Manu S. Goyal

Aerobic Glycolysis in the Human Brain Is Associated with Development and Neotenous Gene Expression

Aerobic glycolysis (AG; i.e., nonoxidative metabolism of glucose despite the presence of abundant oxygen) accounts for 10%-12% of glucose used by the adult human brain. AG varies regionally in the resting state. Brain AG may support synaptic growth and remodeling; however, data supporting this hypothesis are sparse. Here, we report on investigations on the role of AG in the human brain. Meta-analysis of prior brain glucose and oxygen metabolism studies demonstrates that AG increases during childhood, precisely when synaptic growth rates are highest. In resting adult humans, AG correlates with the persistence of gene expression typical of infancy (transcriptional neoteny). In brain regions with the highest AG, we find increased gene expression related to synapse formation and growth. In contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain AG supports developmental processes, particularly those required for synapse formation and growth.

Velocity computation in the primate visual system

Computational neuroscience combines theory and experiment to shed light on the principles and mechanisms of neural computation. This approach has been highly fruitful in the ongoing effort to understand velocity computation by the primate visual system. This Review describes the success of spatiotemporal-energy models in representing local-velocity detection. It shows why local-velocity measurements tend to differ from the velocity of the object as a whole. Certain cells in the middle temporal area are thought to solve this problem by combining local-velocity estimates to compute the overall pattern velocity. The Review discusses different models for how this might occur and experiments that test these models. Although no model is yet firmly established, evidence suggests that computing pattern velocity from local-velocity estimates involves simple operations in the spatiotemporal frequency domain.

Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development

The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2–3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this “microbial organ” and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain’s default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children. Furthermore, we postulate that understanding the interrelationships between microbiota and brain metabolism in childhood undernutrition could provide insights about responses to injury seen in adults. We discuss approaches that can be used to test these hypotheses, their ramifications for optimizing nutritional recommendations that promote healthy brain development and function, and the potential societal implications of this area of investigation.

Gene expression-based modeling of human cortical synaptic density

Postnatal cortical synaptic development is characterized by stages of exuberant growth, pruning, and stabilization during adulthood. How gene expression orchestrates these stages of synaptic development is poorly understood. Here we report that synaptic growth-related gene expression alone does not determine cortical synaptic density changes across the human lifespan, but instead, the dynamics of cortical synaptic density can be accurately simulated by a first-order kinetic model of synaptic growth and elimination that incorporates two separate gene expression patterns. Surprisingly, modeling of cortical synaptic density is optimized when genes related to oligodendrocytes are used to determine synaptic elimination rates. Expression of synaptic growth and oligodendrocyte genes varies regionally, resulting in different predictions of synaptic density among cortical regions that concur with previous regional data in humans. Our analysis suggests that modest rates of synaptic growth persist in adulthood, but that this is counterbalanced by increasing rates of synaptic elimination, resulting in stable synaptic number and ongoing synaptic turnover in the human adult cortex. Our approach provides a promising avenue for exploring how complex interactions among genes may contribute to neurobiological phenomena across the human lifespan.

Clinical features and outcome in North American adults with idiopathic basal arterial occlusive disease without moyamoya collaterals.

OBJECTIVETo define the clinical characteristics and outcome of patients with idiopathic stenosis or occlusion of the basal arteries, without moyamoya collateral vessel formation. METHODSWe identified patients who presented to our institution from 1996 to 2005 with occlusive disease of the distal internal carotid artery or the proximal middle or anterior cerebral arteries demonstrated by digital subtraction cerebral angiography. We excluded those with evidence of atherosclerotic disease, systemic vasculitis, moyamoya phenomenon, or any other condition that could otherwise explain their arterial occlusive disease. Medical records were reviewed for presenting symptoms and clinical characteristics. Outcome was determined from chart review and phone interviews. RESULTSTwelve patients were identified. All presented with transient ischemic attack or stroke. Eleven were women. Age at presentation ranged from 34 to 71 years. Nine had a history of hypertension; 5 had unilateral intracranial disease. Recurrent stroke on medical therapy occurred in none of the 5 during an average follow-up of 29 months. Seven had bilateral disease. Ischemic stroke occurred between 2 and 107 months after the initial event in 5 of 8 medically treated hemispheres. Moyamoya collateral vessels developed in 1 patient as shown on follow-up angiography. CONCLUSIONThe clinical features and outcome of these patients are similar to those reported in large case series of North American patients with moyamoya phenomenon. These data suggest a common etiology for the basal arterial occlusive process and a variable ability to form moyamoya collateral vessels.

Streamlined Hyperacute Magnetic Resonance Imaging Protocol Identifies Tissue-Type Plasminogen Activator–Eligible Stroke Patients When Clinical Impression Is Stroke Mimic

Background and Purpose— Stroke mimics (SM) challenge the initial assessment of patients presenting with possible acute ischemic stroke (AIS). When SM is considered likely, intravenous tissue-type plasminogen activator (tPA) may be withheld, risking an opportunity to treat AIS. Although computed tomography is routinely used for tPA decision making, magnetic resonance imaging (MRI) may diagnose AIS when SM is favored but not certain. We hypothesized that a hyperacute MRI (hMRI) protocol would identify tPA-eligible AIS patients among those initially favored to have SM. Methods— A streamlined hMRI protocol was designed based on barriers to rapid patient transport, MRI acquisition, and post-MRI tPA delivery. Neurologists were trained to order hMRI when SM was favored and tPA was being withheld. The use of hMRI for tPA decision making, door-to-needle times, and outcomes were compared before hMRI implementation (pre-hMRI: August 1, 2011 to July 31, 2013) and after (post-hMRI, August 1, 2013, to January 15, 2015). Results— Post hMRI, 57 patients with suspected SM underwent hMRI (median MRI-order-to-start time, 29 minutes), of whom, 11 (19%) were diagnosed with AIS and 7 (12%) received tPA. Pre-hMRI, no tPA-treated patients were screened with hMRI. Post hMRI, 7 of 106 (6.6%) tPA-treated patients underwent hMRI to aid in decision making because of suspected SM (0% versus 6.6%; P=0.001). To ensure standard care was maintained after implementing the hMRI protocol, pre- versus post-hMRI tPA-treated cohorts were compared and did not differ: door-to-needle time (39 versus 37 minutes; P=0.63), symptomatic hemorrhage rate (4.5% versus 1.9%; P=0.32), and favorable discharge location (85% versus 89%; P=0.37). Conclusions— A streamlined hMRI protocol permitted tPA administration to a small, but significant, subset of AIS patients initially considered to have SM.

Bicuspid aortic valves and thoracic aortic aneurysms in patients with intracranial aneurysms

Objective: The purpose of this study was to determine the prevalence of bicuspid aortic valves (BAVs) and thoracic ascending aortic aneurysms (TAAs) in a retrospective cohort of patients treated for intracranial aneurysms (IAs). Methods: Patients treated for IA at our institution between 2002 and 2011 were identified and their clinical records reviewed. Those without an echocardiogram of sufficient quality to assess the aortic valve were excluded. The prevalence of BAVs and TAAs in this remaining cohort was determined based on echocardiography reports, medical records, and cross-sectional chest imaging. Results: Of 1,047 patients, 317 had adequate echocardiography for assessment of BAV. Of these, 82 also had cross-sectional chest imaging. Of the 317 patients, 2 had BAV and 15 had TAA. The prevalence of BAVs (0.6%, 95% confidence interval 0.2%–2.2%) was similar to population prevalence estimates for this condition; however, the prevalence of TAAs (4.7%, 95% confidence interval 2.9%–7.6%) was larger than expected in a normal age- and sex-matched population. Conclusions: Our data demonstrate an association between IA and TAA, but not independently for BAV.

Advanced Imaging of Chiari 1 Malformations

Type I Chiari malformations are congenital deformities involving cerebellar tonsillar herniation downward through the foramen magnum. Structurally, greater than 5 mm of tonsillar descent in adults and more than 6 mm in children is consistent with type I Chiari malformations. However, the radiographic severity of the tonsillar descent does not always correlate well with the clinical symptomatology. Advanced imaging can help clinically correlate imaging to symptoms. Specifically, cerebrospinal fluid (CSF) flow abnormalities are seen in patients with type I Chiari malformation. Advanced MRI involving cardiac-gated and phase-contrast MRI affords a view of such CSF flow abnormalities.

Brain metabolism and severe pediatric traumatic brain injury

Age-dependent changes in brain metabolism may influence the response to and tolerance of secondary insults, potentially affecting outcomes. More complete characterization of brain metabolism across the clinical trajectory of severe pediatric TBI is needed to improve our ability to measure and better mitigate the impact of secondary insults. Better management of secondary insults will impact clinical care and the probability of success of future neuroprotective clinical trials. Improved bedside monitoring and imaging technologies will be required to achieve these goals. Effective and sustained integration of brain metabolism information into the pediatric critical care setting will be equally challenging and important.

REGIONAL BRAIN AEROBIC GLYCOLYSIS ACROSS THE COGNITIVELY NORMAL ADULT LIFE SPAN

thicknesses. Siemens Healthcare MRIs had very similar fitted curves for surface, thickness, and volume, while Philips Medical Systems MRIs had thickness curves with a wider discrepancy, albeit surfaces and volumes were similar. Conclusions: OEMs andMFS produce small, but non-negligible effects on cortical surfaces, thicknesses, and volumes. These effects need to be taken into account when designing multi-centric studies and/or making between-scanner comparisons.