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Early life stress (ELS) is a risk factor for developing functional gastrointestinal disorders, and has been proposed to be related to a central amplification of sensory input and resultant visceral hyperalgesia. We sought to characterize ELS-related changes in functional brain responses during acute noxious visceral stimulation. Neonatal rats (males/females) were exposed to limited bedding (ELS) or standard bedding (controls) on postnatal days 2–9. Age 10–11 weeks, animals were implanted with venous cannulas and transmitters for abdominal electromyography (EMG). Cerebral blood flow (rCBF) was mapped during colorectal distension (CRD) using [14C]-iodoantipyrine autoradiography, and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping and functional connectivity. EMG responses to CRD were increased after ELS, with no evidence of a sex difference. ELS rats compared to controls showed a greater significant positive correlation of EMG with amygdalar rCBF. Factorial analysis revealed a significant main effect of ‘ELS’ on functional activation of nodes within the pain pathway (somatosensory, insular, cingulate and prefrontal cortices, locus coeruleus/lateral parabrachial n. [LC/LPB], periaqueductal gray, sensory thalamus), as well as in the amygdala, hippocampus and hypothalamus. In addition, ELS resulted in an increase in the number of significant functional connections (i.e. degree centrality) between regions within the pain circuit, including the amygdala, LC/LPB, insula, anterior ventral cingulate, posterior cingulate (retrosplenium), and stria terminalis, with decreases noted in the sensory thalamus and the hippocampus. Sex differences in rCBF were less broadly expressed, with significant differences noted at the level of the cortex, amygdala, dorsal hippocampus, raphe, sensory thalamus, and caudate-putamen. ELS showed a sexually dimorphic effect (‘Sex x ELS’ interaction) at the LC/LPB complex, globus pallidus, hypothalamus, raphe, septum, caudate-putamen and cerebellum. Our results suggest that ELS alters functional activation of the thalamo-cortico-amydala pathway, as well as the emotional-arousal network (amygdala, locus coeruleus), with evidence that ELS may additionally show sexually dimorphic effects on brain function., Highlights • Early life stress (ELS) elicits visceral hyperalgesia in adult offspring. • ELS alters functional activation of the thalamo-cortico-amydala pathway. • ELS shows a sexually dimorphic effects on brain function. • Functional imaging-based endpoints promise improved animal-to-human translation.

Youth with severe conduct problems impose a significant cost on society by engaging in high levels of antisocial and aggressive behavior. Within this group, adolescents with high levels of callous- unemotional traits have been found to exhibit more severe and persistent patterns of antisocial behavior than youth with severe conduct problems but normative levels of callous-unemotional traits. Existing neuroimaging studies, along with theoretical accounts of psychopathology, suggest that dysfunction within the paralimbic cortex and limbic system may underlie elevated levels of callous-unemotional traits. The present study examines this hypothesis by investigating gray matter correlates associated with callous-unemotional traits. A sample of incarcerated male adolescents (N = 269), were assessed using voxel-based morphometry. Callous-unemotional traits were assessed using the Inventory of Callous-Unemotional traits (Frick 2004). Total callous-unemotional traits were negatively correlated with anterior temporal lobe gray matter volume (GMV). Callous traits in particular exhibited a reliable negative correlation with gray matter volume in nearly every paralimbic brain region examined. Uncaring traits were positively correlated with GMV in the orbitofrontal and anterior cingulate cortices. These findings demonstrate specific neural features within the paralimbic cortex and limbic system that accompany elevated callous-unemotional traits and serves to expand our understanding of pathophysiological mechanisms that may give rise to severe conduct problems in youth., Highlights • Total callous-unemotional traits were negatively correlated with anterior temporal lobe gray matter volume (GMV). • Callous traits negatively correlated with GMV in nearly every paralimbic regions examined. • Uncaring traits were positively correlated with GMV in the orbitofrontal and anterior cingulate cortices.

Although brain plasticity in the form of gray matter increases and decreases has been observed in chronic pain, factors determining the patterns of directionality are largely unknown. Here we tested the hypothesis that fibromyalgia interacts with age to produce distinct patterns of gray matter differences, specifically increases in younger and decreases in older patients, when compared to age-matched healthy controls. The relative contribution of pain duration was also investigated. Regional gray matter was measured in younger (n=14, mean age 43, range 29–49) and older (n=14; mean age 55, range 51–60) female fibromyalgia patients and matched controls using voxel-based morphometry and cortical thickness analysis of T1-weighted magnetic resonance images. To examine their functional significance, gray matter differences were compared with experimental pain sensitivity. Diffusion-tensor imaging was used to assess whether white matter changed in parallel with gray matter, and resting-state fMRI was acquired to examine whether pain-related gray matter changes are associated with altered functional connectivity. Older patients showed exclusively decreased gray matter, accompanied by compromised white matter integrity. In contrast, younger patients showed exclusively gray matter increases, namely in the basal ganglia and insula, which were independent of pain duration. Associated white matter changes in younger patients were compatible with gray matter hypertrophy. In both age groups, structural brain alterations were associated with experimental pain sensitivity, which was increased in older patients but normal in younger patients. Whereas more pronounced gray matter decreases in the posterior cingulate cortex were related to increased experimental pain sensitivity in older patients, insular gray matter increases in younger patients correlated with lower pain sensitivity, possibly indicating the recruitment of endogenous pain modulatory mechanisms. This is supported by the finding that the insula in younger patients showed functional decoupling from an important pain-processing region, the dorsal anterior cingulate cortex. These results suggest that brain structure and function shift from being adaptive in younger to being maladaptive in older patients, which might have important treatment implications.