Karl G. Helmer

Regional White Matter Volume Differences in Nondemented Aging and Alzheimer's Disease

Accumulating evidence suggests that altered cerebral white matter (WM) influences normal aging, and further that WM degeneration may modulate the clinical expression of Alzheimers disease (AD). Here we conducted a study of differences in WM volume across the adult age span and in AD employing a newly developed, automated method for regional parcellation of the subcortical WM that uses curvature landmarks and gray matter (GM)/WM surface boundary information. This procedure measures the volume of gyral WM, utilizing a distance constraint to limit the measurements from extending into the centrum semiovale. Regional estimates were first established to be reliable across two scan sessions in 20 young healthy individuals. Next, the method was applied to a large clinically-characterized sample of 299 individuals including 73 normal older adults and 91 age-matched participants with very mild to mild AD. The majority of measured regions showed a decline in volume with increasing age, with strong effects found in bilateral fusiform, lateral orbitofrontal, superior frontal, medial orbital frontal, inferior temporal, and middle temporal WM. The association between WM volume and age was quadratic in many regions suggesting that WM volume loss accelerates in advanced aging. A number of WM regions were further reduced in AD with parahippocampal, entorhinal, inferior parietal and rostral middle frontal WM showing the strongest AD-associated reductions. There were minimal sex effects after correction for intracranial volume, and there were associations between ventricular volume and regional WM volumes in the older adults and AD that were not apparent in the younger adults. Certain results, such as the loss of WM in the fusiform region with aging, were unexpected and provide novel insight into patterns of age associated neural and cognitive decline. Overall, these results demonstrate the utility of automated regional WM measures in revealing the distinct patterns of age and AD associated volume loss that may contribute to cognitive decline.

Microstructural Status of Ipsilesional and Contralesional Corticospinal Tract Correlates with Motor Skill in Chronic Stroke Patients

Greater loss in structural integrity of the ipsilesional corticospinal tract (CST) is associated with poorer motor outcome in patients with hemiparetic stroke. Animal models of stroke have demonstrated that structural remodeling of white matter in the ipsilesional and contralesional hemispheres is associated with improved motor recovery. Accordingly, motor recovery in patients with stroke may relate to the relative strength of CST degeneration and remodeling. This study examined the relationship between microstructural status of brain white matter tracts, indexed by the fractional anisotropy (FA) metric derived from diffusion tensor imaging (DTI) data, and motor skill of the stroke‐affected hand in patients with chronic stroke. Voxelwise analysis revealed that motor skill significantly and positively correlated with FA of the ipsilesional and contralesional CST in the patients. Additional voxelwise analyses showed that patients with poorer motor skill had reduced FA of bilateral CST compared to normal control subjects, whereas patients with better motor skill had elevated FA of bilateral CST compared to controls. These findings were confirmed using a DTI‐tractography method applied to the CST in both hemispheres. The results of this study suggest that the level of motor skill recovery achieved in patients with hemiparetic stroke relates to microstructural status of the CST in both the ipsilesional and contralesional hemispheres, which may reflect the net effect of degeneration and remodeling of bilateral CST. Hum Brain Mapp, 2009.

Data sharing in neuroimaging research

Significant resources around the world have been invested in neuroimaging studies of brain function and disease. Easier access to this large body of work should have profound impact on research in cognitive neuroscience and psychiatry, leading to advances in the diagnosis and treatment of psychiatric and neurological disease. A trend toward increased sharing of neuroimaging data has emerged in recent years. Nevertheless, a number of barriers continue to impede momentum. Many researchers and institutions remain uncertain about how to share data or lack the tools and expertise to participate in data sharing. The use of electronic data capture (EDC) methods for neuroimaging greatly simplifies the task of data collection and has the potential to help standardize many aspects of data sharing. We review here the motivations for sharing neuroimaging data, the current data sharing landscape, and the sociological or technical barriers that still need to be addressed. The INCF Task Force on Neuroimaging Datasharing, in conjunction with several collaborative groups around the world, has started work on several tools to ease and eventually automate the practice of data sharing. It is hoped that such tools will allow researchers to easily share raw, processed, and derived neuroimaging data, with appropriate metadata and provenance records, and will improve the reproducibility of neuroimaging studies. By providing seamless integration of data sharing and analysis tools within a commodity research environment, the Task Force seeks to identify and minimize barriers to data sharing in the field of neuroimaging.

T2* mapping and B0 orientation-dependence at 7 T reveal cyto- and myeloarchitecture organization of the human cortex

Ultra-high field MRI (≥ 7 T) has recently shown great sensitivity to depict patterns of tissue microarchitecture. Moreover, recent studies have demonstrated a dependency between T₂* and orientation of white matter fibers with respect to the main magnetic field B₀. In this study we probed the potential of T₂* mapping at 7 T to provide new markers of cortical architecture. We acquired multi-echo measurements at 7 T and mapped T₂* over the entire cortex of eight healthy individuals using surface-based analysis. B₀ dependence was tested by computing the angle θ(z) between the normal of the surface and the direction of B₀, then fitting T₂*(θ(z)) using model from the literature. Average T₂* in the cortex was 32.20 +/- 1.35 ms. Patterns of lower T₂* were detected in the sensorimotor, visual and auditory cortices, likely reflecting higher myelin content. Significantly lower T₂* was detected in the left hemisphere of the auditory region (p<0.005), suggesting higher myelin content, in accordance with previous investigations. B₀ orientation dependence was detected in some areas of the cortex, the strongest being in the primary motor cortex (∆R₂*=4.10 Hz). This study demonstrates that quantitative T₂* measures at 7 T MRI can reveal patterns of cytoarchitectural organization of the human cortex in vivo and that B₀ orientation dependence can probe the coherency and orientation of gray matter fibers in the cortex, shedding light into the potential use of this type of contrast to characterize cyto-/myeloarchitecture and to understand the pathophysiology of diseases associated with changes in iron and/or myelin concentration.

Separating changes in the intra- and extracellular water apparent diffusion coefficient following focal cerebral ischemia in the rat brain.

Selective intracellular (IC) and extracellular (EC) brain water apparent diffusion coefficient (ADC) values were measured in normal and ischemic rat brain. Selective T1‐relaxation enhancement of the EC water, using intracerebroventricular (ICV) infusion of an NMR contrast reagent (CR), was used to separate the IC and EC signal contributions. In the CR‐infused, normal brain (n = 4), T1 = 235 ± 10 ms and T2 = 46 ± 2 ms for IC water (85%) and T1 = 48 ± 8 ms and T2 = 6 ± 2 ms for EC water (15%). Volume‐localized ADCz (z‐gradient axis) values were 0.90 ± 0.02 (EC+IC), 0.81 ± 0.05 (IC), 0.51 ± 0.02 (EC+IC), and 0.53 ± 0.07 (IC), for normal, CR‐infused, ischemic, and ischemic/CR‐infused groups, respectively (ADC values are ×10‐3 mm2/s; n = 5 for each group). Imaging ADCz values were 0.81 ± 0.03 (EC+IC), 0.75 ± 0.05 (IC), 0.51 ± 0.04 (EC+IC), and 0.52 ± 0.05 (IC), respectively, for the same groups. Imaging ADCav (average diffusivity) values for the same groups were 0.70 ± 0.05 (EC+IC), 0.69 ± 0.06 (IC), 0.45 ± 0.06 (EC+IC), and 0.44 ± 0.06 (IC), respectively. These results suggest that the IC water ADC determines the overall water ADC value in normal and ischemic rat brain. Magn Reson Med 48:826–837, 2002.

Secondary decline in apparent diffusion coefficient and neurological outcomes after a short period of focal brain ischemia in rats

This study was designed to characterize the initial and secondary changes of the apparent diffusion coefficient (ADC) of water with high temporal resolution measurements of ADC values and to correlate ADC changes with functional outcomes. Fourteen rats underwent 30 minutes of temporary middle cerebral artery occlusion (MCAO). Diffusion‐, perfusion‐, and T2‐weighted imaging was performed during MCAO and every 30 minutes for a total of 12 hours after reperfusion (n = 6). Neurological outcomes were evaluated during MCAO, every 30 minutes for a total of 6 hours and at 24 hours after reperfusion (n = 8). The decreased cerebral blood flow during MCAO returned to normal after reperfusion and remained unchanged thereafter. The decreased ADC values during occlusion completely recovered at 1 hour after reperfusion. The renormalized ADC values started to decrease secondarily at 2.5 hours, accompanied by a delayed increase in T2 values. The ADC‐defined secondary lesion grew over time and was 52% of the ADC‐defined initial lesion at 12 hours. Histological evaluation demonstrated neuronal damage in the regions of secondary ADC decline. Complete resolution of neurological deficits was seen in 1 rat at 1 hour and in 6 rats between 2.5 and 6 hours after reperfusion; no secondary neurological deficits were observed at 24 hours. These data suggest that (1) a secondary ADC reduction occurs as early as 2.5 hours after reperfusion, evolves in a slow fashion, and is associated with neuronal injury; and (2) renormalization and secondary decline in ADC are not associated with neurological recovery and worsening, respectively. Ann Neurol 2000;48:236–244

Multispectral analysis of the temporal evolution of cerebral ischemia in the rat brain

A major difficulty in staging and predicting ischemic brain injury by magnetic resonance (MR) imaging is the time‐varying nature of the MR parameters within the ischemic lesion. A new multispectral (MS) approach is described to characterize cerebral ischemia in a time‐independent fashion. MS analysis of five MR parameters (mean diffusivity, diffusion anisotropy, T2, proton density, and perfusion) was employed to characterize the progression of ischemic lesion in the rat brain following 60 minutes of transient focal ischemia. k‐Means (KM) and fuzzy c‐means (FCM) classification methods were employed to define the acute and subacute ischemic lesion. KM produced an estimate of lesion volume that was highly correlated with postmortem infarct volume, independent of the age of the lesion. Overall classification rates for KM exceeded FCM at acute and subacute time points as follows: KM, 90.5%, 94.4%, and 95.9%; FCM, 82.4%, 90.6%, and 82.6% (for 45 minutes, 180 minutes, and 24–120 hours post MCAO groups). MS analysis also offers a formal method of combining diffusion and perfusion parameters to provide an estimate of the ischemic penumbra (KM classification rate = 70.3%). J. Magn. Reson. Imaging 2000;12:842–858.

Hockey Concussion Education Project, Part 2. Microstructural white matter alterations in acutely concussed ice hockey players: a longitudinal free-water MRI study

OBJECT Concussion is a common injury in ice hockey and a health problem for the general population. Traumatic axonal injury has been associated with concussions (also referred to as mild traumatic brain injuries), yet the pathological course that leads from injury to recovery or to long-term sequelae is still not known. This study investigated the longitudinal course of concussion by comparing diffusion MRI (dMRI) scans of the brains of ice hockey players before and after a concussion. METHODS The 2011-2012 Hockey Concussion Education Project followed 45 university-level ice hockey players (both male and female) during a single Canadian Interuniversity Sports season. Of these, 38 players had usable dMRI scans obtained in the preseason. During the season, 11 players suffered a concussion, and 7 of these 11 players had usable dMRI scans that were taken within 72 hours of injury. To analyze the data, the authors performed free-water imaging, which reflects an increase in specificity over other dMRI analysis methods by identifying alterations that occur in the extracellular space compared with those that occur in proximity to cellular tissue in the white matter. They used an individualized approach to identify alterations that are spatially heterogeneous, as is expected in concussions. RESULTS Paired comparison of the concussed players before and after injury revealed a statistically significant (p < 0.05) common pattern of reduced free-water volume and reduced axial and radial diffusivities following elimination of free-water. These free-water-corrected measures are less affected by partial volumes containing extracellular water and are therefore more specific to processes that occur within the brain tissue. Fractional anisotropy was significantly increased, but this change was no longer significant following the free-water elimination. CONCLUSIONS Concussion during ice hockey games results in microstructural alterations that are detectable using dMRI. The alterations that the authors found suggest decreased extracellular space and decreased diffusivities in white matter tissue. This finding might be explained by swelling and/or by increased cellularity of glia cells. Even though these findings in and of themselves cannot determine whether the observed microstructural alterations are related to long-term pathology or persistent symptoms, they are important nonetheless because they establish a clearer picture of how the brain responds to concussion.

Direct Visualization of the Perforant Pathway in the Human Brain with Ex Vivo Diffusion Tensor Imaging

Ex vivo magnetic resonance imaging yields high resolution images that reveal detailed cerebral anatomy and explicit cytoarchitecture in the cerebral cortex, subcortical structures, and white matter in the human brain. Our data illustrate neuroanatomical correlates of limbic circuitry with high resolution images at high field. In this report, we have studied ex vivo medial temporal lobe samples in high resolution structural MRI and high resolution diffusion MRI. Structural and diffusion MRIs were registered to each other and to histological sections stained for myelin for validation of the perforant pathway. We demonstrate probability maps and fiber tracking from diffusion tensor data that allows the direct visualization of the perforant pathway. Although it is not possible to validate the DTI data with invasive measures, results described here provide an additional line of evidence of the perforant pathway trajectory in the human brain and that the perforant pathway may cross the hippocampal sulcus.

Towards structured sharing of raw and derived neuroimaging data across existing resources

Data sharing efforts increasingly contribute to the acceleration of scientific discovery. Neuroimaging data is accumulating in distributed domain-specific databases and there is currently no integrated access mechanism nor an accepted format for the critically important meta-data that is necessary for making use of the combined, available neuroimaging data. In this manuscript, we present work from the Derived Data Working Group, an open-access group sponsored by the Biomedical Informatics Research Network (BIRN) and the International Neuroimaging Coordinating Facility (INCF) focused on practical tools for distributed access to neuroimaging data. The working group develops models and tools facilitating the structured interchange of neuroimaging meta-data and is making progress towards a unified set of tools for such data and meta-data exchange. We report on the key components required for integrated access to raw and derived neuroimaging data as well as associated meta-data and provenance across neuroimaging resources. The components include (1) a structured terminology that provides semantic context to data, (2) a formal data model for neuroimaging with robust tracking of data provenance, (3) a web service-based application programming interface (API) that provides a consistent mechanism to access and query the data model, and (4) a provenance library that can be used for the extraction of provenance data by image analysts and imaging software developers. We believe that the framework and set of tools outlined in this manuscript have great potential for solving many of the issues the neuroimaging community faces when sharing raw and derived neuroimaging data across the various existing database systems for the purpose of accelerating scientific discovery.