Multimodal MRI assessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup.

Multi-institutional brain imaging studies have emerged to resolve conflicting results among individual studies. However, adjusting multiple variables at the technical and cohort levels is challenging. Therefore, it is important to explore approaches that provide meaningful results from relatively small samples at institutional levels. We studied 87 first episode psychosis (FEP) patients and 62 healthy subjects by combining supervised integrated factor analysis (SIFA) with a novel pipeline for automated structure-based analysis, an efficient and comprehensive method for dimensional data reduction that our group recently established. We integrated multiple MRI features (volume, DTI indices, resting state fMRI-rsfMRI) in the whole brain of each participant in an unbiased manner. The automated structure-based analysis showed widespread DTI abnormalities in FEP and rs-fMRI differences between FEP and healthy subjects mostly centered in thalamus. The combination of multiple modalities with SIFA was more efficient than the use of single modalities to stratify a subgroup of FEP (individuals with schizophrenia or schizoaffective disorder) that had more robust deficits from the overall FEP group. The information from multiple MRI modalities and analytical methods highlighted the thalamus as significantly abnormal in FEP. This study serves as a proof-of-concept for the potential of this methodology to reveal disease underpins and to stratify populations into more homogeneous sub-groups.

Mapping tracts in the human subthalamic area by 11.7T ex vivo diffusion tensor imaging.

The cortico-basal ganglia-thalamo-cortical feedback loops that consist of distinct white matter pathways are important for understanding in vivo imaging studies of functional and anatomical connectivity, and for localizing subthalamic white matter structures in surgical approaches for movement disorders, such as Parkinson's disease. Connectomic analysis in animals has identified fiber connections between the basal ganglia and thalamus, which pass through the fields of Forel, where other fiber pathways related to motor, sensory, and cognitive functions co-exist. We now report these pathways in the human brain on ex vivo mesoscopic (250 µm) diffusion tensor imaging and on tractography. The locations of the tracts were identified relative to the adjacent gray matter structures, such as the internal and external segments of the globus pallidus; the zona incerta; the subthalamic nucleus; the substantia nigra pars reticulata and compacta; and the thalamus. The connectome atlas of the human subthalamic region may serve as a resource for imaging studies and for neurosurgical planning.

Cortico-cortical, cortico-striatal, and cortico-thalamic white matter fiber tracts generated in the macaque brain via dynamic programming.

Probabilistic methods have the potential to generate multiple and complex white matter fiber tracts in diffusion tensor imaging (DTI). Here, a method based on dynamic programming (DP) is introduced to reconstruct fibers pathways whose complex anatomical structures cannot be resolved beyond the resolution of standard DTI data. DP is based on optimizing a sequentially additive cost function derived from a Gaussian diffusion model whose covariance is defined by the diffusion tensor. DP is used to determine the optimal path between initial and terminal nodes by efficiently searching over all paths, connecting the nodes, and choosing the path in which the total probability is maximized. An ex vivo high-resolution scan of a macaque hemi-brain is used to demonstrate the advantages and limitations of DP. DP can generate fiber bundles between distant cortical areas (superior longitudinal fasciculi, arcuate fasciculus, uncinate fasciculus, and fronto-occipital fasciculus), neighboring cortical areas (dorsal and ventral banks of the principal sulcus), as well as cortical projections to the hippocampal formation (cingulum bundle), neostriatum (motor cortical projections to the putamen), thalamus (subcortical bundle), and hippocampal formation projections to the mammillary bodies via the fornix. Validation is established either by comparison with in vivo intracellular transport of horseradish peroxidase in another macaque monkey or by comparison with atlases. DP is able to generate known pathways, including crossing and kissing tracts. Thus, DP has the potential to enhance neuroimaging studies of cortical connectivity.

Region-specific gene expression in early postnatal mouse thalamus.

Previous studies in the developing mouse thalamus have demonstrated that regional identity is established during early stages of development (Suzuki-Hirano et al. J. Comp. Neurol. 2011;519:528-543). However, the developing thalamus often shows little resemblance to the anatomical organization of the postnatal thalamus, making it difficult to identify genes that might mediate the organization of thalamic nuclei. We therefore analyzed the expression pattern of genes that we have identified as showing regional expression in embryonic thalamus on postnatal days (P) 6-8 by using in situ hybridization. We also identified several genes expressed only in the postnatal thalamus with restricted expression in specific nuclei. We first demonstrated the selective expression of neurotransmitter-related genes (vGlut2, vGAT, D2R, and HTR2C), identifying the neurotransmitter subtypes of cells in this region, and we also demonstrated selective expression of additional genes in the thalamus (Steel, Slitrk6, and AI852580). In addition, we demonstrated expression of genes specific to somatosensory thalamic nuclei, the ventrobasal posterior nuclei (VP); a visual thalamic nucleus, the dorsal lateral geniculate nucleus (dLGN); and an auditory thalamic nucleus, the medial geniculate body (MGB) (p57Kip, Nr1d1, and GFRα1). We also identified genes that are selectively expressed in multiple different nuclei (Foxp2, Chst2, and EphA8). Finally, we demonstrated that several bone morphogenetic proteins (BMPs) and their inhibitors are expressed in the postnatal thalamus in a nucleus-specific fashion, suggesting that BMPs play roles in the postnatal thalamus unrelated to their known role in developmental patterning. Our findings provide important information for understanding the mechanisms of nuclear specification and connectivity during development, as well as their maintenance in adult thalamus.

Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging.

The development of cortical axonal pathways in the human brain begins during the transition between the embryonic and fetal period, happens in a series of sequential events, and leads to the establishment of major long trajectories by the neonatal period. We have correlated histochemical markers (acetylcholinesterase (AChE) histochemistry, antibody against synaptic protein SNAP-25 (SNAP-25-immunoreactivity) and neurofilament 200) with the diffusion tensor imaging (DTI) database in order to make a reconstruction of the origin, growth pattern and termination of the pathways in the period between 8 and 34 postconceptual weeks (PCW). Histological sections revealed that the initial outgrowth and formation of joined trajectories of subcortico-frontal pathways (external capsule, cerebral stalk-internal capsule) and limbic bundles (fornix, stria terminalis, amygdaloid radiation) occur by 10 PCW. As early as 11 PCW, major afferent fibers invade the corticostriatal junction. At 13-14 PCW, axonal pathways from the thalamus and basal forebrain approach the deep moiety of the cortical plate, causing the first lamination. The period between 15 and 18 PCW is dominated by elaboration of the periventricular crossroads, sagittal strata and spread of fibers in the subplate and marginal zone. Tracing of fibers in the subplate with DTI is unsuccessful due to the isotropy of this zone. Penetration of the cortical plate occurs after 24-26 PCW. In conclusion, frontal axonal pathways form the periventricular crossroads, sagittal strata and 'waiting' compartments during the path-finding and penetration of the cortical plate. Histochemistry is advantageous in the demonstration of a growth pattern, whereas DTI is unique for demonstrating axonal trajectories. The complexity of fibers is the biological substrate of selective vulnerability of the fetal white matter.

Reproducibility of quantitative tractography methods applied to cerebral white matter.

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra- and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T2 of individual white matter tracts. Distinctive features in FA and T2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.