The Clinical Efficacy Of Precise RTMS And Its Neural Mechanism In Treatment-refractory Schizophrenia

BackgroundSchizophrenia is a kind of severe mental illness,which brings an unbearable burden to society and families.Antipsychotic drugs are the first-line treatment for patients with schizophrenia.However,1/3 to 1/2 of the patients still have unsatisfactory effects through drug treatment,and they often have significant negative symptoms and a certain degree of cognitive impairment,namely Treatment-refractory Schizophrenia(TRS).Neuroimaging studies have shown that the stubborn negative symptoms and cognitive impairment in TRS patients are mainly due to the low activity of the prefrontal cortex.At present,in addition to drug therapy,electroconvulsive therapy is often used to control the symptoms of TRS patients.Still,electroconvulsive therapy is often accompanying by severe side effects,such as memory function impairment.Therefore,there is an urgent need to develop new TRS treatment methods.Repetitive Transcranial Magnetic Stimulation(rTMS)has been widely used in the treatment of neuropsychiatric diseases.Previous studies have shown that rTMS has the potential to improve the symptoms of patients with schizophrenia.However,in previous studies,the different stimulation targets,frequencies,and positioning methods used have made the conclusions between various studies more heterogeneous and less Pay attention to the therapeutic effect of rTMS on TRS.As a second-class recommendation in the 2018 guidelines,the rTMS was recommended for the treatment of schizophrenia.Therefore,it was necessary to explore further and optimize the rTMS program for schizophrenia.The traditional high-frequency rTMS(10Hz-25Hz)can significantly affect the cortex,but this effect is weak and short.Intermittent Theta Burst Stimulation(iTBS)is a patterned excitatory stimulation mode that can produce a robust immediate impact after stimulation,which could maintain for a period of time.iTBS only needs 3 minutes each time,which is only one-tenth of the traditional stimulation treatment time.The treatment time is significantly shorter than rTMS,and it has the advantage of short-term high efficiency and adjustability.The positioning method is another factor that affects the treatment of rTMS.Previous studies often used anatomical-based surface positioning methods,and it was hard to stimulate the target point accurately.Stereo navigation guided by external optical tracking and magnetic resonance imaging can use the individualized image data of the subject to focus on the target area and achieve precise intervention.Therefore,the combination of iTBS and personalized MRI neuronavigation may potentially improve the clinical symptoms and cognitive impairment of TRS patients.Previous literature has suggested that the Left Dorsolateral Prefrontal Cortex(LDLPFC)is the core damage target of TRS and the central node of the cognitive-related executive control network.Therefore,regulating the activity of L-DLPFC may improve TRS patient's potential treatment options.Considering the advantages of iTBS parameters and the importance of L-DLPFC in the brain function of TRS patients,we tried to use the optimized iTBS patterns to stimulate L-DLPFC to improve the clinical symptoms and cognitive functions of TRS patients.Although rTMS can improve the mental symptoms of patients with schizophrenia,there is still no reliable conclusion about its underlying neural mechanism.Resting-state functional Magnetic Resonance Imaging(rs-f MRI)is a time-dependent Imaging method using local blood oxygen levels to explore brain function.Including the function of different brain regions,the strength of functional connections between brain regions,and the communication between brain networks in the resting state.Therefore,we use different analysis methods of rs-f MRI to explore the potential mechanism of iTBS treatment.ObjectiveThe first purpose of this study is to explore the cognitive promotion effects of excitatory iTBS and 20 Hz rTMS under a single equal dose stimulation.Then,we used the optimized sequence obtained from the previous study to treat TRS clinical symptoms and cognitive function.Simultaneously,the rs-f MRI of patients was obtained and used to explore the underlying neural mechanism of rTMS intervention in TRS.(1)Explore whether iTBS leads to more robust behavioral modulation than traditional high-frequency stimulation(this study mainly uses 20Hz)and select more optimized stimulation parameters for the treatment of TRS patients.(2)Design a randomized,double-blind control(Randomized Controlled Trial,RCT)experiment to explore whether L-DLPFC precision iTBS intervention under individualized MRI neuronavigation can improve the clinical symptoms of TRS,especially the negative symptoms.At the same time,explore its impact on the cognitive function of patients with TRS,especially the effects on the process of Visual-spatial working memory(vs WM),(3)In addition,we adopted the resting-state functional magnetic resonance to explore the underlying neural mechanism of rTMS intervention in TRS.We revealed the changes in the functions of brain regions,the strength of functional connections between stimulation targets and other brain regions,and brain network functions before and after iTBS treatment and their relationship with the improvement of symptoms or cognition in TRS patients.In order intended to reveal the underlying neural mechanism of iTBS in the treatment of TRS.Methods1.We designed a set of random single-blind experiments to recruit healthy subjects.We randomly divided them into the iTBS group,20 Hz group,and sham stimulation group,using rTMS with different parameters to stimulate the subjects' L-DLPFC.All healthy subjects performed two risky decision-making tasks: Game of Dice Task(GDT)and Risky Gains Task(RGT).We used the performance changes of GDT and RGT as the main observation indicators,and the difference between the three groups was compared.The effect of rTMS stimulation with different parameters on risk decision-making of subjects verified whether iTBS has a better-promoting effect than traditional 20 Hz.The main indicators are the positive feedback and negative feedback utilization of GDT and RGT.2.A randomized,double-blind,controlled design,with TRS patients as the research objects.We randomly assigned the subjects to the real iTBS group/sham stimulation group.Subjects in both groups received precise L-DLPFC stimulation based on individual MRI spatial navigation for two weeks.Both real iTBS group and sham group used the iTBS parameters.Only the stimulation coils were different,and the pseudo-stimulation group used the scientific research-specific pseudo-stimulation coil.TRS patients were evaluated for clinical symptoms before,after,and two months after treatment.At the same time,systematic neuropsychological tests and assessment of visual-spatial working memory were collected before and after treatment.3.In addition to evaluating symptoms and cognitive functions,we collected the resting-state functional magnetic resonance data of TRS patients in Study 2 before and after treatment at the same time.We used the Low fractional Amplitude of Frequency Particles(f ALFF),seed-based functional connectivity analysis,and brain network analysis based on ICA analysis methods to explore the effects of iTBS treatment on brain function.Results1.87 subjects were finally enrolled,29 people in each group.In the performance of GDT and RGT decision-making tasks,both the iTBS group and the 20 Hz group can significantly improve the ability of negative feedback and positive feedback,increase the proportion of safe options and reduce the ratio of risky options(P < 0.05).In addition,in the RGT task,the iTBS group can promote feedback ability and facilitate risk selection.The improvement effect of iTBS is stronger than the 20 Hz and sham stimulation groups(both positive and negative feedback are effective,P < 0.05).2.Finally,73 TRS patients were enrolled in the study,38 in the real iTBS group and35 in the sham group.After two weeks of iTBS treatment,the results showed significant interaction effects on symptoms between different groups before stimulation,after stimulation,and at two months follow-up(all P < 0.05).Further analysis showed that iTBS could effectively improve the clinical symptoms(negative/positive symptoms)of TRS patients,and this improvement could last up to 2 months after treatment.Of the 73 TRS patients included,59 TRS patients completed the visuospatial working memory task,including 33 in the iTBS group and 26 in the sham group.The results showed a significant interaction effect of the accuracy of n-back between groups(iTBS/sham)and time(pre/post iTBS).Further analysis showed that in the iTBS group,the accuracy of n-back,especially the accuracy of 3-back,was significantly improved after the iTBS treatment.The correlation analysis between symptoms and cognition found a significant negative correlation between working memory improvement and the decrease of symptom scores in TRS patients.3.Fractional low-frequency amplitude analysis suggests that there is a significant time(pre/post iTBS)× group(iTBS/sham)interaction in the f ALFF values of the right cuneus and the right precuneus lobe(P < 0.05).The post-hoc analysis showed that local activity in the right cuneus increased and decreased in the right precuneus in TRS patients after iTBS stimulation.Still,we were not found the similar effect in the sham group.The functional connectivity analysis between seed and whole-brain voxels revealed that the functional connectivity between the target of stimulation(L-DLPFC)and the left cuneus increased after iTBS stimulation.ICA analysis shows that iTBS can increase the connectivity between the dorsal attention network and the default network.However,the sham group can't improve the decrease in the connectivity between the dorsal attention network and the executive network.Correlation analysis suggests that the increase in the local activity of the right cuneus lobe was positively correlated with the improvement of vs WM ability.Conclusion1.Both iTBS and 20 Hz single stimulation can significantly improve normal subjects' negative and positive feedback abilities.Compared with 20 Hz,iTBS has a stronger modulating effect on decision-making behavior and is more suitable as a powerful cognitive promotion means.2.Firstly,this study is the first to demonstrate that 2 weeks of iTBS on L-DLPFC can improve the clinical symptoms and cognitive function of TRS patients.Secondly,we affirmed the ability of iTBS for improving the negative symptoms and working memory of TRS patients and confirms the sustained effect of iTBS treatment.In conclusion,this study provides clinical evidence that iTBS can be used as an adjuvant antipsychotic treatment to relieve symptoms of TRS and improve cognitive function.3.iTBS stimulation can effectively regulate the activity of remote areas,and at the same time,improve the clinical symptoms of patients by adjusting the functional connections between different brain areas and the connectivity between brain networks,and at the same time improve cognitive function.