Nathan S. White

Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity

Neuroimaging studies of painful stimuli in humans have identified a network of brain regions that is more extensive than identified previously in electrophysiological and anatomical studies of nociceptive pathways. This extensive network has been described as a pain matrix of brain regions that mediate the many interrelated aspects of conscious processing of nociceptive input such as perception, evaluation, affective response, and emotional memory. We used functional magnetic resonance imaging in healthy human subjects to distinguish brain regions required for pain sensory encoding from those required for cognitive evaluation of pain intensity. The results suggest that conscious cognitive evaluation of pain intensity in the absence of any sensory stimulation activates a network that includes bilateral anterior insular cortex/frontal operculum, dorsal lateral prefrontal cortex, bilateral medial prefrontal cortex/anterior cingulate cortex, right superior parietal cortex, inferior parietal lobule, orbital prefrontal cortex, and left occipital cortex. Increased activity common to both encoding and evaluation was observed in bilateral anterior insula/frontal operculum and medial prefrontal cortex/anterior cingulate cortex. We hypothesize that these two regions play a crucial role in bridging the encoding of pain sensation and the cognitive processing of sensory input. Hum Brain Mapp, 2005.

Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness

Whereas converging lines of evidence suggest that anesthetic-induced unconsciousness may result from disruption of functional interactions within neural networks involving the thalamus and cerebral cortex, the effects anesthetics have on human thalamocortical connectivity remain unexamined with current neuroimaging techniques. To address this issue we retrospectively analyzed positron emission tomography data from 11 volunteers scanned for regional cerebral glucose utilization (rCMRglu) when awake and again during isoflurane- (n = 6) or halothane- (n = 5) induced unconsciousness using statistical parametric mapping (SPM99) and structural equation modeling. A main effect analysis, contrasting awake and unconscious metabolic activity, localized a discrete region of the left va/vl thalamus whose relative rCMRglu activity was significantly suppressed (P < 0.05, corrected) during the unconscious state. To identify brain regions whose functional connectivity with this region of the thalamus was impaired during the unconscious state, a psychophysiological interaction analysis was performed. This analysis revealed effects predominantly in topographically related areas of the primary motor and supplementary motor association cortices. Structural equation modeling of a neuroanatomical network encompassing these empirically identified regions revealed significant state-related changes in effective connectivity (chi(2)diff (6)-15.88; P < 0.05) which primarily involved impairment of thalamocortical and corticocortical projections during the unconscious state. These findings support the hypothesis that a mechanistic component underlying general-anesthetic-induced unconsciousness involves disruption of functional interactions within thalamocortical neural networks.

PROMO: Real-time prospective motion correction in MRI using image-based tracking.

Artifacts caused by patient motion during scanning remain a serious problem in most MRI applications. The prospective motion correction technique attempts to address this problem at its source by keeping the measurement coordinate system fixed with respect to the patient throughout the entire scan process. In this study, a new image‐based approach for prospective motion correction is described, which utilizes three orthogonal two‐dimensional spiral navigator acquisitions, along with a flexible image‐based tracking method based on the extended Kalman filter algorithm for online motion measurement. The spiral navigator/extended Kalman filter framework offers the advantages of image‐domain tracking within patient‐specific regions‐of‐interest and reduced sensitivity to off‐resonance‐induced corruption of rigid‐body motion estimates. The performance of the method was tested using offline computer simulations and online in vivo head motion experiments. In vivo validation results covering a broad range of staged head motions indicate a steady‐state error of less than 10% of the motion magnitude, even for large compound motions that included rotations over 15 deg. A preliminary in vivo application in three‐dimensional inversion recovery spoiled gradient echo (IR‐SPGR) and three‐dimensional fast spin echo (FSE) sequences demonstrates the effectiveness of the spiral navigator/extended Kalman filter framework for correcting three‐dimensional rigid‐body head motion artifacts prospectively in high‐resolution three‐dimensional MRI scans. Magn Reson Med, 2010.

Quantitative Histological Validation of Diffusion MRI Fiber Orientation Distributions in the Rat Brain

Diffusion MRI (dMRI) is widely used to measure microstructural features of brain white matter, but commonly used dMRI measures have limited capacity to resolve the orientation structure of complex fiber architectures. While several promising new approaches have been proposed, direct quantitative validation of these methods against relevant histological architectures remains missing. In this study, we quantitatively compare neuronal fiber orientation distributions (FODs) derived from ex vivo dMRI data against histological measurements of rat brain myeloarchitecture using manual recordings of individual myelin stained fiber orientations. We show that accurate FOD estimates can be obtained from dMRI data, even in regions with complex architectures of crossing fibers with an intrinsic orientation error of approximately 5–6 degrees in these regions. The reported findings have implications for both clinical and research studies based on dMRI FOD measures, and provide an important biological benchmark for improved FOD reconstruction and fiber tracking methods.

A voxel-based morphometric study of nondemented adults with Down Syndrome.

Previous structural brain imaging studies of Down Syndrome (DS) have offered important insights into the underlying morphometric aberrations associated with the condition. These previous studies have relied almost exclusively on classic region-of-interest (ROI)-based morphometry, a method in which a finite number of anatomical structures must be defined and delineated a priori. Here we use the fully automated voxel-based morphometry (VBM) approach on 19 nondemented individuals with DS and 11 age-matched controls in order to provide a full-brain assessment of DS morphology. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) reductions in gray matter (GM) tissue were observed in the cerebellum, cingulate gyrus, left medial frontal lobe, right middle/superior temporal gyrus, and the left CA2/CA3 region of the hippocampus. Significant decreases in white matter (WM) tissue were noted throughout the inferior brainstem. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) increases in GM tissue were observed in a superior/caudal portion of the brainstem and left parahippocampal gyrus. Significant increases in WM tissue were noted bilaterally in the parahippocampal gyrus. We also noted significant increases in cerebral spinal fluid in regions suggesting enlarged lateral ventricles in the DS group. While these results are generally consistent with prior ROI-based imaging studies of nondemented DS individuals, the present findings provide additional understanding of the three-dimensional topography of DS morphology throughout the brain. The consistency of these findings with prior imaging reports demonstrates the utility of the VBM technique for investigating the neuroanatomy of DS.

Individual differences in general intelligence correlate with brain function during nonreasoning tasks

Brain imaging can help identify the functional neuroanatomy of general intelligence (i.e., ‘‘g’’) and indicate how brain areas salient to g relate to information processing. An important question is whether individual differences in g among subjects are related to brain function even when nonreasoning tasks are studied. If so, this would imply that individuals with high g scores may process information differently even when no reasoning or problem solving is required. To further investigate this, we administered the Raven’s Advanced Progressive Matrices (RAPM) test, a strong correlate of g ,t o 22 normal subjects and then measured cerebral glucose metabolic activity with PET while the subjects viewed videos on two occasions, tasks with no inherent reasoning or problem solving. Individual RAPM scores were correlated with regional brain activity using statistical parametric mapping (SPM99) conjunction analysis to combine both video conditions. Results showed greater activation in specific posterior brain areas (left BA37/19) in high RAPM scorers (P=.02, corrected for multiple comparisons). Subsequent analyses revealed a high/low RAPM group difference in functional connectivity between left BA37/19 activity and the left anterior cingulate/medial frontal gyrus. These data provide evidence that individual differences in intelligence correlate to brain function even when the brain is engaged in nonreasoning tasks and suggest that high and low g subjects may preferentially activate different neural circuits, especially nonfrontal areas involved in information processing. D 2003 Elsevier Science Inc. All rights reserved.

Prospective motion correction of high-resolution magnetic resonance imaging data in children

Motion artifacts pose significant problems for the acquisition and analysis of high-resolution magnetic resonance imaging data. These artifacts can be particularly severe when studying pediatric populations, where greater patient movement reduces the ability to clearly view and reliably measure anatomy. In this study, we tested the effectiveness of a new prospective motion correction technique, called PROMO, as applied to making neuroanatomical measures in typically developing school-age children. This method attempts to address the problem of motion at its source by keeping the measurement coordinate system fixed with respect to the subject throughout image acquisition. The technique also performs automatic rescanning of images that were acquired during intervals of particularly severe motion. Unlike many previous techniques, this approach adjusts for both in-plane and through-plane movement, greatly reducing image artifacts without the need for additional equipment. Results show that the use of PROMO notably enhances subjective image quality, reduces errors in Freesurfer cortical surface reconstructions, and significantly improves the subcortical volumetric segmentation of brain structures. Further applications of PROMO for clinical and cognitive neuroscience are discussed.

Probing tissue microstructure with restriction spectrum imaging: Histological and theoretical validation.

Water diffusion magnetic resonance imaging (dMRI) is a powerful tool for studying biological tissue microarchitectures in vivo. Recently, there has been increased effort to develop quantitative dMRI methods to probe both length scale and orientation information in diffusion media. Diffusion spectrum imaging (DSI) is one such approach that aims to resolve such information based on the three‐dimensional diffusion propagator at each voxel. However, in practice, only the orientation component of the propagator function is preserved when deriving the orientation distribution function. Here, we demonstrate how a straightforward extension of the linear spherical deconvolution (SD) model can be used to probe tissue orientation structures over a range (or “spectrum”) of length scales with minimal assumptions on the underlying microarchitecture. Using high b‐value Cartesian q‐space data on a rat brain tissue sample, we demonstrate how this “restriction spectrum imaging” (RSI) model allows for separating the volume fraction and orientation distribution of hindered and restricted diffusion, which we argue stems primarily from diffusion in the extraneurite and intraneurite water compartment, respectively. Moreover, we demonstrate how empirical RSI estimates of the neurite orientation distribution and volume fraction capture important additional structure not afforded by traditional DSI or fixed‐scale SD‐like reconstructions, particularly in gray matter. We conclude that incorporating length scale information in geometric models of diffusion offers promise for advancing state‐of‐the‐art dMRI methods beyond white matter into gray matter structures while allowing more detailed quantitative characterization of water compartmentalization and histoarchitecture of healthy and diseased tissue. Hum Brain Mapp, 2013.

Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia.

Background: Adults with Down syndrome (DS) are at increased risk for dementia and provide an opportunity to identify patterns of brain activity that may precede dementia. Studies of early Alzheimer’s disease (AD) and risk of AD show decreased function in posterior cingulate and temporal cortex as initial indicators of the disease process, but whether the origin and sequence of predementia brain changes are the same in DS is unknown. Methods: The regional cerebral glucose metabolic rates (GMR) among middle-aged nondemented people with DS (n = 17), people with moderate AD (n = 10), and age-matched control subjects (n = 24) were compared using PET during a cognitive task. Results: Statistical parametric mapping conjunction analyses showed that 1) both DS and AD groups had lower GMR than their respective controls primarily in posterior cingulate and 2) compared with respective controls, the subjects with DS had higher GMR in the same areas of inferior temporal/entorhinal cortex where the AD subjects had lower GMR. The same results were replicated after 1 year of follow-up. Conclusions: As the DS subjects were not clinically demented, inferior temporal/entorhinal cortex hypermetabolism may reflect a compensatory response early in disease progression. Compensatory responses may subsequently fail, leading to neurodegenerative processes that the authors anticipate will be detectable in vivo as future GMR decreases in inferior temporal/entorhinal cortex are accompanied by clinical signs of dementia.

Prospective motion correction improves diagnostic utility of pediatric MRI scans

A new technique for prospectively correcting head motion (called PROMO) during acquisition of high-resolution MRI scans has been developed to reduce motion artifacts. To evaluate the efficacy of PROMO, four T1-weighted image volumes (two with PROMO enabled, two uncorrected) were acquired for each of nine children. A radiologist, blind to whether PROMO was used, rated image quality and artifacts on all sagittal slices of every volume. These ratings were significantly better in scans collected with PROMO relative to those collected without PROMO (Mann-Whitney U test, P < 0.0001). The use of PROMO, especially in motion-prone patients, should improve the accuracy of measurements made for clinical care and research, and potentially reduce the need for sedation in children.