Validity of central pain processing biomarkers for predicting the occurrence of oncological chronic pain: a study protocol.

BACKGROUND: Despite recent improvements in cancer detection and survival rates, managing cancer-related pain remains a significant challenge. Compared to neuropathic and inflammatory pain conditions, cancer pain mechanisms are poorly understood, despite pain being one of the most feared symptoms by cancer patients and significantly impairing their quality of life, daily activities, and social interactions. The objective of this work was to select a panel of biomarkers of central pain processing and modulation and assess their ability to predict chronic pain in patients with cancer using predictive artificial intelligence (AI) algorithms. METHODS: We will perform a prospective longitudinal cohort, multicentric study involving 450 patients with a recent cancer diagnosis. These patients will undergo an in-person assessment at three different time points: pretreatment, 6 months, and 12 months after the first visit. All patients will be assessed through demographic and clinical questionnaires and self-report measures, quantitative sensory testing (QST), and electroencephalography (EEG) evaluations. We will select the variables that best predict the future occurrence of pain using a comprehensive approach that includes clinical, psychosocial, and neurophysiological variables. DISCUSSION: This study aimed to provide evidence regarding the links between poor pain modulation mechanisms at precancer treatment in patients who will later develop chronic pain and to clarify the role of treatment modality (modulated by age, sex and type of cancer) on pain. As a final output, we expect to develop a predictive tool based on AI that can contribute to the anticipation of the future occurrence of pain and help in therapeutic decision making.

Conditioned pain modulation (CPM) paradigm type affects its sensitivity as a biomarker of fibromyalgia.

Fibromyalgia (FM) is a widespread chronic pain syndrome, possibly associated with the presence of central dysfunction in descending pain inhibition pathways. Conditioned Pain Modulation (CPM) has been proposed as a biomarker of FM. Nonetheless, the wide variety of methods used to measure CPM has hampered robust conclusions being reached. To clarify the validity of CPM as a biomarker of FM, we tested two CPM paradigms (parallel and sequential) in a sample of 23 female patients and 23 healthy women by applying test (mechanical) stimuli and conditioning (pressure cuff) stimuli. We evaluated whether CPM indices could correctly classify patients and controls, and we also determined the correlations between the indices and clinical variables such as symptomatology, disease impact, depression, quality of life, pain intensity, pain interference, fatigue and numbness. In addition, we compared the clinical status of CPM responders (efficient pain inhibitory mechanism) and non-responders. We observed that only parallel CPM testing correctly classified about 70% of patients with FM. In addition, more than 80% of healthy participants were found to be responders, while the rate was about 50% in the FM patients. The sequential CPM test was not as sensitive, with a decrease of up to 40% in the response rate for both groups. On the other hand, we did not observe any correlation between CPM measures and clinical symptoms. In summary, our findings demonstrate the influence of the CPM paradigm used and confirm that CPM may be a useful marker to complement FM diagnosis. However, the findings also cast doubts on the sensitivity of CPM as a marker of pain severity in FM.

Active and sham transcranial direct current stimulation (tDCS) improved quality of life in female patients with fibromyalgia.

PURPOSE: Fibromyalgia (FM) is a chronic pain syndrome with a strong impact on quality of life (QoL). Treatment of this condition remains a challenge, due to the scarce evidence for the effectiveness of the therapeutic approaches available. Current attention is focused on transcranial direct current stimulation (tDCS), which has yielded promising results for pain treatment. Rather than focusing only on pain relief, in this study, we aimed to determine how active or sham tDCS (over three cortical targets -the primary motor cortex, the dorsolateral prefrontal cortex and the operculo-insular cortex-) affect QoL in patients with FM. METHODS: Using a double-blind, placebo-controlled design, we applied fifteen tDCS sessions of 20' to initial 130 participants (randomized to any of the four treatment groups). We evaluated the QoL (assessed by SF-36) and the symptoms' impact (assessed by FIQ-R) in baseline, after treatment and at 6 months follow-up. RESULTS: All groups were comparable as regards age, medication pattern and severity of symptoms before the treatment. We found that QoL and symptoms' impact improved in all treatment groups (including the sham) and this improvement lasted for up to 6 months. However, we did not observe any group effect nor group*treatment interaction. CONCLUSIONS: After the intervention, we observed a non-specific effect that may be due to placebo, favoured by the expectations of tDCS efficacy and psychosocial variables inherent to the intervention (daily relationship with therapists and other patients in the clinic). Therefore, active tDCS is not superior to sham stimulation in improving QoL in FM.

Effects of intensity, attention and medication on auditory-evoked potentials in patients with fibromyalgia.

Fibromyalgia (FM) has been associated to an increased processing of somatosensory stimuli, but its generalization to other sensory modalities is under discussion. To clarify this, we studied auditory event-related potentials (AEPs) to stimuli of different intensity in patients with FM and healthy controls (HCs), considering the effects of attention mechanisms and medication. We performed two experiments: In study 1 (n = 50 FM, 60 HCs), the stimuli were presented randomly within the sequence; in study 2 (n = 28 FM, 30 HCs), they were presented in blocks of the same intensity. We analyzed intensity and group effects on N1-P2 amplitude and, only for the FM group, the effect of medication and the correlation between AEPs and clinical variables. Contrary to the expectation, the patients showed a trend of reduced AEPs to the loudest tones (study 1) or no significant differences with the HCs (study 2). Medication with central effects significantly reduced AEPs, while no significant relationships between the N1-P2 amplitude/intensity function and patients' symptoms were observed. The findings do not provide evidence of augmented auditory processing in FM. Nevertheless, given the observed effect of medication, the role of sensory amplification as an underlying pathophysiological mechanism in fibromyalgia cannot be discarded.

Neural correlates of cognitive dysfunction in fibromyalgia patients: Reduced brain electrical activity during the execution of a cognitive control task.

OBJECTIVES: Fibromyalgia (FM) is a generalized chronic pain syndrome of unknown aetiology. Although FM patients frequently complain of cognitive dysfunction, this is one of the least studied symptoms. Research on brain activity associated with the perceived cognitive impairment is particularly scarce. To address this gap, we recorded the brain electrical activity in participants during a cognitive control task. METHODS: Electroencephalograms (EEGs) were recorded in 19 FM patients and 22 healthy controls (all women) while they performed the Multi-Source Interference Task (MSIT). We analyzed the amplitude of the frontal N2 and parietal P3 components elicited in control and interference trials and their relation with reaction times. We also explored the relationship of perceived cognitive dysfunction, assessed using visual analogue scales (VAS) and the Memory Failures of Everyday (MFE-30) test, with N2 and P3 amplitudes. RESULTS: The N2 amplitudes were smaller in FM patients than in controls and were negatively associated with cognitive complaints. Unlike patients, healthy controls showed significant differences in the amplitude of P3 obtained from control vs. interference trials of the MSIT. Smaller N2 and P3 amplitudes were associated to longer reaction times. CONCLUSIONS: The findings suggest a reduction in frontal brain activity during performance of an interference task, which was associated with the patients' cognitive complaints. Findings on P3 suggest altered modulation of attention according to the task demands in FM patients. Deficits in flexibility in the allocation of attentional resources and cognitive control during complex tasks may explain the dyscognition reported by chronic pain patients.

Effect of the stop-signal modality on brain electrical activity associated with suppression of ongoing actions.

To clarify how the modality of stop signals affects the ability to suppress ongoing actions, we compared behavioural indices and event-related potentials (ERPs) recorded in healthy volunteers performing visual and auditory stop-signal tasks. Auditory stop signals were associated with faster reaction times and shorter stop-N2 and stop-P3 latencies. Given that the tasks did not differ in attentional/arousal processes (go-P3 or stop-P3 amplitudes) or motor preparation (LRP amplitude, onset or latency), our results suggest that stop signal modality mainly affects bottom-up sensory processes (faster auditory processing). The ERP waveform obtained by subtracting successfully stopped from unsuccessfully stopped trials showed similar amplitude and topography in both tasks, indicating that the strength of top-down processes related to inhibition was independent of modality. The findings contribute further knowledge about the variables associated with efficient inhibition and have practical implications for the design of settings or interventions to improve reactive inhibition.

Pain Expressions and Inhibitory Control in Patients With Fibromyalgia: Behavioral and Neural Correlates.

Fibromyalgia (FM) is a generalized chronic pain condition associated with a variety of symptoms, including altered cognitive and emotional processing. It has been proposed that FM patients show a preferential allocation of attention to information related to the symptoms of the disease, particularly to pain cues. However, the existing literature does not provide conclusive evidence on the presence of this attentional bias, and its effect on cognitive functions such as inhibitory control. To clarify this issue, we recorded the electroencephalographic activity of 31 women diagnosed with FM and 28 healthy women, while performing an emotional Go/NoGo task with micro-videos of pain, happy, and neutral facial expressions. We analyzed behavioral data, performed EEG time-frequency analyses, and obtained the event-related potentials (ERPs) N2 and P3 components in NoGo trials. A series of self-reports was also administered to evaluate catastrophic thinking and the main symptoms of fibromyalgia. Pain expressions were associated with longer reaction times and more errors, as well as with higher theta and delta power, and P3 amplitude to NoGo stimuli. Thus, behavioral and psychophysiological data suggest that increased attention to pain expressions impairs the performance of an inhibitory task, although this effect was similar in FM patients and healthy controls. N2 amplitude was modulated by type of facial expression (larger to pain faces), but only for the control group. This finding suggests that the presentation of pain faces might represent a smaller conflict for the patients, more used to encounter pain stimuli. No main group effects were found significant for N2 or P3 amplitudes, nor for time-frequency data. Using stimuli with greater ecological validity than in previous studies, we could not confirm a greater effect of attentional bias toward negative stimuli over inhibitory performance in patients with FM. Studying these effects allow us to better understand the mechanisms that maintain pain and develop intervention strategies to modify them.

Increased neural noise and impaired brain synchronization in fibromyalgia patients during cognitive interference.

Fibromyalgia (FM) and other chronic pain syndromes are associated with cognitive dysfunction and attentional deficits, but the neural basis of such alterations is poorly understood. Dyscognition may be related to high levels of neural noise, understood as increased random electrical fluctuations that impair neural communication; however, this hypothesis has not yet been tested in any chronic pain condition. Here we compared electroencephalographic activity (EEG) in 18 FM patients -with high self-reported levels of cognitive dysfunction- and 22 controls during a cognitive control task. We considered the slope of the Power Spectrum Density (PSD) as an indicator of neural noise. As the PSD slope is flatter in noisier systems, we expected to see shallower slopes in the EEG of FM patients. Higher levels of neural noise should be accompanied by reduced power modulation and reduced synchronization between distant brain locations after stimulus presentation. As expected, FM patients showed flatter PSD slopes. After applying a Laplacian spatial filter, we found reduced theta and alpha power modulation and reduced midfrontal-posterior theta phase synchronization. Results suggest higher neural noise and impaired local and distant neural coordination in the patients and support the neural noise hypothesis to explain dyscognition in FM.

Filtering out repetitive auditory stimuli in fibromyalgia: a study of P50 sensory gating.

BACKGROUND: It has been suggested that fibromyalgia (FM) patients show increased sensory processing of nociceptive and non-nociceptive stimuli and also reduced habituation. Although this pattern of increased reactivity has been established for the somatosensory modality, its generalization to other sensory modalities remains controversial. METHODS: Auditory evoked potentials were obtained using a paired-stimuli paradigm from a sample of 52 FM female patients and 55 healthy women matched for age and socio-economic status. Sensory gating of the P50 component, as indicated by P50 suppression rates to the second identical stimuli, was analysed in relation to clinical indices of FM, including algometry of tender points and a number of self-reported questionnaires. RESULTS: Sensory gating mechanisms in FM patients proved to be normal, robust and as efficient as those recorded in control subjects. There was no correlation between P50 suppression rates and indices of clinical or experimental (threshold or tolerance) pain. In addition, P50 sensory gating was not related to the other main symptoms of FM, including fatigue, sleep dysfunction or co-morbid depression, nor to hypersensitivity to noise or headache. CONCLUSIONS: The results indicate that FM patients do not present significant deficits in early sensory gating when processing auditory stimuli, and therefore challenge the 'generalized hypersensitivity' hypothesis of FM.

Convergence between the 1990 and 2010 ACR diagnostic criteria and validation of the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ).

(1) To assess the degree of convergence between the 1990 and 2010 American College of Rheumatology (ACR) diagnostic criteria; (2) To evaluate the validity and reliability of the 2010 ACR criteria; (3) To validate the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ); and (4) To assess the utility of the FSQ to differentiate fibromyalgia (FM) subgroups by disease severity. In the first study, agreement between the 1990 and 2010 ACR criteria for FM diagnosis was analyzed in a sample of 80 FM patients and 59 healthy controls. Algometry (mean threshold and tender points count) and the 2010 ACR indices [Symptom Severity Scale (SSS), Widespread Index (WPI) and Polysymptomatic Distress Scale (PSD)] were correlated with the key symptoms of FM and with indices of disease interference and quality of life. In a second study, we evaluated the validity and internal consistency of the Spanish version of the FSQ, as well as its ability to discriminate between groups of FM patients with low and high symptom severity. There is good agreement between the 1990 and 2010 ACR criteria for FM diagnosis. The 2010 ACR indices (SSS, WPI and PSD) demonstrated very adequate construct validity and appeared to be useful in the assessment of disease severity and global impact of FM. The FSQ had good internal consistency and validity and showed 100 % concordance with 2010 ACR criteria applied by a clinician. In addition, the FSQ proved to be useful in differentiating FM severity subgroups.

Equivalent is not equal: primary motor cortex (MI) activation during motor imagery and execution of sequential movements.

The motor hierarchy hypothesis and the related debate about the role of the primary motor cortex (MI) in motor preparation are major topics in cognitive neuroscience today. The present study combines the two strategies that have been followed to clarify the role of MI in motor preparation independently from execution: motor imagery and the use of precueing tasks. Event-related potentials (ERPs) were recorded while subjects either performed or just imagined sequential finger movements in response to a central target (numbers 1, 2 or 3) which was precued by arrows (at both sides of the screen) that provided information about response side. Both motor imagery and execution elicited Lateralized Readiness Potentials (LRPs) with similar morphology and latency. Given that the LRP is generated in MI, the results show that the primary motor cortex is also active during imagery and give support for the hypothesis of a functional equivalence between motor imagery and execution. Nevertheless, the analysis of the different moments of motor preparation (precue vs. target-induced activity) revealed important differences between both conditions: whereas there were no differences in LRPs nor in brain areas estimated by standardized low resolution tomographies (sLORETA) related to precue presentation, larger LRP amplitudes and higher activation of MI were found during motor execution than imagery in the target-related activity. These results have important implications for the development of brain-computer devices and for the use of motor imagery in neurorehabilitation.

Right frontal event related EEG coherence (ERCoh) differentiates good from bad performers of the Wisconsin Card Sorting Test (WCST).

AIM: To investigate changes in Event-Related Coherence (ERCoh) associated to good and bad resolution of the Wisconsin Card Sorting Test (WCST). METHODS: Event-Related Potentials (ERPs) were recorded from a sample of 30 university students while they performed a computerized version of the WCST. ERCoh was calculated for frontal and parietal electrodes for two specific moments: immediately before the response and after the feedback cues. RESULTS: Bad performers presented significantly reduced ERCoh at the right frontal region (in alpha, beta-1 and beta-2 bands), while no consistent group differences emerged for parietal ERCoh. Furthermore, the strength of functional coupling (ERCoh) between midfrontal and right-frontal electrodes was a good predictor of WCST behavioural parameters, such as the percentage of perseverative errors or the number of categories achieved. CONCLUSIONS: The results suggest that the right prefrontal cortex is specifically involved in executive functions, such as planning and foresight, tapped by the WCST. Although the specificity of the WCST to explore frontal lesions has been recently questioned, the present findings support that prefrontal areas are specifically involved in the successful resolution of the test by healthy subjects.

Limb (hand vs. foot) and response conflict have similar effects on event-related potentials (ERPs) recorded during motor imagery and overt execution.

Although there is substantial evidence that motor execution (M-Ex) and motor imagery (M-Im) share a common neural substrate, the role of the primary motor cortex (M1) during imagery is still a matter of debate. The present ERP study tries to clarify the functional similarity between the two processes in respect of (i) the engagement of the corresponding somatotopic M1 areas during execution and imagery of hand vs. foot movements; and (ii) the effect of conflicting information on response preparation. To this end, we recorded ERPs from 28 electrode sites in 19 participants while they performed a conflict task with congruent (target and flanker arrowheads pointing in the same direction) and incongruent (target pointing in the opposite direction to the flanker arrowheads) trials. We obtained the lateralized readiness potential (LRP), a component generated in M1, while subjects physically executed or mentally simulated the task. As expected by the somatotopic organization of M1, the LRP was of opposite polarity when foot, rather than hand, movements were prepared. The inversion of polarity also occurred during M-Im, a result that strongly argues in favour of the participation of M1 in motor imagery. In incongruent trials, longer LRP latencies, a premature preparation of the incorrect response (positive deflection in LRP waveform) and a fronto-central N2 component associated with response conflict appeared during both M-Ex and M-Im. Altogether, the results support the functional equivalence of the two processes and give support to the clinical use of M-Im for the improvement and recovery of motor functions.

Intensity dependence of auditory-evoked cortical potentials in fibromyalgia patients: a test of the generalized hypervigilance hypothesis.

UNLABELLED: On the basis of recent evidence concerning the amplification of incoming stimulation in fibromyalgia (FM) patients, it has been proposed that a generalized hypervigilance of painful and nonpainful sensations may be at the root of this disorder. So far, research into this issue has been inconclusive, possibly owing to the lack of agreement as to the operational definition of "generalized hypervigilance" and to the lack of robust objective measures characterizing the sensory style of FM patients. In this study, we recorded auditory-evoked potentials (AEPs) elicited by tones of increasing intensity (60, 70, 80, 90, and 105 dB) in 27 female FM patients and 25 healthy controls. Fibromyalgia patients presented shorter N1 and P2 latencies and a stronger intensity dependence of their AEPs. Both results suggest that FM patients may be hypervigilant to sensory stimuli, especially when very loud tones are used. The most noteworthy difference between patients and control subjects is at the highest stimulus intensity, for which far more patients maintained increased N1-P2 amplitudes in relation to the 90-dB tones. The larger AEP amplitudes to the 105-dB tones suggest that defects in an inhibitory system protecting against overstimulation may be a crucial factor in the pathophysiology of FM. Because a stronger loudness dependence of AEPs has been related to weak serotonergic transmission, it is hypothesized that for many FM patients deficient inhibition of the response to noxious and intense auditory stimuli may be due to a serotonergic deficit. PERSPECTIVE: The study of auditory-evoked potentials in response to tones of increasing intensity in FM patients may help to clarify the pathophysiology of this disorder, especially regarding the role of inhibition deficits involving serotonergic dysfunction, and may be a useful tool to guide the pharmacologic treatment of FM patients.

One-year test-retest reliability of auditory evoked potentials (AEPs) to tones of increasing intensity.

The one-year reliability of auditory evoked potential (AEP) amplitude/stimulus intensity slopes (obtained for single channels and with dipole source analysis) and the stability and criterion validity of alternative measures to the conventional AEPs augmenting/reducing (A/R) linear slope were explored in a sample of 21 psychology students. AEPs were obtained from two sequences of 288 Ss of different intensities (60, 80, 90, and 110 dB SPL), presented in four blocks of 72 tones of each intensity or in a pseudorandomized order. The Zuckerman's Sensation Seeking Scale, which has been associated to the A/R slope, was used as a criterion measure. The results supported the one-year reliability of N1P2 slopes obtained in single channels (especially for Fz and Cz and for the random presentation of stimuli) and for dipoles obtained with brain electric source analysis (especially for the tangential dipoles). Neither of the A/R measures was significantly related to the criterion. These results support the stability of AEPs A/R, but throw serious doubts on the use of this psychophysiological phenomenon as a correlate of personality dimensions such as sensation seeking.

The effect of motivational instructions on P300 amplitude.

The aim of this investigation was to determine the effect on P300 amplitude of instructions aimed at increasing the subject's degree of task involvement. To this end, two different studies were carried out. In Study 1, 20 university students were tested with an auditory event-related potential (ERP) oddball paradigm (target: 1,100 Hz; standard: 1,000 Hz) in two consecutive runs, each with a different set of instructions; after the first run, subjects were verbally motivated to increase their level of performance in the second run. In Study 2 (performed 1 year later), ERPs were similarly obtained from the same subjects during two oddball runs, but this time both tests were preceded by neutral instructions. The amplitude and latency of N1 and P2 elicited by non-targets and of N2 and P3 in target waveforms were evaluated. The findings showed that following motivating instructions, P3 amplitude increased while P3 latency showed a non-significant decrease. The amplitude of P2 to non-target stimuli--which could be interpreted as P250--was also affected by the instructions provided. The overall results suggest that the presentation of motivating instructions is followed by a higher amount of attentional resources allocated to all stimuli, and a more efficient evaluation and discrimination of relevant targets. The implication of these findings for the clinical use of P300 has been discussed.

Loudness dependence of auditory evoked potentials in obsessive-compulsive disorder: a pilot study.

In recent years it has been suggested that a serotonergic dysfunction is involved in the pathogenesis of obsessive-compulsive disorder (OCD). The loudness dependence of auditory evoked potentials (AEPs) is one of the best validated indicators of the activity of the serotonin system in humans. To explore the validity of the hypothesis of a serotonergic dysfunction in OCD, the loudness dependence of AEPs of 22 medication-free OCD patients were compared with those of 22 age- and gender-matched healthy subjects. Auditory evoked N1/P2 activity to tones of increasing intensity was studied using dipole source analysis. Contrary to the hypothesis, OCD patients and healthy controls did not differ in their LDAEPs of the tangential dipole in particular, located in the primary auditory cortex and closely related to central serotonergic activity. Furthermore, no significant correlation was found between the severity of obsessive-compulsive or depressive symptoms and the loudness dependence of AEPs. These findings do not support the hypothesis of a serotonergic dysfunction in OCD patients.

The effects of stimulus intensity and age on visual-evoked potentials (VEPs) in normal children.

In this study, we explored the effects of flash intensity and age on visual-evoked potentials (VEPs) in a sample of 85 children aged 8-15 years. Results of previous studies are discrepant regarding the extent to which children show an evoked potential augmenting tendency at vertex, which has been reported to be a characteristic of an immature inhibitory control system. In the present study, VEPs to light flashes of four different intensities were recorded at Cz. The results confirmed that P1N1 and N1P2 at Cz were positively related to increases in stimulus intensity, whereas N1 was not related reliably to intensity. This difference between peak-peak and baseline-peak amplitude findings at Cz relative to evoked potential augmenting and reducing may help to explain discrepant results among earlier studies. Developmental changes were found for our sample of children that were independent of stimulus intensity: N1 amplitude increased significantly with age, whereas N1 latency showed a small (nonsignificant) age-related decrease.

On the validity of interblock averaging of P300 in clinical settings.

The reduction of long-latency auditory ERPs amplitude, including P300, to repeated stimuli has been well documented in the literature on habituation. The effect of block repetition on auditory ERPs recorded for clinical purposes, where interblock intervals are commonly longer than those employed in habituation studies, was studied in a sample of 38 adults submitted to two blocks of a counting oddball paradigm. Four different experimental conditions were considered, differing in target probability, delivery or not of a previous passive oddball tone sequence, and the performance or not of other oddball tasks requiring more complex discriminative responses between the two blocks. Results showed that: (1) N1 amplitude to the frequent non-target stimuli decreased in the second block under all the conditions; (2) when the two blocks were consecutive (separated by 2-3 min), P300 amplitudes were unaffected by block repetition, this whatever the probability of the target (25% vs. 10%) and whether or not a passive oddball sequence preceded the two active blocks; (3) P300 amplitude was only affected by stimulus repetition in those subjects who performed more complex cognitive tasks between the first and second blocks and; (4) latency values were unaffected by repetition. It is hypothesised that the N1 amplitude decline may be caused by a decrease in alertness or arousal level produced by stimuli repetition. Reduction in P3 amplitude only appeared when more difficult tasks had to be done between the two oddball blocks and may reflect a decrease in the amount of attentional resources allocated to the second block, due either to fatigue or over training. The practice of using a grand average of several repetitions of the oddball paradigm, as recommended for the clinical use of long-latency ERPs, seems to be adequate provided that long interblock intervals are used and that the subject is not engaged in tasks requiring a high mental workload between the trial blocks.