Neuroimaging-based biomarker discovery and validation

Woo, Choong‐Wan; Wager, Tor D.

doi:10.1097/j.pain.0000000000000223

Cited by 60 publications

(69 citation statements)

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“…Machine learning and statistical techniques are often used to identify patterns in these data, and are optimized to jointly predict patient status, the experience of pain, analgesia, and other outcomes. These approaches have been successfully used to decode some aspects of stimulus-evoked acute pain from patterns of brain activity, at least to some extent 51,[61][62][63][64][65][66][67][68][69][70][71] …”

Section: O N S E N S U S S Tat E M E N Tmentioning

confidence: 99%

Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations

et al. 2017

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624 | OCTOBER 2017 | VOLUME 13 www.nature.com/nrneurol CONSENSUS STATEMENT © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . NeuroethicsA field that studies the implications of neuroscience for human self-understanding, ethics, and policy. Arterial spin labellingAn MRI-based brain imaging technique that detects cerebral blood flow based on magnetic tagging of blood.Nevertheless, diverse groups -including patients, researchers, clinicians, pharmaceutical and medical device companies, insurers and the legal communityseek methods for evaluating chronic pain besides selfreporting. Patients seek objective testing to demonstrate the reality of an invisible condition that is sometimes subject to doubt, researchers seek brain imaging markers that provide scientific, diagnostic and prognostic information that cannot be provided by patient self-reporting, and legal representatives and officials seek techniques to supplement self-reporting and objectively support or challenge claims related to chronic pain. Brain imaging technologies, including functional MRI (fMRI), PET, EEG and magnetoencephalography (MEG), have the potential to provide objective measurements of patterns of brain activity that underlie perceptual experiences (BOX 1). Consequently, some people are looking to brain imaging to provide a window into the experience of chronic pain, particularly because testimony based on fMRI was deemed to be admissible as evidence of pain in a 2015 state trial court in the USA 10,11 . This case was highly publicized, although the judgement was not published so no legal precedent was set, and the grounds on which the fMRI evidence was admitted were criticized by established experts in brain imaging studies of pain 10,11 . In this context, the development of a brain imaging test for chronic pain [12][13][14] has real-world consequences, so appropriate criteria for the use of such a test must be defined. Importantly, the way in which brain imaging evidence might be implemented in legal cases strongly depends on laws that vary greatly between countries. Therefore, examination of the capability of so-called 'pain-o-meter' brain imaging tests is critical, as is consideration of the use of such technology in light of societal views, neuroethics and legal issues. Thus, the aims of this Consensus Statement are to recommend criteria for the evaluation of neuroimaging measures of chronic pain, and to discuss the technical, biological, neuroethical and legal challenges related to establishing brain-based tests for chronic pain. MethodsA presidential task force of the International Association for the Study of Pain (IASP) was established in 2015 to examine the feasibility of a brain-imaging-based diagnostic test for chronic pain. The task force had three purposes: to consider the capacity of brain imaging (in particular fMRI), on the basis of its technical and physiological constraints, to detect whether an individual has chronic pain; to place th...

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Section: O N S E N S U S S Tat E M E N Tmentioning

confidence: 99%

Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations

et al. 2017

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“…As discussed, the task-based patterns of hypo-/hyperactivation demonstrated found in the biomarkers is highly consistent with the current corpus of task-related fMRI findings in PCS. It is felt that the reported biomarkers largely fulfill the criteria of successful neuroimaging biomarkers as described in Woo et al [52]. Lastly, limitations of this study include a potential lack in generalizability of the biomarkers.…”

Section: Discussionmentioning

confidence: 95%

“…Concerning the development of biomarkers, Woo et al [52] describe a set of desirable characteristics that functional biomarkers should display. The first phase of biomarker development is the discovery stage.…”

Section: Discussionmentioning

confidence: 99%

“…In terms of limitations, considering the optimal characteristics of neuroimaging biomarkers laid out by Woo et al [52], it is largely felt that the discovery of the reported five biomarkers meet the four criteria. However, concerning criterion 4, "Generalizability", the argument is less compelling than the first three.…”

Section: Limitationsmentioning

confidence: 99%

“…However, concerning criterion 4, "Generalizability", the argument is less compelling than the first three. According to Woo et al [52], clinically useful neuroimaging biomarkers should have their performance proved across different laboratories, scanners, protocols, populations, and testing conditions. Although methods were employed to improve cross-site imaging stability [22], the fNCI protocol used to discover the five neuroimaging biomarkers is largely confined to the clinic in which the research occurred.…”

Section: Limitationsmentioning

confidence: 99%

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Discovery of Therapy-targeting Biomarkers for Post-Concussion Syndrome using Functional Neurocognitive Imaging

Epps¹,

Allen²

2018

Brain Disord Ther

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Background: Post-concussion syndrome (PCS) occurs in a significant percentage of concussion patients. Functional MRI reveals irregular blood-oxygen level dependent signals in PCS patients. PCS biomarkers with functional predictive values have yet to be discovered and validated. Therefore, this study describes five PCS biomarkers and includes a description of their therapeutic application.Methods: A neurocognitive imaging protocol was developed and a group of healthy control patients was used to generate a normative reference atlas. Biomarker candidate search was performed using an initial sample of PCS patients. Sample validation was applied to each biomarker using a new sample of PCS patients to assess sensitivities/ specificities. A multivariate base rate analysis was performed using 132 new patients and a base rate cutoff matrix was constructed. An example of the biomarker's therapeutic application in a PCS patient is described. Results:The five functional biomarkers included: Frontal Attentional System hypoactivation, Subcortical System hypoactivation, Visual System hyperactivation, Verbal System hypoactivation, and Frontal/Parietal System hyperactivation. Individual biomarker sensitivities and specificities are reported. Collectively, using the base rate cutoff matrix, a threshold using 3/5 biomarkers below the 10 th percentile as the cutoff resulted in a suitable sensitivity (88%) and specificity (99%). The uses of these biomarkers were crucial in guiding the successful treatment of Patient A. Conclusion:We report the discovery of five functional PCS biomarkers. We show an example of the therapeutic application of the five biomarkers in the successful treatment of PCS. These neuroimaging biomarkers serve to advance diagnostic capabilities and subsequent PCS rehabilitation efforts.

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Placebo Effects on the Neurologic Pain Signature

2018

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for the Placebo Imaging Consortium IMPORTANCE Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation.OBJECTIVE We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain.DATA SOURCES Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations.STUDY SELECTION Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data.DATA EXTRACTION AND SYNTHESIS Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. MAIN OUTCOMES AND MEASURESThe main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. RESULTSWe obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = −0.66 [95% CI, −0.80 to −0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = −0.08 [95% CI, −0.15 to −0.01]). Similarly, analyses restricted to studies with low risk of bias (g = −0.07 [95% CI, −0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = −0.22 [95% CI, −0.34 to −0.11]) indicated small effects, as well.CONCLUSIONS AND RELEVANCE Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.

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Neuroimaging-based biomarker discovery and validation

Cited by 60 publications

References 31 publications

Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations

Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations

Discovery of Therapy-targeting Biomarkers for Post-Concussion Syndrome using Functional Neurocognitive Imaging

Placebo Effects on the Neurologic Pain Signature

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