Individual Differences In Temporal Summation Of Pain

Temporal summation(TS)of pain,which is the perception of increasing pain evoked by repeated noxious stimuli delivered at constant intensities,with an interstimulus frequency of 0.33 Hz or less.It is also termed “ wind-up”,a summation of C-fiber-evoked responses of dorsal horn neurons.It is greatly correlated with central sensitization.Central sensitization,refers to the overexcitation of nociceptive neurons in the central nervous system to a normal or suprathreshold stimulus.This central hyperexcitability leading to causes allodynia,hyperalgesia and chronic widespread pain.Temporal summation,may be relevant to dysfunctional descending inhibitory pathway and increased facilitatory modulation,is a possible mechanism contributing to sensitization of the central nervous system.Thus,temporal summation studies has demonstrated that the TS magnitude of various chronic pain disorder patients were enhanced compared to healthy controls,such as fibromyalgia syndrome(FMS),irritable bowel syndrome(IBS)and neuropathic pain etc.,these studies have emphasized that the central pain processing abnormalities.In addition,preoperative TS level is correlated with the postoperative pain intensity and may be a preoperative mechanistic predictor for the development of chronic postoperative pain in chronic patient,for instance,knee osteoarthritis patient.Thus,TS response could make for the understanding in depth of the underlying mechanisms of chronic pain on the one hand,and help us improve the prediction and prevention of high-risk postoperative pain patient in clinical on the another hand.However,to date,it has been greatly difficult to make comparisons of results across the studies due to the lack of standardization of TS testing.Some studies have demonstrated considerable variability in response to TS protocol including temporal summation,little change,or temporal decrease.Although the TS-variability may because of experimental methodology in some degree,including a variety of TSparameters(i.e.,stimulus modalities,stimuli frequency,and body locations)to evoke TS response and different methods of calculating TS value(i.e.,the percentage change of the first pain rating to the peak pain rating),it is most likely the result of the balance of nociceptive and pain-modulatory processes.Thus,to test the individual difference in temporal summation of pain,we tried to characterize the dynamic change process of TS response,and to examine the potential mechanism of temporal summation of pain.We explored this issue through two studies.In study 1,50 pain-free young adults received a sequence of 12 brief,repetitive electrical stimuli(the single stimulus was a train of 5 electrical pulses at 250 Hz,totally 17 ms duration)at a frequency of 1Hz,with the intensity anchored to two times of individual pain threshold.There were totally 10 sequences applied to the left hand of each subject.During the TS procedure,each subject was asked to use visual analog scale(VAS)device to continuously rate the pain intensity of each stimulus,and then was asked to report the rating of the first stimulus,the last stimulus and the peak rating of the TS sequence at the end of each sequence.We calculated temporal summation as the relative difference between the first and the peak pain rating in this study.The results showed that the TS responses exhibited substantial variability: increase,no change,and even a slight decrease.According to the TS magnitudes,the 50 subjects were classified to two groups: low TS efficiency(Group A),high TS efficiency(Group B).The two groups had a significant difference in TS responses,the first rating,the peak rating,and the last rating,but not in pain threshold.And,the group VAS rating also revealed a rise after several stimuli and demonstrated the temporal summation of pain evoked by electrical stimulation.Then,the VAS rating change curves of two groups were compared,they both reached a peak pain rating at about 5th,6thstimulus,then the two groups profiles appeared a different trend,no change or a slight decrease.The statistical result showed a significant difference at the timepoint of the 1st stimulus,and 6th stimulus and afterwards.Thus,this oral ratings and the real-time VAS rating were integrated to demonstrate the individual difference of temporal summation of pain,and the study provided a more dynamic measurement to describe this variability.Individual with different TS efficiency may have a different dynamic TS profile in healthy group.The study 2 explored the underlying mechanism related to the individual difference of temporal summation using functional magnetic resonance imaging(fMRI).The study examined the corresponding brain responses of temporal summation of pain.And the study compared the brain activation and signal change associated with TS between twogroups above.The results exhibited there was no significant difference both.Then we tested resting state functional connectivity(FC)of brain regions in related to individual differences in temporal summation,such as thalamus,primary somatosensory cortex(S1),rostral ventromedial medulla(RVM)and periaqueductal gray(PAG).The results found that the TS magnitude were significantly positive related with the functional connectivity between their RVM with BA1 of S1(RVM-BA1)and thalamus(RVM-thalamus).These may indicate that RVM may play an important role in the process of TS response.In summary,these experiments demonstrated the great variability in the temporal summation of pain evoked by electrical stimulation,and provided a dynamic profile to characterize the TS response process and the difference of two groups.And then,the studies brought us a certain correlate of neurophysiology about the individual difference of TS response.The studies will not only allow a more complete characterization of the TS profile and then bring a prediction for the pronociceptive individuals in healthy group,but also provide a implication in chronic pain states,i.e.,the optimal pharmacological treatment strategies before surgery to prevent the postoperative pain.However,the studies had some limitations.At first,the experimental program could be enriched,that is,the studies could have more comparative groups(i.e.,frequency,number of stimuli and intensity,etc.).if so,we may have a more comprehensive TS model.Then,these results can't be compared with other studies taking the TS experimental methods into consideration.This is the common limitation,a more standardized TS experimental paradigm will be needed.The last but not the least,further TS studies could applied to the clinical samples,aiming to verify predictors of TS response and make sure the clinical significance of the individual difference of TS response.So,studies could be explored to improve the clinical application eventually.