The Thalamus and the Limbic System: Tracing the Structural Connectivity (2019)

Introduction: The limbic system is a phylogenetically old behaviorally defined system that serves as a center for emotions, as it controls anger, fear, and joy and has an influence on sexual behavior, vegetative functions, and memory [1]–[5]. It comprises a collection of tel-, di-, and mesencephalic structures, whose components have increased over time [4], [6]. The previous animal research indicates that the anterior nuclear group of the thalamus (ANT), as well as the Habenula (Hb) and mediodorsal nucleus (MD) each, play a vital role in the limbic circuitry. Accordingly, diffusion imaging data obtained from the Human Connectome Project, and the masks of six (anterodorsal AD, anteromedial AM, anteroventral AV, lateral dorsal LD, habenula Hb, and mediodorsal MD) nuclei served as seed regions for a direct probabilistic tracking to the rest of the brain using diffusion-weighted imaging (DWI) (s. Fig. 1). Methods: Data: The diffusion imaging data of 730 subjects obtained from the Human Connectome Project [7]. The diffusion data were acquired by using a Spin-echo EPI sequence, TR: 5520 ms, TE: 89.5ms, voxel size: 1.25 mm isotropic, b-values: 1000, 2000, and 3000 s/mm2. For details, see [7], [8]. Data analysis: The whole brain multi-shell reconstruction of the diffusion data were performed using the multi-shell model [9] implemented in bedpostx [10]. Connectivity analysis: The masks of six (anterodorsal AD, anteromedial AM, anteroventral AV, lateral dorsal LD, habenula Hb, and mediodorsal MD) nuclei served as seed regions[11] for a direct probabilistic tracking to the rest of the brain using probtrackx [12]. In the direct diffusion tractography, all streamlines passing through other thalamic nuclei were excluded to depict only directly routed connections to the ipsilateral cortex. The resulting tractograms were each normalized, and in the last step, the group fixed effect maps were computed (s. Fig 2). Results: The results revealed that the ANT nuclei are parts of the limbic and memory system as they mainly connect via mammillary tract, mammillary body, anterior commissure, fornix, and retrosplenial cortices to the hippocampus, amygdala, medio-temporal, orbito-frontal and occipital cortices [13]–[15]. Furthermore, the ANT nuclei showed with different extent connections to the mesencephalon and brainstem: a pattern rarely described in experimental findings (s. Fig. 2). The habenula – usually defined as part of the epithalamus – was closely connected to the tectum opticum and seems to serve as a neuroanatomical hub between the visual and limbic system, brainstem and cerebellum [16]–[18]. Finally, in contrast to experimental findings with tracer studies, the direct connections of MD were mainly confined to the brainstem, while the indirect MD fibers form a broad pathway connecting the hippocampus and medio-temporal areas with the mediofrontal cortex. Conclusions: The study presents a first approach in human to examine and verify the structural connectivity between diverse components of the limbic system and selected thalamic nuclei in a whole brain approach. Despite methodological discrepancies between diffusion guided fiber tracking and experimental connectivity studies using ante- and retrograde tracers in animals, we could confirm, that the ANT, Hb, and MD nuclei with different extent connect to major limbic components and with the mesencephalon and brainstem. While ANT nuclei broadly connect the hypothalamus, septal and prefrontal areas via fornix and cingulum with the retrosplenial area and the hippocampus, links the Hb the hypothalamus and orbitofrontal cortices via the stria medullaris and fornix with the tectum and visual cortices. Finally, only indirect MD tracts (i.e., connectivity via other thalamic nuclei) show extensive bilateral connections to the medio-frontal cortex. The determined tracts of the examined six nuclei will be available under https://github.com/vinkrishna/Limbic_Thalamus.