Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group.

BACKGROUND: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. AIM: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. METHODS: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). RESULTS: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. CONCLUSIONS: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

Motor cortex function in fibromyalgia: a pilot study involving near-infrared spectroscopy and co-recording of laser-evoked potentials.

Interaction between the motor and nociceptive systems seems to play an important role in chronic pain. In this pilot study we used a combination of functional near-infrared spectroscopy (FNIRS) and laserevoked potentials (LEPs) during concurrent finger tapping task and noxious laser stimulation in fibromyalgia (FM) patients and controls. The study included 9 healthy subjects and 15 FM patients. During concurrent FNIRS and LEP recording, participants were required either to remain in resting relaxed condition or to execute a finger tapping task with the right hand. In the control group, the left motor cortex showed increased oxyhaemoglobin levels, while the early N1 LEP component was reduced, during the finger tapping task. In FM patients, motor cortex oxyhaemoglobin concentrations were lower during movement, which did not reduce LEPs. The left motor cortex oxyhaemoglobin concentrations had 79.2% diagnostic accuracy. The interplay between motor and pain-related circuits seems to be dysfunctional in FM patients. These results may support a role for motor cortex modulation in the treatment of this disabling disease.

A Delphi consensus statement of the Neuropathic Pain Special Interest Group of the Italian Neurological Society on pharmacoresistant neuropathic pain.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

Trial latencies estimation of event-related potentials in EEG by means of genetic algorithms.

OBJECTIVE: Event-related potentials (ERPs) are usually obtained by averaging thus neglecting the trial-to-trial latency variability in cognitive electroencephalography (EEG) responses. As a consequence the shape and the peak amplitude of the averaged ERP are smeared and reduced, respectively, when the single-trial latencies show a relevant variability. To date, the majority of the methodologies for single-trial latencies inference are iterative schemes providing suboptimal solutions, the most commonly used being the Woody's algorithm. APPROACH: In this study, a global approach is developed by introducing a fitness function whose global maximum corresponds to the set of latencies which renders the trial signals most aligned as possible. A suitable genetic algorithm has been implemented to solve the optimization problem, characterized by new genetic operators tailored to the present problem. MAIN RESULTS: The results, on simulated trials, showed that the proposed algorithm performs better than Woody's algorithm in all conditions, at the cost of an increased computational complexity (justified by the improved quality of the solution). Application of the proposed approach on real data trials, resulted in an increased correlation between latencies and reaction times w.r.t. the output from RIDE method. SIGNIFICANCE: The above mentioned results on simulated and real data indicate that the proposed method, providing a better estimate of single-trial latencies, will open the way to more accurate study of neural responses as well as to the issue of relating the variability of latencies to the proper cognitive and behavioural correlates.

Nociceptive blink reflex habituation biofeedback in migraine.

Reduced habituation of the nociceptive blink reflex (NBR) is considered a trait marker for genetic predisposition to migraine. In this open-label randomized controlled study, we aimed to test the efficacy of a biofeedback training based on learning of habituation of the NBR (NBR biofeedback) compared with pharmacological (topiramate) treatment and NBR biofeedback plus topiramate treatment in a cohort of migraine without aura patients eligible for prophylaxis. Thirty-three migraine patients were randomly assigned to three months of treatment with: 1) NBR biofeedback, 2) NBR biofeedback plus topiramate 50 mg (b.i.d.), or 3) topiramate 50 mg (b.i.d.). Frequency of headache and disability changes were the main study outcomes. Anxiety, depression, sleep, fatigue, quality of life, allodynia and pericranial tenderness were also evaluated. NBR biofeedback reduced the R2 area, without improving R2 habituation. However, it reduced the frequency of headache and disability, similarly to the combined treatment and topiramate alone. Reduced habituation of the NBR is a stable neurophysiological pattern, scarcely modifiable by learning procedures. Training methods able to act on stress-related responses may modulate cortical mechanisms inducing migraine onset and trigeminal activation under stressful trigger factors.

Age-related changes in laser-evoked potentials following trigeminal and hand stimulation in healthy subjects.

OBJECTIVE: This study aimed to evaluate age-related changes in laser-evoked potential (LEP) features, including habituation, via trigeminal and hand stimulation in a large group of healthy volunteers. METHODS: We recorded the LEPs by right-hand stimulation in 237 healthy subjects and by stimulation of the right supraorbital zone in 170 cases. The subjects ranged in age from 7 to 72 years and were divided into six groups by age. RESULTS: At the trigeminal level, the N2 and P2 latencies were significantly shorter and the N2-P2 amplitude was significantly larger in the 7-17 age group than in the other groups. The N2-P2 amplitude of the responses evoked by hand stimulation was significantly larger in the 7-40 age range than in the older subjects. The N1 amplitude and latency were not significantly different among the groups. The N2-P2 habituation increased with age, but no significant changes among groups were revealed by the Bonferroni test. CONCLUSIONS: Trigeminal vertex LEPs have greater amplitudes and appear earlier in children, while a progressive age-related amplitude decrease characterizes the N2-P2 waves associated with hand stimulation. The N2-P2 habituation increases in older people. The N1 latency and amplitude seem to remain stable during ageing and are therefore potentially reliable and useful patterns for nociceptive system examination. SIGNIFICANCE: Standardization of age-related changes in trigeminal and hand LEPs is possible and should improve their reliability in the objective assessment of pain pathways.

Quality of life in fibromyalgia patients with craniomandibular disorders.

Fibromyalgia (FM) is a rheumatic disease which affects fibrous tissues and muscles; it is characterized by chronic pain and it is often associated with craniomandibular disorders (CMD). 31 patients were assessed from March 2012 to October 2012 through the administration of specific questionnaires and following neurologic and gnatologic assessment. A relevant corre-lation between FM and CMD emerges from the present study, as 80.6% of our patients report CMD symptoms with high prevalence of myofascial pain (84%). Multivariate regression analysis revealed that the patients in the present study did not differ in score of quality of life questionnaires from patients with fibromyalgia. The neuropathic pain diagnostic question-naire (DN4) scores were positively affected by belonging to group II of Research Diagnostic Criteria of Temporomandibular Disorders (RDC/ TDM) classification, suggesting the possibility of a neuropathic component in chronic pain in this CMD group, as already speculated in our study on the correlation between burning mouth syndrome and CMD and by other au-thors in studies on chronic low back pain. However, further clinic and instrumental studies are needed in order to test this as-sumption.

Effects of anodal TDCS stimulation of left parietal cortex on visual spatial attention tasks in men and women across menstrual cycle.

Sex hormonal variations have been shown to affect functional cerebral asymmetries in cognitive domains, contributing to sex-related differences in functional cerebral organization. The aim of this study was to investigate spatial attention by means of a bisection line test and computer-supported attention task during the menstrual cycle in healthy women compared to men, in basal condition and under Transcranial Direct Current Stimulation (TDCS) of the left parietal cortex. Women were studied during the menses, follicular and luteal phases, ascertained by transvaginal ultrasounds. In basal conditions, women showed a clear deviation toward the right in the bisection line test during the menstrual phase, similarly to men. The midpoint recognition in the computer-supported attention task was not influenced by the menstrual cycle for women, while men showed a significant increase in errors toward the left side. The anodal activation of the left parietal cortex did not affect the line bisection task, while in men it reduced the total amount of errors in midpoint recognition observed in the computer supported attention task. The hand-use effect demonstrated by the bisection-line test could be influenced by estrogen fluctuations, while the right hemisphere prevalence in spatial attention appears to be gender-related and scarcely influenced by the menstrual cycle. The left parietal cortex seems to exert a scarce effect on hand-use effect, while its activation is able to revert sex related right hemisphere supremacy.

Nociceptive inputs transmission in Huntington's disease: a study by laser evoked potentials.

The aim of the present study was to evaluate pain perception and evoked responses by laser stimuli (LEPs) in mild not demented Huntington's Disease (HD) patients. Twenty-eight HD patients and 30 control subjects were selected. LEPs were obtained by four scalp electrodes, (Fz, Cz, referred to the nasion; T3, T4, referred to Fz), stimulating the dorsum of both hands. All patients were also evaluated by somatosensory evoked potentials (SEPs) by median nerve stimulation. Only 3 patients referred pain of arthralgic type. Laser pain perception was similar between HD patients and controls. An abnormal N2, P2 and N1 latency increase was evident in the majority of HD patients. LEPs features were similar between patients taking and not taking neuroleptics. The N2 and P2 latencies, showed a negative correlation with functional score and Mini Mental State Examination, and a positive correlation with the severity of hyperkinetic movements. A delay in nociceptive input processing emerged in HD, concurring with the main features of the disease, in absence of clinical evidence of abnormalities in pain perception. The dysfunction of pain signals transmission in HD may induce sub-clinical changes of sensory functions, which may probably interfere with sensory-motor integration and contribute to functional impairment.

Redundant variables and Granger causality.

We discuss the use of multivariate Granger causality in presence of redundant variables: the application of the standard analysis, in this case, leads to under estimation of causalities. Using the un-normalized version of the causality index, we quantitatively develop the notions of redundancy and synergy in the frame of causality and propose two approaches to group redundant variables: (i) for a given target, the remaining variables are grouped so as to maximize the total causality and (ii) the whole set of variables is partitioned to maximize the sum of the causalities between subsets. We show the application to a real neurological experiment, aiming to a deeper understanding of the physiological basis of abnormal neuronal oscillations in the migraine brain. The outcome by our approach reveals the change in the informational pattern due to repetitive transcranial magnetic stimulations.

Fibromyalgia comorbidity in primary headaches.

Fibromyalgia syndrome (FMS) is a chronic pain condition of unknown aetiology characterized by diffuse pain and tenderness at tender points. The aim of the study was to assess the prevalence and clinical features of FMS in the different forms of primary headaches, in a tertiary headache centre. Primary headache patients (n = 217) were selected and submitted to the Total Tenderness Score, anxiety and depression scales, Migraine Disability Assessment, allodynia questionnaire, Short Form 36 Health Survey and the Medical Outcomes Study-Sleep Scale. In patients with FMS, the Multidimensional Assessment of Fatigue, the Pain Visual Analog Scale, the Manual Tender Point Survey and the Fibromyalgia Impact Questionnaire were employed. FMS was present in 36.4% of patients and prevailed significantly in tension-type headache and in patients with higher headache frequency. Headache frequency, pericranial muscle tenderness, anxiety and sleep inadequacy were especially associated with FMS comorbidity. In the FMS patients, fatigue and pain at tender points were significantly correlated with headache frequency. FMS seems increasingly prevalent with increased headache frequency, for the facilitation of central sensitization phenomena favoured by anxiety and sleep disturbances.

Successful extension of assessment and rehabilitation intervention for an adolescent with postcoma multiple disabilities through a learning setup.

Prior to the beginning of this study, the participant (an adolescent with postcoma multiple disabilities) had learned to use a forehead-skin response to access environmental stimuli. These learning data seemed to indicate a minimally conscious state (i.e., awareness of the link between response and stimuli) in spite of 1) a previous diagnosis of postcoma vegetative state; and 2) concomitant electrophysiological measurement showing no evidence of a passive P300 response and of mismatch negativity. The present study was an effort to extend the early learning investigation with two additional responses and related stimuli to broaden learning evidence and ascertain possible choice behavior. Results indicated that the participant learned the new responses and also provided evidence of choice behavior. These data were discussed in terms of the usefulness of the learning paradigm in the assessment and rehabilitation of persons with postcoma multiple disabilities and consciousness disorders.

Central sensitisation phenomena in primary headaches: overview of a preventive therapeutic approach.

Central sensitisation phenomena have been well recognized in the development of migraine attacks and tension type headache. It is also known that headache frequency is related to sensitization. Though some studies have focused on the effects of symptomatic treatment on allodynia, few reports have described the action of preventive agents on the facilitating factors for central sensitisation. In this study we aim to review the factors concurrent with an increase in central sensitisation, in view of the choice of preventive agents for primary headaches. Central sensitisation phenomena are increased in pain syndromes with psycho-pathological co-morbidities. For instance, sleep disorders are a frequent symptom in headache, prevailing in chronic forms and in patients with psychiatric comorbidity. Sleep deprivation is also a factor producing hyperalgesic changes. It is known that symptoms attributable to central sensitization are diffusely pronounced in fibromyalgic (FMS) patients, and that FMS co-morbidity is frequent in primary headaches and associated with higher frequency and poorer quality of life. We report our preliminary experience in a group of 20 chronic migraine patients, treated with duloxetine 60 mg/die vs a self-management program including stretching (relaxation training) and exercise (cervical-dorsal flexion and rotation) to decrease strength and flexibility of muscles of cervical and dorsal spine headache patients. Both the treatments were effective on headache frequency and pericranial tenderness, although FMS comorbidity significantly reduced their efficacy on migraine and quality of life. The whole spectrum of action of pharmacological and non pharmacological treatments on central sensitisation mechanisms, and on their facilitating factors, should be taken into account for the best preventive therapeutic approach of primary headaches.

Migraine detection through spontaneous EEG analysis.

Spontaneous EEG patterns are studied to detect migraine patients both during the attack and in headache-free periods. The EEG signals are analyzed through the wavelets and both scale-dependent and scale-independent features are computed to characterize the patterns. The classification is carried out by a supervised neural network. The efficiency of the method is evaluated through the Receiver Operating Characteristic (ROC) analysis and the Wilcoxon-Mann-Whitney (WMW) test. Although a high discrimination is observed with one single neural output, a complete separation among MwA patients and healthy subjects is obtained when a scatter plot is drawn in the plane of two suitable neural outputs.

Effects of the remote C fibres stimulation induced by capsaicin on the blink reflex in chronic migraine.

The aim of this study was to test the function of the diffuse noxious inhibitory control system (DNIC) in chronic and episodic migraine, exploring the blink reflex (BR) modifications induced by topical application of capsaicin on the hand. We evaluated 11 migraine without aura (MA) and nine chronic migraine (CM) patients during the not symptomatic phase; they were compared with 14 non-headache subjects (N). The BR was elicited by weak electrical stimuli delivered to the right supraorbital nerve; it was obtained 10 min and 20 min after the application of 1 ml of 3% capsaicin in a cream base (Teofarma) on the skin of the dorsum of the right hand, and 60 min after capsaicin removal. The subjective pain sensation induced by capsaicin was significantly increased in CM with respect to both MA patients and normal subjects; the R2 area was increased in CM patients during capsaicin application, with respect to controls and MA patients, who did not exhibit any reflex alterations. These results may suggest a failure of DNIC and a disturbed control of the trigeminal reflex at the central level, linked with migraine frequency.

The measure of randomness by leave-one-out prediction error in the analysis of EEG after laser painful stimulation in healthy subjects and migraine patients.

OBJECTIVE: We aimed to perform a quantitative analysis of event-related modulation of EEG activity, resulting from a not-warned and a warned paradigm of painful laser stimulation, in migraine patients and controls, by the use of a novel analysis, based upon a parametric approach to measure predictability of short and noisy time series. METHODS: Ten migraine patients were evaluated during the not-symptomatic phase and compared to seven age and sex matched controls. The dorsum of the right hand and the right supraorbital zone were stimulated by a painful CO(2) laser, in presence or in absence of a visual warning stimulus. An analysis time of 1s after the stimulus was submitted to a time-frequency analysis by a complex Morlet wavelet and to a cross-correlation analysis, in order to detect the development of EEG changes and the most activated cortical regions. A parametric approach to measure predictability of short and noisy time series was applied, where time series were modeled by leave-one-out (LOO) error. RESULTS: The averaged laser-evoked potentials features were similar between the two groups in the alerted and not alerted condition. A strong reset of the beta rhythms after the painful stimuli was seen for three groups of electrodes along the midline in patients and controls: the predictability of the series induced by the laser stimulus changed very differently in controls and patients. The separation was more evident after the warning signal, leading to a separation with P-values of 0.0046 for both the hand and the face. DISCUSSION: As painful stimulus causes organization of the local activity in cortex, EEG series become more predictable after stimulation. This phenomenon was less evident in migraine, as a sign of an inadequate cortical reactivity to pain. SIGNIFICANCE: The LOO method enabled to show in migraine subtle changes in the cortical response to pain.

Effects of amitriptyline and intra-oral device appliance on clinical and laser-evoked potentials features in chronic tension-type headache.

In the present study, we examined clinical and laser-evoked potentials (LEP) features in two groups of chronic tension-type headache (CTTH) patients treated with two different approaches: intra-oral appliance of prosthesis, aiming to reduce muscular tenderness, and 10 mg daily amitriptyline. Eighteen patients suffering from CTTH (IHS, 2004) participated in the study. We performed a basal evaluation of clinical features and LEPs in all patients (T0) vs. 12 age- and sex-matched controls; successively, patients were randomly assigned to a two-month treatment by amitriptyline or intra-oral device appliance. The later LEPs, especially the P2 component, were significantly increased in amplitude in the CTTH group. Both the intra-oral prosthesis and amitriptyline significantly reduced headache frequency. Total Tenderness Score was significantly reduced in the group treated by the prosthesis. The amplitude of P2 response elicited by stimulation of pericranial zones showed a reduction after amitriptyline treatment. The results of this study may confirm that pericranial tenderness is primarily a phenomenon initiating a self-perpetuating circuit, favoured by central sensitisation at the level of the cortical nociceptive areas devoted to the attentive and emotive compounds of pain. Both the interventions at the peripheral and central levels may interrupt this reverberating circuit, improving the outcome of headache.

Effects of symptomatic treatments on cutaneous hyperalgesia and laser evoked potentials during migraine attack.

Previously an amplitude enhancement of laser evoked potentials (LEPs) was detected during migraine attack: we further examined pain threshold to CO2 laser stimuli and LEPs during attacks, evaluating the effect of almotriptan, lysine-acetylsalicylate and placebo treatment on cutaneous hyperalgesia to thermal stimuli delivered by CO2 laser and on LEP components. Eighteen patients suffering from migraine without aura were analysed. They were divided into three groups of six patients each, randomly assigned to lysine acetyl-salicylate, almotriptan or placebo treatments. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and not symptomatic side in all patients. The LEPs were recorded by 25 scalp electrodes. During attacks, the P2 wave was significantly enhanced; the amplitude of the P2 component obtained by the stimulation of the supraorbital zone during the attack on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. Both almotriptan and lysine acetyl-salicylate significantly reduced the P2 amplitude but they showed no effects on hyperalgesia to laser stimulation; headache relief following therapy was correlated with the reduction of the P2 amplitude. The cortical elaboration of laser-induced experimental pain seemed increased during migraine attack, and the severity of headache was mainly related to the increase of the later LEPs components expressing the attentive and emotive compounds of suffering. Reversion of this process appeared to be primarily responsible for the efficacy of drugs in treating migraine, though both almotriptan and lysine-acetil salicilate seemed to have no effect in reducing sensitization at second and third order nociceptive neurons.

Visually evoked phase synchronisation changes of alpha rhythm in migraine. Correlations with clinical features.

We investigate phase synchronisation in EEG recordings from migraine patients. We use the analytic signal technique, based on the Hilbert transform, and find that migraine brains are characterised by enhanced alpha band phase synchronisation in the presence of visual stimuli. In migraine, the brain synchronises to the idling rhythm of the visual areas under certain photic stimulations; hypersynchronisation of the alpha rhythm may suggest a state of cortical hypoexcitability during the interictal phase of migraine.

Steady-state visual evoked potentials and phase synchronization in migraine patients.

We investigate phase synchronization in EEG recordings from migraine patients. We use the analytic signal technique, based on the Hilbert transform, and find that migraine brains are characterized by enhanced alpha band phase synchronization in the presence of visual stimuli. Our findings show that migraine patients have an overactive regulatory mechanism that renders them more sensitive to external stimuli.