Donald G. McLaren

A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches.

Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner. The current implementation of PPI in Statistical Parametric Mapping (SPM8) is configured primarily to assess connectivity differences between two task conditions, when in practice fMRI tasks frequently employ more than two conditions. Here we evaluate how a generalized form of context-dependent PPI (gPPI; http://www.nitrc.org/projects/gppi), which is configured to automatically accommodate more than two task conditions in the same PPI model by spanning the entire experimental space, compares to the standard implementation in SPM8. These comparisons are made using both simulations and an empirical dataset. In the simulated dataset, we compare the interaction beta estimates to their expected values and model fit using the Akaike information criterion (AIC). We found that interaction beta estimates in gPPI were robust to different simulated data models, were not different from the expected beta value, and had better model fits than when using standard PPI (sPPI) methods. In the empirical dataset, we compare the model fit of the gPPI approach to sPPI. We found that the gPPI approach improved model fit compared to sPPI. There were several regions that became non-significant with gPPI. These regions all showed significantly better model fits with gPPI. Also, there were several regions where task-dependent connectivity was only detected using gPPI methods, also with improved model fit. Regions that were detected with all methods had more similar model fits. These results suggest that gPPI may have greater sensitivity and specificity than standard implementation in SPM. This notion is tempered slightly as there is no gold standard; however, data simulations with a known outcome support our conclusions about gPPI. In sum, the generalized form of context-dependent PPI approach has increased flexibility of statistical modeling, and potentially improves model fit, specificity to true negative findings, and sensitivity to true positive findings.

A Population-Average MRI-Based Atlas Collection of the Rhesus Macaque

Magnetic resonance imaging (MRI) studies of non-human primates are becoming increasingly common; however, the well-developed voxel-based methodologies used in human studies are not readily applied to non-human primates. In the present study, we create a population-average MRI-based atlas collection for the rhesus macaque (Macaca mulatta) that can be used with common brain mapping packages such as SPM or FSL. In addition to creating a publicly available T1-weighted atlas (http://www.brainmap.wisc.edu/monkey.html), probabilistic tissue classification maps and T2-weighted atlases were also created. Theses atlases are aligned to the MRI volume from the Saleem, K.S. and Logothetis, N.K. (2006) atlas providing an explicit link to histological sections. Additionally, we have created a transform to integrate these atlases with the F99 surface-based atlas in CARET. It is anticipated that these tools will help facilitate voxel-based imaging methodologies in non-human primate species, which in turn may increase our understanding of brain function, development, and evolution.

Neurophysiology of swallowing: effects of age and bolus type.

This study examined age-related changes in swallowing from an integrated biomechanical and functional imaging perspective in order to more comprehensively characterize changes in swallowing associated with age. We examined swallowing-related fMRI brain activity and videoflouroscopic biomechanics of three bolus types (saliva, water and barium) in 12 young and 11 older adults. We found that age-related neurophysiological changes in swallowing are evident. The group of older adults recruited more cortical regions than young adults, including the pericentral gyri and inferior frontal gyrus pars opercularis and pars triangularis (primarily right-sided). Saliva swallows elicited significantly higher BOLD responses in regions important for swallowing compared to water and barium. In separate videofluoroscopy sessions, we obtained durational measures of supine swallowing. The older cohort had significantly longer delays before the onset of the pharyngeal swallow response and increased residue of ingested material in the pharynx. These findings suggest that older adults without neurological insult elicit more cortical involvement to complete the same swallowing tasks as younger adults.

The influence of parental history of Alzheimer's disease and apolipoprotein E ε4 on the BOLD signal during recognition memory

First-degree family history (FH) of sporadic Alzheimers disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimers disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimers disease.

Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer's disease.

Although it is established that Alzheimers disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

Early deficits in cortical control of swallowing in Alzheimer’s disease

The goal of this study was to determine whether functional changes in cortical control of swallowing are evident in early Alzheimers disease (AD), before dysphagia (swallowing impairment) is evident. Cortical function was compared between an early AD group and a group of age-matched controls during swallowing. Swallowing oropharyngeal biomechanics examined from videofluoroscopic recordings were also obtained to more comprehensively characterize changes in swallowing associated with early AD. Our neuroimaging results show that the AD group had significantly lower Blood-Oxygen-Level-Dependent (BOLD) response in many cortical areas that are traditionally involved in normal swallowing (i.e., pre and postcentral gyri, Rolandic and frontal opercula). There were no regions where the AD group showed more brain activity than the healthy controls during swallowing, and only 13% of all active voxels were unique to the AD group, even at this early stage. This suggests that the AD group is not recruiting new regions, nor are they compensating within regions that are active during swallowing. In videofluoroscopic measures, the AD group had significantly reduced hyo-laryngeal elevation than the controls. Although, swallowing impairment is usually noted in the late stages of AD, changes in cortical control of swallowing may begin long before dysphagia becomes apparent.

Rhesus macaque brain morphometry: A methodological comparison of voxel-wise approaches

Voxel-based morphometry studies have become increasingly common in human neuroimaging over the past several years; however, few studies have utilized this method to study morphometry changes in non-human primates. Here we describe the application of voxel-wise morphometry methods to the rhesus macaque (Macaca mulatta) using the 112RM-SL template and priors (McLaren et al. (2009) [42]) and as an illustrative example we describe age-associated changes in grey matter morphometry. Specifically, we evaluated the unified segmentation routine implemented using Statistical Parametric Mapping (SPM) software and the FMRIBs Automated Segmentation Tool (FAST) in the FMRIB Software Library (FSL); the effect of varying the smoothing kernel; and the effect of the normalization routine. We found that when studying non-human primates, brain images need less smoothing than in human studies, 2-4mm FWHM. Using flow field deformations (DARTEL) improved inter-subject alignment leading to results that were more likely due to morphometry differences as opposed to registration differences.

A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24; 13 males, 11 females) and standard diets (n = 17; 8 males, 9 females). Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A diet × age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Shaped by the Past: The Default Mode Network Supports Cognition that Is Independent of Immediate Perceptual Input

Although many different accounts of the functions of the default mode network (DMN) have been proposed, few can adequately account for the spectrum of different cognitive functions that utilize this network. The current study used functional magnetic resonance imaging (fMRI) to explore the hypothesis that the role of the DMN in higher order cognition is to allow cognition to be shaped by information from stored representations rather than information in the immediate environment. Using a novel task paradigm, we observed increased BOLD activity in regions of the medial prefrontal cortex and posterior cingulate cortex when individuals made decisions on the location of shapes from the prior trial and decreased BOLD activity when individuals made decisions on the location of shapes on the current trial. These data are inconsistent with views of the DMN as a task-negative system or one that is sensitive only to stimuli with strong personal or emotional ties. Instead the involvement of the DMN when people make decisions about where a shape was, rather than where it is now, supports the hypothesis that the core hubs of the DMN allow cognition to be guided by information other than the immediate perceptual input. We propose that a variety of different forms of higher order thought (such as imagining the future or considering the perspective of another person) engage the DMN because these more complex introspective forms of higher order thought all depend on the capacity for cognition to be shaped by representations that are not present in the external environment.

Longitudinal volumetric changes following traumatic brain injury: a tensor-based morphometry study.

After traumatic injury, the brain undergoes a prolonged period of degenerative change that is paradoxically accompanied by cognitive recovery. The spatiotemporal pattern of atrophy and the specific relationships of atrophy to cognitive changes are ill understood. The present study used tensor-based morphometry and neuropsychological testing to examine brain volume loss in 17 traumatic brain injury (TBI) patients and 13 controls over a 4-year period. Patients were scanned at 2 months, 1 year, and 4 years post-injury. High-dimensional warping procedures were used to create change maps of each subjects brain for each of the two intervals. TBI patients experienced volume loss in both cortical areas and white matter regions during the first interval. We also observed continuing volume loss in extensive regions of white matter during the second interval. Neuropsychological correlations indicated that cognitive tasks were associated with subsequent volume loss in task-relevant regions. The extensive volume loss in brain white matter observed well beyond the first year post-injury suggests that the injured brain remains malleable for an extended period, and the neuropsychological relationships suggest that this volume loss may be associated with subtle cognitive improvements.