Objective
The neural mechanisms of pain in knee osteoarthritis (OA) are not fully understood, and some patients have neuropathic‐like pain associated with central sensitization. To address this, we ...undertook the present study in order to identify central sensitization using neuroimaging and PainDETECT and to relate it to postarthroplasty outcome.
Methods
Patients awaiting arthroplasty underwent quantitative sensory testing, psychological assessment, and functional magnetic resonance imaging (fMRI). Neuroimaging (fMRI) was conducted during punctate stimulation (n = 24) and cold stimulation (n = 20) to the affected knee. The postoperative outcome was measured using the Oxford Knee Score, patient‐reported moderate‐to‐severe long‐term pain postarthroplasty, and a range of pain‐related questionnaires.
Results
Patients with neuropathic‐like pain presurgery (identified using PainDETECT; n = 14) reported significantly higher pain in response to punctate stimuli and cold stimuli near the affected joint (P < 0.05). Neural activity in these patients, compared to those without neuropathic‐like pain, was significantly lower in the rostral anterior cingulate cortex (P < 0.05) and higher in the rostral ventromedial medulla (RVM) during punctate stimulation (P < 0.05), with significant functional connectivity between these two areas (r = 0.49, P = 0.018). Preoperative neuropathic‐like pain and higher neural activity in the RVM were associated with moderate‐to‐severe long‐term pain after arthroplasty (P = 0.0356).
Conclusion
The psychophysical and neuroimaging data suggest that a subset of OA patients have centrally mediated pain sensitization. This was likely due to supraspinally mediated reductions in inhibition and increases in facilitation of nociceptive signaling, and was associated with a worse outcome following arthroplasty. The neurobiologic confirmation of central sensitization in patients with features of neuropathic pain, identified using PainDETECT, provides further support for the investigation of such bedside measures for patient stratification, to better predict postsurgical outcomes.
Neural basis of induced phantom limb pain relief Kikkert, Sanne; Mezue, Melvin; O'Shea, Jacinta ...
Annals of neurology,
January 2019, 2019-01-00, 20190101, Letnik:
85, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objective
Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP‐related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to ...modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS‐induced PLP relief is needed for future implementation of such treatment and generalization to related conditions.
Methods
We used a within‐participants, double‐blind, and sham‐controlled design to alleviate PLP via task‐concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation.
Results
A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid‐ and posterior insula and secondary somatosensory cortex (S2).
Interpretation
The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid‐ and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task‐concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59–73.
An interesting and valuable discussion has arisen from our recent article (Segerdahl, Mezue
et al., 2015) and we are pleased here to have the opportunity to expand on the various points we made. ...Equally important, we wish to correct several important misunderstandings that were made by Davis and colleagues that possibly contributed to their concerns about power when assessing our paper (e.g. actual subject numbers used in control experiment and the reality of the signal-to-noise and sampling of the multi-TI technique we employed). Here, we clarify the methods and analysis plus discuss how we interpret the data in the Brief Communication noting that the extrapolation and inferences made by Davis and colleagues are not consistent with our report or necessarily, in our opinion, what the data supports. We trust this reassures the
F1000Research readership regarding the robustness of our results and what we actually concluded in the paper regarding their possible meaning. We are pleased, though, that Davis and colleagues have used our article to raise an important discussion around pain perception, and here offer some further insights towards that broader discussion.
Several brain regions have been implicated in human painful experiences, but none have been proven to be specific to pain. We exploited arterial spin-labeling quantitative perfusion imaging and a ...newly developed procedure to identify a specific role for the dorsal posterior insula (dpIns) in pain. Tract tracing studies in animals identify a similar region as fundamental to nociception, which suggests the dpIns is its human homolog and, as such, a potential therapeutic target.
Noninvasive neuromodulatory techniques such as transcranial direct current stimulation (tDCS) are attracting increasing interest as potential therapies for a wide range of neurological and ...psychiatric conditions. When targeted to the dorsolateral prefrontal cortex (DLPFC), anodal, facilitatory tDCS has been shown to improve symptoms in a range of domains including working memory, mood, and pain perception (Boggio et al., 2008a; Dockery et al., 2009; Kalu et al., 2012). However, the mechanisms underlying these promising behavioral effects are not well understood. Here, we investigated brain perfusion changes, as assessed using whole-brain arterial spin labeling (ASL), during tDCS applied to the left DLPFC in healthy humans. We demonstrated increased perfusion in regions closely anatomically connected to the DLPFC during anodal tDCS in conjunction with a decreased functional coupling between the left DLPFC and the thalami bilaterally. Despite highly similar effects on cortical excitability during and after stimulation (Nitsche and Paulus, 2000, 2001), cortical perfusion changes were markedly different during these two time periods, with widespread decreases in cortical perfusion being demonstrated after both anodal and cathodal tDCS compared to the period during stimulation. These findings may at least partially explain the different effects on behavior in these time periods described previously in the motor system (Stagg et al., 2011). In addition, the data presented here provide mechanistic explanations for the behavioral effects of anodal tDCS applied to the left DLPFC in terms of modulating functional connectivity between the DLPFC and thalami, as has been hypothesized previously (Lorenz et al., 2003).
Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor.
The authors assessed the utility of ...functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses.
Only gabapentin suppressed the secondary mechanical hyperalgesia-evoked neural response in a region of the brainstem's descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6.
Functional imaging with central sensitization can be used as a sensitive mechanism-based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.
Objective
The neural mechanisms of pain in knee osteoarthritis (
OA
) are not fully understood, and some patients have neuropathic‐like pain associated with central sensitization. To address this, we ...undertook the present study in order to identify central sensitization using neuroimaging and Pain
DETECT
and to relate it to postarthroplasty outcome.
Methods
Patients awaiting arthroplasty underwent quantitative sensory testing, psychological assessment, and functional magnetic resonance imaging (
fMRI
). Neuroimaging (
fMRI
) was conducted during punctate stimulation (n = 24) and cold stimulation (n = 20) to the affected knee. The postoperative outcome was measured using the Oxford Knee Score, patient‐reported moderate‐to‐severe long‐term pain postarthroplasty, and a range of pain‐related questionnaires.
Results
Patients with neuropathic‐like pain presurgery (identified using Pain
DETECT
; n = 14) reported significantly higher pain in response to punctate stimuli and cold stimuli near the affected joint (
P
< 0.05). Neural activity in these patients, compared to those without neuropathic‐like pain, was significantly lower in the rostral anterior cingulate cortex (
P
< 0.05) and higher in the rostral ventromedial medulla (
RVM
) during punctate stimulation (
P
< 0.05), with significant functional connectivity between these two areas (r = 0.49,
P
= 0.018). Preoperative neuropathic‐like pain and higher neural activity in the
RVM
were associated with moderate‐to‐severe long‐term pain after arthroplasty (
P
= 0.0356).
Conclusion
The psychophysical and neuroimaging data suggest that a subset of
OA
patients have centrally mediated pain sensitization. This was likely due to supraspinally mediated reductions in inhibition and increases in facilitation of nociceptive signaling, and was associated with a worse outcome following arthroplasty. The neurobiologic confirmation of central sensitization in patients with features of neuropathic pain, identified using PainDETECT, provides further support for the investigation of such bedside measures for patient stratification, to better predict postsurgical outcomes.
Arterial spin labeling (ASL) MRI is a non-invasive technique for the quantification of cerebral perfusion, and pseudo-continuous arterial spin labeling (PCASL) has been recommended as the standard ...implementation by a recent consensus of the community. Due to the low spatial resolution of ASL images, perfusion quantification is biased by partial volume effects. Consequently, several partial volume correction (PVEc) methods have been developed to reduce the bias in gray matter (GM) perfusion quantification. The efficacy of these methods relies on both the quality of the ASL data and the accuracy of partial volume estimates. Here we systematically investigate the sensitivity of different PVEc methods to variability in both the ASL data and partial volume estimates using simulated PCASL data and in vivo PCASL data from a reproducibility study. We examined the PVEc methods in two ways: the ability to preserve spatial details and the accuracy of GM perfusion estimation. Judging by the root-mean-square error (RMSE) between simulated and estimated GM CBF, the spatially regularized method was superior in preserving spatial details compared to the linear regression method (RMSE of 1.2 vs 5.1 in simulation of GM CBF with short scale spatial variations). The linear regression method was generally less sensitive than the spatially regularized method to noise in data and errors in the partial volume estimates (RMSE 6.3 vs 23.4 for SNR = 5 simulated data), but this could be attributed to the greater smoothing introduced by the method. Analysis of a healthy cohort dataset indicates that PVEc, using either method, improves the repeatability of perfusion quantification (within-subject coefficient of variation reduced by 5% after PVEc).
•PVEc is effective for ASL even when there are errors in the PV estimates.•The spatially regularized method was superior at preserving spatial details.•The linear regression method was less sensitive to errors in PV estimates.•PVEc improves repeatability of CBF estimation in ASL MRI.
Motor correlates of phantom limb pain Kikkert, Sanne; Mezue, Melvin; Henderson Slater, David ...
Cortex,
October 2017, 2017-10-00, 20171001, Letnik:
95
Journal Article
Recenzirano
Odprti dostop
Following amputation, individuals ubiquitously report experiencing lingering sensations of their missing limb. While phantom sensations can be innocuous, they are often manifested as painful. Phantom ...limb pain (PLP) is notorious for being difficult to monitor and treat. A major challenge in PLP management is the difficulty in assessing PLP symptoms, given the physical absence of the affected body part. Here, we offer a means of quantifying chronic PLP by harnessing the known ability of amputees to voluntarily move their phantom limbs. Upper-limb amputees suffering from chronic PLP performed a simple finger-tapping task with their phantom hand. We confirm that amputees suffering from worse chronic PLP had worse motor control over their phantom hand. We further demonstrate that task performance was consistent over weeks and did not relate to transient PLP or non-painful phantom sensations. Finally, we explore the neural basis of these behavioural correlates of PLP. Using neuroimaging, we reveal that slower phantom hand movements were coupled with stronger activity in the primary sensorimotor phantom hand cortex, previously shown to associate with chronic PLP. By demonstrating a specific link between phantom hand motor control and chronic PLP, our findings open up new avenues for PLP management and improvement of existing PLP treatments.
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