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Background Chronic fatigue syndrome is diagnosed by a set of clinical criteria and therefore is probably heterogeneous. Earlier reports tested the hypothesis that the syndrome had a neurological substrate by doing studies of cerebral blood flow (CBF) but with discrepant results. One possible reason for the discrepancy was that relative CBF was assessed. We found reduced CBF in an earlier study of absolute CBF using xenon-CT. The purpose of this study was to use a second method of assessing CBF and to look within the study group for heterogeneity of responses. Method Eleven CFS patients and 10 age matched healthy controls underwent neuro-imaging using arterial spin labeling to determine their regional and global absolute CBF. A template was constructed based on the control data, and individual patient montages were compared on a case by case basis to determine if differences in regions of interest occurred. Results The patients as a group had significantly lower global CBF than the controls. The reduction in CBF occurred across nearly every region assessed. Nine of the 11 patients showed these reductions compared to the average control data, while two patients showed actual increases relative to the controls. Conclusion The data extend our earlier observation that CFS patients as a group have broad decreases in CBF compared to healthy controls. However, as expected, the effect was not homogeneous in that 2 of the 11 patients studied showed actual increases in CBF relative to controls.

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala plays a central role in the processing of novelty and emotion in the brain. While there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory, and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioural assessment made in the laboratory at four months of age. This is the earliest known human behavioural phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high-levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or “endophenotypes”) indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically-defined disorder. Because the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory, and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the four-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.

Context The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviours first observed in infancy or early childhood. High reactive infants are characterized at 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low reactive infants show low motor activity and low vocal distress to the same stimuli. High reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects and situations. In contrast, low reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. Objective To examine whether differences in the structure of ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. Design Structural MRI in a cohort of 18-year olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. Setting Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital Participants 76 subjects who were high reactive or low reactive infants at 4 months of age. Main Outcome Measures Cortical thickness Results Adults with a low reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in right ventromedial prefrontal cortex. This is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.