Scam Psychology Research

Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation

Principal Category: Trauma/PTSD

Authors: Marla J.S. Mickleborough, Judith K. Daniels, Nicholas J. Coupland, Raymond Kao, Peter C. Williamson, Ulrich F. Lanius, Kathy Hegadoren, Allan Schore, Maria Densmore, Todd Stevens and Ruth A. Lanius

Date: January 01, 2011

DOI LINK: J Psychiatry Neurosci  36 (1) 6-14; DOI: https://doi.org/10.1503/jpn.080188

LICENSE: CC BY-NC-ND

Source: Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation | JPN

Abstract:

Background: Imaging studies of pain processing in primary psychiatric disorders are just emerging. This study explored the neural correlates of stress-induced analgesia in individuals with posttraumatic stress disorder (PTSD). It combined functional magnetic resonance imaging (fMRI) and the traumatic script-driven imagery symptom provocation paradigm to examine the effects of trauma-related cues on pain perception in individuals with PTSD.

Methods: The study included 17 patients with PTSD and 26 healthy, trauma-exposed controls. Participants received warm (nonpainful) or hot (painful) thermal stimuli after listening to a neutral or a traumatic script while they were undergoing an fMRI scan at a 4.0 T field strength.

Results: Between-group analyses revealed that after exposure to the traumatic scripts, the blood oxygen level–dependent (BOLD) signal during pain perception was greater in the PTSD group than the control group in the head of the caudate. In the PTSD group, strong positive correlations resulted between BOLD signal and symptom severity in a number of brain regions previously implicated in stress-induced analgesia, such as the thalamus and the head of the caudate nucleus. Trait dissociation as measured by the Dissociative Experiences Scale correlated negatively with the right amygdala and the left putamen.

Limitations: This study included heterogeneous traumatic experiences, a different proportion of military trauma in the PTSD versus the control group and medicated patients with PTSD.

Conclusion: These data indicate that in patients with PTSD trauma recall will lead in a state-dependent manner to greater activation in brain regions implicated in stress-induced analgesia. Correlational analyses lend support to cortical hyperinhibition of the amygdala as a function of dissociation.

Research Study/Article/Document

Introduction

Despite evidence that pain preferentially recruits affective pain systems in patients with chronic pain1–3 and strong epidemiological links between disorders of mood, anxiety and chronic pain,4 imaging studies of pain processing in primary psychiatric disorders are just emerging.5–7 Posttraumatic stress disorder (PTSD) is associated with significantly elevated prevalence of chronic pain,5 ranging from 25%–80% in veterans8,9 and up to 50% in motor-vehicle collision survivors.10 Conversely, rates of PTSD in patients attending tertiary pain clinics range from 10% to 33%.2 Comparing patients with combat-related PTSD to patients with other anxiety disorders and healthy controls, Defrin and colleagues11 report higher rates of chronic pain and more intense chronic pain in the PTSD group than the anxiety and the healthy control groups. In the PTSD group, the chronic pain started immediately to a few months after exposure to the traumatic incident, whereas no specific onset could be determined in the anxiety group. The most frequent pain-aggravating factors were psychological distress (80%) and tension (32%). Whereas PTSD severity correlated significantly with chronic pain severity, the participants with PTSD exhibited significantly higher pain thresholds.

Alterations in pain threshold in PTSD

The finding of increased thresholds for pain has been corroborated in samples of patients with PTSD but without comorbid chronic pain. Significantly higher pain thresholds were reported by veterans with PTSD than combat-exposed veterans without PTSD at baseline9 and after exposure to a trauma reminder.12,13 However, this difference could not be replicated in the study by Kraus and colleagues,14 who established elevated thresholds in combat-exposed groups both with and without PTSD compared with healthy controls without combat experience but reported significantly lower pain ratings in the PTSD sample compared with the healthy control groups when using long-lasting (30 s) pain stimuli. Interestingly, pain thresholds were also comparable for patients with borderline personality disorder with and without comorbid PTSD,15 a disorder that has been linked to prior trauma experience and is characterized by frequent dissociative coping.

In the only functional magnetic resonance imaging (fMRI) investigation of pain processing in PTSD to date, the PTSD sample exhibited increased activation in the putamen and bilateral anterior insula and decreased activation in the right amygdala compared with combat-exposed veterans without PTSD.9 Interestingly, the PTSD group exhibited significantly higher state dissociation and aversive inner tension scores before the scan than the control group, but no correlations with blood oxygen level–dependent (BOLD) signal were reported.

Neither the neurobiological mechanisms underlying the alterations in pain perception among patients with PTSD nor the comorbidity of PTSD with chronic pain are well understood. Sharp and Harvey16 presented a model of mutual maintenance in which pain serves as a reminder of the traumatic event and the resulting arousal exacerbates the pain. Whereas the aggravating effects of psychological distress reported by Defrin and colleagues11 support this hypothesis, the higher pain thresholds commonly reported in PTSD samples cannot be directly explained by this model. Therefore stress-induced analgesia has been put forward as a possible mediator variable.9

Stress-induced analgesia

Experimental evidence suggests that whereas induced negative emotions can exacerbate pain perception,17,18 acute stress can induce analgesia.19–21 Stress-induced analgesia is a pain suppression response that occurs during or after exposure to a stressful or fearful stimulus. As the release of endogenous opiates in the thalamus, extended amygdala, insula, medial prefrontal cortex, anterior cingulate cortex and dorsal striatum diminishes pain sensation,22 opiates are thought to be key agents in stress-induced analgesia.23,24 In patients with PTSD, stress-induced analgesia is a key component of the broader phenomenon of dissociation, which also entails depersonalization and derealization.25 Dissociation may reflect a compensatory response to greater distress involving a complex corticolimbic network, possibly mediated by alterations in thalamic activation. During dissociative states, the connectivity between subcortical and cortical structures seems to be altered, with greater covariation between the thalamus, right insula and middle frontal regions.26 A recent study revealed a direct link between script-induced dissociative states and increased insula activations in conjunction with reduced pain sensitivity.27

Taken together, these results lead to the hypothesis that elevated pain thresholds reported in studies of people with PTSD with and without comorbid chronic pain could result from stress-induced analgesia in patients with elevated levels of dissociation.

In the present study, we examined the neural circuitry underlying pain processing in patients with PTSD after traumatic symptom provocation using fMRI at a 4.0 T field strength. Alterations in brain activation were measured during application of warm (nonpainful) versus hot (painful) stimuli. To test the hypothesis that trauma recall does not lead to the expected exacerbation in pain perception in patients with PTSD, we compared activations after neutral versus traumatic memories both within and between study groups. We expected that the traumatic script would exacerbate pain perception in trauma-exposed controls owing to induced negative emotions, but that for the patients with PTSD, the traumatic script would induce stress-induced analgesia. We thus hypothesized that the controls would report increased pain after the trauma script, whereas the patients with PTSD would report decreased pain. In addition, we expected trauma recall in participants with PTSD to lead to differential activation of brain regions involved in stress-induced analgesia and dissociation (dorsal striatum, thalamus, insula, anterior and midcingulate cortices, and extended amygdala) in a state-dependent manner. More precisely, we hypothesized that dissociation and PTSD symptom severity would be closely correlated to activation in these areas after trauma recall in the patients with PTSD.

Methods

Participants

The study involved patients with PTSD and healthy controls who had experienced a criterion A traumatic event but never developed PTSD. We included participants who were right-handed, aged 20–50 years and matched for age and sex. Participants gave written informed consent for inclusion and the study was approved by the Office of Research Ethics at the University of Western Ontario.

All participants met criterion A for PTSD, but it never developed in the control group. Individuals were included in the PTSD group if they met PTSD DSM-IV criteria, as assessed by the Structured Clinical Interview for DSM-IV (SCID28) and the Clinician Administered PTSD Scale (CAPS29). The PTSD group exhibited current DSM-IV comorbid diagnoses (major depression, dysthymia, panic disorder, anorexia, generalized anxiety disorder and social phobia). We also rated participants based on the Beck Depression Inventory-II30 and the Dissociative Experiences Scale (DES31). To examine dissociative symptoms during the scanning session, we used the Clinician-Administered Dissociative State Scale (CADSS32), a measure of state dissociation. The CADSS was scored as symptoms being present or absent. All healthy participants and most of the patients with PTSD were medication-free for at least 2 weeks before scanning, and none of the participants had received antipsychotic agents before the drug washout. We excluded participants if they met the criteria for pain disorder, had any history (current or within the last 6 mo) of drug or alcohol abuse, history of psychotic disorders and bipolar disorder, history of head injury (unconsciousness for any length of time) or any other neurologic disorder or presence of metallic or electronic implants that would preclude fMRI. Specific clinical characteristics of participants, including the nature of the trauma experienced, DSM-IV comorbid diagnoses and prescribed medications, are reported in Results.

Pain thresholding

We carried out thresholding for individual pain temperatures in the scanning room before scanning according to standard procedures.33 The thermal stimulation was applied to the area superior to the lateral malleolus (above the inner ankle) and was produced by the Neurosensory Analyzer TSA-II (Medoc Ltd. Advanced Medical Systems). The Neurosensory Analyzer TSA-II is a computer-controlled device that produces a rapid reproducible onset and offset of nontraumatic, individually titrated thermal nociceptive stimulation, a method that is well established in the pain literature.34 Heat was applied beginning at 38ºC for 12 seconds. One full minute was allowed to pass between stimulations, and the participant verbally rated the stimulus for “intensity of pain” and “unpleasantness” on a scale of 0 (no pain) to 100 (intense pain) according to standard methods.35 The stimulations increased by 1ºC until the participant deemed that the temperature he or she was receiving “painful, but tolerable.” A nonpainful warm temperature (1° higher than the initial temperature the participant was able to detect on his or her skin) was also identified during thresholding. The 2 stimuli were again tested on the participant, but this time for 25 seconds (the length of stimuli used in the imaging paradigm), to make sure that the participant still identified them as warm (non-painful) and hot (painful), but tolerable.

Functional imaging paradigm

The functional paradigm began with 60 seconds of baseline, when participants were instructed to “focus on your breathing,” followed by a 30-second prerecorded script (neutral or trauma). Participants were asked to focus on the script and imagine all the feelings and sensations associated with the memory while listening to the script and for 30 seconds after the script ended. A bell-tone indicated the end of this section, and the participant was instructed to “focus on the stimulation on your leg.” After a 25-second stimulation (warm or hot), a researcher asked the participant to rate pain intensity and unpleasantness (each on 0–100 scales); 120 seconds passed between stimulation and the beginning of the next script.

Participants heard 6 neutral scripts followed by 6 traumatic scripts (played in blocks of 3) prepared according to reported methods.36 The neutral scripts always preceded the trauma scripts, because anxiety elicited by trauma cues has been seen to persist into subsequent neutral conditions.37 This type of paradigm has been well established in the PTSD literature.26,36,38 For each script type, there were 3 warm (non-painful) and 3 hot (painful) stimulations. The warm and painful stimuli were presented in a pseudorandomized order, counterbalanced across groups, because anticipation can affect pain ratings and related activations.39 The participant was then removed from the scanner, completed postscan questionnaires and was debriefed.

Imaging protocol

We scanned participants on a 4.0 T Varian/Siemens ^UNITYINOVA whole-body imaging system at the Robarts Research Institute. We used a hybrid birdcage radiofrequency coil40 placed around the participant’s head for magnetic resonance signal transmission and reception, packed with foam to reduce head motion. We performed manual and automated shimming procedures using first- and second-order shims to optimize the magnetic field homogeneity over the imaging volume of interest. Using sagittal localizing images, we prescribed 21 contiguous, transversely orientated, 5-mm functional slices and acquired BOLD functional brain volumes with a navigator echo corrected, interleaved, multishot T₂*-weighted pulse sequence using an outwardly spiralling k-space trajectory (64 × 64 matrix size, volume acquisition time 2.5 s, echo time [TE] 15 ms, flip angle 30º, field of view [FOV] 22.0 cm). We acquired high-resolution T₁-weighted anatomic images using a 3-dimensional spiral sequence using the same FOV and orientation as the functional images (256 × 256 matrix size, TE 3.0 ms, flip angle 20º, repetition time [TR] 50 ms, inversion time [TI] 1.3 s). This acquisition produced 64 contiguous 1.25 mm–thick structural images with excellent grey/white matter contrast for the purpose of BOLD activation registration.

Image processing

We performed image processing and statistical analyses with Statistical Parametric Mapping (SPM 2; Wellcome Department of Neurology, London, UK, www.fil.ion.ucl.ac.uk/spm). For each series, we aligned all volumes to the first volume of series to reduce the effects of head motion and determined normalization parameters from the mean functional image. We normalized the realigned images to an echoplanar imaging template supplied by SPM 2 and smoothed the data with an 8-mm full-width at half-maximum isotropic Gaussian kernel.

Statistical analysis

Group statistics were calculated as Pearson correlations and 2-tailed 2-sample t tests. In case of unequal variances, we used Satterthwaite’s approximation to estimate the degrees of freedom. In all statistics, we considered p < 0.05 to be significant. We carried out our statistical analyses using SPSS version 15.0.

We employed a 2-stage random-effects analysis for the neuroimaging data. At the first level, we analyzed each participant’s functional data separately by modelling the evoked BOLD responses for each task epoch of interest as basis functions (i.e., a boxcar function convolved with a hemodynamic response function). For each participant, 2 contrasts were created: painful-warm after the neutral script and painful-warm after the trauma script. These contrasts were entered into a second-level analysis to make inferences about regionally specific correlates. Analyses examined activations related to the hot and warm stimuli, contrasting the thermal stimulation minus baseline for each, as generally reported for pain neuroimaging studies.41 We examined correlations between participants’ ratings on the DES, CAPS and CADSS and the BOLD response to quantify the influence of PTSD symptom severity as well as state and trait dissociation. Results were converted to Talairach coordinates42 using the program Talairach Client (www.talairach.org).

We set the threshold for statistical analyses at a cluster size of κ > 5 and an α-level of p = 0.001 with a family-wise error correction using 10-mm spheres around regions of interest (ROI; i.e., dorsal striatum, thalamus, insula, anterior and midcingulate and extended amygdala), which were identified on the basis of previous studies examining stress-induced analgesia and pain processing in healthy participants and patients with PTSD.7,14,21,43–45 All analyses were covaried for use of medication. We did not include BDI-II scores as covariates owing to their high correlation with the CAPS scores (r = 0.76, p < 0.001).

Results

Participants

The study included 17 patients with PTSD (assault n = 5, childhood abuse n = 3, military trauma n = 2, workplace trauma n = 2, motor vehicle collision n = 1, other n = 4) and 26 healthy controls who had experienced a criterion A traumatic event (military trauma n = 10, motor vehicle collision n = 8, assault n = 2, other n = 6) but never had PTSD. The participants were matched for age (mean age 36.8, standard deviation [SD] 8.2 yr in the control group v. 36.7, SD 9.7 yr in the PTSD group; t₄₀ = 0.043, p = 0.97) and sex (female controls, n = 11; PTSD n = 9; Fisher exact test p = 0.54). Participants in the PTSD group exhibited the following current DSM-IV comorbid diagnoses: major depression (n = 5), dysthymia (n = 1), panic disorder (n = 2), anorexia (n = 1), generalized anxiety disorder (n = 1) and social phobia (n = 1). The 3 medicated patients with PTSD received fluoxetine (n = 1), quetiapine and bupropion (n = 1), and citalopram and olanzapine (n = 1).

Clinical rating scales and pain ratings

Significant group differences were established for all clinical rating scales (Table 1), including trait dissociation and state dissociation after exposure to the trauma script. There was no significant difference between hot (painful) and warm (nonpainful) temperatures chosen during thresholding by patients with PTSD and controls. After the traumatic script as compared with the neutral script, the painful stimulus was rated as significantly more painful (t₂₅ = 2.502, p = 0.019) and unpleasant (t₂₅ = 3.233, p = 0.003) in the control group (Table 1). We noted a tendency for lower pain ratings after the trauma script as compared with the neutral script in the PTSD group, although it failed to reach statistical significance. In a direct group comparison, patients with PTSD reported significantly lower pain intensity and unpleasantness after the trauma script than the control group.

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