Michael L. Keaser

Cognitive behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain

UNLABELLED Several studies have reported reduced cerebral gray matter (GM) volume or density in chronic pain conditions, but there is limited research on the plasticity of the human cortex in response to psychological interventions. We investigated GM changes after cognitive-behavioral therapy (CBT) in patients with chronic pain. We used voxel-based morphometry to compare anatomic magnetic resonance imaging scans of 13 patients with mixed chronic pain types before and after an 11-week CBT treatment and to 13 healthy control participants. CBT led to significant improvements in clinical measures. Patients did not differ from healthy controls in GM anywhere in the brain. After treatment, patients had increased GM in the bilateral dorsolateral prefrontal, posterior parietal, subgenual anterior cingulate/orbitofrontal, and sensorimotor cortices, as well as hippocampus, and reduced GM in supplementary motor area. In most of these areas showing GM increases, GM became significantly higher than in controls. Decreased pain catastrophizing was associated with increased GM in the left dorsolateral prefrontal and ventrolateral prefrontal cortices, right posterior parietal cortex, somatosensory cortex, and pregenual anterior cingulate cortex. Although future studies with additional control groups will be needed to determine the specific roles of CBT on GM and brain function, we propose that increased GM in the prefrontal and posterior parietal cortices reflects greater top-down control over pain and cognitive reappraisal of pain, and that changes in somatosensory cortices reflect alterations in the perception of noxious signals. PERSPECTIVE An 11-week CBT intervention for coping with chronic pain resulted in increased GM volume in prefrontal and somatosensory brain regions, as well as increased dorsolateral prefrontal volume associated with reduced pain catastrophizing. These results add to mounting evidence that CBT can be a valuable treatment option for chronic pain.

Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome

Summary Patients with burning mouth syndrome had altered structure and function of the medial prefrontal cortex and hippocampus, which was partially explained by ongoing pain and depression scores. ABSTRACT Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel‐based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC‐Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC‐Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain‐related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS.

Altered Brain Structure and Function Correlate with Disease Severity and Pain Catastrophizing in Migraine Patients

Our study provides a new and comprehensive look at how migraine affects brain structure, how these changes in structure are related to functional brain networks, and how coping and disease severity influence both structure and functional networks. Specifically, we demonstrate concomitant functional and structural brain changes related to pain catastrophizing and disease severity in migraine patients. Abstract Cover Figure Migraine patients (Pts) show widespread structural and functional brain changes that are associated with symptoms and increased pain catastrophizing A, Migraine patients showed (i) increased gray matter volume (GMV) in the left (L) hippocampus and (ii) decreased cortical thickness in the L anterior midcingulate cortex (aMCC) compared to healthy control subjects. B, Pain catastrophizing correlated with GMV reductions in the (i) L primary somatosensory cortex (S1) and (ii) L medial prefrontal cortex (mPFC), and cortical thinning in the (iii) L dorsolateral prefrontal cortex (DLPFC) and middle temporal gyrus (MTG) in migraine patients. C, GMV reductions correlated with (i) disease duration (ii), attack frequency, and (iii) migraine pain intensity in patients. D, Whole-brain overlay maps for migraine patients and healthy controls for the (i) L PCC, (ii) L aINS, and (iii) aMCC seed regions rendered onto inflated brains. Red represents resting-state functional connectivity for healthy controls and green represents the same maps in migraine patients. Yellow represents areas showing overlap in functional connectivity in controls and migraineurs. Images are thresholded at T = 4.5 (cluster extent = 25) for visualization purposes. The schematic illustrates the relationship between disease severity measures and pain catastrophizing and disruptions in functional connectivity between the default mode network (DMN), central executive network (CEN), and salience network (SN) in migraine patients. In patients, pain catastrophizing correlated with increased coupling between DMN and CEN nodes (PCC-DLPFC), whereas disease duration and migraine pain intensity correlated with SN-DMN network decoupling (aINS/aMCC-mPFC), and increased SN-CEN (aMCC-aINS) network coupling, respectively. To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.

Differential brain activation associated with laser-evoked burning and pricking pain: An event-related fMRI study.

Abstract An important question remains as to how the brain differentially processes first (pricking) pain mediated by Aδ‐nociceptors versus second (burning) pain mediated by C‐nociceptors. In the present cross‐over randomized, within‐subjects controlled study, brain activity patterns were examined with event‐related fMRI while pricking and burning pain were selectively evoked using a diode laser. Stimuli evoking equivalent pain intensities were delivered to the dorsum of the left foot. Different laser parameters were used to elicit pricking (60 ms pulse duration) and burning (2.0 s pulse duration) pain. Whole brain group analysis showed that several brain areas were commonly activated by pricking and burning pain, including bilateral thalamus, bilateral anterior insula, bilateral posterior parietal lobule, contralateral dorsolateral prefrontal cortex, ipsilateral cerebellum, and mid anterior cingulate cortex. These findings show that pricking and burning pain were associated with activity in many of the same nociceptive processing brain regions. This may be expected given that Aδ‐and C‐nociceptive signals converge to a great extent at the level of the dorsal horn. Other brain regions showed differential processing. Stronger activation in the pricking pain condition was found in the ipsilateral hippocampus, bilateral parahippocampal gyrus, bilateral fusiform gyrus, contralateral cerebellum and contralateral cuneus/parieto‐occipital sulcus. Stronger activation in the burning pain condition was found in the ipsilateral dorsolateral prefrontal cortex. These differential activation patterns suggest preferential importance of Aδ‐fiber signals versus C‐fiber signals for these specific brain regions.

The role of circulating sex hormones in menstrual cycle-dependent modulation of pain-related brain activation.

Summary Pain‐related brain activation varies across the menstrual cycle in normally cycling, healthy women, but these effects are generally independent from fluctuating sex hormone levels. Abstract Sex differences in pain sensitivity have been consistently found, but the basis for these differences is incompletely understood. The present study assessed how pain‐related neural processing varies across the menstrual cycle in normally cycling, healthy women, and whether menstrual cycle effects are based on fluctuating sex hormone levels. Fifteen subjects participated in 4 test sessions during their menstrual, midfollicular, ovulatory, and midluteal phases. Brain activity was measured while nonpainful and painful stimuli were applied with a pressure algometer. Serum hormone levels confirmed that scans were performed at appropriate cycle phases in 14 subjects. No significant cycle phase differences were found for pain intensity or unpleasantness ratings of stimuli applied during functional magnetic resonance imaging scans. However, lower pressure pain thresholds were found for follicular compared with other phases. Pain‐specific brain activation was found in several regions traditionally associated with pain processing, including the medial thalamus, anterior and middle insula, midcingulate, primary and secondary somatosensory cortices, cerebellum, and frontal regions. The inferior parietal lobule, occipital gyrus, cerebellum, and several frontal regions showed interaction effects between stimulus level and cycle phase, indicating differential processing of pain‐related responses across menstrual cycle phases. Correlational analyses indicated that cycle‐related changes in pain sensitivity measures and brain activation were only partly explained by varying sex hormone levels. These results show that pain‐related cerebral activation varies significantly across the menstrual cycle, even when perceived pain intensity and unpleasantness remain constant. The involved brain regions suggest that cognitive pain or more general bodily awareness systems are most susceptible to menstrual cycle effects.

Age-related changes in nociceptive processing in the human brain.

Abstract:  Functional magnetic resonance imaging (fMRI) was used to compare cortical nociceptive responses to painful contact heat in healthy young (ages 22–30, n= 7) and older (ages 56–75, n= 7) subjects. Compared to young subjects, older subjects had significantly smaller pain‐related fMRI responses in anterior insula (aINS) (P < 0.04), primary somatosensory cortex (S1) (P= 0.03), and supplementary motor area (P= 0.02). Gray matter volumes in S1 and aINS were significantly smaller for the older group (P= 0.02 and 0.0001, respectively), suggesting reduced processing capacity in these regions that might account for smaller pain‐related fMRI responses.

Altered cognition-related brain activity and interactions with acute pain in migraine

Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain–cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain–task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.

Intersession reliability of fMRI activation for heat pain and motor tasks

As the practice of conducting longitudinal fMRI studies to assess mechanisms of pain-reducing interventions becomes more common, there is a great need to assess the test–retest reliability of the pain-related BOLD fMRI signal across repeated sessions. This study quantitatively evaluated the reliability of heat pain-related BOLD fMRI brain responses in healthy volunteers across 3 sessions conducted on separate days using two measures: (1) intraclass correlation coefficients (ICC) calculated based on signal amplitude and (2) spatial overlap. The ICC analysis of pain-related BOLD fMRI responses showed fair-to-moderate intersession reliability in brain areas regarded as part of the cortical pain network. Areas with the highest intersession reliability based on the ICC analysis included the anterior midcingulate cortex, anterior insula, and second somatosensory cortex. Areas with the lowest intersession reliability based on the ICC analysis also showed low spatial reliability; these regions included pregenual anterior cingulate cortex, primary somatosensory cortex, and posterior insula. Thus, this study found regional differences in pain-related BOLD fMRI response reliability, which may provide useful information to guide longitudinal pain studies. A simple motor task (finger-thumb opposition) was performed by the same subjects in the same sessions as the painful heat stimuli were delivered. Intersession reliability of fMRI activation in cortical motor areas was comparable to previously published findings for both spatial overlap and ICC measures, providing support for the validity of the analytical approach used to assess intersession reliability of pain-related fMRI activation. A secondary finding of this study is that the use of standard ICC alone as a measure of reliability may not be sufficient, as the underlying variance structure of an fMRI dataset can result in inappropriately high ICC values; a method to eliminate these false positive results was used in this study and is recommended for future studies of test–retest reliability.

Motor Cortex Stimulation Suppresses Cortical Responses to Noxious Hindpaw Stimulation After Spinal Cord Lesion in Rats

BACKGROUND Motor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. The neural mechanisms underlying the reduction of hyperalgesia and allodynia after MCS are not completely understood. OBJECTIVE To investigate the neural mechanisms responsible for analgesic effects after MCS. We test the hypothesis that MCS attenuates evoked blood oxygen-level dependent signals in cortical areas involved in nociceptive processing in an animal model of chronic neuropathic pain. METHODS We used adult female Sprague-Dawley rats (n = 10) that received unilateral electrolytic lesions of the right spinal cord at the level of C6 (SCL animals). In these animals, we performed magnetic resonance imaging (fMRI) experiments to study the analgesic effects of MCS. On the day of fMRI experiment, 14 days after spinal cord lesion, the animals were anesthetized and epidural bipolar platinum electrodes were placed above the left primary motor cortex. Two 10-min sessions of fMRI were performed before and after a session of MCS (50 μA, 50 Hz, 300 μs, for 30 min). During each fMRI session, the right hindpaw was electrically stimulated (noxious stimulation: 5 mA, 5 Hz, 3 ms) using a block design of 20 s stimulation off and 20 s stimulation on. A general linear model-based statistical parametric analysis was used to analyze whole brain activation maps. Region of interest (ROI) analysis and paired t-test were used to compare changes in activation before and after MCS in these ROI. RESULTS MCS suppressed evoked blood oxygen dependent signals significantly (Family-wise error corrected P < 0.05) and bilaterally in 2 areas heavily implicated in nociceptive processing. These areas consisted of the primary somatosensory cortex and the prefrontal cortex. CONCLUSIONS These findings suggest that, in animals with SCL, MCS attenuates hypersensitivity by suppressing activity in the primary somatosensory cortex and prefrontal cortex.

High Frequency Migraine Is Associated with Lower Acute Pain Sensitivity and Abnormal Insula Activity Related to Migraine Pain Intensity, Attack Frequency, and Pain Catastrophizing

Migraine is a pain disorder associated with abnormal brain structure and function, yet the effect of migraine on acute pain processing remains unclear. It also remains unclear whether altered pain-related brain responses and related structural changes are associated with clinical migraine characteristics. Using fMRI and three levels of thermal stimuli (non-painful, mildly painful, and moderately painful), we compared whole-brain activity between 14 migraine patients and 14 matched controls. Although, there were no significant differences in pain thresholds nor in pre-scan pain ratings to mildly painful thermal stimuli, patients did have aberrant suprathreshold nociceptive processing. Brain imaging showed that, compared to controls, patients had reduced activity in pain modulatory regions including left dorsolateral prefrontal, posterior parietal, and middle temporal cortices and, at a lower-threshold, greater activation in the right mid-insula to moderate pain vs. mild pain. We also found that pain-related activity in the insula was associated with clinical variables in patients, including associations between: bilateral anterior insula and pain catastrophizing (PCS); bilateral anterior insula and contralateral posterior insula and migraine pain intensity; and bilateral posterior insula and migraine frequency at a lower-threshold. PCS and migraine pain intensity were also negatively associated with activity in midline regions including posterior cingulate and medial prefrontal cortices. Diffusion tensor imaging revealed a negative correlation between fractional anisotropy (a measure of white matter integrity; FA) and migraine duration in the right mid-insula and a positive correlation between left mid-insula FA and PCS. In sum, while patients showed lower sensitivity to acute noxious stimuli, the neuroimaging findings suggest enhanced nociceptive processing and significantly disrupted modulatory networks, particularly involving the insula, associated with indices of disease severity in migraine.