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Background and Purpose: Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose‐effect relationships of morphine, we investigated the effects of its non‐linear blood–brain barrier (BBB) transport on μ‐receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. Experimental Approach: CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate‐ and extended‐release formulations were generated using a physiology‐based pharmacokinetic model of the CNS, with non‐linear BBB transport of morphine. The simulated CNS exposure profiles were then used to derive corresponding μ‐receptor occupancies at multiple CNS pain matrix locations. Key Results: Simulated CNS exposure profiles for morphine, M3G and M6G, associated with non‐linear BBB transport of morphine resulted in varying μ‐receptor occupancies between different dose regimens, formulations and CNS locations. At lower doses, the μ‐receptor occupancy of morphine was relatively higher than at higher doses of morphine, due to the relative contribution of M3G and M6G. At such higher doses, M6G showed higher occupancy than morphine, whereas M3G occupancy was low throughout the dose ranges. Conclusion and Implications: Non‐linear BBB transport of morphine affects the μ‐receptor occupancy ratios of morphine with its metabolites, depending on dose and route of administration, and CNS location. These predictions need validation in animal or clinical experiments, to understand the clinical implications. [ABSTRACT FROM AUTHOR]

Discogenic low back pain (LBP) is a significant clinical condition arising from degeneration of the intervertebral disc, a common yet complex cause of chronic pain, defined by fissuring in the annulus fibrosus resulting in vascularization of growing granulation tissue and growth of nociceptive nerve fibers along the laceration area. This paper delves into the anatomical and pathophysiological underpinnings of discogenic LBP, emphasizing the role of intervertebral disc degeneration in the onset of pain. The pathogenesis is multifactorial, involving processes like mitochondrial dysfunction, accumulation of advanced glycation end products, and pyroptosis, all contributing to disc degeneration and subsequent pain. Despite its prevalence, diagnosing discogenic LBP is challenging due to the overlapping symptoms with other forms of LBP and the absence of definitive diagnostic criteria. Current diagnostic approaches include clinical evaluations, imaging techniques, and the exploration of potential biomarkers. Treatment strategies range from conservative management, such as physical therapy and pharmacological interventions, to more invasive procedures such as spinal injections and surgery. Emerging therapies targeting molecular pathways involved in disc degeneration are under investigation and hold potential for future clinical application. This paper highlights the necessity of a multidisciplinary approach combining clinical, imaging, and molecular data to enhance the accuracy of diagnosis and the effectiveness of treatment for discogenic LBP, ultimately aiming to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Shingles can cause long-term pain and negative emotions, along with changes in brain function. In this study, Granger Causality Analysis (GCA) was used to compare herpes zoster (HZ) and postherpetic neuralgia (PHN) differences in effective connections within the "pain matrix" between patients and healthy controls to further understand patterns of interaction between brain regions and explore the relationship between changes in effective connections and clinical features. Methods: Resting-state functional magnetic resonance imaging (fMRI) scans were performed on 55 HZ; 55 PHN; and 50 age-, sex- matched healthy controls (HCs). The brain regions associated with the pain matrix are used as the seeds of effective connectivity. GCA was used to analyze effective connections in brain regions that differed significantly between groups. Then the correlation between GCA values and clinical indicators was studied. Results: Compared with HC, GCA values between the thalamus and the amygdala, between the thalamus and the precentral gyrus, from the thalamus to the postcentral gyrus, and from the parahippocampal gyrus to the amygdala, anterior cingulate gyrus were significantly reduced in HZ patients. Compared with HC, GCA values between the insular and the postcentral gyrus, from the insular to the inferior parietal lobe, and from the postcentral gyrus to the amygdala were significantly reduced in PHN patients. Compared with HZ, GCA values between the inferior parietal lobe and the parahippocampal gyrus, between the inferior parietal lobe and the anterior cingulate gyrus, and from the anterior cingulate gyrus to the amygdala were significantly increased in PHN patients. The visual analogue scale (VAS) score of PHN patients was positively correlated with the GCA value from the central posterior lobe to the insula. Conclusions: PHN and HZ patients showed a broad reduction in effective connections, mainly reflected in abnormal pain pathway regulation, pain perception, negative emotion and memory production, providing new perspectives to understand the neuroimaging mechanisms of shingles. [ABSTRACT FROM AUTHOR]

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety–depressive disorders, anhedonia and motor and cognitive deficits gathered under the term "pain matrix". The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between "pain matrix" circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal's pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain. [ABSTRACT FROM AUTHOR]

Yingxuan Hu,1,* Junqin Ma,1,* Bingmei Chen,2 Jiahui Pang,1 Wen Liang,2 Wen Wu1 1Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Radiology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Wu; Wen Liang, Email wuwen66@163.com; liangwendoc@163.comPurpose: This study was conducted to explore the differences in functional changes in the pain matrix in patients with chronic back pain (CBP) at different stages and identify whether these brain changes were related to the pain duration.Patients and Methods: In this study, 29 healthy individuals and 54 patients with CBP were recruited. According to the pain duration, 25 patients (3 to 12 months) were divided into the CBP-S group and 29 patients (≥ 24 months) were divided into the CBP-L group. All subjects completed clinical pain-related measurement and functional magnetic resonance imaging (fMRI) scans. Moreover, the amplitude of low-frequency fluctuation (ALFF), functional connectivity (FC), and correlation analysis were conducted in this study.Results: Compared with healthy controls, patients in the CBP-L group showed significantly decreased ALFF in the left precuneus. In the FC analysis, patients in the CBP-S and CBP-L groups showed significantly decreased FC in several regions in the bilateral orbitofrontal cortices (OFC) and the left ventral posterior insula. Moreover, there were significant differences in the FC between the left hyper granular insula and the probabilistic area in OFC in pairwise group comparisons. The correlation analysis results demonstrated that pain duration was correlated with these functional brain changes, and the ANCOVA results revealed that pain intensity and pain interference scores did not affect the FC analysis results.Conclusion: There are different changes in the pain neural matrix in patients with chronic pain at different stages. Furthermore, the pain duration is related to brain functional changes.Keywords: chronic back pain, pain duration, fMRI, resting-state, pain matrix

Postherpetic neuralgia (PHN) is a typical chronic neuropathic pain syndrome. Both peripheral and central nervous system mechanisms are believed to be involved in PHN, but the central nervous system-related brain network structure and function are not yet fully elucidated, limiting the study on the clinical analgesic drugs and other intervention strategies. In recent years, the research on pain matrix-related brain networks has helped to reveal the central nervous system regulation mechanism of pain, but there are few reports on the PHN pain matrix. This review summarizes the recent studies on the PHN pain matrix, retrospectively analyzes the functional and structural changes in specific pain-related brain regions, in order to provide the new insights for exploring the effective targeted analgesic treatments. [ABSTRACT FROM AUTHOR]

Practical relevance: Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care. Clinical approach: Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways. Aim: This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions. Evidence base: The review draws on current literature, where available, along with the author's extensive experience and research. [ABSTRACT FROM AUTHOR]

Chronic stress and chronic pain share neuro-anatomical, endocrinological, and biological features. However, stress prepares the body for challenging situations or mitigates tissue damage, while pain is an unpleasant sensation due to nociceptive receptor stimulation. When pain is chronic, it might lead to an allostatic overload in the body and brain due to the chronic dysregulation of the physiological systems that are normally involved in adapting to environmental challenges. Managing stress and chronic pain (CP) in neurorehabilitation presents a significant challenge for healthcare professionals and researchers, as there is no definitive and effective solution for these issues. Patients suffering from neurological disorders often complain of CP, which significantly reduces their quality of life. The aim of this narrative review is to examine the correlation between stress and pain and their potential negative impact on the rehabilitation process. Moreover, we described the most relevant interventions used to manage stress and pain in the neurological population. In conclusion, this review sheds light on the connection between chronic stress and chronic pain and their impact on the neurorehabilitation pathway. Our results emphasize the need for tailored rehabilitation protocols to effectively manage pain, improve treatment adherence, and ensure comprehensive patient care. [ABSTRACT FROM AUTHOR]

The effects of acute and chronic intakes of high doses of alcohol on pain perception are well known, ranging from short-term analgesic effects to long-term sensitization and polyneuropathies. The short-term analgesic effects of ethanol consumption on subjective pain perception have been well studied in the literature. Recent advances in neuroimaging allow for an insight into pain-related structures in the brain, fostering the mechanistic understanding of the processing of nociceptive input and pain. We aimed to utilize EEG, combined with standardized noxious mechanical/thermal stimulation and subjective pain testing, to research the effects of acute alcohol intake on nociceptive processing and pain perception. We recruited 12 healthy subjects in an unblinded cross-over study design and aimed at achieving a blood alcohol level of 0.1%. Our data revealed a significant reduction in subjective pain ratings to noxious thermal and mechanical stimuli after alcohol ingestion. Our EEG data revealed suppressing effects on the cortical structures responsible for processing pain, the "pain matrix". We conclude that in addition to its analgesic effects, as expressed by the reduction in subjective pain, alcohol has a further impact on the "pain matrix" and directly affects the salience to a nociceptive stimulus. [ABSTRACT FROM AUTHOR]

Pain is a multifaceted process that encompasses unpleasant sensory and emotional experiences. The essence of the pain process is aversion, or perceived negative emotion. Central sensitization plays a significant role in initiating and perpetuating of chronic pain. Melzack proposed the concept of the "pain matrix", in which brain regions associated with pain form an interconnected network, rather than being controlled by a singular brain region. This review aims to investigate distinct brain regions involved in pain and their interconnections. In addition, it also sheds light on the reciprocal connectivity between the ascending and descending pathways that participate in pain modulation. We review the involvement of various brain areas during pain and focus on understanding the connections among them, which can contribute to a better understanding of pain mechanisms and provide opportunities for further research on therapies for improved pain management. [ABSTRACT FROM AUTHOR]

Yoga is an ancient wisdom comprising a multitude of physical and mental practices that are aimed toward a state of optimum physical, mental, social, and spiritual health. Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory nervous system that is often unresponsive to currently available modes of treatment, portending an inferior quality of life for patients. This systematic review and meta-analysis aim to investigate the effect and the potential role of yoga in NP syndromes. PubMed, Scopus, Elton Bryson Stephens Company (EBSCO), and Cochrane Library were screened for randomized controlled trials (RCTs) assessing the effects of yoga in patients on NP. Usual care, no treatment, or any active treatments were acceptable as control interventions. Primary outcome measures were objective or subjective assessment measures of pain intensity. For each outcome, standardized mean differences and 95% confidence intervals (CIs) were calculated. A total of four studies were included for qualitative synthesis. Meta-analysis of three studies revealed an overall effect (Z) in the favor of yoga as an intervention for NP, when compared to controls, although the effect was not statistically significant (three RCTs; Z = 1.10 [P = 0.27]; Heterogeneity: τ2 = 0.37; χ2 = 27.78, df = 2 [P < 0.00001]; I2 = 93%). This review divulged the overall favorable effect of yoga in NP, although it was not statistically significant. It highlights the promising role of yoga on pain intensity and quality of life in NP syndromes while showing that yoga has the advantage of being an inexpensive and easily accessible mode of therapy. Extensive research on the efficiency and safety of yoga must be conducted using robust RCTs with rigorous methodologies.

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety–depressive disorders, anhedonia and motor and cognitive deficits gathered under the term “pain matrix”. The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between “pain matrix” circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal’s pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain.

The purpose of this study was to explore the resting-state functional connectivity (FC) changes among the pain matrix and other brain regions in herpes zoster (HZ) and postherpetic neuralgia (PHN) patients. Fifty-four PHN patients, 52 HZ patients, and 54 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We used a seed-based FC approach to investigate whether HZ and PHN patients exhibited abnormal FC between the pain matrix and other brain regions compared to HCs. A random forest (RF) model was constructed to explore the feasibility of potential neuroimaging indicators to distinguish the two groups of patients. We found that PHN patients exhibited decreased FCs between the pain matrix and the putamen, superior temporal gyrus, middle frontal gyrus, middle cingulate gyrus, amygdala, precuneus, and supplementary motor area compared with HCs. Similar results were observed in HZ patients. The disease durations of PHN patients were negatively correlated with those aforementioned impaired FCs. The results of machine learning experiments showed that the RF model combined with FC features achieved a classification accuracy of 75%. Disrupted FC among the pain matrix and other regions in HZ and PHN patients may affect multiple dimensions of pain processing. [ABSTRACT FROM AUTHOR]

Yoga is an ancient wisdom comprising a multitude of physical and mental practices that are aimed toward a state of optimum physical, mental, social, and spiritual health. Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory nervous system that is often unresponsive to currently available modes of treatment, portending an inferior quality of life for patients. This systematic review and meta-analysis aim to investigate the effect and the potential role of yoga in NP syndromes. PubMed, Scopus, Elton Bryson Stephens Company (EBSCO), and Cochrane Library were screened for randomized controlled trials (RCTs) assessing the effects of yoga in patients on NP. Usual care, no treatment, or any active treatments were acceptable as control interventions. Primary outcome measures were objective or subjective assessment measures of pain intensity. For each outcome, standardized mean differences and 95% confidence intervals (CIs) were calculated. A total of four studies were included for qualitative synthesis. Meta-analysis of three studies revealed an overall effect (Z) in the favor of yoga as an intervention for NP, when compared to controls, although the effect was not statistically significant (three RCTs; Z = 1.10 [P = 0.27]; Heterogeneity: τ2 = 0.37; χ² = 27.78, df = 2 [P < 0.00001]; I 2 = 93%). This review divulged the overall favorable effect of yoga in NP, although it was not statistically significant. It highlights the promising role of yoga on pain intensity and quality of life in NP syndromes while showing that yoga has the advantage of being an inexpensive and easily accessible mode of therapy. Extensive research on the efficiency and safety of yoga must be conducted using robust RCTs with rigorous methodologies. [ABSTRACT FROM AUTHOR]

Chronic stress and chronic pain share neuro-anatomical, endocrinological, and biological features. However, stress prepares the body for challenging situations or mitigates tissue damage, while pain is an unpleasant sensation due to nociceptive receptor stimulation. When pain is chronic, it might lead to an allostatic overload in the body and brain due to the chronic dysregulation of the physiological systems that are normally involved in adapting to environmental challenges. Managing stress and chronic pain (CP) in neurorehabilitation presents a significant challenge for healthcare professionals and researchers, as there is no definitive and effective solution for these issues. Patients suffering from neurological disorders often complain of CP, which significantly reduces their quality of life. The aim of this narrative review is to examine the correlation between stress and pain and their potential negative impact on the rehabilitation process. Moreover, we described the most relevant interventions used to manage stress and pain in the neurological population. In conclusion, this review sheds light on the connection between chronic stress and chronic pain and their impact on the neurorehabilitation pathway. Our results emphasize the need for tailored rehabilitation protocols to effectively manage pain, improve treatment adherence, and ensure comprehensive patient care.

The use of advanced imaging in routine diagnostic practice appears to provide only limited value in patients with migraine who have not experienced recent changes in headache characteristics or symptoms. However, advanced imaging may have potential for studying the biological manifestations and pathophysiology of migraine headaches. Migraine with aura appears to have characteristic spatiotemporal changes in structural anatomy, function, hemodynamics, metabolism, and biochemistry, whereas migraine without aura produces more subtle and complex changes. Large, controlled, multicenter imaging-based observational trials are needed to confirm the anecdotal evidence in the literature and test the scientific hypotheses thought to underscore migraine pathophysiology.

Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations. [ABSTRACT FROM AUTHOR]

Francisco Pellicer,1 Juan M Ortega-Legaspi,2 Rodrigo Martín,3 Sergio Solís-Nájera,4 Lucía Magis-Weinberg,5 Martha León-Olea,6 Ariel Graff-Guerrero,7,8 Camilo de la Fuente-Sandoval,9 Alfredo O Rodriguez3 1Laboratorio de Neurofisiología Integrativa, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 2Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 3Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana Iztapalapa, CDMX, México; 4Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, México; 5Department of Psychology, University of Washington Guthrie Hall (GTH), Seattle, WA, USA; 6Departamento de Neuromorfología Funcional, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 7Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada; 8Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 9Laboratorio de Psiquiatría Experimental, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, CDMX, MéxicoCorrespondence: Francisco Pellicer, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México Xochimilco 101, San Lorenzo Huipulco, Alcaldía Tlalpan, CDMX, 14370, México, Tel +52 55 41605063, Email pellicer@imp.edu.mxObjective: Pain constitutes an essential alarm for preserving the organism’s integrity. Damage to the nervous system produces a pathological condition known as neuropathic pain.Purpose: Blood oxygenation level-dependent (BOLD) and functional magnetic resonance imaging (fMRI) have been widely used to map neuroanatomy and the active regions of interest (ROI) of nociceptive processing. Our study explored the brain’s BOLD response in rats after thermal noxious stimulation, immediately after sciatic nerve damage and during 75 minutes after surgical lesion of the sciatic nerve.Methods: Nine male Wistar rats were tested; the experiments were performed on a 7-Tesla /21-cm Varian Agilent system. This approach allowed, for the first time, to measure in vivo the BOLD changes in brain regions involved with the pain process: cingulated (ACC), somatosensory (S1), and insular cortices (IC), as well as thalamus (Th) and ventral tegmental area (VTA) related with acute thermal pain and during the early stages of sciatic denervation that produce neuropathic pain.Results: During thermonociception scan, all subjects showed BOLD activation in the ROIs determined as ACC, S1, Th, IC and VTA. After denervation, these regions continued to show activation with a slow decrement in intensity for the duration of the experiment. The results suggest that these brain structures are overactive during the genesis of neuropathic pain.Conclusion: The study shows for the first time continuous activation of the pain matrix following an acute thermal nociceptive stimulus followed by neuropathic damage. These results have given insight into the early stages of the development of neuropathic pain in vivo.Keywords: fMRI, resting state, neuropathic pain, pain matrix, chronic pain, acute pain

The purpose of this study was to explore the resting-state functional connectivity (FC) changes among the pain matrix and other brain regions in herpes zoster (HZ) and postherpetic neuralgia (PHN) patients. Fifty-four PHN patients, 52 HZ patients, and 54 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We used a seed-based FC approach to investigate whether HZ and PHN patients exhibited abnormal FC between the pain matrix and other brain regions compared to HCs. A random forest (RF) model was constructed to explore the feasibility of potential neuroimaging indicators to distinguish the two groups of patients. We found that PHN patients exhibited decreased FCs between the pain matrix and the putamen, superior temporal gyrus, middle frontal gyrus, middle cingulate gyrus, amygdala, precuneus, and supplementary motor area compared with HCs. Similar results were observed in HZ patients. The disease durations of PHN patients were negatively correlated with those aforementioned impaired FCs. The results of machine learning experiments showed that the RF model combined with FC features achieved a classification accuracy of 75%. Disrupted FC among the pain matrix and other regions in HZ and PHN patients may affect multiple dimensions of pain processing.

ObjectiveThe purposes of this study are to explore (1) whether comorbid depressive symptoms in patients with chronic back pain (CBP) affect the pain matrix. And (2) whether the interaction of depression and CBP exacerbates impaired brain function.MethodsThirty-two patients with CBP without comorbid depressive symptoms and thirty patients with CBP with comorbid depressive symptoms were recruited. All subjects underwent functional magnetic resonance imaging (fMRI) scans. The graph theory analysis, mediation analysis, and functional connectivity (FC) analysis were included in this study. All subjects received the detection of clinical depressive symptoms and pain-related manifestations.ResultCompared with the CBP group, subjects in the CBP with comorbid depressive symptoms (CBP-D) group had significantly increased FC in the left medial prefrontal cortex and several parietal cortical regions. The results of the graph theory analyses showed that the area under the curve of small-world property (t = −2.175, p = 0.034), gamma (t = −2.332, p = 0.023), and local efficiency (t = −2.461, p = 0.017) in the CBP-D group were significantly lower. The nodal efficiency in the ventral posterior insula (VPI) (t = −3.581, p = 0.0007), and the network efficiency values (t = −2.758, p = 0.008) in the pain matrix were significantly lower in the CBP-D group. Both the topological properties and the FC values of these brain regions were significantly correlated with self-rating depression scale (SDS) scores (all FDR corrected) but not with pain intensity. Further mediation analyses demonstrated that pain intensity had a mediating effect on the relationship between SDS scores and Pain Disability Index scores. Likewise, the SDS scores mediated the relationship between pain intensity and PDI scores.ConclusionOur study found that comorbid depressive symptoms can aggravate the impairment of pain matrix function of CBP, but this impairment cannot directly lead to the increase of pain intensity, which may be because some brain regions of the pain matrix are the common neural basis of depression and CBP.

Objective: Leveraging an integrative multimodal MRI paradigm to elaborate on the hippocampus-derived structural and functional changes in children and adolescents with juvenile idiopathic arthritis (JIA) and to explore potential correlations within the "joint-inflammation-brain" axis during the period of central neural system (CNS) development. Methods: Twenty-one patients with JIA all completed the multimodal MRI scanning, laboratory tests, and neuropsychological assessments; meanwhile, 23 matched controls were recruited. We then harnessed the spherical harmonics with a point distribution model (SPHARM-PDM) and the ROI-to-voxel functional connectivity (FC) to measure the hippocampal shape and hippocampo-cortical FC patterns. Correlation analysis was performed to explore the potential links in neuroimaging features with disease-related indices. Results: Compared to controls, JIA patients only presented an atrophic tendency in the posterior part of the bilateral hippocampus. The hippocampo-cortical FC revealed the between-group divergences mainly located at the pain matrix, striatum, and temporal lobe. Remarkably, the enhanced FC between the right hippocampus and postcentral cortex is positively correlated with the disability index, while the weakened FC of right anterior hippocampus with right insula and that of left posterior hippocampus with left superior temporal gyrus was inversely related to the erythrocyte sedimentation rate and anxiety status, separately. Conclusion: As with macroscopic damages, the altered functional-connectome patterns of the hippocampus in JIA patients might be more sensitive to detect the early neuropathological changes. Moreover, the functional disturbances were demonstrated associated with the physical disability, inflammation, and emotional status. These findings may enlighten us on the underlying neuropathological mechanism of CNS comorbidities in JIA. [ABSTRACT FROM AUTHOR]

ObjectiveLeveraging an integrative multimodal MRI paradigm to elaborate on the hippocampus-derived structural and functional changes in children and adolescents with juvenile idiopathic arthritis (JIA) and to explore potential correlations within the “joint-inflammation-brain” axis during the period of central neural system (CNS) development.MethodsTwenty-one patients with JIA all completed the multimodal MRI scanning, laboratory tests, and neuropsychological assessments; meanwhile, 23 matched controls were recruited. We then harnessed the spherical harmonics with a point distribution model (SPHARM-PDM) and the ROI-to-voxel functional connectivity (FC) to measure the hippocampal shape and hippocampo-cortical FC patterns. Correlation analysis was performed to explore the potential links in neuroimaging features with disease-related indices.ResultsCompared to controls, JIA patients only presented an atrophic tendency in the posterior part of the bilateral hippocampus. The hippocampo-cortical FC revealed the between-group divergences mainly located at the pain matrix, striatum, and temporal lobe. Remarkably, the enhanced FC between the right hippocampus and postcentral cortex is positively correlated with the disability index, while the weakened FC of right anterior hippocampus with right insula and that of left posterior hippocampus with left superior temporal gyrus was inversely related to the erythrocyte sedimentation rate and anxiety status, separately.ConclusionAs with macroscopic damages, the altered functional-connectome patterns of the hippocampus in JIA patients might be more sensitive to detect the early neuropathological changes. Moreover, the functional disturbances were demonstrated associated with the physical disability, inflammation, and emotional status. These findings may enlighten us on the underlying neuropathological mechanism of CNS comorbidities in JIA.

Background: Shingles can cause long-term pain and negative emotions, along with changes in brain function. In this study, Granger Causality Analysis (GCA) was used to compare herpes zoster (HZ) and postherpetic neuralgia (PHN) differences in effective connections within the "pain matrix" between patients and healthy controls to further understand patterns of interaction between brain regions and explore the relationship between changes in effective connections and clinical features., Methods: Resting-state functional magnetic resonance imaging (fMRI) scans were performed on 55 HZ; 55 PHN; and 50 age-, sex- matched healthy controls (HCs). The brain regions associated with the pain matrix are used as the seeds of effective connectivity. GCA was used to analyze effective connections in brain regions that differed significantly between groups. Then the correlation between GCA values and clinical indicators was studied., Results: Compared with HC, GCA values between the thalamus and the amygdala, between the thalamus and the precentral gyrus, from the thalamus to the postcentral gyrus, and from the parahippocampal gyrus to the amygdala, anterior cingulate gyrus were significantly reduced in HZ patients. Compared with HC, GCA values between the insular and the postcentral gyrus, from the insular to the inferior parietal lobe, and from the postcentral gyrus to the amygdala were significantly reduced in PHN patients. Compared with HZ, GCA values between the inferior parietal lobe and the parahippocampal gyrus, between the inferior parietal lobe and the anterior cingulate gyrus, and from the anterior cingulate gyrus to the amygdala were significantly increased in PHN patients. The visual analogue scale (VAS) score of PHN patients was positively correlated with the GCA value from the central posterior lobe to the insula., Conclusions: PHN and HZ patients showed a broad reduction in effective connections, mainly reflected in abnormal pain pathway regulation, pain perception, negative emotion and memory production, providing new perspectives to understand the neuroimaging mechanisms of shingles., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations.

Objective: This study investigated the impact of neurofeedback training on the deeper cortical structures that comprise the "pain matrix" and are involved in processing neuropsychological functions. Methods: Five paraplegic patients with central neuropathic pain received up to 40 sessions of neurofeedback training. They were asked to simultaneously modulate the relative power of the theta, alpha and beta bands, provided as a feedback from the sensorimotor cortex. The source localization technique was applied on EEG data recorded with 16 electrodes placed over the whole head. Results: Neurofeedback training from the sensorimotor cortex induced effects on the pain matrix and in the areas involved in processing neuropsychological functions such as memory, executive functions and emotional regulations. Alpha and beta band activity was most increased in insular, cingulate and frontal cortex regions, and other areas corresponding to executive and emotional function processing. Theta band decreases were noted in the frontal, cingulate and motor cortices. In group analysis, theta and beta band activity was significantly reduced. Conclusion: The single channel electroencephalogram-based neurofeedback training produced effects on similar areas that are targeted in 19 channels standardized low-resolution brain electromagnetic tomography and expensive time-delayed functional magnetic resonance imaging feedback studies. [ABSTRACT FROM AUTHOR]

Abstract Objective To investigate the whole-brain resting-state functional connectivity in patients with chronic migraine (CM) using a data-driven method. Methods We prospectively recruited patients with either episodic migraine (EM) or CM aged 18–60 years who visited the headache clinic of the Samsung Medical Center from July 2016 to December 2017. All patients underwent 3 T MRI using an identical scanner. Patients were considered interictal if they did not have a migraine headache at the day and ± 1 days of functional MRI acquisition. Using the group-independent component analysis (ICA), connectivity analysis with a weighted and undirected network model was performed. The between-group differences in degree centrality (DC) values were assessed using 5000 permutation tests corrected with false discovery rate (FDR). Results A total of 62 patients (44 EM and 18 CM) were enrolled in this study. Among the seven functionally interpretable spatially independent components (ICs) identified, only one IC, interpreted as the pain matrix, showed a significant between-group difference in DC (CM > EM, p = 0.046). This association remained significant after adjustment for age, sex, migraine with aura (MWA), allodynia, depression, and anxiety (p = 0.038). The pain matrix was functionally correlated with the hypothalamus (p = 0.040, EM > CM) and dorsal raphe nucleus (p = 0.039, CM > EM) with different levels of strength in EM and CM. Conclusion CM patients have a stronger connectivity in the pain matrix than do EM patients. Functional alteration of the pain network might play a role in migraine chronification.

Nociceptive signals are processed within a pain‐related network of the brain. Migraine is a rather specific model to gain insight into this system. Brain networks may be described by white matter tracts interconnecting functionally defined gray matter regions. Here, we present an overview of the migraine‐related pain network revealed by this strategy. Based on diffusion tensor imaging data from subjects in the Human Connectome Project (HCP) database, we used a global tractography approach to reconstruct white matter tracts connecting brain regions that are known to be involved in migraine‐related pain signaling. This network includes an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain‐processing and modulatory areas. The insular cortex emerged as the central interface of this network. Direct connections to visual and auditory cortical association fields suggest a potential neural basis of phono‐ or photophobia and aura phenomena. The intra‐axonal volume (Vintra) as a measure of fiber integrity based on diffusion microstructure was extracted using an innovative supervised machine learning approach in form of a Bayesian estimator. Self‐reported pain levels of HCP subjects were positively correlated with tract integrity in subcortical tracts. No correlation with pain was found for the cortical processing systems. [ABSTRACT FROM AUTHOR]

Pain is a conscious experience and a highly subjective sensation with a complex and often non‐linear relationship between nociceptive input and pain perception. Our understanding of the neural correlates of pain perception in humans has increased significantly since the advent of neuroimaging. Relating neural activity changes to the varied pain experiences has led to the concept that cognition, emotion, context, and injury can separately influence pain perception. In this mini review, the current concept of the central pain mechanism (CPM) is described. First, the concept of the "pain matrix" is stated: Nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular, and cingulate areas, as well as frontal and parietal areas. Then, electrophysiological assessments of the CPM are reviewed based on the literature and our recent studies. In particular, supraspinal (cortical) mechanisms for pain perception and pain relief are outlined. The insular cortex has key roles in sensory‐associated as well as cognitive‐associated processing for pain perception. [ABSTRACT FROM AUTHOR]

Exploring the potential of eucalyptol as a masking agent for aversive odors, we found that eucalyptol masks the olfactory but not the trigeminal sensation of ammonia in a previous study. Here, we further investigate the processing of a mixture consisting of eucalyptol and ammonia, two olfactory–trigeminal stimuli. We presented the two pure odors and a mixture thereof to 33 healthy participants. The nostrils were stimulated alternately (monorhinal application). We analyzed the behavioral ratings (intensity and pleasantness) and functional brain images. First, we replicated our previous finding that, within the mixture, the eucalyptol component suppressed the olfactory intensity of the ammonia component. Second, mixture pleasantness was rated differently by participants depending on which component dominated their mixture perception. Approximately half of the volunteers rated the eucalyptol component as more intense and evaluated the mixture as pleasant (pleasant group). The other half rated the ammonia component as more intense and evaluated the mixture as unpleasant (unpleasant group). Third, these individual differences were also found in functional imaging data. Contrasting the mixture either to eucalyptol or to both single odors, neural activation was found in the unpleasant group only. Activation in the anterior insula and SII was interpreted as evidence for an attentional shift towards the potentially threatening mixture component ammonia and for trigeminal enhancement. In addition to insula and SII, further regions of the pain matrix were involved when assessing all participant responses to the mixture. Both a painful sensation and an attentional shift towards the unpleasant mixture component complicates the development of an efficient mask because a pleasant perception is an important requirement for malodor coverage. [ABSTRACT FROM AUTHOR]

Chronic pain affects a substantial portion of the global population, significantly impacting quality of life and well-being. This condition involves complex mechanisms, including dysfunction of the autonomic nervous system, which plays a crucial role in pain perception. The insula, a key brain region involved in pain processing, plays a critical role in pain perception and modulation. Lesions in the insula can result in pain asymbolia, where pain perception remains intact but emotional responses are inappropriate. The insula is anatomically and functionally divided into anterior and posterior regions, with the posterior insula processing nociceptive input based on intensity and location before relaying it to the anterior insula for emotional mediation. Understanding the insula's intricate role in pain processing is crucial, as it is involved in encoding prediction errors and mediating emotional dimensions of pain perception. The focus of this review was on synthesizing existing literature on the role of the insula in chronic pain and associated structural changes. The goal was to integrate findings from various sources to provide a comprehensive overview of the topic. The search strategy included a combination of Medical Subject Headings (MeSH) and relevant keywords related to insula and chronic pain. The following databases were surveyed: PubMed, Embase, Scopus, and Web of Science. We identified a total of 2515 articles, and after following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline based on eligibility criteria, 46 articles were used to synthesize this review. Our study highlights the pivotal role of the insula in chronic pain processing and associated structural changes, integrating findings from diverse studies and neuroimaging investigations. Beyond mere pain sensation, the insula contributes to emotional awareness, attention, and salience detection within the pain network. Various chronic pain conditions reveal alterations in insular activity and connectivity, accompanied by changes in gray matter volume and neurochemical profiles. Interventions targeting the insula show promise in alleviating chronic pain symptoms. However, further research is needed to understand underlying mechanisms, which can aid in developing more effective therapeutic interventions for pain., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, McBenedict et al.)

Background and Objective Successful preventive treatment in chronic migraine (CM) remains an unmet need in some cases, and new therapeutic strategies are emerging. We aimed to test the effect of noninvasive, transcutaneous supraorbital nerve stimulation (tSNS) in a group of patients with CM. Patients and Methods This was an open label, quasi-experimental design. Twenty-five CM patients were recruited from two hospital headache clinics. After a one-month baseline period, monthly visits were scheduled during three months. Headache occurrence, its intensity, and symptomatic medication intake were recorded through a diary kept by each patient. Both a per-protocol analysis and an intention-to-treat analysis were performed for the main outcome measures. Results Twenty-one and 24 patients were included in the per-protocol and the intention-to-treat analyses, respectively. In the per-protocol analysis, a significant four-day decrease in the mean monthly days with moderate or severe headache was observed from baseline to the end of the study (t test, P  = 0.0163), and there was a nonsignificant reduction of 2.95 in the mean monthly total headache days. In the intention-to-treat analysis, a nonsignificant 3.37 reduction in the mean monthly days with moderate or severe headache was observed for the same period, and there was a significant 2.75 reduction in the mean monthly days with any headache (t test, P  = 0.016). Conclusions tSNS could hold preventive properties in the treatment of CM, but the effect may be either mild or controversial. Double blind, sham-controlled studies are essential to confirm these findings and to outline their clinical relevance in the CM therapeutic scenario. [ABSTRACT FROM AUTHOR]

Burning mouth syndrome (BMS) is classified into idiopathic orofacial pain conditions. Although central and peripheral neuropathic mechanisms are believed to be involved, the etiology remains to be fully elucidated. The present study examined temporal brain responses to an ongoing hot stimulus to investigate the pain modulating system in patients with BMS. The thermal stimulation sequence comprised baseline (32°C, 40 s) to warm (40°C, 32 s) to baseline (32°C, 40 s) to hot (49°C, 32 s), which was repeated four times using a Peltier thermode. These warm and hot stimuli were applied on the right palm and right lower lip in two separate sessions. Functional magnetic resonance imaging data were acquired by recording echo-planar images with a block design. Brain activity induced by purely hot stimulation (49°C vs. 40°C) applied to the palm was more pronounced than that induced by lip stimulation and in patients with BMS compared with controls. Comparison of brain activity between the first 16 s and second 16 s of the stimulus revealed pronounced time-dependent facilitation in patients with BMS during lip stimulation. These findings indicate that the pain modulating system in patients with BMS is dysregulated and that the brain in BMS is highly sensitized to pain information originating from the trigeminal system. [ABSTRACT FROM AUTHOR]

Yoshimasa Motoyama,1,2,* Katsuya Ogata,1,* Sumio Hoka,2 Shozo Tobimatsu1 1Department of Clinical Neurophysiology, Neurological Institute, 2Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan *These authors contributed equally to this work Background: Empathy for pain helps us to understand the pain of others indirectly. To better comprehend the processing of empathic pain, we report the frequency-dependent modulation of cortical oscillations induced by watching movies depicting pain using high-density electroencephalography (EEG), magnetoencephalography (MEG), and motor evoked potentials (MEP). Methods: Event-related desynchronization of EEG and MEG was assessed while participants viewed videos of painful (needle) or neutral (cotton swab) situations. The amplitudes of MEPs were also compared between the needle and cotton swab conditions.Results: The degree of suppression in α/β band power was significantly increased, whereas that of γ band power was significantly decreased, in the needle condition compared with the cotton swab condition. EEG revealed that significant differences in α/β band were distributed in the right frontocentral and left parietooccipital regions, whereas significant γ band differences were distributed predominantly over the right hemisphere, which were confirmed by source estimation using MEG. There was a significant positive correlation between the difference in γ power of the two conditions and the visual analog scale subjective rating of aversion, but not in the α/β band. The amplitude of MEPs decreased in the needle condition, which confirmed the inhibition of the primary motor cortex.Conclusion: MEP suppression supports that modulation of cortical oscillations by viewing movies depicting pain involves sensorimotor processing. Our results suggest that α/β oscillations underlie the sensory qualities of others’ pain, whereas the γ band reflects the cognitive aspect. Therefore, α/β and γ band oscillations are differentially involved in empathic pain processing under the condition of motor cortical suppression. Keywords: empathy for pain, pain matrix, neural oscillations, electroencephalography, magnetoencephalography, motor-evoked potentials

Several control conditions, such as penetrating sham acupuncture and non-penetrating placebo needles, have been used in clinical trials on acupuncture effects in chronic pain syndromes. All these control conditions are surprisingly effective with regard to their analgesic properties. These findings have fostered a discussion as to whether acupuncture is merely a placebo. Meta-analyses on the clinical effectiveness of placebo revealed that placebo interventions in general have minor, clinically important effects. Only in trials on pain and nausea, including acupuncture studies, did placebo effects vary from negligible to clinically important. At the same time, individual patient meta-analyses confirm that acupuncture is effective for the treatment of chronic pain, including small but statistically significant differences between acupuncture and sham acupuncture. All acupuncture control conditions induce de qi , a distinct stimulation associated with pain and needling which has been shown to be a nociceptive/pain stimulus. Acupuncture therefore probably activates the pain matrix in the brain in a bottom-up fashion via the spino-thalamic tract. Central nervous system effects of acupuncture can be modulated through expectations, which are believed to be a central component of the placebo response. However, further investigation is required to determine how strong the influence of placebo on the attenuation of activity in the pain matrix really is. A meta-analysis of individual participant functional magnetic imaging data reveals only weak effects of placebo on the activity of the pain network. The clinical acupuncture setting is comprised of a combination of a distinct neurophysiological stimulus, the needling stimulus/experience, and a complex treatment situation. A broader definition of placebo, such as that proposed by Howick (2017) acknowledges a role for expectation, treatment context, emotions, learning, and other contextual variables of a treatment situation. The inclusion of particular treatment feature as a definitional element permits a contextual definition of placebo, which in turn can be helpful in constructing future clinical trials on acupuncture. [ABSTRACT FROM AUTHOR]

Painful legs and moving toes (PLMT) syndrome is a clinical entity characterized by persistent pain in the feet or legs and involuntary movements of one or more toes. The precise patho-mechanisms of PLMT still remain unknown. Herein, we examined ten patients clinically identified with PLMT syndrome. All patients first presented persistent pain prior to the onset of motor symptoms. Each patient was examined by neurological investigation, neuro-imaging methods including brain magnetic resonance imaging (MRI) and electrophysiological methods. The brain single photon emission computed tomography (SPECT) images of eight patients indicated hypoperfusion of frontal lobes and cerebellum. The conjunction analysis of brain SPECT imaging data of all eight patients, using the 3D-SSP program, compared to 34 controls indicated significant hypoperfusion in the prefrontal cortical, occipital cortical, and cerebellar surfaces, and thalamus, and hyperperfusion in the surface of the anterior cingulate gyrus and parietal cortices including primary and secondary somatosensory cortices, bilaterally. These areas reflected on a part of the pain matrix. Other electrophysiological examinations did not indicate specific abnormalities to explain the patients' symptoms. On treatment with clonazepam, four out of nine patients could resolve their foot-related motor symptoms, but not the sensory symptoms. Overall, their pain was an intractable and persistent symptom throughout their clinical course. Our study infers that PLMT syndrome is fundamentally a chronic pain disorder, possibly relating to the central sensitization, involving the region of a part of pain matrix. Further studies need to confirm our results by adding more patients. [ABSTRACT FROM AUTHOR]

Many fMRI studies have shown activity in the cerebellum after peripheral nociceptive stimulation. We investigated whether the areas in the cerebellum that were activated after nociceptive thumb stimulation were separate from those after nociceptive toe stimulation. In an additional experiment, we investigated the same for the anticipation of a nociceptive stimulation on the thumb or toe. For his purpose, we used fMRI after an electrical stimulation of the thumb and toe in 19 adult healthy volunteers. Following nociceptive stimulation, different areas were activated by stimulation on the thumb (lobule VI ipsilaterally and Crus II mainly contralaterally) and toe (lobules VIII-IX and IV-V bilaterally and lobule VI contralaterally), i.e., were somatotopically organized. Cerebellar areas innervated non-somatotopically by both toe and thumb stimulation were the posterior vermis and Crus I, bilaterally. In the anticipation experiment, similar results were found. However, here, the somatotopically activated areas were relatively small for thumb and negligible for toe stimulation, while the largest area was innervated non-somatotopically and consisted mainly of Crus I and lobule VI bilaterally. These findings indicate that nociceptive stimulation and anticipation of nociceptive stimulation are at least partly processed by the same areas in the cerebellum. This was confirmed by an additional conjunction analysis. Based on our findings, we hypothesize that input that is organized in a somatotopical manner reflects direct input from the spinal cord, while non-somatotopically activated parts of the cerebellum receive their information indirectly through cortical and subcortical connections, possibly involved in processing contextual emotional states, like the expectation of pain. [ABSTRACT FROM AUTHOR]

The neuromatrix, or “pain matrix”, is a network of cortical brain areas which is activated by noxious as well as salient somatosensory stimulation. This has been studied in mice and humans using blood oxygenation level-dependent (BOLD) fMRI. Here we demonstrate that BOLD effects observed in the murine neuromatrix in response to salient somatosensory stimuli are prone to reflect mean arterial blood pressure (MABP) changes, rather than neural activity. We show that a standard electrostimulus typically used in murine somatosensory fMRI can induce substantial elevations in MABP. Equivalent drug-induced MABP changes — without somatosensory stimulation — evoked BOLD patterns in the neuromatrix strikingly similar to those evoked by electrostimulation. This constitutes a serious caveat for murine fMRI. The regional specificity of these BOLD patterns can be attributed to the co-localization of the neuromatrix with large draining veins. Based on these findings we propose a cardiovascular support mechanism whereby abrupt elevations in MABP provide additional energy supply to the neuromatrix and other essential brain areas in fight-or-flight situations. [ABSTRACT FROM AUTHOR]

Background Cluster headache is a disorder characterized by intermittent, severe unilateral head pain accompanied by cranial autonomic symptoms. Most cases of CH are episodic, manifesting as “in-bout” periods of frequent headache separated by month-to-year-long “out-of-bout” periods of remission. Previous imaging studies have implicated the hypothalamus and pain matrix in the pathogenesis of episodic CH. However, the pathophysiology driving the transition between in- and out-of-bout periods remains unclear. Methods The present study provides a narrative review of previous neuroimaging studies on the pathophysiology of episodic CH, addressing alterations in brain structures, metabolism, and structural and functional connectivity occurring between bout periods. Results Although the precise brain structures responsible for episodic CH are unknown, major roles are indicated for the posterior hypothalamus (especially in acute attacks), the pain neuromatrix with an emphasis on central descending pain modulation, and non-traditional pain processing networks including the occipital, cerebellar, and salience networks. These areas are potentially related to dynamic transitioning between in- and out-of-bout periods. Conclusion Recent progress in magnetic resonance imaging of episodic CH has provided additional insights into dynamic bout-associated structural and functional connectivity changes in the brain, especially in non-traditional pain processing network areas. These areas warrant future investigations as targets for neuromodulation in patients with CH. [ABSTRACT FROM AUTHOR]