Nathalie Erpelding

Cortical thickness correlates of pain and temperature sensitivity.

Summary Individual pain and temperature sensitivity correlated with cortical thickness of the primary somatosensory, midcingulate, and orbitofrontal cortices, linking thermal and pain perception with structure. Abstract It is well established that there is individual variability in pain and temperature sensitivity. Functional brain imaging studies have found that interindividual heat pain variability correlates with brain activity in sensory and pain modulation areas. Thus, it is possible that these individual differences are associated with variability in gray matter thickness of cortical regions involved in thermoreception and pain. To test this, we investigated the relationship between thermal thresholds and cortical thickness in 80 healthy subjects. Subjects underwent a psychophysical session to determine their cool detection (CD), warm detection (WD), cold pain (CP), and heat pain (HP) threshold. A high‐resolution structural magnetic resonance imaging scan was acquired for each subject. We correlated each threshold measure to cortical thickness of regions associated with thermoreception and pain. The mean (± SD) thresholds were 30.7°C (± 0.8) for CD, 33.8°C (± 0.7) for WD, 11.7°C (± 9.7) for CP, and 45.3°C (± 2.8) for HP. The brain gray matter analysis revealed a strong correlation between greater thermal and pain sensitivity and cortical thickening of the primary somatosensory cortex. Additionally, greater sensitivity to cool stimuli correlated with cortical thickening in the paracentral lobule, and greater WD correlated with cortical thinning in the anterior midcingulate cortex. We also found that greater HP sensitivity correlated with thickening in the posterior midcingulate cortex and the orbitofrontal cortex. These cortical gray matter correlates of thermal and pain sensitivity provide a neural basis for individual differences in thermal sensitivity.

Sex differences in connectivity of the subgenual anterior cingulate cortex.

Summary Functional and structural connectivity of the subgenual ACC indicated greater connectivity with descending antinociceptive areas in women and greater connectivity with salience areas in men. ABSTRACT We previously reported that women exhibit greater heat pain adaptation to a prolonged painful stimulus and greater habituation to repeated painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, Bingel et al. (2007) have shown that pain habituation after 8 days of daily pain testing is associated with an increase in pain‐evoked activity of the subgenual anterior cingulate cortex (sgACC), suggesting that pain habituation may be mediated via connectivity between the sgACC and the descending pain antinociceptive system. Therefore, we investigated whether women have stronger functional connectivity (FC) and greater structural connectivity (SC) compared to men between the sgACC and the descending antinociceptive system. Our analyses revealed that 1) women exhibited greater FC between the sgACC and the periaqueductal gray (PAG), raphe nucleus, medial thalamus, and anterior midcingulate cortex (aMCC) than men; 2) men had stronger sgACC FC with the anterior insula and temporoparietal junction than women; 3) women and men exhibited comparable SC of the sgACC with the PAG, thalamus, aMCC, anterior insula, and amygdala; and 4) men have stronger sgACC SC with the hypothalamus than women. These data indicate that brain circuitry in women may provide for greater engagement of the descending modulation system mediating pain habituation. In contrast, in men, the salience network may be more engaged, which could support greater sustained attention to pain, thereby preventing pain habituation. Furthermore, the hypothalamus findings suggest a more powerful stress and endorphin‐based system at play in men than women.

Neural underpinnings of behavioural strategies that prioritize either cognitive task performance or pain.

Summary We report brain structure, function and connectivity characteristics that distinguish A‐type individuals who prioritize cognitive performance over pain from P‐type individuals, whose cognitive performance declines during pain. Abstract We previously discovered that when faced with a challenging cognitive task in the context of pain, some people prioritize task performance, while in others, pain results in poorer performance. These behaviours, designated respectively as A‐ and P‐types (for attention dominates vs pain dominates), may reflect pain coping strategies, resilience or vulnerabilities to develop chronic pain, or predict the efficacy of treatments such as cognitive behavioural therapy. Here, we used a cognitive interference task and pain stimulation in 80 subjects to interrogate psychophysical, psychological, brain structure and function that distinguish these behavioural strategies. During concurrent pain, the A group exhibited faster task reaction times (RTs) compared to nonpain trials, whereas the P group had slower RTs during pain compared to nonpain trials, with the A group being 143 ms faster than the P group. Brain imaging revealed structural and functional brain features that characterized these behavioural strategies. Compared to the performance‐oriented A group, the P group had (1) more gray matter in regions implicated in pain and salience (anterior insula, anterior midcingulate cortex, supplementary motor area, orbitofrontal cortex, thalamus, caudate), (2) greater functional connectivity in sensorimotor and salience resting‐state networks, (3) less white matter integrity in the internal and external capsule, anterior thalamic radiation and corticospinal tract, but (4) were indistinguishable based on sex, pain sensitivity, neuroticism, and pain catastrophizing. These data may represent neural underpinnings of how task performance vs pain is prioritized and provide a framework for developing personalized pain therapy approaches that are based on behaviour–structure–function organization.

The responsive amygdala: Treatment-induced alterations in functional connectivity in pediatric complex regional pain syndrome

Summary Amygdala connectivity is altered in children with chronic neuropathic pain and is responsive to intensive interdisciplinary treatment, with an associated decrease in pain‐related fear. ABSTRACT The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear, and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age‐sex matched control subjects before and after intensive physical‐biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared with control subjects, with differences predominantly in the left amygdala in the pretreated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy control subjects from time 1 to time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain‐related fear scores; and (4) decreases in pain‐related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity after an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response.

A brief cognitive-behavioural intervention for pain reduces secondary hyperalgesia

Summary A brief cognitive behavioural intervention reduces pain unpleasantness and secondary hyperalgesia elicited by repeated nociceptive thermal stimuli. ABSTRACT Repeated exposure to pain can result in sensitization of the central nervous system, enhancing subsequent pain and potentially leading to chronicity. The ability to reverse this sensitization in a top‐down manner would be of tremendous clinical benefit, but the degree that this can be accomplished volitionally remains unknown. Here we investigated whether a brief (˜5 min) cognitive‐behavioural intervention could modify pain perception and reduce central sensitization (as reflected by secondary hyperalgesia). In each of 8 sessions, 2 groups of healthy human subjects received a series of painful thermal stimuli that resulted in secondary hyperalgesia. One group (regulate) was given brief pain‐focused cognitive training at each session, while the other group (control) received a non‐pain‐focused intervention. The intervention selectively reduced pain unpleasantness but not pain intensity in the regulate group. Furthermore, secondary hyperalgesia was significantly reduced in the regulate group compared with the control group. Reduction in secondary hyperalgesia was associated with reduced pain catastrophizing, suggesting that changes in central sensitization are related to changes in pain‐related cognitions. Thus, we demonstrate that central sensitization can be modified volitionally by altering pain‐related thoughts.

Sex and the migraine brain.

The brain responds differently to environmental and internal signals that relate to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

The Insula A “Hub of Activity” in Migraine

The insula, a “cortical hub” buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new potential clinical perspectives for migraine treatment.

Intrinsic functional connectivity of periaqueductal gray subregions in humans

The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting‐state fMRI‐based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting‐state fMRI scans from 79 healthy subjects and (1) used a data‐driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)‐PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women. Hum Brain Mapp 37:1514‐1530, 2016.

The migraine brain in transition: girls vs boys.

Abstract The prevalence of migraine has an exponential trajectory that is most obvious in young females between puberty and early adulthood. Adult females are affected twice as much as males. During development, hormonal changes may act on predetermined brain circuits, increasing the probability of migraine. However, little is known about the pediatric migraine brain and migraine evolution. Using magnetic resonance imaging, we evaluated 28 children with migraine (14 females and 14 males) and 28 sex-matched healthy controls to determine differences in brain structure and function between (1) females and males with migraine and (2) females and males with migraine during earlier (10-11 years) vs later (14-16 years) developmental stages compared with matched healthy controls. Compared with males, females had more gray matter in the primary somatosensory cortex (S1), supplementary motor area, precuneus, basal ganglia, and amygdala, as well as greater precuneus resting state functional connectivity to the thalamus, amygdala, and basal ganglia and greater amygdala resting state functional connectivity to the thalamus, anterior midcingulate cortex, and supplementary motor area. Moreover, older females with migraine had more gray matter in the S1, amygdala, and caudate compared to older males with migraine and matched healthy controls. This is the first study showing sex and developmental differences in pediatric migraineurs in brain regions associated with sensory, motor, and affective functions, providing insight into the neural mechanisms underlying distinct migraine sex phenotypes and their evolution that could result in important clinical implications increasing treatment effectiveness.

Losses and gains: chronic pain and altered brain morphology

As in many fields of neuroscience, alterations in brain morphology, and specifically gray matter volume and cortical thickness, have been repeatedly linked to chronic pain disorders. Numerous studies have shown changes in cortical and subcortical brain regions suggesting a dynamic process that may be a result of chronic pain or contributing to a more generalized phenomenon in chronic pain including comorbid anxiety and depression. In this review, we provide a perspective of pain as an innate state of pain based on alterations in structure and by inference, brain function. A better neurobiological understanding of gray matter changes will contribute to our understanding of how structural changes contribute to chronic pain (disease driver) and how these changes may be reversed (disease modification or treatment).