Circadian blood pressure dysregulation in children with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) adversely affects normal blood pressure (BP) and may disrupt circadian BP patterns. We sought to examine 24-hour circadian BP rhythms in children with OSA and healthy controls. METHODS: Children 5-14 years with OSA and healthy controls underwent 24-hour BP monitoring and actigraphy to quantify sleep. Shape invariant statistical models compared circadian BP patterns (e.g. times of BP peaks, time arrived at peak BP velocity [TAPV]) in the OSA and control groups. RESULTS: The analytic sample included 219 children (mild OSA: n = 52; moderate-to-severe OSA (MS-OSA): n = 50; controls: n = 117). In the morning, the MS-OSA group had earlier TAPV for DBP than controls (51 minutes, p < 0.001). TAPV in the evening was earlier for the MS-OSA group than controls (SBP: 95 minutes, p < 0.001; DBP: 28 minutes, p = 0.028). At mid-day, SBP and DBP velocity nadirs were earlier for the MS-OSA group than controls (SBP: 57 minutes, p < 0.001; DBP: 38 minutes, p < 0.01). The MS-OSA group reached most BP values significantly earlier than controls; the largest differences were 118 minutes (SBP) and 43 minutes (DBP) (p < 0.001). SBP and DBP were elevated in the MS-OSA group (hours 18-21 and 7--12, respectively, p < 0.01) compared to controls. The MS-OSA group was prone to "non-dipping" compared to controls (SBP: odds ratio [OR] = 2.16, 95% CI: 1.09, 4.29; DBP: OR = 3.45, 95% CI: 1.21, 10.23). CONCLUSIONS: Children with MS-OSA had changes in circadian BP patterns, namely earlier TAPV and BP peaks and nadirs than controls. Circadian disturbances in BP rhythms may be key to mapping the natural history of BP dysregulation in children with OSA.

Altered neuronal response to visual food stimuli in adolescents undergoing chronic sleep restriction.

STUDY OBJECTIVES: Poor sleep in adolescents can increase the risk of obesity, possibly due to changes in dietary patterns. Prior neuroimaging evidence, mostly in adults, suggests that lacking sleep results in increased response to food cues in reward-processing brain regions. Needed is a clarification of the mechanisms by which food reward processing is altered by the kind of chronic sleep restriction (SR) typically experienced by adolescents. This study aimed to elucidate the impact of sleep duration on response to visual food stimuli in healthy adolescents using functional neuroimaging, hypothesizing increased reward processing response after SR compared to a well-rested condition. METHODS: Thirty-nine healthy adolescents, 14-17 years old, completed a 3-week protocol: (1) sleep phase stabilization; (2) SR (~6.5 h nightly); and (3) healthy sleep (HS) duration (~9 h nightly). Participants underwent functional MRI while performing a visual food paradigm. Contrasts of food versus nonfood responses were compared within-subject between conditions of SR and HS. RESULTS: Under SR, there was a greater response to food stimuli compared to HS in a voxel cluster including the left ventral tegmental area and substantia nigra. No change in food appeal rating due to the sleep manipulation was detected. CONCLUSIONS: Outcomes of this study suggest that SR, as commonly experienced by healthy adolescents, results in the elevated dopaminergic drive of the reward network that may augment motivation to seek food in the context of individual food appeal and inhibitory profiles. Countermeasures that reduce food salience could include promoting consistent HS habits.

Categorizing cortical dysplasia lesions for surgical outcome using network functional connectivity.

OBJECTIVE: Focal cortical dysplasia (FCD) is often associated with drug-resistant epilepsy, leading to a recommendation to surgically remove the seizure focus. Predicting outcome for resection of FCD is challenging, requiring a new approach. Lesion-symptom mapping is a powerful and broadly applicable method for linking neurological symptoms or outcomes to damage to particular brain regions. In this work, the authors applied lesion network mapping, an expansion of the traditional approach, to search for the association of lesion network connectivity with surgical outcomes. They hypothesized that connectivity of lesion volumes, preoperatively identified by MRI, would associate with seizure outcomes after surgery in a pediatric cohort with FCD. METHODS: This retrospective study included 21 patients spanning the ages of 3 months to 17.7 years with FCD lesions who underwent surgery for drug-resistant epilepsy. The mean brain-wide functional connectivity map of each lesion volume was assessed across a database of resting-state functional MRI data from healthy children (spanning approximately 2.9 to 18.9 years old) compiled at the authors' institution. Lesion connectivity maps were averaged across age and sex groupings from the database and matched to each patient. The authors sought to associate voxel-wise differences in these maps with subject-specific surgical outcome (seizure free vs persistent seizures). RESULTS: Lesion volumes with persistent seizures after surgery tended to have stronger connectivity to attention and motor networks and weaker connectivity to the default mode network compared with lesion volumes with seizure-free surgical outcome. CONCLUSIONS: Network connectivity-based lesion-outcome mapping may offer new insight for determining the impact of lesion volumes discerned according to both size and specific location. The results of this pilot study could be validated with a larger set of data, with the ultimate goal of allowing examination of lesions in patients with FCD and predicting their surgical outcomes.

Neuronal activation and performance changes in working memory induced by chronic sleep restriction in adolescents.

Most adolescents get less than the recommended 8-10 hr of sleep per night. Functional deficits from lack of sleep include disruption of working memory. Adult neuroimaging studies of sleep deprivation suggest diminished responses in task-related brain networks if performance degrades, but compensatory increased responses with maintained performance. This study utilized functional magnetic resonance imaging to examine compensatory and diminished brain responses in adolescents during working memory performance, comparing chronic sleep restriction and healthy sleep duration. Thirty-six healthy adolescents, 14-17 years old, experienced a 3-week protocol: (a) sleep phase stabilization; (b) sleep restriction (~6.5 hr nightly); and (c) healthy sleep duration (~9 hr nightly). After each sleep manipulation, we acquired functional magnetic resonance imaging with an NBack working memory task with four difficulty levels (0 to 3-back). NBack performance degraded with higher task difficulty, but without a detectable effect of sleep duration. ANOVA revealed main effects of both NBack difficulty and sleep in widespread brain networks. Planned contrasts showed that, compared with healthy sleep, sleep restriction resulted in greater medial prefrontal activation and weaker activation in the precuneus for the most difficult task condition. During sleep restriction, we found compensatory functional responses in brain regions that process sensory input and vigilance. However, adolescents also showed impaired performance and diminished brain responses during the hardest task level under a week of chronic sleep restriction. Chronic sleep restriction during adolescence is common. Understanding the impact of ongoing functional compensation and performance breakdown during this developmental period can have important implications for learning and educational strategies.

Cerebral microvascular and microstructural integrity is regionally altered in patients with systemic lupus erythematosus.

BACKGROUND: To measure regional brain microvascular and microstructural changes in childhood-onset SLE (cSLE) using diffusion-weighted imaging (DWI) at multiple b values and investigate relationships of those measures with neurocognitive function and disease activity. METHODS: In this cross-sectional, case-control study, vascular volume fraction, effective diffusion, parenchymal diffusion, and blood flow parameters were regionally compared in cSLE patients and matched healthy controls. These markers of microvascular and microstructural integrity were derived by diffusion-weighted brain MRI and intravoxel incoherent motion (IVIM) modeling. Formal neurocognitive testing was completed focused on the domains of attention, visuoconstructional ability, working memory, and psychomotor speed. Test scores and measures of disease severity were regressed against regional microvascular integrity parameters among cSLE patients. RESULTS: Formal cognitive testing confirmed normal cognitive ability among all cSLE patients included in the analysis (n = 11). Nevertheless, reduction in blood volume fraction coincided with increased effective diffusion and flow parameters in cSLE patients vs. controls in posterior brain regions including the cuneus and precuneus. Regional microvascular measures correlated (|r| = 0.54-0.66) with neuropsychiatric scores and disease activity among cSLE patients. CONCLUSIONS: There is imaging evidence, using IVIM, of degraded microvascular integrity in cSLE patients with normal cognitive ability. The observed regional changes correspond with posterior vascular border zones. These outcomes appear consistent with regional gray matter volume loss previously observed in cSLE patients with overt neurocognitive deficits, supporting the notion that adverse vascular changes precede loss of cognitive ability in cSLE. Longitudinal studies are needed to confirm the findings of this initial study.

Age-related changes in baroreflex sensitivity and cardiac autonomic tone in children mirrored by regional brain gray matter volume trajectories.

BackgroundThe baroreflex and central autonomic brain regions together control the cardiovascular system. Baroreflex sensitivity (BRS) decreases with age in adults. Age-related changes in brain regions for cardiovascular control in children are unknown. We studied age-related changes in BRS, cardiac autonomic tone, and gray matter volume (GMV) of brain regions associated with cardiovascular control.MethodsBeat-to-beat blood pressure and heart rate (HR) were recorded in 49 children (6-14 years old). Spontaneous BRS was calculated by the sequence method. Cardiac autonomic tone was measured by spectral analysis of HR variability. GMV was measured using voxel-based morphometryin 112 healthy children (5-18 years old).ResultsAge-related changes in BRS were significantly different in children <10 years and ≥10 years. Age-related changes in GMV in regions of interest (ROI) were also significantly different between children <10 and ≥10 years and between children <11 and ≥11 years. However, age-related changes in cardiac autonomic tone were progressive.ConclusionsSignificant changes in BRS trajectories between <10 and ≥10 years may be associated with similar age-related changes of GMV in brain ROI. This new knowledge will guide future studies examining whether childhood cardiovascular disruption manifests as deviated maturation trajectories of specific brain regions.

Relationship Between Alpha Rhythm and the Default Mode Network: An EEG-fMRI Study.

PURPOSE: Reports of the relationship between the default mode network (DMN) and alpha power are conflicting. Our goal was to assess this relationship by analyzing concurrently obtained EEG/functional MRI data using hypothesis-independent methods. METHODS: We collected functional MRI and EEG data during eyes-closed rest in 20 participants aged 19 to 37 (10 females) and performed independent component analysis on the functional MRI data and a Hamming-windowed fast Fourier transform on the EEG data. We correlated functional MRI fluctuations in the DMN with alpha power. RESULTS: Of the six independent components found to have significant relationships with alpha, four contained DMN-associated regions: One independent component was positively correlated with alpha power, whereas all others were negatively correlated. Furthermore, two independent components with opposite relationships with alpha had overlapping voxels in the medial prefrontal cortex and posterior cingulate cortex, suggesting that subpopulations of neurons within these classic nodes within the DMN may have different relationships to alpha power. CONCLUSIONS: Different parts of the DMN exhibit divergent relationships to alpha power. Our results highlight the relationship between DMN activity and alpha power, indicating that networks, such as the DMN, may have subcomponents that exhibit different behaviors.

Altered Blood-Brain Barrier Permeability in Patients With Systemic Lupus Erythematosus: A Novel Imaging Approach.

OBJECTIVE: To evaluate a safe, noninvasive magnetic resonance imaging (MRI) method to measure regional blood-brain barrier integrity and investigate its relationship with neurocognitive function and regional gray matter volume in juvenile-onset systemic lupus erythematosus (SLE). METHODS: In this cross-sectional, case-control study, capillary permeability was measured as a marker of blood-brain barrier integrity in juvenile SLE patients and matched healthy controls, using a combination of arterial spin labeling and diffusion-weighted brain MRI. Regional gray matter volume was measured by voxel-based morphometry. Correlation analysis was done to investigate the relationship between regional capillary permeability and regional gray matter volume. Formal neurocognitive testing was completed (measuring attention, visuoconstructional ability, working memory, and psychomotor speed), and scores were regressed against regional blood-brain barrier integrity among juvenile SLE patients. RESULTS: Formal cognitive testing confirmed normal cognitive ability in all juvenile SLE subjects (n = 11) included in the analysis. Regional capillary permeability was negatively associated (P = 0.026) with neurocognitive performance concerning psychomotor speed in the juvenile SLE cohort. Compared with controls (n = 11), juvenile SLE patients had significantly greater capillary permeability involving Brodmann's areas 19, 28, 36, and 37 and caudate structures (P < 0.05 for all). CONCLUSION: There is imaging evidence of increased regional capillary permeability in juvenile SLE patients with normal cognitive performance using a novel noninvasive MRI technique. These blood-brain barrier outcomes appear consistent with functional neuronal network alterations and gray matter volume loss previously observed in juvenile SLE patients with overt neurocognitive deficits, supporting the notion that blood-brain barrier integrity loss precedes the loss of cognitive ability in juvenile SLE. Longitudinal studies are needed to confirm the findings of this pilot study.

BOLD fMRI in infants under sedation: Comparing the impact of pentobarbital and propofol on auditory and language activation.

PURPOSE: To elucidate differences in the disruption of language network function, as measured by blood oxygenation level-dependent (BOLD) contrast functional MRI (fMRI), attributable to two common sedative agents administered to infants under clinical imaging protocols. MATERIALS AND METHODS: The sedatives pentobarbital (Nembutal) and Propofol, administered clinically to infants at 1 year of age, were compared with respect to BOLD activation profiles in response to passive story-listening stimulation. An intermittent event-related imaging protocol was used with which the temporal evolution of language processing resulting from this stimulation was explored. RESULTS: Propofol and Nembutal were found to have distinct and complementary responses to story-listening. Propofol exhibited more activation in higher processing networks with increasing response toward the end of narrative stimulus. Nembutal, in contrast, had much more robust activation of primary and secondary sensory cortices but a decreasing response over time in fronto-parietal default-mode regions. This may suggest a breakdown of top-down feedback for Propofol versus the lack of bottom-up feed-forward processing for Nembutal. CONCLUSION: Two popular sedative agents for use in children for clinical fMRI were found to induce distinct alteration of activation patterns from a language stimulus. This has ramifications for clinical fMRI of sedated infants and encourages further study to build a framework for more confident interpretation.

Functional neuronal network activity differs with cognitive dysfunction in childhood-onset systemic lupus erythematosus.

INTRODUCTION: Neuropsychiatric manifestations are common in childhood-onset systemic lupus erythematosus (cSLE) and often include neurocognitive dysfunction (NCD). Functional magnetic resonance imaging (fMRI) can measure brain activation during tasks that invoke domains of cognitive function impaired by cSLE. This study investigates specific changes in brain function attributable to NCD in cSLE that have potential to serve as imaging biomarkers. METHODS: Formal neuropsychological testing was done to measure cognitive ability and to identify NCD. Participants performed fMRI tasks probing three cognitive domains impacted by cSLE: visuoconstructional ability (VCA), working memory, and attention. Imaging data, collected on 3-Tesla scanners, included a high-resolution T1-weighted anatomic reference image followed by a T2*-weighted whole-brain echo planar image series for each fMRI task. Brain activation using blood oxygenation level-dependent contrast was compared between cSLE patients with NCD (NCD-group, n = 7) vs. without NCD (noNCD-group, n = 14) using voxel-wise and region of interest-based analyses. The relationship of brain activation during fMRI tasks and performance in formal neuropsychological testing was assessed. RESULTS: Greater brain activation was observed in the noNCD-group vs. NCD-group during VCA and working memory fMRI tasks. Conversely, compared to the noNCD-group, the NCD-group showed more brain activation during the attention fMRI task. In region of interest analysis, brain activity during VCA and working memory fMRI tasks was positively associated with the participants' neuropsychological test performance. In contrast, brain activation during the attention fMRI task was negatively correlated with neuropsychological test performance. While the NCD group performed worse than the noNCD group during VCA and working memory tasks, the attention task was performed equally well by both groups. CONCLUSIONS: NCD in patients with cSLE is characterized by differential activation of functional neuronal networks during fMRI tasks probing working memory, VCA, and attention. Results suggest a compensatory mechanism allows maintenance of attentional performance under NCD. This mechanism appears to break down for the VCA and working memory challenges presented in this study. The observation that neuronal network activation is related to the formal neuropsychological testing performance makes fMRI a candidate imaging biomarker for cSLE-associated NCD.

Reduced default mode network connectivity in treatment-resistant idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsy (IGE) resistant to treatment is common, but its neuronal correlates are not entirely understood. Therefore, the aim of this study was to examine resting-state default mode network (DMN) functional connectivity in patients with treatment-resistant IGE. METHODS: Treatment resistance was defined as continuing seizures despite an adequate dose of valproic acid (valproate, VPA). Data from 60 epilepsy patients and 38 healthy controls who underwent simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) were included (EEG/fMRI). Independent component analysis (ICA) and dual regression were used to quantify DMN connectivity. Confirmatory analysis using seed-based voxel correlation was performed. KEY FINDINGS: There was a significant reduction of DMN connectivity in patients with treatment-resistant epilepsy when compared to patients who were treatment responsive and healthy controls. Connectivity was negatively correlated with duration of epilepsy. SIGNIFICANCE: Our findings in this large sample of patients with IGE indicate the presence of reduced DMN connectivity in IGE and show that connectivity is further reduced in treatment-resistant epilepsy. DMN connectivity may be useful as a biomarker for treatment resistance.

Moderating effects of music on resting state networks.

Resting state networks (RSNs) are spontaneous, synchronous, low-frequency oscillations observed in the brains of subjects who are awake but at rest. A particular RSN called the default mode network (DMN) has been shown to exhibit changes associated with neurological disorders such as temporal lobe epilepsy or Alzheimer's disease. Previous studies have also found that differing experimental conditions such as eyes-open versus eyes-closed can produce measurable changes in the DMN. These condition-associated changes have the potential of confounding the measurements of changes in RSNs related to or caused by disease state(s). In this study, we use fMRI measurements of resting-state connectivity paired with EEG measurements of alpha rhythm and employ independent component analysis, undirected graphs of partial spectral coherence, and spatiotemporal regression to investigate the effect of music-listening on RSNs and the DMN in particular. We observed similar patterns of DMN connectivity in subjects who were listening to music compared with those who were not, with a trend toward a more introspective pattern of resting-state connectivity during music-listening. We conclude that music-listening is a valid condition under which the DMN can be studied.

Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia.

BACKGROUND: Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca's area for chronic aphasia treatment. MATERIAL/METHODS: We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca's area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca's. RESULTS: 6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS. CONCLUSIONS: FMRI-guided, excitatory rTMS applied to the affected Broca's area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.

Preliminary fMRI findings in experimentally sleep-restricted adolescents engaged in a working memory task.

Here we report preliminary findings from a small-sample functional magnetic resonance imaging (fMRI) study of healthy adolescents who completed a working memory task in the context of a chronic sleep restriction experiment. Findings were consistent with those previously obtained on acutely sleep-deprived adults. Our data suggest that, when asked to maintain attention and burdened by chronic sleep restriction, the adolescent brain responds via compensatory mechanisms that accentuate the typical activation patterns of attention-relevant brain regions. Specifically, it appeared that regions that are normally active during an attention-demanding working memory task in the well-rested brain became even more active to maintain performance after chronic sleep restriction. In contrast, regions in which activity is normally suppressed during such a task in the well-rested brain showed even greater suppression to maintain performance after chronic sleep restriction. Although limited by the small sample, study results provide important evidence of feasibility, as well as guidance for future research into the functional neurological effects of chronic sleep restriction in general, the effects of sleep restriction in children and adolescents, and the neuroscience of attention and its disorders in children.

Simultaneous EEG/functional magnetic resonance imaging at 4 Tesla: correlates of brain activity to spontaneous alpha rhythm during relaxation.

SUMMARY: : Simultaneous EEG and functional magnetic resonance imaging have been applied to the study of brain states associated with alpha waves using a magnetic field strength of 1.5 Tesla and has been shown in recent years to be feasible up to 3 Tesla for other applications. This study demonstrates this technique's continued viability at a field strength of 4 Tesla, affording a proportionally greater sensitivity to changes in Blood Oxygen Level Dependent (BOLD) signal. In addition, for the study of alpha correlations, the authors used a larger number of subjects and scanning sessions than in the previous work. Random effects group regression analysis of 35 EEG/functional magnetic resonance imaging sessions against occipital alpha magnitude in a relaxed state detected bilateral widespread activation of dorsal thalamus and portions of the anterior cingulate and cerebellum. In the same group analysis, deactivations arose predominantly in the fusiform and adjacent visual association areas with a small activation cluster also detected in dorsolateral prefrontal cortex. This pattern is consistent with a correspondence between alpha magnitude variations and resting state network dynamics ascertained by recent studies of low frequency spontaneous BOLD fluctuations. The central role of the thalamus in resting state networks correlated with alpha activity is highlighted. Demonstrating the applicability of simultaneous EEG/functional magnetic resonance imaging up to 4 Tesla is particularly important for clinically relevant research involving challenging spontaneous EEG abnormalities, such as those of epilepsy.

Functional magnetic resonance imaging assessment of cognitive function in childhood-onset systemic lupus erythematosus: a pilot study.

OBJECTIVE: To investigate changes in brain activation patterns detected by functional magnetic resonance imaging (FMRI), and the relationship between FMRI activation patterns and results of formal neuropsychological testing, in patients with childhood-onset systemic lupus erythematosus (SLE). METHODS: Ten patients with childhood-onset SLE underwent formal neuropsychological testing and FMRI using 3 paradigms: a continuous performance task (CPT) to evaluate attention, an N-Back task to assess working memory, and verb generation to evaluate language processing. Composite Z maps were generated to summarize the brain activation patterns for each FMRI paradigm in patients with childhood-onset SLE and to compare these patterns with those observed in healthy controls. Between-group comparison Z maps showing differences in activation between childhood-onset SLE patients and controls were generated, using a significance level of P < 0.05 in a general linear model. RESULTS: Compared with the control group, the childhood-onset SLE group showed statistically significant increased activation of brain areas involved in the CPT, N-Back, and verb generation tasks. In contrast, in the absence of active stimulus, e.g., during times of the paradigm control tasks, childhood-onset SLE patients consistently undersuppressed activity in the expected brain areas. Activation in selected cortical areas was found to correlate negatively with results of a subset of individual neuropsychological test scores. CONCLUSION: FMRI abnormalities are present in childhood-onset SLE, manifesting as an imbalance between active and inhibitory responses to an array of stimuli. Differences in brain activation patterns compared with those observed in controls suggest that childhood-onset SLE may be associated with abnormalities in white matter connectivity resulting in neuronal network dysfunction, rather than injury of specific gray matter areas.