Itamar Ronen

Spatial relationship between neuronal activity and BOLD functional MRI

Despite the ubiquitous use of functional magnetic resonance imaging (fMRI), the extent to which the magnitude and spatial scale of the fMRI signal correlates with neuronal activity is poorly understood. In this study, we directly compared single and multiunit neuronal activity with blood oxygenation level-dependent (BOLD) fMRI responses across a large area of the cat area 18. Our data suggest that at the scale of several millimeters, the BOLD contrast correlates linearly with the underlying neuronal activity. At the level of individual electrode recording sites, however, the correlation between the two signals varied substantially. We conclude from our study that T(2)*-based positive BOLD signals are a robust predictor for neuronal activity only at supra-millimeter spatial scales.

Histological Validation of DW-MRI Tractography in Human Postmortem Tissue

Despite several previous attempts, histological validation of diffusion-weighted magnetic resonance imaging (DW-MRI)-based tractography as true axonal fiber pathways remains difficult. In the present study, we establish a method to compare histological and tractography data precisely enough for statements on the level of single tractography pathways. To this end, we used carbocyanine dyes to trace connections in human postmortem tissue and aligned them to high-resolution DW-MRI of the same tissue processed within the diffusion tensor imaging (DTI) formalism. We provide robust definitions of sensitivity (true positives) and specificity (true negatives) for DTI tractography and characterize tractography paths in terms of receiver operating characteristics. With sensitivity and specificity rates of approximately 80%, we could show a clear correspondence between histological and inferred tracts. Furthermore, we investigated the effect of fractional anisotropy (FA) thresholds for the tractography and identified FA values between 0.02 and 0.08 as optimal in our study. Last, we validated the course of entire tractography curves to move beyond correctness determination based on pairs of single points on a tract. Thus, histological techniques, in conjunction with alignment and processing tools, may serve as an important validation method of DW-MRI on the level of inferred tractography projections between brain areas.

High-Resolution Diffusion Tensor Imaging and Tractography of the Human Optic Chiasm at 9.4 T

The optic chiasm with its complex fiber micro-structure is a challenge for diffusion tensor models and tractography methods. Likewise, it is an ideal candidate for evaluation of diffusion tensor imaging tractography approaches in resolving inter-regional connectivity because the macroscopic connectivity of the optic chiasm is well known. Here, high-resolution (156 microm in-plane) diffusion tensor imaging of the human optic chiasm was performed ex vivo at ultra-high field (9.4 T). Estimated diffusion tensors at this high resolution were able to capture complex fiber configurations such as sharp curves, and convergence and divergence of tracts, but were unable to resolve directions at sites of crossing fibers. Despite the complex microstructure of the fiber paths through the optic chiasm, all known connections could be tracked by a line propagation algorithm. However, fibers crossing from the optic nerve to the contralateral tract were heavily underrepresented, whereas ipsilateral nerve-to-tract connections, as well as tract-to-tract connections, were overrepresented, and erroneous nerve-to-nerve connections were tracked. The effects of spatial resolution and the varying degrees of partial volume averaging of complex fiber architecture on the performance of these methods could be investigated. Errors made by the tractography algorithm at high resolution were shown to increase at lower resolutions closer to those used in vivo. This study shows that increases in resolution, made possible by higher field strengths, improve the accuracy of DTI-based tractography. More generally, post-mortem investigation of fixed tissue samples with diffusion imaging at high field strengths is important in the evaluation of MR-based diffusion models and tractography algorithms.

Diffusion tensor spectroscopy and imaging of the arcuate fasciculus

The arcuate fasciculus (AF) is a fiber pathway in the human brain relevant for language processes and has recently been characterized by means of diffusion tensor tractography. The observations made concerning the left and right hemisphere AF include a characterization of the trajectories and quantification of physical properties such as fractional anisotropy, DTI-based fiber density and volume. However, these observations were based on the diffusion of water, which is not particular to either the intra- or extra-axonal compartments, and thus its usefulness for tissue characterization is limited. If the diffusion properties and in turn the geometric properties of only one tissue compartment can be isolated and characterized, a better microstructural characterization of AF is possible. In this study, water-based diffusion tensor probabilistic mapping was first implemented to segment the AF. Subsequently, diffusion tensor spectroscopic measurements of N-acetyl aspartate (NAA) were performed to measure the intra-axonal specific diffusion in left and right AF. Diffusion properties of NAA, which solely reflect the intra-axonal space, indicated possible leftward asymmetry in axonal diameter, where those of water, which are not compartment-specific, showed laterality to a lesser extent.

Investigating Axonal Damage in Multiple Sclerosis by Diffusion Tensor Spectroscopy

Sensitive and specific in vivo measures of axonal damage, an important determinant of clinical status in multiple sclerosis (MS), might greatly benefit prognostication and therapy assessment. Diffusion tensor spectroscopy (DTS) combines features of diffusion tensor imaging and magnetic resonance spectroscopy, allowing measurement of the diffusion properties of intracellular, cell-type-specific metabolites. As such, it may be sensitive to disruption of tissue microstructure within neurons. In this cross-sectional pilot study, diffusion of the neuronal metabolite N-acetylaspartate (NAA) was measured in the human normal-appearing corpus callosum on a 7 tesla MRI scanner, comparing 15 MS patients and 14 healthy controls. We found that NAA parallel diffusivity is lower in MS (p = 0.030) and inversely correlated with both water parallel diffusivity (p = 0.020) and clinical severity (p = 0.015). Interpreted in the context of previous experiments, our findings provide preliminary evidence that DTS can distinguish axonopathy from other processes such as inflammation, edema, demyelination, and gliosis. By detecting reduced diffusion of NAA parallel to axons in white matter, DTS may thus be capable of distinguishing axonal disruption in MS in the setting of increased parallel diffusion of water, which is commonly observed in MS but pathologically nonspecific.

Spatial resolution dependence of DTI tractography in human occipito-callosal region.

Diffusion tensor imaging (DTI) and fiber tracking have been used to measure the fiber structural connectivity in humans in a non-invasive manner. However, low sensitivity is a principal limitation of these methods, causing a large number of possibly missing fiber tracts (FTs). Here we studied how the spatial resolution affects the sensitivity of the fiber tracing by rescaling data to different resolutions. Our data suggest that the spatial resolution can change the degree of the asymmetric cross-callosal connections in the lower visual field (loVF) compared to the upper visual field (upVF). Among connections from loVF, a larger voxel size resulted in a smaller number of FTs that was not commensurate to the number of seed points, while the number of connections from upVF was not significantly affected by variation in seeding point numbers. We conclude from our study that the spatial resolution of the acquired data will have to be taken into consideration in interpreting DTI fiber tracking data. Our results further suggest that the acquisition resolution of around 2 mm iso-voxel in the conventional DTI scheme can reconstruct the asymmetric upper and lower white matter structure in occipito-callosal region.

Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy.

In diffusion tensor imaging (DTI) the anisotropic movement of water is exploited to characterize microstructure. One confounding issue of DTI is the presence of intra‐ and extracellular components contributing to the measured diffusivity. This causes an ambiguity in determining the underlying cause of diffusion properties, particularly the fractional anisotropy (FA). In this study an intracellular constituent, N‐acetyl aspartate (NAA), was used to probe intracellular diffusion, while water molecules were used to probe the combined intra‐ and extracellular diffusion. NAA and water diffusion measurements were made in anterior and medial corpus callosum (CC) regions, which are referred to as R1 and R2, respectively. FA(NAA) was found to be greater than FA(Water) in both CC regions, thus indicating a higher degree of anisotropy within the intracellular space in comparison to the combined intra‐ and extracellular spaces. A decreasing trend in the FA of NAA and water was observed between R1 and R2, while the radial diffusivity (RD) for both molecules increased. The increase in RD(NAA) is particularly significant, thus explaining the more significant decrease in FA(NAA) between the two regions. It is suggested that diffusion tensor spectroscopy of NAA can potentially be used to further characterize microscopic anatomic organization in white matter. Magn Reson Med 58:1045–1053, 2007.

Identification of atherosclerotic lipid deposits by diffusion-weighted imaging.

Objectives—The content and distribution of lipids is an important aspect of plaque vulnerability, but lipids are present within a heterogeneous environment, impeding detection by magnetic resonance imaging. Our goal was to achieve accurate detection of mobile lipids by a single magnetic resonance imaging sequence. Methods and Results—Carotid endarectomy specimens (n=23) were imaged ex vivo at a high magnetic field (11.7 T) within 24 hours after surgery. Three contrast-weighted (T1W, T2W, and diffusion-weighted imaging [DWI]) image sequences were acquired and then coregistered with histological preparations for lipids (Oil red O and polarized light microscopy) and fibrous tissue (trichrome). Contrast-to-noise ratios were measured and compared for the 3 contrast weightings. Contrast-to-noise ratio measurement in regions identified as lipid versus fibrous tissue showed greater differences by DWI (4.5±0.63 versus 0.64±0.08; P<0.05) as compared with T2W (2.83±0.36 versus 1.36±0.37; P<0.05). We validated the presence and distribution of lipids (mainly cholesteryl esters) by both histology and image-guide spectroscopy. The basis for distinguishing mobile lipid and water inside the plaque was illustrated by diffusion-weighted spectroscopy. Conclusions—Biophysical properties of plaque lipids can confer selective identification by DWI, as opposed to standard T1W and T2W imaging sequences. Successful translation of DWI in vivo could identify of features of vulnerable plaque.

Differences in apparent diffusion coefficients of brain metabolites between grey and white matter in the human brain measured at 7 T.

Diffusion weighted spectroscopy can provide microstructural information that is specific to compartmental geometry. So far, in human brain, apparent diffusion coefficients (ADCs) of only the metabolites N‐acetyl aspartate, creatine (tCr) and choline (tCho) have been assessed. High field MR at 7 T allows the collection and analysis of diffusion weighted spectroscopy data of additional metabolites of interest such as glutamate (Glu), N‐acetyl aspartyl glutamate, and glutamine (Gln), which are of interest due to their different compartmentalization and role in brain physiology. In this study, we performed 1H diffusion weighted spectroscopy at 7 T using a diffusion‐weighted PRESS sequence in parietal white matter (n = 6) and occipital grey matter (n = 7). Data were analyzed using the LCmodel. ADCs could reliably be obtained of N‐acetyl aspartate, tCr, tCho, Glu, Gln in grey and white matter, and N‐acetyl aspartyl glutamate in white matter. Significant differences in ADC values were observed between grey and white matter for all metabolites. ADCs in grey matter were consistently lower than in white matter. These differences can probably be attributed to different compartmentalization as well as to the differential impact of diffusion time on ADC of different molecules under conditions of restricted diffusion. Magn Reson Med, 2012.

Long-term effects of contralesional rTMS in severe stroke: Safety, cortical excitability, and relationship with transcallosal motor fibers

BACKGROUND Contralesional hemispheric repetitive transcranial magnetic stimulation (rTMS) may improve motor function in mild to moderate stroke and effects are considered to be mediated through transcallosal motor fibers. OBJECTIVE This study aimed to investigate the safety of contralesional rTMS in a selected group of severe chronic stroke patients. METHODS Ten sessions of 1 Hz rTMS were applied to contralesional primary motor cortex (M1) using neuronavigated stimulation and changes in motor impairment were evaluated before, during and after rTMS applications and at 4-weeks follow-up. Neurophysiological response to stimulation was assessed through cortical excitability evaluations. The relationship between functional and neurophysiological response to rTMS and microstructural integrity of transcallosal motor fibers were searched using diffusion tensor imaging (DTI) based fractional anisotropy (FA). RESULTS rTMS was well-tolerated with high compliance and no dropouts; no seizures or motor worsening occurred. Transcallosal FA values revealed a positive linear relationship with the mild motor improvement detected after rTMS while higher FA values were observed in subjects with better motor outcome. Cortical excitability showed a significant change in contralesional short-interval intracortical inhibition indicating altered plasticity following rTMS. CONCLUSIONS Our results suggest that noninvasive neuromodulation of the contralesional hemisphere may present a possibility to assist adaptive neuroplastic changes in severe chronic stroke. Implementation of DTI-derived measures of transcallosal microstructural integrity may allow for individually-tailored interventions to guide processes of interhemispheric neuroplasticity. Further research is warranted to establish the clinical value of these findings in neurorehabilitation settings for subjects with chronic severe stroke.