The Influence Of Multiple Dose Nasal Spray Of Oxytocin On Human Behavior And Brain Imaging

The neuropeptide oxytocin?OT?,which plays a key role in social and emotional functioning in both animals and humans,and is increasingly proposed as a promising therapy for social dysfunction in neuropsychiatric disorders such as autism,anxiety disorder and schizophrenia,particularly by modulating amygdala-mediated social-emotional behavior.Altered amygdala function is considered to be one of the most important biomarkers for social dysfunction in neuropsychiatric disorders and a 24IU dose of intranasal OT together with a 45 minute time course have been shown to be optimal for a single acute dose strategy in a previous study.Previous single dose OT studies have revealed that it can significantly influence emotional and social behaviors although to date clinical trials have reported only some or no benefit of chronic treatment where it is administered either once or twice daily.It is unclear whether efficacy of the chronic treatment of OT might be influenced by dose frequency or subject characteristics such as trait anxiety and oxytocin receptor genotype.In this thesis three different studies are described which have investigated the influence of dose frequency,and modulation of trait anxiety of subject and oxytocin receptor genotype?OXTR rs53576 and rs2254298?on the effects of chronic doses of OT.Behavior and brain imaging?functional task,resting state brain imaging and brain structure imaging?methods were conducted to explore the chronic effect of intranasal OT and particularly the effects of dose frequency.In addition,interactions between trait anxiety/oxytocin receptor genotype with chronic effects of OT were investigated.Study 1 investigated the influence of dose frequency of intranasal OT on brain and behavior.In a randomized,placebo-controlled,between subject designed,pharmaco-f MRI trial,150 male subjects were recruited.We investigated acute and different chronic intranasal oxytocin dose frequencies on changes in brain structure,amygdala function and behavioral ratings of emotional stimuli.Subjects were randomly assigned to three parallel repeated intranasal treatment groups?single daily dose on five consecutive days?of placebo?PLC?,oxytocin?OT₅?,or interleaved OT and PLC?OT on days 1,3,5,PLC on days 2,4;OT₃?.On the 1^st and 5^th days,45 minutes after treatment,subjects were required to perform an implicit emotional face processing task in the MRI scanner and brain responses recorded using functional MRI following 3D T1 brain structure and resting state scans.When subjects completed the f MRI tasks they were instructed to evaluate the face stimuli outside of the scanner.The results showed that although acute and repeated OT administration didn't change the structure of brain,it did markedly influence amygdala function.A major finding was that oxytocin-induced reduction in amygdala reactivity to all face emotions observed following a single dose was abolished after daily doses for 5 days but maintained or significantly enhanced by doses given every other day.Doses given every other day also enhanced associated anxious-arousal attenuation revealed by decreased behavioral ratings of emotional arousal and intensity to fear faces.Interestingly,the functional connectivity between amygdala and prefrontal cortex,which is considered as another important biomarker of OT treatment,was increased equivalently in both repeated dose groups?both OT₃ and OT₅?compared with the acute effect(single dose on the 1^st day).These findings indicate that infrequent chronic oxytocin administration may be therapeutically most efficient with the lower frequency OT administration group showing both improved amygdala and anxiolytic effects.Resting state functional connectivity in intrinsic networks may on the other hand be less sensitive to frequency effects of repeated OT administration.However,it was unclear whether this dose-frequency dependent effect of OT on amygdala and anxiolytic responses was influenced by trait anxiety levels in different individuals and so in a further study we investigated this.Study 2 investigated the modulatory effect of trait anxiety on dose frequency effects of intranasal OT.Given the anxiolytic actions observed in study 1,high and low trait anxiety subgroups were recruited to investigate the interaction effect between trait anxiety and dose frequency.145 subjects completed the experimental tasks.The study protocol for intranasal OT administration was identical to that used in study 1,although an implicit emotional scene processing task was included along with the implicit emotional face processing task.The results showed that for the acute effect on the 1^st day there was a significant decreased amygdala response to fear faces in the low trait anxiety group but there was no significant effect on implicit emotional scene processing for either the low or high anxiety groups.On the other hand for the chronic effect of OT the high trait anxiety subgroup showed a reduced amygdala response to both fear faces and negative valence scenes with the low but not high dose frequency strategy.No effect of acute or chronic administration of intranasal OT was found on behavioral ratings in the different trait anxiety groups.These findings indicate that infrequent chronic oxytocin administration may produce anxiolytic actions in higher anxiety individuals particularly in response to fear faces and threatening scenes.The OXTR SNPs rs2254298 and rs53576are associated with social behaviors,autism,social and emotional processing and anxiety and may therefore also influence sensitivity of behavioral and neural responses to intranasal OT.However,it is still unknown whether these two OXTR SNPs modulate either neural or behavioral responses to acute or chronic doses of OT.A further study was therefore designed to investigate this.Study 3 investigated the modulatory influence of OXTR rs2254298 and rs53576 on acute and chronic doses of intranasal OT.A total of 120 subjects who participated in study1 were called back to collect their buccal cells for the genetic analysis.Based on the f MRI and behavioral data collected in the study one,the new factor of OXTR genotype were included in the data analysis model.Results showed that only G non-carriers of rs53576and A carriers of rs2254298 exhibited significant reductions in amygdala responses to emotional faces in response to intranasal OT.Furthermore,only A carriers of rs2254298showed significant reductions in arousal and intensity ratings following the low dose frequency strategy.However,OXTR genotype did not modulate resting state effects of intranasal OT.Taken together findings from the three studies performed suggest that an infrequent chronic OT administration strategy may be therapeutically most efficient and especially in individuals who are G non-carriers of rs53576 and A carriers of rs2254298.The anxiolytic actions on the brain using the low dose frequency strategy were also specific to high anxiety trait males.Further research on clinical populations such as anxiety disorder or autism patients are therefore needed to determine if an infrequent dose frequency protocol can produce greater therapeutic effects.