Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

AbstractThere is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored.Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded.Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes.Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.

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The Role of Stress Regulation on Neural Plasticity in Pain Chronification

Neural Plasticity ◽

10.1155/2016/6402942 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Xiaoyun Li ◽

Li Hu

Keyword(s):

Chronic Pain ◽

Animal Models ◽

Neural Plasticity ◽

Clinical Symptoms ◽

Brain Plasticity ◽

Brain Regions ◽

Stress Regulation ◽

Pain Chronification ◽

A Chain

Pain, especially chronic pain, is one of the most common clinical symptoms and has been considered as a worldwide healthcare problem. The transition from acute to chronic pain is accompanied by a chain of alterations in physiology, pathology, and psychology. Increasing clinical studies and complementary animal models have elucidated effects of stress regulation on the pain chronification via investigating activations of the hypothalamic-pituitary-adrenal (HPA) axis and changes in some crucial brain regions, including the amygdala, prefrontal cortex, and hippocampus. Although individuals suffer from acute pain benefit from such physiological alterations, chronic pain is commonly associated with maladaptive responses, like the HPA dysfunction and abnormal brain plasticity. However, the causal relationship among pain chronification, stress regulation, and brain alterations is rarely discussed. To call for more attention on this issue, we review recent findings obtained from clinical populations and animal models, propose an integrated stress model of pain chronification based on the existing models in perspectives of environmental influences and genetic predispositions, and discuss the significance of investigating the role of stress regulation on brain alteration in pain chronification for various clinical applications.

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Imaging Acute and Chronic Pain in the Human Brainstem and Spinal Cord

The Neuroscientist ◽

10.1177/1073858417703911 ◽

2017 ◽

Vol 24 (1) ◽

pp. 84-96 ◽

Cited By ~ 8

Author(s):

Luke A. Henderson ◽

Kevin A. Keay

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Human Brain ◽

Brain Imaging ◽

Imaging Techniques ◽

Brain Regions ◽

Protective Mechanism ◽

Animal Data ◽

Central Representation ◽

Spinal Cord Function

While acute pain serves as a protective mechanism designed to warn an individual of potential or actual damaging stimuli, chronic pain provides no benefit and is now considered a disease in its own right. Since the advent of human brain imaging techniques, many investigations that have explored the central representation of acute and chronic pain have focused on changes in higher order brain regions. In contrast, far fewer have explored brainstem and spinal cord function, mainly due to significant technical difficulties. In this review, we present some of the recent human brain imaging studies that have specifically explored brainstem and spinal cord function during acute noxious stimuli and in individuals with chronic pain. We focus particularly on investigations that explore changes in areas that receive nociceptor afferents and compare humans and experimental animal data in an attempt to describe both microscopic and macroscopic changes associated with acute and chronic pain.

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(327) Alterations in mood are associated with dysfunctional effective connectivity in the default mode network (DMN), reward and memory related brain regions in a chronic pain population

Journal of Pain ◽

10.1016/j.jpain.2017.02.220 ◽

2017 ◽

Vol 18 (4) ◽

pp. S56-S57

Author(s):

A. Smith ◽

J. Weber ◽

K. Boland ◽

J. Craggs

Keyword(s):

Chronic Pain ◽

Default Mode Network ◽

Effective Connectivity ◽

Brain Regions ◽

Default Mode

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Inherent Sex Differences in the Expression of the Endocannabinoid System within V1M Cortex and PAG of Sprague Dawley Rats

10.21203/rs.3.rs-606890/v1 ◽

2021 ◽

Author(s):

Aidan Levine ◽

Erika Liktor-Busa ◽

Austin A Lipinski ◽

Sarah Couture ◽

Shreya Balasubramanian ◽

...

Keyword(s):

Mass Spectrometry ◽

Chronic Pain ◽

Sex Differences ◽

Cannabinoid Receptors ◽

Endocannabinoid System ◽

Brain Regions ◽

Sprague Dawley ◽

Female Population ◽

Sprague Dawley Rats ◽

Chronic Pain Conditions

Abstract Background: Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system is comprised of the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods: Brain tissue from naïve male and female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unbiased proteomic analysis, and immunohistochemistry. Results: Mass spectrometry revealed cortical AEA levels were significantly higher in males compared to females (p<0.001), whereas 2-AG levels in periaqueductal grey were significantly higher in females compared to males (p<0.0001). Immunohistochemistry followed by unbiased proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG.Conclusions: Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

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Analgesic and Antidepressant Effects of the Clinical Glutamate Modulators Acetyl-L-Carnitine and Ketamine

Frontiers in Neuroscience ◽

10.3389/fnins.2021.584649 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ulderico Freo ◽

Viola Brugnatelli ◽

Fabio Turco ◽

Gastone Zanette

Keyword(s):

Chronic Pain ◽

Depressive Disorders ◽

Day Surgery ◽

Brain Regions ◽

Stressful Events ◽

Prefrontal Cortical ◽

Post Operative Pain ◽

Antidepressant Effects ◽

Sparing Effect ◽

Glutamate Modulators

Pain and depression are leading causes of disability and of profound social and economic burden. Their impact is aggravated by their chronicity and comorbidity and the insufficient efficacy of current treatments. Morphological and functional metabolism studies link chronic pain and depressive disorders to dysfunctional neuroplastic changes in fronto-limbic brain regions that control emotional responses to painful injuries and stressful events. Glutamate modulators are emerging new therapies targeting dysfunctional brain areas implicated in the generation and maintenance of chronic pain and depression. Here, we report the effects of two clinically approved glutamate modulators: acetyl-L-carnitine (ALCAR) and S, R(±)ketamine (KET). ALCAR is a natural neurotrophic compound currently marketed for the treatment of neuropathies. KET is the prototypical non-competitive antagonist at N-methyl-D-aspartate glutamate receptors and a clinically approved anesthetic. Although they differ in pharmacological profiles, ALCAR and KET both modulate aminergic and glutamatergic neurotransmissions and pain and mood. We assessed in rats the effects of ALCAR and KET on cerebral metabolic rates for glucose (rCMRglc) and assessed clinically the effects of ALCAR in chronic pain and of KET in post-operative pain. ALCAR and KET increased rCMRglc at similar degrees in prefrontal, somatosensory, and cingulate cortices, and KET increased rCMRglc at a different, much larger, degree in limbic and dopaminergic areas. While rCMRglc increases in prefrontal cortical areas have been associated with analgesic and antidepressant effects of ALCAR and KET, the marked metabolic increases KET induces in limbic and dopaminergic areas have been related to its psychotomimetic and abuse properties. In patients with chronic neuropathic pain, ALCAR (1,000 mg/day) yielded to a fast (2 weeks) improvement of mood and then of pain and quality of life. In day-surgery patients, KET improved dischargeability and satisfaction. In obese patients undergoing bariatric surgery, a single, low dose of KET (0.5 mg/kg) at induction of anesthesia determined a very fast (hours) amelioration of post-operative depression and pain and an opioid-sparing effect. These findings indicate that ALCAR and KET, two non-selective glutamate modulators, still offer viable therapeutic options in comorbid pain and depression.

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Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

Biology of Sex Differences ◽

10.1186/s13293-021-00402-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Aidan Levine ◽

Erika Liktor-Busa ◽

Austin A. Lipinski ◽

Sarah Couture ◽

Shreya Balasubramanian ◽

...

Keyword(s):

Mass Spectrometry ◽

Chronic Pain ◽

Sex Differences ◽

Cannabinoid Receptors ◽

Endocannabinoid System ◽

Brain Regions ◽

Sprague Dawley ◽

Female Population ◽

Sprague Dawley Rats ◽

Chronic Pain Conditions

Abstract Background Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods Brain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry. Results Mass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG. Conclusions Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

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Changes in resting-state brain networks after cognitive–behavioral therapy for chronic pain

Psychological Medicine ◽

10.1017/s0033291717002598 ◽

2017 ◽

Vol 48 (7) ◽

pp. 1148-1156 ◽

Cited By ~ 13

Author(s):

A. Yoshino ◽

Y. Okamoto ◽

G. Okada ◽

M. Takamura ◽

N. Ichikawa ◽

...

Keyword(s):

Chronic Pain ◽

Cognitive Behavioral Therapy ◽

Pain Intensity ◽

Resting State ◽

Clinical Symptoms ◽

Behavioral Therapy ◽

Brain Regions ◽

Posterior Cingulate Cortex ◽

Cognitive Behavioral ◽

Connectivity Strength

AbstractBackgroundCognitive–behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive–emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response.MethodsWe performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data.ResultsAbnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT-related clinical improvements.ConclusionsWe conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT.

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Neural Oscillations: Understanding a Neural Code of Pain

The Neuroscientist ◽

10.1177/1073858420958629 ◽

2020 ◽

pp. 107385842095862

Author(s):

Junseok A. Kim ◽

Karen D. Davis

Keyword(s):

Chronic Pain ◽

Brain Regions ◽

Oscillatory Activity ◽

Neural Oscillations ◽

Brain Functions ◽

Disease States ◽

Efficient Communication ◽

Nociceptive Processing ◽

The Brain

Neural oscillations play an important role in the integration and segregation of brain regions that are important for brain functions, including pain. Disturbances in oscillatory activity are associated with several disease states, including chronic pain. Studies of neural oscillations related to pain have identified several functional bands, especially alpha, beta, and gamma bands, implicated in nociceptive processing. In this review, we introduce several properties of neural oscillations that are important to understand the role of brain oscillations in nociceptive processing. We also discuss the role of neural oscillations in the maintenance of efficient communication in the brain. Finally, we discuss the role of neural oscillations in healthy and chronic pain nociceptive processing. These data and concepts illustrate the key role of regional and interregional neural oscillations in nociceptive processing underlying acute and chronic pains.

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