Neural Cognitive Correlates Underlying Fear Of Pain

Chronic pain,persisting for more than three months after injuries healing,has high prevalence and causes substantial burdens for individual sufferers,their family and the society.The fear-avoidance model(F-A model)has been proposed to explain the development and maintenance of chronic pain and its disability with underscoring the role of fear of pain(FOP),which had been defined as negative interpretations that pain is equivalent to harm and catastrophic beliefs that result in fear and nervous emotional response to anticipation or experiences of pain.Direct experience,verbal threat information,and observational learning induce fear of pain,and it can be generalized to similar novel stimuli/contexts resembling the original fear-relevant ones.Previous studies have evidenced the association between elevations in fear-avoidance spectrum beliefs to poorer functioning non-clinical groups confronting noxious laboratory stimuli and clinical samples living with ongoing chronic pain.However,comparatively less is known about neurophysiological correlates underlying FOP in healthy and chronic pain sample.Moreover,a motivational perspective may provide further insights into the processes hypothesized by the F-A model,for instance,the avoidance behavior of individuals who are highly pain-fearful in conflict situations or in temporally delayed situations.Studies 1 and 2 were designed to evaluate neurophysiological mechanisms related to fear of pain and different pain cues(images and words)during exposure to potential threatening context in healthy sample.In study 1,event-related potentials(ERPs)were recorded as 39 high pain-fearful(H-FOP)and 36 low pain-fearful(L-FOP)adults(1)viewed non-painful and painful images and(2)subsequently received non-painful versus potential painful somatosensory stimulation,respectively.The H-FOP group judged all somatosensory stimulation to be more intense than L-FOP group members did.L-FOP group members showed larger P3 amplitudes when processing potential painful somatosensory stimulation compared to non-painful stimulation did,while no such difference was observed in H-FOP group members.In study 2,the procedure was the same as that of study 1 except using sensory pain words and neutral words as cues.H-FOP group members VI displayed slower reaction times in judging somatosensory stimulation and rated stimulation to be more intense than L-FOP group members did.H-FOP group members exhibited comparatively earlier peak latencies of P2 and N2 components during exposure to word cues as well as weaker P3 amplitudes in processing non-painful stimulation cued by sensory pain words than L-FOP members did.In study 3,functional Magnetic Resonance Imaging(fMRI)were recorded among 25 high pain-fearful(H-FOP)and 25 low pain-fearful(L-FOP)young adults with chronic pain exposed to potentially painful somatosensory stimulation cued by symbolic cues signaling possible pain versus non-painful stimulation cued by symbolic cues signaling never pain.Compared to cues signaling never pain,cues signaling possible pain corresponded weaker activation in bilateral amygdala,bilateral parahippocampa gyrus,right posterior cingulated cortex(PCC),right ventromedial prefrontal cortex(vmPFC),bilateral postcentral gyrus,and middle temporal gyrus(MTG),indicating the involvement of task-negative network and the regulation of amygdala during the exposure to anticipation of aversive stimuli.In addition,H-FOP group members rated non-painful stimulation from P-N trials to be more intense than that from N-N trials.Despite no group differences were observed on skin conductance response(SCR)and neural responses during the cue presentation and the cued non-painful stimulation phase,the reduced activation of amygdala during cues signaling possible pain showed a significant association with weaker fear of pain in the H-FOP group members.In study 4,regional gray matter volume(GMV)differences were examined between 34 individuals with chronic pain(CP)and 34 demographically-matched healthy controls(HC)in initial voxel-based morphometry(VBM)analyses.Subsequently,we examined associations of GMV in regions on which groups differed with self-reported fear of pain as well as follow-up pain intensity and interference within the CP group.Compared to controls,the CP group displayed significantly smaller GMV in the right insula and prefrontal regions including the left superior frontal gyrus(SFG),right medial frontal gyrus(MFG)and inferior frontal gyrus(IFG)as well as larger GMV in the left parahippocampa gyrus and right superior temporal gyrus(STG).Within the CP group,GMV in the STG had positive correlations with fear of pain.Moreover,less GMV in the left SFG was associated with reduced pain intensity and interference at 6-month follow-up,after controlling for baseline correlates.In study 5,34 young adults with chronic pain(CP)and 34 age-matched healthy controls with an absence of ongoing pain(HC)underwent resting-state fMRI,and completed demographics,pain relevant measures and fear of pain questionnaire.Brain regions with fractional amplitude of low-frequency fluctuations(fALFF)changes were examined in individuals with chronic pain,and the significance of these regions in chronic pain was also explored by analyzing its alteration in functional connectivity(FC).The relevance of such alterations was further explored with clinical symptoms and self-report fear of pain.CP group members showed significant fALFF value increases within several areas of amygdala,insula,parahippocampus gyrus,orbitofrontal cortex(OFC),precuneus,precentral gyrus,and the temporal lobe compared with controls.CP group members also displayed reduced FC between key emotion regulation regions,specifically the right amygdala and orbitofrontal cortex(OFC)as well as increased FC of the right amygdala with posterior cingulate cortex(PCC)and insula.Alterations of amygdala FC showed no significant correlations with clinical symptoms(pain intensity,and pain interference)and fear of pain.In study 6,50 more pain-fearful(H-FOP)and 50 less pain-fearful(L-FOP)young adults completed decision making tasks with conflict situations of approach-avoidance and avoidance-avoidance featured monetary rewards or losses corresponding to fear-relevant stimuli(e.g.,painful facial expression images paired occasionally with painful stimulation).H-FOP group members displayed more switches in choice after receiving painful stimulation compared to L-FOP group members did in approach-avoidance task,indicating an avoidance tendency from nociceptive stimuli.However,no clear overall differences were observed between fear of pain groups in choice behaviors(i.e.,advantageous-pain choice,switches in choice,and number of painful stimulation)of both tasks.Study 7 examined the role of fear of dental pain in choices between immediate and delayed monetary and pain-related rewards and losses.High(n = 100)and low(n = 100)dental pain-fearful young adults completed the monetary choices questionnaire and its modified assessments to examine delay discounting of monetary and pain-related outcomes.Participants first performed discounting of monetary rewards and monetary losses.Then,before performing pain-related tasks,participants recalled their worst dental pain experience and filled fear of dental pain measures.Proportion measures of self-control responses were calculated as main dependent variables in each task.Compared to L-FOP members,H-FOP members reported higher dread score,and displayed a positive association of fear of dental pain score with proportion of immediate shorter days responses of discounting additional pain,which may result from minimizing negative emotions elicited by the delayed aversive stimuli and during the waiting process.H-FOP group members also presented variable proportions of between medium and small magnitude of monetary rewards as well as between large and medium magnitude of monetary losses,while L-FOP group members did not show such differences.It is presumed that the hyper-vigilance toward monetary magnitude in individuals who are highly dental pain-fearful may be associated with their coping resources within threatening contexts.In conclusion,the present thesis has several important findings.First,supporting the tenets of fear-avoidance model,individuals who are high trait pain-fearful,both from healthy sample and chronic pain sample,reported higher intensity rating on non-painful stimulation with cues signaling possible pain relative to that with cues signaling no pain.Second,the pain-fearful healthy individuals allocated fewer cognitive resources in processing possible pain after exposure to cues(images and words)signaling potential pain indicated by ERP findings.In addition,the reduced activation of amygdala during cues signaling possible pain showed a significant association with weaker fear of pain in individuals with chronic pain who reported highly pain-fearful,suggesting that amygdala-associated modulation during anticipation of potentially threatening stimuli may be involved in the role of pain-related fear played in chronic pain.These neurophysiological findings helped us to uncover the mechanisms underlying fear of pain and its role played in pain chronification.Third,chronic pain individuals displayed different GMV in several regions,fALFF in multiple brain regions,and FC of amygdala relative to controls,which is in line with previous studies demonstrating anatomical plasticity and altered spontaneous neural activation of chronic pain.However,the association of fear of pain in those differences still needs to be explored.Finally,highly pain-fearful individuals displayed more avoidance behavior after receiving painful stimulation in conflict situations,while other behavioral performance were unaffected by fear of pain,which may due to the interaction effect of motivation to gain rewards and avoid pain and fear of pain on the decision-making performance in conflict situations.H-FOP members displayed a positive association of fear of dental pain score with proportion of self-control responses in discounting of additional pain,and were hyper-vigilant toward monetary magnitude in discounting rewards and losses.These preliminary findings extended the fear-avoidance model from a motivational perspective.However,future research is needed to further investigate the association of fear of pain and decision-making utilizing alternate methodologies.