Emi Takahashi

Hemispheric asymmetry in human lateral prefrontal cortex during cognitive set shifting

Functional organization of human cerebral hemispheres is asymmetrically specialized, most typically along a verbal/nonverbal axis. In this event-related functional MRI study, we report another example of the asymmetrical specialization. Set-shifting paradigms derived from the Wisconsin card sorting test were used, where subjects update one behavior to another on the basis of environmental feedback. The cognitive requirements constituting the paradigms were decomposed into two components according to temporal stages of task events. Double dissociation of the component brain activity was found in the three bilateral pairs of regions in the lateral frontal cortex, the right regions being activated during exposure to negative feedback and the corresponding left regions being activated during updating of behavior, to suggest that both hemispheres contribute to cognitive set shifting but in different ways. The asymmetrical hemispheric specialization within the same paradigms further implies an interhemispheric interaction of these task components that achieve a common goal.

Emerging Cerebral Connectivity in the Human Fetal Brain: An MR Tractography Study

Cerebral axonal connections begin to develop before birth during radial migration in each brain area. A number of theories are still actively debated regarding the link between neuronal migration, developing connectivity, and gyrification. Here, we used high angular resolution diffusion tractography on postmortem fetal human brains (postconception week (W) 17-40) to document the regression of radial and tangential organization likely to represent migration pathways and the emergence of corticocortical organization and gyrification. The dominant radial organization at W17 gradually diminished first in dorsal parieto-occipital and later in ventral frontotemporal regions with regional variation: radial organization persisted longer in the crests of gyri than at the depths of sulci. The dominant tangential organization of the ganglionic eminence at W17 also gradually disappeared by term, together with the disappearance of the ganglionic eminence. A few immature long-range association pathways were visible at W17, gradually became evident by term. Short-range corticocortical tracts emerged prior to gyrification in regions where sulci later developed. Our results suggest that the regional regression of radial organization and regional emergence of fetal brain connectivity proceeds in general from posterodorsal to anteroventral with local variations.

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

Abstract The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Developing Neocortex Organization and Connectivity in Cats Revealed by Direct Correlation of Diffusion Tractography and Histology

The immature cortex (cortical plate [CP]) and underlying subplate (SP), a transient cell layer just below the CP, play critical roles in the formation of intracerebral connections. The purpose of this study was to examine the diffusion characteristics of the developing cortex and subcortical structures and compare to histology. We obtained high-resolution diffusion spectrum images of postnatal day (P) 0 (newborn), P35 (pediatric), and P100 (adult) cat brains, performed tractography analysis, and correlated with histological findings. Tractography revealed radial organization and radial afferent/efferent tracts not only in the CP but also in external SP at P0. Radial organization persisted only in the cortex but decreased at P35 and P100. Radial organization correlated with radial cellular organization, with highest cellular density at P0 (Cresyl Violet staining). At P0, the internal SP contained abundant corticocortical and projection tractography pathways, crossing at wide angles in areas with no myelination by Luxol Fast Blue staining. At P35 and P100, increased directional coherence of white matter was observed, with fewer local tracts, but more long association pathways. These results suggest that diffusion tractography can differentially characterize internal and external SP zones and their transition into mature cortical pathways.

Development of cerebral fiber pathways in cats revealed by diffusion spectrum imaging.

Examination of the three-dimensional axonal pathways in the developing brain is key to understanding the formation of cerebral connectivity. By tracing fiber pathways throughout the entire brain, diffusion tractography provides information that cannot be achieved by conventional anatomical MR imaging or histology. However, standard diffusion tractography (based on diffusion tensor imaging, or DTI) tends to terminate in brain areas with low water diffusivity, indexed by low diffusion fractional anisotropy (FA), which can be caused by crossing fibers as well as fibers with less myelin. For this reason, DTI tractography is not effective for delineating the structural changes that occur in the developing brain, where the process of myelination is incomplete, and where crossing fibers exist in greater numbers than in the adult brain. Unlike DTI, diffusion spectrum imaging (DSI) can define multiple directions of water diffusivity; as such, diffusion tractography based on DSI provides marked flexibility for delineation of fiber tracts in areas where the fiber architecture is complex and multidirectional, even in areas of low FA. In this study, we showed that FA values were lower in the white matter of newborn (postnatal day 0; P0) cat brains than in the white matter of infant (P35) and juvenile (P100) cat brains. These results correlated well with histological myelin stains of the white matter: the newborn kitten brain has much less myelin than that found in cat brains at later stages of development. Using DSI tractography, we successfully identified structural changes in thalamo-cortical and cortico-cortical association tracts in cat brains from one stage of development to another. In newborns, the main body of the thalamo-cortical tract was smooth, and fibers branching from it were almost straight, while the main body became more complex and branching fibers became curved reflecting gyrification in the older cats. Cortico-cortical tracts in the temporal lobe were smooth in newborns, and they formed a sharper angle in the later stages of development. The cingulum bundle and superior longitudinal fasciculus became more visible with time. Within the first month after birth, structural changes occurred in these tracts that coincided with the formation of the gyri. These results show that DSI tractography has the potential for mapping morphological changes in low FA areas associated with growth and development. The technique may also be applicable to the study of other forms of brain plasticity, including future studies in vivo.

Diffusion tensor studies dissociated two fronto-temporal pathways in the human memory system

Recent functional neuroimaging studies have shown that multiple cortical areas are involved in memory encoding and retrieval. However, the underlying anatomical connections among these memory-related areas in humans remain elusive due to methodological limitations. Diffusion tensor imaging (DTI) is a technique based on detecting the diffusion of water molecules from magnetic resonance images. DTI allows non-invasive mapping of anatomical connections and gives a comprehensive picture of connectivity throughout the entire brain. By combining functional magnetic resonance imaging (fMRI) and DTI, we show that memory-related areas in the left dorsolateral prefrontal cortex (DLPFC) and the left ventrolateral prefrontal cortex (VLPFC) each connect with memory-related areas in the left temporal cortex. This result suggests there are two pathways between prefrontal cortex and temporal cortex related to the human memory system.

Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons

The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Slc17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.

Dynamics of a morbillivirus at the domestic -wildlife interface

Significance Morbilliviruses are a growing concern because of their ability to infect multiple species. The spill-over of canine distemper virus (CDV) from domestic dogs has been associated with severe declines in wild carnivores worldwide, and therefore mass dog vaccination has been suggested as a potential control strategy. Focusing on three decades of CDV exposure data in dogs and lions of the Serengeti, we show that cyclic infection dynamics in lions initially driven by dogs became more frequent and asynchronous, suggesting that the wider dog population and other wildlife species drive CDV dynamics. Hence, although widespread dog vaccination reduced the infection in dogs, transmission to lion populations still occurred, warranting further investigation into effective management options of CDV in this species-rich ecosystem. Morbilliviruses cause many diseases of medical and veterinary importance, and although some (e.g., measles and rinderpest) have been controlled successfully, others, such as canine distemper virus (CDV), are a growing concern. A propensity for host-switching has resulted in CDV emergence in new species, including endangered wildlife, posing challenges for controlling disease in multispecies communities. CDV is typically associated with domestic dogs, but little is known about its maintenance and transmission in species-rich areas or about the potential role of domestic dog vaccination as a means of reducing disease threats to wildlife. We address these questions by analyzing a long-term serological dataset of CDV in lions and domestic dogs from Tanzania’s Serengeti ecosystem. Using a Bayesian state–space model, we show that dynamics of CDV have changed considerably over the past three decades. Initially, peaks of CDV infection in dogs preceded those in lions, suggesting that spill-over from dogs was the main driver of infection in wildlife. However, despite dog-to-lion transmission dominating cross-species transmission models, infection peaks in lions became more frequent and asynchronous from those in dogs, suggesting that other wildlife species may play a role in a potentially complex maintenance community. Widespread mass vaccination of domestic dogs reduced the probability of infection in dogs and the size of outbreaks but did not prevent transmission to or peaks of infection in lions. This study demonstrates the complexity of CDV dynamics in natural ecosystems and the value of long-term, large-scale datasets for investigating transmission patterns and evaluating disease control strategies.

The role of the parahippocampal gyrus in source memory for external and internal events.

We can discriminate between the memories of real and imagined events. In this study, the traces of the perceived external events and the imagined internal events were investigated in the established paradigm of reality monitoring using event-related fMRI. In the retrieval phase, we found that the left parahippocampal gyrus represented the traces of visually encoded memory. The right inferior parietal cortex was activated when subjects judged that the original event was imagined. We suggest that these traces are used to distinguish what is seen from what is thought during reality monitoring. Furthermore, we found that the incorrect judgments were associated with signal increases in the left frontal operculum, suggesting that this area is a candidate for the monitoring system of contextual information or failure in the retrieval phase.

Radial Coherence of Diffusion Tractography in the Cerebral White Matter of the Human Fetus: Neuroanatomic Insights

High angular resolution diffusion imaging (HARDI) demonstrates transient radial coherence of telencephalic white matter in the human fetus. Our objective was to define the neuroanatomic basis of this radial coherence through correlative HARDI- and postmortem tissue analyses. Applying immunomarkers to radial glial fibers (RGFs), axons, and blood vessels in 18 cases (19 gestational weeks to 3 postnatal years), we compared their developmental profiles to HARDI tractography in brains of comparable ages (n = 11). At midgestation, radial coherence corresponded with the presence of RGFs. At 30-31 weeks, the transition from HARDI-defined radial coherence to corticocortical coherence began simultaneously with the transformation of RGFs to astrocytes. By term, both radial coherence and RGFs had disappeared. White matter axons were radial, tangential, and oblique over the second half of gestation, whereas penetrating blood vessels were consistently radial. Thus, radial coherence in the fetal white matter likely reflects a composite of RGFs, penetrating blood vessels, and radial axons of which its transient expression most closely matches that of RGFs. This study provides baseline information for interpreting radial coherence in tractography studies of the preterm brain in the assessment of the encephalopathy of prematurity.