Pain Modulatory Network Research Articles

Хроническая боль в спине: от патогенеза к адекватной фармакотерапии

Chronic back pain is an actual problem of clinical medicine, the pathogenesis of which includes peripheral nociceptive stimulation, peripheral and/or central inflammation, abnormality of the central pain modulation network and mixed onset of various pathological mechanisms. Sources of nociceptive signal generation include the intervertebral disc, muscles, fasciae, facet joints, sacroiliac joints, pubic symphysis, ligaments and joint capsule, and other structures that contain nociceptors. Any event that causes tissue degeneration activates a massive inflammatory response that infiltrates the MPD, joints, muscles, fascia and other tissues, stimulates nociceptive receptors to produce inflammatory substances, which directly damages the nerve root and causes pain. Simultaneously, the damaged MPD and endplate stimulate pathological and invasive growth and proliferation of vessels and nerves in the MPD. Increasing evidence also suggests that systemic inflammation plays a crucial role in the pathogenesis of chronic back pain. The central mechanism of back pain involves altered sensory processing in the brain. Dysfunction of the descending pain modulation system results in amplification of pain information in the brain. Since monotherapy for chronic back pain is not optimal, it is necessary to promote the comprehensive treatment recommended by current international clinical guidelines and it is reasonable to combine several therapies to improve the clinical effect of therapy. The combination of Tizanidine and Mirtazapine is an effective pharmacotherapy for chronic back pain. KEYWORDS: Chronic back pain, pathogenesis of dorsalgia, Tizanidine, Mirtazapine

Conditioned pain modulation is associated with heightened connectivity between the periaqueductal grey and cortical regions.

Conditioned pain modulation (CPM) is a psychophysical assessment used to estimate the efficiency of an individual's endogenous modulatory mechanisms. Conditioned pain modulation has been used as a predictive assessment for the development of chronic pain and responses to pain interventions. Although much is known about the spinal cord mechanisms associated with descending pain modulation, less is known about the contribution of supraspinal and especially cortical regions. We aimed to explore how whole-brain connectivity of a core modulatory region, the periaqueductal grey (PAG), is associated with conditioned pain modulation, and endogenous pain modulation more broadly. We measured CPM and resting-state connectivity of 35 healthy volunteers, absent of chronic pain diagnoses. As a region of interest, we targeted the PAG, which is directly involved in endogenous modulation of input to the spinal cord and is a key node within the descending pain modulation network. We found that CPM was associated with heightened connectivity between the PAG and key regions associated with pain processing and inhibition, such as the primary and secondary somatosensory cortices, as well as the motor, premotor, and dorsolateral prefrontal cortices. These findings are consistent with connectivity findings in other resting-state and event-related fMRI studies. These findings indicate that individuals who are efficient modulators have greater functional connectivity between the PAG and regions involved in processing pain. The heightened connectivity of these regions may contribute to the beneficial outcomes in clinical pain management, as quantified by CPM. These results may function as brain-based biomarkers for vulnerability or resilience to pain.

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats.

Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre-OA) and during the early and late phases of monosodium iodoacetate (MIA)-induced OA in male and female Fischer 344 rats (young, 3-6 mo / old, 20-24 mo). For functional MRI, rats were scanned using a Bruker 7T MRI (TR = 1500 ms, in plane resolution = 400 μm, slice thickness 1 mm, acquisition time: 15 minutes) and under isoflurane anesthesia ≤ 1.5%. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients. NIH-NIA grant AG053783 (JYR) and NIH-NIDCR grant DE0027808 (JYR).

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats.

Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre‐OA) and during the early and late phases of monosodium iodoacetate‐induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients.

Altered Brainstem Pain Modulating Circuitry Functional Connectivity in Chronic Painful Temporomandibular Disorder

There is evidence from preclinical models of chronic pain and human psychophysical investigations to suggest that alterations in endogenous brainstem pain-modulation circuit functioning are critical for the initiation and/or maintenance of pain. Whilst preclinical models have begun to explore the functioning of this circuitry in chronic pain, little is known about such functioning in humans with chronic pain. The aim of this investigation was to determine whether individuals with chronic non-neuropathic pain, painful temporomandibular disorders (TMD), display alterations in brainstem pain-modulating circuits. Using resting-state functional magnetic resonance imaging, we performed static and dynamic functional connectivity (FC) analyses to assess ongoing circuit function in 16 TMD and 45 control subjects. We calculated static FC as the correlation of functional magnetic resonance imaging signals between regions over the entire scan and dynamic FC as the correlation of signals in short (50s) windows. Compared with controls, TMD subjects showed significantly greater (static) FC between the rostral ventromedial medulla and both the subnucleus reticularis dorsalis and the region that receives orofacial nociceptive afferents, the spinal trigeminal nucleus. No differences were found in other brainstem pain-modulating regions such as the midbrain periaqueductal gray matter and locus coeruleus. We also identified that TMD subjects experience greater variability in the dynamic functional connections between the rostral ventromedial medulla and both the subnucleus reticularis dorsalis and spinal trigeminal nucleus. These changes may underlie enhanced descending pain-facilitating actions over the region that receives nociceptive afferents, ultimately leading to enhanced nociceptive transmission to higher brain regions and thus contributing to the ongoing perception of pain. PerspectivePsychophysical studies suggest that brainstem pain-modulation circuits contribute to the maintenance of chronic pain. We report that individuals with painful TMD display altered static and dynamic FC within the brainstem pain-modulation network. Modifying this circuitry may alter an individual's ongoing pain.

Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain.

Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top-down engagement of the circuitry alongside altered reward processing in pain conditions.SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies.

Altered functional connectivity of the periaqueductal gray in chronic neck and shoulder pain

Chronic neck and shoulder pain with cervical spondylotic radiculopathy (CNSP-CSR) is one of the most common clinical chronic pain diseases. This study aimed to investigate the abnormal patterns in functional connectivity (FC) pertaining to the periaqueductal gray matter (PAG) in patients with CNSP-CSR. A seed-based FC analysis was carried out for the right ventrolateral PAG and a correlation analysis was carried out with pain intensity, duration, and the extracted mean z scores. The PAG FC was significantly positively associated with the right orbital inferior frontal gyrus, supramarginal gyrus/postcentral gyrus, putamen, and the left anterior cingulate cortex, and significant negative FC was observed in the right lingual gyrus/occipital cortex in patients with CNSP-CSR. A significant negative correlation was found between the pain intensity and the mean z scores in the left anterior cingulate cortex. Our study provides evidence to show that patients with CNSP-CSR have abnormal FC in the PAG-centered pain modulation network. Knowledge of this abnormal FC might lead to a better understanding of the mechanism underlying CNSP-CSR, especially the descending pain modulation system involved in chronic pain.

Disrupted functional connectivity of the periaqueductal gray in chronic low back pain.

Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG–vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG–insula and PAG–amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.

Altered gray matter volume in the frontal pain modulation network in patients with cluster headache

Previous functional imaging studies in episodic cluster headache (CH) patients revealed altered brain metabolism concentrated on the central descending pain control system. However, it remains unclear whether changes in brain metabolism during the “in bout” period are due to structural changes and whether these structural changes vary between the “in bout” and “out of bout” periods. To quantify brain structural changes in CH patients, the regional gray matter volume (GMV) was compared among 49 episodic CH patients during the “in bout” period and 49 age- and sex-matched controls. Twelve patients were rescanned during the “out of bout” period to evaluate the changes, if any, between these 2 periods. Compared with healthy controls, CH patients showed significant “in bout” GMV reductions in the bilateral middle frontal, left superior, and medial frontal gyri. Compared to “out of bout” scans, the “in bout” scans revealed significant GMV increases in the left anterior cingulate, insula, and fusiform gyrus. Additionally, compared to healthy controls, the “out of bout” scans revealed a trend of GMV reduction in the left middle frontal gyrus. These affected regions primarily belong to frontal pain modulation areas, and thus these GMV changes may reflect insufficient pain-modulating capacity in the frontal areas of CH patients.

Chronic Low-Back Pain Modulation Is Enhanced by Hypnotic Analgesic Suggestion by Recruiting an Emotional Network: A PET Imaging Study

This study aimed to characterize the neural networks involved in patients with chronic low-back pain during hypnoanalgesia. PET was performed in 2 states of consciousness, normal alertness and hypnosis. Two groups of patients received direct or indirect analgesic suggestion. The normal alertness state showed activations in a cognitive-sensory pain modulation network, including frontotemporal cortex, insula, somatosensory cortex, and cerebellum. The hypnotic state activated an emotional pain modulation network, including frontotemporal cortex, insula, caudate, accumbens, lenticular nuclei, and anterior cingulate cortex (ACC). Direct suggestion activated cognitive processes via frontal, prefrontal, and orbitofrontal cortices, while indirect suggestion activated a widespread and more emotional network including frontal cortex, anterior insula, inferior parietal lobule, lenticular nucleus, and ACC. Confirmed by visual analog scale data, these results suggest that chronic pain modulation is greater with hypnosis, which enhances both activated networks.

5-HT modulation of pain in SI and SII revealed by fMRI.

To observe the different cerebral activations between pre-administration and post-administration of tryptophan-depleted amino acid mixture (TRP-)/balanced amino acid mixture (BAL) in healthy volunteers through functional magnetic resonance imaging (fMRI) when they received electrical stimulation at the same time. Furthermore, the effects of 5-hydroxytryptamine (5-HT) were explored in pain modulation network. Two-phase crossover design was adopted. Six right-handed healthy volunteers participated in the experiment. TRP- and BAL were administered to each participant according to the Young's method. Volunteers were scanned under fMRI with or without administration of TRP- or BAL when receiving electrical stimulation simultaneously. Analysis of functional neuroimages (AFNI) software was used to show the different activations in the human brain between pre- and post-administration of TRP-/BAL. Then all the results were analyzed by SPSS 14.0. (1) Bilateral primary somatosensory cortex (SI) and secondary somatosensory cortex (SII) were activated during pre-administration and post-administration of TRP-, but the activated volumes of bilateral SI and SII during post-administration of TRP- were found significantly larger than that during pre-administration of TRP (P<0.05). (2) All the activated regions showed no difference between pre- and post-administration of BAL. (3) There were significant differences of pain threshold between pre- and post-administration of TRP- (P<0.01), which meant that pain threshold reduced remarkably after TRP- administration, while it showed no difference between pre- and post-administration of BAL (P>0.05). 5-HT plays an important role in pain modulation in the central nervous system, TRP- causes acute tryptophan depletion (ATD) through reducing the level of 5-HT in the human brain, which can induce the decrease of volunteers' pain threshold. The activated volumes of bilateral SI and SII display significant difference between pre- and post-administration of TRP-, suggesting these brain areas may not only involve in the 5-HT related activities but in pain modulation network as well.

Anterior cingulate cortex involving in pain modulation-an functional magnetic resonance imaging study

To investigate the functional activation patterns of the subregions of anterior cingulate cortex (ACC) in human to electrical stimulation of different intensity with functional Magnetic Resonance Imaging (fMRI) and probe the contribution of this area in pain modulation network. 10 healthy right-handed volunteers were studied with different electrical intensity stimulation of 1-, 2-, or 3-time pain threshold. The fMRI data were collected by GE signa 1.5T MRI system and postprocessed with software of Analysis of Functional Neuroimages (AFNI) to generate the regional activation maps of ACC, furthermore, the distinctive characteristics of stimulation-BOLD signal in ACC subregions were analyzed according to the fMRI maps from the average of the 10 subjects. The anterior portion of ACC (aACC) showed moderate pain-attention-related activation but not statistically related to the strength of stimulation (average activated pixels of P1, P2, P3 amounted to 324, 429, 562 respectively). The BOLD signal showed a positive linear relation with the increasing stimulation at the dorsal-posterior portion of ACC (average activated pixels of P1, P2, P3 were 311, 964, 1414), which indicated stimulus intensity-dependent responses. The ventral-posterior area of ACC (vpACC) demonstrated pain intensity encoding because the BOLD signal had no significant difference during innocuous condition but displayed remarkable distinction during noxious stimulation in this area (average activated pixels of P1, P2, P3 were 324, 429, 562). Subregions in ACC may play a varied role in the network of pain modulation. Each area of ACC displays segregated activation patterns in response to electrical stimulation with different strength.