Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Pharmacology & Pharmacy, Psychiatry, Neurosciences & Neurology, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, 3209 Neurosciences, 5202 Biological psychology

Abstract:

Background. Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with no established pharmacological treatment. The past decade, intranasal administration of the ‘prosocial’ neuropeptide oxytocin is increasingly explored as a potential treatment for targeting the core symptoms of ASD. While initial neuroimaging studies provided important insights into the immediate neural effects of single-dose administrations of oxytocin, the impact of continual (multiple-dose) oxytocin treatment on human neural circuitry is largely unknown and also the possibility that long-term treatment may induce long-lasting neurobehavioral changes that outlast the period of actual administration remains unexplored. Aim. With this double-blind, randomized, placebo-controlled, between-subject clinical trial, we investigated the possibility of long-lasting neural and behavioral effects of continual oxytocin treatment (four weeks of daily administrations: 24 IU/ day) in 38 adult males with ASD (mean age: 24 years) (21 oxytocin, 17 placebo). Methods. Oxytocin-induced changes in ‘intrinsic’ functional connectivity of the amygdala to core regions of the ‘social brain’ were investigated based on resting-state functional magnetic resonance imaging (fMRI). MRI scans were acquired at baseline (T0), immediately after the multiple-dose oxytocin treatment (T1) and at two follow-up sessions, four weeks (T2) and one year (T3) after cessation of the treatment. Also behavioral effects of the multiple-dose oxytocin treatment were evaluated on core autism symptoms (social functioning, repetitive behavior), attachment and quality of life. Pre-to-post changes were calculated for each assessment session and difference scores were subjected to a linear mixed-effects model with the random factor ‘subject’, and the fixed factors ‘treatment’ (oxytocin, placebo) and ‘session’ (T1, T2, T3). Results. A main effect of ‘treatment’ (across sessions T1, T2, T3) was revealed (F= 6.65, p=.014; ηp2 = .16, medium-size effect); indicating that the four-weeks of continual oxytocin administration significantly diminished connectivity of the amygdala to other regions of the social brain (most pronounced for orbitofrontal cortex, medial prefrontal cortex and right posterior superior temporal sulcus). Importantly, the oxytocin-induced changes in amygdala circuitry were shown to outlast the period of actual administration until four weeks (T2) and even one year (T3) post-treatment (all, pBonferonni < .001). At the behavioral level, the oxytocin treatment induced medium- to large-sized improvements in repetitive behaviors (Repetitive Behavior Scale - Revised) and reduced feelings of avoidance towards others (State Adult Attachment Measure) which also persited until four weeks and one year post-treatment. Importantly, the neural adaptations in functional coupling of the amygdala were associated with these behavioral improvements (i.e., participants with the strongest reduction in amygdala connectivity displayed more behavioral improvement). Conclusion. The observation that the neurobehavioral effects outlasted the period of actual administration provides strong indications that continual oxytocin treatment induced a long-lasting re-shaping of amygdala-centered circuits in an adaptive, experience-dependent manner. Together these findings are of relevance for ASD and the broad range of neuropsychiatric conditions for which oxytocin is considered as a potential treatment.