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.

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.

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.

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.

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.

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.

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.

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.

Reduced habituation to experimental pain in migraine patients: a CO(2) laser evoked potential study.

The habituation to sensory stimuli of different modalities is reduced in migraine patients. However, the habituation to pain has never been evaluated. Our aim was to assess the nociceptive pathway function and the habituation to experimental pain in patients with migraine. Scalp potentials were evoked by CO(2) laser stimulation (laser evoked potentials, LEPs) of the hand and facial skin in 24 patients with migraine without aura (MO), 19 patients with chronic tension-type headache (CTTH), and 28 control subjects (CS). The habituation was studied by measuring the changes of LEP amplitudes across three consecutive repetitions of 30 trials each (the repetitions lasted 5 min and were separated by 5-min intervals). The slope of the regression line between LEP amplitude and number of repetitions was taken as an index of habituation. The LEPs consisted of middle-latency, low-amplitude responses (N1, contralateral temporal region, and P1, frontal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). The latency and amplitude of these responses were similar in both patients and controls. While CS and CTTH patients showed a significant habituation of the N2/P2 response, in MO patients this LEP component did not develop any habituation at all after face stimulation and showed a significantly lower habituation than in CS after hand stimulation. The habituation index of the vertex N2/P2 complex exceeded the normal limits in 13 out of the 24 MO patients and in none of the 19 CTTH patients (P<0.0001; Fisher's exact test). Moreover, while the N1-P1 amplitude showed a significant habituation in CS after hand stimulation, it did not change across repetitions in MO patients. In conclusion, no functional impairment of the nociceptive pathways, including the trigeminal pathways, was found in either MO or CTTH patients. But patients with migraine had a reduced habituation, which probably reflects an abnormal excitability of the cortical areas involved in pain processing.

Detection of subclinical brain electrical activity changes in Huntington's disease using artificial neural networks.

OBJECTIVE: The aim of this study was to analyze EEG background activity in Huntington's disease (HD) patients and relatives at risk, in relation to CAG repeat size and clinical state, in order to detect an electrophysiological marker of early disease. METHODS: We selected 13 patients and 7 subjects at risk. Thirteen normal subjects, sex- and age-matched, were also evaluated. Artifact-free epochs were selected and analyzed through Fast-Fourier Transform. EEG background activity was tested using both linear analysis and artificial neural network (ANN) classifier in order to evaluate whether EEG abnormalities were linked to functional changes preceding the onset of the disease. RESULTS: The most important EEG classification pattern was the absolute alpha power not correlated with cognitive decline. The ANN correctly classified 11/13 patients and 12/13 normals. Moreover, the neural scores for subjects at risk seemed to be correlated to the expected time before the onset of the disease. CONCLUSIONS: ANN is a very powerful method to discriminate between normals and patients. It could be used as an automatic diagnostic tool. EEG changes in positive gene-carriers for HD confirm an early functional impairment which should be taken into account in the genetic counseling and in the management of the early stages of the disease.

Zolmitriptan reverses blink reflex changes induced during the migraine attack in humans.

The question about the 5-hydroxytryptamine (5-HT)(1B-1D) receptors agonists, if the clinical efficacy in migraine attacks is linked with the action at the central level or at the peripheral one, is still unresolved. We evaluated the effects of zolmitriptan and sumatriptan on blink reflex in thirty migraine without aura patients during the attacks in order to assess the central action on the trigeminal system. Both drugs were effective in reducing headache severity compared to placebo. In the migraine attack an increased area of the R3 component on the pain side was observed; it was suppressed by zolmitriptan, which confirmed its action on the central trigeminal circuits, though the clinical relevance of this effect could be questioned.

The blink reflex and the corneal reflex are followed by cortical activity resembling the nociceptive potentials induced by trigeminal laser stimulation in man.

Laser stimulation of the supraorbital regions evokes brain potentials (LEPs) related to trigeminal nociception. The aim of this study was to record the R2 component of the blink reflex and the corneal reflex in 20 normal subjects, comparing the scalp activity following these reflexes with the nociceptive potentials evoked by CO2 laser stimulation of supraorbital regions. Cortical and muscular reflexes evoked by stimulation of the first trigeminal branch were recorded simultaneously. The R2 component of the blink reflex and the corneal reflex were followed by two cortical peaks, which resembled morphologically N-P waves of LEPs. The two peaks demonstrated a difference in latency of approximately 40 ms, which is consistent with activation time of nociception. This finding suggests that these reflexes are induced by activation of small pain-related fibers.

The three responses of the blink reflex in adult and juvenile migraine.

Recent theories about migraine pathogenesis have emphasized the role of the trigeminal system in the pathogenesis of migraine attacks (Moskowitz, 1997). The blink reflex (BR) could be a suitable method to evaluate the trigeminal system in migraine, as it is generally elicited by stimulation of the trigeminal ophthalmic division (Kimura et al., 1967), involved in migraine attacks. Sixty one adult and 15 juvenile migraine without aura subjects were selected, in order to evaluate the BR features, including the subjective perceptive and pain thresholds and the R1, R2 and R3 components intensity thresholds and amplitudes. The electrophysiological procedure was carried out during the pain free phase. The findings were compared with those of 28 healthy controls, 18 adults and 10 children. In both adult and juvenile migraine sufferers an early appearance of the R3 response at almost the R2 threshold was observed in comparison with age-matched controls. Unfortunately, the anatomic and physiologic organization of the R3 component is uncertain: its early onset could suggest a dysfunction of the inhibitory control system on the trigeminal networks, which may predispose to migraine attacks.

Somatosensory evoked potentials in migraine.

Twenty-six patients suffering from migraine with aura and without aura were examined using somatosensory evoked potentials (SEPs) during the intercritical phase. The mean amplitude of the prerolandic component was significantly reduced in migraine patients with and without aura on the right hemisphere; the ratio between the parietal N20/P25 and the prerolandic P22/N30 was significantly enhanced in migraine groups over the left and the right hemisphere. A significant interside asymmetry of the N30 amplitude was observed in the migraine with aura group in comparison with control subjects. The occurrence of SEP abnormalities was not correlated with the age of the patients, with illness duration or with the frequency of migraine attacks. SEP abnormalities observed in migraine with and without aura may have an underlying primary neural disorder probably based on a chronic dopaminergic dysfunction.

Discrimination between migraine patients and normal subjects based on steady state visual evoked potentials: discriminant analysis and artificial neural network classifiers.

Fifty-one migraine patients and 19 control subjects were examined by steady state visual evoked potentials (SSVEPs) procedure. The aim of this study was to develop a discriminant analysis and an artificial neural network (NN) classifier in order to discriminate between migraneurs during attack-free periods and normal subjects. Discriminant analysis correctly classified 72.5% of migraine patients with a false positive rate of 36.8%. The NN method had a sensitivity of 100% with a false positive rate of 15%. The results of this study confirm SSVEP pattern as a marker of migraine and demonstrate that NNs could be a useful method in the statistical analysis of topographic EEG data.

Topographic classification of EEG patterns in Huntington's disease.

The aim of this study is to perform a topographic classification of electroencephalographic (EEG) patterns in subjects affected by the Huntington's disease (HD). The alpha activity is a discriminating feature for HD, as its amplitude reduction turns out to be a clear mark of the illness. When used as input variable to a supervised neural network, a good classification of pathological patterns and control ones is achieved with high values of sensitivity and specificity. It should be useful to get more insight into the local discriminating capabilities of the alpha rhythm by implementing a neural network approach to classify EEG patterns extracted from groups of channels corresponding to specific regions of the scalp. Receiver operating characteristic (ROC) curve analysis enables one to label each region with the value of the area under the curve, thus providing a local significance for HD classification. A reduction of the area when processing regions of the scalp, with respect to the whole, suggests that all channels provide significant contribution to HD pattern discrimination. These results can be interpreted as an effect of an abnormal subcortical modulation of the alpha rhythm, due to the dysfunctional action of the thalamus on the cortical activities. In a further study, morphometric features of thalamus and basal ganglia, evaluated by MRI, will be matched with the electrophysiological findings.

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.

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.