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Introduction: Maximal grip strength, a measure of how much force a person's hand can generate when squeezing an object, may be an effective method for understanding potential neurobiological differences during motor tasks. Grip strength in autistic individuals may be of particular interest due to its unique developmental trajectory. While autism-specific differences in grip-brain relationships have been found in adult populations, it is possible that such differences in grip-brain relationships may be present at earlier ages when grip strength is behaviorally similar in autistic and non-autistic groups. Further, such neural differences may lead to the later emergence of diagnostic-group grip differences in adolescence. The present study sought to examine this possibility, while also examining if grip strength could elucidate the neuro-motor sources of phenotypic heterogeneity commonly observed within autism., Methods: Using high resolution, multi-shell diffusion, and quantitative R1 relaxometry imaging, this study examined how variations in key sensorimotor-related white matter pathways of the proprioception input, lateral grasping, cortico-cerebellar, and corticospinal networks were associated with individual variations in grip strength in 68 autistic children and 70 non-autistic (neurotypical) children (6-11 years-old)., Results: In both groups, results indicated that stronger grip strength was associated with higher proprioceptive input, lateral grasping, and corticospinal (but not cortico-cerebellar modification) fractional anisotropy and R1, indirect measures concordant with stronger microstructural coherence and increased myelination. Diagnostic group differences in these grip-brain relationships were not observed, but the autistic group exhibited more variability particularly in the cortico-cerebellar modification indices. An examination into the variability within the autistic group revealed that attention-deficit/hyperactivity disorder (ADHD) features moderated the relationships between grip strength and both fractional anisotropy and R1 relaxometry in the premotor-primary motor tract of the lateral grasping network and the cortico-cerebellar network tracts. Specifically, in autistic children with elevated ADHD features (60% of the autistic group) stronger grip strength was related to higher fractional anisotropy and R1 of the cerebellar modification network (stronger microstructural coherence and more myelin), whereas the opposite relationship was observed in autistic children with reduced ADHD features., Discussion: Together, this work suggests that while the foundational elements of grip strength are similar across school-aged autistic and non-autistic children, neural mechanisms of grip strength within autistic children may additionally depend on the presence of ADHD features. Specifically, stronger, more coherent connections of the cerebellar modification network, which is thought to play a role in refining and optimizing motor commands, may lead to stronger grip in children with more ADHD features, weaker grip in children with fewer ADHD features, and no difference in grip in non-autistic children. While future research is needed to understand if these findings extend to other motor tasks beyond grip strength, these results have implications for understanding the biological basis of neuromotor control in autistic children and emphasize the importance of assessing co-occurring conditions when evaluating brain-behavior relationships in autism., Competing Interests: AA is part owner of ImgGyd, LLC and inseRT MRI, Inc. (also listed as TherVoyant). While both companies are involved in developing MRI-based surgery techniques, neither are associated with any current areas of his research, including the present publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Surgent, Guerrero-Gonzalez, Dean, Adluru, Kirk, Kecskemeti, Alexander, Li and Travers.)

Although multiple theories have speculated about the brainstem reticular formation's involvement in autistic behaviors, the in vivo imaging of brainstem nuclei needed to test these theories has proven technologically challenging. Using methods to improve brainstem imaging in children, this study set out to elucidate the role of the autonomic, nociceptive, and limbic brainstem nuclei in the autism features of 145 children (74 autistic children, 6.0-10.9 years). Participants completed an assessment of core autism features and diffusion- and T1-weighted imaging optimized to improve brainstem images. After data reduction via principal component analysis, correlational analyses examined associations among autism features and the microstructural properties of brainstem clusters. Independent replication was performed in 43 adolescents (24 autistic, 13.0-17.9 years). We found specific nuclei, most robustly the parvicellular reticular formation-alpha (PCRtA) and to a lesser degree the lateral parabrachial nucleus (LPB) and ventral tegmental parabrachial pigmented complex (VTA-PBP), to be associated with autism features. The PCRtA and some of the LPB associations were independently found in the replication sample, but the VTA-PBP associations were not. Consistent with theoretical perspectives, the findings suggest that individual differences in pontine reticular formation nuclei contribute to the prominence of autistic features. Specifically, the PCRtA, a nucleus involved in mastication, digestion, and cardio-respiration in animal models, was associated with social communication in children, while the LPB, a pain-network nucleus, was associated with repetitive behaviors. These findings highlight the contributions of key autonomic brainstem nuclei to the expression of core autism features., (© 2024 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: Alzheimer's disease involves accumulating amyloid (A) and tau (T) pathology, and progressive neurodegeneration (N), leading to the development of the AD clinical syndrome. While several markers of N have been proposed, efforts to define normal vs. abnormal neurodegeneration based on neuroimaging have been limited. Sensitive markers that may account for or predict cognitive dysfunction for individuals in early disease stages are critical., Methods: Participants (n = 296) defined on A and T status and spanning the AD-clinical continuum underwent multi-shell diffusion-weighted magnetic resonance imaging to generate Neurite Orientation Dispersion and Density Imaging (NODDI) metrics, which were tested as markers of N. To better define N, we developed age- and sex-adjusted robust z-score values to quantify normal and AD-associated (abnormal) neurodegeneration in both cortical gray matter and subcortical white matter regions of interest. We used general logistic regression with receiver operating characteristic (ROC) and area under the curve (AUC) analysis to test whether NODDI metrics improved diagnostic accuracy compared to models that only relied on cerebrospinal fluid (CSF) A and T status (alone and in combination)., Results: Using internal robust norms, we found that NODDI metrics correlate with worsening cognitive status and that NODDI captures early, AD neurodegenerative pathology in the gray matter of cognitively unimpaired, but A/T biomarker-positive, individuals. NODDI metrics utilized together with A and T status improved diagnostic prediction accuracy of AD clinical status, compared with models using CSF A and T status alone., Conclusion: Using a robust norms approach, we show that abnormal AD-related neurodegeneration can be detected among cognitively unimpaired individuals. Metrics derived from diffusion-weighted imaging are potential sensitive markers of N and could be considered for trial enrichment and as outcomes in clinical trials. However, given the small sample sizes, the exploratory nature of the work must be acknowledged., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Maximal grip strength is associated with a variety of health-related outcome measures and thus may be reflective of the efficiency of foundational brain-body communication. Non-human primate models of grip strength strongly implicate the cortical lateral grasping network, but little is known about the translatability of these models to human children. Further, it is unclear how supplementary networks that provide proprioceptive information and cerebellar-based motor command modification are associated with maximal grip strength. Therefore, this study employed high resolution, multi-shell diffusion and quantitative T1 imaging to examine how variations in lateral grasping, proprioception input, and cortico-cerebellar modification network white matter microstructure are associated with variations in grip strength across 70 children. Results indicated that stronger grip strength was associated with higher lateral grasping and proprioception input network fractional anisotropy and R1, indirect measures consistent with stronger microstructural coherence and increased myelination. No relationships were found in the cerebellar modification network. These results provide a neurobiological mechanism of grip behavior in children which suggests that increased myelination of cortical sensory and motor pathways is associated with stronger grip. This neurobiological mechanism may be a signature of pediatric neuro-motor behavior more broadly as evidenced by the previously demonstrated relationships between grip strength and behavioral outcome measures across a variety of clinical and non-clinical populations., Competing Interests: Declaration of Competing Interest Dr. Andrew L. Alexander has an independent consulting business, which is related to paid professional activities including journal editing, grant reviews and professional presentations and is part owner of a company called ImgGyd, LLC, which is developing technologies for image-guided surgery. The ImgGyd technology is not directly associated with any current areas of his research related to brain imaging. No other authors have declarations of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Elevated or reduced responses to sensory stimuli, known as sensory features, are common in autistic individuals and often impact quality of life. Little is known about the neurobiological basis of sensory features in autistic children. However, the brainstem may offer critical insights as it has been associated with both basic sensory processing and core features of autism., Methods: Diffusion-weighted imaging (DWI) and parent-report of sensory features were acquired from 133 children (61 autistic children with and 72 non-autistic children, 6-11 years-old). Leveraging novel DWI processing techniques, we investigated the relationship between sensory features and white matter microstructure properties (free-water-elimination-corrected fractional anisotropy [FA] and mean diffusivity [MD]) in precisely delineated brainstem white matter tracts. Follow-up analyses assessed relationships between microstructure and sensory response patterns/modalities and analyzed whole brain white matter using voxel-based analysis., Results: Results revealed distinct relationships between brainstem microstructure and sensory features in autistic children compared to non-autistic children. In autistic children, more prominent sensory features were generally associated with lower MD. Further, in autistic children, sensory hyporesponsiveness and tactile responsivity were strongly associated with white matter microstructure in nearly all brainstem tracts. Follow-up voxel-based analyses confirmed that these relationships were more prominent in the brainstem/cerebellum, with additional sensory-brain findings in the autistic group in the white matter of the primary motor and somatosensory cortices, the occipital lobe, the inferior parietal lobe, and the thalamic projections., Limitations: All participants communicated via spoken language and acclimated to the sensory environment of an MRI session, which should be considered when assessing the generalizability of this work to the whole of the autism spectrum., Conclusions: These findings suggest unique brainstem white matter contributions to sensory features in autistic children compared to non-autistic children. The brainstem correlates of sensory features underscore the potential reflex-like nature of behavioral responses to sensory stimuli in autism and have implications for how we conceptualize and address sensory features in autistic populations., (© 2022. The Author(s).)

Introduction: White matter (WM) degeneration is a critical component of early Alzheimer's disease (AD) pathophysiology. Diffusion-weighted imaging (DWI) models, including diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and mean apparent propagator MRI (MAP-MRI), have the potential to identify early neurodegenerative WM changes associated with AD., Methods: We imaged 213 (198 cognitively unimpaired) aging adults with DWI and used tract-based spatial statistics to compare 15 DWI metrics of WM microstructure to 9 cerebrospinal fluid (CSF) markers of AD pathology and neurodegeneration treated as continuous variables., Results: We found widespread WM injury in AD, as indexed by robust associations between DWI metrics and CSF biomarkers. MAP-MRI had more spatially diffuse relationships with Aβ 42/40 and pTau, compared with NODDI and DTI., Discussion: Our results suggest that WM degeneration may be more pervasive in AD than is commonly appreciated and that innovative DWI models such as MAP-MRI may provide clinically viable biomarkers of AD-related neurodegeneration in the earliest stages of AD progression., Competing Interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. All other authors have no competing interests to disclose. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Alterations in white matter (WM) development are associated with many neuropsychiatric and neurodevelopmental disorders. Most MRI studies examining WM development employ diffusion tensor imaging (DTI), which relies on estimating diffusion patterns of water molecules as a reflection of WM microstructure. Quantitative relaxometry, an alternative method for characterizing WM microstructural changes, is based on molecular interactions associated with the magnetic relaxation of protons. In a longitudinal study of 34 infant non-human primates (NHP) (Macaca mulatta) across the first year of life, we implement a novel, high-resolution, T1-weighted MPnRAGE sequence to examine WM trajectories of the longitudinal relaxation rate (qR 1 ) in relation to DTI metrics and gestational age at scan. To the best of our knowledge, this is the first study to assess developmental WM trajectories in NHPs using quantitative relaxometry and the first to directly compare DTI and relaxometry metrics during infancy. We demonstrate that qR 1 exhibits robust logarithmic growth, unfolding in a posterior-anterior and medial-lateral fashion, similar to DTI metrics. On a within-subject level, DTI metrics and qR 1 are highly correlated, but are largely unrelated on a between-subject level. Unlike DTI metrics, gestational age at birth (time in utero) is a strong predictor of early postnatal qR 1 levels. Whereas individual differences in DTI metrics are maintained across the first year of life, this is not the case for qR 1 . These results point to the similarities and differences in using quantitative relaxometry and DTI in developmental studies, providing a basis for future studies to characterize the unique processes that these measures reflect at the cellular and molecular level., Competing Interests: Declaration of Competing Interest NHK reported receiving grants from the National Institute of Mental Health; consulting to CME Outfitters, the Pritzker Neuropsychiatric Disorders Research Consortium, the Skyland Trail Advisory Board, the Early Life Adversity Research External Scientific Advisory Board at the University of Texas at Austin, and Corcept Therapeutics Incorporated; and serving as editor-in-chief of The American Journal of Psychiatry during the conduct of the study. The other authors report no potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diffusion-weighted magnetic resonance imaging (dMRI) of the brainstem is technically challenging, especially in young autistic children as nearby tissue-air interfaces and motion (voluntary and physiological) can lead to artifacts. This limits the availability of high-resolution images, which are desirable for improving the ability to study brainstem structures. Furthermore, inherently low signal-to-noise ratios, geometric distortions, and sensitivity to motion not related to molecular diffusion have resulted in limited techniques for high-resolution data acquisition compared to other modalities such as T1-weighted imaging. Here, we implement a method for achieving increased apparent spatial resolution in pediatric dMRI that hinges on accurate geometric distortion correction and on high fidelity within subject image registration between dMRI and magnetization prepared rapid acquisition gradient echo (MPnRAGE) images. We call this post-processing pipeline T1 weighted-diffusion fused, or "TiDi-Fused". Data used in this work consists of dMRI data (2.4 mm resolution, corrected using FSL's Topup) and T1-weighted (T1w) MPnRAGE anatomical data (1 mm resolution) acquired from 128 autistic and non-autistic children (ages 6-10 years old). Accurate correction of geometric distortion permitted for a further increase in apparent resolution of the dMRI scan via boundary-based registration to the MPnRAGE T1w. Estimation of fiber orientation distributions and further analyses were carried out in the T1w space. Data processed with the TiDi-Fused method were qualitatively and quantitatively compared to data processed with conventional dMRI processing methods. Results show the advantages of the TiDi-Fused pipeline including sharper brainstem gray-white matter tissue contrast, improved inter-subject spatial alignment for group analyses of dMRI based measures, accurate spatial alignment with histology-based imaging of the brainstem, reduced variability in brainstem-cerebellar white matter tracts, and more robust biologically plausible relationships between age and brainstem-cerebellar white matter tracts. Overall, this work identifies a promising pipeline for achieving high-resolution imaging of brainstem structures in pediatric and clinical populations who may not be able to endure long scan times. This pipeline may serve as a gateway for feasibly elucidating brainstem contributions to autism and other conditions., Competing Interests: AA is part owner of ImgGyd, LLC and inseRT MRI, Inc. (also listed as TherVoyant). While both companies are involved in developing MRI-based surgery techniques, neither are associated with any current areas of his research, including the present publication. All other authors report no biomedical financial interests of potential conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guerrero-Gonzalez, Surgent, Adluru, Kirk, Dean, Kecskemeti, Alexander and Travers.)

Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric-fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO-is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer's disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD., (© 2022 The Authors.)

Introduction: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment., Methods: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ) 42 /Aβ 40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4., Results: We observed a significant CSF Aβ 42 /Aβ 40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes., Discussion: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment., (© 2021 the Alzheimer's Association.)

White matter (WM) development early in life is a critical component of brain development that facilitates the coordinated function of neuronal pathways. Additionally, alterations in WM have been implicated in various neurodevelopmental disorders, including psychiatric disorders. Because of the need to understand WM development in the weeks immediately following birth, we characterized changes in WM microstructure throughout the postnatal macaque brain during the first year of life. This is a period in primates during which genetic, developmental, and environmental factors may have long-lasting impacts on WM microstructure. Studies in nonhuman primates (NHPs) are particularly valuable as a model for understanding human brain development because of their evolutionary relatedness to humans. Here, 34 rhesus monkeys (23 females, 11 males) were imaged longitudinally at 3, 7, 13, 25, and 53 weeks of age with T1-weighted (MPnRAGE) and diffusion tensor imaging (DTI). With linear mixed-effects (LME) modeling, we demonstrated robust logarithmic growth in FA, MD, and RD trajectories extracted from 18 WM tracts across the brain. Estimated rate of change curves for FA, MD, and RD exhibited an initial 10-week period of exceedingly rapid WM development, followed by a precipitous decline in growth rates. K-means clustering of raw DTI trajectories and rank ordering of LME model parameters revealed distinct posterior-to-anterior and medial-to-lateral gradients in WM maturation. Finally, we found that individual differences in WM microstructure assessed at 3 weeks of age were significantly related to those at 1 year of age. This study provides a quantitative characterization of very early WM growth in NHPs and lays the foundation for future work focused on the impact of alterations in early WM developmental trajectories in relation to human psychopathology., Competing Interests: Declaration of competing interest At the time of writing, NHK had received honoraria from CME Outfitters and the Pritzker Consortium; serves on the advisory board of Skyland Trail; serves on the scientific advisory boards of Pritzker Neuropsychiatric Disorders Research Consortium and University of Texas at Austin Institute for Early Life Adversity Research; consults to Corcept Therapeutics; and serves as editor-in-chief of The American Journal of Psychiatry. The other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Test-retest of automated image segmentation algorithms (FSL FAST, FSL FIRST, and FREESURFER) are computed on magnetic resonance images from 12 unsedated children aged 9.4±2.6 years ([min,max] ​= ​[6.5 years, 13.8 years]) using different approaches to motion correction (prospective versus retrospective). The prospective technique, PROMO MPRAGE, dynamically estimates motion using specially acquired navigator images and adjusts the remaining acquisition accordingly, whereas the retrospective technique, MPnRAGE, uses a self-navigation property to retrospectively estimate and account for motion during image reconstruction. To increase the likelihood and range of motions, participants heads were not stabilized with padding during repeated scans. When motion was negligible both techniques had similar performance. When motion was not negligible, the automated image segmentation and anatomical labeling software tools showed the most consistent performance with the retrospectively corrected MPnRAGE technique (≥80% volume overlaps for 15 of 16 regions for FIRST and FREESURFER, with greater than 90% volume overlaps for 12 regions with FIRST and 11 regions with FREESURFER). Prospectively corrected MPRAGE with linear view-ordering also demonstrated lower performance than MPnRAGE without retrospective motion correction., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: NODDI is widely used in parameterizing microstructural brain properties. The model includes three signal compartments: intracellular, extracellular, and free water. The neurite compartment intrinsic parallel diffusivity (d∥) is set to 1.7 μm2⋅ms-1, though the effects of this assumption have not been extensively explored. This work investigates the optimality of d∥ = 1.7 μm2⋅ms-1 under varying imaging protocol, age groups, sex, and tissue type in comparison to other biologically plausible values of d∥., Methods: Model residuals were used as the optimality criterion. The model residuals were evaluated in function of d∥ over the range from 0.5 to 3.0 μm2⋅ms-1. This was done with respect to tissue type (i.e., white matter versus gray matter), sex, age (infancy to late adulthood), and diffusion-weighting protocol (maximum b-value). Variation in the estimated parameters with respect to d∥ was also explored., Results: Results show d∥ = 1.7 μm2⋅ms-1 is appropriate for adult brain white matter but it is suboptimal for gray matter with optimal values being significantly lower. d∥ = 1.7 μm2⋅ms-1 was also suboptimal in the infant brain for both white and gray matter with optimal values being significantly lower. Minor optimum d∥ differences were observed versus diffusion protocol. No significant sex effects were observed. Additionally, changes in d∥ resulted in significant changes to the estimated NODDI parameters., Conclusion: The default (d∥) of 1.7 μm2⋅ms-1 is suboptimal in gray matter and infant brains., Competing Interests: The authors have declared that no competing interests exist.

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Maternal depression and anxiety can have deleterious and lifelong consequences on child development. However, many aspects of the association of early brain development with maternal symptoms remain unclear. Understanding the timing of potential neurobiological alterations holds inherent value for the development and evaluation of future therapies and interventions., Objective: To examine the association between exposure to prenatal maternal depression and anxiety symptoms and offspring white matter microstructure at 1 month of age., Design, Setting, and Participants: This cohort study of 101 mother-infant dyads used a composite of depression and anxiety symptoms measured in mothers during the third trimester of pregnancy and measures of white matter microstructure characterized in the mothers' 1-month offspring using diffusion tensor imaging and neurite orientation dispersion and density imaging performed from October 1, 2014, to November 30, 2016. Magnetic resonance imaging was performed at an academic research facility during natural, nonsedated sleep., Main Outcomes and Measures: Brain mapping algorithms and statistical models were used to evaluate the association between maternal depression and anxiety and 1-month infant white matter microstructure as measured by diffusion tensor imaging and neurite orientation dispersion and density imaging findings., Results: In the 101 mother-infant dyads (mean [SD] age of mothers, 33.22 [3.99] years; mean age of infants at magnetic resonance imaging, 33.07 days [range, 18-50 days]; 92 white mothers [91.1%]; 53 male infants [52.5%]), lower 1-month white matter microstructure (decreased neurite density and increased mean, radial, and axial diffusivity) was associated in right frontal white matter microstructure with higher prenatal maternal symptoms of depression and anxiety. Significant sex × symptom interactions with measures of white matter microstructure were also observed, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period., Conclusions and Relevance: These data highlight the importance of the prenatal period to early brain development and suggest that the underlying white matter microstructure is associated with the continuum of prenatal maternal depression and anxiety symptoms.

The authors regret that, in this article, there was an error in the analyses comparing infant male and female regional brain volume differences.

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.

White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth.

Importance: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging., Objective: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content., Design, Setting, and Participants: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals., Main Outcomes and Measures: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction., Results: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction., Conclusions and Relevance: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials., Competing Interests: Disclosures: Dr Carlsson serves as a site principal investigator for a study that is jointly funded by the National Institutes of Health and Eli Lilly and Company and receives funding from the US Department of Veterans Affairs through the Veterans Affairs Merit grant program. Dr Blennow has served as a consultant at and on advisory boards for IBL International, Fujirebio Europe, Eli Lilly, and Novartis. No other disclosures were reported.

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: White matter tractography reconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spaces are often adversely affected by CSF partial volume effects (PVEs). This study evaluates the ability of free water elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractography applications., Materials and Methods: Ten healthy individuals were scanned with "traditional," FLAIR (fluid-attenuated inversion recovery), and FWE DTI scans. The fornix, corpus callosum, and cingulum bundles were reconstructed using deterministic tractography. The FWE DTI scan was performed twice to separately match total acquisition time (long FWE) and number of measurements (encoding directions, short FWE) to the FLAIR and "traditional" DTI scans. PVE resolution was determined based on reconstructed tract volume. All reconstructions underwent blinded review for anatomical correctness, symmetry, and completeness., Results: Reconstructions of the fornix demonstrated that the FWE and FLAIR scans produce more complete, anatomically plausible reconstructions than "traditional" DTI. Additionally, the tract reconstructions using FWE-DTI were significantly larger than when FLAIR was used with DTI (P < 0.0005). FLAIR and the FWE methods led to signal-to-noise ratio (SNR) reductions of 33% and 11%, respectively, compared with conventional DTI. The long and short FWE acquisitions did not significantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts., Conclusion: The FWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penalties inherent to FLAIR DTI., (© 2015 Wiley Periodicals, Inc.)

Diffusion tensor imaging is used to measure the diffusion of water in tissue. The diffusion properties carry information about the relative organization and structure of the underlying tissue. In the case of a single voxel containing both tissue and a fast diffusing component such as free water, a single diffusion tensor is no longer appropriate. A two-tensor free water elimination model has previously been proposed to correct for the case of volume mixing. Here, this model was implemented in a straightforward but novel manner without the use of spatial constraints. The optimal acquisition parameters were investigated through Monte Carlo simulations and human brain imaging studies. At a signal-to-noise ratio of 40 with 64 diffusion-weighted encoding images, the most accurate estimates of fast diffusion signal were obtained with two diffusion-weighted shells (b-value in s/mm(2)×number of directions) of 500×32 and 1500×32. The potential bias in fractional anisotropy induced by this two-compartment model was more than an order of magnitude less than the error of using the single diffusion tensor model in the presence of partial volume effects with free water. This strategy may be useful for characterizing the diffusion of tissues adjacent to cerebral spinal fluid (CSF), tissues affected by edema, and removing artifacts from blurring and ghosting of the CSF signal., (Published by Elsevier Inc.)

Time-resolved contrast-enhanced magnetic resonance angiography of the brain is challenging due to the need for rapid imaging and high spatial resolution. Moreover, the significant dispersion of the intravenous contrast bolus as it passes through the heart and lungs increases the overlap between arterial and venous structures, regardless of the acquisition speed and reconstruction window. An innovative technique is presented that divides a single dose contrast into two injections. Initially a small volume of contrast material (2-3 mL) is used to acquiring time-resolved weighting images with a high frame rate (2 frames/s) during the first pass of the contrast agent. The remaining contrast material is used to obtain a high resolution whole brain contrast-enhanced (CE) magnetic resonance angiography (0.57 × 0.57 × 1 mm(3) ) that is used as the spatial constraint for Local Highly Constrained Projection Reconstruction (HYPR LR) reconstruction. After HYPR reconstruction, the final dynamic images (HYPR CE) have both high temporal and spatial resolution. Furthermore, studies of contrast kinetics demonstrate that the shorter bolus length from the reduced contrast volume used for the first injection significantly improves the arterial and venous separation., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: To investigate the feasibility of using time-of-flight (TOF) images as a constraint in the reconstruction of a series of highly undersampled time-resolved contrast-enhanced MR images (HYPR TOF), to allow simultaneously high temporal and spatial resolution and increased SNR., Materials and Methods: Ten healthy volunteers and three patients with aneurysms underwent a HYPR TOF study, which includes a clinical routine TOF scan followed by a first pass time-resolved contrast-enhanced exam using an undersampled three-dimensional (3D) projection trajectory (VIPR). Image quality, waveform fidelity and signal to background variation ratio measurements were compared between HYPR TOF images and VIPR images without HYPR reconstruction., Results: Volunteer results demonstrated the feasibility of using the clinical routine TOF as the spatial constraint to reconstruct the first pass time-resolved contrast-enhanced MRA acquired using highly undersampled 3D projection trajectory (VIPR). All the HYPR TOF images are superior to the corresponding VIPR images with the same temporal reconstruction window on both spatial resolution and SNR., Conclusion: HYPR TOF improves the spatial resolution and SNR of the rapidly acquired dynamic images without losing the temporal information., (Copyright © 2011 Wiley-Liss, Inc.)