Sabine Hofer

Topography of the human corpus callosum revisited—Comprehensive fiber tractography using diffusion tensor magnetic resonance imaging

Several tracing studies have established a topographical distribution of fiber connections to the cortex in midsagittal cross-sections of the corpus callosum (CC). The most prominent example is Witelsons scheme, which defines five vertical partitions mainly based on primate data. Conventional MRI of the human CC does not reveal morphologically discernable structures, although microscopy techniques identified myelinated axons with a relatively small diameter in the anterior and posterior third of the CC as opposed to thick fibers in the midbody and posterior splenium. Here, we applied diffusion tensor imaging (DTI) in conjunction with a tract-tracing algorithm to gain cortical connectivity information of the CC in individual subjects. With DTI-based tractography, we distinguished five vertical segments of the CC, containing fibers projecting into prefrontal, premotor (and supplementary motor), primary motor, and primary sensory areas as well as into parietal, temporal, and occipital cortical areas. Striking differences to Witelsons classification were recognized in the midbody and anterior third of the CC. In particular, callosal motor fiber bundles were found to cross the CC in a much more posterior location than previously indicated. Differences in water mobility were found to be in qualitative agreement with differences in the microstructure of transcallosal fibers yielding the highest anisotropy in posterior regions of the CC. The lowest anisotropy was observed in compartments assigned to motor and sensory cortical areas. In conclusion, DTI-based fiber tractography of healthy human subjects suggests a modification of the widely accepted Witelson scheme and a new classification of vertical CC partitions.

Reconstruction and dissection of the entire human visual pathway using diffusion tensor MRI.

The human visual system comprises elongated fiber pathways that represent a serious challenge for diffusion tensor imaging (DTI) and fiber tractography: while tracking of frontal fiber bundles may be compromised by the nearby presence of air-filled cavities, nerves, and eye muscles, the anatomic courses of the three main fiber bundles of the optic radiation are subject to pronounced inter-subject variability. Here, tractography of the entire visual pathway was achieved in six healthy subjects at high spatial accuracy, that is, at 1.8 mm isotropic spatial resolution, without susceptibility-induced distortions, and in direct correspondence to anatomic MRI structures. Using a newly developed diffusion-weighted single-shot STEAM MRI sequence, we were able to track the thin optic nerve including the nasal optic nerve fibers, which cross the optic chiasm, and to dissect the optic radiation into the anterior ventral bundle (Meyers loop), the central bundle, and the dorsal bundle. Apart from scientific applications these results in single subjects promise advances in the planning of neurosurgical procedures to avoid unnecessary damage to the visual fiber system.

A myelin gene causative of a catatonia-depression syndrome upon aging

Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2′,3′‐cyclic nucleotide 3′‐phosphodiesterase) is among the oligodendrocyte/myelin‐associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional ‘pro‐inflammatory hit’. This phenotype is strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species with their partial CNP ‘loss‐of‐function’ genotype are best described as ‘catatonia‐depression’ syndrome. As a consequence of perturbed CNP expression, mice show secondary low‐grade inflammation/neurodegeneration. Analogously, in man, diffusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases.

Callosal dysfunction in amyotrophic lateral sclerosis correlates with diffusion tensor imaging of the central motor system

We investigated the frequency and functional relevance of corpus callosum degeneration in amyotrophic lateral sclerosis (ALS). A total of 22 ALS patients and 29 healthy controls performed the newly developed Contralateral Co-Movement Test as indicator of callosal dysfunction. Diffusion tensor imaging was applied to determine fractional anisotropy values in the callosal area containing the crossing motor fibers and in the pyramidal tracts in 13 subjects of each group. ALS patients had more than twice the amount of co-movements as compared to healthy subjects. Contralateral co-movements correlated with fractional anisotropy values of the corpus callosum motor region as did ALS Functional Rating Scale as measure of disease progression. In both groups, contralateral co-movements correlated with the central motor index (ratio of the mean of fractional anisotropy values of both pyramidal tracts and corpus callosum motor region). Neuropsychological test results failed to show correlations with functional or morphological parameters. Combining Contralateral Co-Movement Test and diffusion tensor imaging in ALS revealed the close relation between functional and morphological impairment in the degenerating central motor-neuronal network. The Contralateral Co-Movement Test delivers simple means of symptom quantification, independent of ALS Functional Rating Scale, for future neuroprotective trials.

Separation of fiber tracts within the human cingulum bundle using single-shot STEAM DTI.

The cingulum bundle is a complex white matter fiber tract of the human brain that comprises long association fibers, commissural fibers, and various U-fibers. It is located above the corpus callosum and interconnects limbic structures. A decline of the cingulum fiber integrity has been observed in patients with mental disorders such as schizophrenia. In this work a separation of the bi-hemispheric lateral longitudinal striae and selected U-fibers was achieved by fiber tractography of the cingulum bundle based on diffusion tensor imaging at 1.8 mm isotropic spatial resolution. Anatomic accuracy without susceptibility-induced distortions was ensured by diffusion-weighted single-shot STEAM MRI with 24 gradient directions and b values of 0 and 1000 s mm -2 . Extending earlier versions, the STEAM sequence combined variable flip angles, centrically reordered phase encoding, partial Fourier encoding, and parallel imaging.

In Vivo Mapping of Fiber Pathways in the Rhesus Monkey Brain

The study of complex fiber systems in relation to the cognitive abilities of humans is a long-standing challenge for neuroscientists. With the development of diffusion tensor imaging (DTI) it is now possible to visualize large fiber bundles non-invasively. The existing knowledge of the white matter architecture largely stems from either lesion studies of human patients or, in more detail, tracer injection studies of non-human primates. Hence, it seems mandatory to com- pare DTI results with histochemical findings obtained for the same species. Using a geometrically undistorted DTI tech- nique and fiber tractography, we examined the fiber anatomy of the macaque brain in vivo and related the results to fiber pathways previously identified in monkeys with conventional tract tracing. The approach identified multiple fiber tracts including the main association and projection pathways as well as fibers of the limbic system, commissural system, optic system, and cerebellar system. In conclusion, in vivo fiber tractography based on current-state DTI allows for a compre- hensive analysis of major fiber pathways in the intact macaque brain.

Sexual dimorphism of AMBRA1 -related autistic features in human and mouse

Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1+/− mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.

Rapid Diffusion-weighted Magnetic Resonance Imaging of the Brain Without Susceptibility Artifacts: Single-shot Steam With Radial Undersampling and Iterative Reconstruction.

Objective The aim of this study was to develop a rapid diffusion-weighted (DW) magnetic resonance imaging (MRI) technique for whole-brain studies without susceptibility artifacts and measuring times below 3 minutes. Materials and Methods The proposed method combines a DW spin-echo module with a single-shot stimulated echo acquisition mode MRI sequence. Previous deficiencies in image quality due to limited signal-to-noise ratio are compensated for (1) by radial undersampling to enhance the flip angle and thus the signal strength of stimulated echoes; (2) by defining the image reconstruction as a nonlinear inverse problem, which is solved by the iteratively regularized Gauss-Newton method; and (3) by denoising with use of a modified nonlocal means filter. The method was implemented on a 3 T MRI system (64-channel head coil, 80 mT · m gradients) and evaluated for 10 healthy subjects and 2 patients with an ischemic lesion and epidermoid cyst, respectively. Results High-quality mean DW images of the entire brain were obtained by acquiring 1 non-DW image and 6 DW images with different diffusion directions at b = 1000 s · mm. The achievable resolution for a total measuring time of 84 seconds was 1.5 mm in plane with a section thickness of 4 mm (55 sections). A measuring time of 168 seconds allowed for an in-plane resolution of 1.25 mm and a section thickness of 3 mm (54 sections). Apparent diffusion coefficient values were in agreement with literature data. Conclusions The proposed method for DW MRI offers immunity against susceptibility problems, high spatial resolution, adequate signal-to-noise ratio and clinically feasible scan times of less than 3 minutes for whole-brain studies. More extended clinical trials require accelerated computation and online reconstruction.

Single-shot T1 mapping of the corpus callosum: A rapid characterization of fiber bundle anatomy.

Using diffusion-tensor magnetic resonance imaging and fiber tractography the topographic organization of the human corpus callosum (CC) has been described to comprise five segments with fibers projecting into prefrontal (I), premotor and supplementary motor (II), primary motor (III), and primary sensory areas (IV), as well as into parietal, temporal, and occipital cortical areas (V). In order to more rapidly characterize the underlying anatomy of these segments, this study used a novel single-shot T1 mapping method to quantitatively determine T1 relaxation times in the human CC. A region-of-interest analysis revealed a tendency for the lowest T1 relaxation times in the genu and the highest T1 relaxation times in the somatomotor region of the CC. This observation separates regions dominated by myelinated fibers with large diameters (somatomotor area) from densely packed smaller axonal bundles (genu) with less myelin. The results indicate that characteristic T1 relaxation times in callosal profiles provide an additional means to monitor differences in fiber anatomy, fiber density, and gray matter in respective neocortical areas. In conclusion, rapid T1 mapping allows for a characterization of the axonal architecture in an individual CC in less than 10 s. The approach emerges as a valuable means for studying neocortical brain anatomy with possible implications for the diagnosis of neurodegenerative processes.

Topographical organization of the pyramidal fiber system - Diffusion tensor MRI of the human and rhesus monkey brain.

The fibers of the pyramidal tract (PT) that connect the precentral and postcentral gyrus with the spinal cord are organized in a topological manner. However, their exact arrangement and orientation in the internal capsule is still a mat- ter of debate. Here, we applied magnetic resonance diffusion tensor imaging and tract tracing techniques to determine and compare the pyramidal fibers from the primary motor and somatosensory system in humans and rhesus monkeys in vivo. The results demonstrate that the pyramidal systems of the human and monkey brain differ in their orientation at the level of the internal capsule, whereas track orientations in the gyrus and brainstem appear similar. In the monkey internal cap- sule the somatotopic arrangement of PT fibers from the upper and lower extremities form an angle with the left-right axis of 146° ± 23° (n=4). Thus, fibers from lateral areas of the gyrus are located more anterior-medial to fibers from medial cortical areas. In contrast, in humans the angle is only 50° ± 16° (n=9) yielding a more anterior-lateral orientation of PT fibers along the short axis of the internal capsule. These species dependencies may possibly be due to structural con- straints of the smaller and differently shaped monkey brain.