Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study.

Neuroimaging studies have shown that changes in brain morphology often accompany chronic pain conditions. However, brain biomarkers that are sensitive and specific to chronic pelvic pain (CPP) have not yet been adequately identified. Using data from the Trans-MAPP Research Network, we examined the changes in brain morphology associated with CPP. We used a multivariate pattern classification approach to detect these changes and to identify patterns that could be used to distinguish participants with CPP from age-matched healthy controls. In particular, we used a linear support vector machine (SVM) algorithm to differentiate gray matter images from the 2 groups. Regions of positive SVM weight included several regions within the primary somatosensory cortex, pre-supplementary motor area, hippocampus, and amygdala were identified as important drivers of the classification with 73% overall accuracy. Thus, we have identified a preliminary classifier based on brain structure that is able to predict the presence of CPP with a good degree of predictive power. Our regional findings suggest that in individuals with CPP, greater gray matter density may be found in the identified distributed brain regions, which are consistent with some previous investigations in visceral pain syndromes. Future studies are needed to improve upon our identified preliminary classifier with integration of additional variables and to assess whether the observed differences in brain structure are unique to CPP or generalizable to other chronic pain conditions.

Brain white matter structural properties predict transition to chronic pain.

Neural mechanisms mediating the transition from acute to chronic pain remain largely unknown. In a longitudinal brain imaging study, we followed up patients with a single sub-acute back pain (SBP) episode for more than 1 year as their pain recovered (SBPr), or persisted (SBPp) representing a transition to chronic pain. We discovered brain white matter structural abnormalities (n=24 SBP patients; SBPp=12 and SBPr=12), as measured by diffusion tensor imaging (DTI), at entry into the study in SBPp in comparison to SBPr. These white matter fractional anisotropy (FA) differences accurately predicted pain persistence over the next year, which was validated in a second cohort (n=22 SBP patients; SBPp=11 and SBPr=11), and showed no further alterations over a 1-year period. Tractography analysis indicated that abnormal regional FA was linked to differential structural connectivity to medial vs lateral prefrontal cortex. Local FA was correlated with functional connectivity between medial prefrontal cortex and nucleus accumbens in SBPr. As we have earlier shown that the latter functional connectivity accurately predicts transition to chronic pain, we can conclude that brain structural differences, most likely existing before the back pain-inciting event and independent of the back pain, predispose subjects to pain chronification.

Psychophysical properties of female genital sensation.

Provoked vestibulodynia (PVD) is characterized by the presence of vulvar touch and pain hypersensitivity. Pain with vaginal distension, which motivates treatment seeking and perpetuates distress, is frequently reported with PVD. However, the concordance between the perception of vulvar and vaginal sensation (ie, somatic and visceral genital sensations, respectively) remains unstudied in healthy women, as well as in clinical populations such as PVD. To evaluate the static and dynamic (time-varying) properties of somatic and visceral genital sensation, women with PVD (n=14) and age- and contraceptive-matched healthy controls (n=10) rated varying degrees of nonpainful and painful genital stimulation. Somatic (vulvar) mechanical sensitivity to nonpainul and painful degrees of force were compared to visceral (vaginal) sensitivity to nonpainful and painful distension volumes. Results indicated that healthy women showed substantial individual variation in and high discrimination of vulvar and vaginal sensation. In contrast, PVD was associated with vulvar allodynia and hyperalgesia, as well as vaginal allodynia. Modeling of dynamic perception revealed novel properties of abnormal PVD genital sensation, including temporal delays in vulvar touch perception and reduced perceptual thresholds for vaginal distension. The temporal properties and magnitude of PVD distension pain were indistinguishable from vaginal fullness in healthy controls. These results constitute the first empirical comparison of somatic and visceral genital sensation in healthy women. Findings provide novel insights into the sensory abnormalities that characterize PVD, including an experimental demonstration of visceral allodynia. This investigation challenges the prevailing diagnostic assessment of PVD and reconceptualizes PVD as a chronic somatic and visceral pain condition.

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain.

A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses--that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.

Chronic neuropathic pain-like behavior correlates with IL-1ß expression and disrupts cytokine interactions in the hippocampus.

We have proposed that neuropathic pain engages emotional learning, suggesting the involvement of the hippocampus. Because cytokines in the periphery contribute to induction and maintenance of neuropathic pain but might also participate centrally, we used 2 neuropathic pain models, chronic constriction injury (CCI) and spared nerve injury (SNI), to investigate the temporal profile of hippocampal cytokine gene expression in 2 rat strains that show different postinjury behavioral threshold sensitivities. SNI induced long-lasting allodynia in both strains, while CCI induced allodynia with time-dependent recovery in Sprague Dawley (SD) and no allodynia in Wistar Kyoto (WK) rats. In WK rats, only SNI induced sustained upregulation of hippocampal interleukin (IL)-1ß, while IL-6 expression was transiently increased and no significant changes in IL-1ra expression were detected. Conversely, in SD rats, SNI resulted in sustained and robust increased hippocampal IL-1ß expression, which was only transient in rats with CCI. In this strain, IL-6 expression was not affected in any of the 2 injury models and IL-1ra expression was significantly increased in rats with SNI or CCI at late phases. We found that the degree and development of neuropathic pain depend on the specific nerve injury model and rat strain; that hippocampal IL-1ß mRNA levels correlate with neuropathic pain behavior; that, in contrast to sham-operated animals, there are no correlations between hippocampal IL-1ß and IL-1ra or IL-6 in neuropathic rats; and that alterations in cytokine expression are restricted to the hippocampus contralateral to the injury side, again implying that the observed changes reflect nociception.

Increased taste intensity perception exhibited by patients with chronic back pain.

There is overlap between brain regions involved in taste and pain perception, and cortical injuries may lead to increases as well as decreases in sensitivity to taste. Recently it was shown that chronic back pain (CBP) is associated with a specific pattern of brain atrophy. Since CBP is characterized by increased sensitivity to pain, we reasoned that the sense of taste might also be enhanced in CBP. Detection and recognition thresholds were established for a sour taste and ratings of both suprathreshold taste intensity and pleasantness-unpleasantness perception were collected for sweet, sour, salty and bitter stimuli in 11 CBP patients and 11 matched control subjects. As a control, ratings were also collected for visual assessment of degree of grayness. There was no difference between CBP and control subjects for visual grayness rating. On the other hand, CBP patients in comparison to control subjects rated gustatory stimuli as significantly more intense but no more or less pleasant and showed a trend towards a lower detection threshold (i.e. increased sensitivity). The selectivity of the taste disturbance suggests interaction between pain and taste at specific brain sites and provides further evidence that CBP involves specific brain abnormalities.

Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

The neurobiology of chronic pain, including chronic back pain, is unknown. Structural imaging studies of the spine cannot explain all cases of chronic back pain. Functional brain imaging studies indicate that the brain activation patterns are different between chronic pain patients and normal subjects, and the thalamus, and prefrontal and cingulate cortices are involved in some types of chronic pain. Animal models of chronic pain suggest abnormal spinal cord chemistry. Does chronic pain cause brain chemistry changes? We examined brain chemistry changes in patients with chronic back pain using in vivo single- voxel proton magnetic resonance spectroscopy ((1)H-MRS). In vivo (1)H-MRS was used to measure relative concentrations of N-acetyl aspartate, creatine, choline, glutamate, glutamine, gamma-aminobutyric acid, inositol, glucose and lactate in relation to the concentration of creatine. These measurements were performed in six brain regions of nine chronic low back pain patients and 11 normal volunteers. All chronic back pain subjects underwent clinical evaluation and perceptual measures of pain and anxiety. We show that chronic back pain alters the human brain chemistry. Reductions of N-acetyl aspartate and glucose were demonstrated in the dorsolateral prefrontal cortex. Cingulate, sensorimotor, and other brain regions showed no chemical concentration differences. In chronic back pain, the interrelationship between chemicals within and across brain regions was abnormal, and there was a specific relationship between regional chemicals and perceptual measures of pain and anxiety. These findings provide direct evidence of abnormal brain chemistry in chronic back pain, which may be useful in diagnosis and future development of more effective pharmacological treatments.

Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus.

Many lines of evidence implicate the somatosensory areas near the lateral sulcus (Sylvian fissure) in the cortical representation of pain. Anatomical tracing studies in the monkey show nociceptive projection pathways to the vicinity of the secondary somatosensory cortex in the parietal operculum, and to anterior parts of insular cortex deep inside the Sylvian fissure. Clinical observations demonstrate alterations in pain sensation following lesions in these two areas in human parasylvian cortex. Imaging studies in humans reveal increased blood flow in parasylvian cortex, both contralaterally and ipsilaterally, in response to painful stimuli. Painful stimuli (such as laser radiant heat) evoke potentials with a scalp maximum at anterior temporal positions (T3 and T4). Several dipole source analyses as well as subdural recordings have confirmed that the earliest evoked potential following painful laser stimulation of the skin derives from sources in the parietal operculum. Thus, imaging and electrophysiological studies in humans suggest that parasylvian cortex is activated by painful stimuli, and is one of the first cortical relay stations in the central processing of these stimuli. There is mounting evidence for closely located but separate representations of pain (deep parietal operculum and anterior insula) and touch (secondary somatosensory cortex and posterior insula) in parasylvian cortex. This anatomical separation may be one of the reasons why single unit recordings of nociceptive neurons are scarce within regions comprising low-threshold mechanoreceptive neurons. The functional significance (sensory-discriminative, affective-motivational, cognitive-evaluative) of the closely spaced parasylvian cortical areas in acute and chronic pain is only poorly understood. It is likely that some of these areas are involved in sensory-limbic projection pathways that may subserve the recognition of potentially tissue damaging stimuli as well as pain memory.