Background: Multiple studies have found a male prevalence in childhood ischemic stroke regardless of age. Causes for this sex difference are not fully understood. We hypothesized there may be potential differences in hemodynamic reserve, measured by cerebrovascular reactivity (CVR). Methods: Children ages 8-24 years with and without sickle cell anemia (SCA) underwent cerebrovascular reactivity (CVR) measurement using computer-controlled carbon dioxide manipulation during blood-oxygen level dependent (BOLD) MRI, along with MRI- measurements of cerebral blood flow (CBF; multi-post-label delay arterial spin labeling) and oxygen extraction (asymmetric spin echo). Cerebrovascular reactivity (CVR) was assessed voxel-wise within the gray matter (GM) in two ways: Magnitude CVR (mCVR) was defined as the slope of Δ %BOLD signal per Δ mmHg end-tidal CO 2 (ETCO 2 ). We then modeled the dynamic response as the convolution of ETCO 2 with an exponential hemodynamic response function (HRF), yielding two metrics: the time constant τ, representing the latency and speed of the vascular response, and the steady-state CVR (ssCVR), defined as the slope of BOLD signal versus the convolved ETCO 2 regressor, reflecting time-independent reactivity. Group comparisons used the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables, with Benjamini–Hochberg correction for multiple comparisons. A bidirectional stepwise linear regression modeled each CVR, allowing for entry/removal of all potential predictors, with candidate variables including age, sex, SCA status, hemoglobin, GM CBF, GM arterial transit time (ATT), GM OEF, GM cerebral metabolic rate of oxygen utilization (GM CMRO 2 ). Results: CVR data was available in 69 children median age 15 years [IQR 12-18], 46 females. The 17 SCA and 52 control participants were age (p=0.34) and sex (p=0.18) matched. Males had lower mCVR (p=0.009) and ssCVR (p=0.01) than females. On stepwise variable selection for multivariable modeling of mCVR, hemoglobin (p=0.006), sex (p=0.002) and GM arterial transit time (p=0.02) remained significant. In ssCVR, only hemoglobin (p<0.001) and sex (p=0.03) remained significant. Conclusion: Sex influences CVR in youth, even after adjusting for hemoglobin and potential differences in cerebral blood flow in a steady state CVR measurement. Further understanding of this may elucidate mechanisms of sex stroke risk differences in children.

PURPOSE:To characterize a novel magnetic resonance imaging (MRI) finding affecting the optic chiasm in patients with optic nerve hypoplasia (ONH). METHODS:This was a retrospective case-control study including 78 patients diagnosed as having ONH at a single institution, with an average age at MRI of 2.66 years. The control group included 70 patients of similar demographics without a diagnosis of ONH or gross abnormalities on MRI. MRI images obtained on a Siemens 3T Prisma or Siemens 1.5T Aera (Siemens Healthineers) were examined for all patients by two independent graders for presence of an optic chiasm deviation termed the Y-sign. Main outcome measures were presence of the Y-sign on MRI imaging in the coronal view. RESULTS:The Y-sign was identified in 55.1% of patients with ONH and 0% of control patients. Odds of the Y-sign were significantly higher in patients younger than 1 year (odds ratio [OR]: 3.58, 95% CI: 1.4 to 9.14; P = .008) and in patients with bilateral ONH (OR: 2.82, 95% CI: 1.08 to 7.33; P = .034). No association was found between the Y-sign and visual acuity or endocrine abnormalities (P = .11 and P = .78, respectively). However, there was a moderate effect size noted between the Y-sign and absence of the septum pellucidum (P = .052). CONCLUSIONS:The authors present a novel MRI finding seen in more than half of patients with ONH that appears to be highly specific and mildly sensitive for the condition. Results indicate that the Y-sign may be a sign for absence of the septum pellucidum, but other clinical outcomes require further investigation.

Functional MRI (fMRI) data are severely distorted by magnetic field (B0) inhomogeneities, which currently must be corrected using separately acquired field map data. However, changes in the head position of a participant across fMRI frames cause changes in the B0 field, preventing accurate correction of geometric distortions. Movement during field map acquisitions corrupts field maps, preventing distortion correction altogether. In this study, we use multi-echo (ME) fMRI data to dynamically sample and correct for magnetic field image distortions caused by head motion. Our distortion correction pipeline, MEDIC (Multi-Echo DIstortion Correction), leverages magnetic field inhomogeneity information found in the difference between echoes and uses it to correct for distortion on a frame-by-frame basis. Here, we demonstrate that MEDIC's frame-wise distortion correction decreases the impact of head motion on resting-state functional connectivity (RSFC) maps and improves alignment to anatomy when compared with the prior gold standard approach (i.e., FSL TOPUP). Enhanced frame-wise distortion correction with MEDIC, without the requirement for field map collection, furthers the benefit of cutting-edge multi-echo fMRI imaging over single-echo fMRI.

The red nucleus, a large brainstem structure, coordinates limb movement for locomotion in quadrupedal animals. In humans, its pattern of anatomical connectivity differs from that of quadrupeds, suggesting a different purpose. Here, we apply our most advanced resting-state functional connectivity based precision functional mapping in highly sampled individuals (n = 5), resting-state functional connectivity in large group-averaged datasets (combined n ~ 45,000), and task based analysis of reward, motor, and action related contrasts from group-averaged datasets (n > 1000) and meta-analyses (n > 14,000 studies) to precisely examine red nucleus function. Notably, red nucleus functional connectivity with motor-effector networks (somatomotor hand, foot, and mouth) is minimal. Instead, connectivity is strongest to the action-mode and salience networks, which are important for action/cognitive control and reward/motivated behavior. Consistent with this, the red nucleus responds to motor planning more than to actual movement, while also responding to rewards. Our results suggest the human red nucleus implements goal-directed behavior by integrating behavioral valence and action plans instead of serving a pure motor-effector function.

Oxygen utilization is important for studies of brain metabolism, alongside other measurements such as for glucose metabolism. Oxygen and other measurements with [ 15 O] tracers and PET, however, are significantly more challenging than measurements of [ 18 F]fluorodeoxyglucose, the standard for probing tissue glucose metabolism in vivo, in part due to the much shorter radioactive half-life of [ 15 O]. This work examines details of precision measurement of [ 15 O] tracers and their kinetics. Investigations of arterial input functions (AIFs) and image-derived input functions (IDIFs) have figured prominently for PET, but [ 15 O] tracers are rarely studied given the small numbers of PET facilities equipped to work with these tracers, particularly in their inhaled form. Estimates of IDIFs and AIFs for [ 15 O] tracers have demonstrably distinct characteristics arising from instrumentation as well as circulatory physiology. To reconcile IDIFs and AIFs, we developed a generalizable model for bolus tracer transport, corrected for known effects of instrumentation for measuring IDIFs and AIFs, and found intravascular[ 15 O]CO to be especially suited for constructing a robust recovery coefficient for IDIFs compared against AIFs. Within a Bayesian framework for posterior estimation and estimating data evidence, IDIFs provide parameter estimates compatible with AIFs in the setting of biological variability. IDIFs also provide data evidence that exceeds that of results from AIFs. These suggest that scalar recovery coefficients may be adequate to estimate partial volume effects, and that the circulatory consistency of internal carotid IDIFs with brain tissue perfusion provides greater precision than what can be estimated using radial artery AIFs, which exhibit greater variability of recirculation wave forms.

OBJECTIVE:Everyday functional capacity in older adults is influenced by several factors, with prior studies finding that cognition mediates the relationship between depression and everyday functioning. However, these studies utilized samples with low depression severity and used only one type of functional assessment. We aimed to examine whether cognition mediates the relationship between depression and functioning in older adults with a history of treatment-resistant depression. METHOD:Data from 383 participants enrolled in the OPTIMUM Neuro study were analyzed. Participants completed a neuropsychological assessment battery, depression severity interview, self-/informant-rated functioning measures and a performance-based functioning measure. Linear regression was used to determine whether depression scores predicted cognitive domain and everyday functioning scores. Cognitive domain scores predicted by depression were then tested as mediators between depression and functioning. RESULTS:Higher depression symptoms predicted poorer performance on all measures of functioning as well as the cognitive domains of attention, executive functioning, and immediate memory. Immediate memory partially mediated the relationship between depression and a performance-based measure of functioning, while attention and executive functioning partially mediated the relationship between a self-report measure of functioning and depression. CONCLUSIONS:The relationship between depression severity and poorer functional performance was partially mediated by attention, executive functioning, and immediate memory, with results differing based on the measure of functioning used. Our findings suggest that there may be additional non-cognitive factors influencing this relationship and highlight the importance of using multiple methods to assess functional performance.

Spatial similarity of functional connectivity profiles across matching anatomical locations in individuals is often calculated to delineate individual differences in functional networks. Likewise, spatial similarity is assessed across average functional connectivity profiles of groups to evaluate the maturity of functional networks during development. Despite its widespread use, spatial similarity is limited to comparing two samples at a time. In this study, we employed a variational autoencoder to embed functional connectivity profiles from various anatomical locations, individuals, and group averages for simultaneous comparison. We demonstrate that our variational autoencoder, with pre-trained weights, can project new functional connectivity profiles from the vertex space to a latent space with as few as two dimensions, yet still retain meaningful global and local structures in the data. Functional connectivity profiles from various functional networks occupy distinct compartments of the latent space. Moreover, the variability of functional connectivity profiles from the same anatomical location is readily captured in the latent space. We believe that this approach could be useful for visualization and exploratory analyses in precision functional mapping.

PURPOSE:This prospective observational study employed resting-state functional magnetic resonance imaging (rs-fMRI) to investigate network-level disturbances associated with neurocognitive function (NCF) changes in patients with gliomas following partial-brain radiation therapy (RT). METHODS AND MATERIALS:Adult postoperative patients with either isocitrate dehydrogenase (IDH)-wild-type or IDH-mutant gliomas underwent computerized NCF testing and rs-fMRI at baseline and 6 months post-RT. rs-fMRI data were assessed using seed-based functional connectivity (FC). NCF changes were quantified by the percent change in age-normalized composite scores from baseline (ΔNCFcomp). Connectivity regression analysis assessed the association between network FC changes and NCF changes, using a split-sample approach with a 26-patient training set and a 6-patient validation set, iterated 200 times. Permutation tests evaluated the significance of network selection. RESULTS:Between September 2020 and December 2023, 43 patients were enrolled, with 32 completing both baseline and follow-up evaluations. The mean ΔNCFcomp was 2.9% (SD, 13.7%), with 38% experiencing a decline. Patients with IDH-mutant glioma had similar NCF changes compared with those with IDH-wild-type glioma. Intrahemispheric FC was similar between ipsilateral and contralateral hemispheres for 91% of patients at baseline, and 69% had similar intrahemispheric FC change posttreatment. FC changes accounted for a moderate fraction of variance in NCF changes (mean R2, 0.301; SD, 0.249), with intranetwork FC of the parietal memory network (PMN-PMN, P = .001) and internetwork FC between the PMN and the visual network (PMN-VN, P = .002) as the most significant factors. Similar findings were obtained by sensitivity analyses using only the FC data from the hemisphere contralateral to the tumor. CONCLUSIONS:Post-RT rs-fMRI changes significantly reflected NCF decline, highlighting rs-fMRI as a promising imaging biomarker for neurocognitive decline after RT.

Purpose:Cerebral blood flow (CBF) is commonly measured by pseudo-continuous arterial spin labeling (PCASL) in human research, but recent advancements in methodology have limited data reuse. The object of this work is to harmonize two distinct PCASL techniques within a cohort with a wide range of CBF values. Methods:Participants had two PCASL sequences collected within a single session: a single post-label delay sequence with a 2D echo-planar imaging (EPI) readout, " CBF 2 D , 1 PLD ", and a five post-label delay sequence with gradient and spin echo (GRASE) 3D readout, " CBF 3 D , 5 PLD ". Linear regression modeling to impute CBF 3 D , 5 PLD from CBF 2 D , 1 PLD , hemoglobin, and age were assessed within gray matter (GM) and white matter (WM) using leave-one-out cross-validation for prediction errors and confidence intervals. Within-subject coefficient of variation (wsCV) and inter-class correlation coefficient (ICC) were calculated using CBF 3 D , 5 PLD imputed vs. measured as pseudo test-retest pairs. Results:Fifty participants, ages 8-45 (median 25) years, had usable CBF 3 D , 5 PLD and CBF 2 D , 1 PLD , including 17 participants with sickle cell disease (SCD), who were matched by age ( p = 0.90 ) and sex ( p = 0.16 ) to those without SCD. A multiple linear regression model including hemoglobin and age fit GM CBF ( R 2 adj. = 0.82 ; for WM CBF R 2 adj. = 0.78 ). The wsCV for CBF 3 D , 5 PLD was 9.1% for GM, 11.3% for WM. ICC was 0.89 for GM and 0.87 for WM. Models without age or hemoglobin fit slightly worse. Conclusion:Our study demonstrates feasibility to impute 3D-GRASE multi-PLD CBF from a 2D-EPI single-PLD technique, which promotes data sharing and harmonization.

Determining the validity and reliability of a test is crucial when the results inform clinical decision-making. Voets et al. highlight priority areas where progress is needed to resolve long-standing controversies surrounding clinical applications of functional MRI in neurosurgery.

Objective To compare placental volumes between pregnancies with and without fetal CHD, including fetuses with CHD and genetic abnormalities, and to investigate the association between placental volume and regional fetal brain volumes. Method Pregnant women carrying a fetus with critical CHD with or without a genetic abnormality (CHD Genetic or CHD Isolated) or a fetus without CHD (Control) had placental and fetal brain volumes measured from MRI. Mixed effects linear regression models examined the associations between study group and placental and fetal brain volumes. Results Seventy-one pregnant women/fetuses underwent 124 MRIs. In multivariate analysis, placental volume was 33% smaller among CHD Genetic males, 15% smaller among CHD Isolated males, and 7% smaller among CHD Genetic females compared to Control males. Adjusting for placental volume and confounders, CHD Genetic had smaller total and regional brain volumes compared to Controls. Fetal cortex was not smaller at baseline, but the difference grew over gestation. Reduced brain volumes were present, but less pronounced, for CHD Isolated. Placental volume was independently associated with subcortical gray matter, total brain, and intracranial volumes. Conclusion Impaired placental and fetal brain development are most prominent for CHD fetuses with genetic abnormalities.

Objectives Examine the role of depression severity in linking subjective and objective indicators of cognitive decline. Methods 354 participants (60+) were drawn from a multicenter longitudinal neuroimaging and neurocognitive study of TRLLD (the "OPTIMUM-NEURO" study). Subjective cognitive decline (SCD) was assessed using the everyday cognition scale. Objective cognitive performance (OCP) was assessed using the Repeatable Battery for Neuropsychological Status and subtests of the Delis-Kaplan Executive Functioning System. Depression severity was assessed using the clinician-administered Montgomery-Asberg Depression Rating Scale. Statistical analysis involved demographic-adjusted linear regression models and causal mediation analysis. Results Participant and study partner-reported SCD were associated with OCP in a broad range of cognitive domains. Greater depression severity was related to worse SCD and OCP but did not statistically mediate any SCD-OCP relationships. Conclusions Among individuals with TRLLD, higher SCD is related to greater depression severity; however, SCD and depression severity each independently relate to OCP.

OBJECTIVE:To examine the mediating and moderating associations between prenatal exposure to adversity and neonatal white matter (WM) development on language outcomes at age 2 years. STUDY DESIGN:This longitudinal study includes 160 infants (gestational ages 41 - 39 weeks, n = 83; 38 - 37 weeks, n = 62; 36 - 34 weeks, n = 15) with neonatal diffusion MRI and language assessments at age 2 years using the Bayley Scales of Infant and Toddler Development-III. Prenatal social disadvantage (PSD) and maternal psychosocial stress were assessed throughout the prenatal period. Multivariable and stepwise linear regression, mediation, and moderation analyses were used to investigate associations between prenatal adversities and neonatal WM on language outcomes. Maternal cognition and stimulation provided in the home were included as covariates. RESULTS:PSD and maternal psychosocial stress were associated with poorer language outcomes (P < .001). When PSD and maternal Psychosocial Stress were modeled simultaneously, only PSD was associated with language outcomes (P < .001). Independent of PSD (P < .001), lower neonatal fractional anisotropy (FA) in the corpus callosum (CC) was associated with poorer language outcomes (P = .02). CC FA did not mediate the association between PSD and language outcomes (indirect effect 95% CIs: -0.96 - 0.15), and there was no interaction between PSD and CC FA on language outcomes (P > .05). CONCLUSIONS:PSD and neonatal CC FA were independently related to language outcomes, with no significant mediating or moderating pathways at this stage of development. These findings suggest the need for investigation of prenatal provision of poverty-reducing services and maternal psychosocial intervention services to promote offspring WM and language development.

Unsedated MRI use in pediatric clinical and research settings is often feasible, but advanced imaging techniques like cerebrovascular reactivity (CVR) may affect tolerability of unsedated MRIs. Exogenous carbon dioxide (CO2) provides a CVR vasodilatory challenge, but its impact on unsedated children’s MRI tolerability is unknown. We hypothesized that children would tolerate MRI with exogenous CO2 as well as children undergoing only MRI. Children with and without sickle cell disease and/or reactive airway disease participated in prospective, single-site unsedated MRI observational studies and completed a post-scan questionnaire. A RespirAct® device delivered CO2 during the scan for MRI-measured CVR. Head displacement across frames quantified motion. Tolerability was defined as MRI study completion without lasting symptoms or serious adverse events. One-hundred children participated, with a median age of 14.0 years [11.0, 16.3]. Sickle cell disease and/or reactive airway disease was present in 35

Older adults with treatment-resistant depression are at significant risk for cognitive impairment. The relationship between treatment response and cognitive function in this population is not well-established. We examined neural correlates of executive and memory function, and their relationship with prospective treatment outcomes. In the context of a longitudinal biomarker study embedded within a multi-center randomized controlled trial for late-life treatment-resistant depression, 397 participants completed baseline neuropsychological testing, and of these 234 adults successfully completed a baseline MRI scan. Multivariate regressions were used to test for brain-cognition associations between memory and executive function and brain functional connectivity, white matter integrity, and gray matter structure. Further, we employed regularized elastic net regressions to identify biomarkers predicting depression remission (MADRS≤10) in the clinical trial. Among participants who completed neuroimaging better cognition was associated with lower connectivity between components of the default mode and the frontoparietal networks and within the frontoparietal network (multivariate r=0.37, p<0.01). Using diffusion imaging data, lower tract integrity in a distributed set of tracts was associated with poorer executive function (multivariate r=0.27, p<0.05). Additionally, gray matter structure was positively associated with cognition (multivariate r=0.38, p<0.05). Education and better structural brain maintenance but not overall health were associated with better cognition. Ongoing treatment resistance was predicted by poorer cognition and gray matter structure. We identified distinct cross-sectional associations between specific neural circuits and variation in cognitive function in people with treatment-resistant late-life depression. We also found worse cognitive function and gray matter structure predicted ongoing treatment resistance to medication offered in the clinical trial.

BACKGROUND:Excessive exposure to manganese (Mn) causes parkinsonism. Occupational Mn exposure is associated with increased T1-weighted globus pallidus signal on magnetic resonance imaging (MRI) secondary to in-vivo Mn deposition. METHODS:The present study evaluated the T1-weighted pallidal index (PI) as an in-vivo marker of Mn exposure and neurotoxicity in chronic environmental Mn exposure. A total of 53 Black South African participants with a range of residential environmental Mn exposures due to proximity to one of the world's largest smelters underwent T1-weighted MRI. RESULTS:The PI was associated with parkinsonism as measured by the total Unified Parkinson's Disease Rating Scale motor subsection part 3 (UPDRS3) in all participants (β=0.10, confidence interval 0.01, 0.18). Further, the PI was positively associated with total UPDRS3 scores (β=0.14, confidence interval 0.03, 0.25) and the lower limb rigidity subscore (β=0.04, confidence interval 0.005, 0.07) among those who regularly consumed alcohol (>3 drinks/week), but not in those who occasionally consumed alcohol (<3 drinks/week). CONCLUSION:Our findings suggest T1-weighted PI is associated with clinical neurotoxicity in environmental Mn exposure. This association is amplified by regular consumption of alcohol.