Brain structural differences in children with fetal alcohol spectrum disorder and its subtypes.

Introduction: The teratogenic effects of prenatal alcohol exposure (PAE) have been examined in animal models and humans. The current study extends the prior literature by quantifying differences in brain structure for individuals with a fetal alcohol spectrum disorder (FASD) compared to typically developing controls, as well as examining FASD subtypes. We hypothesized the FASD group would reveal smaller brain volume, reduced cortical thickness, and reduced surface area compared to controls, with the partial fetal alcohol syndrome (pFAS)/fetal alcohol syndrome (FAS) subtypes showing the largest effects and the PAE/alcohol-related neurodevelopmental disorder (ARND) subtype revealing intermediate effects. Methods: The sample consisted of 123 children and adolescents recruited from a single site including children with a diagnosis of FASD/PAE (26 males, 29 females) and controls (34 males, 34 females). Structural T1-weighted MRI scans were obtained on a 3T Trio TIM scanner and FreeSurfer v7.2 was used to quantify brain volume, cortical thickness, and surface area. Analyses examined effects by subgroup: pFAS/FAS (N = 32, Mage = 10.7 years, SEage = 0.79), PAE/ARND (N = 23, Mage = 10.8, SEage = 0.94), and controls (N = 68, Mage = 11.1, SEage = 0.54). Results: Total brain volume in children with an FASD was smaller relative to controls, but subtype analysis revealed only the pFAS/FAS group differed significantly from controls. Regional analyses similarly revealed reduced brain volume in frontal and temporal regions for children with pFAS/FAS, yet children diagnosed with PAE/ARND generally had similar volumes as controls. Notable differences to this pattern occurred in the cerebellum, caudate, and pallidum where children with pFAS/FAS and PAE/ARND revealed lower volume relative to controls. In the subset of participants who had neuropsychological testing, correlations between volume and IQ scores were observed. Goodness-of-Fit analysis by age revealed differences in developmental patterns (linear vs. quadratic) between groups in some cases. Discussion: This study confirmed prior results indicating decreased brain volume in children with an FASD and extended the results by demonstrating differential effects by structure for FASD subtypes. It provides further evidence for a complex role of PAE in structural brain development that is likely related to the cognitive and behavioral effects experienced by children with an FASD.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic time course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months postinjury, which would be inversely associated with age at injury. METHODS: Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). RESULTS: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d = -0.49) and hippocampal volumes (d = -0.24) observed for pmTBI, but not associated with age at injury. Hippocampal volume recovery was mediated by loss of consciousness/posttraumatic amnesia. Significantly greater postconcussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). DISCUSSION: Current findings indicate that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Age dependent neural correlates of inhibition and control mechanisms in moderate to heavy drinkers.

BACKGROUND: Long-term, heavy alcohol consumption has been associated with impairments in control over alcohol use, but whether this extends to other areas of cognitive and behavioral control such as response inhibition remains unclear. Understanding individual differences in the neural correlates of response inhibition will provide further insight into the neurobiology of heavy drinking. The current study investigated response inhibition in a large sample of moderate to heavy drinkers METHODS: One hundred fifty-three individuals completed a stop signal task while undergoing functional magnetic resonance imaging. Multiple regression analyses focused on blood oxygen level-dependent (BOLD) response contrasts of correct inhibition and failed inhibition as dependent variables and included age, sex, and hazardous drinking (as measured by the Alcohol Use Disorders Identification Test (AUDIT)), and their interactions, as independent variables RESULTS: Age was negatively associated with BOLD response in lateral inferior and middle frontal gyri, anterior cingulate cortex, and inferior parietal lobe for both successful inhibition and failed inhibition contrasts. In addition, there was a significant age × AUDIT interaction in the successful inhibition contrast in the left middle frontal gyrus, with significant negative correlations between AUDIT and BOLD response in older participants, and a significant positive correlation between AUDIT and BOLD response in younger participants CONCLUSIONS: Age appears to be a particularly important factor in predicting BOLD response and may be a critical variable to include in future studies of heavy drinking and alcohol use disorder, particularly those that assess cognitive function. Finally, the age × AUDIT interaction observed in the current study may represent evidence for accelerated aging effects of alcohol on cognitive function.

Neural correlates of alcohol use disorder severity among nontreatment-seeking heavy drinkers: An examination of the incentive salience and negative emotionality domains of the alcohol and addiction research domain criteria.

BACKGROUND: The Alcohol and Addiction Research Domain Criteria (AARDoC) propose that alcohol use disorder is associated with neural dysfunction in three primary domains: incentive salience, negative emotionality, and executive function. Prior studies in heavy drinking samples have examined brain activation changes associated with alcohol and negative affect cues, representing the incentive salience and negative emotionality domains, respectively. Yet studies examining such cue-induced changes in functional connectivity (FC) are relatively sparse. METHODS: Nontreatment-seeking heavy drinking adults (N = 149, 56.0% male, 48.6% non-white, mean age 34.8 years (SD = 10.0)) underwent functional magnetic resonance imaging during presentation of alcohol, negative, and neutral pictures. We focused on FC changes involving the nucleus accumbens and amygdala in addition to activation and FC correlations with self-reported AUD severity. RESULTS: For alcohol cues versus neutral cues, we observed accumbens FC changes in the cerebellum and prefrontal cortex (PFC), and amygdala FC changes with occipital, parietal, and hippocampal regions. AUD severity correlated positively with activation in the cerebellum (p < 0.05), accumbens FC in the cingulate gyri, somatosensory gyri, and cerebellum (p < 0.05), and with amygdala FC in the PFC and inferior parietal lobule (p < 0.05) for alcohol cues versus neutral cues. For negative cues versus neutral cues, we observed accumbens FC changes in the lateral temporal, occipital, and parietal regions, and amygdala FC changes in the fusiform and lingual gyri (p < 0.05). CONCLUSIONS: The present findings provide empirical support for the AARDoC domains of incentive salience and negative emotionality and indicate that AUD severity is associated with salience and response control for reward cues. When covarying for differences in nonalcohol substance use and mood disorder diagnoses, AUD severity was also associated with emotional reactivity for negative cues.

On the acquisition of the water signal during water suppression: High-speed MR spectroscopic imaging with water referencing and concurrent functional MRI.

This study evaluated the utility of concurrent water signal acquisition as part of the water suppression in MR spectroscopic imaging (MRSI), to allow simultaneous water referencing for metabolite quantification, and to concurrently acquire functional MRI (fMRI) data. We integrated a spatial-spectral binomial water excitation RF pulse and a short spatial-spectral echo-planar readout into the water suppression module of 2D and 3D proton-echo-planar-spectroscopic-imaging (PEPSI) with a voxel size as small as 4 x 4 x 6 mm3 . Metabolite quantification in reference to tissue water was validated in healthy controls for different prelocalization methods (spin-echo, PRESS and semi-LASER) and the clinical feasibility of a 3-minute 3D semi-Laser PEPSI scan (TR/TE: 1250/32 ms) with water referencing in patients with brain tumors was demonstrated. Spectral quality, SNR, Cramer-Rao-lower-bounds and water suppression efficiency were comparable with conventional PEPSI. Metabolite concentration values in reference to tissue water, using custom LCModel-based spectral fitting with relaxation correction, were in the range of previous studies and independent of the prelocalization method used. Next, we added a phase-encoding undersampled echo-volumar imaging (EVI) module during water suppression to concurrently acquire metabolite maps with water referencing and fMRI data during task execution and resting state in healthy controls. Integration of multimodal signal acquisition prolongated minimum TR by less than 50 ms on average. Visual and motor activation in concurrent fMRI/MRSI (TR: 1250-1500 ms, voxel size: 4 x 4 x 6 mm3 ) was readily detectable in single-task blocks with percent signal change comparable with conventional fMRI. Resting-state connectivity in sensory and motor networks was detectable in 4 minutes. This hybrid water suppression approach for multimodal imaging has the potential to significantly reduce scan time and extend neuroscience research and clinical applications through concurrent quantitative MRSI and fMRI acquisitions.

Real-Time Resting-State Functional Magnetic Resonance Imaging Using Averaged Sliding Windows with Partial Correlations and Regression of Confounding Signals.

Background/Introduction: There is considerable interest in using real-time functional magnetic resonance imaging (fMRI) for monitoring functional connectivity dynamics. To date, the majority of real-time resting-state fMRI studies have examined a limited number of brain regions. This is, in part, due to the computational demands of traditional seed- and independent component analysis-based methods, in particular when using increasingly available high-speed fMRI methods. Methods: This study describes a computationally efficient, real-time, seed-based, resting-state fMRI analysis pipeline using moving averaged sliding-windows (ASW) with partial correlations and regression of motion parameters and signals from white matter and cerebrospinal fluid. Results: Analytical and numerical analyses of ASW correlation and sliding-window regression as a function of window width show selectable bandpass filter characteristics and effective suppression of artifactual correlations resulting from signal drifts and transients. The analysis pipeline is compatible with multislab echo-volumar imaging and simultaneous multislice echo-planar imaging with repetition times as short as 136 msec. High-speed, resting-state fMRI data in healthy controls demonstrate the effectiveness of this approach for minimizing artifactual correlations in white and gray matter, which was comparable to conventional regression across the entire scan. Integrating sliding-window averaging (width: W1) within a second-level sliding-window (width: W2) enabled monitoring of intra- and internetwork correlation dynamics of up to 12 resting-state networks with bandpass filter characteristics determined by the first-level sliding-window and temporal resolution W1 + W2. Conclusions: The computational performance and confound tolerance make this seed-based, resting-state fMRI approach suitable for real-time monitoring of data quality and resting-state connectivity dynamics in neuroscience and clinical research studies. Impact statement Using averaged sliding-windows for seed-based correlation and regression of confounding signals provides a powerful model-free approach to increase tolerance to artifactual signal transients in resting-state analysis. The algorithmic efficiency of this sliding-window approach enables real-time, seed-based, resting-state functional magnetic resonance imaging (fMRI) of multiple networks with computation of connectivity matrices and online monitoring of data quality. Integration of a second-level sliding-window enables mapping of resting-state connectivity dynamics. Sensitivity and tolerance to confounding signals compare favorably with conventional correlation and confound regression across the entire scan. This methodological advance has the potential to enhance the clinical utility of resting-state fMRI and facilitate neuroscience applications.

Real-time presurgical resting-state fMRI in patients with brain tumors: Quality control and comparison with task-fMRI and intraoperative mapping.

Resting-state functional magnetic resonance imaging (rsfMRI) is a promising task-free functional imaging approach, which may complement or replace task-based fMRI (tfMRI) in patients who have difficulties performing required tasks. However, rsfMRI is highly sensitive to head movement and physiological noise, and validation relative to tfMRI and intraoperative electrocortical mapping is still necessary. In this study, we investigate (a) the feasibility of real-time rsfMRI for presurgical mapping of eloquent networks with monitoring of data quality in patients with brain tumors and (b) rsfMRI localization of eloquent cortex compared with tfMRI and intraoperative electrocortical stimulation (ECS) in retrospective analysis. Five brain tumor patients were studied with rsfMRI and tfMRI on a clinical 3T scanner using MultiBand(8)-echo planar imaging (EPI) with repetition time: 400 ms. Moving-averaged sliding-window correlation analysis with regression of motion parameters and signals from white matter and cerebrospinal fluid was used to map sensorimotor and language resting-state networks. Data quality monitoring enabled rapid optimization of scan protocols, early identification of task noncompliance, and head movement-related false-positive connectivity to determine scan continuation or repetition. Sensorimotor and language resting-state networks were identifiable within 1 min of scan time. The Euclidean distance between ECS and rsfMRI connectivity and task-activation in motor cortex, Broca's, and Wernicke's areas was 5-10 mm, with the exception of discordant rsfMRI and ECS localization of Wernicke's area in one patient due to possible cortical reorganization and/or altered neurovascular coupling. This study demonstrates the potential of real-time high-speed rsfMRI for presurgical mapping of eloquent cortex with real-time data quality control, and clinically acceptable concordance of rsfMRI with tfMRI and ECS localization.

On the detection of high frequency correlations in resting state fMRI.

Current studies of resting-state connectivity rely on coherent signal fluctuations at frequencies below 0.1 Hz, however, recent studies using high-speed fMRI have shown that fluctuations above 0.5 Hz may exist. This study replicates the feasibility of measuring high frequency (HF) correlations in six healthy controls and a patient with a brain tumor while analyzing non-physiological signal sources via simulation. Resting-state data were acquired using a high-speed multi-slab echo-volumar imaging pulse sequence with 136 ms temporal resolution. Bandpass frequency filtering in combination with sliding window seed-based connectivity analysis using running mean of the correlation maps was employed to map HF correlations up to 3.7 Hz. Computer simulations of Rician noise and the underlying point spread function were analyzed to estimate baseline spatial autocorrelation levels in four major networks (auditory, sensorimotor, visual, and default-mode). Using seed regions based on Brodmann areas, the auditory and default-mode networks were observed to have significant frequency band dependent HF correlations above baseline spatial autocorrelation levels. Correlations in the sensorimotor network were at trend level. The auditory network was still observed using a unilateral single voxel seed. In the patient, HF auditory correlations showed a spatial displacement near the tumor consistent with the displacement seen at low frequencies. In conclusion, our data suggest that HF connectivity in the human brain may be observable with high-speed fMRI, however, the detection sensitivity may depend on the network observed, data acquisition technique, and analysis method.

Safety and EEG data quality of concurrent high-density EEG and high-speed fMRI at 3 Tesla.

PURPOSE: Concurrent EEG and fMRI is increasingly used to characterize the spatial-temporal dynamics of brain activity. However, most studies to date have been limited to conventional echo-planar imaging (EPI). There is considerable interest in integrating recently developed high-speed fMRI methods with high-density EEG to increase temporal resolution and sensitivity for task-based and resting state fMRI, and for detecting interictal spikes in epilepsy. In the present study using concurrent high-density EEG and recently developed high-speed fMRI methods, we investigate safety of radiofrequency (RF) related heating, the effect of EEG on cortical signal-to-noise ratio (SNR) in fMRI, and assess EEG data quality. MATERIALS AND METHODS: The study compared EPI, multi-echo EPI, multi-band EPI and multi-slab echo-volumar imaging pulse sequences, using clinical 3 Tesla MR scanners from two different vendors that were equipped with 64- and 256-channel MR-compatible EEG systems, respectively, and receive only array head coils. Data were collected in 11 healthy controls (3 males, age range 18-70 years) and 13 patients with epilepsy (8 males, age range 21-67 years). Three of the healthy controls were scanned with the 256-channel EEG system, the other subjects were scanned with the 64-channel EEG system. Scalp surface temperature, SNR in occipital cortex and head movement were measured with and without the EEG cap. The degree of artifacts and the ability to identify background activity was assessed by visual analysis by a trained expert in the 64 channel EEG data (7 healthy controls, 13 patients). RESULTS: RF induced heating at the surface of the EEG electrodes during a 30-minute scan period with stable temperature prior to scanning did not exceed 1.0° C with either EEG system and any of the pulse sequences used in this study. There was no significant decrease in cortical SNR due to the presence of the EEG cap (p > 0.05). No significant differences in the visually analyzed EEG data quality were found between EEG recorded during high-speed fMRI and during conventional EPI (p = 0.78). Residual ballistocardiographic artifacts resulted in 58% of EEG data being rated as poor quality. CONCLUSION: This study demonstrates that high-density EEG can be safely implemented in conjunction with high-speed fMRI and that high-speed fMRI does not adversely affect EEG data quality. However, the deterioration of the EEG quality due to residual ballistocardiographic artifacts remains a significant constraint for routine clinical applications of concurrent EEG-fMRI.