Diffusion-weighted MRI has become a popular method for investigating white matter non-invasively. It has great potential for probing both white matter microstructure, using indices such as fractional anisotropy (FA), and macrostructure, based on tracing of fiber tracts (“tractography”). Although there is now substantial literature reporting the use of diffusion imaging across a broad range of white matter regions, species, and pathologies, the link between this data and the (even richer) literature based on classical examination of post mortem tissue (dissection or histological staining) is relatively sparse.
A number of studies have demonstrated the feasibility and utility of diffusion imaging of ex vivo
animal brains (Guilfoyle et al., 2003; Verma et al., 2005; Kroenke et al., 2005; D'Arceuil et al., 2007, 2008; Dyrby et al., 2007
; Tyszka and Frank, 2009
), spinal cord (Schwartz et al., 2005; Kim et al., 2009
) and brain tissue sections (Guilfoyle et al., 2003; D'Arceuil et al., 2005
). These studies have utilized small-bore, high-field scanners, typically with a maximum gradient amplitude of 400 mT/m or greater (10 times that available on most clinical systems). These specialized systems are ideal for ex vivo
scanning because they are able to achieve high b-values (indicating strong diffusion contrast) with short echo times (enabling high signal-to-noise ratio, SNR). Unfortunately these systems typically have a bore size that is too small to fit whole human brains, and are less commonly available than human scanners, particularly in a clinical setting.
Although much can be learned from these studies on animal brains and spinal cord, the possibility of scanning whole human brains is particularly compelling. The use of human tissue is critical to study uniquely-human pathologies where animal models are inappropriate or limited, such as psychiatric disorders, high-level cognitive dysfunction or even multiple sclerosis. Moreover, the validation of long-range tracts in human brains is important, and would be particularly valuable in the context of conditions affecting global connectivity, such as schizophrenia and autism. This data could also go beyond what is achievable in vivo, enabling higher spatial resolution. Routine scanning of whole human brains donated to brain bank facilities could be used to provide databases of matched diffusion and histology, provided MRI scans could be obtained reliably and at a reasonable expense. Given that most brain bank resources are sited in or near research hospitals, this could be achieved provided clinical scanners could provide sufficiently good data. In the present work, we consider the longest conceivable scan time in a hospital setting, 24 h. Ultimately we would hope to reduce this time to an overnight scan.
Several studies have previously acquired diffusion-weighted data in whole, post mortem
human brains (Pfefferbaum et al., 2004; Larsson et al., 2004
) or brain slices (Schmierer et al., 2007; Gouw et al., 2008
). Unfortunately, changes in tissue properties with fixation compromise conventional sequences. Large voxel dimensions are typically prescribed to combat reductions in SNR due to shortened T 2
. In addition, the reductions in diffusion coefficient are rarely compensated for with increased b-value, resulting in lower overall sensitivity to diffusion. Finally, the use of single-shot EPI introduces a tradeoff between image resolution and distortion. As a result, the image quality and diffusion contrast in these studies are generally worse than those achievable in vivo
. These issues make straightforward application of protocols developed for in vivo
imaging inappropriate for many of the goals discussed above.
In this manuscript, we present initial results demonstrating the feasibility of scanning whole, fixed, human brains on a clinical 3 T scanner. The approach considered here can be achieved with straightforward modification of conventional spin-echo diffusion sequences. Instead of acquiring data using a single-shot EPI readout, as is used in vivo, we acquire data using a 3D, segmented EPI acquisition. We explore the achievable data quality when scan time is limited to a 24-hour period, and also present data at higher resolution from a 5-day scan. We study the impact of tissue preparation on the derived diffusion indices, present tractography results from major pathways and discuss some interesting properties of our diffusion data.