Brian L. Edlow

The Human Connectome Project and beyond: initial applications of 300 mT/m gradients.

The engineering of a 3 T 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 HCPs 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 300 mT/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 are 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.

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

Abstract 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. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the 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 affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Minimizing acquisition time of arterial spin labeling at 3T.

An improved arterial spin labeling (ASL) perfusion technique that combines pseudo‐continuous labeling and a T2*‐insensitive sequence (GRASE) with background suppression was used to acquire perfusion maps in normal volunteers and stroke patients. It is shown that perfusion measurements obtained in less than 1 min of scan time are reproducible, with a coefficient of variation of 7%. The perfusion maps generated from these data can be used to characterize the stroke lesion. Magn Reson Med 59:1467–1471, 2008.

The effects of healthy aging on cerebral hemodynamic responses to posture change

Aging is associated with an increased incidence of orthostatic hypotension, impairment of the baroreceptor reflex and lower baseline cerebral blood flow. The effect of aging on cerebrovascular autoregulation, however, remains to be fully elucidated. We used a novel optical instrument to assess microvascular cerebral hemodynamics in the frontal lobe cortex of 60 healthy subjects ranging from ages 20-78. Diffuse correlation spectroscopy (DCS) and near-infrared spectroscopy (NIRS) were used to measure relative cerebral blood flow (rCBF), total hemoglobin concentration (THC), oxyhemoglobin concentration (HbO(2)) and deoxyhemoglobin concentration (Hb). Cerebral hemodynamics were monitored for 5 min at each of the following postures: head-of-bed 30 degrees , supine, standing and supine. Supine-to-standing posture change caused significant declines in rCBF, THC and HbO(2), and an increase in Hb, across the age continuum (p < 0.01). Healthy aging did not alter postural changes in frontal cortical rCBF (p = 0.23) and was associated with a smaller magnitude of decline in HbO(2) (p < 0.05) during supine-to-standing posture change. We conclude that healthy aging does not alter postural changes in frontal cortical perfusion.

Physiological Modulations in Arterial Spin Labeling Perfusion Magnetic Resonance Imaging

The purpose of this study is to evaluate cardiac and respiratory modulations in the signals of arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) using RETROICOR, an image domain based retrospective correction method. Systematic comparisons were conducted for tagging schemes, pulsed (PASL) versus frequency-modulated continuous (CASL) methods, and the use of background suppression (BGS). Results showed that cardiac pulsation accounted for more signal fluctuation in PASL than in CASL (two-tailed paired students t-test, p<10-3), whereas no significant difference was found in the effect of respiratory motion (p=0.55) on the two tagging schemes studied. For PASL, significantly more improvement was achieved by the inclusion of cardiac pulsation than respiratory motion in (p<0.01). On the contrary, the inclusion of respiratory motion offers more improvement for CASL (p<0.02). BGS effectively improved the temporal signal-to-noise ratio (tSNR) as previous studies reported, but no significant difference was measured in the spectral power of physiological modulations relative to the entire spectrum of PASL signals before and after the superimposition of BGS (p=0.63 for cardiac component, p=0.67 for respiratory component). Thus, we conclude that BGS reduces noise without spectral selectivity, and the improvements of tSNR from RETROICOR and BGS are additive. CASL with a labeling duration at a multiple of an R-R interval can be used to minimize signal fluctuation originating from cardiac pulsation.

A human brain network derived from coma-causing brainstem lesions

Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

Microinfarct disruption of white matter structure A longitudinal diffusion tensor analysis

Objective: 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). Methods: 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. Results: 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. Conclusions: 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.

Advanced Neuroimaging in Traumatic Brain Injury

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.

EEG functional connectivity is partially predicted by underlying white matter connectivity

Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales.

Posterior Circulation Stroke after C1–C2 Intraarticular Facet Steroid Injection: Evidence for Diffuse Microvascular Injury

CERVICAL pain is increasingly being treated with invasive procedures such as transforaminal and intraarticular facet steroid injections. Most patients experience at least transient symptomatic benefit after transforaminal injection for cervical radicular pain, but catastrophic complications, including stroke and spinal cord infarction, can occur. Although ischemic complications of facet injections have not been reported, their benefit has not been clearly demonstrated. The overall incidence of complications with cervical steroid injections is unknown. However, a recent survey by American Pain Society physicians identified 78 ischemic neurologic events, including 13 fatalities. The mechanism of stroke after cervical steroid injection remains unclear. During cervical transforaminal and intraarticular facet injections, the needle tip comes into close proximity with the vertebral artery. Thus, potential stroke mechanisms include vertebral artery dissection, vasospasm, and intravascular injection of steroid suspension causing microvascular embolization of particulate macromolecules. We describe a patient who became comatose immediately after an intraarticular cervical facet steroid injection (fig. 1) and discuss the implications of the clinical, radiologic, and histopathologic data. To our knowledge, this is the first reported case of posterior circulation stroke related to cervical intraarticular facet steroid injection. The pattern of tissue damage on serial magnetic resonance imaging and postmortem microscopy provides strong evidence for microvascular embolization of particulate macromolecules as the etiology of stroke.