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| Brain regions showing significant gray matter volume difference between trigeminal neuralgia (TN) patients and matched healthy controls.
Source publication
Classical trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder associated with increased risks of anxiety and depression. Converging evidence suggests that chronic pain pathophysiology involves dysfunctional pain-related and emotion-related networks. However, whether these systems are also among the culprit networks for TN remains...
Context in source publication
Citations
... The structural changes in the brain may be intricately linked with the pain perception and modulation. Zhang et al. (2018), in these exploration of structural and functional deficits in pain-related and emotion-related networks in TN patients, reported that pain relief had protective effects on brain functional connectivity. Existing evidence supports the idea that regional gray matter decreases can partially return to normal following successful amelioration of chronic pain (Gwilym et al., 2010;Moayedi et al., 2011;Čeko et al., 2015). ...
Background
Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder that not only causes intense pain but also affects the psychological health of patients. Since TN pain intensity and negative emotion may be grounded in our own pain experiences, they exhibit huge inter-individual differences. This study investigates the effect of inter-individual differences in pain intensity and negative emotion on brain structure in patients with TN and the possible pathophysiology mechanism underlying this disease.
Methods
T1 weighted magnetic resonance imaging and diffusion tensor imaging scans were obtained in 46 patients with TN and 35 healthy controls. All patients with TN underwent pain-related and emotion-related questionnaires. Voxel-based morphometry and regional white matter diffusion property analysis were used to investigate whole brain grey and white matter quantitatively. Innovatively employing partial least squares correlation analysis to explore the relationship among pain intensity, negative emotion and brain microstructure in patients with TN.
Results
Significant difference in white matter integrity were identified in patients with TN compared to the healthy controls group; The most correlation brain region in the partial least squares correlation analysis was the genus of the corpus callosum, which was negatively associated with both pain intensity and negative emotion.
Conclusion
The genu of corpus callosum plays an important role in the cognition of pain perception, the generation and conduction of negative emotions in patients with TN. These findings may deepen our understanding of the pathophysiology of TN.
... With the exception of previously reported hypertrophy of the PAG in the context of chronic headache, structural changes regarding PAG-RVM axis in chronic musculoskeletal pain and fibromyalgia, commonly seen in Gulf War veterans, has to our knowledge never been reported before. Previous structural MRI studies, however, have consistently reported that other chronic pain states are associated with smaller gray matter volume (Zhang et al., 2018) and lower fiber integrity (Geisler et al., 2020;Zhang et al., 2020b) of the PAG-RVM axis. In this study, we observed a significant correlation between increased pain intensity and decreased RVM volume, and a trend of negative relationship between increased pain intensity and disrupted connection (FA reduction) in the DLF (fiber tract linking hypothalamus, PAG, and RVM) in the ODS/DS veterans. ...
Introduction
Gulf War Illness is a type of chronic multisymptom illness, that affects about 30% of veterans deployed to the 1990–91 Persian Gulf War. Veterans deployed to Iraq/Afghanistan after 2000 are reported to have a similar prevalence of chronic multisymptom illness. More than 30 years after the Persian Gulf War, Gulf War Illness still has an unexplained symptom complex, unknown etiology and lacks definitive diagnostic criteria and effective treatments. Our recent studies have found that substantially smaller brainstem volumes and lower fiber integrity are associated with increased sleep difficulty and pain intensity in 1990–91 Persian Gulf War veterans. This study was conducted to investigate whether veterans deployed to Iraq/Afghanistan present similar brainstem damage, and whether such brainstem structural differences are associated with major symptoms as in Gulf War Illness.
Methods
Here, we used structural magnetic resonance imaging and diffusion tensor imaging to measure the volumes of subcortices, brainstem subregions and white matter integrity of brainstem fiber tracts in 188 veterans including 98 Persian Gulf War veterans and 90 Iraq/Afghanistan veterans.
Results
We found that compared to healthy controls, veterans of both campaigns presented with substantially smaller volumes in brainstem subregions, accompanied by greater periaqueductal gray matter volumes. We also found that all veterans had reduced integrity in the brainstem-spinal cord tracts and the brainstem-subcortical tracts. In veterans deployed during the 1990–91 Persian Gulf War, we found that brainstem structural deficits significantly correlated with increased sleep difficulties and pain intensities, but in veterans deployed to Iraq/Afghanistan, no such effect was observed.
Discussion
These structural differences in the brainstem neurons and tracts may reflect autonomic dysregulation corresponding to the symptom constellation, which is characteristic of Gulf War Illness. Understanding these neuroimaging and neuropathological relationships in Gulf War and Iraq/Afghanistan veterans may improve clinical management and treatment strategies for modern war related chronic multisymptom illness.
... Surgical removal remains the cornerstone of treatment; other therapies are indicated in cases of disease-related clinical complication and/or significant tumor progression on MRI [4]. Despite the possibility of a good prognosis of the neoplasm, when there is involvement of trigeminal nerve, this could have a detrimental impact on the patient's quality of life in terms of pain and the appearance of facial dysmorphisms [5]. ...
... The nucleus accumbens, located at the junction of the basal nucleus and the limbic system, is an important part of the reward pathway and plays an important role in the occurrence and development of pain and depression (68, 69), The anterior cingulate cortex has been recognized as a key hub for NP comorbid mood disorder symptoms. The periaqueductal gray matter in the midbrain plays an important role in the descending regulation of nociceptive sensation and regulates emotional behavior (70). The mPFC is critical for both the sensory and emotional/cognitive components of pain (71). ...
Introduction
Neuropathic Pain (NP) is often accompanied by mood disorders, which seriously affect the quality of life of patients. This study aimed to analyze the hotspots and trends in NP-related mood disorder research using bibliometric methods and to provide valuable predictions for future research in this field.
Methods
Articles and review articles on NP-related mood disorders published from January 2003 to May 2023 were retrieved from the Web of Science Core Collection. We used CiteSpace to analyze publications, countries, institutions, authors, cited authors, journals, cited journals, references, cited references, and keywords. We also analyzed collaborative network maps and co-occurrence network maps.
Results
A total of 4,540 studies were collected for analysis. The number of publications concerning NP-related mood disorders every year shows an upward trend. The United States was a major contributor in this field. The University of Toronto was the most productive core institution. C GHELARDINI was the most prolific author, and RH DWORKIN was the most frequently cited author. PAIN was identified as the journal with the highest productivity and citation rate. The current research hotspots mainly included quality of life, efficacy, double-blind methodology, gabapentin, pregabalin, postherpetic neuralgia, and central sensitization. The frontiers in research mainly focused on the mechanisms associated with microglia activation, oxidative stress, neuroinflammation, and NP-related mood disorders.
Discussion
In conclusion, the present study provided insight into the current state and trends in NP-related mood disorder research over the past 20 years. Consequently, researchers will be able to identify new perspectives on potential collaborators and cooperative institutions, hot topics, and research frontiers in this field.
... Voxel-based morphometry (VBM) is a hypothesis-free technique that allows voxelwise comparisons of the whole brain tissue volume between groups in vivo (7). VBM studies have reported decreased or increased gray matter volume (GMV) in various brain regions in patients with TN, including the secondary somatosensory cortex, insula, thalamus, anterior cingulate cortex, cerebellum, caudate nucleus, amygdala, postcentral gyrus, and precuneus compared to healthy controls (HCs) (8)(9)(10)(11)(12)(13)(14)(15), while functional studies using function MRI also detected increased or decreased brain activation in the thalamus, postcentral gyrus, cerebellum, anterior cingulate cortex, and other cortical and subcortical brain regions (10,11,16,17). However, these structural and functional studies often reported different or even contradictory results. ...
... Twenty studies (8-14, 16, 17, 25-35) were finally included in the current meta-analyses. Among these studies, three studies (11,13,33) reported both structural and functional results. Three fMRI studies (16,17,29) shared the same sample but reported results with different imaging measures, while another two pairs of fMRI studies (13,26,27,31) examined another same dataset with different imaging measures. ...
... Among these studies, three studies (11,13,33) reported both structural and functional results. Three fMRI studies (16,17,29) shared the same sample but reported results with different imaging measures, while another two pairs of fMRI studies (13,26,27,31) examined another same dataset with different imaging measures. One fMRI study and one VBM study divided patients into two subgroups and conducted two comparisons respectively, so two sets of data were obtained from each of these two studies (11,12). ...
Background
Brain gray matter alterations in patients with trigeminal neuralgia (TN) have been detected in prior neuroimaging studies, but the results are heterogeneous. The current study conducted coordinate-based meta-analyses across neuroimaging studies, aiming to find the pattern of brain anatomic and functional alterations in patients with TN.
Methods
We performed a systematic literature search of PubMed, Embase, and Web of Science to identify relevant publications. A multimodal meta-analysis for whole-brain voxel-based morphometry (VBM) studies and functional imaging studies in TN was performed using anisotropic effect size-based signed differential mapping.
Results
The meta-analysis comprised 10 VBM studies with 398 TN patients and 275 healthy controls, and 13 functional magnetic resonance imaging studies with 307 TN patients and 264 healthy controls. The multimodal meta-analysis showed conjoint structural and functional brain alterations in the right fusiform gyrus and inferior temporal gyrus, bilateral thalamus, left superior temporal gyrus, left insula, and inferior frontal gyrus. The unimodal meta-analysis showed decreased gray matter volume alone in the left putamen, left postcentral gyrus, and right amygdala as well as only functional abnormalities in the left cerebellum, bilateral precuneus, and left middle temporal gyrus.
Conclusion
This meta-analysis revealed overlapping anatomic and functional gray matter abnormalities in patients with TN, which may help provide new insights into the neuropathology and potential treatment biomarkers of TN.
... *P <0.05, **P <0.01, ***P <0.001. which found altered rsFC, [145][146][147][148][149][150][151][152] altered effective rsFC (effFC) 153 and altered task rsFC (during observation of harmful activities) 154 in the amygdala-mPFC-PAG circuit in chronic pain patients compared to pain-free controls. Altered supratentorial input to the PAG might be associated with dysregulated PAG metabolites and PAG-driven descending inhibition, such as the decreased Glx/GABA and the lacking association between Glx/GABA and experimental pressure pain sensitivity in CLBP patients observed in the present study. ...
Mechanisms underlying chronic pain are insufficiently understood. Preclinical evidence suggests a potential contribution of excitatory glutamatergic and inhibitory GABAergic imbalances in pain-relevant brain areas, such as a lower excitatory/inhibitory tone in the brainstem periaqueductal grey (PAG). This cross-sectional magnetic resonance spectroscopy (MRS) study investigated whether a lower excitatory/inhibitory tone is also observed in the PAG of patients with non-specific chronic low back pain (CLBP) and whether this would relate to altered psychophysical measures of descending pain modulation and experimental pressure pain sensitivity. Specifically, the ratio between pooled glutamate and glutamine and GABA levels (Glx/GABA), Glx and GABA in the PAG were compared between CLBP patients and pain-free controls. Further, associations of Glx/GABA with conditioned pain modulation (CPM) effects and pressure pain thresholds (PPTs) were assessed.
MRS was acquired on a 3T Philipps MR system using a point-resolved spectroscopy sequence optimized with very selective saturation pulses (OVERPRESS) and voxel-based flip angle calibration in a 1.1 mL volume of interest. Data from 41 CLBP patients (median [interquartile range]: 54 years [41 - 65], 22 females) and 29 age- and sex-matched controls (47 years [34 - 67], 17 females) fulfilled MRS quality criteria. CPM and PPTs were assessed at the lower back as most painful area and the non-dominant hand as pain-free control area. The CPM paradigm consisted of PPTs applied before, during (parallel CPM effect) and after a cold water bath and an ambient temperature water bath as control paradigm to identify 'true' CPM effects.
In the PAG of CLBP patients, a lower Glx/GABA ratio, i.e. a lower excitatory/inhibitory tone, was observed (P = 0.002, partial η2 = 0.14) driven by decreased Glx (P = 0.012, partial η2 = 0.11) and increased GABA (P = 0.038, d = 0.46). CLBP patients showed disrupted associations between Glx/GABA and PPTs compared to controls in both areas (lower back: P = 0.004, partial η2 = 0.12; hand: P = 0.002, partial η2 = 0.16). In controls, lower Glx/GABA was associated with lower PPTs (lower back: r = 0.48, P = 0.009, hand: r = 0.53, P = 0.003), but this link was missing in CLBP patients (r's > -0.23, P's > 0.150). Additionally, CLBP patients with more severe clinical pain showed smaller CPM effects at the hand (rho = 0.54, P = 0.003).
These findings suggest a dysfunction of the PAG in patients with CLBP and might indicate altered descending inhibition of deep tissue afferents.
... Functional connectivity alterations associated with neuropathic pain severity were isolated to intralimbic and limbostriatal patterns, with lower connectivity identified between the right posterior parahippocampal gyrus and right putamen and amygdala. Prior studies suggest the parahippocampal gyrus and amygdala contribute to psychological and emotional regulation of pain processing (Allen et al., 2021;Meerwijk et al., 2013;Naor et al., 2020) and sensitivity (Grant et al., 2010;Meerwijk et al., 2013;Naor et al., 2020), and have been implicated in other populations with neuralgia (Geha et al., 2007;Tang et al., 2021;Zhang et al., 2018). The putamen, a part of the striatum and basal ganglia, is involved with production of movement, reward, and multisensory integration of noxious and non-noxious stimuli, with previously demonstrated pain-related activation hypothesized to be involved in motor responses for withdrawal from painful stimuli or inhibition of painful movement (Bingel et al., 2002;Borsook et al., 2010;Chudler and Dong, 1995). ...
... Pain intensity and functional connectivity were negatively correlated in the right pPaHC gyrus to the right angular and supramarginal gyri and lateral occipital cortex, and positively correlated in the left amygdala to the left supramarginal gyrus and superior parietal lobule. Prior studies suggest the parahippocampal gyrus and amygdala contribute to psychological and emotional regulation of pain processing (Allen et al., 2021;Meerwijk et al., 2013;Naor et al., 2020) and sensitivity (Grant et al., 2010;Meerwijk et al., 2013;Naor et al., 2020), and have been implicated in other populations with neuralgia (Geha et al., 2007;Tang et al., 2021;Zhang et al., 2018). The angular and supramarginal gyri hold roles in multisensory integration (Seghier, 2013) and regulation of emotional and empathetic responses to pain (Naor et al., 2020;Zhao et al., 2021). ...
Many individuals with spinal cord injury live with debilitating chronic pain that may be neuropathic, nociceptive, or a combination of both in nature. Identification of brain regions demonstrating altered connectivity associated with the type and severity of pain experience may elucidate underlying mechanisms, as well as treatment targets. Resting state and sensorimotor task-based magnetic resonance imaging data were collected in 37 individuals with chronic spinal cord injury. Seed-based correlations were utilized to identify resting state functional connectivity of regions with established roles in pain processing: the primary motor and somatosensory cortices, cingulate, insula, hippocampus, parahippocampal gyri, thalamus, amygdala, caudate, putamen, and periaqueductal gray matter. Resting state functional connectivity alterations and task-based activation associated with individuals’ pain type and intensity ratings on the International Spinal Cord Injury Basic Pain Dataset (0–10 scale) were evaluated. We found that intralimbic and limbostriatal resting state connectivity alterations are uniquely associated with neuropathic pain severity, whereas thalamocortical and thalamolimbic connectivity alterations are associated specifically with nociceptive pain severity. The joint effect and contrast of both pain types were associated with altered limbocortical connectivity. No significant differences in task-based activation were identified. These findings suggest that the experience of pain in individuals with spinal cord injury may be associated with unique alterations in resting state functional connectivity dependent upon pain type.
... This finding and experimental evidence coming from studies with spinal neuropathic pain (Brightwell and Taylor, 2009;Viisanen and Pertovaara, 2007;Alba-Delgado et al., 2021; suggest that chronic pain may result in altered functioning of pain-modulation circuits including in the LC. Indeed, neuroimaging studies have shown that patients with TN had reduced gray matter volume in various brain regions related to sensory-and cognitive-affective dimensions of pain including the PFC, anterior cingulate cortex, cerebellum, amygdala, periaqueductal gray, insula, thalamus, hypothalamus, putamen, and nucleus accumbens (Zhang, 2018;Tsai et al., 2018;Li et al., 2017;Hayes, 2017). Additionally, patients with trigeminal neuropathy had altered LC functional connectivity with increased connectivity between the rostral ventromedial medulla and decreased connectivity between the ventrolateral periaqueductal gray matter (Mills et al., 2018) which might be related to decreased descending control in the chronic pain patients. ...
... Optogenetic activation of noradrenergic projections from LC that project to BLA were shown to cause NA release in the BLA and induce anxiety-like behavior mediated by β-ARs (McCall et al., 2017). A neuroimaging study has also demonstrated that patients with TN had decreased gray matter volume in corticolimbic regions, including BLA (Zhang, 2018). Hirschberg et al. also showed that chemogenetic activation of LC-noradrenergic neurons innervating the PFC increased anxiety-like behavior in rats (Hirschberg et al., 2017). ...
Trigeminal neuralgia is the most common neuropathic pain involving the craniofacial region. Due to the complex pathophysiology, it is therapeutically difficult to manage. Noradrenaline plays an essential role in the modulation of arousal, attention, cognitive function, stress, and pain. The locus coeruleus, the largest source of noradrenaline in the brain, is involved in the sensory and emotional processing of pain. This review summarizes the knowledge about the involvement of noradrenaline in acute and chronic trigeminal pain conditions and how the activity of the locus coeruleus noradrenergic neurons changes in response to acute and chronic pain conditions and how these changes might be involved in pain-related comorbidities including anxiety, depression, and sleep disturbance.
... A certain correlation existed between the TGN morphology and the changing brain structure of patients with CTN [17,18]. Many recent studies showed that the brain structure changed in patients with CTN, which included the gray matter volume (GMV) [2,12,16,[19][20][21][22][23][24][25][26][27] and cortical morphology. The brain regions in which the GMV changed were mainly the frontal lobe, temporal lobe, parietal lobe, thalamus, hippocampus, and cerebellum; the GMV changed differently in different studies. ...
Objective
This study aimed to combine voxel-based morphometry, deformation-based morphometry, and surface-based morphometry to analyze gray matter volume and cortex shape in classical trigeminal neuralgia patients.
Methods
This study included 79 classical trigeminal neuralgia patients and age- and sex-matched 81 healthy controls. The aforementioned three methods were used to analyze brain structure in classical trigeminal neuralgia patients. Spearman correlation analysis was used to analyze the correlation of brain structure with the trigeminal nerve and clinical parameters.
Results
The bilateral trigeminal nerve was atrophied, and the ipsilateral trigeminal nerve volume was smaller than the contralateral volume in the classical trigeminal neuralgia. The gray matter volume of Temporal_Pole_Sup_R and Precentral_R was found to be decreased using voxel-based morphometry. The gray matter volume of Temporal_Pole_Sup_R had a positive correlation with disease duration and a negative correlation with the cross-section area of the compression point and the quality-of-life score in trigeminal neuralgia. The gray matter volume of Precentral_R was negatively correlated with the ipsilateral volume of the trigeminal nerve cisternal segment, cross-section area of compression point, and visual analogue scale. The gray matter volume of Temporal_Pole_Sup_L was found to be increased using deformation-based morphometry and had a negative correlation with the self-rating anxiety scale. The gyrification of the middle temporal gyrus_L increased and the Postcentral_L thickness decreased, as detected using surface-based morphometry.
Conclusions
The gray matter volume and cortical morphology of pain-related brain regions were correlated with clinical and trigeminal nerve parameters. voxel-based morphometry, deformation-based morphometry, and surface-based morphometry complemented each other in analyzing the brain structures of patients with classical trigeminal neuralgia and provided a basis for studying the pathophysiology of classical trigeminal neuralgia.
Graphical Abstract
... Of the remaining 27 analyses reporting significant results, the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), prefrontal cortex (PFC), insula, hippocampus/amygdala, caudate, thalamus and subregions of the temporal lobes and cerebellum were most frequently identified as key brain regions. The amygdala/hippocampus were both identified as regions in which minimal to moderate pain and minimal to mild depression showed a positive correlation in a task-fMRI study [35], rs-fMRI studies [36][37][38], and structural MRI studies of grey matter [39,40]. One structural MRI study [39] identified the thalamus as a region where mild pain and depression were negatively correlated. ...
... We analysed a total of 76 foci (20 studies, 586 participants) in studies of pain with reported depression scores, and 39 foci (5 studies, 119 participants) in studies of depression with reported pain scores (see Table 3). The ALE analysis identified the right parahippocampal gyrus/amygdala (p = 4.21E-07, Z = 4.92) as a neural correlate of pain associated with depression (Fig. 2), data contributed by five studies [35][36][37][38]48]all were studies of pain correlated with depression. Both the left superior frontal gyrus (cluster 1, p = 3.59E-07, Z = 4.96) and the left thalamus (cluster 2, p = 8.51E-07, Z = 4.78) were also identified as neural correlates of depression associated with pain (Fig. 3), data contributed by four studies (Berna et al., 2010;Strigo et al., 2008 for cluster 1; [47,49] for cluster 2all were studies of depression versus healthy controls contrast with pain scores adjusted. ...
The relationship between pain and depression is thought to be bidirectional and the underlying neurobiology ‘shared’ between the two conditions. However, these claims are often based on qualitative comparisons of brain regions implicated in pain or depression, while focused quantitative studies of the neurobiology of pain-depression comorbidity are lacking. Particularly, the direction of comorbidity, i.e., pain with depression vs. depression with pain, is rarely addressed. In this systematic review (PROSPERO registration CRD42020219876), we aimed to delineate brain correlates associated with primary pain with concomitant depression, primary depression with concurrent pain, and equal pain and depression comorbidity, using activation likelihood estimation (ALE) meta-analysis. Neuroimaging studies published in English until the 28th of September 2021 were evaluated using PRISMA guidelines. A total of 70 studies were included, of which 26 reported stereotactic coordinates and were analysed with ALE. All studies were assessed for quality by two authors, using the National Institute of Health Quality Assessment Tool. Our results revealed paucity of studies that directly investigated the neurobiology of pain-depression comorbidity. The ALE analysis indicated that pain with concomitant depression was associated with the right amygdala, while depression with concomitant pain was related primarily to the left dorsolateral prefrontal cortex (DLPFC). We provide evidence that pain and depression have a cumulative negative effect on a specific set of brain regions, distinct for primary diagnosis of depression vs. pain.
