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.

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.

CPAP combined with oral appliance therapy reduces CPAP requirements and pharyngeal pressure swings in obstructive sleep apnea.

Oral appliance (OA) therapy is the leading alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). It is well tolerated compared with CPAP. However, ≥50% of patients using OA therapy have incomplete resolution of their OSA. Combination therapy with CPAP and oral appliance (CPAP + OA) is a potential alternative for incomplete responders to OA therapy. This study aimed to determine the extent to which combination therapy reduces therapeutic CPAP requirements using gold-standard physiological methodology in those who have an incomplete response to OA therapy alone. Sixteen incomplete responders [residual apnea/hypopnea index (AHI) > 10 events/h] to a novel OA with a built-in oral airway were recruited (3 women:13 men, aged 31-65 yr, body mass index: 22-38 kg/m2, residual AHI range: 13-63 events/h). Participants were fitted with a nasal mask, pneumotachograph, epiglottic pressure catheter, and standard polysomnography equipment. CPAP titrations were performed during non-rapid eye movement (NREM) supine sleep in each participant during three conditions (order randomized): CPAP only, CPAP + OA (oral airway open), and CPAP + OA (oral airway closed). OSA was resolved at pressures of 4 ± 2 and 5 ± 2 cmH2O during CPAP + OA (oral airway open) and CPAP + OA (oral airway closed) conditions versus 8 ± 2 cmH2O during CPAP only (P < 0.01). Negative epiglottic pressure swings in oral airway open and closed conditions were normalized to CPAP only levels [-2.5(-3.7, -2.6) vs. -2.3(-3.2, -2.4) vs. -2.1(-2.7, -2.3) cmH2O]. Combined CPAP and OA therapy reduces therapeutic CPAP requirements by 35%-45% and minimizes epiglottic pressure swings. This combination may be a therapeutic alternative for patients with incomplete responses to OA therapy alone and those who cannot tolerate high CPAP levels.NEW & NOTEWORTHY Combined CPAP and oral appliance therapy has been suggested as an alternative for incomplete responders to oral appliance therapy. We used a novel oral appliance incorporating an oral airway together with CPAP to show that pharyngeal pressure swings were normalized at reduced CPAP levels. Our findings demonstrate that using CPAP and oral appliance together may be a beneficial alternative for incomplete responders to oral appliance therapy and intolerant CPAP users due to high-pressure requirements.

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).