Truman R. Brown

An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus

With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.

Differential Targeting of the CA1 Subfield of the Hippocampal Formation by Schizophrenia and Related Psychotic Disorders

CONTEXT Because schizophrenia and related disorders have a chronic time course and subtle histopathology, it is difficult to identify which brain regions are differentially targeted. OBJECTIVE To identify brain sites differentially targeted by schizophrenia, we applied a high-resolution variant of functional magnetic resonance imaging to clinically characterized patients and matched healthy controls and to a cohort of prodromal subjects who were prospectively followed up. Additionally, to explore the potential confound of medication use, the fMRI variant was applied to rodents receiving an antipsychotic agent. DESIGN Cross-sectional and prospective cohort designs. SETTING Hospital clinic and magnetic resonance imaging laboratory. PARTICIPANTS Eighteen patients with schizophrenia, 18 controls comparable in age and sex, and 18 prodromal patients followed up prospectively for 2 years. Ten C57-B mice received an antipsychotic agent or vehicle control. MAIN OUTCOME MEASURES Regional cerebral blood volume (CBV), as measured with magnetic resonance imaging, and symptom severity, as measured with clinical rating scales. RESULTS In a first between-group analysis that compared patients with schizophrenia with controls, results revealed abnormal CBV increases in the CA1 subfield and the orbitofrontal cortex and abnormal CBV decreases in the dorsolateral prefrontal cortex. In a second longitudinal analysis, baseline CBV abnormalities in the CA1 subfield differentially predicted clinical progression to psychosis from a prodromal state. In a third correlational analysis, CBV levels in the CA1 subfield differentially correlated with clinical symptoms of psychosis. Finally, additional analyses of the human data set and imaging studies in mice suggested that antipsychotic agents were not confounding the primary findings. CONCLUSIONS Taken as a whole, the results suggest that the CA1 subfield of the hippocampal subregion is differentially targeted by schizophrenia and related psychotic disorders. Interpreted in the context of previous studies, these findings inform underlying mechanisms of illness progression.

Nonnegative matrix factorization for rapid recovery of constituent spectra in magnetic resonance chemical shift imaging of the brain

We present an algorithm for blindly recovering constituent source spectra from magnetic resonance (MR) chemical shift imaging (CSI) of the human brain. The algorithm, which we call constrained nonnegative matrix factorization (cNMF), does not enforce independence or sparsity, instead only requiring the source and mixing matrices to be nonnegative. It is based on the nonnegative matrix factorization (NMF) algorithm, extending it to include a constraint on the positivity of the amplitudes of the recovered spectra. This constraint enables recovery of physically meaningful spectra even in the presence of noise that causes a significant number of the observation amplitudes to be negative. We demonstrate and characterize the algorithms performance using /sup 31/P volumetric brain data, comparing the results with two different blind source separation methods: Bayesian spectral decomposition (BSD) and nonnegative sparse coding (NNSC). We then incorporate the cNMF algorithm into a hierarchical decomposition framework, showing that it can be used to recover tissue-specific spectra given a processing hierarchy that proceeds coarse-to-fine. We demonstrate the hierarchical procedure on /sup 1/H brain data and conclude that the computational efficiency of the algorithm makes it well-suited for use in diagnostic work-up.

Total Homocysteine Is Associated With White Matter Hyperintensity Volume The Northern Manhattan Study

Background— Total homocysteine (tHcy) has been implicated as a risk factor for stroke and dementia, but the mechanism is unclear. White matter hyperintensities may be a risk factor for both, but studies of the relationship between tHcy and quantitative measures of white matter hyperintensity volume (WMHV) are lacking, especially in minority populations. Methods— A community-based sample of 259 subjects with baseline tHcy levels underwent pixel-based quantitative measurement of WMHV. We examined the relationship between tHcy and WMHV adjusting for age, sociodemographics, vascular risk factors, and B12 deficiency. Results— Higher levels of tHcy were associated with WMHV adjusting for sociodemographics and vascular risk factors. Conclusions— These cross-sectional data provide evidence that tHcy is a risk factor for white matter damage.

White Matter Hyperintensities and Cognition: Testing the Reserve Hypothesis

OBJECTIVE White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition.

Brain Morphology in Older African Americans, Caribbean Hispanics, and Whites From Northern Manhattan

BACKGROUND Aging is accompanied by a decrease in brain volume and by an increase in cerebrovascular disease. OBJECTIVE To examine the effects of age, sex, race/ethnicity, and vascular disease history on measures of brain morphology, including relative brain volume, ventricular volume, hippocampus and entorhinal cortex volumes, and white matter hyperintensity (WMH) burden, in a large community-based cohort of racially/ethnically diverse older adults without dementia. DESIGN The associations of age, sex, race/ethnicity, and self-reported vascular disease history with brain morphology were examined in a cross-sectional study using multiple linear regression analyses. Sex x race/ethnicity interactions were also considered. SETTING The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from 3 racial/ethnic groups (white, Hispanic, and African American) from northern Manhattan. PARTICIPANTS Beginning in 2003, high-resolution quantitative magnetic resonance (MR) images were acquired in 769 participants without dementia. MAIN OUTCOME MEASURES Relative brain volume (total brain volume/intracranial volume), ventricular volume, and hippocampus and entorhinal cortex volumes were derived manually on high-resolution MR images. White matter hyperintensities were quantified semiautomatically on fluid-attenuated inversion recovery-T2-weighted MR images. RESULTS Older age was associated with decreased relative brain volume and with increased ventricular and WMH volumes. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than white participants, but the associations of these variables with age were similar across racial/ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and with higher WMH burden, particularly among African Americans. CONCLUSIONS Older age and vascular disease, particularly among African Americans, are associated with increased brain atrophy and WMH burden. African American and Hispanic subjects have larger relative brain volumes and more WMH than white subjects. Racial/ethnic group differences in WMH severity seem to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.

Long-term Blood Pressure Fluctuation and Cerebrovascular Disease in an Elderly Cohort

BACKGROUND The importance of subclinical cerebrovascular disease in the elderly is increasingly recognized, but its determinants have not been fully explicated. Elevated blood pressure (BP) and fluctuation in BP may lead to cerebrovascular disease through ischemic changes and compromised cerebral autoregulation. OBJECTIVE To determine the association of BP and long-term fluctuation in BP with cerebrovascular disease. DESIGN A community-based epidemiological study of older adults from northern Manhattan. SETTING The Washington Heights-Inwood Columbia Aging Project. PARTICIPANTS A total of 686 nondemented older adults who had BP measurements during 3 study visits at 24-month intervals and underwent structural magnetic resonance imaging (corresponding temporally with the third assessment). We derived the mean (SD) of the mean BP for each participant during the 3 intervals and divided the participants into 4 groups defined as below or above the group median (<or=96.48 or >96.48 mm Hg) and further subdivided them as below or above the median SD (<or=7.21 or >7.21 mm Hg). This scheme yielded 4 groups representing the full range of BPs and fluctuations in BP. MAIN OUTCOME MEASURES Differences in white matter hyperintensity (WMH) volume and presence of brain infarctions across groups. RESULTS White matter hyperintensity volume increased across the 4 groups in a linear manner, with the lowest WMH volume in the lowest mean/lowest SD group and the highest WMH volume in the highest mean/highest SD group (F(3,610) = 3.52, P = .02). Frequency of infarction also increased monotonically across groups (from 22% to 41%, P for trend = .004). CONCLUSIONS Compared with individuals with low BP and low fluctuations in BP, the risk of cerebrovascular disease increased with higher BP and BP fluctuations. Given that cerebrovascular disease is associated with disability, these findings suggest that interventions should focus on long-term fluctuating BP and elevated BP.

White Matter Hyperintensities and Subclinical Infarction Associations With Psychomotor Speed and Cognitive Flexibility

Background and Purpose— We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability. Methods— The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, Black, and White participants. A subsample (n=656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear regression was used to examine WMHV and SI in relation to performance on tests of sequencing as measured by Color Trails 1, cognitive flexibility as measured by Color Trails 2, and sensorimotor ability as measured by Grooved Pegboard, using generalized estimating equations (GEE) to account for the correlation among the cognitive tests and other covariates. Results— Considering performance on the tests of sequencing, cognitive flexibility, and sensorimotor ability simultaneously using GEE, WMHV and subclinical infarction were each associated with worse cognitive performance globally. There was a threshold effect for WMHV with those in the upper quartile performing significantly worse on the tests of cognitive flexibility and sensorimotor ability. Those with frontal SI performed worse on the test of cognitive flexibility and those with deep SI, worse on the test of sequencing. Conclusions— Both SI and WMHV were associated with globally worse cognitive performance. Participants with WMH affecting more than 0.75% of cranial volume had significantly slower performance on a task of cognitive flexibility and sensorimotor ability than those in the lowest quartile. The effects of SI on cognitive performance varied by location.

Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound

The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.

Prospective real-time correction for arbitrary head motion using active markers.

Patient motion during an MRI exam can result in major degradation of image quality, and is of increasing concern due to the aging population and its associated diseases. This work presents a general strategy for real‐time, intraimage compensation of rigid‐body motion that is compatible with multiple imaging sequences. Image quality improvements are established for structural brain MRI acquired during volunteer motion. A headband integrated with three active markers is secured to the forehead. Prospective correction is achieved by interleaving a rapid track‐and‐update module into the imaging sequence. For every repetition of this module, a short tracking pulse‐sequence remeasures the marker positions; during head motion, the rigid‐body transformation that realigns the markers to their initial positions is fed back to adaptively update the image‐plane—maintaining it at a fixed orientation relative to the head—before the next imaging segment of k‐space is acquired. In cases of extreme motion, corrupted lines of k‐space are rejected and reacquired with the updated geometry. High‐precision tracking measurements (0.01 mm) and corrections are accomplished in a temporal resolution (37 ms) suitable for real‐time application. The correction package requires minimal additional hardware and is fully integrated into the standard user interface, promoting transferability to clinical practice. Magn Reson Med, 2009.