Specialization and integration of functional thalamocortical connectivity in the human infant

Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.The formation of topographically organized neural connections between cerebral cortex and thalamus is necessary for normal cortical morphogenesis (1), and development of these connections requires thalamocortical projections to synapse transiently in the temporary cortical subplate before penetrating the cortical plate (2–4). In humans, the subplate is at maximal extent in the last trimester of gestation (5), a time of rapid growth for thalamocortical fibers and the cortical dendritic tree, particularly in heteromodal cortex (6, 7). This process has been shown to be disrupted by preterm birth (8). Premature delivery is associated with increased risk of neurocognitive impairment, and it is widely hypothesized that abnormal development of brain structure during this period is the cause of these problems and may also underlie the development of autistic spectrum disorders and attention deficit disorders in genetically predisposed individuals.During the last trimester of pregnancy, functional MRI (fMRI) detects the emergence of coordinated, spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signals, which are closely linked with the development of electroencephalographic activity (9–11) and develop into a near-facsimile of the mature adult resting-state network architecture by the normal age of birth at 38–42 wk gestational age (12). However, little is known about the growth of functional connectivity between the thalamus and cortex during this period.Anatomical studies in animals and postmortem adult human subjects have defined the thalamic microstructure and described a corticotopic parcellation of the thalamus with precise connectivity to specific cortical regions (13, 14). Diffusion tensor imaging studies have described a similar pattern of structural thalamocortical connectivity (15, 16), with evidence in adults that some thalamocortical circuits share common thalamic territory, giving the potential for integrative functions (17). Functional connectivity MRI analysis between the thalamus and the cortex has also shown corticotopic organization in the thalamus (18, 19).It is not known, however, when this thalamocortical mapping develops or how it might be disrupted during development. We, therefore, used connectivity fMRI to address a series of questions. First, is the pattern of dominant thalamocortical connectivity at the time of normal birth already similar to the mature adult pattern? Second, in addition to the dominant thalamocortical correlations, is there a pattern of overlapping cortical representations in the neonatal thalamus that might reflect developing integration of functional cortical regions? Third, does the experience of preterm delivery and premature extrauterine life affect the development of thalamocortical connectivity, and is the effect more marked in rapidly developing heteromodal cortex than in more mature primary cortex?