Motor network dynamic resting state fMRI connectivity of neurotypical children in regions affected by cerebral palsy.

Background: Normative childhood motor network resting-state fMRI effective connectivity is undefined, yet necessary for translatable dynamic resting-state-network-informed evaluation in pediatric cerebral palsy. Methods: Cross-spectral dynamic causal modeling of resting-state-fMRI was investigated in 50 neurotypically developing 5- to 13-year-old children. Fully connected six-node network models per hemisphere included primary motor cortex, striatum, subthalamic nucleus, globus pallidus internus, thalamus, and contralateral cerebellum. Parametric Empirical Bayes with exhaustive Bayesian model reduction and Bayesian modeling averaging informed the model; Purdue Pegboard Test scores of hand motor behavior were the covariate at the group level to determine the effective-connectivity-functional behavior relationship. Results: Although both hemispheres exhibited similar effective connectivity of motor cortico-basal ganglia-cerebellar networks, magnitudes were slightly greater on the right, except for left-sided connections of the striatum which were more numerous and of opposite polarity. Inter-nodal motor network effective connectivity remained consistent and robust across subjects. Age had a greater impact on connections to the contralateral cerebellum, bilaterally. Motor behavior, however, affected different connections in each hemisphere, exerting a more prominent effect on the left modulatory connections to the subthalamic nucleus, contralateral cerebellum, primary motor cortex, and thalamus. Discussion: This study revealed a consistent pattern of directed resting-state effective connectivity in healthy children aged 5-13 years within the motor network, encompassing cortical, subcortical, and cerebellar regions, correlated with motor skill proficiency. Both hemispheres exhibited similar effective connectivity within motor cortico-basal ganglia-cerebellar networks reflecting inter-nodal signal direction predicted by other modalities, mainly differing from task-dependent studies due to network differences at rest. Notably, age-related changes were more pronounced in connections to the contralateral cerebellum. Conversely, motor behavior distinctly impacted connections in each hemisphere, emphasizing its role in modulating left sided connections to the subthalamic nucleus, contralateral cerebellum, primary motor cortex, and thalamus. Motor network effective connectivity was correlated with motor behavior, validating its physiological significance. This study is the first to evaluate a normative effective connectivity model for the pediatric motor network using resting-state functional MRI correlating with behavior and serves as a foundation for identifying abnormal findings and optimizing targeted interventions like deep brain stimulation, potentially influencing future therapeutic approaches for children with movement disorders.

Resting-State Functional Magnetic Resonance Imaging Network Association With Mortality, Epilepsy, Cognition, and Motor Two-Year Outcomes in Suspected Severe Neonatal Acute Brain Injury.

BACKGROUND AND OBJECTIVES: In acute brain injury of neonates, resting-state functional magnetic resonance imaging (MRI) (RS) showed incremental association with consciousness, mortality, cognitive and motor development, and epilepsy, with correction for multiple comparisons, at six months postgestation in neonates with suspected acute brain injury (ABI). However, there are relatively few developmental milestones at six months to benchmark against, thus, we extended this cohort study to evaluate two-year outcomes. METHODS: In 40 consecutive neonates with ABI and RS, ordinal scores of resting-state networks; MRI, magnetic resonance spectroscopy, and electroencephalography; and up to 42-month outcomes of mortality, general and motor development, Pediatric Cerebral Performance Category Scale (PCPC), and epilepsy informed associations between tests and outcomes. RESULTS: Mean gestational age was 37.8 weeks, 68% were male, and 60% had hypoxic-ischemic encephalopathy. Three died in-hospital, four at six to 42 months, and five were lost to follow-up. Associations included basal ganglia network with PCPC (P = 0.0003), all-mortality (P = 0.005), and motor (P = 0.0004); language/frontoparietal network with developmental delay (P = 0.009), PCPC (P = 0.006), and all-mortality (P = 0.01); default mode network with developmental delay (P = 0.003), PCPC (P = 0.004), neonatal intensive care unit mortality (P = 0.01), and motor (P = 0.009); RS seizure onset zone with epilepsy (P = 0.01); and anatomic MRI with epilepsy (P = 0.01). CONCLUSION: For the first time, at any age, resting state functional MRI in ABI is associated with long-term epilepsy and RSNs predicted mortality in neonates. Severity of RSN abnormality was associated with incrementally worsened neurodevelopment including cognition, language, and motor function over two years.

Proceedings of the First Pediatric Coma and Disorders of Consciousness Symposium by the Curing Coma Campaign, Pediatric Neurocritical Care Research Group, and NINDS: Gearing for Success in Coma Advancements for Children and Neonates.

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community.

Discerning Seizure-Onset v. Propagation Zone: Pre-and-Post-Operative Resting-State fMRI Directionality and Boerwinkle Neuroplasticity Index.

The goal of this study was to determine resting state fMRI (rs-fMRI) effective connectivity (RSEC) capacity, agnostic of epileptogenic events, in distinguishing seizure onset zones (SOZ) from propagation zones (pZ). Consecutive patients (2.1-18.2 years old), with epilepsy and hypothalamic hamartoma, pre-operative rs-fMRI-directed surgery, post-operative imaging, and Engel class I outcomes were collected. Cross-spectral dynamic causal modelling (DCM) was used to estimate RSEC between the ablated rs-fMRI-SOZ to its region of highest connectivity outside the HH, defined as the propagation zone (pZ). Pre-operatively, RSEC from the SOZ and PZ was expected to be positive (excitatory), and pZ to SOZ negative (inhibitory), and post-operatively to be either diminished or non-existent. Sensitivity, accuracy, positive predictive value were determined for node-to-node connections. A Parametric Empirical Bayes (PEB) group analysis on pre-operative data was performed to identify group effects and effects of Engel class outcome and age. Pre-operative RSEC strength was also evaluated for correlation with percent seizure frequency improvement, sex, and region of interest size. Of the SOZ's RSEC, only 3.6% had no connection of significance to the pZ when patient models were individually reduced. Among remaining, 96% were in expected (excitatory signal found from SOZ â†’ pZ and inhibitory signal found from pZ â†’ SOZ) versus 3.6% reversed polarities. Both pre-operative polarity signals were equivalently as expected, with one false signal direction out of 26 each (3.7% total). Sensitivity of 95%, specificity 73%, accuracy of 88%, negative predictive value 88%, and positive predictive value of 88% in identifying and differentiating the SOZ and pZ. Groupwise PEB analysis confirmed SOZ â†’ pZ EC was excitatory, and pZ â†’ SOZ EC was inhibitory. Patients with better outcomes (Engel Ia vs. Ib) showed stronger inhibitory signal (pZ â†’ SOZ). Age was negatively associated with absolute RSEC bidirectionally but had no relationship with Directionality SOZ identification performance. In an additional hierarchical PEB analysis identifying changes from pre-to-post surgery, SOZ â†’ pZ modulation became less excitatory and pZ â†’ SOZ modulation became less inhibitory. This study demonstrates the accuracy of Directionality to identify the origin of excitatory and inhibitory signal between the surgically confirmed SOZ and the region of hypothesized propagation zone in children with DRE due to a HH. Thus, this method validation study in a homogenous DRE population may have potential in narrowing the SOZ-candidates for epileptogenicity in other DRE populations and utility in other neurological disorders.

Is Resting State Functional MRI Effective Connectivity in Movement Disorders Helpful? A Focused Review Across Lifespan and Disease.

In the evolving modern era of neuromodulation for movement disorders in adults and children, much progress has been made recently characterizing the human motor network (MN) with potentially important treatment implications. Herein is a focused review of relevant resting state fMRI functional and effective connectivity of the human motor network across the lifespan in health and disease. The goal is to examine how the transition from functional connectivity to dynamic effective connectivity may be especially informative of network-targeted movement disorder therapies, with hopeful implications for children.

Association of network connectivity via resting state functional MRI with consciousness, mortality, and outcomes in neonatal acute brain injury.

BACKGROUND: An accurate and comprehensive test of integrated brain network function is needed for neonates during the acute brain injury period to inform on morbidity. This retrospective cohort study assessed whether integrated brain network function acquired by resting state functional MRI during the acute period in neonates with brain injury, is associated with acute exam, neonatal mortality, and 6-month outcomes. METHODS: Study subjects included 40 consecutive neonates with resting state functional MRI acquired within 31 days after suspected brain insult from March 2018 to July 2019 at Phoenix Children's Hospital. Acute-period exam and test results were assigned ordinal scores based on severity as documented by respective treating specialists. Analyses (Fisher exact, Wilcoxon-rank sum test, ordinal/multinomial logistic regression) examined association of resting state networks with demographics, presentation, neurological exam, electroencephalogram, anatomical MRI, magnetic resonance spectroscopy, passive task functional MRI, and outcomes of discharge condition, outpatient development, motor tone, seizure, and mortality. RESULTS: Subjects had a mean (standard deviation) gestational age of 37.8 (2.6) weeks, a majority were male (63%), with a diagnosis of hypoxic ischemic encephalopathy (68%). Findings at birth included mild distress (48%), moderately abnormal neurological exam (33%), and consciousness characterized as awake but irritable (40%). Significant associations after multiple testing corrections were detected for resting state networks: basal ganglia with outpatient developmental delay (odds ratio [OR], 14.5; 99.4% confidence interval [CI], 2.00-105; P < .001) and motor tone/weakness (OR, 9.98; 99.4% CI, 1.72-57.9; P < .001); language/frontoparietal network with discharge condition (OR, 5.13; 99.4% CI, 1.22-21.5; P = .002) and outpatient developmental delay (OR, 4.77; 99.4% CI, 1.21-18.7; P=.002); default mode network with discharge condition (OR, 3.72; 99.4% CI, 1.01-13.78; P=.006) and neurological exam (P = .002 (FE); OR, 11.8; 99.4% CI, 0.73-191; P = .01 (OLR)); and seizure onset zone with motor tone/weakness (OR, 3.31; 99.4% CI, 1.08-10.1; P=.003). Resting state networks were not detected in three neonates, who died prior to discharge. CONCLUSIONS: This study provides level 3 evidence (OCEBM Levels of Evidence Working Group) demonstrating that in neonatal acute brain injury, the degree of abnormality of resting state networks is associated with acute exam and outcomes. Total lack of brain network detection was only found in patients who did not survive.

Automated seizure onset zone locator from resting-state functional MRI in drug-resistant epilepsy.

Objective: Accurate localization of a seizure onset zone (SOZ) from independent components (IC) of resting-state functional magnetic resonance imaging (rs-fMRI) improves surgical outcomes in children with drug-resistant epilepsy (DRE). Automated IC sorting has limited success in identifying SOZ localizing ICs in adult normal rs-fMRI or uncategorized epilepsy. Children face unique challenges due to the developing brain and its associated surgical risks. This study proposes a novel SOZ localization algorithm (EPIK) for children with DRE. Methods: EPIK is developed in a phased approach, where fMRI noise-related biomarkers are used through high-fidelity image processing techniques to eliminate noise ICs. Then, the SOZ markers are used through a maximum likelihood-based classifier to determine SOZ localizing ICs. The performance of EPIK was evaluated on a unique pediatric DRE dataset (n = 52). A total of 24 children underwent surgical resection or ablation of an rs-fMRI identified SOZ, concurrently evaluated with an EEG and anatomical MRI. Two state-of-art techniques were used for comparison: (a) least squares support-vector machine and (b) convolutional neural networks. The performance was benchmarked against expert IC sorting and Engel outcomes for surgical SOZ resection or ablation. The analysis was stratified across age and sex. Results: EPIK outperformed state-of-art techniques for SOZ localizing IC identification with a mean accuracy of 84.7% (4% higher), a precision of 74.1% (22% higher), a specificity of 81.9% (3.2% higher), and a sensitivity of 88.6% (16.5% higher). EPIK showed consistent performance across age and sex with the best performance in those < 5 years of age. It helped achieve a ~5-fold reduction in the number of ICs to be potentially analyzed during pre-surgical screening. Significance: Automated SOZ localization from rs-fMRI, validated against surgical outcomes, indicates the potential for clinical feasibility. It eliminates the need for expert sorting, outperforms prior automated methods, and is consistent across age and sex.

Resting State Functional Magnetic Resonance Imaging Elucidates Neurotransmitter Deficiency in Autism Spectrum Disorder.

Resting-state functional magnetic resonance imaging provides dynamic insight into the functional organization of the brains' intrinsic activity at rest. The emergence of resting-state functional magnetic resonance imaging in both the clinical and research settings may be attributed to recent advancements in statistical techniques, non-invasiveness and enhanced spatiotemporal resolution compared to other neuroimaging modalities, and the capability to identify and characterize deep brain structures and networks. In this report we describe a 16-year-old female patient with autism spectrum disorder who underwent resting-state functional magnetic resonance imaging due to late regression. Imaging revealed deactivated networks in deep brain structures involved in monoamine synthesis. Monoamine neurotransmitter deficits were confirmed by cerebrospinal fluid analysis. This case suggests that resting-state functional magnetic resonance imaging may have clinical utility as a non-invasive biomarker of central nervous system neurochemical alterations by measuring the function of neurotransmitter-driven networks. Use of this technology can accelerate and increase the accuracy of selecting appropriate therapeutic agents for patients with neurological and neurodevelopmental disorders.

Locked-in Intact Functional Networks in Children with Autism Spectrum Disorder: A Case-Control Study.

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to investigate abnormalities in brain network structure and connectivity on an individual level in neurodevelopmental disorders, such as autism spectrum disorder (ASD), paving the way toward using this technology for a personalized, precision medicine approach to diagnosis and treatment. Using a case-control design, we compared five patients with severe regressive-type ASD to five patients with temporal lobe epilepsy (TLE) to examine the association between brain network characteristics and diagnosis. All children with ASD and TLE demonstrated intact motor, language, and frontoparietal (FP) networks. However, aberrant networks not usually seen in the typical brain were also found. These aberrant networks were located in the motor (40%), language (80%), and FP (100%) regions in children with ASD, while children with TLE only presented with aberrant networks in the motor (40%) and language (20%) regions, in addition to identified seizure onset zones. Fisher's exact test indicated a significant relationship between aberrant FP networks and diagnosis (p = 0.008), with ASD and atypical FP networks co-occurring more frequently than expected by chance. Despite severe cognitive delays, children with regressive-type ASD may demonstrate intact typical cortical network activation despite an inability to use these cognitive facilities. The functions of these intact cognitive networks may not be fully expressed, potentially because aberrant networks interfere with their long-range signaling, thus creating a unique "locked-in network" syndrome.

A randomized-controlled neurofeedback trial in adult attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood onset disorder persisting into adulthood for a large proportion of cases. Neurofeedback (NF) has shown promising results in children with ADHD, but randomized controlled trials in adults with ADHD are scarce. We aimed to compare slow cortical potential (SCP)- and functional near-infrared spectroscopy (fNIRS) NF to a semi-active electromyography biofeedback (EMG-BF) control condition regarding changes in symptoms and the impact of learning success, as well as changes in neurophysiological parameters in an adult ADHD population. Patients were randomly assigned to SCP-NF (n = 26), fNIRS-NF (n = 21) or EMG-BF (n = 20). Outcome parameters were assessed over 30 training sessions (pre, intermediate, post) and at 6-months follow-up (FU) including 3 booster sessions. EEG was recorded during two auditory Go/NoGo paradigms assessing the P300 and contingent negative variation (CNV). fNIRS measurements were conducted during an n-back- as well as a Go/NoGo task. All three groups showed equally significant symptom improvements suggesting placebo- or non-specific effects on the primary outcome measure. Only when differentiating between learners and non-learners, fNIRS learners displayed stronger reduction of ADHD global scores compared to SCP non-learners at FU, and fNIRS learners showed specifically low impulsivity ratings. 30.8% in the SCP-NF and 61.9% of participants in the fNIRS-NF learned to regulate the respective NF target parameter. We conclude that some adults with ADHD learn to regulate SCP amplitudes and especially prefrontal hemodynamic activity during NF. We did not find any significant differences in outcome between groups when looking at the whole sample. When evaluating learners only, they demonstrate superior effects as compared to non-learners, which suggests specific effects in addition to non-specific effects of NF when learning occurs.

Validation of a wireless dry electrode system for electroencephalography.

BACKGROUND: Electroencephalography (EEG) is a widely used neuroimaging technique with applications in healthcare, research, assessment, treatment, and neurorehabilitation. Conventional EEG systems require extensive setup time, expensive equipment, and expertise to utilize and therefore are often limited to clinical or laboratory settings. Technological advancements have made it possible to develop wireless EEG systems with dry electrodes to reduce many of these barriers. However, due to the lack of homogeneity in hardware, electrode evaluation, and methodological procedures the clinical acceptance of these systems has been limited. METHODS: In this investigation the validity of a wireless dry electrode system compared to a conventional wet electrode system was assessed, while addressing methodological limitations. In Experiment 1, the signal output of both EEG systems was examined at Fz, C3, Cz, C4, and Pz using a conductive head model and generated test signals at 2.5 Hz, 10 Hz, and 39 Hz. In Experiment 2, two-minutes of eyes-closed and eyes-open EEG data was recorded simultaneously with both devices from the adjacent electrode sites in a sample of healthy adults. RESULTS: Between group effects and frequency*device and electrode*device interactions were assessed using a mixed ANOVA for the simulated and in vivo signal output, producing no significant effects . Bivariate correlation coefficients were calculated to assess the relationship between electrode pairs during the simultaneous in vivo recordings, indicating a significant positive relationship (all p's < .05) and larger correlation coefficients (r > ± 0.5) between the dry and wet electrode signal amplitude were observed for theta, alpha, beta 1, beta 2, beta 3, and gamma in both the eyes-closed and eyes-open conditions. CONCLUSIONS: This report demonstrates preliminary but compelling evidence that EEG data recorded from the wireless dry electrode system is comparable to data recorded from a conventional system. Small correlation values in delta activity were discussed in relation to minor differences in hardware filter settings, variation in electrode placement, and participant artifacts observer during the simultaneous EEG recordings. Study limitations and impact of this research on neurorehabilitation were discussed.

One size fits all? Slow cortical potentials neurofeedback: a review.

OBJECTIVE: The intent of this manuscript was to review all published studies on slow cortical potentials (SCP) neurofeedback for the treatment of ADHD, with emphasis on neurophysiological rationale, study design, protocol, outcomes, and limitations. METHOD: For review, PubMed, MEDLINE, ERIC, and Google Scholar searches identified six studies and six subsequent publications. In addition to five studies focusing on children with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV)-diagnosed ADHD, one study reports on adults. RESULTS: SCP protocols utilize unipolar-electrode placement at Cz, randomized bidirectional signal regulation, feedback/transfer trials, and discrete feedback/rewards. Results demonstrated learning of SCP self-regulation, moderate to large within group effect sizes for core ADHD symptom reduction, and enhancement of event-related potentials/electroencephalogram components. Neurophysiological and session variables were predictive of treatment outcome, but open questions of specific and nonspecific effects remain. Study limitations and future directions are discussed. CONCLUSION: SCP is an efficacious and standardized neurofeedback protocol that addresses behavioral and neurophysiological deficits in ADHD.