Outcome Prediction And RTMS Efficacy Assessment In Patients With Chronic Disorders Of Consciousness Based On Resting State FMRI

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Resting brain network and its relevance to recovery outcome in patients with chronic disorders of consciousnessObjective:Chronic disorders of consciousness(DOC)is a clinical manifestation emerged from severe brain injury,however,it is quite challenging to identify its residual awareness and predict its outcome.Previous studies have indicated that resting brain network abnormalities involve in the state of DOC.Therefore,this study intends to analyze the characteristics of resting brain network among patients with unresponsive arousal syndrome/vegetative state(UWS/VS),minimally conscious state(MCS)and healthy controls,thus to explore the neural mechanism of consciousness disturbance.Moreover,based on longitudinal resting-state functional magnetic resonance imaging(fMRI)and behavioral data,the second objective is to investigate whether the recovery outcome of DOC after brain injury is regulated by the resting neural network,especially to clarify the effect of medial prefrontal cortex(mPFC)in consciousness recovery,so as to deeply understand the underlying mechanism of consciousness recovery,and explore the prognostic indicators.MethodsThis study was designed to employ a two-batch and two-stage approach to enrol DOC patients after acquired brain injury.In the first batch,21 patients in a state of DOC,including 10 patients in UWS/VS and 11 patients in MCS,and 11 healthy controls were included.The coma recovery scale-revised(CRS-R)and glasgow coma scale(GCS)were used to assess their consciousness level,synchronized with resting-state fMRI scan,amplitude of low frequency fluctuations(ALFF)and seed-based correlation analyses of the posterior cingulate cortex/precuneus(PCC/PCU)were performed to measure their resting brain network.In the follow-up,UWS/VS patients were further divided into two subgroups in accordance with their recovery,some emerged from UWS/VS(UWS-E),the others remained in UWS/VS(UWS-R).Then,resting brain network was analyzed,by comparing DOC patients to healthy controls,UWS/VS to MCS patients,and also UWS-E to UWS-R patients.In the second batch,34 patients in a state of DOC were finally enrolled,including 17 patients in UWS/VS and 17 patients in MCS.Consciousness level was evaluated as above,synchronized with fMRI scan.In the follow-up,the CRS-R and glasgow outcome scale(GOS)were adopted to detect their recovery outcome,together with a second fIRI scan.Then,resting brain network connectivity within the default mode network(DMN)was analyzed by graph theory,especially the mPFC connectivity.On the one hand,this study differently compared DOC patients to healthy controls,UWS/VS patients to controls,MCS patients to controls.On the other hand,we longitudinally compared "awakened" patients and"non-awakened" patients at 3 month follow-up,as indicated by GOS score? 3 points or not,moreover,compared the DMN connectivity at baseline and follow-up in the patients with consciousness improvement.Results1)According to the baseline data in the first batch,ALFF analyses in this study demonstrated that,compared to healthy controls,DOC patients revealed significant lower ALFF intensity in the region of PCC/PCU among the 0.01-0.08 Hz,0-0.01 Hz,and 0.027-0.073 Hz bands.Besides,based on a seed-based correlation analyses of the PCC/PCU,DOC patients revealed significantly weakened functional connectivity of the PCC/PCU with multiple brain regions,involving frontal and partial lobe as well as cerebellum.According to the baseline data in the second batch,graph theory-based correlation analyses suggested that,when compared with healthy controls,a significantly enhanced connectivity in the mPFC was revealed in the DOC patients,acompanied with a significantly reduced connectivity in the PCC/PCU and right lateral parietal cortex(LPC).Namely,a dissociation of anterior and posterior brain region connectivity was indicated in the DOC patients.Subgroup analyses were further performed,as a result,UWS/VS patients mainly showed a significantly decreased connectivity in the PCC/PCU,while MCS patients had a significantly enhanced connectivity in the mPFC,thus suggesting the pattern of DMN connectivity was correlated with the severity of consciousness loss,in particular,a connectivity enhancement of the mPFC,as a representative of anterior brain regions,was a potential source of compensation for the connectivity decline of the posterior brain regions in the status of MCS,not in the status of UWS/VS.2)The overall analyses of the first batch data indicated,increased ALFF intensity in the right cerebellum,not enhanced PCC/PCU connectivity,was demonstrated in the 3 UWS-E patients,when compared to the UWS-R patients.However,the individual analyses suggested that,the 3 UWS-E patients all revealed enhanced PCC/PCU connectivity with the left middle temporal gyrus.The second batch data showed that,11 patients in a state of DOC achieved a GOS score of>3 at three month after brain injury,and 18 patients had a score of<3,as a result,the former over the latter had a significant enhanced connectivity in the region of mPFC.During the follow up,5 DOC patients were converted from UWS/VS to MCS or emerged from MCS(EMCS)status,or from MCS status to EMCS status,and they showed an enhanced tendency of the PCC/PCU,mPFC,right LPC,bilateral ITC,right cerebellum and thalamic connectivity.ConclusionsThese findings indicate consciousness level of acquired brain-injured patients is correlated with the DMN connectivity integrity,especially the PCC/PCU,mPFC and right LPC.And conscious-related processes of interruption and remodelling is more possibly in a dynamic state,the mPFC connectivity could possibly serve as a mark to track the recovery outcome of DOC.Part ? Behavioral and resting state functional connectivity effects of 20 Hz rTMS on disorders of consciousnessObjectives:A combined approach of behavioral characteristics and network properties was applied to preliminarily explore the effect of repetitive transcranial magnetic stimulation(rTMS)on disorders of consciousness(DOC)and to observe changes in neural network connections before and after the stimulation.Methods:A total of 7 DOC patients and 11 healthy controls were enrolled.The study was designed as a randomized,sham-controlled study.All DOC patients were given 20 Hz rTMS real and sham stimuli to the left M1 region,with each stimulus lasting for 5 consecutive working days and the interval between two stimuli being one week.Coma Recovery Scale-Revised(CRS-R)and resting state functional MRI(fMRI)data before and after stimuli were collected.Functional connectivity of the DMN and the frontoparietal network,including posterior cingulated cortex/precuneus,medial prefrontal cortex,bilateral lateral parietal cortex(LPC),bilateral inferior temporal cortex(ITC),thalamus and bilateral dorsolateral prefrontal cortex(DLPFC),were chosen as the central target to compare differences in network connectivity between the DOC group and the normal control group.For DOC patients,changes in behavior and brain function before and after real and sham stimuli were also assessed as a group and individually.Results:1)No significant side effects from rTMS were observed.2)Compared to controls,DOC patients presented with significantly altered connectivity in several brain regions of the DMN and the frontoparietal network,including the right LPC,left ITC,and left DLPFC.3)The results of the overall behavioral study indicated a slight improvement in CRS-R total scores of the DOC patients following real rTMS,the difference was insignificant.However,there was no improvement in CRS-R score following sham simulation.The results of the individual behavioral study indicated that the CRS-R score was improved in one MCS patient during the study.4)The results of an overall longitudinal study showed that,compared to the findings before stimulation,connectivity was not significantly enhanced in the DOC patients following real rTMS,nevertheless,a trend toward enhanced FC was indicated,including that the node of left LPC with the right cingulate gyrus and inferior frontal cortex;the node of left ITC with the cuneus;and the node of right DLPFC with the right cerebellum.In contrast,after sham rTMS,when compared with that before stimulation,neither significant enhancement of brain network in the ROIs,nor a enhanced trend was revealed in the DOC patients.The results of individual longitudinal study also confirmed,that for one MCS patient with significant improvement of consciousness in terms of behavioral study,connectivity was increased for the connectivity of the left LPC,the left ITC and the right DLPFC.Conclusion:Our findings could not provide sufficient evidence of therapeutic effect of 20 Hz rTMS over the left Ml in DOC.And Reconstruction of the left LPC,the left ITC and the right DLPFC that explored with the resting state functional connectivity,may be the neural networking foundation of improvements in consciousness from rTMS.