Focusing on Positive Listening Experiences Improves Speech Intelligibility in Experienced Hearing Aid Users.

Negativity bias is a cognitive bias that results in negative events being perceptually more salient than positive ones. For hearing care, this means that hearing aid benefits can potentially be overshadowed by adverse experiences. Research has shown that sustaining focus on positive experiences has the potential to mitigate negativity bias. The purpose of the current study was to investigate whether a positive focus (PF) intervention can improve speech-in-noise abilities for experienced hearing aid users. Thirty participants were randomly allocated to a control or PF group (N = 2 × 15). Prior to hearing aid fitting, all participants filled out the short form of the Speech, Spatial and Qualities of Hearing scale (SSQ12) based on their own hearing aids. At the first visit, they were fitted with study hearing aids, and speech-in-noise testing was performed. Both groups then wore the study hearing aids for two weeks and sent daily text messages reporting hours of hearing aid use to an experimenter. In addition, the PF group was instructed to focus on positive listening experiences and to also report them in the daily text messages. After the 2-week trial, all participants filled out the SSQ12 questionnaire based on the study hearing aids and completed the speech-in-noise testing again. Speech-in-noise performance and SSQ12 Qualities score were improved for the PF group but not for the control group. This finding indicates that the PF intervention can improve subjective and objective hearing aid benefits.

Measuring hearing aid satisfaction in everyday listening situations: Retrospective and in-situ assessments complement each other.

BACKGROUND: Recently, we developed a hearing-related lifestyle questionnaire (HEARLI-Q) which asks respondents to rate their hearing aid (HA) satisfaction in 23 everyday listening situations. It is unknown how HA satisfaction on the retrospective HEARLI-Q scale compares to HA satisfaction measured on the same scale implemented in Ecological Momentary Assessments (EMA). PURPOSE: To learn how retrospective (HEARLI-Q) and in-situ (EMA) assessments can complement each other. RESEARCH DESIGN: An observational study. STUDY SAMPLE: Twenty-one experienced HA users. DATA COLLECTION AND ANALYSIS: The participants first filled out the HEARLI-Q questionnaire, followed by a one-week EMA trial using their own hearing aids. HA satisfaction ratings were compared between the two questionnaires and the underlying drivers of discrepancies in HA satisfaction ratings were evaluated. RESULTS: HA satisfaction scores were significantly higher in EMA for speech communication with one or several people. Hearing difficulty in these situations was rated higher in HEARLI-Q than in EMA, but occurrence of those difficult listening situations was also rated to be lower. When comparing only the situations that occur on daily or weekly basis, the two questionnaires had similar HA satisfaction ratings. CONCLUSIONS: Lower occurrence of difficult listening situations seems to be the key driver of discrepancies in HA satisfaction ratings between EMA and HEARLI-Q. The advantage of EMA is that it provides insight into an individual's day-to-day life and is not prone to memory bias. HEARLI-Q, on the other hand, can capture situations which occur infrequently or are inconvenient to report in the moment. Administering HEARLI-Q and EMA in combination could give a more holistic view of HA satisfaction.

Reasons for ceiling ratings in real-life evaluations of hearing aids: the relationship between SNR and hearing aid ratings.

Introduction: In past Ecological Momentary Assessment (EMA) studies, hearing aid outcome ratings have often been close to ceiling. Methods: To analyze the underlying reasons for the very positive ratings, we conducted a study with 17 experienced hearing aid wearers who were fitted with study hearing aids. The acceptable noise level and the noise level where participants were unable to follow speech were measured. The participants then rated hearing aid satisfaction, speech understanding and listening effort for pre-defined SNRs between -10 and +20 dB SPL in the laboratory. These ratings were compared to ratings of a two-week EMA trial. Additionally, estimates of SNRs were collected from hearing aids during the EMA trial and we assessed whether the participants experienced those SNRs rated poorly in the laboratory in real life. Results: The results showed that for hearing aid satisfaction and speech understanding, the full rating scale was used in the laboratory, while the ratings in real life were strongly skewed towards the positive end of the scale. In the laboratory, SNRs where participants indicated they could not follow the narrator ("unable to follow" noise level) were rated clearly better than the lowest possible ratings. This indicates that very negative ratings may not be applicable in real-life testing. The lower part of the distribution of real-life SNR estimates was related to participants' individual "unable to follow" noise levels and the SNRs which were rated poorly in the laboratory made up less than 10% of the speech situations experienced in real life. Discussion: This indicates that people do not seem to frequently experience listening situations at SNRs where they are dissatisfied with their hearing aids and this could be the reason for the overly positive hearing aid outcome ratings in EMA studies. It remains unclear to what extent the scarcity of such situations is due lack of encounters or intentional avoidance.

Focusing on positive listening experiences improves hearing aid outcomes in experienced hearing aid users.

OBJECTIVE: The purpose of this study was to investigate whether focusing on positive listening experiences improves hearing aid outcomes in experienced hearing aid users. DESIGN: The participants were randomised into a control or positive focus (PF) group. At the first laboratory visit, the Client-Oriented Scale of Improvement (COSI) questionnaire was administered followed by hearing aid fitting. The participants wore the hearing aids for three weeks. The PF group was asked to report their positive listening experiences via an app. During the third week, all the participants answered questionnaires related to hearing aid benefit and satisfaction. This was followed by the second laboratory visit where the COSI follow-up questionnaire was administered. STUDY SAMPLE: Ten participants were included in the control and eleven in the PF group. RESULTS: Hearing aid outcome ratings were significantly better in the PF group in comparison to the control group. Further, COSI degree of change and the number of positive reports were positively correlated. CONCLUSIONS: These results point to the importance of asking hearing aid users to focus on positive listening experiences and talk about them. The potential outcome is increased hearing aid benefit and satisfaction which could lead to more consistent use of the devices.

Hearing aid delay in open-fit devices: Preferred sound quality in listeners with normal and impaired hearing.

A key factor influencing sound quality in open-fit digital hearing aids is the processing delay. So far, the delay limit needed for ensuring optimal (rather than tolerable) sound quality has not been established. Using a realistic hearing aid simulator, the current study investigated the relationship between preferred sound quality and five processing delays ranging from 0.5 to 10 ms in listeners with normal and impaired hearing. The listeners with normal hearing showed a strong preference for the shortest delay. For the listeners with impaired hearing, participants with mild hearing losses below 2 kHz also preferred the shortest delay.

Assessment of Hearing-Related Lifestyle Based on the Common Sound Scenarios Framework.

PURPOSE: Auditory lifestyle can play a role in hearing care needs, and, as such, it needs to be considered when treating people with hearing loss. In this study, we propose a questionnaire consisting of 24 listening situations based on the Common Sound Scenarios (CoSS) framework. METHOD: Seventeen experienced hearing aid (HA) users filled out the Hearing-Related Lifestyle Questionnaire four times: Days 1, 2, 15, and 29. The questionnaire consisted of 24 listening situations that participants rated on frequency of occurrence, importance to hear well, difficulty to hear, and HA satisfaction. Four questionnaire outcomes were extracted from these ratings: richness of hearing-related lifestyle, hearing demand, hearing difficulty, and HA satisfaction. Additionally, the participants were asked whether any listening situations are not understandable or relatable, whether any situations are missing from the questionnaire, and whether the number of questions is acceptable. Test-retest reliability analyses were done to assess whether the questionnaire outcomes are reliable across the four reports. Correlation analyses were done to assess whether there is a relationship between the questionnaire outcomes. RESULTS: The questionnaire outcomes have excellent reliability. The listening situations in the questionnaire are generally complete and relatable, and the number of questions is acceptable. Correlation analyses revealed that the questionnaire outcomes are related to each other. CONCLUSIONS: Currently, there are no other hearing-related lifestyle questionnaires that purely assess listening situations. The proposed questionnaire has the potential to add to our understanding of hearing-related lifestyle of people needing or undergoing hearing care. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21514044.

The Acoustics of Instant Ear Tips and Their Implications for Hearing-Aid Fitting.

OBJECTIVES: Today, approximately 70 to 80% of hearing aid fittings are made with silicone instant ear tips rather than custom earmolds. Nevertheless, little is known about the impact of instant ear tips on the acoustic coupling between the hearing aid receiver and the individual ear canal, even though it can have a major impact on the overall sound of the hearing aids. This study aimed to investigate the acoustic properties of different instant ear tip types and their across-subject variability, the within-subject reliability of those properties, and the influence of the users' level of experience with ear-tip insertion on the acoustics. Furthermore, subjective ratings of occlusion produced by the ear tips were considered. DESIGN: Five types of instant ear tips (Open, Tulip, Round [2-vent], Round [1-vent], Double Domes) provided by the hearing aid manufacturer Widex were considered in this study. Probe-microphone measurements were performed at the eardrums of 30 participants (60 ears). In the first experiment, the real ear occluded insertion gain and the vent effect (VE) were measured, and the listeners rated the subjective occlusion experienced with each ear tip. In the second experiment, the same measurements were repeated six times per participant. The within-subject variability of the acoustic ear tip properties was investigated as well as the impact of the degree of users' experience with ear tip insertion on the resulting real ear measurements. RESULTS: All tested ear tips were, on average, acoustically transparent up to 1 kHz except Double Domes, which were only transparent up to 600 Hz. Distinct VE profiles were found for each ear tip type, but a large across-subject variability was observed for both real ear occluded insertion gain and VE. However, the within-subject reliability was high. The measured VE was highly correlated with the perceived occlusion. Finally, no significant effect of the level of experience in ear tip insertion on the acoustic properties of the ear tips was found, but the within-subject variability was larger in the less experienced group. CONCLUSIONS: These results suggest that the acoustic properties of instant ear tips and their coupling to the individual ear canal impact the resulting hearing aid fitting and should be considered by the hearing care professionals and reflected in the fitting software. The high within-subject reliability indicates that the ear tip acoustics remain stable for the individual in daily use. Finally, real ear measurements should be considered an essential part of the hearing aid fitting process in clinical practice to ensure an optimal fit for the individual hearing aid user.

Critical hearing experiences manifest differently across individuals: insights from hearing aid data captured in real-life moments.

OBJECTIVE: We investigated whether contrasts between situations of good and difficult listening experiences could be identified in objective hearing aid (HA) data, with the aim to use these insights for personalisation of hearing care. DESIGN: The participants were asked to fill out an ecological momentary assessment (EMA) report every time they encountered a good or difficult listening experience for a period of two weeks. During EMA reporting, the participants described their listening environment and why it was difficult while objective HA data describing the sound environment, activated HA features and gain were logged. STUDY SAMPLE: Sixteen experienced HA users completed the study. RESULTS: The group level objective HA data indicated that participants experienced difficulties in typical speech in noise environments. Data from 14/16 participants showed individual contrasts that were not seen on the group level, indicating that hearing challenges do not manifest themselves the same across persons. CONCLUSIONS: The objective data from real-life experiences add to our understanding of the difficulty of the situation. The fact that data between individuals varied so much emphasises the importance of considering each person as an individual when treating their hearing loss.

Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study.

Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test - hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. PERSPECTIVE: This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.

Chiropractic Spinal Adjustment Increases the Cortical Drive to the Lower Limb Muscle in Chronic Stroke Patients.

This study aimed to investigate the effects of a single session of chiropractic spinal adjustment on the cortical drive to the lower limb in chronic stroke patients. In a single-blinded, randomized controlled parallel design study, 29 individuals with chronic stroke and motor weakness in a lower limb were randomly divided to receive either chiropractic spinal adjustment or a passive movement control intervention. Before and immediately after the intervention, transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) muscle of the lower limb with the greatest degree of motor weakness. Differences in the averaged peak-peak MEP amplitude following interventions were calculated using a linear regression model. Chiropractic spinal adjustment elicited significantly larger MEP amplitude (pre = 0.24 ± 0.17 mV, post = 0.39 ± 0.23 mV, absolute difference = +0.15 mV, relative difference = +92%, p < 0.001) compared to the control intervention (pre = 0.15 ± 0.09 mV, post = 0.16 ± 0.09 mV). The results indicate that chiropractic spinal adjustment increases the corticomotor excitability of ankle dorsiflexor muscles in people with chronic stroke. Further research is required to investigate whether chiropractic spinal adjustment increases dorsiflexor muscle strength and walking function in people with stroke.

Investigating the Effects of Chiropractic Spinal Manipulation on EEG in Stroke Patients.

: Objective: The purpose of this study was to evaluate the impact of chiropractic spinal manipulation on the early somatosensory evoked potentials (SEPs) and resting-state electroencephalography (EEG) recorded from chronic stroke patients. Methods: Seventeen male patients (53 ± 12 years old) participated in this randomized cross-over study. The patients received chiropractic spinal manipulation and control intervention, in random order, separated by at least 24 hours. EEG was recorded before and after each intervention during rest and stimulation of the non-paretic median nerve. For resting-state EEG, the delta-alpha ratio, brain-symmetry index, and power-spectra were calculated. For SEPs, the amplitudes and latencies of N20 and N30 peaks were assessed. Source localization was performed on the power-spectra of resting-state EEG and the N30 SEP peak. Results: Following spinal manipulation, the N30 amplitude increased by 39%, which was a significant increase compared to the control intervention (p < 0.01). The latency and changes to the strength of the cortical sources underlying the N30 peak were not significant. The N20 peak, the resting-state power-spectra, delta-alpha ratio, brain-symmetry index, and resting-state source localization showed no significant changes after either intervention. Conclusion: A single session of chiropractic spinal manipulation increased the amplitude of the N30 SEP peak in a group of chronic stroke patients, which may reflect changes to early sensorimotor function. More research is required to investigate the long-term effects of chiropractic spinal manipulation, to better understand what impact it may have on the neurological function of stroke survivors.

The Effects of Filter's Class, Cutoff Frequencies, and Independent Component Analysis on the Amplitude of Somatosensory Evoked Potentials Recorded from Healthy Volunteers.

OBJECTIVE: The aim of this study was to investigate the effects of different preprocessing parameters on the amplitude of median nerve somatosensory evoked potentials (SEPs). METHODS: Different combinations of two classes of filters (Finite Impulse Response (FIR) and Infinite Impulse Response (IIR)), three cutoff frequency bands (0.5-1000 Hz, 3-1000 Hz, and 30-1000 Hz), and independent component analysis (ICA) were used to preprocess SEPs recorded from 17 healthy volunteers who participated in two sessions of 1000 stimulations of the right median nerve. N30 amplitude was calculated from frontally placed electrode (F3). RESULTS: The epochs classified as artifacts from SEPs filtered with FIR compared to those filtered with IIR were 1% more using automatic and 140% more using semi-automatic methods (both p < 0.001). There were no differences in N30 amplitudes between FIR and IIR filtered SEPs. The N30 amplitude was significantly lower for SEPs filtered with 30-1000 Hz compared to the bandpass frequencies 0.5-1000 Hz and 3-1000 Hz. The N30 amplitude was significantly reduced when SEPs were cleaned with ICA compared to the SEPs from which non-brain components were not removed using ICA. CONCLUSION: This study suggests that the preprocessing of SEPs should be done carefully and the neuroscience community should come to a consensus regarding SEP preprocessing guidelines, as the preprocessing parameters can affect the outcomes that may influence the interpretations of results, replicability, and comparison of different studies.

The effects of chiropractic spinal manipulation on central processing of tonic pain - a pilot study using standardized low-resolution brain electromagnetic tomography (sLORETA).

The objectives of the study were to investigate changes in pain perception and neural activity during tonic pain due to altered sensory input from the spine following chiropractic spinal adjustments. Fifteen participants with subclinical pain (recurrent spinal dysfunction such as mild pain, ache or stiffness but with no pain on the day of the experiment) participated in this randomized cross-over study involving a chiropractic spinal adjustment and a sham session, separated by 4.0 ± 4.2 days. Before and after each intervention, 61-channel electroencephalography (EEG) was recorded at rest and during 80 seconds of tonic pain evoked by the cold-pressor test (left hand immersed in 2 °C water). Participants rated the pain and unpleasantness to the cold-pressor test on two separate numerical rating scales. To study brain sources, sLORETA was performed on four EEG frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (12-32 Hz). The pain scores decreased by 9% after the sham intervention (p < 0.05), whereas the unpleasantness scores decreased by 7% after both interventions (p < 0.05). sLORETA showed decreased brain activity following tonic pain in all frequency bands after the sham intervention, whereas no change in activity was seen after the chiropractic spinal adjustment session. This study showed habituation to pain following the sham intervention, with no habituation occurring following the chiropractic intervention. This suggests that the chiropractic spinal adjustments may alter central processing of pain and unpleasantness.

Offset Analgesia and The Impact of Treatment with Oxycodone and Venlafaxine: A Placebo-Controlled, Randomized Trial in Healthy Volunteers.

Offset analgesia (OA) is a pain-modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a discrete decrease in stimulus temperature. The role of the opioidergic, serotonergic and noradrenergic systems on OA remains unclear. The aim of this study was to evaluate whether OA is modulated by an opioid (oxycodone) and a serotonin and noradrenaline reuptake inhibitor (venlafaxine) in terms of psychophysical assessments. In this randomized, double-blinded, placebo-controlled cross-over study, 20 healthy male participants (mean age: 24.6 ± 2.5 years) received 10 mg oxycodone, 37.5 mg venlafaxine or placebo twice daily for 5 days in three periods. OA was induced by noxious thermal stimulation on the forearm at baseline and last day of treatment. A control session of constant stimulus intensity was included for comparison. OA magnitude was unaffected by oxycodone and venlafaxine (p = 0.20 and p = 0.90, respectively). Oxycodone affected the control paradigm where a decreased rating of pain intensity was observed compared to placebo (p = 0.001). OA could not be modulated by oxycodone or venlafaxine and may be a robust phenomenon in healthy volunteers and not suitable for exploring pharmacological mechanisms of analgesia in human beings.

Neuroimaging of the human visceral pain system-A methodological review.

During the last decades there has been a tremendous development of non-invasive methods for assessment of brain activity following visceral pain. Improved methods for neurophysiological and brain imaging techniques have vastly increased our understanding of the central processing of gastrointestinal sensation and pain in both healthy volunteers as well as in patients suffering from gastrointestinal disorders. The techniques used are functional magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalography (EEG)/evoked brain potentials (EPs), magnetoencephalography (MEG), single photon emission computed tomography (SPECT), and the multimodal combinations of these techniques. The use of these techniques has brought new insight into the complex brain processes underlying pain perception, including a number of subcortical and cortical regions, and paved new ways in our understanding of acute and chronic pain. The pathways are dynamic with a delicate balance between facilitatory and inhibitory pain mechanisms, and with modulation of the response to internal or external stressors with a high degree of plasticity. Hence, the ultimate goal in imaging of pain is to follow the stimulus response throughout the neuraxis. Brain activity measured by fMRI is based on subtracting regional changes in blood oxygenation during a resting condition from the signal during a stimulus condition, and has high spatial resolution but low temporal resolution. SPECT and PET are nuclear imaging techniques where radiolabeled molecules are injected with visualization of the distribution, density and activity of receptors in the brain allowing not only assessment of brain activity but also study of receptor sites. EEG is based on assessment of electrical activity in the brain, and recordings of the resting EEG and evoked potentials following an external stimulus are used to study normal visceral pain processing, alterations of pain processing in different patient groups and the effect of pharmacological intervention. EEG has high temporal resolution, but relative poor spatial resolution, which however to some extent can be overcome by applying inverse modelling algorithms and signal decomposition procedures. MEG is based on recording the magnetic fields produced by electrical currents in the brain, has high spatial resolution and is especially suitable for the study cortical activation. The treatment of chronic abdominal pain is often ineffective and dissapointing, which leads to search for optimized treatment achieved on the basis of a better understanding of underlying pain mechanisms. Application of the recent improvements in neuroimaging on the visceral pain system may likely in near future contribute substantially to our understanding of the functional and structural pathophysiology underlying chronic visceral pain disorders, and pave the road for optimized individual and mechanism based treatments. The purpose of this review is to give a state-of-the-art overview of these methods, with focus on EEG, and especially the advantages and limitations of the single methods in clinical gastrointestinal pain esearch including examples from relevant studies.

Differential effects of oxycodone and venlafaxine on resting state functional connectivity-A randomized placebo-controlled magnetic resonance imaging study.

AIM: Different mechanisms may be involved in the antinociceptive effects of oxycodone (opioid) and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and the aim of this study was to investigate the effect of these drugs on brain functional connectivity. METHODS: Resting state functional magnetic resonance imaging was acquired in 20 healthy volunteers before and after a 5-day treatment with oxycodone, venlafaxine, or placebo in a randomized, double-blind, crossover study. Functional connectivity analyses were performed between four predefined seeds (dorsal anterior cingulate cortex, rostral anterior cingulate cortex, posterior insula, and prefrontal cortex), and the whole brain. RESULTS: The overall interpretation was that there were differences between the effects of oxycodone and venlafaxine on functional connectivity. Oxycodone mainly showed decreased functional connectivity between limbic structures and to supralimbic areas (all P < 0.05). Venlafaxine also showed decreased functional connectivity between limbic structures and to supralimbic areas, but increased functional connectivity to structures in the midbrain and brain stem was also found (all P < 0.05). CONCLUSIONS: Oxycodone and venlafaxine showed differential effects on resting-state functional connectivity as compared to placebo. This supports that the two drugs exert different mechanisms, and that the drugs in combination may exert additive effects and could potentially improve pain therapy.

Objective methods for the assessment of the spinal and supraspinal effects of opioids.

BACKGROUND AND PURPOSE: Opioids are potent analgesics. Opioids exert effects after interaction with opioid receptors. Opioid receptors are present in the peripheral- and central nervous system (CNS), but the analgesic effects are primarily mediated via receptors in the CNS. Objective methods for assessment of opioid effects may increase knowledge on the CNS processes responsible for analgesia. The aim of this review was to provide an overview of the most common objective methods for assessment of the spinal and supraspinal effects of opioids and discuss their advantages and limitations. METHOD: The literature search was conducted in Pub Med (http://www.ncbi.nlm.nih.gov/pubmed) from November 2014 to June 2016, using free-text terms: "opioid", "morphine" and "oxycodone" combined with the terms "pupillometry," "magnetic resonance spectroscopy," "fMRI," "BOLD," "PET," "pharmaco-EEG", "electroencephalogram", "EEG," "evoked potentials," and "nociceptive reflex". Only original articles published in English were included. RESULTS: For assessment of opioid effects at the supraspinal level, the following methods are evaluated: pupillometry, proton magnetic resonance spectroscopy, functional resonance magnetic imaging (fMRI), positron emission tomography (PET), spontaneous electroencephalogram (EEG) and evoked potentials (EPs). Pupillometry is a non-invasive tool used in research as well as in the clinical setting. Proton magnetic resonance spectroscopy has been used for the last decades and it is a non-invasive technique for measurement of in vivo brain metabolite concentrations. fMRI has been a widely used non-invasive method to estimate brain activity, where typically from the blood oxygen level-dependent (BOLD) signal. PET is a nuclear imaging technique based on tracing radio labeled molecules injected into the blood, where receptor distribution, density and activity in the brain can be visualized. Spontaneous EEG is typically quantified in frequency bands, power spectrum and spectral edge frequency. EPs are brain responses (assessed by EEG) to a predefined number of short phasic stimuli. EPs are quantified by their peak latencies and amplitudes, power spectrum, scalp topographies and brain source localization. For assessment of opioid effects at the spinal level, the following methods are evaluated: the nociceptive withdrawal reflex (NWR) and spinal EPs. The nociceptive withdrawal reflex can be recorded from all limbs, but it is standard to record the electromyography signal at the biceps femoris muscle after stimulation of the ipsilateral sural nerve; EPs can be recorded from the spinal cord and are typically recorded after stimulation of the median nerve at the wrist. CONCLUSION AND IMPLICATIONS: The presented methods can all be used as objective methods for assessing the centrally mediated effects of opioids. Advantages and limitations should be considered before implementation in drug development, future experimental studies as well as in clinical settings. In conclusion, pupillometry is a sensitive measurement of opioid receptor activation in the CNS and from a practical and economical perspective it may be used as a biomarker for opioid effects in the CNS. However, if more detailed information is needed on opioid effects at different levels of the CNS, then EEG, fMRI, PET and NWR have the potential to be used. Finally, it is conceivable that information from different methods should be considered together for complementary information.

The effects of analgesics on central processing of tonic pain: A cross-over placebo controlled study.

INTRODUCTION: Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat moderate to severe pain, but the central mechanisms underlying their analgesia remain unclear. This study investigated how brain activity at rest and exposed to tonic pain is modified by oxycodone (opioid) and venlafaxine (SNRI). METHODS: Twenty healthy males were included in this randomized, cross-over, double-blinded study. 61-channel electroencephalogram (EEG) was recorded before and after five days of treatment with placebo, oxycodone (10 mg extended release b.i.d) or venlafaxine (37.5 mg extended release b.i.d) at rest and during tonic pain (hand immersed in 2 °C water for 80 s). Subjective pain and unpleasantness scores of tonic pain were recorded. Spectral analysis and sLORETA source localization were done in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz) frequency bands. RESULTS: Oxycodone decreased pain and unpleasantness scores (P < 0.05), whereas venlafaxine decreased the pain scores (P < 0.05). None of the treatments changed the spectral indices or brain sources underlying resting EEG. Venlafaxine decreased spectral indices in alpha band of the EEG to tonic pain, whereas oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands (all P < 0.05). The brain source activity predominantly decreased in the insula and inferior frontal gyrus. CONCLUSION: The decrease of activity within insula and inferior frontal gyrus is likely involved in pain inhibition due to oxycodone treatment, whereas the decrease in alpha activity is likely involved in pain inhibition due to venlafaxine treatment.

Venlafaxine and oxycodone have different effects on spinal and supraspinal activity in man: a somatosensory evoked potential study.

AIMS: Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat severe and moderate pain, but their mechanisms of action in humans remain unclear. The present study aimed to explore how oxycodone (an opioid) and venlafaxine (an SNRI) modulate spinal and supraspinal sensory processing. METHODS: Twenty volunteers were included in a randomized, double-blinded, three-way (placebo, oxycodone, venlafaxine), crossover study. Spinal and full scalp cortical evoked potentials (EPs) to median nerve stimulation were recorded before and after 5 days of treatment. Assessment of the central effects of the three treatments involved: (i) amplitudes and latencies of spinal EPs (spinal level); (ii) amplitudes and latencies of the P14 potential (subcortical level); (iii) amplitudes and latencies of early and late cortical EPs (cortical level); (iv) brain sources underlying early cortical Eps; and (v) brain networks underlying the late cortical EPs. RESULTS: In the venlafaxine arm, the spinal P11 and the late cortical N60-80 latencies were reduced by 1.8% [95% confidence interval (CI) 1.7%, 1.9%) and 5.7% (95% CI 5.3%, 6.1%), whereas the early cortical P25 amplitude was decreased by 7.1% (95%CI 6.1%, 8.7%). Oxycodone increased the subcortical P14 [+25% (95% CI 22.2%, 28.6%)], early cortical N30 [+12.9% (95% CI 12.5%, 13.2%)] amplitudes and the late cortical N60-80 latency [+2.9% (95% CI 1.9%, 4.0%)]. The brainstem and primary somatosensory cortex source strengths were increased by 66.7% (95% CI 62.5%, 75.0%) and 28.8% (95% CI 27.5%, 29.6%) in the oxycodone arm, whereas the primary somatosensory cortex strength was decreased in the venlafaxine arm by 18.3% (95% CI 12.0%, 28.1%). CONCLUSIONS: Opioids and SNRI drugs exert different central effects. The present study contributed to the much-needed human models of the mechanisms of action of drugs with effects on the central nervous system.

Manipulation of Dysfunctional Spinal Joints Affects Sensorimotor Integration in the Prefrontal Cortex: A Brain Source Localization Study.

Objectives. Studies have shown decreases in N30 somatosensory evoked potential (SEP) peak amplitudes following spinal manipulation (SM) of dysfunctional segments in subclinical pain (SCP) populations. This study sought to verify these findings and to investigate underlying brain sources that may be responsible for such changes. Methods. Nineteen SCP volunteers attended two experimental sessions, SM and control in random order. SEPs from 62-channel EEG cap were recorded following median nerve stimulation (1000 stimuli at 2.3 Hz) before and after either intervention. Peak-to-peak amplitude and latency analysis was completed for different SEPs peak. Dipolar models of underlying brain sources were built by using the brain electrical source analysis. Two-way repeated measures ANOVA was used to assessed differences in N30 amplitudes, dipole locations, and dipole strengths. Results. SM decreased the N30 amplitude by 16.9 ± 31.3% (P = 0.02), while no differences were seen following the control intervention (P = 0.4). Brain source modeling revealed a 4-source model but only the prefrontal source showed reduced activity by 20.2 ± 12.2% (P = 0.03) following SM. Conclusion. A single session of spinal manipulation of dysfunctional segments in subclinical pain patients alters somatosensory processing at the cortical level, particularly within the prefrontal cortex.