Intralipid infusion therapy as an adjunct treatment in women experiencing adenomyosis-related infertility.

Background: Currently, there is some evidence that adenomyosis patients using gonadotropin-releasing hormone (GnRH) agonist long downregulation (LDR) prior to embryo transfer may improve in vitro fertilization (IVF) success rate, but not to the baseline expected success where there is no adenomyosis. Given the association between adenomyosis and an aberrant endometrial immune environment, many physicians also use prednisolone or Intralipid adjuvant treatments in combination with GnRH agonist therapy, despite neither being of proven benefit. Objective: The purpose of this study was to investigate whether the addition of prednisolone or Intralipid immune therapy to GnRH agonist LDR improves fertility outcomes in patients with adenomyosis. Methods: This is a retrospective cohort study of 116 consecutive adenomyosis patients who underwent their first transfer of a genetically screened euploid embryo between January 2019 and December 2020 at a private IVF clinic. Results: There was no difference in maternal age, body mass index, number of embryo's transferred and gravidity or parity among the three treatment groups. Patients who received Intralipid had a poorer prognosis with a longer duration of infertility (4 years) and a higher number of previous embryo transfers (ETs, 5 previous ETs) compared to the comparison groups. Logistic regression analysis adjustment for all covariates revealed that LDR plus Intralipid therapy produced significantly higher live birth rates (LBRs; 60%) compared to LDR alone (40% LBR); yet, the addition of prednisolone to GnRH agonist LDR (30% LBR) provided no additional live birth benefit. Conclusion: In this retrospective analysis, we showed Intralipid adjuvant treatment in combination with GnRH agonist therapy in adenomyosis patients undergoing IVF resulted in a LBR expected in women without adenomyosis using preimplantation genetic testing screened embryos. This benefit was not seen when using prednisolone as an adjuvant to GnRH agonist LDR. Future randomized clinical trials will be required to confirm the therapeutic benefit of Intralipid in combination with GnRH agonist therapy.

Frontal alpha asymmetry: A potential biomarker of approach-withdrawal motivation towards pain.

Pain-related catastrophising is a maladaptive coping strategy known to have a strong influence on clinical pain outcomes and treatment efficacy. Notwithstanding, little is known about its neurophysiological correlates. There is evidence to suggest catastrophising is associated with resting-state EEG frontal alpha asymmetry (FAA) patterns reflective of greater relative right frontal activity, which is known to be linked to withdrawal motivation and avoidance of aversive stimuli. The present study aims to investigate whether such a relationship occurs in the situational context of experimental pain. A placebo intervention was also included to evaluate effects of a potential pain-relieving intervention on FAA. 35 participants, including both chronic pain patients and healthy subjects, completed the Pain Catastrophising Scale (PCS) questionnaire followed by EEG recordings during cold pressor test (CPT)-induced tonic pain with or without prior application of placebo cream. There was a negative correlation between FAA and PCS-subscale helplessness scores, but not rumination or magnification, during the pre-placebo CPT condition. Moreover, FAA scores were shown to increase significantly in response to pain, indicative of greater relative left frontal activity that relates to approach-oriented behaviours. Placebo treatment elicited a decrease in FAA in low helplessness scorers, but no significant effects in individuals scoring above the mean on PCS-helplessness. These findings suggest that, during painful events, FAA may reflect the motivational drive to obtain reward of pain relief, which may be diminished in individuals who are prone to feel helpless about their pain. This study provides valuable insights into biomarkers of pain-related catastrophising and prospects of identifying promising targets of brain-based therapies for chronic pain management.

Alpha entrainment drives pain relief using visual stimulation in a sample of chronic pain patients: a proof-of-concept controlled study.

One-third of the population in the UK and worldwide struggle with chronic pain. Entraining brain alpha activity through noninvasive visual stimulation has been shown to reduce experimental pain in healthy volunteers. Neural oscillations entrainment offers a potential noninvasive and nonpharmacological intervention for patients with chronic pain, which can be delivered in the home setting and has the potential to reduce use of medications. However, evidence supporting its use in patients with chronic pain is lacking. This study explores whether (a) alpha entrainment increase alpha power in patients and (b) whether this increase in alpha correlates with analgesia. In total, 28 patients with chronic pain sat in a comfortable position and underwent 4-min visual stimulation using customised goggles at 10 Hz (alpha) and 7 Hz (control) frequency blocks in a randomised cross-over design. 64-channel electroencephalography and 11-point numeric rating scale pain intensity and pain unpleasantness scores were recorded before and after stimulation. Electroencephalography analysis revealed frontal alpha power was significantly higher when stimulating at 10 Hz when compared to 7 Hz. There was a significant positive correlation between increased frontal alpha and reduction in pain intensity (r = 0.33; P < 0.05) and pain unpleasantness (r = 0.40; P < 0.05) in the 10 Hz block. This study provides the first proof of concept that changes in alpha power resulting from entrainment correlate with an analgesic response in patients with chronic pain. Further studies are warranted to investigate dose-response parameters and equivalence to analgesia provided by medications.

Entraining Alpha Activity Using Visual Stimulation in Patients With Chronic Musculoskeletal Pain: A Feasibility Study.

Entraining alpha activity with rhythmic visual, auditory, and electrical stimulation can reduce experimentally induced pain. However, evidence for alpha entrainment and pain reduction in patients with chronic pain is limited. This feasibility study investigated whether visual alpha stimulation can increase alpha power in patients with chronic musculoskeletal pain and, secondarily, if chronic pain was reduced following stimulation. In a within-subject design, 20 patients underwent 4-min periods of stimulation at 10 Hz (alpha), 7 Hz (high-theta, control), and 1 Hz (control) in a pseudo-randomized order. Patients underwent stimulation both sitting and standing and verbally rated their pain before and after each stimulation block on a 0-10 numerical rating scale. Global alpha power was significantly higher during 10 Hz compared to 1 Hz stimulation when patients were standing (t = -6.08, p < 0.001). On a more regional level, a significant increase of alpha power was found for 10 Hz stimulation in the right-middle and left-posterior region when patients were sitting. With respect to our secondary aim, no significant reduction of pain intensity and unpleasantness was found. However, only the alpha stimulation resulted in a minimal clinically important difference in at least 50% of participants for pain intensity (50%) and unpleasantness ratings (65%) in the sitting condition. This study provides initial evidence for the potential of visual stimulation as a means to enhance alpha activity in patients with chronic musculoskeletal pain. The brief period of stimulation was insufficient to reduce chronic pain significantly. This study is the first to provide evidence that a brief period of visual stimulation at alpha frequency can significantly increase alpha power in patients with chronic musculoskeletal pain. A further larger study is warranted to investigate optimal dose and individual stimulation parameters to achieve pain relief in these patients.

Effects of neurofeedback in the management of chronic pain: A systematic review and meta-analysis of clinical trials.

BACKGROUND AND OBJECTIVE: Neurofeedback (NFB) provides real-time feedback about neurophysiological signals to patients, thereby encouraging modulation of pain-associated brain activity. This review aims to evaluate the effectiveness and safety of NFB in alleviating pain and pain-associated symptoms in chronic pain patients. METHODS: MEDLINE, PUBMED, Web of Science and PsycINFO databases were searched using the strategy: ("Neurofeedback" OR "EEG Biofeedback" OR "fMRI Biofeedback") AND ("Pain" or "Chronic Pain"). Clinical trials reporting changes in pain following electroencephalogram (EEG) or functional magnetic resonance imaging (fMRI) NFB in chronic pain patients were included. Only Randomized-controlled trials (RCT), non-randomized controlled trials (NRCT) and case series were included. Effect size was pooled for all RCTs in a meta-analysis. RESULTS: Twenty-one studies were included. Reduction in pain following NFB was reported by one high-quality RCT, five of six low-quality RCT or NRCT and 13 of 14 case-series. Pain reduction reported by studies ranged from 6% to 82%, with 10 studies reporting a clinically significant reduction in pain of >30%. The overall effect size was medium (cohen's d -0.76, 95% confidence interval -1.31 to -0.20). Studies were highly heterogeneous (Q [df = 5] = 18.46, p = .002, I2  = 73%). Improvements in depression, anxiety, fatigue and sleep were also seen in some studies. Common side-effects included headache, nausea and drowsiness. These generally did not lead to withdrawal of therapy except in one study. CONCLUSIONS: Neurofeedback is a safe and effective therapy with promising but largely low-quality evidence supporting its use in chronic pain. Further high-quality trials comparing different protocols is warranted to determine the most efficacious way to deliver NFB. SIGNIFICANCE: Neurofeedback is a novel neuromodulatory approach which can be used to reduce the severity of pain and pain-associated symptoms such as sleep disturbances, mood disturbances, fatigue and anxiety in a number of chronic pain conditions. It has a potential to provide integrative non-pharmacological management for chronic pain patients with pain refractory to pharmacological agents with high side-effect profiles. Further high-quality double-blinded randomized sham-controlled trials are needed in order to fully explore the potential of this therapy.

Using EEG Alpha States to Understand Learning During Alpha Neurofeedback Training for Chronic Pain.

OBJECTIVE: Alpha-neurofeedback (α-NFB) is a novel therapy which trains individuals to volitionally increase their alpha power to improve pain. Learning during NFB is commonly measured using static parameters such as mean alpha power. Considering the biphasic nature of alpha rhythm (high and low alpha), dynamic parameters describing the time spent by individuals in high alpha state and the pattern of transitioning between states might be more useful. Here, we quantify the changes during α-NFB for chronic pain in terms of dynamic changes in alpha states. METHODS: Four chronic pain and four healthy participants received five NFB sessions designed to increase frontal alpha power. Changes in pain resilience were measured using visual analogue scale (VAS) during repeated cold-pressor tests (CPT). Changes in alpha state static and dynamic parameters such as fractional occupancy (time in high alpha state), dwell time (length of high alpha state) and transition probability (probability of moving from low to high alpha state) were analyzed using Friedman's Test and correlated with changes in pain scores using Pearson's correlation. RESULTS: There was no significant change in mean frontal alpha power during NFB. There was a trend of an increase in fractional occupancy, mean dwell duration and transition probability of high alpha state over the five sessions in chronic pain patients only. Significant correlations were observed between change in pain scores and fractional occupancy (r = -0.45, p = 0.03), mean dwell time (r = -0.48, p = 0.04) and transition probability from a low to high state (r = -0.47, p = 0.03) in chronic pain patients but not in healthy participants. CONCLUSION: There is a differential effect between patients and healthy participants in terms of correlation between change in pain scores and alpha state parameters. Parameters providing a more precise description of the alpha power dynamics than the mean may help understand the therapeutic effect of neurofeedback on chronic pain.