Longitudinal Lesion Expansion in Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a risk factor for neurodegeneration and cognitive decline, yet the underlying pathophysiologic mechanisms are incompletely understood. This gap in knowledge is in part related to the lack of analytic methods to account for cortical lesions in prior neuroimaging studies. The objective of this study was to develop a lesion detection tool and apply it to an investigation of longitudinal changes in brain structure among individuals with chronic TBI. We identified 24 individuals with chronic moderate-to-severe TBI enrolled in the Late Effects of TBI (LETBI) study who had cortical lesions detected by T1-weighted MRI at two time points. Initial MRI scans were performed more than 1-year post-injury and follow-up scans were performed 3.1 (IQR=1.7) years later. We leveraged FreeSurfer parcellations of T1-weighted MRI volumes and a recently developed super-resolution technique, SynthSR, to identify cortical lesions in this longitudinal dataset. Trained raters received the data in a randomized order and manually corrected the automated lesion segmentation, yielding a final lesion mask for each scan at each timepoint. Lesion volume significantly increased between the two time points with a median volume change of 3.2 (IQR=5.9) mL (p<0.001), and the increases significantly exceeded the possible variance in lesion volume changes due to manual tracing errors (p < 0.001). Lesion volume significantly expanded longitudinally in 23 of 24 subjects, with all FDR corrected p-values ≤ 0.02. Inter-scan duration was not associated with the magnitude of lesion growth. We also demonstrated that the semi-automated tool showed a high level of accuracy compared to "ground truth" manual lesion segmentation. Semi-automated lesion segmentation is feasible in TBI studies and creates opportunities to elucidate mechanisms of post-traumatic neurodegeneration.

Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness.

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

Sustaining wakefulness: Brainstem connectivity in human consciousness.

Consciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data from ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesla functional MRI to map the connectivity of a subcortical arousal network that we postulate sustains wakefulness in the resting, conscious human brain, analogous to the cortical default mode network (DMN) that is believed to sustain self-awareness. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain by correlating ex vivo diffusion MRI with immunohistochemistry in three human brain specimens from neurologically normal individuals scanned at 600-750 µm resolution. We performed deterministic and probabilistic tractography analyses of the diffusion MRI data to map dAAN intra-network connections and dAAN-DMN internetwork connections. Using a newly developed network-based autopsy of the human brain that integrates ex vivo MRI and histopathology, we identified projection, association, and commissural pathways linking dAAN nodes with one another and with cortical DMN nodes, providing a structural architecture for the integration of arousal and awareness in human consciousness. We release the ex vivo diffusion MRI data, corresponding immunohistochemistry data, network-based autopsy methods, and a new brainstem dAAN atlas to support efforts to map the connectivity of human consciousness.

Toward Uniform Insurer Coverage for Functional MRI Following Severe Brain Injury.

Functional magnetic resonance imaging (fMRI) now promises to improve diagnostic and prognostic accuracy for patients with disorders of consciousness, and accordingly has been endorsed by professional society guidelines, including those of the American Academy of Neurology, American College of Rehabilitation Medicine, National Institute on Disability, Independent Living, and Rehabilitation Research, and the European Academy of Neurology. Despite multiple professional society endorsements of fMRI in evaluating patients with disorders of consciousness following severe brain injury, insurers have yet to issue clear guidance regarding coverage of fMRI for this indication. Lack of insurer coverage may be a rate-limiting barrier to accessing this technique, which could uncover essential diagnostic and prognostic information for patients and their families. The emerging clinical and ethical case for harmonized insurer recognition and reimbursement of fMRI for vulnerable persons following severe brain injury with disorders of consciousness is explained and critically evaluated.