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Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have shown that brain characteristics can serve as robust predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.
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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.
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Núcleo Amigdalino Central , Núcleo Motor del Nervio Trigémino , Animales , Humanos , Núcleo Amigdalino Central/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiología , Imagen de Difusión por Resonancia Magnética , Tronco EncefálicoRESUMEN
OBJECTIVE: Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. METHODS: Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. RESULTS: The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). CONCLUSIONS: These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.
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Hiperalgesia , Neuralgia , Analgésicos/uso terapéutico , Método Doble Ciego , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Pregabalina/uso terapéuticoRESUMEN
Chronic pain is associated with anhedonia and decreased motivation. These behavioral alterations have been linked to alterations in the limbic brain and could explain the increased risk for obesity in pain patients. The mechanism of these behavioral changes and how they set in in relation to the development of chronic pain remain however poorly understood. Here we asked how eating behavior was affected in low-back pain patients before and after they transitioned to chronic pain, compared to patients whose pain subsided. Additionally, we assessed how the hedonic perception of fat-rich food, which is altered in chronic pain patients, related to the properties of the nucleus accumbens in this patients' population. We hypothesized that the accumbens would be directly implicated in the hedonic processing of fat-rich food in pain patients because of its well-established role in hedonic feeding and fat ingestion, and its emerging role in chronic pain. Accordingly, we used behavioral assays and structural brain imaging to test sub-acute back pain patients (SBP) and healthy control subjects at baseline and at approximately one-year follow-up. We also studied a sample of chronic low-back pain patients (CLBP) at one time point only. We found that SBP patients who recovered at follow-up (SBPr) and CLBP patients showed disrupted eating behaviors. In contrast, SBP patients who persisted in having pain at follow-up (SBPp) showed intact eating behavior. From a neurological standpoint, only SBPp and CLBP patients showed a strong and direct relationship between hedonic perception of fat-rich food and nucleus accumbens volume. This suggests that accumbens alterations observed in SBPp patients in previous works might protect them from hedonic eating disruptions during the early course of the illness. We conclude that disrupted eating behavior specifically sets in after pain chronification and is accompanied by structural changes in the nucleus accumbens.
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Conducta Alimentaria , Dolor de la Región Lumbar/fisiopatología , Núcleo Accumbens , Adulto , Apetito , Dolor Crónico , Grasas de la Dieta , Femenino , Estudios de Seguimiento , Preferencias Alimentarias , Humanos , Dolor de la Región Lumbar/psicología , Imagen por Resonancia Magnética , Masculino , Núcleo Accumbens/fisiopatología , PlacerRESUMEN
ABSTRACT: Low back pain is the most common pain condition and cause for disability in older adults. Older adults suffering from low back pain are more disabled than their healthy peers, are more predisposed to frailty, and tend to be undertreated. The cause of increased prevalence and severity of this chronic pain condition in older adults is unknown. Here, we draw on accumulating data demonstrating a critical role for brain limbic and sensory circuitries in the emergence and experience of chronic low back pain (CLBP) and the availability of resting-state brain activity data collected at different sites to study how brain activity patterns predictive of CLBP differ between age groups. We apply a data-driven multivariate searchlight analysis to amplitude of low-frequency fluctuation brain maps to classify patients with CLBP with >70% accuracy. We observe that the brain activity pattern including the paracingulate gyrus, insula/secondary somatosensory area, inferior frontal, temporal, and fusiform gyrus predicted CLBP. When separated by age groups, brain patterns predictive of older patients with CLBP showed extensive involvement of limbic brain areas including the ventromedial prefrontal cortex, the nucleus accumbens, and hippocampus, whereas only anterior insula paracingulate and fusiform gyrus predicted CLBP in the younger patients. In addition, we validated the relationships between back pain intensity ratings and CLBP brain activity patterns in an independent data set not included in our initial patterns' identification. Our results are the first to directly address how aging affects the neural signature of CLBP and point to an increased role of limbic brain areas in older patients with CLBP.
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Dolor Crónico , Dolor de la Región Lumbar , Anciano , Mapeo Encefálico/métodos , Enfermedad Crónica , Dolor Crónico/diagnóstico por imagen , Humanos , Dolor de la Región Lumbar/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Dimensión del Dolor/métodosRESUMEN
Why is psychiatry unable to define clinically useful biomarkers? We explore this question from the vantage of data and decision science and consider biomarkers as a form of phenotypic data that resolves a well-defined clinical decision. We introduce a framework that systematizes different forms of phenotypic data and further introduce the concept of decision model to describe the strategies a clinician uses to seek out, combine, and act on clinical data. Though many medical specialties rely on quantitative clinical data and operationalized decision models, we observe that, in psychiatry, clinical data are gathered and used in idiosyncratic decision models that exist solely in the clinician's mind and therefore are outside empirical evaluation. This, we argue, is a fundamental reason why psychiatry is unable to define clinically useful biomarkers: because psychiatry does not currently quantify clinical data, decision models cannot be operationalized and, in the absence of an operationalized decision model, it is impossible to define how a biomarker might be of use. Here, psychiatry might benefit from digital technologies that have recently emerged specifically to quantify clinically relevant facets of human behavior. We propose that digital tools might help psychiatry in two ways: first, by quantifying data already present in the standard clinical interaction and by allowing decision models to be operationalized and evaluated; second, by testing whether new forms of data might have value within an operationalized decision model. We reference successes from other medical specialties to illustrate how quantitative data and operationalized decision models improve patient care.
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Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.
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Analgésicos Opioides/uso terapéutico , Encéfalo/patología , Encéfalo/fisiopatología , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Dolor de la Región Lumbar/tratamiento farmacológico , Dolor de la Región Lumbar/fisiopatología , Adulto , Analgésicos Opioides/farmacología , Encéfalo/efectos de los fármacos , Femenino , Humanos , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/patología , Núcleo Accumbens/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , Relación Señal-Ruido , Tálamo/efectos de los fármacos , Tálamo/patología , Tálamo/fisiopatologíaRESUMEN
The prevalence of chronic pain has reached epidemic levels. In addition to personal suffering chronic pain is associated with psychiatric and medical co-morbidities, notably substance misuse, and a huge a societal cost amounting to hundreds of billions of dollars annually in medical cost, lost wages, and productivity. Chronic pain does not have a cure or quantitative diagnostic or prognostic tools. In this manuscript we provide evidence that this situation is about to change. We first start by summarizing our current understanding of the role of the brain in the pathogenesis of chronic pain. We particularly focus on the concept of learning in the emergence of chronic pain, and the implication of the limbic brain circuitry and dopaminergic signaling, which underly emotional learning and decision making, in this process. Next, we summarize data from our labs and from other groups on the latest brain imaging findings in different chronic pain conditions focusing on results with significant potential for translation into clinical applications. The gaps in the study of chronic pain and brain imaging are highlighted in throughout the overview. Finally, we conclude by discussing the costs and benefits of using brain biomarkers of chronic pain and compare to other potential markers.
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Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit a smaller nucleus accumbens volume, which persists in the chronic phase, compared to healthy controls. The smaller accumbens volume was also observed in a separate cohort of chronic low-back pain patients and was associated with dynamic changes in functional connectivity. At baseline, subacute back pain patients showed altered local nucleus accumbens connectivity between putative shell and core, irrespective of the risk of transition to chronic pain. At follow-up, connectivity changes were observed between nucleus accumbens and rostral anterior cingulate cortex in the patients with persistent pain. Analysis of the power spectral density of nucleus accumbens resting-state activity in the subacute and chronic back pain patients revealed loss of power in the slow-5 frequency band (0.01 to 0.027 Hz) which developed only in the chronic phase of pain. This loss of power was reproducible across two cohorts of chronic low-back pain patients obtained from different sites and accurately classified chronic low-back pain patients in two additional independent datasets. Our results provide evidence that lower nucleus accumbens volume confers risk for developing chronic pain and altered nucleus accumbens activity is a signature of the state of chronic pain.
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Dolor de Espalda/fisiopatología , Dolor Crónico/fisiopatología , Giro del Cíngulo/fisiopatología , Núcleo Accumbens/fisiopatología , Adulto , Dolor de Espalda/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico/métodos , Dolor Crónico/diagnóstico por imagen , Femenino , Giro del Cíngulo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Núcleo Accumbens/diagnóstico por imagen , Factores de RiesgoRESUMEN
Inherited erythromelalgia (IEM) is a chronic pain disorder caused by gain-of-function mutations of peripheral sodium channel Nav1.7, in which warmth triggers severe pain. Little is known about the brain representation of pain in IEM. Here we study two subjects with the IEM Nav1.7-S241T mutation using functional brain imaging (fMRI). Subjects were scanned during each of five visits. During each scan, pain was first triggered using a warming boot and subjects rated their thermal-heat pain. Next, the thermal stimulus was terminated and subjects rated stimulus-free pain. Last, subjects performed a control visual rating task. Thermal-heat induced pain mapped to the frontal gyrus, ventro-medial prefrontal cortex, superior parietal lobule, supplementary motor area, insula, primary and secondary somato-sensory motor cortices, dorsal and ventral striatum, amygdala, and hippocampus. Stimulus-free pain, by contrast, mapped mainly to the frontal cortex, including dorsal, ventral and medial prefrontal cortex, and supplementary motor area. Examination of time periods when stimulus-free pain was changing showed further activations in the valuation network including the rostral anterior cingulate cortex, striatum and amygdala, in addition to brainstem, thalamus, and insula. We conclude that, similar to other chronic pain conditions, the brain representation of stimulus-free pain during an attack in subjects with IEM engages brain areas involved in acute pain as well as valuation and learning.
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Pain and stress share significant conceptual and physiological overlaps. Both phenomena challenge the body's homeostasis and necessitate decision-making to help animals adapt to their environment. In addition, chronic stress and chronic pain share a common behavioral model of failure to extinguish negative memories. Yet, they also have discrepancies such that the final brain endophenotype of posttraumatic stress disorder, depression, and chronic pain appears to be different among the three conditions, and the role of the hypothalamic-pituitary-adrenal axis remains unclear in the physiology of pain. Persistence of either stress or pain is maladaptive and could lead to compromised well-being. In this brief review, we highlight the commonalities and differences between chronic stress and chronic pain, while focusing particularly on the central role of the limbic brain. We assess the current attempts in the field to conceptualize and understand chronic pain, within the context of knowledge gained from the stress literature. The limbic brain-including hippocampus, amygdala, and ventromedial pre-frontal cortex-plays a critical role in learning. These brain areas integrate incoming nociceptive or stress signals with internal state, and generate learning signals necessary for decision-making. Therefore, the physiological and structural remodeling of this learning circuitry is observed in conditions such as chronic pain, depression, and posttraumatic stress disorder, and is also linked to the risk of onset of these conditions.
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Canales de Sodio/metabolismo , Trastornos Somatomorfos/metabolismo , Trastornos Somatomorfos/fisiopatología , Animales , Humanos , Nociceptores/efectos de los fármacos , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/genética , Trastornos Somatomorfos/tratamiento farmacológico , Trastornos Somatomorfos/genéticaRESUMEN
Global brain connectivity (GBC) identifies regions of the brain, termed "hubs," which are densely connected and metabolically costly, and have a wide influence on brain function. Since obesity is associated with central and peripheral metabolic dysfunction we sought to determine if GBC is altered in obesity. Two independent fMRI data sets were subjected to GBC analyses. The first data set was acquired while participants (n = 15 healthy weight and 15 obese) tasted milkshake and the second with participants at rest (n = 33 healthy weight and 28 obese). In the resting state and during milkshake consumption GBC is consistently decreased in the ventromedial and ventrolateral prefrontal cortex, insula and caudate nucleus, and increased in brain regions belonging to the dorsal attention network including premotor areas, superior parietal lobule, and visual cortex. During milkshake consumption, but not at rest, additional decreases in GBC are observed in feeding-related circuitry including the insula, amygdala, anterior hippocampus, hypothalamus, midbrain, brainstem and somatomotor cortex. Additionally, GBC differences were not accounted for by age. These results demonstrate that obesity is associated with decreased GBC in prefrontal and feeding circuits and increased GBC in the dorsal attention network. We therefore conclude that global brain organization is altered in obesity to favor networks important for external orientation over those monitoring homeostatic state and guiding feeding decisions. Furthermore, since prefrontal decreases are also observed at rest in obese individuals future work should evaluate whether these changes are associated with neurocognitive impairments frequently observed in obesity and diabetes. Hum Brain Mapp 38:1403-1420, 2017. © 2016 Wiley Periodicals, Inc.
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Mapeo Encefálico , Encéfalo/fisiopatología , Vías Nerviosas/fisiopatología , Obesidad/patología , Adulto , Factores de Edad , Encéfalo/diagnóstico por imagen , Ingestión de Alimentos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Movimiento (Física) , Vías Nerviosas/diagnóstico por imagen , Obesidad/diagnóstico por imagen , Oxígeno/sangreRESUMEN
Capitalizing on recent advances in resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24 h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected α<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants' development.
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Antidepresivos/farmacología , Núcleo Caudado , Cerebelo , Corteza Cerebral , Conectoma , Trastorno Depresivo Mayor , Ketamina/farmacología , Adulto , Antidepresivos/administración & dosificación , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/fisiopatología , Cerebelo/diagnóstico por imagen , Cerebelo/efectos de los fármacos , Cerebelo/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Femenino , Humanos , Ketamina/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. METHODS: A total of 82 subjects, including medication-free patients with major depression (n = 57) and healthy volunteers (n = 25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel's time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. RESULTS: Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges' g = -1.48, P < 0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = -0.47, P = 0.0005). CONCLUSIONS: Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder. Hum Brain Mapp 37:3214-3223, 2016. © 2016 Wiley Periodicals, Inc.
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Trastorno Depresivo Mayor/fisiopatología , Vías Nerviosas/fisiopatología , Corteza Prefrontal/fisiopatología , Adulto , Mapeo Encefálico , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
IMPORTANCE: There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. OBJECTIVE: To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling. DESIGN, SETTING, AND PARTICIPANTS: Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels. MAIN OUTCOMES AND MEASURES: Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. RESULTS: This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T NaV1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine. CONCLUSIONS AND RELEVANCE: Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.
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Analgésicos no Narcóticos/uso terapéutico , Carbamazepina/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/etiología , Eritromelalgia/complicaciones , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Dolor Crónico/diagnóstico por imagen , Análisis Mutacional de ADN , Método Doble Ciego , Estimulación Eléctrica , Eritromelalgia/genética , Femenino , Ganglios Espinales/citología , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Dimensión del Dolor , Análisis de Regresión , Células Receptoras Sensoriales/efectos de los fármacosRESUMEN
Chronic low back pain (CLBP) and obesity are interrelated, but the physiological mechanisms linking the 2 conditions remain to be determined. Functional brain imaging data from CLBP patients show functional and structural alterations in areas mediating the attribution of hedonic value to food. Accordingly, we hypothesized that CLBP patients would exhibit alteration in the hedonic perception of highly palatable, calorie-containing foods. CLBP patients and matched healthy controls initially rated their perception of highly palatable puddings of varying fat content and sugary drinks of varying sucrose content without ingesting significant amounts of either stimulus. In a subsequent intake test, hungry participants ingested their preferred pudding ad libitum. Compared to healthy controls, CLBP patients exhibited significantly lower ratings of food pleasure when sampling the fat puddings but not when sampling the sugary drinks. In contrast, the patients' sensory evaluation of these stimuli was not different from those of healthy controls. In addition, whereas in healthy controls caloric intake from pudding closely matched hedonic ratings and decreased hunger after ad libitum pudding intake, such effect was totally abolished in CLBP patients. Our data thus reveal a decoupling between hedonic perception and fat calorie intake in CLBP patents, suggesting altered hedonic perception of fat as a potential mechanism linking CLBP to overeating and obesity.
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Alimentos , Dolor de la Región Lumbar/fisiopatología , Dolor de la Región Lumbar/psicología , Placer/fisiología , Saciedad/fisiología , Gusto , Adulto , Análisis de Varianza , Enfermedad Crónica , Ingestión de Energía , Femenino , Humanos , Masculino , Dimensión del Dolor , PsicofísicaRESUMEN
BACKGROUND: Preclinical evidence implicates the serotonin receptor 5-hydroxytryptamine 1B (5-HT1B) in the effects of cocaine. This study explores 5-HT1B in humans by examining receptor availability in vivo in subjects whose primary addiction is cocaine dependence (CD) using positron emission tomography. METHODS: Study participants included 14 medically healthy subjects with CD (mean age = 41 ± 6 years) who were compared with 14 age-matched healthy control subjects (mean age = 41 ± 8 years) with no past or current history of cocaine or other illicit substance abuse. Participants underwent magnetic resonance imaging followed by positron emission tomography with the highly selective 5-HT1B tracer, [(11)C]P943, for purposes of quantifying regional binding potential. Voxel-based morphometry and gray matter masking also were employed to control for potential partial volume effects. RESULTS: The [(11)C]P943 positron emission tomography imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus, and ventral striatum) showed significant or nearly significant reductions of regional binding potential in subjects with CD in three regions: anterior cingulate (-16%, p < .01), hypothalamus (-16%, p = .03), and frontal cortex (-7%, p = .08). Voxel-based morphometry showed significant gray matter reductions in the frontal cortex of subjects with CD. After gray matter masking, statistically significant reductions in the [(11)C]P943 regional binding potential were either retained (anterior cingulate, -14%, p = .01; hypothalamus, -20%, p < .01) or achieved (frontal cortex, -14%, p < .01). Whole-brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use. CONCLUSIONS: The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology or expression of CD and potentially represent a target for medication development.
Asunto(s)
Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Receptor de Serotonina 5-HT1B/metabolismo , Adulto , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Trastornos Relacionados con Cocaína/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de PositronesRESUMEN
There is now widespread agreement that individual variation in the neural circuits representing the reinforcing properties of foods may be associated with risk for overeating and obesity. What is currently unknown is how and whether brain response to a food is related to immediate subsequent intake of that food. Here we used functional magnetic resonance imaging (fMRI) to test whether response to a palatable milkshake is associated with subsequent ad libitum milkshake consumption. We predicted that enhanced responses in key reward regions (insula, striatum, midbrain, medial orbitofrontal cortex) and decreased responses in regions implicated in self-control (lateral prefrontal and lateral orbitofrontal cortex) would be associated with greater intake. We found a significant positive association between response to milkshake in the periaqueductal gray region of the midbrain and ad libitum milkshake intake. Although strong bilateral insular responses were observed during consumption of the milkshake this response did not correlate with subsequent intake. The associations observed in the midbrain and orbitofrontal cortex were uninfluenced by ratings of hunger, which were near neutral. We conclude that midbrain response to a palatable food is related to eating in the absence of hunger.