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.

Combined transcranial magnetic stimulation and electroencephalography reveals alterations in cortical excitability during pain.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

Alterations in cortical excitability during pain: A combined TMS-EEG Study.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n = 29), multiple sustained thermal stimuli were administered to the forearm, with the first, second and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n = 10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

A Silent Disco: Differential Effects of Beat-based and Pattern-based Temporal Expectations on Persistent Entrainment of Low-frequency Neural Oscillations.

The brain uses temporal structure in the environment, like rhythm in music and speech, to predict the timing of events, thereby optimizing their processing and perception. Temporal expectations can be grounded in different aspects of the input structure, such as a regular beat or a predictable pattern. One influential account posits that a generic mechanism underlies beat-based and pattern-based expectations, namely, entrainment of low-frequency neural oscillations to rhythmic input, whereas other accounts assume different underlying neural mechanisms. Here, we addressed this outstanding issue by examining EEG activity and behavioral responses during silent periods following rhythmic auditory sequences. We measured responses outlasting the rhythms both to avoid confounding the EEG analyses with evoked responses, and to directly test whether beat-based and pattern-based expectations persist beyond stimulation, as predicted by entrainment theories. To properly disentangle beat-based and pattern-based expectations, which often occur simultaneously, we used non-isochronous rhythms with a beat, a predictable pattern, or random timing. In Experiment 1 (n = 32), beat-based expectations affected behavioral ratings of probe events for two beat-cycles after the end of the rhythm. The effects of pattern-based expectations reflected expectations for one interval. In Experiment 2 (n = 27), using EEG, we found enhanced spectral power at the beat frequency for beat-based sequences both during listening and silence. For pattern-based sequences, enhanced power at a pattern-specific frequency was present during listening, but not silence. Moreover, we found a difference in the evoked signal following pattern-based and beat-based sequences. Finally, we show how multivariate pattern decoding and multiscale entropy-measures sensitive to non-oscillatory components of the signal-can be used to probe temporal expectations. Together, our results suggest that the input structure used to form temporal expectations may affect the associated neural mechanisms. We suggest climbing activity and low-frequency oscillations may be differentially associated with pattern-based and beat-based expectations.

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.

The influence of sensory potentials on transcranial magnetic stimulation - Electroencephalography recordings.

OBJECTIVE: It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two. METHODS: Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants. RESULTS: Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone. CONCLUSIONS: Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both. SIGNIFICANCE: Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation.

The Effect of Acute and Sustained Pain on Corticomotor Excitability: A Systematic Review and Meta-Analysis of Group and Individual Level Data.

Pain alters motor function. This is supported by studies showing reduced corticomotor excitability in response to experimental pain lasting <90 minutes. Whether similar reductions in corticomotor excitability are present with pain of longer durations or whether alterations in corticomotor excitability are associated with pain severity is unknown. Here we evaluated the evidence for altered corticomotor excitability in response to experimental pain of differing durations in healthy individuals. Databases were systematically searched for eligible studies. Measures of corticomotor excitability and pain were extracted. Meta-analyses were performed to examine: (1) group-level effect of pain on corticomotor excitability, and (2) individual-level associations between corticomotor excitability and pain severity. 49 studies were included. Corticomotor excitability was reduced when pain lasted milliseconds-seconds (hedges g's = -1.26 to -1.55) and minutes-hours (g's = -0.55 to -0.9). When pain lasted minutes-hours, a greater reduction in corticomotor excitability was associated with lower pain severity (g = -0.24). For pain lasting days-weeks, there were no group level effects (g = -0.18 to 0.27). However, a greater reduction in corticomotor excitability was associated with higher pain severity (g = 0.229). In otherwise healthy individuals, suppression of corticomotor excitability may be a beneficial short-term strategy with long-term consequences. PERSPECTIVE: This systematic review synthesised the evidence for altered corticomotor excitability in response to experimentally induced pain. Reduced corticomotor excitability was associated with lower acute pain severity but higher sustained pain severity, suggesting suppression of corticomotor excitability may be a beneficial short-term adaptation with long-term consequences.

No indications for altered EEG oscillatory activity in patients with chronic post-burn itch compared to healthy controls.

A large proportion of patients with burn injuries develop chronic itch, which impacts quality of life. The underlying pathophysiological mechanisms are poorly understood. This cross-sectional pilot study investigates whether altered cortical oscillatory processes are involved in chronic post-burn itch. Continuous electroencephalography (EEG) data were recorded during rest and stimulation of non-injured skin, inducing itch (histamine and electrical) and cold-pressor task pain for 15 adults with chronic post-burn itch and 15 matched healthy controls. Quantitative metrics comprised oscillatory power and peak frequencies in theta, alpha, and beta bands. No statistical differences between patients and healthy controls were found in oscillatory activity during rest or stimulation, with Bayesian analysis suggesting equivocal evidence. However, post-traumatic stress symptoms and duration of chronic itch may be associated with changes in oscillatory activity. A lack of differences in cortical oscillatory processing and itch levels at non-injured sites, suggests that itch symptoms have a localised character in this sample of patients with post-burn itch. For future studies, a biopsychological approach with integration of peripheral and central nervous system techniques, linear and non-linear EEG analysis, injured and non-injured stimulation sites, and incorporation of individual characteristics is recommended. Insight into pathophysiological mechanisms underlying chronic post-burn itch could improve diagnostics and treatments.

"Just not knowing" can make life sweeter (and saltier): Reward uncertainty alters the sensory experience and consumption of palatable food and drinks.

Reward uncertainty can prompt exploration and learning, strengthening approach and consummatory behaviors. For humans, these phenomena are exploited in marketing promotions and gambling products, sometimes spurring hedonic consumption. Here, in four experiments, we sought to identify whether reward uncertainty-as a state of "not knowing" that exists between an action and a positively valanced outcome-enhances the in-the-moment consumption and experience of other palatable food and drink rewards. In Experiment 1, we demonstrate that reward uncertainty can increase consumption of commercial alcoholic drinks and energy-dense savory snacks. In Experiment 2, we show that reward uncertainty is unlikely to promote consumption through gross increases in impulsivity (expressed as higher discounting rates) or risk tolerance (expressed as lower probability discounting rates). In Experiment 3, we find that reward uncertainty intensifies the taste of, and hedonic responses to, sucrose solutions in a concentration-dependent manner among individuals with heightened preferences for sweet tastes. Finally, in Experiment 4, we replicate and extend these findings by showing that reward uncertainty intensifies the taste of palatable foods and drinks in ways that are independent of individuals' discounting rates, motor control, reflection impulsivity, and momentary happiness but are strongly moderated by recent depressive symptoms. These data suggest a working hypothesis that (incidental) reward uncertainty, as a state of not knowing, operates as a mood-dependent "taste intensifier" of palatable food and drink rewards, possibly sustaining reward seeking and consumption. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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. REGISTRATION DETAILS: ClinicalTrials.gov: NCT04241562 (prospective).

Cancer Pain in People With Intellectual Disabilities: Systematic Review and Survey of Health Care Professionals.

CONTEXT: Owing to life expectancy improvements for people with intellectual disabilities, their risk of developing cancer is increasing. Pain is an inevitable aspect of cancerous diseases. However, as pain experience and expression can be atypical in people with intellectual disabilities, this population is vulnerable to late diagnosis of cancer and undertreatment of cancer pain. OBJECTIVES: The objective of this study was to investigate what is currently known about cancer pain in people with intellectual disabilities and provide specific recommendations to improve this knowledge. METHODS: A systematic review using PubMed, PsycINFO, and CINAHL and an anonymous online survey of Dutch health care professionals were conducted. RESULTS: From 10,146 publications, with intellectual disabilities in the title, and pain or cancer in the title or abstract, 11 articles underwent qualitative synthesis. Discussions within these articles were predominantly unspecific and brief, frequently indicating challenges in symptom presentation, communication, as well as assessment and treatment of cancer pain. The survey received 102 responses. The 63 health care professionals experienced with cancer in people with intellectual disabilities indicated challenges recognizing, assessing, and treating their cancer pain. CONCLUSION: Cancer pain in people with intellectual disabilities is a topic lacking specific and comprehensive research within scientific literature. We suggest this is due to inherent difficulties regarding the complex interplay of comorbidities and communication issues in people with intellectual disabilities.