Nathaniel David Mercaldo

Autism spectrum disorder (ASD) is characterized by differences in social communication and interaction, alongside restricted and repetitive behaviors. The hypothesis that ASD is associated with an altered cortical excitation-inhibition (EI) balance has been the subject of extensive investigations, yet the evidence supporting it remains mixed. A key challenge in testing this hypothesis is that the EI balance also changes substantially during typical maturation, from childhood through adolescence and into early adulthood. We used resting-state magnetoencephalography (MEG) recordings to examine the developmental trajectory of cortical EI alterations, with regional specificity, in a large cross-sectional cohort (N = 172), comprised of 92 typically developing (TD) individuals and 80 individuals diagnosed with ASD, spanning ages 6-32. To that end, functional EI (fEI), derived from critical brain dynamics, was estimated across 500 cortical parcellations in cortical space. Group-averaged fEI maps revealed broadly similar large-scale topographic patterns in the TD and ASD groups when averaged across all ages. When divided by age into childhood (6-12 years, N ASD = 18, N TD = 16), adolescence (13-18 years, N ASD = 27, N TD = 41) and adulthood (19-32 years, N ASD = 28, N TD = 26), we found an overall pattern of increased global fEI in childhood and decreased fEI in adolescence in the ASD group, with no evidence of a difference between groups in fEI in adulthood. Additional parcel-wise regression analyses identified a significant main effect of diagnostic group, independent of age, in the right dorsolateral prefrontal cortex, where TD individuals showed higher fEI than those with ASD across all ages. Furthermore, a significant group-by-age interaction was observed in the left inferior parietal cortex, where we found evidence that fEI increased with age in TD individuals (beta = 0.012, p = 0.006) but no evidence of a similar age-dependent increase in those with ASD (beta = 0.001, p = 0.84), indicating diverging developmental trajectories. Finally, fEI in paracentral and precuneus cortical regions was associated with ASD symptom severity. Together, these findings support a scenario in which EI imbalance, as assessed with fEI, is not globally distributed in ASD, and is not static through development, but is instead expressed through regionally and developmentally specific differences, with implications for understanding the neural substrates of ASD phenotypic heterogeneity.

The human hippocampal tail is the posterior‐most portion of the hippocampus and has been implicated in brain disorders, such as depression, panic disorder, and epilepsy. The tail's clinical relevance and volumetric variability exhibit a need for improved characterization with high‐resolution imaging and histology at baseline. MRI provides three‐dimensional context without missing slices and histology validates with architecture; combining these methods provides an optimal approach. Twenty control brain hemispheres were evaluated, including 10 males and 10 females. We scanned the hemispheres using ex vivo MRI at 120 μm isotropic resolution. The tissue was then processed and histologically stained. We manually labeled the hippocampal tail in high‐resolution MRI, using six distinct coronal levels of the tail as guideposts, validating histologically. The volume and length of the tails were calculated using 3D MRI reconstructions; the median tail volume (median ± interquartile range) of our sample set was 715.6 ± 227.5 mm ³ . These data contribute a validated hippocampal tail volume. We calculated and quantified the medial flexure of the tail and compared sex as a biological variable. Male tail samples exhibited significantly larger angles than female samples (Mann–Whitney U test, p = 0.01). Our findings enable precise hippocampal tail delineation and may facilitate future research on function and mental health disorders.

Arterial spin-labeling (ASL) MRI with a single postlabeling delay (PLD) of 1800 msec is recommended for quantifying CBF when the PLD is sufficiently longer than the arterial transit time. However, this condition may not be satisfied in older participants or individuals with dementia, for whom multiple PLDs may be more beneficial. This work assessed the intermediate-term (4-week) test-retest reliability and accuracy of single- versus multiple-PLD ASL for quantifying CBF relative to [¹⁵O]water PET acquired using PET/MRI imaging in a study of aging and Alzheimer disease (AD). Cognitively normal young (n=3) and older participants (n=5) and patients with AD (n=3) underwent PET/MRI sessions. ASL CBF was quantified separately using PLDs of 1800, 2000, 2200, and 2400 msec, and using multiple-PLD approach combining all 4 PLDs. A subset of participants (1 AD, 4 older cognitively normal) underwent repeated ASL MRI after approximately 4 weeks for test-retest evaluation, assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs). Accuracy was assessed by comparing ASL CBF with [¹⁵O]water PET using Spearman correlation across cortical regions and vascular territories. The 4-week test-retest reliability was highest for single-PLD ASL using 1800 msec (ICC > 0.75) and lowest for single-PLD of 2400 msec (ICC: 0.1-0.8). Multiple-PLD ASL showed better reliability than the 2400 msec PLD but was not superior to shorter PLDs. Correlations with [¹⁵O]water PET were strongest for 1800 msec single-PLD and generally decreased with longer PLDs, except the occipital lobe, where all PLDs showed poor agreement. Multiple-PLD ASL showed similar correlation strengths as 2000 msec single-PLD. Single-PLD ASL with 1800 msec PLD demonstrated the best balance of reliability and agreement with [¹⁵O]water PET, suggesting it may be an effective choice for studying CBF in aging and AD populations. While multiple-PLD ASL offered comparable performance, it did not confer notable benefits compared with the best-performing single-PLD under similar acquisition time constraints. These findings underscore the importance of PLD selection in ASL protocols in older or cognitively impaired cohorts and highlight the value of assessing intermediate-term reliability in longitudinal studies.

BACKGROUND AND PURPOSE: Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the longitudinal impact of LLLT on brain metabolites has not been studied. The purpose of this study was to use magnetic resonance spectroscopic imaging (MRSI) to assess the metabolic response of LLLT in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. MATERIALS AND METHODS: This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients with moderate TBI. Participants were randomized for LLLT and sham treatment. Three Tesla two-dimensional MRSI was acquired. Our focus of investigation was the metabolic change in the corpus callosum (CC) and the changes in myo-inositol/N-acetyl aspartate (mI/NAA), representing the combined effect of elevated neuroinflammation (mI) and decreased neuronal/axonal health (NAA). A linear mixed-effects model was constructed to quantify the association between mI/NAA and treatment, scan, and the interaction between treatment and scan. RESULTS: Thirty-four participants (18 male, age 49±17 (20 to 79); 15 LLLT, 19 sham) were included in the final data set and were scanned at the following timepoints: acute (N=24), subacute (N=27) and late subacute (N=23). The mI/NAA ratio in the CC of the sham-treated participants increased over time. Sham-treated participants revealed a significant increase in mI/NAA from the acute to the late subacute phases (0.19, 95%CI: 0.09, 0.29; p_Holm=0.005). mI/NAA stayed relatively stable in participants undergoing LLLT treatment (all p_Holm>0.64). Consequently, mI/NAA was significantly higher in the sham-treated participants compared to the LLLT-treated participants during the late subacute phase of recovery (-0.31, 95%CI: -0.50, -0.12; p_Holm=0.019). CONCLUSIONS: Despite the small sample size, MRSI indicates a metabolic response in participants treated with LLLT compared to those receiving sham treatment. This potentially suggests a neuroprotective and anti-inflammatory effect from the acute administration of LLLT in individuals with moderate TBI. ABBREVIATIONS: LLLT＝Low-level light therapy; TBI＝traumatic brain injury; MRSI = magnetic resonance spectroscopic imaging; CC = corpus callosum; mI = in myo-inositol; NAA = N-acetyl aspartate; ATP = adenosine triphosphate; GCS = Glasgow Coma Scale; LASER = Localization by Adiabatic SElective Refocusing.