In the present analysis we observed diminished grey matter in the hypothalamus in children with autism compared to healthy controls. Given the tight matching for age, IQ, and gender, as well as the additional inclusion of these parameters as covariates, this difference seems to be independent of these possible confounds. We therefore interpret this finding to be associated with the defining criteria of autism, which according to the DSM IV (3
) include impaired social interaction and stereotyped behaviors. The locally diminished grey matter was observed in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin. This reduction may therefore reflect the mounting evidence that the oxytocin/vasopressin system is affected in individuals with autism (5
). The analysis of total brain volume, however, did not reveal significant differences between the two groups. This is well in line with the theory, that a difference in total brain or tissue volumes might only be observed within discrete developmental epochs, reflecting specific disruptions in brain development, which may not remain apparent at later stages of brain maturation (1
Empathy, eye contact and face memory have been described as altered in autism (1
). Reinforced by the two hormones oxytocin and arginine vasopressin, these adaptive traits allow us to create and maintain successful social interaction (25
). Oxytocin, which is sometimes described as the “cuddling hormone”, is responsible for milk let down and uterus contractions after birth. It also increases trust, empathy, eye contact, face memory, and strengthens the bonds between individuals (5
). Arginine vasopressin, which is well known for its anti-diuretic effect, influences social behavior as well, although its effects are more diverse. For example, in males arginine vasopressin was described to enhance aggression against other males, while females tended to perceive other females as more friendly (33
). Also effects on altruism, stronger bonding and enhanced encoding of emotional faces have been described, which may be relayed by specific receptors (33
). Interestingly, arginine vasopressin also binds to oxytocin receptors, where it might elicit similar effects as oxytocin (5
). Both substances are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus, with arginine vasopressin synthesized in the suprachiasmatic nucleus as well (5
). From here, they are transported to the posterior part of the hypophysis, the location where both hormones are released into the blood. Also an additional direct release within the brain was described for both hormones, which facilitates them to work directly as neuromodulators (5
The observed diminished grey matter volume in this study might be due to a diminished number and/or a smaller size of neurons. Another possible explanation may be a compacting of the neuropil, which consists in particular of glia, axons and dendrites, synapses, and blood vessels. This compacting may be caused for example by an accelerated synaptic pruning as described by Giorgio et al. (42
), fewer connections to other brain regions, or an alteration of the glia. In the following, we will briefly discuss the potential relations between these possible morphological changes and deviations in the oxytocin/vasopressin system.
Deviations in the oxytocin/vasopressin system in autism may comprise globally diminished hormonal levels due to diminished synthesis, a dysregulation of hormonal release, or a relative local deficit of these hormones as neuromodulators in the brain. Of these possibilities, a dysregulation of hormonal release may present most variable, ranging from globally diminished hormonal levels to an inadequate hormonal release with a seemingly unaffected hormonal concentration in the blood. A relative deficit of the hormones as neuromodulators, however, might present with otherwise normal hormonal levels, normal capacity for synthesis, and normal regulation of hormonal release.
A diminished capacity to synthesize oxytocin and arginine vasopressin may be due to fewer or smaller neurons that synthesize these hormones. Mechanisms for a dysregulation of hormonal release may be an accelerated synaptic pruning, an alteration of the glia, which was reported to modulate directly the neuronal activity in the hypothalamus of the rat (43
), or a change in the sensitivity of the hormonal receptors, which was previously observed in autism (38
). Finally, a relative deficit of these hormones as neuromodulators may be caused by a reduced connectivity to other brain areas (5
). However, as the present data cannot directly address the link between volumetric changes and possible deviations in the oxytocin/vasopressin system, further studies will be needed to illuminate the exact pathophysiology of the oxytocin/vasopressin system in autism.
While we were able to detect significantly diminished grey matter in the hypothalamus, no other region throughout the brain showed significant morphometric differences after correction for multiple comparisons. Previous VBM studies in children reported varying effects of autism on grey matter throughout the brain. For example, Bonilha et al. reported widespread augmented grey matter in autism, which comprised frontal, parietal and temporal lobes (12
). Similarly, another study also reported augmented grey matter in these regions (13
), with an additional isolated reduction in the right parahippocampal gyrus. In contrast to this, McAlonan et al. found widespread grey matter reductions in frontal, parietal and temporal lobes (7
) and another study reported localized grey matter reductions in the superior temporal sulcus only (11
). While in all studies the mean age difference between the autism and control groups was within 1.5 years, no study reported including age as a covariate in the model. Furthermore, only Boddaert et al. included IQ as a covariate (11
), since the group with autism in their study had a mean IQ of 55.8 and thus differed substantially from their control group. Seeing that age and IQ effects on brain morphometry between subjects with autism and healthy controls are assumed (1
), these factors may well have influenced the findings of prior investigations. Since, in previous studies, group size varied between 12 and 21 subjects with autism and between 12 and 17 controls, this might be a confounding factor for previous analyses.
Recent research provides suggestive evidence that the administration of oxytocin to individuals with autism is associated with improvements in measures of social information processing, and possibly reductions in impairments in social interaction (25
). Furthermore, although data are limited, some data suggest that plasma levels of oxytocin might be lower in children with autism than in age-matched controls (49
). The reduction of grey matter observed here might therefore constitute a link between neuroanatomy and models of hormonal dysregulation in autism. Although this hypothesis may not explain all neurobiological aspects of the disorder, the convergence of findings of hypothalamic dysmorphology and dysfunction could provide more support for research focused on therapeutic interventions based on these systems, and for better understanding the neurobiological mechanisms associated with autism.
In a relatively large sample, we identified significantly lower grey matter volume in the hypothalamus of children with autism relative to control children, independent of age, IQ, or gender. This observation suggests that morphological change in the hypothalamus may serve as an anatomical correlate for the defining features of autism that include impairment in social interaction and restricted or stereotyped patterns of behavior, interests and activities (3
). Since the hypothalamus synthesizes behaviorally relevant hormones (oxytocin and arginine vasopressin) our findings also support a direct link between neuroanatomy, endocrine function, and diagnosis. Future studies are required to further explore the links between hypothalamic hormonal dysregulation and autism. Optimally, replication studies would measure hormonal blood levels and characterize genetic alterations in the hormone specific receptors. This would be particularly salient, as the present results are concordant with a candidate pharmacologic intervention in autism, which has rendered early promising results (25
). Subsequent studies, which investigate longitudinal hormonal effects on brain development and behavior, as well as similarities and differences across subtypes of autism, are also considered of fundamental importance.