Connectomic assessment of injury burden and longitudinal structural network alterations in moderate-to-severe traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.

Neuroimaging Findings in US Government Personnel With Possible Exposure to Directional Phenomena in Havana, Cuba.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm3; controls: 569.61 cm3; difference, -27.39 [95% CI, -37.93 to -16.84] cm3; P < .001), with no significant difference in the whole brain gray matter volume (patients: 698.55 cm3; controls: 691.83 cm3; difference, 6.72 [95% CI, -4.83 to 18.27] cm3; P = .25). Among patients compared with controls, there were significantly greater ventral diencephalon and cerebellar gray matter volumes and significantly smaller frontal, occipital, and parietal lobe white matter volumes; significantly lower mean diffusivity in the inferior vermis of the cerebellum (patients: 7.71 × 10-4 mm2/s; controls: 8.98 × 10-4 mm2/s; difference, -1.27 × 10-4 [95% CI, -1.93 × 10-4 to -6.17 × 10-5] mm2/s; P < .001); and significantly lower mean functional connectivity in the auditory subnetwork (patients: 0.45; controls: 0.61; difference, -0.16 [95% CI, -0.26 to -0.05]; P = .003) and visuospatial subnetwork (patients: 0.30; controls: 0.40; difference, -0.10 [95% CI, -0.16 to -0.04]; P = .002) but not in the executive control subnetwork (patients: 0.24; controls: 0.25; difference: -0.016 [95% CI, -0.04 to 0.01]; P = .23). CONCLUSIONS AND RELEVANCE: Among US government personnel in Havana, Cuba, with potential exposure to directional phenomena, compared with healthy controls, advanced brain magnetic resonance imaging revealed significant differences in whole brain white matter volume, regional gray and white matter volumes, cerebellar tissue microstructural integrity, and functional connectivity in the auditory and visuospatial subnetworks but not in the executive control subnetwork. The clinical importance of these differences is uncertain and may require further study.

Free Water Volume Fraction: An Imaging Biomarker to Characterize Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major clinical and public health problem with few therapeutic interventions successfully translated to the clinic. Identifying imaging-based biomarkers characterizing injury severity and predicting long-term functional and cognitive outcomes in TBI patients is crucial for treatment. TBI results in white matter (WM) injuries, which can be detected using diffusion tensor imaging (DTI). Trauma-induced pathologies lead to accumulation of free water (FW) in brain tissue, and standard DTI is susceptible to the confounding effects of FW. In this study, we applied FW DTI to estimate free water volume fraction (FW-VF) in patients with moderate-to-severe TBI and demonstrated its association with injury severity and long-term outcomes. DTI scans and neuropsychological assessments were obtained longitudinally at 3, 6, and 12 months post-injury for 34 patients and once in 35 matched healthy controls. We observed significantly elevated FW-VF in 85 of 90 WM regions in patients compared to healthy controls (p < 0.05). We then presented a patient-specific summary score of WM regions derived using Mahalanobis distance. We observed that MVF at 3 months significantly predicted functional outcome (p = 0.008), executive function (p = 0.005), and processing speed (p = 0.01) measured at 12 months and was significantly correlated with injury severity (p < 0.001). Our findings are an important step toward implementing MVF as a biomarker for personalized therapy and rehabilitation planning for TBI patients.

Analysis of Consistency in Structural and Functional Connectivity of Human Brain.

Analysis of structural and functional connectivity of brain has become a fundamental approach in neuroscientific research. Despite several studies reporting consistent similarities as well as differences for structural and resting state (rs) functional connectomes, a comparative investigation of connectomic consistency between the two modalities is still lacking. Nonetheless, connectomic analysis comprising both connectivity types necessitate extra attention as consistency of connectivity differs across modalities, possibly affecting the interpretation of the results. In this study, we present a comprehensive analysis of consistency in structural and rs-functional connectomes obtained from longitudinal diffusion MRI and rs-fMRI data of a single healthy subject. We contrast consistency of deterministic and probabilistic tracking with that of full, positive, and negative functional connectivities across various connectome generation schemes, using correlation as a measure of consistency.

Connectomic consistency: a systematic stability analysis of structural and functional connectivity.

OBJECTIVE: Connectomics, the study of brain connectivity, has become an indispensable tool in neuroscientific research as it provides insights into brain organization. Connectomes are generated using different modalities such as diffusion MRI to capture structural organization of the brain or functional MRI to elaborate brain's functional organization. Understanding links between structural and functional organizations is crucial in explaining how observed behavior emerges from the underlying neurobiological mechanisms. Many studies have investigated how these two organizations relate to each other; however, we still lack a comparative understanding on how much variation should be expected in the two modalities, both between people and within a single person across scans. APPROACH: In this study, we systematically analyzed the consistency of connectomes, that is the similarity between connectomes in terms of individual connections between brain regions and in terms of overall network topology. We present a comprehensive study of consistency in connectomes for a single subject examined longitudinally and across a large cohort of subjects cross-sectionally, in structure and function separately. Within structural connectomes, we compared connectomes generated by different tracking algorithms, parcellations, edge weighting schemes, and edge pruning techniques. In functional connectomes, we compared full, positive, and negative connectivity separately along with thresholding of weak edges. We evaluated consistency using correlation (incorporating information at the level of individual edges) and graph matching accuracy (evaluating connectivity at the level of network topology). We also examined the consistency of connectomes that are generated using different communication schemes. MAIN RESULTS: Our results demonstrate varying degrees of consistency for the two modalities, with structural connectomes showing higher consistency than functional connectomes. Moreover, we observed a wide variation in consistency depending on how connectomes are generated. SIGNIFICANCE: Our study sets a reference point for consistency of connectome types, which is especially important for structure-function coupling studies in evaluating mismatches between modalities.

Graph Matching Based Connectomic Biomarker with Learning for Brain Disorders.

Advances in neuroimaging techniques such as diffusion MRI and functional MRI enabled evaluation of the brain as an information processing network that is called connectome. Connectomic analysis has led to numerous findings on the organization of the brain its pathological changes with diseases, providing imaging-based biomarkers that help in diagnosis and prognosis. A large majority of connectomic biomarkers benefit either from graph-theoretical measures that evaluate brain's network structure, or use standard metrics such as Euclidean distance or Pearson's correlation to show between-connectomes relations. However, such methods are limited in diagnostic evaluation of diseases, because they do not simultaneously measure the difference between individual connectomes, incorporate disease-specific patterns, and utilize network structure information. To address these limitations, we propose a graph matching based method to quantify connectomic similarity, which can be trained for diseases at functional systems level to provide a subject-specific biomarker assessing the disease. We validate our measure on a dataset of patients with traumatic brain injury and demonstrate that our measure achieves better separation between patients and controls compared to commonly used connectomic similarity measures. We further evaluate the vulnerability of the functional systems to the disease by utilizing the parameter tuning aspect of our method. We finally show that our similarity score correlates with clinical scores, highlighting its potential as a subject-specific biomarker for the disease.

Deviation from normative brain development is associated with symptom severity in autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition. The degree to which the brain development in ASD deviates from typical brain development, and how this deviation relates to observed behavioral outcomes at the individual level are not well-studied. We hypothesize that the degree of deviation from typical brain development of an individual with ASD would relate to observed symptom severity. Methods: The developmental changes in anatomical (cortical thickness, surface area, and volume) and diffusion metrics (fractional anisotropy and apparent diffusion coefficient) were compared between a sample of ASD (n = 247) and typically developing children (TDC) (n = 220) aged 6-25. Machine learning was used to predict age (brain age) from these metrics in the TDC sample, to define a normative model of brain development. This model was then used to compute brain age in the ASD sample. The difference between chronological age and brain age was considered a developmental deviation index (DDI), which was then correlated with ASD symptom severity. Results: Machine learning model trained on all five metrics accurately predicted age in the TDC (r = 0.88) and the ASD (r = 0.85) samples, with dominant contributions to the model from the diffusion metrics. Within the ASD group, the DDI derived from fractional anisotropy was correlated with ASD symptom severity (r = - 0.2), such that individuals with the most advanced brain age showing the lowest severity, and individuals with the most delayed brain age showing the highest severity. Limitations: This work investigated only linear relationships between five specific brain metrics and only one measure of ASD symptom severity in a limited age range. Reported effect sizes are moderate. Further work is needed to investigate developmental differences in other age ranges, other aspects of behavior, other neurobiological measures, and in an independent sample before results can be clinically applicable. Conclusions: Findings demonstrate that the degree of deviation from typical brain development relates to ASD symptom severity, partially accounting for the observed heterogeneity in ASD. Our approach enables characterization of each individual with reference to normative brain development and identification of distinct developmental subtypes, facilitating a better understanding of developmental heterogeneity in ASD.

Music and Emotion-A Case for North Indian Classical Music.

The ragas of North Indian Classical Music (NICM) have been historically known to elicit emotions. Recently, Mathur et al. (2015) provided empirical support for these historical assumptions, that distinct ragas elicit distinct emotional responses. In this review, we discuss the findings of Mathur et al. (2015) in the context of the structure of NICM. Using, Mathur et al. (2015) as a demonstrative case-in-point, we argue that ragas of NICM can be viewed as uniquely designed stimulus tools for investigating the tonal and rhythmic influences on musical emotion.