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Although recent studies support significant differences in intrinsic structure, function, and connectivity along the longitudinal axis of the hippocampus, few studies have investigated the normative development of this dimension. In addition, factors known to influence hippocampal structure, such as sex or puberty, have yet to be characterized when assessing age-related effects on its subregions. This study addresses this gap by investigating the relationship of the anterior (antHC) and posterior (postHC) hippocampus volumes with age, and how these are moderated by sex or puberty, in structural magnetic resonance imaging scans from 183 typically developing participants aged 6-21 years. Based on previous literature, we first anticipated that non-linear models would best represent the relationship between age and the antHC and postHC volumes. We found that age-related effects are region-specific, such that the antHC volume remains stable with increasing age, while the postHC shows a cubic function characterized by overall volume increase with age but a slower rate during adolescence. Second, we hypothesized that models, which include biological sex or pubertal status would best describe these relationships. Contrary to expectation, models comprising either biological sex or pubertal status did not significantly improve model performance. Further longitudinal research is needed to evaluate their effects on the antHC and postHC development.

The neuroanatomical circuitry of jaw muscles has been mostly explored in non-human animals. A recent rodent study revealed a novel circuit from the central amygdala (CeA) to the trigeminal motor nucleus (5M), which controls biting attacks. This circuit has yet to be delineated in humans. Ultra-high diffusion-weighted imaging data from the Human Connectome Project (HCP) allow in vivo delineation of circuits identified in other species-for example, the CeA-5M pathway-in humans. We hypothesized that the CeA-5M circuit could be resolved in humans at both 7 and 3 T. We performed probabilistic tractography between the CeA and 5M in 30 healthy young adults from the HCP database. As a negative control, we performed tractography between the basolateral amygdala (BLAT) and 5M, as CeA is the only amygdalar nucleus with extensive projections to the brainstem. Connectivity strength was operationalized as the number of streamlines between each region of interest. Connectivity strength between CeA-5M and BLAT-5M within each hemisphere was compared, and CeA-5M circuit had significantly stronger connectivity than the BLAT-5M circuit, bilaterally at both 7 T (all p .001) and 3 T (all p .001). This study is the first to delineate the CeA-5M circuit in humans.

Artifact reduction (AR) software has been incorporated into some cone-beam computed tomographic (CBCT) systems to reduce the severity of beam hardening (BH) artifacts and improve image quality. This study quantifies BH artifact and evaluates the effectiveness of AR in 2 CBCT systems.Palatal roots of Dent-Alike (Dentsply Sirona, Tulsa, OK) teeth were prepared and root filled with gutta-percha and EndoSequence BC Sealer (Brasseler, Savannah, GA). Six teeth were imaged with and without AR software using the ProMax3D (Planmeca Oy, Helsinki, Finland) and the Pax-i3D (Vatech, Hwaseong-si, South Korea) systems. FSL (FMRIB, Oxford, UK) software was used to quantify the light and dark components of the BH artifact along the tooth root using a specific region of interest approach and an image-wide analysis approach. Statistical analysis was performed using paired t tests and corrected for multiple comparisons with cluster mass correction using a nonparametric statistical analysis to evaluate the differences in the artifact volumes and areas with and without AR.A significant reduction in the light artifact was observed with the Planmeca system (P.05), but no significant differences were observed for either the light or dark artifacts with the Vatech system when AR was applied. There were also significant reductions in the volumes of light and dark artifacts along the entire root length when the AR was applied with the Planmeca system (cluster mass P.05), but no significant differences were observed with the Vatech system.Proprietary AR software is not equally effective in reducing the light and/or dark components of CBCT BH artifacts.

IntroductionCurrent treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches.Methods and analysisHere we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function.Ethics and disseminationThe study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children’s Hospital Medical Center Review Board as the reviewing IRB. Stanford’s IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories.Trial registration numberNCT04285112.

Objective: To assess thermal-sensory thresholds and psychosocial factors in children with Complex Regional Pain Syndrome Type 1 (CRPS-I) compared to healthy children. Methods: We conducted quantitative sensory testing on 34 children with CRPS-I and 56 pain-free children. Warm, cool, heat, and cold stimuli were applied to the forearm. Children with CRPS-I had the protocol administered to the pain site and the contralateral-pain site. Participants completed the self-report Behavior Assessment System for Children. Results: Longer pain durations (>5.1 months) were associated with decreased sensitivity to cold pain on the pain site ( P = .04). Higher pain-intensity ratings were associated with elevated anxiety scores ( P = .03). Anxiety and social stress were associated with warmth sensitivity (both P < .05) on the contralateral-pain site. Conclusions: Pain duration is an important factor in assessing pediatric CRPS-I. Hyposensitivity in the affected limb may emerge due to degeneration of nociceptive nerves. Anxiety may contribute to thermal-sensory perception in childhood CRPS-I.

Supplemental Digital Content is Available in the Text. Cage-lid hanging behavior is impaired by sustained pain in mice and can be used as an ethologically valid and translationally relevant pain outcome measure., The development of new analgesic drugs has been hampered by the inability to translate preclinical findings to humans. This failure is due in part to the weak connection between commonly used pain outcome measures in rodents and the clinical symptoms of chronic pain. Most rodent studies rely on the use of experimenter-evoked measures of pain and assess behavior under ethologically unnatural conditions, which limits the translational potential of preclinical research. Here, we addressed this problem by conducting an unbiased, prospective study of behavioral changes in mice within a natural homecage environment using conventional preclinical pain assays. Unexpectedly, we observed that cage-lid hanging, a species-specific elective behavior, was the only homecage behavior reliably impacted by pain assays. Noxious stimuli reduced hanging behavior in an intensity-dependent manner, and the reduction in hanging could be restored by analgesics. Finally, we developed an automated approach to assess hanging behavior. Collectively, our results indicate that the depression of hanging behavior is a novel, ethologically valid, and translationally relevant pain outcome measure in mice that could facilitate the study of pain and analgesic development.

Chronic multisite musculoskeletal pain (CMP) is common and highly morbid. However, vulnerability factors for CMP are poorly understood. Previous studies have independently shown that both small hippocampal brain volume and genetic risk alleles in a key stress system gene, FKBP5, increase vulnerability for chronic pain. However, little is known regarding the relationship between these factors and CMP. Here we tested the hypothesis that both small hippocampal brain volume and FKBP5 genetic risk, assessed using the tagging risk variant, FKBP5rs3800373, increase vulnerability for CMP. We used participant data from 36,822 individuals with available genetic, neuroimaging, and chronic pain data in the UK Biobank study. Although no main effects were observed, the interaction between FKBP5 genetic risk and right hippocampal volume was associated with CMP severity (β = -0.020, p

How we perceive our bodies is fundamental to our self‐consciousness and our experience in the world. There are two types of interrelated internal body representations—a subjective experience of the position of a limb in space (body schema) and the subjective experience of the shape and size of the limb (body image). Body schema has been extensively studied, but there is no evidence of the brain structure and network dynamics underpinning body image. Here, we provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger‐stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants' susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances., We provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger‐stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants' susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances. ​

Chronic pain patients frequently report memory and concentration difficulties. Objective testing in this population points to poor performance on memory and cognitive tests, and increased comorbid anxiety and depression. Recent evidence has suggested convergence between chronic pain and memory deficits onto the hippocampus. The hippocampus consists of heterogenous subfields involved in memory consolidation, behavior regulation, and stress modulation. Despite significant studies outlining hippocampal changes in human and chronic pain animal models, the effect of pain relief on hippocampal abnormalities remains unknown. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder which is highly amenable to surgical interventions, providing a unique opportunity to investigate the effect of pain relief. This study investigates the effect of pain relief on hippocampal subfields in TN. Anatomical MR images of 61 TN patients were examined before and 6 months after surgery. Treatment responders (n = 47) reported 95% pain relief, whereas non-responders (n = 14) reported 40% change in pain on average. At baseline, patients had smaller hippocampal volumes, compared to controls. After surgery, responders’ hippocampal volumes normalized, largely driven by CA2/3, CA4, and dentate gyrus, which are involved in memory consolidation and neurogenesis. We propose that hippocampal atrophy in TN is pain-driven and successful treatment normalizes such abnormalities. Perspective Chronic pain patients have structural abnormalities in the hippocampus and its subfields. Pain relief normalizes these structural abnormalities and impacts patients in a sex-dependent manner.

Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure—the insertion of an elastomeric separator between teeth—which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

How we perceive our bodies is fundamental to our self-consciousness and our experience in the world. There are two types interrelated internal body representations—a subjective experience of the position of a limb in space (body schema) and the subjective experience of the shape and size of the limb (body image). Body schema has been extensively studied, but there is no evidence of the brain structure and network dynamics underpinning body image. Here, we provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger-stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants’ susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances.

Some forms of chronic pain are thought to be driven and maintained by nociceptive input, which can drive plasticity within nociceptive pathways. We have previously identified abnormalities along the entire nociceptive pathway in chronic myalgic temporomandibular disorders (mTMD), including the trigeminal nerves, brainstem pathways, and in the thalamus and somatosensory cortex. These data suggest that there is a peripheral nociceptive drive in mTMD, but the source of this nociceptive activity remains unknown. Here, our aim was to determine whether structural abnormalities exist in the muscles of mastication of patients with chronic mTMD. Specifically, we tested whether the volume of the temporalis muscle and its tendon-aponeurosis complex (TAC, a structure that dissipates forces in a muscle) in mTMD patients differ compared to age- and sex-matched controls. To do so, we segmented these structures on T1-weighted structural magnetic resonance images. We found that muscle volumes in mTMD were not different to controls. However, the mTMD group had significantly smaller volumes of the bilateral temporalis TAC, and thus a smaller TAC-to-muscle volume ratio. These findings were consistent across 2 independent cohorts of 17 mTMD patients, compared to 17 age- and sex-matched controls. We propose a model where reduced TAC-to-muscle ratio could result in a predisposition to muscle tissue injury. In sum, abnormalities of the temporalis muscles in mTMD supports our hypothesis that chronic mTMD pathophysiology may be related to peripheral nociceptive barrage originating from the muscles of mastication.

Objective In this experimental study, we aimed to determine whether guided music listening (GML) - a music intervention based on models of mood mediation and attention modulation - modulates masticatory muscle activity and awake bruxism in subjects with chronic painful muscular temporomandibular disorders (TMD myalgia, mTMD), a condition causing a significant burden to patients, their families, and healthcare systems. Background Awake bruxism - a stress behavior characterized by clenching of the teeth - is a strong contributor to chronic mTMD. GML modulates psychological stress and motor responses and could thus reduce muscle activity in chronic musculoskeletal conditions, including mTMD. Methods We recorded the electromyographic (EMG) activity in the right masseter of 14 women with chronic (>6 months) mTMD (median [IQR] = 39.5.3 [24.3] years) and 15 pain-free women (median [IQR] = 30.0 [3.5] years) during a GML session, including 3 music (stressful, relaxing, and participants' favorite music) and a no-music (pink noise) control blocks, each lasting 15 minutes. We measured the motor effort of the right masseter relative to the participants' maximum voluntary contraction (MVC), the muscular effort to maintain mandibular posture (EMGposture ), and to produce spontaneous awake bruxism episodes (EMGbruxism ), and the duration and frequency of spontaneous awake bruxism episodes. We tested between-group and within-group (between blocks) differences, as well as the effect of the interaction group by experimental block on these outcome measures. Results In both groups, EMGposture was significantly affected by the interaction group by experimental block (P .05]. EMGbruxism was significantly greater in mTMD participants than controls during the stressful music block [contrast estimate (95% CI): +12.9 (1.6-24.2) %MVC; P = .026). GML did not affect the duration or the frequency of awake bruxism in either group (median [IQR], mTMD: 23.5 [96.7] s, range 1-1300 seconds; Controls: 5.5 [22.5], range 0-246 seconds; P = .108). The frequency of awake bruxism episodes was greater in the mTMD group compared to controls only during the pink noise block (median [IQR], mTMD: 5 [15.3] episodes, range 0-62 episodes; Controls: 1 [3] episode, range 0-27 episodes; P = .046). No significant between-group differences were found in either the overall time spent engaging in awake bruxism (median [IQR], mTMD: 23.5 [96.7] s, range 1-1300 seconds; Controls: 5.5 [22.5], range 0-246 seconds; P = .108), or during each block (all P > .05). Conclusions In subjects with chronic mTMD, relaxing music and the individual's favorite music decreased the muscular effort during spontaneous awake bruxism episodes by 26% and 44% (relative changes), respectively. In contrast, stressful music increases it by about 43%. Because of its positive effects on awake bruxism, GML with selected music could be a promising and non-invasive component of a multimodal approach for the management of chronic mTMD.

Nervous systems exploit regularities in the sensory environment to predict sensory input, adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g., >0.5 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here, we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultralow-frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultralow frequency did not entrain ultralow-frequency oscillations. These results demonstrate that a functionally significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultralow-frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities.

BACKGROUND Many diseases and conditions can disrupt the normal function of the salivary glands, and imaging can be an important tool in the formulation of a diagnosis. With sialography being the imaging modality of choice for obstructive conditions of the major salivary glands, our group has previously demonstrated that cone beam computed tomography (CBCT) sialography offers enhanced visualization of inflammatory changes and obstructions, such as sialoliths and strictures, over plain film sialography.1 However, because ionizing radiation is a concern, optimizing imaging protocols is crucial in order to minimize the radiation dose to the patient while still producing images of high diagnostic quality. OBJECTIVE(S) As a first step in the optimization of a new imaging protocol for CBCT sialography, this study aimed to determine effective dose (E) for a range of exposure parameters using 2 field of view (FOV) sizes for submandibular and parotid gland CBCT sialography. STUDY DESIGN Using a RANDO male phantom, we determined site-specific radiation doses to 25 sites in the head and neck and calculated E across a range of operating kilovoltage peak and milliamperage settings of the J. Morita Veraview X800 (J. Morita Mfg. Corp., Kyoto, Japan). RESULTS The E for the submandibular gland study using an 8 cm (diameter) × 5 cm (height) FOV size ranged from 22.7 to 171.1 µSv, when varied across the unit's allowable kilovoltage peak and milliamperage range. For the parotid gland study using an 8 cm (diameter) × 8 cm (height) FOV size, the E ranged from 21.5 to 160.4 µSv. DISCUSSION/CONCLUSIONS The use of variable FOV sizes for the submandibular and parotid glands may allow reductions in E compared with our earlier work2 and allow us to further optimize sialography imaging protocols for future patients.

The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region and a key node of several brain networks, implicated in cognitive, affective, and sensory processing. As such, the DLPFC is commonly activated in experimental pain studies, and shows abnormally increased function in chronic pain populations. Furthermore, several studies have shown that some chronic pains are associated with decreased left DLPFC gray matter and that successful interventions can reverse this structural abnormality. In addition, studies have indicated that noninvasive stimulation of the left DLPFC effectively treats some chronic pains. In this article, we review the neuroimaging literature regarding the role of the DLPFC and its potential as a therapeutic target for chronic pain conditions, including studies showing the involvement of the DLPFC in encoding and modulating acute pain and studies demonstrating the reversal of DLPFC functional and structural abnormalities after successful interventions for chronic pain. We also review studies of noninvasive brain stimulation of the DLPFC showing acute pain modulation and some effectiveness as a treatment for certain chronic pain conditions. We further discuss the network architecture of the DLPFC, and postulate mechanisms by which DLPFC stimulation alleviates chronic pain. Future work testing these mechanisms will allow for more effective therapies. Perspective The structure and function of the DLPFC is abnormal in some chronic pain conditions. Upon successful resolution of pain, these abnormalities are reversed. Understanding the underlying mechanisms and the role of this region can lead to the development of an effective therapeutic target for some chronic pain conditions.

Nervous systems exploit regularities in the sensory environment to predict sensory input and adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g. >1 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultra-low frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultra-low frequency did not entrain ultra-low frequency oscillations. These results demonstrate that a functionally-significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultra-low frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities.

Medial temporal lobe activity is investigated in meta-analyses of experimental and chronic pain. Abnormal hippocampal connectivity is found in patients with chronic low back pain., The orofacial region is psychologically important, given that it serves fundamental and important biological purposes. Chronic orofacial pain disorders affect the head and neck region. Although some have clear peripheral etiologies, eg, classic trigeminal neuralgia, others do not have a clear etiology (eg, muscular temporomandibular disorders). However, these disorders provide a unique opportunity in terms of elucidating the neural mechanisms of these chronic pain conditions: both the peripheral and central nervous systems can be simultaneously imaged. Diffusion-weighted imaging and diffusion tensor imaging have provided a method to essentially perform in vivo white matter dissections in humans, and to elucidate abnormal structure related to clinical correlates in disorders, such as chronic orofacial pains. Notably, the trigeminal nerve anatomy and architecture can be captured using diffusion imaging. Here, we review the trigeminal somatosensory pathways, diffusion-weighted imaging methods, and how these have contributed to our understanding of the neural mechanisms of chronic pain disorders affecting the trigeminal system. We also discuss novel findings indicating the potential for trigeminal nerve diffusion imaging to develop diagnostic and precision medicine biomarkers for trigeminal neuralgia. In sum, diffusion imaging serves both an important basic science purpose in identifying pain mechanisms, but is also a clinically powerful tool that can be used to improve treatment outcomes.

Objective To evaluate how physical photostimulable phosphor (PSP) plate artifacts, such as those created by scratches, phosphor degradation, and surface peeling, affect the radiologic interpretation of periapical inflammatory disease. Study Design A novel technique was developed to digitally superimpose 25 real PSP artifact masks over 100 clinical complementary metal oxide semiconductor (CMOS) periapical images with known radiologic interpretations. These images were presented to 25 general dentists, who were asked to state their radiologic interpretations, their confidence in their interpretations, and their opinions on whether the plates should be discarded. Statistical analyses were conducted by using random intercept mixed models for repeated measures and χ2 tests of the pooled data. Results No statistically significant adverse effect on interpretation was seen, even at severe artifact levels. There was a statistically significant decrease in the clinicians’ confidence and an increase in discard proportions when interpreting images with severe PSP plate artifacts (P Conclusions Although diagnostic efficacy was unaffected, clinicians’ confidence decreased and proportionally more clinicians opted to discard sensors when interpreting images with severe artifacts. Future studies on the effects of artifacts on the efficacy of diagnosis of other dental diseases are recommended. Ultimately, these results can guide recommendations for PSP plate quality assurance.

Recent neuroimaging studies implicate the medial temporal lobe (MTL) in nociception and pain modulation. Here, we aim to identify which subregions of the MTL are involved in human pain and to test its connectivity in a cohort of chronic low-back pain patients (CBP). We conducted 2 coordinate-based meta-analyses to determine which regions within the MTL showed consistent spatial patterns of functional activation (1) in response to experimental pain in healthy participants and (2) in chronic pain compared with healthy participants. We followed PRISMA guidelines and performed activation likelihood estimate (ALE) meta-analyses. The first meta-analysis revealed consistent activation in the right anterior hippocampus (right antHC), parahippocampal gyrus, and amygdala. The second meta-analysis revealed consistently less activation in patients' right antHC, compared with healthy participants. We then conducted a seed-to-voxel resting state functional connectivity of the right antHC seed with the rest of the brain in 77 CBP and 79 age-matched healthy participants. We found that CBP had significantly weaker antHC functional connectivity to the medial prefrontal cortex compared with healthy participants. Taken together, these data indicate that the antHC has abnormally lower activity in chronic pain and reduced connectivity to the medial prefrontal cortex in CBP. Future studies should investigate the specific role of the antHC in the development and management of chronic pain.

Supplemental Digital Content is Available in the Text., Introduction: Multimodal characterisation with questionnaires, Quantitative Sensory Testing (QST), and neuroimaging will improve understanding of neuropathic pain (NeuP) in adolescents. Magnetic resonance imaging (MRI) data in adolescents with NeuP are limited, and the perceived practical or ethical burden of scanning may represent a barrier to research. Objective: To determine the feasibility of MRI scanning in adolescents with moderate–severe NeuP, with respect to consent rate, postscan acceptability, and data quality. Methods: This prospective cohort study evaluating questionnaires and QST recruited adolescents aged 10 to 18 years with clinically diagnosed NeuP from a tertiary clinic. Eligible adolescents aged 11 years and older could additionally agree/decline an MRI scan. After the scan, families rated discomfort, perceived risk, and acceptability of current and future MRI scans (0–10 numerical rating scales). Head motion during scanning was compared with healthy controls to assess data quality. Results: Thirty-four families agreed to MRI (72% recruitment), and 21 adolescents with moderate–severe pain (average last week 6.7 ± 1.7; mean ± SD) and with neuropathic QST profiles were scanned. Three adolescents reported positional or noise-related discomfort during scanning. Perceived risk was low, and acceptability of the current scan was high for parents (range [median]: 7 to 10/10 [10]) and adolescents (8–10/10 [10]). Willingness to undergo a future research scan was high for parents (7–10/10 [10]) and adolescents (5–10/10 [10]) and did not differ from future scans for clinical purposes. Mean head motion during resting state functional MRI did not differ from control adolescents. Conclusion: Research MRI is feasible and acceptable for many adolescents with moderate–severe NeuP.

The chapter reviews brain imaging studies investigating the sensory, affective, cognitive, and motivational components of pain. It highlights the historical development and significant advancements in thinking about pain, its representation in the brain, its interactions with and impact on cognition, and how it motivates defensive behaviors. Modern imaging and electro-physiological approaches that are currently being applied to study pain are rapidly accumulating data pertaining to acute pain and its transition to chronic pain states in the context of individual psychological factors and behavioral responses so that in the coming era pain science can work toward a more precise and personalized approach to chronic pain treatment.

Background The diagnosis of temporomandibular disorders (TMDs), specifically TMD myalgia, can be challenging. Although the anatomy of the jaw muscles has been extensively characterized, a structural difference in TMD-myalgia individuals has never been demonstrated. Tendons are a highly specialized tissue with a predominately mechanical function. Collagen fibrils, the main contributor to tendon mechanical properties, begin macroscopic failure at 8% to 10% strain. The characterization of tendon/muscle abnormalities in individuals with chronic, painful TMD myalgia will lay the groundwork for utilizing noninvasive magnetic resonance imaging (MRI) for screening and objective monitoring of patients with TMD myalgia. A structural marker unique to TMD myalgia will aid in its diagnosis and treatment. Objective(s) This study aimed to determine differences in the tendon/muscle volume ratio of the temporalis muscle in patients with TMD myalgia compared with age-/gender-matched controls without facial pain. Study Design This was a retrospective, observational study of the temporalis muscle and tendon on MRI images. The comparison between groups was based on a voxel-based morphometry of anatomic T1-weighted MRI images and analyzed for differences in the tendon/muscle volume ratio. The study included at least 14 patients per group to detect a 5% difference in tendon/muscle volume ratio. An intraclass correlation coefficient was used to evaluate the intrarater test–retest reliability. General linear models were used to test whether the outcome measures (muscle/tendon volume, muscle/tendon T1 signal intensity, tendon/muscle ratio) are different between groups. Results Our pilot data demonstrated similar muscle volumes but significantly smaller tendon volumes and signal intensity when comparing patients with TMD myalgia with healthy controls (P Discussion/Conclusions Preliminary data suggest that chronic TMD myalgia may be associated with structural abnormalities of the temporalis tendon. Should the temporalis tendon/muscle volume ratio prove to be a reliable marker, this metric may be used to evaluate different treatment modalities in a noninvasive manner.

The field of human pain neuroimaging has exploded in the last two decades. During this time, the broader neuroimaging community has continued to investigate and refine methods. Another key to progress is exchange with clinicians and pain scientists working with other model systems and approaches. These collaborative efforts require that non-imagers be able to evaluate and assess the evidence provided in these papers. Likewise, new trainees must design rigorous and reliable pain imaging experiments. Here, we provide a guideline for designing, reading, evaluating, analyzing, and reporting results of a pain neuroimaging experiment, with a focus on functional and structural MRI. We focus in particular on considerations that are unique to neuroimaging studies of pain in humans, including study design and analysis, inferences that can be drawn from these studies, and the strengths and limitations of the approach. This article provides an overview of the concepts and considerations of structural and functional MRI neuroimaging studies. The primer is written for those who are not familiar with brain imaging. We review key concepts related to recruitment and study sample, experimental design, data analysis and data interpretation. [Abstract copyright: Copyright © 2018. Published by Elsevier Inc.]

Pedophilia is a principal motivator of child molestation, incurring great emotional and financial burdens on victims and society. Even among pedophiles who never commit any offense,the condition requires lifelong suppression and control. Previous comparison using voxel-based morphometry (VBM)of MR images from a large sample of pedophiles and controls revealed group differences in white matter. The present study therefore sought to verify and characterize white matter involvement using diffusion tensor imaging (DTI), which better captures the microstructure of white matter than does VBM. Pedophilics ex offenders (n=24) were compared with healthy, age-matched controls with no criminal record and no indication of pedophilia (n=32). White matter microstructure was analyzed with Tract-Based Spatial Statistics, and the trajectories of implicated fiber bundles were identified by probabilistic tractography. Groups showed significant, highly focused differences in DTI parameters which related to participants’ genital responses to sexual depictions of children, but not to measures of psychopathy or to childhood histories of physical abuse, sexual abuse, or neglect. Some previously reported gray matter differences were suggested under highly liberal statistical conditions (p(uncorrected)

Background Approximately 30% of patients with major depressive disorder develop treatment-nonresponsive depression (TNRD); novel interventions targeting the substrates of this illness population are desperately needed. Convergent evidence from lesion, stimulation, connectivity, and functional neuroimaging studies implicates the frontopolar cortex (FPC) as a particularly important region in TNRD pathophysiology; regions functionally connected to the FPC, once identified, could present favorable targets for novel brain stimulation treatments. Methods We recently published a parcellation of the FPC based on diffusion tensor imaging data, identifying distinct medial and lateral subregions. Here, we applied this parcellation to resting-state functional magnetic resonance imaging scans obtained in 56 patients with TNRD and 56 matched healthy control subjects. Results In patients, the medial FPC showed reduced connectivity to the anterior midcingulate cortex and insula. The left lateral FPC showed reduced connectivity to the right lateral orbitofrontal cortex and increased connectivity to the fusiform gyri. In addition, TNRD symptom severity correlated significantly with connectivity of the left lateral FPC subregion to a medial orbitofrontal cortex region of the classical reward network. Conclusions Taken together, these findings suggest that changes in FPC subregion connectivity may underlie several dimensions of TNRD pathology, including changes in reward/positive valence, nonreward/negative valence, and cognitive control domains. Nodes of functional networks showing abnormal connectivity to the FPC could be useful in generating novel candidates for therapeutic brain stimulation in TNRD.

Tooth loss is associated with altered sensory, motor, cognitive and emotional functions. These changes vary highly in the population and are accompanied by structural and functional changes in brain regions mediating these functions. It is unclear to what extent this variability in behavior and function is caused by genetic and/or environmental determinants and which brain regions undergo structural plasticity that mediates these changes. Thus, the overall goal of our research program is to identify genetic variants that control structural and functional plasticity following tooth loss. As a step toward this goal, here our aim was to determine whether structural magnetic resonance imaging (sMRI) is sensitive to detect quantifiable volumetric differences in the brains of mice of different genetic background receiving tooth extraction or sham operation. We used 67 adult female mice of 7 strains, comprising the A/J (A) and C57BL/6J (B) strains and a randomly selected sample of 5 of the 23 AXB-BXA strains (AXB1, AXB4, AXB24, BXA14, BXA24) that were produced from the A and B parental mice by recombinations and inbreeding. This panel of 25 inbred strains of genetically diverse inbred strains of mice is used for mapping chromosomal intervals throughout the genome that harbor candidate genes controlling the phenotypic variance of any trait under study. Under general anesthesia, 39 mice received extraction of 3 right maxillary molar teeth and 28 mice received sham operation. On post-extraction day 21, post-mortem whole-brain high-resolution sMRI was used to quantify the volume of 160 brain regions. Compared to sham operation, tooth extraction was associated with a significantly reduced regional and voxel-wise volumes of cortical brain regions involved in processing somatosensory, motor, cognitive and emotional functions, and increased volumes in subcortical sensorimotor and temporal limbic forebrain regions including the amygdala. Additionally, comparison of the 10 BXA14 and 21 BXA24 mice revealed significant volumetric differences between the two strains in several brain regions. These findings highlight the utility of high-resolution sMRI for studying tooth loss-induced structural brain plasticity in mice, and provide a foundation for further phenotyping structural brain changes following tooth loss in the full AXB-BXA panel to facilitate mapping genes that control brain plasticity following orofacial injury.

Rumination is a form of thought characterized by repetitive focus on discomforting emotions or stimuli. In chronic pain disorders, rumination can impede treatment efficacy. The brain mechanisms underlying rumination about chronic pain are not understood. Interestingly, a link between rumination and functional connectivity (FC) of the brain's default mode network (DMN) has been identified within the context of mood disorders. We, and others, have also found DMN dysfunction in chronic pain populations. The medial prefrontal cortex (mPFC) is a key node of the DMN that is anatomically connected with the descending pain modulatory system. Therefore, we tested the hypothesis that in patients with chronic pain, the mPFC exhibits abnormal FC related to the patient's degree of rumination about their pain. Seventeen patients with idiopathic temporomandibular disorder (TMD) and 17 age- and sex-matched healthy controls underwent resting state functional MRI, and rumination about pain was assessed through the rumination subscale of the Pain Catastrophizing Scale. Compared with healthy controls, we found that TMD patients exhibited enhanced mPFC FC with other DMN regions, including the posterior cingulate cortex (PCC)/precuneus (PCu) and retrosplenial cortex. We also found that individual differences in pain rumination in the chronic pain patients (but not in healthy controls) were positively correlated to mPFC FC with the PCC/PCu, retrosplenial cortex, medial thalamus, and periaqueductal/periventricular gray. These data implicate communication within the DMN and of the DMN with the descending modulatory system as a mechanism underlying the degree to which patients ruminate about their chronic pain.

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

MR-based brain imaging technologies provide a suite of functional and structural metrics that can be used to test hypotheses about the CNS mechanisms underlying pain perception and chronification, from a cellular level to a systems level. Two types of functional MRI discussed in this review provide insight into pain mechanisms: stimulus-evoked fMRI and task-free ("resting state") fMRI. The former can assess how the brain responds to noxious or non-noxious stimuli normally or in a chronic pain state as a window into understanding pain, hyperalgesia and allodynia. The latter can assess functional connectivity reflecting synchronous ultra-slow frequency oscillation between brain areas. This provides insight into how brain areas work together as networks to produce pain and how these networks may be modified due to chronic pain. Perfusion MR (e.g., arterial spin labeling) can also provide task-free information pertaining to ongoing brain activity that may reflect spontaneous (ongoing) chronic pain. Structural MR techniques can be used to delineate gray and white matter abnormalities and markers of neuroinflammation associated with chronic pains. Functional and structural MRI findings point to brain and peripheral nerve abnormalities in patients with chronic pain, some of which are pre-existing and others that develop with prolonged pain (and related neuroinflammation) over time. Recent studies indicate that some structural brain abnormalities associated with chronic pain are reversible following effective pain treatment. These data together with findings from studies of individual differences suggest that some chronic pains arise from a combination of pre-existing vulnerabilities and sustained abnormal input.

Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired motor escape responses, reduced motivation and learning deficits. There are important individual differences in the likelihood of becoming helpless following exposure to uncontrollable stress but little is known about the neural mechanisms underlying these individual differences. Here we used structural MRI to measure gray and white matter in individuals with chronic pain, a population at high risk for helplessness due to prolonged exposure to a poorly controlled stressor (pain). Given that self-reported helplessness is predictive of treatment outcomes in chronic pain, understanding such differences might provide valuable clinical insight. We found that the magnitude of self-reported helplessness correlated with cortical thickness in the supplementary motor area (SMA) and midcingulate cortex, regions implicated in cognitive aspects of motor behavior. We then examined the white matter connectivity of these regions and found that fractional anisotropy of connected white matter tracts along the corticospinal tract was associated with helplessness and mediated the relationship between SMA cortical thickness and helplessness. These data provide novel evidence that links individual differences in the motor output pathway with perceived helplessness over a chronic and poorly controlled stressor.

Patients with temporomandibular disorder (TMD) perform poorly in neuropsychological tests of cognitive function. These deficits might be related to dysfunction in brain networks that support pain and cognition, due to the impact of chronic pain and its related emotional processes on cognitive ability. We therefore tested whether patients with TMD perform poorly in cognitive and emotion tasks and whether they had abnormal task-evoked brain activity. Seventeen female subjects with nontraumatic TMD and 17 age-matched healthy female subjects underwent functional magnetic resonance imaging while performing counting Stroop tasks comprising neutral words, incongruent numbers, or emotional words, including TMD-specific words. Group differences in task-related brain responses were assessed. Connectivity between 2 pairs of coupled brain regions during the cognitive and emotional tasks (prefrontal-cingulate and amygdala-cingulate) was also examined. The patients had sluggish Stroop reaction times for all Stroop tasks. Furthermore, compared to controls, patients showed increased task-evoked responses in brain areas implicated in attention (eg, lateral prefrontal, inferior parietal), emotional processes (eg, amygdala, pregenual anterior cingulate), motor planning and performance (eg, supplementary and primary motor areas), and activation of the default-mode network (medial prefrontal and posterior cingulate). The patients also exhibited decoupling of the normally correlated activity between the prefrontal and cingulate cortices and between the amygdala and cingulate cortex. These findings suggest that the slow behavioral responses in idiopathic TMD may be due to attenuated, slower, and/or unsynchronized recruitment of attention/cognition processing areas. These abnormalities may be due to the salience of chronic pain, which inherently requires attention. Sluggish performance in cognitive and emotional interference tasks in patients with nontraumatic temporomandibular disorder is associated with pronounced and unsynchronized task-evoked fMRI brain responses.