A novel cortical biomarker signature for predicting pain sensitivity : protocol for the PREDICT longitudinal analytical validation study

Introduction: Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan. Methods: This study uses a multisite longitudinal, experimental study to follow individuals for a period of 30 days as they progressively develop and experience complete resolution of NGF-induced muscle pain. One hundred fifty healthy participants will be recruited. Participants will complete twice daily electronic pain diaries from day 0 to day 30 and undergo assessment of pressure pain thresholds, and recording of PAF and CME on days 0, 2, and 5. Intramuscular injection of NGF will be given into the right masseter muscle on days 0 and 2. The primary outcome is pain sensitivity. Perspective: PREDICT is the first study to undertake analytical validation of a PAF and CME biomarker signature. The study will determine the sensitivity, specificity, and accuracy of the biomarker signature to predict an individual's sensitivity to pain

Can non‐invasive brain stimulation modulate peak alpha frequency in the human brain? A systematic review and meta‐analysis

Peak alpha frequency (PAF), the dominant oscillatory frequency within the alpha range (8–12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions, potentially providing new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non‐invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre‐ and post‐NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk‐of‐bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta‐analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk‐of‐bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta‐analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = −0.12, 95% CI = −0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. However, it is crucial to note that small sample sizes were used, there was substantial variation in stimulation protocols, and most studies did not specifically target PAF alteration. Further studies are needed to determine NIBS's potential for modulating PAF

Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured three times: before and after a cosyntropin (1.0 microgram/kg) stimulation test (performed prior to the ligation), and at 10–12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified Inotrope Score (1 x dopamine (μg/kg/min) + 1 x dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their highest Inotrope Score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low post-operative cortisol levels were not associated with the overall incidence of hypotension following ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the odds ratio for developing catecholamine-resistant hypotension was OR=36.6, CI=2.8–476, p=0.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not due to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations following PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production

Does cognitive control ability mediate the relationship between impulsivity/reward drive and maladaptive outcomes in adolescence and young adulthood?

Supplementary results of the project associated with the pre-print paper of 2018 by McKewen, Skippen, Cooper, Wong, Michie, Lenroot, and Karayanidis "Does cognitive control ability mediate the relationship between impulsivity/reward drive and maladaptive outcomes in adolescence and young adulthood?

Electrophysiological analysis of a difficult stop-signal task

Ongoing project analysing the Stop-signal Task from the Age-ility project (Karayanidis et al., 2013) using EEG

Reliability of triggering inhibitory process is a better predictor of impulsivity than SSRT

The ability to control behaviour is thought to rely at least partly on adequately suppressing impulsive responses to external stimuli. However, the evidence for a relationship between response inhibition ability and impulse control is weak and inconsistent. This study investigates the relationship between response inhibition and both self-report and behavioural measures of impulsivity as well as engagement in risky behaviours in a large community sample (N=174) of healthy adolescents and young adults (15-35yrs). Using a stop-signal paradigm with a number parity go task, we implemented a novel hierarchical Bayesian model of response inhibition that estimates stop-signal reaction time (SSRT) as a distribution and also accounts for failures to react to the stop-signal (i.e., “trigger failure”), and failure to react to the choice stimulus (i.e., “go failure” or omission errors). In line with previous studies, the model reduced estimates of SSRT by approximately 100ms compared with traditional non-parametric SSRT estimation techniques. We found significant relationships between behavioural and self-report measures of impulsivity and traditionally estimated SSRT, that did not hold for the model-based SSRT estimates. Instead, behavioural impulsivity measures were correlated with rate of trigger failure. The relationship between trigger failure and impulsivity suggests that the former may index a higher order inhibition process, whereas SSRT may index a more automatic inhibition process. We suggest that the existence of distinct response inhibition processes that may be associated with different levels of cognitive control

Reliability of triggering inhibitory process is a better predictor of impulsivity than SSRT

The ability to control behaviour is thought to rely at least partly on adequately suppressing impulsive responses to external stimuli. However, the evidence for a relationship between response inhibition ability and impulse control is weak and inconsistent. This study investigates the relationship between response inhibition and both self-report and behavioural measures of impulsivity as well as engagement in risky behaviours in a large community sample (N=174) of healthy adolescents and young adults (15-35yrs). Using a stop-signal paradigm with a number parity go task, we implemented a novel hierarchical Bayesian model of response inhibition that estimates stop-signal reaction time (SSRT) as a distribution and also accounts for failures to react to the stop-signal (i.e., “trigger failure”), and failure to react to the choice stimulus (i.e., “go failure” or omission errors). In line with previous studies, the model reduced estimates of SSRT by approximately 100ms compared with traditional non-parametric SSRT estimation techniques. We found significant relationships between behavioural and self-report measures of impulsivity and traditionally estimated SSRT, that did not hold for the model-based SSRT estimates. Instead, behavioural impulsivity measures were correlated with rate of trigger failure. The relationship between trigger failure and impulsivity suggests that the former may index a higher order inhibition process, whereas SSRT may index a more automatic inhibition process. We suggest that the existence of distinct response inhibition processes that may be associated with different levels of cognitive control

The reliability of two prospective cortical biomarkers for pain : EEG peak alpha frequency and TMS corticomotor excitability

Background: Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and an inability to accurately classify at-risk individuals. Preliminary evidence has shown that high pain sensitivity is associated with slow peak alpha frequency (PAF), and depression of corticomotor excitability (CME), potentially due to impairments in ascending sensory and descending motor pathway signalling respectively New method: The present study evaluated the reliability of PAF and CME responses during sustained pain. Specifically, we determined whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. Results: Using a weighted peak estimate, PAF reliability (n = 75) was in the excellent range even without standard pre-processing and ∼2 min recording length. Using a single peak estimate, PAF reliability was in the moderate-good range. For CME (n = 74), 80% of participants showed facilitation or depression of CME beyond an optimal cut-off point, with the stability of these changes in the good range. Comparison with existing methods: No study has assessed the reliability of PAF or feasibility of classifying individuals as facilitators/depressors, in response to sustained pain. PAF was reliable even in the presence of pain. The use of a weighted peak estimate for PAF is recommended, as excellent test-retest reliability can be obtained even when using minimal pre-processing and ∼2 min recording. We also showed that 80% of individuals exhibit either facilitation or depression of CME, with these changes being stable across sessions. Conclusions: Our study provides support for the reliability of PAF and CME as prospective cortical biomarkers. As such, our paper adds important methodological advances to the rapidly growing field of pain biomarkers

OSARI, an Open-Source Anticipated Response Inhibition Task

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referredto as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with astop-signal on stop trials. Currently, the most popular version of the stop-signal task is the ‘choice-reaction’ variant, whereparticipants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to thechoice-reaction variant of the stop-signal task is the ‘anticipated response inhibition’ task. In anticipated response inhibition tasks,participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from acomputer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over themore traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are noopenly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source,free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-SourceAnticipated Response Inhibition) task