| Epilepsy is a common nervous system disease caused by abnormal synchronized discharges of neurons.The main clinical manifestations of epilepsy are disturbance of consciousness,rigidity or convulsion of limbs,and cognitive impairment.Cognitive impairment includes declined abilities of learning,memory impairment,mental and emotional abnormalities,etc.Epidemiological studies showed that about 70%-80%of patients with chronic epilepsy suffer from cognitive impairment,especially memory impairment,which seriously affects the life quality and personal development of patients,and brings heavy burden to patients’families and society.Although memory impairment is a common concomitant symptom of epilepsy,we know little about it and lack of effective interventions.Therefore,it is of vital importance to elucidate the neural mechanism of memory impairment in epileptic patients for early diagnosis and personalized treatment of epilepsy-related memory impairment.Intracranial electroencephalogram（i EEG）is a high-resolution technique that measures electrical activity in the brain by placing electrodes inside the skull or brain tissue.Because i EEG can record neuronal activity in multiple areas of the brain,it can be used to determine the origin and spread of epilepsy,and identify the type and severity of epilepsy,thus guiding treatment.Intracranial EEG can provide higher resolution and more accurate EEG activity data than traditional scalp EEG,which makes it become an important tool for studying brain function and EEG activity,and is helpful for us to better understand the neural mechanism of memory impairment in epileptic patients.Deeper understanding of the neural mechanism could provide us new ideas for treatment.Ripple oscillation is a kind of high-frequency electrical activity in the brain with a frequency band of 70-250Hz,and its duration usually does not exceed 150 milliseconds in usual.Previous animal studies have found that artificial intervention of hippocampal ripple oscillation can lead to long-term memory impairment in mice,suggesting that hippocampal ripple oscillation is widely involved in the process of memory encoding,retrieval and consolidation.In recent years,studies based on human intracranial EEG have confirmed that hippocampal ripple oscillations in humans also mediate the retrieval process of episodic memory and are related to the selective reinstatement of cortical representations during recall.Meanwhile,the coupled ripple oscillations between hippocampus and anterior temporal cortex mediates the successful retrieval of verbal memory.The above studies all suggest that ripple oscillations in the brain may be an important neural representation of memory retrieval,but whether they relate to the pathogenesis of memory impairment in epileptic patients remains unknown.Therefore,this study attempts to observe the activity pattern of ripple oscillations in the brain of epileptic patients performing a multi-day memory test,by intracranial EEG recording of patients with drug-refractory epilepsy.We aim to clarify the relationship between ripple oscillations and memory impairment of epileptic patients,so as to provide theoretical basis and effective target for early evaluation,diagnosis and precise treatment of epileptic memory impairment.Objectives:1.To explore the correlation between hippocampal ripple oscillation and memory performance in humans;2.To explore the correlation between cortical ripple oscillations and memory performance in humans;3.To explore the relationship between hippocampal and cortical ripple oscillation and memory impairment in epileptic patients;Methods:1.Inclusion and grouping of patientsA total of 31 patients（16 females）with intractable epilepsy,aged 16-65 years（28.3±9.5）,were included in this study.Each patient was implanted with intracranial electrodes to record i EEG signals.We applied each patient’s memory quotient（MQ）to make a basic assessment of their memory ability.Memory quotients were obtained from the Wechsler Memory Scale（WMS）.According to the standard,the average MQ of the normal population is 90-110.Using 90 as a standard,we divided 31 patients into below-average memory group（MQ<90,n=17）and average memory group（MQ≥90,n=14）.Nineteen of these patients participated in an episodic memory test,and 30 patients were included in the analysis in quiet wakefulness（non-memory test state）.2.Experimental paradigmSix consecutive days were required for this experiment,one task per day.Tasks for each day differed in pictures but shared the same procedure derived from the previous study.One task consisted of two runs,each run consists of two parts:picture viewing and free-recall.In picture viewing of each run,28 pictures were presented to participants and repeated 4 cycles.Each cycle contained all 28 pictures in a different and random order.In1st cycle,participants were asked to judge whether they had seen the picture before,just after each picture ended.Following the picture viewing,participants began a short interference task with a blindfold（counting back from 150 to 0 in steps of 5）.Upon completion,they were instructed to freely recall the pictures.We encouraged them to describe the pictures with more details（at least 3 features）besides the name of the person or place.3.Ripple detectionWe applied the method of ripple detection established by Norman,et al.A Bandpass filter between 70-180 Hz followed by Hilbert transformation was used to extract the instantaneous amplitude.Then,the ripple signal is detected according to the signal amplitude,duration and other constraints.Pathological and sham ripple events could also be detected by the method above,so we attempted to discriminate the physiological ripples from the inter-ictal epileptic discharges（IEDs）and artifacts emulating procedures from previous studies.The ripple events that were within 50 ms of them were excluded.4.Memory-related cortical sites（MR cortical sites）We identify a memory-related cortical site by the ripple oscillations in the cortex when patients were viewing novel and recently learned pictures.If the ripple oscillation activity of a cortical site,when the patients was viewing the recently learned pictures,is significantly stronger than viewing novel picture,we define it as a memory-related cortical site.5.Coupled ripplesCoupled ripples are defined as instances when a hippocampal ripple and a neocortical ripple occur within 100 ms.Results:1.The peak ripple rate in hippocampus and MR cortical sites was positively correlated with memory performance.In this part of the study,we focused on the relationship between ripple oscillation and memory-related task performance under physiological conditions.Over the course of 6 days,the patient’s task performance gradually increased（1-3 days）and then reached a plateau（3-6 days）.The peak ripple rate in hippocampus and MR cortical sites also showed a similar trend,increasing in the first three days and then reaching a stable level.The results revealed that peak ripple rate in hippocampus and MR cortical sites was closely related to memory performance.2.Patterns of ripple activity in the hippocampus and MR cortical sites are various across different memory stages（novel,recent memory,and remote memory）.In this part of the study,we focused on whether ripple oscillations in the human hippocampus and memory-related cortex can characterize different memory stages under physiological conditions.The systematic consolidation theory of memory divides memory stages into novel（first encoding）,recent memory and remote memory.They correspond to the brain activity evoked by novel images,recently learned images and familiar images in our experiment,respectively.Through pattern classification analysis,we found that the three stages of memory can be clearly distinguished by the ripple activity pattern of hippocampus and MR cortical sites（SVM classifier;classification accuracy,novel vs recent memory:novel vs remote memory:96.4%;recent memory vs remote memory:96%）.This suggests that ripple oscillations in the hippocampus and MR cortical sites is closely related to the formation and development of memory.3.The hippocampus and MR cortical sites coupled ripples contribute to memory retrieval.In this part of the study,we focused on the relationship between ripple coupling and memory retrieval under physiological conditions.The coupled ripples in the hippocampus and MR cortical sites were significantly stronger when viewing recently learned and familiar images than viewing novel pictures(P novel vs 2-6 d repeated=0.0092,P novel vs familiar=0.0022,paired t-test).At the same time,during free recall,the coupled ripple in hippocampus and MR cortical sites showed a significant increase preceding the onset of verbal recall.The results showed that coupled ripples between the hippocampus and MR cortical sites contributed to the memory retrieval.4.During memory retrieval,the peak ripple rate in hippocampus and MR cortical sites of patients in below-average memory group was significantly lower than that of patients in average memory group.In this part of the study,we focused on the correlation between ripple oscillations and memory ability in patients.The results showed that the ripple activity of hippocampus and MR cortical sites in below-average memory group was significantly weaker than that in average memory group during memory retrieval,and their peak ripple rate was significantly different(P=9.9×10-4,cluster-based permutation test).It is suggested that the memory impairment of epileptic patients is related to the decrease of the ability of generating ripple oscillation in hippocampus and MR cortical sites.5.In memory retrieval,coupled ripple in hippocampus and MR cortical sites of patients in below-average memory group was significantly weaker than that of patients in average memory group.In this part of the study,we focused on the relationship between the coupling of ripple oscillations in hippocampus and cortex and the memory ability of patients.The coupled ripples in hippocampus and MR cortical sites of below-average memory group were significantly weaker than that of average memory group during memory retrieval（P=0.008,cluster-based permutation test）.It shows that in epileptic patients with memory impairment,the communication between hippocampus and cortex is disturbed.Conclusions:1.Ripple oscillations in human hippocampus and memory-related cortex were positively correlated with memory behavior;2.Activity patterns of ripple oscillations in human hippocampus and memory-related cortex are various across different stages of memory;3.Ripple oscillatory coupling between hippocampus and memory-related cortex is associated with successful memory retrieval and is gradually enhanced during memory formation;4.Epilepsy-related memory impairment is associated with decreased ripple oscillation activity in the hippocampus and memory-related cortex. |
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