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1.  Toward an In Vivo Neuroimaging Template of Human Brainstem Nuclei of the Ascending Arousal, Autonomic, and Motor Systems 
Brain Connectivity  2015;5(10):597-607.
Brainstem nuclei (Bn) in humans play a crucial role in vital functions, such as arousal, autonomic homeostasis, sensory and motor relay, nociception, sleep, and cranial nerve function, and they have been implicated in a vast array of brain pathologies. However, an in vivo delineation of most human Bn has been elusive because of limited sensitivity and contrast for detecting these small regions using standard neuroimaging methods. To precisely identify several human Bn in vivo, we employed a 7 Tesla scanner equipped with multi-channel receive-coil array, which provided high magnetic resonance imaging sensitivity, and a multi-contrast (diffusion fractional anisotropy and T2-weighted) echo-planar-imaging approach, which provided complementary contrasts for Bn anatomy with matched geometric distortions and resolution. Through a combined examination of 1.3 mm3 multi-contrast anatomical images acquired in healthy human adults, we semi-automatically generated in vivo probabilistic Bn labels of the ascending arousal (median and dorsal raphe), autonomic (raphe magnus, periaqueductal gray), and motor (inferior olivary nuclei, two subregions of the substantia nigra compatible with pars compacta and pars reticulata, two subregions of the red nucleus, and, in the diencephalon, two subregions of the subthalamic nucleus) systems. These labels constitute a first step toward the development of an in vivo neuroimaging template of Bn in standard space to facilitate future clinical and research investigations of human brainstem function and pathology. Proof-of-concept clinical use of this template is demonstrated in a minimally conscious patient with traumatic brainstem hemorrhages precisely localized to the raphe Bn involved in arousal.
PMCID: PMC4684653  PMID: 26066023
7 Tesla; ascending arousal system; autonomic system; high spatial resolution diffusion-weighted imaging; human brainstem nuclei; in vivo preliminary neuroimaging template; motor system; multi-contrast EPI
2.  Unexpected Recovery of Function after Severe Traumatic Brain Injury: The Limits of Early Neuroimaging-Based Outcome Prediction 
Neurocritical care  2013;19(3):364-375.
Prognostication in the early stage of traumatic coma is a common challenge in the neuro-intensive care unit. We report the unexpected recovery of functional milestones (i.e., consciousness, communication, and community reintegration) in a 19-year-old man who sustained a severe traumatic brain injury. The early magnetic resonance imaging (MRI) findings, at the time, suggested a poor prognosis.
During the first year of the patient’s recovery, MRI with diffusion tensor imaging (DTI) and T2*-weighted imaging was performed on day 8 (coma), day 44 (minimally conscious state), day 198 (post-traumatic confusional state), and day 366 (community reintegration). Mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in the corpus callosum, cerebral hemispheric white matter and thalamus were compared with clinical assessments using the Disability Rating Scale (DRS).
Extensive diffusion restriction in the corpus callosum and bihemispheric white matter was observed on day 8, with ADC values in a range typically associated with neurotoxic injury (230 to 400 × 10−6 mm2/sec). T2*-weighted MRI revealed widespread hemorrhagic axonal injury in the cerebral hemispheres, corpus callosum, and brainstem. Despite the presence of severe axonal injury on early MRI, the patient regained the ability to communicate and perform activities of daily living independently at one year post-injury (DRS = 8).
MRI data should be interpreted with caution when prognosticating for patients in traumatic coma. Recovery of consciousness and community reintegration are possible even when extensive traumatic axonal injury is demonstrated by early MRI.
PMCID: PMC3902071  PMID: 23860665
Traumatic brain injury; Coma; Magnetic resonance imaging; Traumatic axonal injury; Diffusion-weighted imaging; Apparent diffusion coefficient; Diffusion tensor imaging
3.  Diffusion tensor imaging in acute-to-subacute traumatic brain injury: a longitudinal analysis 
BMC Neurology  2016;16:2.
Diffusion tensor imaging (DTI) may have prognostic utility in patients with traumatic brain injury (TBI), but the optimal timing of DTI data acquisition is unknown because of dynamic changes in white matter water diffusion during the acute and subacute stages of TBI. We aimed to characterize the direction and magnitude of early longitudinal changes in white matter fractional anisotropy (FA) and to determine whether acute or subacute FA values correlate more reliably with functional outcomes after TBI.
From a prospective TBI outcomes database, 11 patients who underwent acute (≤7 days) and subacute (8 days to rehabilitation discharge) DTI were retrospectively analyzed. Longitudinal changes in FA were measured in 11 white matter regions susceptible to traumatic axonal injury. Correlations were assessed between acute FA, subacute FA and the disability rating scale (DRS) score, which was ascertained at discharge from inpatient rehabilitation.
FA declined from the acute-to-subacute period in the genu of the corpus callosum (0.70 ± 0.02 vs. 0.55 ± 0.11, p < 0.05) and inferior longitudinal fasciculus (0.54+/−0.07 vs. 0.49+/−0.07, p < 0.01). Acute correlations between FA and DRS score were variable: higher FA in the body (R = −0.78, p = 0.02) and splenium (R = −0.83, p = 0.003) of the corpus callosum was associated with better outcomes (i.e. lower DRS scores), whereas higher FA in the genu of the corpus callosum (R = 0.83, p = 0.02) corresponded with worse outcomes (i.e. higher DRS scores). In contrast, in the subacute period higher FA in the splenium correlated with better outcomes (R = −0.63, p < 0.05) and no inverse correlations were observed.
White matter FA declined during the acute-to-subacute stages of TBI. Variability in acute FA correlations with outcome suggests that the optimal timing of DTI for TBI prognostication may be in the subacute period.
PMCID: PMC4707723  PMID: 26754948
Traumatic axonal injury (TAI); Fractional anisotropy (FA); Corpus callosum; Disability rating scale (DRS)
4.  The Human Connectome Project and Beyond: Initial Applications of 300 mT/m Gradients 
NeuroImage  2013;80:10.1016/j.neuroimage.2013.05.074.
The engineering of a 3T human MRI scanner equipped with 300 mT/m gradients – the strongest gradients ever built for an in vivo human MRI scanner – was a major component of the NIH Blueprint Human Connectome Project (HCP). This effort was motivated by the HCP’s goal of mapping, as completely as possible, the macroscopic structural connections of the in vivo healthy, adult human brain using diffusion tractography. Yet, the 300 mT/m gradient system is well suited to many additional types of diffusion measurements. Here, we present three initial applications of the 300mT/m gradients that fall outside the immediate scope of the HCP. These include: 1) diffusion tractography to study the anatomy of consciousness and the mechanisms of brain recovery following traumatic coma; 2) q-space measurements of axon diameter distributions in the in vivo human brain and 3) postmortem diffusion tractography as an adjunct to standard histopathological analysis. We show that the improved sensitivity and diffusion-resolution provided by the gradients is rapidly enabling human applications of techniques that were previously possible only for in vitro and animal models on small-bore scanners, thereby creating novel opportunities to map the microstructure of the human brain in health and disease.
PMCID: PMC3812060  PMID: 23711537
human connectome; diffusion MRI; tractography; traumatic coma; consciousness; axon diameter; corpus callosum; in vivo; postmortem
5.  Disconnection of the Ascending Arousal System in Traumatic Coma 
Traumatic coma is associated with disruption of axonal pathways throughout the brain but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging (HARDI) to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness – arousal and awareness – in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. HARDI tractography guided tissue sampling in the neuropathological analysis. HARDI tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical “awareness pathways.” Neuropathologic examination, which utilized β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of HARDI tract disruption. Axonal injury was also present within the grey matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain.
PMCID: PMC3761353  PMID: 23656993
Ascending reticular activating system (ARAS); Coma; Consciousness; High angular resolution diffusion imaging (HARDI); Tractography; Traumatic axonal injury (TAI); Traumatic brain injury (TBI)
6.  Advanced Neuroimaging in Traumatic Brain Injury 
Seminars in neurology  2013;32(4):374-400.
Advances in structural and functional neuroimaging have occurred at a rapid pace over the past two decades. Novel techniques for measuring cerebral blood flow, metabolism, white matter connectivity, and neural network activation have great potential to improve the accuracy of diagnosis and prognosis for patients with traumatic brain injury (TBI), while also providing biomarkers to guide the development of new therapies. Several of these advanced imaging modalities are currently being implemented into clinical practice, whereas others require further development and validation. Ultimately, for advanced neuroimaging techniques to reach their full potential and improve clinical care for the many civilians and military personnel affected by TBI, it is critical for clinicians to understand the applications and methodological limitations of each technique. In this review, we examine recent advances in structural and functional neuroimaging and the potential applications of these techniques to the clinical care of patients with TBI. We also discuss pitfalls and confounders that should be considered when interpreting data from each technique. Finally, given the vast amounts of advanced imaging data that will soon be available to clinicians, we discuss strategies for optimizing data integration, visualization and interpretation.
PMCID: PMC3779469  PMID: 23361483
traumatic brain injury (TBI); susceptibility-weighted imaging (SWI); diffusion tensor imaging (DTI); high angular resolution diffusion imaging (HARDI); functional MRI (fMRI); traumatic axonal injury (TAI)
7.  Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders 
The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. HARDI tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, hypothalamus, and basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may impact the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
PMCID: PMC3387430  PMID: 22592840
Arousal; Ascending reticular activating system (ARAS); Brainstem; Consciousness; High angular resolution diffusion imaging (HARDI); Neuroanatomy; Tractography
8.  Microinfarct disruption of white matter structure 
Neurology  2014;83(2):182-188.
To evaluate the local effect of small asymptomatic infarctions detected by diffusion-weighted imaging (DWI) on white matter microstructure using longitudinal structural and diffusion tensor imaging (DTI).
Nine acute to subacute DWI lesions were identified in 6 subjects with probable cerebral amyloid angiopathy who had undergone high-resolution MRI both before and after DWI lesion detection. Regions of interest (ROIs) corresponding to the site of the DWI lesion (lesion ROI) and corresponding site in the nonlesioned contralateral hemisphere (control ROI) were coregistered to the pre- and postlesional scans. DTI tractography was additionally performed to reconstruct the white matter tracts containing the ROIs. DTI parameters (fractional anisotropy [FA], mean diffusivity [MD]) were quantified within each ROI, the 6-mm lesion-containing tract segments, and the entire lesion-containing tract bundle. Lesion/control FA and MD ratios were compared across time points.
The postlesional scans (performed a mean 7.1 ± 4.7 months after DWI lesion detection) demonstrated a decrease in median FA lesion/control ROI ratio (1.08 to 0.93, p = 0.038) and increase in median MD lesion/control ROI ratio (0.97 to 1.17, p = 0.015) relative to the prelesional scans. There were no visible changes on postlesional high-resolution T1-weighted and fluid-attenuated inversion recovery images in 4 of 9 lesion ROIs and small (2–5 mm) T1 hypointensities in the remaining 5. No postlesional changes in FA or MD ratios were detected in the 6-mm lesion-containing tract segments or full tract bundles.
Asymptomatic DWI lesions produce chronic local microstructural injury. The cumulative effects of these widely distributed lesions may directly contribute to small-vessel–related vascular cognitive impairment.
PMCID: PMC4117171  PMID: 24920857
9.  Continuous Optical Monitoring of Cerebral Hemodynamics during Head-of-Bed Manipulation in Brain-Injured Adults 
Neurocritical care  2014;20(3):443-453.
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
PMCID: PMC3883971  PMID: 23653267
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
10.  Functional MRI and Outcome in Traumatic Coma 
Current neurology and neuroscience reports  2013;13(9):10.1007/s11910-013-0375-y.
Advances in task-based functional MRI (fMRI), resting-state fMRI (rs-fMRI), and arterial-spin labeled (ASL) perfusion MRI have occurred at a rapid pace in recent years. These techniques for measuring brain function have great potential to improve the accuracy of prognostication for civilian and military patients with traumatic coma. In addition, fMRI, rs-fMRI, and ASL have provided novel insights into the pathophysiology of traumatic disorders of consciousness, as well as mechanisms of recovery from coma. However, functional neuroimaging techniques have yet to achieve widespread clinical use as prognostic tests for patients with traumatic coma. Rather, a broad spectrum of methodological hurdles currently limits the feasibility of clinical implementation. In this review, we discuss the basic principles of fMRI, rs-fMRI and ASL and their potential applications as prognostic tools for patients with traumatic coma. We also discuss future strategies for overcoming the current barriers to clinical implementation.
PMCID: PMC3811121  PMID: 23881623
traumatic brain injury (TBI); traumatic axonal injury (TAI); coma; functional MRI (fMRI); resting state functional MRI (rs-fMRI); arterial-spin labeled (ASL) perfusion MRI; default mode network (DMN); traumatic coma
11.  The Pattern and Pace of Hyperacute Hemorrhage Expansion 
Neurocritical care  2012;17(2):250-254.
Intracerebral hemorrhage (ICH) expansion is common during the first 24 hours after onset, but the pattern and pace of hyperacute hemorrhage growth have not been described because serial imaging is typically performed over the course of hours and days, not minutes. The purpose of this study is to elucidate the spatial and temporal characteristics of hyperacute hemorrhage expansion within minutes of ICH onset.
An 86-year-old man with probable cerebral amyloid angiopathy developed an ICH while in the MRI scanner. Hyperacute hemorrhage growth was captured at three time points over a 14-minute interval of MRI data acquisition and at a fourth time point with CT 22 hours later. MRI and CT datasets were spatially coregistered, and three-dimensional models of ICH expansion were generated.
Longitudinal analysis revealed that the spatial pattern of ICH growth was asymmetric at each time point. Maximal expansion occurred along the anterior-posterior plane during the first four minutes but along the superior-inferior plane during the next 10 minutes. The temporal pace of ICH expansion was also non-uniform, as growth along the anterior-posterior plane outpaced medial-lateral growth during the first 4 minutes (2.8 cm vs. 2.5 cm), but medial-lateral growth outpaced anterior-posterior growth over the next 10 minutes (1.0 cm vs. 0.2 cm).
We provide evidence for asymmetric, non-uniform expansion of a hyperacute hemorrhage. These serial imaging observations suggest that hemorrhage expansion may be caused by local cascades of secondary vessel rupture as opposed to ongoing bleeding from a single ruptured vessel.
PMCID: PMC3552298  PMID: 22826138
intracerebral hemorrhage; MRI; cerebral amyloid angiopathy; cerebral microbleed
12.  Noninvasive Measurement of Cerebral Blood Flow and Blood Oxygenation Using Near-Infrared and Diffuse Correlation Spectroscopies in Critically Brain-Injured Adults 
Neurocritical care  2010;12(2):173-180.
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
13.  Transcranial Optical Monitoring of Cerebrovascular Hemodynamics in Acute Stroke Patients 
Optics express  2009;17(5):3884-3902.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658  PMID: 19259230
14.  Teaching About the Brain and Reaching the Community: Undergraduates in the Pipeline Neuroscience Program at the University of Pennsylvania 
This article provides an overview of the University of Pennsylvania School of Medicine’s Pipeline Neuroscience Program, a multi-tiered mentorship and education program for Philadelphia high school students in which University of Pennsylvania undergraduates are integrally involved. The Pipeline Neuroscience Program provides mentorship and education for students at all levels. High school students are taught by undergraduates, who learn from medical students who, in turn, are guided by neurology residents and fellows.
Throughout a semester-long course, undergraduates receive instruction in neuroanatomy, neuroscience, and clinical neurology as part of the Pipeline’s case-based curriculum. During weekly classes, undergraduates make the transition from students to community educators by integrating their new knowledge into lesson plans that they teach to small groups of medically and academically underrepresented Philadelphia high school students. The Pipeline program thus achieves the dual goals of educating undergraduates about neuroscience and providing them with an opportunity to perform community service.
PMCID: PMC3592656  PMID: 23493190
community educators; mentoring; community service; service learning; case-based curriculum; neuroscience; neuroanatomy; clinical neurology

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