Functional Magnetic Resonance Imaging Study On Early Intervention Of RTMS In Neurodevelopmental Animal Models Of Schizophrenia

Object: Schizophrenia(SZ)is a neurodevelopmental disorder that becomes symptomatic between late adolescence to young adulthood.A growing number of studies have shown that in the early stage of SZ,including premorbid and prodrome,non-specific and psychotic symptoms as well as pathological changes in the brain have already appeared.Thus,the early intervention may delay or even prevent the progression of SZ.But so far,no effective treatment has been developed,there is a pressing need for early effective interventions to alleviate SZ symptoms and delay the progression of SZ.The researches on longitudinal study and preventive intervention are time-intensive and face considerable logistical and methodological obstacles in human.Consequently,valid animal models become critical and valuable tools to advance neuromodulatory strategies in SZ.In this study,we employed function magnetic resonance imaging(f MRI)to identified a candidate target(critical timing and brain locus)for early intervention based on the longitudinal brain activity changes from adolescence to adulthood in neurodevelopmental animal model of SZ.We then performed early intervention of the candidate target in the neurodevelopmental animal model with follow-up f MRI to determine subsequent brain activity alterations in adulthood.Methods: We established a neurodevelopmental animal model of SZ by randomly intraperitoneal injecting with saline or methylazoxymethanol acetate(MAM)at 17 days of pregnant rats,and collecting their male offspring rats which were weaned at 21 days after postnatal day(PD).Male offspring rats were divided into vehicle group and MAM group.All the experiment were divided into two parts.In the first past,we proposed to observed longitudinal f MRI changes from adolescence to adulthood in MAM.In the second part,we investigated the effect of rTMS on the f MRI of MAM rats in adulthood.For the first part,the rats were divided into two groups: vehicle group and MAM group.f MRI study with Bruker 7.0T MRI scanner in vehicle group and MAM group in adolescence(PD21-35)and adulthood(PD63?80)were undergone.Both voxel-based analysis and region of interest(ROI)approach were used to analyze regional homogeneity(Re Ho)difference between vehicle group and MAM group at adolescence and adulthood.ROI was defined as the posterior(primary sensory cortex)ROI and the frontal(prefrontal cortex)ROI.The posterior ROI included three subareas: bilateral visual cortex,bilateral auditory cortex,and bilateral temporal association cortex,and the frontal ROI included three subareas: bilateral medial prefrontal cortex,bilateral orbital frontal cortex,and bilateral anterior cingulate cortex.For the second part,(1)the rats were randomly divided into four groups:1.vehiclesham group,rTMS pseudo-stimulation was given to vehicle rats;2.vehicle-rTMS group,the vehicle rats were given rTMS intervention;3.MAM-sham group,rTMS pseudo-stimulation was given to MAM rats;4.MAM-rTMS group,the MAM rats were given rTMS intervention.(2)rTMS or sham treatment targeting the primary sensory cortex was conducted in adolescence(PD42?62).Each animal was administered daily stimulation treatment for 2 weeks.The daily stimulation parameters were 15 trains of 60 pulses with a 15 s interval between trains at a frequency of 10 Hz.(3)After rTMS intervention,Bruker 7.0T MRI scanner was used in the adulthood(PD63?75)of the four groups for f MRI imaging.MRI data analysis was carried out using voxel-based analysis.In addition,ROI was used to further analysis Re Ho in primary sensory cortex and frontal regions.Result: For the first part,in adolescence,voxel-based analysis revealed that MAM rats had significantly decreased Re Ho in the posterior regions,including left visual cortex,left auditory cortex,left temporal association cortex,left somatosensory cortex,left entorhinal cortex,bilateral amygdala,and bilateral hippocampus,compared to vehicle rats(P<0.05,Gaussian Random Field,GRF).For ROI analysis,MAM rats had significantly decreased mean Re Ho value within the primary sensory cortex in adolescence compared to vehicle rats(T =-3.241,P<0.01).In adulthood,for voxelbased analysis,compared to vehicle rats,MAM rats had significantly decreased Re Ho in posterior regions,including left visual cortex,left auditory cortex,left temporal association cortex,and bilateral hippocampus,and significantly increased Re Ho in anterior regions,including bilateral medial prefrontal cortices,bilateral orbital frontal cortex,bilateral nucleus accumbens,and bilateral striatum(P<0.05,GRF corrected).For ROI analysis,mean Re Ho value was significantly decreased within the primary sensory cortex in MAM rats(T =-5.694,P<0.001),and significantly increased within the prefrontal cortex(T = 3.364,P<0.01),compared to vehicle rats.For the second part,The interaction effect of perinatal MAM exposure × rTMS intervention was significant across all four groups in three primary clusters: 1)one in the posterior region,including right auditory cortex,right temporal association cortex,right entorhinal cortex,right somatosensory cortex,right amygdala and right hippocampus,2)one in the posterior region,including left visual cortex,and 3)another in the anterior region,including right medial prefrontal cortices,right orbital frontal cortex,bilateral anterior cingulate cortex,bilateral motor cortices,and right corpus callosum(P<0.05,GRF corrected).For post hoc comparisons,MAM-sham rats had significantly decreased Re Ho valued in the primary sensory cortex(P<0.01)and increased Re Ho value in the prefrontal cortex(P<0.01)compared to vehicle-sham rats.MAM-rTMS rats had significantly decreased Re Ho value in the prefrontal cortex,compared to MAM-sham rats(P<0.05).MAM-rTMS rats had no significant Re Ho differences in the primary sensory cortex compared to MAM-sham rats(P> 0.05).Conclusion:(1)Longitudinal analysis of brain function changes in MAM rats revealed that the aberrant posterior-frontal functional patterns progressed from adolescent to adulthood.(2)Excitedly,we successfully implemented rTMS targeting the adolescent primary sensory cortex in MAM rats to reduce the prefrontal Re Ho and deter the progression of posterior-frontal functional imbalance.These findings may have significant translational value,suggesting that rTMS targeting to the adolescent primary sensory cortex may be a viable treatment strategy for deterring the progression of SZ.