Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Contributions to auditory system conduction velocity: insights with multi-modal neuroimaging and machine learning in children with ASD and XYY syndrome.

Introduction: The M50 electrophysiological auditory evoked response time can be measured at the superior temporal gyrus with magnetoencephalography (MEG) and its latency is related to the conduction velocity of auditory input passing from ear to auditory cortex. In children with autism spectrum disorder (ASD) and certain genetic disorders such as XYY syndrome, the auditory M50 latency has been observed to be elongated (slowed). Methods: The goal of this study is to use neuroimaging (diffusion MR and GABA MRS) measures to predict auditory conduction velocity in typically developing (TD) children and children with autism ASD and XYY syndrome. Results: Non-linear TD support vector regression modeling methods accounted for considerably more M50 latency variance than linear models, likely due to the non-linear dependence on neuroimaging factors such as GABA MRS. While SVR models accounted for ~80% of the M50 latency variance in TD and the genetically homogenous XYY syndrome, a similar approach only accounted for ~20% of the M50 latency variance in ASD, implicating the insufficiency of diffusion MR, GABA MRS, and age factors alone. Biologically based stratification of ASD was performed by assessing the conformance of the ASD population to the TD SVR model and identifying a sub-population of children with unexpectedly long M50 latency. Discussion: Multimodal integration of neuroimaging data can help build a mechanistic understanding of brain connectivity. The unexplained M50 latency variance in ASD motivates future hypothesis generation and testing of other contributing biological factors.

Maturation of auditory cortex neural responses during infancy and toddlerhood.

The infant auditory system rapidly matures across the first years of life, with a primary goal of obtaining ever-more-accurate real-time representations of the external world. Our understanding of how left and right auditory cortex neural processes develop during infancy, however, is meager, with few studies having the statistical power to detect potential hemisphere and sex differences in primary/secondary auditory cortex maturation. Using infant magnetoencephalography (MEG) and a cross-sectional study design, left and right auditory cortex P2m responses to pure tones were examined in 114 typically developing infants and toddlers (66 males, 2 to 24 months). Non-linear maturation of P2m latency was observed, with P2m latencies decreasing rapidly as a function of age during the first year of life, followed by slower changes between 12 and 24 months. Whereas in younger infants auditory tones were encoded more slowly in the left than right hemisphere, similar left and right P2m latencies were observed by ∼21 months of age due to faster maturation rate in the left than right hemisphere. No sex differences in the maturation of the P2m responses were observed. Finally, an earlier left than right hemisphere P2m latency predicted better language performance in older infants (12 to 24 months). Findings indicate the need to consider hemisphere when examining the maturation of auditory cortex neural activity in infants and toddlers and show that the pattern of left-right hemisphere P2m maturation is associated with language performance.

A comparison of resting-state eyes-closed and dark-room alpha-band activity in children.

In a relaxed and awake state with the eyes closed, 8-12 Hz neural oscillations are the dominant rhythm, most prominent in parietal-occipital regions. Resting-state (RS) alpha is associated with processing speed and is also thought to be central to how networks process information. Unfortunately, the RS eyes-closed (EC) exam can only be used with individuals who can remain awake with their eyes closed for an extended period. As such, infants, toddlers, and individuals with intellectual disabilities are usually excluded from RS alpha studies. Previous research suggests obtaining RS alpha measures in a dark room with the eyes open as a viable alternative to the traditional RS EC exam. To further explore this, RS EC and RS dark room (DR) eyes-open alpha activity was recorded using magnetoencephalography in children with typical development (TD; N = 37) and children with autism spectrum disorder (ASD; N = 30) 6.9-12.6 years old. Findings showed good reliability for the RS EC and DR peak alpha frequency (frequency with strongest alpha power; interclass correlation (ICC) = 0.83). ICCs for posterior alpha power were slightly lower (ICCs in the 0.70 s), with an ~ 5% reduction in posterior alpha power in the DR than EC condition. No differences in the EC and DR associations were observed between the TD and ASD groups. Finally, age was associated with both EC and DR peak alpha frequency. Findings thus indicate the DR exam as a viable way to obtain RS alpha measures in populations frequently excluded from electrophysiology RS studies.

Resting-State Activity in Children: Replicating and Extending Findings of Early Maturation of Alpha Rhythms in Autism Spectrum Disorder.

Resting-state alpha brain rhythms provide a foundation for basic as well as higher-order brain processes. Research suggests atypical maturation of the peak frequency of resting-state alpha activity (= PAF) in autism spectrum disorder (ASD). The present study examined resting-state alpha activity in young school-aged children, obtaining magnetoencephalographic (MEG) eyes-closed resting-state data from 47 typically developing (TD) males and 45 ASD males 6.0 to 9.3 years old. Results confirmed a higher PAF in ASD versus TD, and demonstrated that alpha power differences between groups were linked to the shift of PAF in ASD. Additionally, a higher PAF was associated with better cognitive performance in TD but not ASD. Finding thus suggested functional consequences of group differences in resting-state alpha activity.

Effects of 1.5-T versus 3-T magnetic resonance imaging in fetuses: is there a difference in postnatal neurodevelopmental outcome? Evaluation in a fetal population with left-sided congenital diaphragmatic hernia.

BACKGROUND: The utilization of 3-T magnetic field strength in obstetric imaging is increasingly common. It is important to ensure that magnetic resonance (MR) imaging with higher magnetic field strength is safe for the fetus. Comparison of neurodevelopmental outcome in neonates undergoing prenatal MR imaging with 1.5-T versus 3-T is of interest but has not yet been examined. OBJECTIVE: We hypothesized no clinically meaningful difference in neurodevelopmental outcome between fetuses undergoing 1.5-T versus 3-T fetal MR imaging. As imaging a normal fetus for research purposes is illegal in Pennsylvania, this study was conducted in a population of fetuses with left congenital diaphragmatic hernia (left-CDH). MATERIALS AND METHODS: A retrospective review of neurodevelopmental outcome of fetuses with left-CDH scanned at 1.5-T (n=75) versus 3-T (n=25) magnetic field strength between July of 2012 and December of 2019 was performed. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development, 3rd Edition (BSID-III). RESULTS: There were no statistical differences in median age of assessment (1.5-T: 18 [12, 25] versus 3-T: 21 [11, 26], P=0.79), in mean BSID-III cognitive (1.5-T: 91 ± 14 versus 3-T: 90 ± 16, P=0.82), language (1.5-T: 92 ± 20 versus 3-T: 91 ± 20, P=0.91), and motor composite (1.5-T: 89 ± 15 versus 3-T: 87 ± 18, P=0.59) scores, subscales scores (for all, P>0.50), or in risk of abnormal neuromuscular exam (P=0.29) between neonates with left-CDH undergoing a 1.5-T versus 3-T MR imaging during fetal life. Additionally, the distribution of patients with average, mildly delayed, and severely delayed BSID-III scores was similar between the two groups (for all, P>0.50). The overall distribution of the composite scores in this CDH population was similar to the general population independent of exposure to 1.5-T or 3-T fetal MR imaging. Two 3-T patients (8%) and five 1.5-T patients (7%) scored within the significant delayed range for all BSID-III domains. Subjects with lower observed-to-expected fetal lung volume (O/E FLV) and postnatal need for ECMO had lower cognitive, language, motor, and subscales scores (for all, P<0.03) regardless of being imaged at 1.5-T versus 3-T. CONCLUSION: This preliminary study suggests that, compared to 1.5-T MR imaging, fetal exposure to 3-T MR imaging does not increase the risk of neurodevelopmental impairment in fetuses with left-CDH. Additional MR imaging studies in larger CDH cohorts and other fetal populations are needed to replicate and extend the present findings.

Differential Maturation of Auditory Cortex Activity in Young Children with Autism and Typical Development.

Maturation of auditory cortex neural encoding processes was assessed in children with typical development (TD) and autism. Children 6-9 years old were enrolled at Time 1 (T1), with follow-up data obtained ~ 18 months later at Time 2 (T2), and ~ 36 months later at Time 3 (T3). Findings suggested an initial period of rapid auditory cortex maturation in autism, earlier than TD (prior to and surrounding the T1 exam), followed by a period of faster maturation in TD than autism (T1-T3). As a result of group maturation differences, post-stimulus group differences were observed at T1 but not T3. In contrast, stronger pre-stimulus activity in autism than TD was found at all time points, indicating this brain measure is stable across time.

Early stressful experiences are associated with reduced neural responses to naturalistic emotional and social content in children.

How do children's experiences relate to their naturalistic emotional and social processing? Because children can struggle with tasks in the scanner, we collected fMRI data while 4-to-11-year-olds watched a short film with positive and negative emotional events, and rich parent-child interactions (n = 70). We captured broad, normative stressful experiences by examining socioeconomic status (SES) and stressful life events, as well as children's more proximal experiences with their parents. For a sub-sample (n = 30), parenting behaviors were measured during a parent-child interaction, consisting of a picture book, a challenging puzzle, and free play with novel toys. We characterized positive parenting behaviors (e.g., warmth, praise) and negative parenting behaviors (e.g., harsh tone, physical control). We found that higher SES was related to greater activity in medial orbitofrontal cortex during parent-child interaction movie events. Negative parenting behaviors were associated with less activation of the ventral tegmental area and cerebellum during positive emotional events. In a region-of-interest analysis, we found that stressful life events and negative parenting behaviors were associated with less activation of the amygdala during positive emotional events. These exploratory results demonstrate the promise of using movie fMRI to study how early experiences may shape emotional, social, and motivational processes.

Maturational trajectory of fusiform gyrus neural activity when viewing faces: From 4 months to 4 years old.

Infant and young child electrophysiology studies have provided information regarding the maturation of face-encoding neural processes. A limitation of previous research is that very few studies have examined face-encoding processes in children 12-48 months of age, a developmental period characterized by rapid changes in the ability to encode facial information. The present study sought to fill this gap in the literature via a longitudinal study examining the maturation of a primary node in the face-encoding network-the left and right fusiform gyrus (FFG). Whole-brain magnetoencephalography (MEG) data were obtained from 25 infants with typical development at 4-12 months, and with follow-up MEG exams every ∼12 months until 3-4 years old. Children were presented with color images of Face stimuli and visual noise images (matched on spatial frequency, color distribution, and outer contour) that served as Non-Face stimuli. Using distributed source modeling, left and right face-sensitive FFG evoked waveforms were obtained from each child at each visit, with face-sensitive activity identified via examining the difference between the Non-Face and Face FFG timecourses. Before 24 months of age (Visits 1 and 2) the face-sensitive FFG M290 response was the dominant response, observed in the left and right FFG ∼250-450 ms post-stimulus. By 3-4 years old (Visit 4), the left and right face-sensitive FFG response occurred at a latency consistent with a face-sensitive M170 response ∼100-250 ms post-stimulus. Face-sensitive left and right FFG peak latencies decreased as a function of age (with age explaining greater than 70% of the variance in face-sensitive FFG latency), and with an adult-like FFG latency observed at 3-4 years old. Study findings thus showed face-sensitive FFG maturational changes across the first 4 years of life. Whereas a face-sensitive M290 response was observed under 2 years of age, by 3-4 years old, an adult-like face-sensitive M170 response was observed bilaterally. Future studies evaluating the maturation of face-sensitive FFG activity in infants at risk for neurodevelopmental disorders are of interest, with the present findings suggesting age-specific face-sensitive neural markers of a priori interest.

Pre- and postnatal antibiotic exposure and risk of developing attention deficit hyperactivity disorder-A systematic review and meta-analysis combining evidence from human and animal studies.

This study investigated the effects of early antibiotic exposure on ADHD risk by (1) integrating meta-analytical evidence from human observational studies examining the association between prenatal or early postnatal antibiotic exposure on the risk of developing ADHD; and (2) reviewing evidence from experimental animal studies on the effects of early antibiotic exposure on behavior. Sixteen human studies and five rodent studies were reviewed. A quantitative meta-analysis with 10 human studies indicated an increased risk for ADHD after prenatal antibiotic exposure (summary effect estimate Hazard Ratio (HR) 1.23, 95% CI 1.09-1.38; N = 2,398,475 subjects) but not after postnatal exposure within the first two years of life (summary effect estimate HR 1.12, 95% CI 0.95-1.32; N = 1,863,867 subjects). The rodent literature suggested that peri-natal antibiotic exposure has effects on social behavior, anxiety and aggression, alongside changes in gut microbial composition. Human and rodent findings thus suggest prenatal antibiotic exposure as a possible risk factor for ADHD, and suggest that an early disruption of the gut microbiome by antibiotics may interfere with neurodevelopment.

Two mechanisms facilitate regional independence between brain regions based on an examination of alpha-band activity in healthy control adult males.

BACKGROUND: At rest, 8 to 12 Hz alpha rhythms are the dominant rhythm in the brain, with a common peak alpha frequency (PAF = the frequency at which alpha generators show maximum power) observed across brain regions. Although a common PAF across brain regions should result in high between-region connectivity, especially connectivity measures assessing the phase-similarity between alpha generators, high inter-regional alpha connectivity has not been observed. The present study was conducted as an initial step toward identifying mechanisms that allow brain regions to maintain functional independence in the presence of a common PAF. METHODS: MEG data were obtained from 16 healthy control male adults (mean age = 24 years; range 21 to 30 years). A task requiring participants to alternate between a 10 s eyes-closed condition and a 5 s eyes-open condition was used to drive parietal-occipital alpha generators, with the 10 s eyes-closed condition eliciting large-amplitude alpha activity and thus providing alpha measures with good signal-to-noise ratio for source localization. Alpha source-space measures were obtained using Vector-based Spatial-Temporal Analysis using L1-minimum-norm. In each participant, the four strongest parietal-occipital alpha generators were identified. Connectivity between sources was assessed via a measure of phase-based connectivity called inter-site phase clustering (ISPC). RESULTS: Intra-class correlations (ICC) showed very high similarity in the average PAF (=computed using all eyes-closed data) between the four alpha sources (ICC single measure = 0.88, p < 0.001). Despite a common average PAF, across participants, significant ISPC was often observed no more than that expected by chance. Examination of the alpha time course data indicated that low ISPC was often due to instantaneous changes in alpha phase (phase slips). ISPC analyses removing data with phase slips indicated that low ISPC was also due to slight continuous changes in the alpha frequency, with frequency drift more likely in non-significant than significant ISPC trials. CONCLUSIONS: The present exploratory effort suggested two processes underlying the lack of observed inter-regional alpha phase coherence that may help maintain regional functional independence even in the presence of a common PAF. In particular, although the alpha generators were observed to oscillate at the same rate on average, across time each alpha generator oscillated a little slower or faster, and about every one and a half seconds an alpha generator abruptly lost the beat. Because of this, functional independence among alpha generators (and thus brain regions) was the rule rather than the exception. Studies replicating these processes that allow brain regions to maintain functional independence, using different source localization methods and in different conditions (e.g., a true resting state), are warranted. IMPACT STATEMENT: Using source localization to measure parietal-occipital alpha generator activity, two properties that limit between-region alpha functional connectivity are proposed. In particular, a model of alpha generator activity is offered where via transient phase slips occurring approximately every 1.5 s, as well as slight non-stationarity in the alpha frequency, brain regions retain a common alpha frequency while also maintaining regional identity and presumably functionality. Findings also suggest novel markers for use in studies examining changes in alpha activity across maturation as well as in studies examining alpha activity in patient populations where alpha abnormalities have been reported.

Transdiagnostic alterations in neural emotion regulation circuits - neural substrates of cognitive reappraisal in patients with depression and post-traumatic stress disorder.

BACKGROUND: Impaired cognitive reappraisal, associated with the social functioning and well-being of patients affected by mood or anxiety disorders, is characterized by distinct neural activation patterns across clinical populations. To date, studies dedicated to identifying common and distinct neural activation profiles need to be clarified. The aim of the present study was to investigate transdiagnostic differences and commonalities in brain activation patterns during reappraisal-mediated downregulation of emotions. METHODS: Cognitive reappraisal of negative images was contrasted with maintaining emotions during a control viewing condition. Brain activation in 35 patients with major depressive disorder (MDD), 20 patients with post-traumatic stress disorder (PTSD), and 34 healthy controls (HC) during cognitive reappraisal was compared. Moreover, the neural circuitry of emotion regulation in these clinical populations was examined using seed-to-voxel and voxel-to-voxel functional connectivity analyses. RESULTS: Whole-brain fMRI analyses showed less right-lateralized activation of the inferior, middle, and superior frontal gyrus during cognitive reappraisal compared to viewing of negative images in MDD and PTSD patients compared to HCs. Right IFG activation was negatively correlated with the severity of anxiety and depressive symptomatology. In addition, increased seed-to-voxel connectivity of the right IFG as well as increased voxel-to-voxel connectivity was observed in PTSD patients compared to HCs and MDD patients. CONCLUSIONS: FMRI results therefore suggested a common deficit of depression and anxiety symptomatology reflected by reduced activation in right IFG during cognitive reappraisal as well as diagnosis specific effects in patients with PTSD based on seed-to-voxel and voxel-to-voxel connectivity showing an overactive and hyperconnected salience network. Findings highlight the role of transdiagnostic research to identify disorder specific brain patterns as well as patterns common across disorders.

Can Radiology Technologists be Trained to Measure Leg Length Discrepancies as Accurately as Pediatric Radiologists?

RATIONALE AND OBJECTIVES: Leg length discrepancy studies are labor intensive. They are procedurally simple and represent inefficient use of the radiologists' time and expertise. We hypothesized that radiology technologists could be trained to measure leg length discrepancies, and that their performance would be statistically equivalent to that of board-certified, fellowship-trained pediatric radiologists. MATERIAL AND METHODS: Four radiology technologists were selected to participate in a supervised practice session. They independently measured and calculated leg length discrepancies on 10 randomly selected cases. Their performance was compared to measurements obtained by an experienced pediatric radiologist (reference standard). After 1 week, the technologists repeated their measurements on the same cases, which were resorted to simulate new cases. Intraclass correlation coefficients (ICC) determined interobserver agreement between the technologists and radiologist and intra-observer reliability among the technologists. RESULTS: Among the four technologists, similarity in measurements between session 1 and the reference standard was very high, with ICC values ranging from 0.93 to 0.98 (p < 0.001). The ICC between session 2 and the reference standard was also high, ranging from 0.93 to 0.98 (p < 0.001). Finally, among the four technologists, ICC values between session 1 and session 2 were ≥ 0.96 (p < 0.001). CONCLUSION: Radiology technologists can be rapidly trained to calculate leg length discrepancies as accurately as a board-certified pediatric radiologist. Delegation of this time-consuming task to technologists or radiology assistants will permit radiologists to spend time on more demanding studies, such as studies that require subspecialty training.

Peak Alpha Frequency and Thalamic Structure in Children with Typical Development and Autism Spectrum Disorder.

Associations between age, resting-state (RS) peak-alpha-frequency (PAF = frequency showing largest amplitude alpha activity), and thalamic volume (thalamus thought to modulate alpha activity) were examined to understand differences in RS alpha activity between children with autism spectrum disorder (ASD) and typically-developing children (TDC) noted in prior studies. RS MEG and structural-MRI data were obtained from 51 ASD and 70 TDC 6- to 18-year-old males. PAF and thalamic volume maturation were observed in TDC but not ASD. Although PAF was associated with right thalamic volume in TDC (R2 = 0.12, p = 0.01) but not ASD (R2 = 0.01, p = 0.35), this group difference was not large enough to reach significance. Findings thus showed unusual maturation of brain function and structure in ASD as well as an across-group thalamic contribution to alpha rhythms.

Biomarkers for autism spectrum disorder: opportunities for magnetoencephalography (MEG).

This paper reviews a candidate biomarker for ASD, the M50 auditory evoked response component, detected by magnetoencephalography (MEG) and presents a position on the roles and opportunities for such a biomarker, as well as converging evidence from allied imaging techniques (magnetic resonance imaging, MRI and spectroscopy, MRS). Data is presented on prolonged M50 latencies in ASD as well as extension to include children with ASD with significant language and cognitive impairments in whom M50 latency delays are exacerbated. Modeling of the M50 latency by consideration of the properties of auditory pathway white matter is shown to be successful in typical development but challenged by heterogeneity in ASD; this, however, is capitalized upon to identify a distinct subpopulation of children with ASD whose M50 latencies lie well outside the range of values predictable from the typically developing model. Interestingly, this subpopulation is characterized by low levels of the inhibitory neurotransmitter GABA. Following from this, we discuss a potential use of the M50 latency in indicating "target engagement" acutely with administration of a GABA-B agonist, potentially distinguishing "responders" from "non-responders" with the implication of optimizing inclusion for clinical trials of such agents. Implications for future application, including potential evaluation of infants with genetic risk factors, are discussed. As such, the broad scope of potential of a representative candidate biological marker, the M50 latency, is introduced along with potential future applications.This paper outlines a strategy for understanding brain dysfunction in individuals with intellectual and developmental disabilities (IDD). It is proposed that a multimodal approach (collection of brain structure, chemistry, and neuronal functional data) will identify IDD subpopulations who share a common disease pathway, and thus identify individuals with IDD who might ultimately benefit from specific treatments. After briefly demonstrating the need and potential for scope, examples from studies examining brain function and structure in children with autism spectrum disorder (ASD) illustrate how measures of brain neuronal function (from magnetoencephalography, MEG), brain structure (from magnetic resonance imaging, MRI, especially diffusion MRI), and brain chemistry (MR spectroscopy) can help us better understand the heterogeneity in ASD and form the basis of multivariate biological markers (biomarkers) useable to define clinical subpopulations. Similar approaches can be applied to understand brain dysfunction in neurodevelopmental disorders (NDD) in general. In large part, this paper represents our endeavors as part of the CHOP/Penn NICHD-funded intellectual and developmental disabilities research center (IDDRC) over the past decade.

Predicting neonatal outcomes in infants with giant omphalocele using prenatal magnetic resonance imaging calculated observed-to-expected fetal lung volumes.

OBJECTIVE: To examine the association between prenatal magnetic resonance imaging (MRI) based observed/expected total lung volume (O/E TLV) and outcome in neonates with giant omphalocele (GO). METHODS: Between 06/2004 and 12/2019, 67 cases with isolated GO underwent prenatal and postnatal care at our institution. MRI-based O/E TLVs were calculated based on normative data from Meyers and from Rypens and correlated with postnatal survival and morbidities. O/E TLV scores were grouped based on severity into <25% (severe), between 25% and 50% (moderate), and >50% (mild) for risk stratification. RESULTS: O/E TLV was calculated for all patients according to Meyers nomograms and for 49 patients according to Rypens nomograms. Survival for GO neonates with severe, moderate, and mild pulmonary hypoplasia based on Meyers O/E TLV categories was 60%, 92%, and 96%, respectively (p = 0.04). There was a significant inverse association between Meyers O/E TLV and risk of neonatal morbidities (p < 0.05). A similar trend was observed with Rypens O/E TLV, but associations were less often significant likely related to the smaller sample size. CONCLUSION: Neonatal outcomes are related to fetal lung size in isolated GO. Assessment of Meyers O/E TLV allows identification of GO fetuses at greatest risk for complications secondary to pulmonary hypoplasia.

Image-Guided Biopsy for Relapsed Neuroblastoma: Focus on Safety, Adequacy for Genetic Sequencing, and Correlation of Tumor Cell Percent With Quantitative Lesion MIBG Uptake.

PURPOSE: Many novel therapies for relapsed and refractory neuroblastoma require tumor tissue for genomic sequencing. We analyze our experience with image-guided biopsy in these patients, focusing on safety, yield, adequacy for next-generation sequencing (NGS), and correlation of tumor cell percent (TC%) with quantitative uptake on 123I-meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography with computed tomography (SPECT/CT). MATERIALS AND METHODS: An 11-year retrospective review of image-guided biopsy on 66 patients (30 female), with a median age of 8.7 years (range, 0.9-49 years), who underwent 95 biopsies (55 bone and 40 soft tissue) of relapsed or refractory neuroblastoma lesions was performed. RESULTS: There were seven minor complications (7%) and one major complication (1%). Neuroblastoma was detected in 88% of MIBG- or fluorodeoxyglucose-avid foci. The overall NGS adequacy was 69% (64% in bone and 74% in soft tissue, P = .37). NGS adequacy within neuroblastoma-positive biopsies was 88% (82% bone and 96% soft tissue, P = .11). NGS-adequate biopsies had a greater mean TC% than inadequates (51% v 18%, P = .03). NGS-adequate biopsies had a higher mean number of needle passes (7.5 v 3.4, P = .0002). The mean tissue volume from NGS-adequate soft-tissue lesions was 0.16 cm3 ± 0.12. Lesion:liver and lesion:psoas MIBG uptake ratios correlated with TC% (r = 0.74, r = 0.72, and n = 14). Mean TC% in NGS-adequate samples was 51%, corresponding to a lesion:liver ratio of 2.9 and a lesion:psoas ratio of 9.0. Thirty percent of biopsies showed an actionable ALK mutation or other therapeutically relevant variant. CONCLUSION: Image-guided biopsy for relapsed or refractory neuroblastoma was safe and likely to provide NGS data to guide therapy decisions. A lesion:liver MIBG uptake ratio of ≥ 3 or a lesion:psoas ratio of > 9 was associated with a TC% sufficient to deliver NGS results.

Maturation of hemispheric specialization for face encoding during infancy and toddlerhood.

Little is known about the neural processes associated with attending to social stimuli during infancy and toddlerhood. Using infant magnetoencephalography (MEG), fusiform gyrus (FFG) activity while processing Face and Non-Face stimuli was examined in 46 typically developing infants 3 to 24 months old (28 males). Several findings indicated FFG maturation throughout the first two years of life. First, right FFG responses to Face stimuli decreased as a function of age. Second, hemispheric specialization to the face stimuli developed somewhat slowly, with earlier right than left FFG peak activity most evident after 1 year of age. Right FFG activity to Face stimuli was of clinical interest, with an earlier right FFG response associated with better performance on tests assessing social and cognitive ability. Building on the above, clinical studies examining maturational change in FFG activity (e.g., lateralization and speed) in infants at-risk for childhood disorders associated with social deficits are of interest to identify atypical FFG maturation before a formal diagnosis is possible.

MEG-PLAN: a clinical and technical protocol for obtaining magnetoencephalography data in minimally verbal or nonverbal children who have autism spectrum disorder.

BACKGROUND: Neuroimaging research on individuals who have autism spectrum disorder (ASD) has historically been limited primarily to those with age-appropriate cognitive and language performance. Children with limited abilities are frequently excluded from such neuroscience research given anticipated barriers like tolerating the loud sounds associated with magnetic resonance imaging and remaining still during data collection. To better understand brain function across the full range of ASD there is a need to (1) include individuals with limited cognitive and language performance in neuroimaging research (non-sedated, awake) and (2) improve data quality across the performance range. The purpose of this study was to develop, implement, and test the feasibility of a clinical/behavioral and technical protocol for obtaining magnetoencephalography (MEG) data. Participants were 38 children with ASD (8-12 years) meeting the study definition of minimally verbal/nonverbal language. MEG data were obtained during a passive pure-tone auditory task. RESULTS: Based on stakeholder feedback, the MEG Protocol for Low-language/cognitive Ability Neuroimaging (MEG-PLAN) was developed, integrating clinical/behavioral and technical components to be implemented by an interdisciplinary team (clinicians, behavior specialists, scientists, and technologists). Using MEG-PLAN, a 74% success rate was achieved for acquiring MEG data, with a 71% success rate for evaluable and analyzable data. Exploratory analyses suggested nonverbal IQ and adaptive skills were related to reaching the point of acquirable data. No differences in group characteristics were observed between those with acquirable versus evaluable/analyzable data. Examination of data quality (evaluable trial count) was acceptable. Moreover, results were reproducible, with high intraclass correlation coefficients for pure-tone auditory latency. CONCLUSIONS: Children who have ASD who are minimally verbal/nonverbal, and often have co-occurring cognitive impairments, can be effectively and comfortably supported to complete an electrophysiological exam that yields valid and reproducible results. MEG-PLAN is a protocol that can be disseminated and implemented across research teams and adapted across technologies and neurodevelopmental disorders to collect electrophysiology and neuroimaging data in previously understudied groups of individuals.