibit brain dynamic patterns associated with poorer cognitive flexibility compared with younger adults. Our findings link changes in cognitive flexibility observed with age with the underlying brain dynamics supporting these changes. Preventative and intervention measures should prioritize targeting these networks with cognitive flexibility training to promote optimal outcomes across the lifespan.

Whole-Brain Functional Dynamics Track Depressive Symptom Severity.

Depressive symptoms are reported by 20% of the population and are related to altered functional integrity of large-scale brain networks. The link between moment-to-moment brain function and depressive symptomatology, and the implications of these relationships for clinical and community populations alike, remain understudied. The present study examined relationships between functional brain dynamics and subclinical-to-mild depressive symptomatology in a large community sample of adults with and without psychiatric diagnoses. This study used data made available through the Enhanced Nathan Kline Institute-Rockland Sample; 445 participants between 18 and 65 years of age completed a 10-min resting-state functional MRI scan. Coactivation pattern analysis was used to examine the dimensional relationship between depressive symptoms and whole-brain states. Elevated levels of depressive symptoms were associated with increased frequency and dwell time of the default mode network, a brain network associated with self-referential thought, evaluative judgment, and social cognition. Furthermore, increased depressive symptom severity was associated with less frequent occurrences of a hybrid brain network implicated in cognitive control and goal-directed behavior, which may impair the inhibition of negative thinking patterns in depressed individuals. These findings demonstrate how temporally dynamic techniques offer novel insights into time-varying neural processes underlying subclinical and clinically meaningful depressive symptomatology.

Functional connectivity and upper limb function in patients after pediatric arterial ischemic stroke with contralateral corticospinal tract wiring.

To develop individualized motor rehabilitation, knowledge of the relationship between neuroplastic reorganization and motor recovery after pediatric arterial ischemic stroke (AIS) is crucial. Thus, we investigated functional connectivity in patients after AIS with good motor outcome and in patients with hemiparesis compared with typically developing peers. We included 18 patients (n = 9 with hemiparesis, n = 9 with good motor outcome) with pediatric AIS in the chronic phase (≥ 2 years after diagnosis, diagnosed > 16 years) and 18 peers matched by age and gender. Participants underwent a standardized motor assessment, single-pulse transcranial magnetic stimulation to determine the type of corticospinal tract wiring, and resting-state functional magnetic resonance imaging to examine motor network connectivity. Corticospinal tract wiring was contralateral in all participants. Patients with hemiparesis had lower interhemispheric connectivity strength compared with patients with good clinical outcome and peers. Patients with good clinical outcome had higher intrahemispheric connectivity strength compared with peers. Further, higher intrahemispheric connectivity was related to better motor outcome in patients. Our findings suggest that better motor outcome after pediatric AIS is related to higher motor network connectivity strength. Thus, resting-state functional connectivity might be predictive for motor recovery after pediatric AIS.

Neurovisceral integration in the executive control network: A resting state analysis.

Neurovisceral integration models emphasize the role of frontal lobes in cognitive, behavioral, and emotional regulation. Two candidate hubs for the regulation of cardio-autonomic control, anxiety, and executive attention are the dorsolateral prefrontal cortex (DLPFC) and middle frontal gyrus (MFG). Two-hundred and seventy-one adults (62.9 % female) aged 18-85 years were selected from the NKI-Rockland Sample. Resting state functional imaging data was preprocessed, and seeds extracted from bilateral DLPFC and MFG to test 4 regression models predicting connectivity with high frequency HRV (HF-HRV), trait anxiety (TA), and reaction time on an executive attention task. After controlling for age, sex, body mass index and head motion, the right DLPFC-MFG seed pair provided strongest support for neurovisceral integration indexed by HF-HRV, low TA and shorter reaction time on the attention network task. This hemispheric effect may underlie the inhibitory role of right PFC in the regulation of cardio-autonomic function, emotion, and executive attention.

Cerebral blood flow imbalance is associated with motor outcome after pediatric arterial ischemic stroke.

Cerebral hemodynamics after arterial ischemic stroke (AIS) in children are largely unknown. This study aims to explore long-term cerebral perfusion balance of vital tissue and its relation to motor outcome after childhood AIS. Patients diagnosed with childhood AIS (≤16 years at diagnosis, time since stroke ≥2 years) and typically developing peers were examined. Hemiparesis was classified according to the Pediatric Stroke Outcome Measure. Manual ability was assessed using the ABILHAND-Kids questionnaire. Cerebral blood flow was measured by arterial spin labeling and analyzed in the following brain regions: the hemispheres, the territory of the anterior cerebral artery (ACA), the middle cerebral artery (MCA), and in subregions of the MCA territory (MCA anterior, middle, posterior). To assess cerebral perfusion balance, laterality indices were calculated using cerebral blood flow in the ipsi- and contralesional hemisphere. Laterality indices were compared between stroke patients with and without hemiparesis, and peers. Twenty participants diagnosed with AIS were included (12 boys, 8 girls; mean age 14.46±4.96 years; time since stroke 8.08±3.62 years); 9 (45%) were diagnosed with hemiparesis. Additionally, 47 typically developing peers (21 boys, 26 girls; mean age 14.24±5.42 years) were studied. Laterality indices were higher in stroke patients and oriented to the contralesional hemisphere in all brain regions except the ACA territory and MCA posterior subregion. This was significantly different from peers, who showed balanced laterality indices. There was a significant correlation between laterality indices and manual ability, except in the ACA territory. AIS is associated with long-term alterations of cerebral blood flow in vital tissue, even in patients without hemiparesis. The degree of imbalance of cerebral perfusion in children after AIS is associated with manual ability.

Resting-state connectivity and executive functions after pediatric arterial ischemic stroke.

BACKGROUND: The aim of this study was to compare the relationship between core executive functions and frontoparietal network connections at rest between children who had suffered an arterial ischemic stroke and typically developing peers. METHODS: Children diagnosed with arterial ischemic stroke more than two years previously and typically developing controls were included. Executive function (EF) measures comprised inhibition (Go-NoGo task), fluency (category fluency task), processing speed (processing speed tasks), divided attention, working memory (letter-number sequencing), conceptual reasoning (matrices) and EF in everyday life (questionnaire). High-resolution T1-weighted magnetic resonance (MR) structural images and resting-state functional MR imaging were acquired. Independent component analysis was used to identify the frontoparietal network. Functional connections were obtained through correlation matrices; associations between cognitive measures and functional connections through Pearson's correlations. RESULTS: Twenty participants after stroke (7 females; mean age 16.0 years) and 22 controls (13 females; mean age 14.8 years) were examined. Patients and controls performed within the normal range in all executive tasks. Patients who had had a stroke performed significantly less well in tests of fluency, processing speed and conceptual reasoning than controls. Resting-state functional connectivity between the left and right inferior parietal lobe was significantly reduced in patients after pediatric stroke. Fluency, processing speed and perceptual reasoning correlated positively with the interhemispheric inferior parietal lobe connection in patients and controls. CONCLUSION: Decreased interhemispheric connections after stroke in childhood may indicate a disruption of typical interhemispheric interactions relating to executive functions. The present results emphasize the relationship between functional organization of the brain at rest and cognitive processes.

Quality of life after paediatric ischaemic stroke.

AIM: Paediatric arterial ischaemic stroke can lead to reduced quality of life (QoL). It is important to identify predictors of QoL to support recovery. We examined long-term QoL after arterial ischaemic stroke concerning different variables. METHOD: Children registered in the Swiss Neuropediatric Stroke Registry and suffering from arterial ischaemic stroke between 2000 and 2008 were included. Two years post-stroke, assessments included intelligence quotient tests for cognitive impairment and modified Rankin Scale (mRS) for neurological impairment; 5 years post-stroke, the Kidscreen-27 was used for QoL, DSM-IV criteria screening was used for attention deficits, and the ABILHAND-Kids was used for manual motor skills. Age at stroke, sex, socioeconomic status, lesion characteristics, neuropsychological and motor outcome, and mRS were correlated with QoL measures. RESULTS: Seventy children were examined (49 males, 21 females; mean age 7y 2wks). Age at stroke, sex, socioeconomic status, and lesion characteristics did not influence QoL; IQ below average and attention deficits partially influenced QoL. The highest predictive value for QoL was found for manual motor impairment (p=0.002) and mRS scores (p=0.013). Combined motor, cognitive, and attention impairment negatively affected QoL (p=0.001). INTERPRETATION: Neurological and cognitive impairments after paediatric arterial ischaemic stroke negatively influence QoL. Children with motor and neurological problems, as well as those with combined motor, cognitive, and attention problems, are at higher risk for low QoL.

Cortical reorganisation of cerebral networks after childhood stroke: impact on outcome.

BACKGROUND: Recovery after arterial ischaemic stroke is known to largely depend on the plastic properties of the brain. The present study examines changes in the network topography of the developing brain after stroke. Effects of brain damage are best assessed by examining entire networks rather than single sites of structural lesions. Relating these changes to post-stroke neuropsychological variables and motor abilities will improve understanding of functional plasticity after stroke. Inclusion of healthy controls will provide additional insight into children's normal brain development. Resting state functional magnetic resonance imaging is a valid approach to topographically investigate the reorganisation of functional networks after a brain lesion. Transcranial magnetic stimulation provides complementary output information. This study will investigate functional reorganisation after paediatric arterial ischaemic stroke by means of resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a cross-sectional plus longitudinal study design. The general aim of this study is to better understand neuroplasticity of the developing brain after stroke in order to develop more efficacious therapy and to improve the post-stroke functional outcome. METHODS: The cross-sectional part of the study will investigate the functional cerebral networks of 35 children with chronic arterial ischaemic stroke (time of the lesion >2 years). In the longitudinal part, 15 children with acute arterial ischaemic stroke (shortly after the acute phase of the stroke) will be included and investigations will be performed 3 times within the subsequent 9 months. We will also recruit 50 healthy controls, matched for age and sex. The neuroimaging and neurophysiological data will be correlated with neuropsychological and neurological variables. DISCUSSION: This study is the first to combine resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a paediatric population diagnosed with arterial ischaemic stroke. Thus, this study has the potential to uniquely contribute to the understanding of neuronal plasticity in the brains of healthy children and those with acute or chronic brain injury. It is expected that the results will lead to the development of optimal interventions after arterial ischaemic stroke.