Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurring abdominal pain associated with alterations in bowel habits. We hypothesized that patients with chronic visceral pain associated with IBS may have microstructural differences in the brain compared with healthy control subjects (HCs), indicative of long-term neural reorganization of chronic pain pathways and regions associated with sensory integration. In the current study we performed population-based voxel-wise diffusion tensor imaging (DTI) comparisons and probabilistic tractography in a large sample of phenotyped patients with IBS (n = 33) and in HCs (n = 93). Patients had lower fractional anisotropy (FA) in thalamic regions, the basal ganglia (BG) and sensory/motor association/integration regions as well as higher FA in frontal lobe regions and the corpus callosum. In addition, patients had reduced mean diffusivity (MD) within the globus pallidus (GP) and higher MD in the thalamus, internal capsule, and coronal radiata projecting to sensory/motor regions, suggestive of differential changes in axon/dendritic density in these regions. Sex differences in FA and MD were also observed in the patients but not in HCs. Probabilistic tractography in patients confirmed a higher degree of connectivity between the thalamus and prefrontal cortex, as well as between the medial dorsal thalamic nuclei and anterior cingulate cortex, and a lower degree of connectivity between the GP and thalamus. Together, these results support the hypothesis that patients with chronically recurring visceral pain from IBS have long-term microstructural changes within the brain, particularly in regions associated with integration of sensory information and corticothalamic modulation.     

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain

A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses—that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.     

Pain sensitisers exhibit grey matter changes after repetitive pain exposure: A longitudinal voxel-based morphometry study

Previous research in health and disease has shown that exposure to pain changes the density of cortical grey matter (GM). Such structural changes of the brain might, however, depend crucially on how this pain experience is evaluated and processed in the brain. In the present study we aimed to detect pain-rating patterns and underlying GM changes after the application of repetitive painful stimulation using voxel-based morphometry (VBM). Healthy volunteers were investigated (n = 27), receiving 8 noxious and 8 innocuous thermal stimuli on the right forearm for 11 consecutive working days. Data were compared with a control group without any intervention (n = 18). Behavioural data demonstrated that a subgroup of volunteers (n = 14) sensitised, whereas the others (n = 13) habituated over the stimulation days. The VBM analysis revealed no increase but a significant reduction of GM density, eg, in the anterior cingulate cortex, the insular cortex and the frontal cortex, exclusively in the group of sensitisers. By contrast, pain habituaters did not show any density changes in the GM.     

Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury

Mild traumatic brain injury (mTBI) due to explosive blast is common among military service members and often associated with long term psychological and cognitive disruptions. Little is known about the neurological effects of blast-related mTBI and whether they differ from those of civilian, non-blast mTBI. Given that brain damage from blasts may be diffuse and heterogeneous, we tested the hypothesis that blast mTBI is associated with subtle white matter disruptions in the brain that are spatially inconsistent across individuals. We used diffusion tensor imaging to examine white matter integrity, as quantified by fractional anisotropy (FA), in a group of American military service members with (n = 25) or without (n = 33) blast-related mTBI who had been deployed as part of Operation Iraqi Freedom or Operation Enduring Freedom. History of civilian non-blast mTBI was equally common across groups, which enabled testing of both blast and non-blast mTBI effects on measures sensitive to (1) concentrated, spatially consistent (average FA within a region of interest [ROI]), (2) concentrated, spatially variable (number of ROIs with low average FA), and (3) diffuse (number of voxels with low FA) disruptions of white matter integrity. Blast mTBI was associated with a diffuse, global pattern of lower white matter integrity, and this pattern was not affected by previous civilian mTBI. Neither type of mTBI had an effect on the measures sensitive to more concentrated and spatially consistent white matter disruptions. Additionally, individuals with more than one blast mTBI tended to have a larger number of low FA voxels than individuals with a single blast injury. These results indicate that blast mTBI is associated with disrupted integrity of several white matter tracts, and that these disruptions are diluted by averaging across the large number of voxels within an ROI. The reported pattern of effects supports the conclusion that the neurological effects of blast mTBI are diffuse, widespread, and spatially variable.     

Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects

Greater responsiveness of emotional arousal circuits in relation to delivered visceral pain has been implicated as underlying central pain amplification in irritable bowel syndrome (IBS), with female subjects showing greater responses than male subjects. Functional magnetic resonance imaging was used to measure neural responses to an emotion recognition paradigm, using faces expressing negative emotions (fear and anger). Sex and disease differences in the connectivity of affective and modulatory cortical circuits were studied in 47 IBS (27 premenopausal female subjects) and 67 healthy control subjects (HCs; 38 premenopausal female subjects). Male subjects (IBS + HC) showed greater overall brain responses to stimuli than female subjects in prefrontal cortex, insula, and amygdala. Effective connectivity analyses identified major sex- and disease-related differences in the functioning of brain networks related to prefrontal regions, cingulate, insula, and amygdala. Male subjects had stronger connectivity between anterior cingulate subregions, amygdala, and insula, whereas female subjects had stronger connectivity to and from the prefrontal modulatory regions (medial/dorsolateral cortex). Male IBS subjects demonstrate greater engagement of cortical and affect-related brain circuitry compared to male control subjects and female subjects, when viewing faces depicting emotions previously shown to elicit greater behavioral and brain responses in male subjects.     

Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke

Previous brain imaging work suggests that stroke alters the effective connectivity (the influence neural regions exert upon each other) of motor execution networks. The present study examines the intrinsic effective connectivity of top-down motor control in stroke survivors (n = 13) relative to healthy participants (n = 12). Stroke survivors exhibited significant deficits in motor function, as assessed by the Fugl-Meyer Motor Assessment. We used structural equation modeling (SEM) of resting-state fMRI data to investigate the relationship between motor deficits and the intrinsic effective connectivity between brain regions involved in motor control and motor execution. An exploratory adaptation of SEM determined the optimal model of motor execution effective connectivity in healthy participants, and confirmatory SEM assessed stroke survivors' fit to that model. We observed alterations in spontaneous resting-state effective connectivity from fronto-parietal guidance systems to the motor network in stroke survivors. More specifically, diminished connectivity was found in connections from the superior parietal cortex to primary motor cortex and supplementary motor cortex. Furthermore, the paths demonstrated large individual variance in stroke survivors but less variance in healthy participants. These findings suggest that characterizing the deficits in resting-state connectivity of top-down processes in stroke survivors may help optimize cognitive and physical rehabilitation therapies by individually targeting specific neural pathway.     

The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: a preliminary report

A fundamental component of brain development is the formation of large-scale networks across the cortex. One such network, the default network, undergoes a protracted development, displaying weak connectivity in childhood that strengthens in adolescence and becomes most robust in adulthood. Little is known about the genetic contributions to default network connectivity in adulthood or during development. Alterations in connectivity between posterior and frontal portions of the default network have been associated with several psychological disorders, including anxiety, autism spectrum disorders, schizophrenia, depression, and attention-deficit/hyperactivity disorder. These disorders have also been linked to variants of the serotonin transporter linked polymorphic region (5-HTTLPR). The L_A allele of 5-HTTLPR results in higher serotonin transporter expression than the S allele or the rarer L_G allele. 5-HTTLPR may influence default network connectivity, as the superior medial frontal region has been shown to be sensitive to changes in serotonin. Also, serotonin as a growth factor early in development may alter large-scale networks such as the default network. The present study examined the influence of 5-HTTLPR variants on connectivity between the posterior and frontal structures and its development in a cross-sectional study of 39 healthy children and adolescents. We found that children and adolescents homozygous for the S allele (S/S, n = 10) showed weaker connectivity in the superior medial frontal cortex compared to those homozygous for the L_A allele (L_A/L_A, n = 13) or heterozygotes (S/L_A, S/L_G, n = 16). Moreover, there was an age-by-genotype interaction, such that those with L_A/L_A genotype had the steepest age-related increase in connectivity between the posterior hub and superior medial frontal cortex, followed by heterozygotes. In contrast, individuals with the S/S genotype had the least age-related increase in connectivity strength. This preliminary report expands our understanding of the genetic influences on the development of large-scale brain connectivity and lays down the foundation for future research and replication of the results with a larger sample.     

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain

A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10 mg (n = 321) or 20 mg (n = 527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient’s Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20 mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10 mg, n = 2; tanezumab 20 mg, n = 4); 9 additional patients (tanezumab 10 mg, n = 7; tanezumab 20 mg, n = 2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n = 0), worsening osteoarthritis (n = 5; 1 rapidly progressive), and another diagnosis or indeterminate (n = 5). Tanezumab 10 mg had better tolerability than tanezumab 20 mg, and may represent an effective long-term treatment for chronic low back pain.     

Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.     

Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome

Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel-based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC-Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC-Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain-related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS.     

Visceral sensitivity correlates with decreased regional gray matter volume in healthy volunteers: A voxel-based morphometry study

Regional changes in brain structure have been reported in patients with altered visceral sensitivity and chronic abdominal pain, such as in irritable bowel syndrome. It remains unknown whether structural brain changes are associated with visceral sensitivity. Therefore, we present the first study in healthy individuals to address whether interindividual variations in gray matter volume (GMV) in pain-relevant regions correlate with visceral sensitivity. In 92 healthy young adults (52 female), we assessed rectal sensory and pain thresholds and performed voxel-based morphometry (VBM) to compute linear regression models with visceral sensory and pain thresholds, respectively, as independent variable and GMV in a priori-defined regions of interest (ROIs) as dependent variable. All results were familywise error (FWE) corrected at a level of P_FWE < .05 and covaried for age. The mean (±SEM) rectal thresholds were 14.78 ± 0.46 mm Hg for first sensation and 33.97 ± 1.13 mm Hg for pain, without evidence of sex differences. Lower rectal sensory threshold (ie, increased sensitivity) correlated significantly with reduced GMV in the thalamus, insula, posterior cingulate cortex, ventrolateral and orbitofrontal prefrontal cortices, amygdala, and basal ganglia (all P_FWE < .05). Lower rectal pain threshold was associated with reduced GMV in the right thalamus (P_FWE = .051). These are the first data supporting that increased visceral sensitivity correlates with decreased gray matter volume in pain-relevant brain regions. These findings support that alterations in brain morphology not only occur in clinical pain conditions but also occur according to normal interindividual variations in visceral sensitivity.     

Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N = 18), patients with OCD (N = 18) and SDIs (N = 18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories.     

Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats

C-nociceptors do not normally fire action potentials unless challenged by adequate noxious stimuli. However, in pathological states nociceptors may become hyperexcitable and may generate spontaneous ectopic discharges. The aim of this study was to compare rat neuropathic pain models and to assess their suitability to model the spontaneous C-nociceptor activity found in neuropathic pain patients. Studies were performed in normal rats (n = 40), healthy human subjects (n = 15), peripheral neuropathic pain patients (n = 20), and in five rat neuropathic pain models: nerve crush (n = 24), suture (n = 14), chronic constriction injury (n = 12), STZ-induced diabetic neuropathy (n = 56), and ddC-induced neuropathy (n = 15).Microneurographic recordings were combined with electrical stimulation to monitor activity in multiple C fibers. Stimulation at 0.25 Hz allowed spontaneous impulses to be identified by fluctuations in baseline latency. Abnormal latency fluctuations could be produced by several mechanisms, and spontaneous activity was most reliably identified by the presence of unexplained latency increases corresponding to two or more additional action potentials. Spontaneous activity was present in a proportion of mechano-insensitive C-nociceptors in the patients and all rat models. The three focal traumatic nerve injury models provided the highest proportion (59.5%), whereas the two polyneuropathy models had fewer (18.6%), and the patients had an intermediate proportion (33.3%). Spontaneously active mechano-sensitive C-nociceptors were not recorded. Microneurographic recordings of spontaneous activity in diseased C-nociceptors may be useful for both short- and long-term drug studies, both in animals and in humans.     

Establishing the reproducibility of two approaches to quantify white matter tract integrity in stroke

Diffusion tensor imaging can provide unique and detailed information about white matter anatomy following stroke. Fiber tract reconstruction using tract-based techniques and cross-sectional region of interest delineation are two common approaches to quantify white matter integrity. After stroke, white matter tract integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption is associated with degree of functional impairment and response to skill training in participants with stroke. However, the reliability and validity of these approaches has not been systematically evaluated nor have the two approaches been directly compared in individuals with chronic stroke.Ten well-recovered individuals with chronic, right-sided, ischemic stroke in the sub-cortex and ten age-, gender- and handedness-matched healthy participants were studied. Semi-automated tractography of the ipsi- and contralesional corticospinal tract and cross-sectional region of interest drawing of the posterior limb of the internal capsule were performed bilaterally. Fractional anisotropy (FA) values and the hemispheric asymmetry in FA were the primary measures of tract integrity. Two raters performed each analysis method twice to evaluate inter- and intra-rater reliability. Participants with stroke were compared to healthy individuals to determine validity of each analysis approach. Correlational analyses were conducted to examine the relationships between the two approaches and the association between approaches and upper extremity motor impairment.Both analyses methods generally demonstrated good to excellent intra- and inter-rater reliability in each group (p < 0.05). Stroke participants demonstrated lower mean FA values in both ipsi- and contralesional tract integrity, and larger FA hemispheric asymmetry as compared with healthy individuals (p < 0.05). Comparison between the analysis approaches revealed significant associations between approaches across both groups and within each group (p < 0.05). In stroke, individual tract integrity was not correlated between approaches for ipsilesional (r = 0.26) or contralesional (0.15) tracts, nor was FA hemispheric asymmetry (r = 0.18). Additionally, contralesional mean FA quantified with the cross-sectional approach correlated with upper extremity motor impairment (r = 0.69).Importantly, this study is the first to systematically characterize the reliability of tract-based and cross-sectional DTI analysis approaches in well-recovered individuals with chronic stroke and matched healthy participants. Results suggest both tract-based and cross-sectional approaches to evaluate white matter tract integrity are reliable, can differentiate between groups of stroke and healthy participants, and are associated with one another. However, only mean FA values for the contralesional side derived using the cross-sectional approach were related to upper extremity impairment. Our findings suggest that each approach provides complimentary rather than redundant information regarding integrity and support the use of both approaches in combination in future investigations in well-recovered individuals with stroke.     

Avoidance of affective pain stimuli predicts chronicity in patients with acute low back pain

This prospective study of acute and sub-acute low back pain (LBP) patients was conducted to assess whether attentional biases predicted chronic pain status 3 and 6 months later. The attentional biases of 100 LBP patients were assessed within 3 months of developing pain and 6 months later. Participants also completed measures associated with outcome at 3 assessment points: baseline, 3 and 6 months later. Current pain status was assessed at follow-ups. Patients were classified as those that met standard criteria for chronic pain or those who did not (i.e., the comparison group). At baseline, participants demonstrated a bias toward sensory pain words. However, biases toward sensory pain words did not differentiate those who subsequently developed chronic pain and those who did not at either follow-up. The same bias was observed 6 months later, but again it failed to distinguish between the chronic pain and comparison groups. However, subjects who developed chronic pain at both 3 (n = 22) and 6 (n = 21) months demonstrated biases away from affective pain words at baseline but not 6 months later, in comparison to other participants. These results remained significant in multivariate analyses. These findings are consistent with patterns observed in the previous research, and suggest that avoidance of emotionally laden pain-related stimuli (i.e., affective pain words) is associated with negative outcomes for LBP patients in the acute and sub-acute phase. This research suggests that attentional biases in relation to pain-related stimuli are important for the development of chronic pain, but are more complex than initially thought.     

Efficacy and safety of tanezumab in the treatment of chronic low back pain

Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 μg/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ?30% or ?50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ?30% and ?50% reduction in aLBPI with tanezumab vs naproxen (P ? 0.013) and placebo (P < 0.001), and greater improvements in Roland-Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.     

Optimizing prediction of back pain outcomes

An accurate means of identifying patients at high risk for chronic disabling pain could lead to more cost-effective care, with more intensive interventions targeted to those likely to benefit most. The Chronic Pain Risk Score is a tool developed to predict risk for chronic pain. The aim of this study was to examine whether its predictive ability could be enhanced by: (1) improved measures of the constructs it assesses (Improved Chronic Pain Risk Model); and (2) adding other predictors (Expanded Chronic Pain Risk Model). Patients initiating primary care for back pain (N = 571) completed measures used in the Chronic Pain Risk Score, Improved Model, and Expanded Model, then completed the Graded Chronic Pain Scale (GCPS) 4 months later (n = 521; 91% response rate). In predicting 4-month GCPS grade III or IV (moderate or severe pain-related activity interference), the Improved Model performed better than did the Chronic Pain Risk Score (Net Reclassification Index [NRI] = 0.32, P = 0.003). The Expanded Model improved significantly on the prediction of the Improved Model (NRI = 0.56, P < 0.001) and demonstrated excellent discriminative ability (AUC = 0.84, 95% CI = 0.79-0.88). The Improved Model (AUC = 0.79, 95% CI = 0.75-0.84) and the Chronic Pain Risk Score (AUC = 0.76, 95% CI = 0.71-0.81) showed acceptable discriminative ability. A limited set of measures may be used to predict risk for future clinically significant pain in patients initiating primary care for back pain, but further evaluation of prognostic models is needed.     

膝骨性关节炎患者脑结构和功能变化的多模态MRI

目的  联合基于体素的形态学测量（VBM）技术和静息态功能磁共振成像（rs-fMRI）技术探究膝骨性关节炎（KOA）患者静息状态下脑灰质体积、脑神经元活动强度及基于种子点的功能连接强度改变,综合分析KOA相关异常脑网络。方法  前瞻性收集30例KOA患者（KOA组）及30例健康人（HC组）的3D高分辨率T1WI像和rs-fMRI图像,采用VBM、低频振幅、功能连接3种方法分析两组间脑灰质结构和功能数据差异。结果  与HC组相比,KOA组双侧梭状回、右侧颞中回低频振幅值增高,右侧楔前叶、右侧内侧前额叶皮质、左侧额中回低频振幅值减低（体素水平P<0.005,团块水平P<0.05）;右侧楔前叶、右侧顶下小叶、右侧初级视觉皮层、左侧颞中回、左侧中央后回灰质体积减小（体素水平P<0.002,团块水平P<0.05）;以右侧楔前叶为种子点,与右侧颞中回的功能连接增强,与左侧前扣带回、左侧背外侧前额叶皮质的功能连接降低（体素水平P<0.005,团块水平P<0.05）。结论  KOA患者感知皮层系统及联合皮层系统阵营均存在血氧水平依赖信号及灰质微结构的改变且有重叠,主要涉及视觉网络、感觉运动网络、默认状态网络、执行控制网络内及默认状态网络、执行控制网络、突显网络的部分脑区间,这可能提示KOA患者不仅处于慢性疼痛的病理状态,还伴有信息整合、注意力控制、情绪反应、情感解读等功能活动的异常。     

Increased Salience Network Connectivity Following Manual Therapy is Associated with Reduced Pain in Chronic Low Back Pain Patients

Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Nonpharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salience network (SLN) connectivity, and whether this was associated with changes in clinical pain. Fifteen cLBP patients, and 16 matched healthy controls (HC) were scanned with resting functional Magnetic Resonance Imaging (fMRI), before and immediately after a MT intervention (cross-over design with two separate visits, pseudorandomized, grades V ‘Manipulation’ and III ‘Mobilization’ of the Maitland Joint Mobilization Grading Scale). Patients rated clinical pain (0–100) pre- and post-therapy. SLN connectivity was assessed using dual regression probabilistic independent component analysis. Both manipulation (Pre: 39.43 ± 16.5, Post: 28.43 ± 16.5) and mobilization (Pre: 38.83 ± 17.7, Post: 31.76 ± 19.4) reduced clinical back pain (P < .05). Manipulation (but not mobilization) significantly increased SLN connectivity to thalamus and primary motor cortex. Additionally, a voxelwise regression indicated that greater MT-induced increase in SLN connectivity to the lateral prefrontal cortex was associated with greater clinical back pain reduction immediately after intervention, for both manipulation (r = -0.8) and mobilization (r = -0.54). Our results suggest that MT is successful in reducing clinical low back pain by both spinal manipulation and spinal mobilization. Furthermore, this reduction post-manipulation occurs via modulation of SLN connectivity to sensorimotor, affective, and cognitive processing regions.PerspectiveMT both reduces clinical low back pain and modulates brain activity important for the processing of pain. This modulation was shown by increased functional brain connectivity between the salience network and brain regions involved in cognitive, affective, and sensorimotor processing of pain.     

Identifying neuropathic back and leg pain: a cross-sectional study

Low back pain is a widespread debilitating problem with a lifetime prevalence of 80%, with the underlying pain mechanism unknown in approximately 90% of cases. We used the painDETECT neuropathic pain screening questionnaire to identify likely pain mechanisms in 343 patients with low back pain with or without leg pain in southeastern England referred for physiotherapy. We related the identified possible pain mechanisms nociceptive, unclear, and neuropathic to standardised measures of pain severity (Numeric Rating Scale), disability (Roland Morris Low Back Pain Disability Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), and quality of life (Short Form 36 Health Survey Questionnaire Version 2). In addition, we investigated any relationship between these possible pain mechanisms and leg pain, passive straight leg raise, and magnetic resonance imaging evidence confirming or eliminating nerve root compression. A total of 59% of participants (n = 204) reported likely nociceptive pain, 25% (n = 85) unclear, and 16% (n = 54) possible neuropathic pain. The possible neuropathic pain group reported significantly higher pain, disability, anxiety, and depression, reduced quality of life and passive straight leg raise compared to the other pain groups (P < .05). A total of 96% of participants with possible neuropathic pain reported pain radiating to the leg (76% below the knee); however, leg pain was still more common in patients with nociceptive pain, suggesting that leg pain is sensitive to, but not specific to, possible neuropathic pain. No relationship was demonstrated between possible neuropathic pain and evidence for or absence of nerve root compression on magnetic resonance imaging scans. These findings suggest possible neuropathic pain is less common in low back pain patients referred through primary care and clarifies the usefulness of clinical tests for identifying possible neuropathic pain.