Autism-related Brain Networks On Touch And Oxytocin's Modulatory Effects

Autism spectrum disorders(ASD)are a group of heterogeneous developmental disorders which can severely compromise a child's social motivation,communication and interaction skills for the whole of their lives.Currently there is no successful treatment for these disorders which in China,as well as internationally,affect around 1% of the population.Up till now,there have not been any specific bio-markers yet successfully identified for the diagnosis of ASD and or effective therapeutic treatment been developed.Previous studies have implicated both structural and interhemispheric functional connectivity alterations in autism spectrum disorder(ASD)although findings are inconsistent.There is evidence that connectivity between corresponding regions in each hemisphere(homotopic)may be of particular importance.It is shown that blood concentrations of oxytocin reduce in individuals with ASD and this is associated to some extent with symptom severity in both healthy and clinical populations.Massage,as a non-invasive and pleasant experience of social touch,may be an important method for increasing endogenous oxytocin concentrations and of potential therapeutic benefit in disorders with social dysfunction such as autism.This dissertation consists of three main studies.Study 1 identifies the altered resting-state functional connectivities between homotopic brain regions by analyzing ABIDE data,while study 2 focuses on healthy subjects with high and low autistic traits and conduct massage experiment to see the effects of pleasant social touch on blood oxytocin concentration and neural activities in targeted regions.Study 3 further explores intranasal oxytocin in its modulatory effects on behavioral and neural responses towards social touch and essentially its correlation with autistic trait.In study 1,we used the Autism Brain Imaging Data Exchange data to investigate ASD-related resting-state and structural alterations as well as associations with symptom severity(Autism Diagnostic Observation Scale – ADOS).We employed a voxel-mirrored homotopic connectivity analysis to compare interhemispheric functional connectivity in 409 ASD and 455 typically developing subjects.Additionally,voxel-based morphology was used to investigate volumetric differences in corpus callosum,the major commissure for interhemispheric communication.ASD subjects demonstrated significant reductions in interhemispheric functional connections between regions in the default mode network(medial prefrontal,posterior cingulate and precuneus),salience network(anterior cingulate and insula),mirror neuron/motor systems(inferior frontal gyrus,inferior parietal lobule,precentral gyrus,supplementary motor area),thalamus and auditory(superior temporal gyrus)and visual systems(lingual,fusiform and inferior occipital gyri).A support vector machine analysis based on interhemispheric connectivity(but not all homotopic)revealed an average classification accuracy of 88.70% for distinguishing ASD from controls across different sites.In ASD subjects symptom severity as measured by ADOS was negatively associated with posterior cingulate,insula and superior temporal gyrus homotopic functional connectivity.While ASD subjects displayed reduced anterior and posterior callosal volumes they were not associated with either ADOS scores or functional connectivity changes.In study 2,we investigated oxytocin release and associated neural responses using functional near infrared spectroscopy(fNIRS)during hand or machine administered massage.40 adult male subjects received 10 min of light foot massage either by hand or machine in a counterbalanced order and then rated pleasure,intensity,arousal and how much they would pay for the massage.Blood samples were taken before and after each massage condition to determine plasma oxytocin concentrations.Neural responses from medial and lateral orbitofrontal cortex,superior temporal sulcus and somatosensory cortex were measured(fNIRS oxy-Hb)together with skin conductance responses(SCR),ratings of the massage experience,autistic traits and sensitivity to social touch.Results showed subjects gave higher ratings of pleasure,but not intensity or arousal,after hand compared with machine massage and there were no differential effects on SCR.Subjects were also willing to pay more for the hand massage.Plasma oxytocin increased after both hand and machine massage,but more potently after hand massage.Both basal oxytocin concentrations and increases evoked by hand,but not machine massage,were negatively associated with trait autism and attitudes towards social touch,but hand-massage evoked changes were significant in higher as well as lower trait individuals.Increased neural responses to hand vs.machine massage were found in posterior superior temporal sulcus and medial/lateral orbitofrontal cortex but not somatosensory cortex.Orbitofrontal cortex and superior temporal cortex activation during hand massage was associated with the amount of money subjects were willing to pay and between orbitofrontal cortex activation and autism scores.In study 3,we investigated whether intranasal oxytocin modulates behavioral and neural responses to affective touch administered either as foot massage applied by hand or by machine using a within-suject placebo/oxytocin contrast design.Subjects underwent blocks of massage of each type where they received the massage and subsequently also imagined it.As hypothesized,intranasal oxytocin significantly increased subjective pleasantness ratings of the manual but not machine massage.Results showed that oxytocin increased responses to experiencing manual massage in key regions involved in reward(orbitofrontal cortex,dorsal striatum and ventral tegmental area),social cognition(superior temporal gyrus and inferior parietal lobule),emotional and salience(amygdala and anterior cingulate and insula),visual(fusiform gyrus and occipital cortex),auditory(medial temporal gyrus)and sensorimotor(cerebellum processing as well as in the default mode network(medial prefrontal cortex,parahippocampal gyrus,posterior cingulate and precuneus)and some sensorimotor regions(cerebellum and pre-and post-central gyrus).Oxytocin also altered functional homotopic connectivity in the dorsomedial prefrontal cortex,insula and thalamus).Findings in study 3 generally support and extend the modulating effects of social touch and oxytocin on subjects' behavioral and neural activities reported in study 2.Overall,our findings suggest that reduced interhemispheric connectivity involving homotopic regions may be a potential biomarker for ASD with bilateral posterior cingulate,insula and superior temporal gyrus connections being associated with symptom severity.Hand massage can potently increase oxytocin release and activity in brain regions involved in social cognition and reward but not sensory aspects of affective touch.Hand-massage induced changes in both oxytocin concentrations and neural circuits involved in processing social affective trust may have therapeutic potential in the context of autism.