Publications by authors named "Gianluca Coppola"

133 Publications

An artificial neural network approach to detect presence and severity of Parkinson's disease via gait parameters.

PLoS One 2021 19;16(2):e0244396. Epub 2021 Feb 19.

Department of Medico-Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy.

Introduction: Gait deficits are debilitating in people with Parkinson's disease (PwPD), which inevitably deteriorate over time. Gait analysis is a valuable method to assess disease-specific gait patterns and their relationship with the clinical features and progression of the disease.

Objectives: Our study aimed to i) develop an automated diagnostic algorithm based on machine-learning techniques (artificial neural networks [ANNs]) to classify the gait deficits of PwPD according to disease progression in the Hoehn and Yahr (H-Y) staging system, and ii) identify a minimum set of gait classifiers.

Methods: We evaluated 76 PwPD (H-Y stage 1-4) and 67 healthy controls (HCs) by computerized gait analysis. We computed the time-distance parameters and the ranges of angular motion (RoMs) of the hip, knee, ankle, trunk, and pelvis. Principal component analysis was used to define a subset of features including all gait variables. An ANN approach was used to identify gait deficits according to the H-Y stage.

Results: We identified a combination of a small number of features that distinguished PwPDs from HCs (one combination of two features: knee and trunk rotation RoMs) and identified the gait patterns between different H-Y stages (two combinations of four features: walking speed and hip, knee, and ankle RoMs; walking speed and hip, knee, and trunk rotation RoMs).

Conclusion: The ANN approach enabled automated diagnosis of gait deficits in several symptomatic stages of Parkinson's disease. These results will inspire future studies to test the utility of gait classifiers for the evaluation of treatments that could modify disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894951PMC
February 2021

Genetics Influences Drug Consumption in Medication Overuse Headache, Not in Migraine: Evidence From Wolframin His611Arg Polymorphism Analysis.

Front Neurol 2020 22;11:599517. Epub 2021 Jan 22.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.

The Wolframin His611Arg polymorphism can influence drug consumption in psychiatric patients with impulsive addictive behavior. This cross-sectional study aims to assess the prevalence of the Wolframin His611Arg polymorphism in MOH, a secondary headache belonging to the spectrum of addictive disorders, episodic migraine (EM), and healthy subjects (HS), and its influence on drug consumption. One-hundred and seventy-two EM, 107 MOH, and 83 HS were enrolled and genotyped for the Wolframin His611Arg polymorphism. Subjects were classified as homozygous for allele His (H/H subjects), homozygous for allele Arg (R/R subjects), and heterozygous (H/R subjects), regrouped as R/R and carriers of allele H (non-R/R), and matched for clinical data. There were no differences in allelic distributions between the three groups ( = 0.19). Drug consumption and other clinical characteristics were not influenced by the Wolframin His611Arg polymorphism ( = 0.42; β = 0.04) in the EM group. Among the MOH population, R/R subjects consumed more analgesics ( < 0.0001; β = -0.38), particularly combination drugs ( = 0.0001; = 2.32). The Wolframin His611Arg polymorphism has a similar prevalence between the MOH, EM, and HS groups. The presence of the R/R genotype does not influence symptomatic drug consumption in EM, whereas it determines an increased use of symptomatic drugs in the MOH group, in particular combination drugs (i.e., drugs containing psychoactive compounds). Our findings are consistent with the hypothesis that the Wolframin His611Arg polymorphism plays its effect only in the MOH population, influencing the impulsivity control underlying addictive behavior.
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http://dx.doi.org/10.3389/fneur.2020.599517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862332PMC
January 2021

How does the brain change in chronic migraine? Developing disease biomarkers.

Cephalalgia 2020 Dec 8:333102420974359. Epub 2020 Dec 8.

Neurology Department, Mayo Clinic, Scottsdale, AZ, USA.

Background: Validated chronic migraine biomarkers could improve diagnostic, prognostic, and predictive abilities for clinicians and researchers, as well as increase knowledge on migraine pathophysiology.

Objective: The objective of this narrative review is to summarise and interpret the published literature regarding the current state of development of chronic migraine biomarkers.

Findings: Data from functional and structural imaging, neurophysiological, and biochemical studies have been utilised towards the development of chronic migraine biomarkers. These biomarkers could contribute to chronic migraine classification/diagnosis, prognosticating patient outcomes, predicting response to treatment, and measuring treatment responses early after initiation. Results show promise for using measures of brain structure and function, evoked potentials, and sensory neuropeptide concentrations for the development of chronic migraine biomarkers, yet further optimisation and validation are still required.

Conclusions: Imaging, neurophysiological, and biochemical changes that occur with the progression from episodic to chronic migraine could be utilised for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies. Ultimately, validated biomarkers could move us closer to being able to practice precision medicine in the field and thus improve patient care.
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http://dx.doi.org/10.1177/0333102420974359DOI Listing
December 2020

Investigating the Effects of COVID-19 Quarantine in Migraine: An Observational Cross-Sectional Study From the Italian National Headache Registry (RICe).

Front Neurol 2020 10;11:597881. Epub 2020 Nov 10.

Applied Neurophysiology and Pain Unit, Scienze Mediche di Base, Neuroscienze e Organi di Senso Department, Bari Aldo Moro University, Bari, Italy.

Previous studies during SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects, such as post-traumatic stress symptoms, confusion, and anger. These conditions may affect the course of many diseases, including migraine. Although it is possible that the quarantine measures for the current COVID-19 pandemic affect migraine burden, no information is currently available on this issue. In this study, we aimed to: (1) explore the possible changes in migraine frequency, severity, and days with acute medication intake during quarantine period; (2) evaluate possible differences in migraine outcomes in consideration of lifestyle changes, emotions, pandemic diffusion, and COVID-19 infection. We interviewed patients who were included in the observational Italian Headache Registry (Registro Italiano Cefalee, RICE), retrospectively collecting information on main headache features, lifestyle factors, emotions, individual infection status, and perception of COVID-19 for 2 months before (pre-quarantine) and after the beginning of the quarantine (quarantine). Inclusion criteria were: age > 18, diagnosis of migraine without aura, migraine with aura and chronic migraine, last in-person visit more than 3 months preceding the beginning of quarantine. A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency (9.42 ± 0.43 days with headache vs. 8.28 ± 0.41) and intensity (6.57 ± 0.19 vs. 6.59 ± 0.21) during the quarantine, compared to pre-quarantine. There was a correlation between improvement and number of days of stay-at-home. When results were stratified for geographic area, we found a tendency toward worsening of headache frequency in northern Italy. Disgust regarding viral infection corresponded to a minor improvement in migraine. Migraine patients showed a mild improvement of migraine features, probably attributable to resilient behavior toward pandemic distress. Disgust regarding the contagion whereas potentially favoring defensive behavior, could potentially worsen migraine. The spontaneous limitation of migraine burden during quarantine could favor patient follow-up via the use of telemedicine visits, reliable diaries, and frequent remote contacts.
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http://dx.doi.org/10.3389/fneur.2020.597881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683429PMC
November 2020

Impaired short-term visual paired associative plasticity in patients with migraine between attacks.

Pain 2021 Mar;162(3):803-810

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.

Abstract: A common experimental neurophysiological method to study synaptic plasticity is pairing activity of somatosensory afferents and motor cortical circuits, so-called paired associative stimulation (PAS). Dysfunctional inhibitory and excitatory PAS mechanisms within the sensorimotor system were described in patients with migraine without aura (MO) between attacks. We have recently observed that the same bidirectional PAS rules also apply to the visual system. Here, we have tested whether dysfunctioning associative plasticity might characterize the visual system of patients with MO. In 14 patients with MO between attacks and in 15 healthy volunteers, we performed a previously validated visual PAS (vPAS) protocol by coupling 90 black-and-white checkerboard reversals with low-frequency transcranial magnetic stimulation pulses over the occipital cortex at 2 interstimulus intervals of -25/+25 ms around the visual-evoked potential (VEP) P1 latency. We recorded VEPs (600 sweeps) before, immediately after, and 10 min after each vPAS session. We analysed VEP N1-P1 amplitude and delayed habituation. Although vPAS-25 significantly enhanced and vPAS + 25 reduced VEP amplitude habituation in healthy volunteers, the same protocols did not significantly change VEP amplitude habituation in MO between attacks. We provide evidence for lack of habituation enhancing and habituation suppressing visual PAS mechanisms within the visual system in interictal migraine. This finding, in combination with those previously obtained studying the sensorimotor system, leads us to argue that migraine disease-related dysrhythmic thalamocortical activity prevents the occurrence of physiological bidirectional synaptic plasticity induced by vPAS.
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http://dx.doi.org/10.1097/j.pain.0000000000002085DOI Listing
March 2021

Neuromagnetic Amygdala Response to Pain-Related Fear as a Brain Signature of Fibromyalgia.

Pain Ther 2020 Dec 22;9(2):765-781. Epub 2020 Oct 22.

Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Introduction: Fibromyalgia (FM) is a chronic pain condition characterized by impaired emotional regulation. This study explored the brain response to pain-related fear as a potential brain signature of FM.

Methods: We used a conditioned fear task and magnetoencephalography to record pain-related fear responses in patients with FM. Two blocks of 30 fear responses were collected to compute the response strength in the first block and the strength difference between the first and second blocks (fear habituation). These measurements were investigated for their clinical relevance and compared with measurements obtained from healthy controls and patients with chronic migraine (CM), a different chronic pain condition often comorbid with FM.

Results: Pain-related fear clearly activated the bilateral amygdala and anterior insula in patients with FM (n = 52), patients with CM (n = 50), and the controls (n = 30); the response strength in the first block was consistent across groups. However, fear habituation in the right amygdala decreased in the FM group (vs. CM and control groups, both p ≤ 0.001, no difference between CM and control groups). At the 3-month follow-up, the patients with FM reporting < 30% improvement in pain severity (n = 15) after pregabalin treatment exhibited lower fear habituation in the left amygdala at baseline (vs. ≥ 30% improvement, n = 22, p = 0.019). Receiver operating characteristic analysis confirmed that amygdala fear habituation is a suitable predictor of diagnosis and treatment outcomes of FM (area under the curve > 0.7).

Conclusions: Amygdala activation to pain-related fear is maladaptive and linked to treatment outcomes in patients with FM. Because the aberrant amygdala response was not observed in the CM group, this response is a potential brain signature of FM.

Trial Registration: ClinicalTrials.gov Identifier, NCT02747940.
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http://dx.doi.org/10.1007/s40122-020-00206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648811PMC
December 2020

Haemodynamic activity characterization of resting state networks by fractal analysis and thalamocortical morphofunctional integrity in chronic migraine.

J Headache Pain 2020 Sep 14;21(1):112. Epub 2020 Sep 14.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.

Background: Chronic migraine (CM) can be associated with aberrant long-range connectivity of MRI-derived resting-state networks (RSNs). Here, we investigated how the fractal dimension (FD) of blood oxygenation level dependent (BOLD) activity may be used to estimate the complexity of RSNs, reflecting flexibility and/or efficiency in information processing in CM patients respect to healthy controls (HC).

Methods: Resting-state MRI data were collected from 20 untreated CM without history of medication overuse and 20 HC. On both groups, we estimated the Higuchi's FD. On the same subjects, fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from diffusion tensor imaging and correlated with the FD values.

Results: CM showed higher FD values within dorsal attention system (DAS) and the anterior part of default-mode network (DMN), and lower FD values within the posterior DMN compared to HC. Although FA and MD were within the range of normality, both correlated with the FD values of DAS.

Conclusions: FD of DAS and DMN may reflect disruption of cognitive control of pain in CM. Since the normal microstructure of the thalamus and its positive connectivity with the cortical networking found in our CM patients reminds similar results obtained assessing the same structures but with the methods of neurophysiology, in episodic migraine during an attack, this may be yet another evidence in supporting CM as a never-ending migraine attack.
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http://dx.doi.org/10.1186/s10194-020-01181-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490862PMC
September 2020

Patients with chronic migraine without history of medication overuse are characterized by a peculiar white matter fiber bundle profile.

J Headache Pain 2020 Jul 18;21(1):92. Epub 2020 Jul 18.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.

Background: We investigated intracerebral fiber bundles using a tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) data to verify microstructural integrity in patients with episodic (MO) and chronic migraine (CM).

Methods: We performed DTI in 19 patients with MO within interictal periods, 18 patients with CM without any history of drug abuse, and 18 healthy controls (HCs) using a 3 T magnetic resonance imaging scanner. We calculated diffusion metrics, including fractional anisotropy (FA), axial diffusion (AD), radial diffusion (RD), and mean diffusion (MD).

Results: TBSS revealed no significant differences in the FA, MD, RD, and AD maps between the MO and HC groups. In comparison to the HC group, the CM group exhibited widespread increased RD (bilateral superior [SCR] and posterior corona radiata [PCR], bilateral genu of the corpus callosum [CC], bilateral posterior limb of internal capsule [IC], bilateral superior longitudinal fasciculus [LF]) and MD values (tracts of the right SCR and PCR, right superior LF, and right splenium of the CC). In comparison to the MO group, the CM group showed decreased FA (bilateral SCR and PCR, bilateral body of CC, right superior LF, right forceps minor) and increased MD values (bilateral SCR and right PCR, right body of CC, right superior LF, right splenium of CC, and right posterior limb of IC).

Conclusion: Our results suggest that chronic migraine can be associated with the widespread disruption of normal white matter integrity in the brain.
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http://dx.doi.org/10.1186/s10194-020-01159-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368770PMC
July 2020

Impairment of Global Lower Limb Muscle Coactivation During Walking in Cerebellar Ataxias.

Cerebellum 2020 Aug;19(4):583-596

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

The aim of this study was to investigate the time-varying multi-muscle coactivation function (TMCf) in the lower limbs during gait and its relationship with the biomechanical and clinical features of patients with cerebellar ataxia. A total of 23 patients with degenerative cerebellar ataxia (16 with spinocerebellar ataxia, 7 with adult-onset ataxia of unknown etiology) and 23 age-, sex-, and speed-matched controls were investigated. The disease severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) in all patients. During walking, simultaneous acquisition of kinematic, kinetic, and electromyography data was performed using a motion analysis system. The coactivation was processed throughout the gait cycle using the TMCf, and the following parameters were measured: synthetic coactivation index, full width at half maximum, and center of activity. Spatiotemporal (walking speed, stance duration, swing duration, first and second double-support durations, step length, step width, stride length, Center of Mass displacement), kinetic (vertical component of GRFs), and energy consumption (total energy consumption and mechanical energy recovered) parameters were also measured. The coactivation variables were compared between patients and controls and were correlated with both clinical and gait variables. A significantly increased global TMCf was found in patients compared with controls. In addition, the patients showed a significant shift of the center of activity toward the initial contact and a significant reduction in energy recovery. All coactivation parameters were negatively correlated with gait speed, whereas the coactivation index and center of activity were positively correlated with both center-of-mass mediolateral displacement values and SARA scores. Our findings suggest that patients use global coactivation as a compensatory mechanism during the earliest and most challenging subphase (loading response) of the gait cycle to reduce the lateral body sway, thus improving gait stability at the expense of effective energy recovery. This information could be helpful in optimizing rehabilitative treatment aimed at improving lower limb muscle control during gait in patients with cerebella ataxia.
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http://dx.doi.org/10.1007/s12311-020-01142-6DOI Listing
August 2020

Short-latency afferent inhibition and somato-sensory evoked potentials during the migraine cycle: surrogate markers of a cycling cholinergic thalamo-cortical drive?

J Headache Pain 2020 Apr 16;21(1):34. Epub 2020 Apr 16.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Corso della Repubblica 79, 04100, Latina, Italy.

Background: Short-latency afferent inhibition (SAI) consists of motor cortex inhibition induced by sensory afferents and depends on the excitatory effect of cholinergic thalamocortical projections on inhibitory GABAergic cortical networks. Given the electrophysiological evidence for thalamo-cortical dysrhythmia in migraine, we studied SAI in migraineurs during and between attacks and searched for correlations with somatosensory habituation, thalamocortical activation, and clinical features.

Methods: SAI was obtained by conditioning the transcranial magnetic stimulation-induced motor evoked potential (MEP) with an electric stimulus on the median nerve at the wrist with random stimulus intervals corresponding to the latency of individual somatosensory evoked potentials (SSEP) N20 plus 2, 4, 6, or 8 ms. We recruited 30 migraine without aura patients, 16 between (MO), 14 during an attack (MI), and 16 healthy volunteers (HV). We calculated the slope of the linear regression between the unconditioned MEP amplitude and the 4-conditioned MEPs as a measure of SAI. We also measured SSEP amplitude habituation, and high-frequency oscillations (HFO) as an index of thalamo-cortical activation.

Results: Compared to HV, SAI, SSEP habituation and early SSEP HFOs were significantly reduced in MO patients between attacks, but enhanced during an attack. There was a positive correlation between degree of SAI and amplitude of early HFOs in HV, but not in MO or MI.

Conclusions: The migraine cycle-dependent variations of SAI and SSEP HFOs are further evidence that facilitatory thalamocortical activation (of GABAergic networks in the motor cortex for SAI), likely to be cholinergic, is reduced in migraine between attacks, but increased ictally.
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http://dx.doi.org/10.1186/s10194-020-01104-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164277PMC
April 2020

The function of the lateral inhibitory mechanisms in the somatosensory cortex is normal in patients with chronic migraine.

Clin Neurophysiol 2020 04 3;131(4):880-886. Epub 2020 Feb 3.

Sapienza University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechnologies, Latina, Italy; IRCCS Neuromed, Pozzilli, IS, Italy.

Objective: To study lateral inhibition and habituation/sensitization in the somatosensory cortex of patients with chronic migraine (CM) and to identify correlations with clinical migraine features.

Methods: Sixteen patients with CM without medication overuse, and 17 healthy volunteers (HVs) received somatosensory evoked potentials (SSEPs) elicited by separate electrical stimulation of the right median (M) and ulnar (U) nerves at the wrist and by simultaneous nerve stimulation (MU). We measured the N20-P25 amplitudes and calculated the lateral inhibition (LI) percentage using the formula {100-[MU/(M + U) * 100]}. We also calculated sensitization (SSEP amplitude during block 1) and delayed habituation to M-nerve stimulation.

Results: The percentage of LI did not differ between the groups (40.2% in HV, 47.4% in CM, p = 0.276) and was negatively correlated with the monthly headache-day number (r = -0.532, p = 0.034). Patients showed a generalized increase in SSEP amplitudes compared to HVs and habituated normally.

Conclusions: We showed a pattern of somatosensory response in CM similar to that observed during attacks of episodic migraine.

Significance: In the transition process between episodic migraine and CM, LI attempts to physiologically counteract the mounting increase in attack frequency, but this is insufficient to allow patients to exit the chronic phase.
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http://dx.doi.org/10.1016/j.clinph.2020.01.009DOI Listing
April 2020

Board Walk - January 2020.

Cephalalgia 2020 01;40(1):127-128

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http://dx.doi.org/10.1177/0333102419893552DOI Listing
January 2020

Increased neural connectivity between the hypothalamus and cortical resting-state functional networks in chronic migraine.

J Neurol 2020 Jan 12;267(1):185-191. Epub 2019 Oct 12.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy.

Objective: The findings of resting-state functional MRI studies have suggested that abnormal functional integration between interconnected cortical networks characterises the brain of patients with migraine. The aim of this study was to investigate the functional connectivity between the hypothalamus, brainstem, considered as the migraine generator, and the following areas/networks that are reportedly involved in the pathophysiology of migraine: default mode network (DMN), executive control network, dorsal attention system, and primary and dorsoventral visual networks.

Methods: Twenty patients with chronic migraine (CM) without medication overuse and 20 healthy controls (HCs) were prospectively recruited. All study participants underwent 3-T MRI scans using a 7.5-min resting-state protocol. Using a seed-based approach, we performed a ROI-to-ROI analysis selecting the hypothalamus as the seed.

Results: Compared to HCs, patients with CM showed significantly increased neural connectivity between the hypothalamus and brain areas belonging to the DMN and dorsal visual network. We did not detect any connectivity abnormalities between the hypothalamus and the brainstem. The correlation analysis showed that the severity of the migraine headache was positively correlated with the connectivity strength of the hypothalamus and negatively with the connectivity strength of the medial prefrontal cortex, which belongs to the DMN.

Conclusion: These data provide evidence for hypothalamic involvement in large-scale reorganisation at the functional-network level in CM and in proportion with the perceived severity of the migraine pain.
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http://dx.doi.org/10.1007/s00415-019-09571-yDOI Listing
January 2020

Cortical pain processing in migraine.

J Neural Transm (Vienna) 2020 04 9;127(4):551-566. Epub 2019 Oct 9.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Corso della Repubblica 79, 04100, Latina, Italy.

Among painful disorders, migraine is distinguishable by its chronic pathology and episodic clinical manifestation. Only a small percentage of patients with migraine progress to a chronic form of migraine. Both peripheral and central portions of the trigeminal system are involved in the pathophysiology of migraine pain, as they are involved in the processes of peripheral and central sensitization, alongside various subcortical and cortical brain structures. This review focuses on clinical, neurophysiological, and neuroimaging data underscoring cortical pain processing in migraine. Data obtained from quantitative sensory testings are inconclusive and support the involvement of the peripheral portion of the trigeminovascular system as indirect evidence of peripheral sensitization, solely during the headache phase. The assessment of subjective pain intensity in response to several painful modalities has not been conclusive for the clear state of central sensitization in between migraine attacks but for the subclinical allodynia state that defines the boundary between behavioural responses and an irritable nervous state. Modulation of the brainstem and midbrain pain pathways, in conjunction with the thalamic and thalamocortical pathways, may be critical for the initiation and maintenance of migraine attacks. Several studies using different neuroimaging techniques have demonstrated that brains experiencing migraine undergo plastic changes in both microstructure and macrostructure and in the functioning of cortical networks, which may manifest early in the life of a patient with migraine. Further studies are required to understand how specific these results are to migraine relative to other painful disorders.
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http://dx.doi.org/10.1007/s00702-019-02089-7DOI Listing
April 2020

Headache Related Alterations of Visual Processing in Migraine Patients.

J Pain 2020 May - Jun;21(5-6):593-602. Epub 2019 Oct 3.

Headache Research Unit, CHR Citadelle Hospital, CHU de Liège, University of Liège Belgium. Electronic address:

Migraine is characterized by an increased sensitivity to visual stimuli that worsens during attacks. Recent evidence has shown that feedforward volleys carrying incoming visual information induce high-frequency (gamma) oscillations in the visual cortex, while feedback volleys arriving from higher order brain areas induce oscillatory activity at lower frequencies (theta/alpha/low beta). We investigated visually induced high (feedforward) and low (feedback) frequency activations in healthy subjects and various migraine patients. Visual evoked potentials from 20 healthy controls and 70 migraine patients (30 interictal and 20 ictal episodic migraineurs, 20 chronic migraineurs) were analyzed in the frequency domain. We compared power in the theta-alpha-low beta and gamma range between groups, and searched for correlations between the low-to-high frequency activity ratio and number of monthly headache and migraine days. Compared to healthy controls, interictal migraine patients had increased visually induced low frequency (feedback) activity. Conversely, ictal and chronic migraine patients showed an augmented gamma band (feedforward) power. The low-frequency-to-gamma (feedback/feedforward) activity ratio correlated negatively with monthly headache days and tended to do so with migraine days. Our findings show that visual processing is differentially altered depending on migraine cycle and type. Feedback control from higher order cortical areas predominates interictally in episodic migraine while migraine attacks and chronic migraine are associated with enhanced incoming afferent activity, confirming their similar electrophysiological profile. The presence of headache is associated with proportionally higher gamma (feedforward) activities. PERSPECTIVE: This study provides an insight into the pathophysiology of migraine headache from the perspective of cortical sensory processing dynamics. Patients with migraine present alterations in feedback and feedforward visual signaling that differ with the presence of headache.
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http://dx.doi.org/10.1016/j.jpain.2019.08.017DOI Listing
October 2019

Prediction of Responsiveness of Gait Variables to Rehabilitation Training in Parkinson's Disease.

Front Neurol 2019 2;10:826. Epub 2019 Aug 2.

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.

Gait disorders represent one of the most disabling features of Parkinson's disease, which may benefit from rehabilitation. No consistent evidence exists about which gait biomechanical factors can be modified by rehabilitation and which clinical characteristic can predict rehabilitation-induced improvements. The aims of the study were as follows: (i) to recognize the gait parameters modifiable by a short-term rehabilitation program; (ii) to evaluate the gait parameters that can normalize after rehabilitation; and (iii) to identify clinical variables predicting improvements in gait function after rehabilitation. Thirty-six patients affected by idiopathic Parkinson's disease in Hoehn-Yahr stage 1-3 and 22 healthy controls were included in the study. Both clinical and instrumental (gait analysis) evaluations were performed before and after a 10-weeks rehabilitation treatment. Time-distance parameters, lower limb joint, and trunk kinematics were measured. At baseline evaluation with matched speed, almost all gait parameters were significantly different between patients and healthy controls. After the 10-weeks rehabilitation, most gait parameters improved, and spatial asymmetry and trunk rotation normalized. Multiple linear regression of gender combined with Unified Parkinson's Disease Rating Scale-III predicted both ΔSpeed and ΔStep length of both sides; gender combined with Unified Parkinson's Disease Rating Scale-II predicted ΔCadence; age combined with Hoehn-Yahr score and disease duration predicted Δtrunk rotation range of motion. Impaired gait parameters are susceptible to improvement by rehabilitation, and younger men with Parkinson's disease who are less severely affected and at early disease stage are more susceptible to improvements in gait function after a 10-weeks rehabilitation program.
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http://dx.doi.org/10.3389/fneur.2019.00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688512PMC
August 2019

A Randomized Double-Blind, Cross-Over Trial of very Low-Calorie Diet in Overweight Migraine Patients: A Possible Role for Ketones?

Nutrients 2019 Jul 28;11(8). Epub 2019 Jul 28.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Roma, Italy.

Here we aimed at determining the therapeutic effect of a very low-calorie diet in overweight episodic migraine patients during a weight-loss intervention in which subjects alternated randomly between a very low-calorie ketogenic diet (VLCKD) and a very low-calorie non-ketogenic diet (VLCnKD) each for one month. In a nutritional program, 35 overweight obese migraine sufferers were allocated blindly to 1-month successive VLCKD or VLCnKD in random order (VLCKD-VLCnKD or VLCnKD-VLCD). The primary outcome measure was the reduction of migraine days each month compared to a 1-month pre-diet baseline. Secondary outcome measures were 50% responder rate for migraine days, reduction of monthly migraine attacks, abortive drug intake and body mass index (BMI) change. Only data from the intention-to-treat cohort ( = 35) will be presented. Patients who dropped out ( = 6) were considered as treatment failures. Regarding the primary outcome, during the VLCKD patients experienced -3.73 (95% CI: -5.31, -2.15) migraine days respect to VLCnKD ( < 0.0001). The 50% responder rate for migraine days was 74.28% (26/35 patients) during the VLCKD period, but only 8.57% (3/35 patients) during VLCnKD. Migraine attacks decreased by -3.02 (95% CI: -4.15, -1.88) during VLCKD respect to VLCnKD ( < 0.00001). There were no differences in the change of acute anti-migraine drug consumption ( = 0.112) and BMI ( = 0.354) between the 2 diets. A VLCKD has a preventive effect in overweight episodic migraine patients that appears within 1 month, suggesting that ketogenesis may be a useful therapeutic strategy for migraines.
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http://dx.doi.org/10.3390/nu11081742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722531PMC
July 2019

Neuroenhancement and neuroprotection by oral solution citicoline in non-arteritic ischemic optic neuropathy as a model of neurodegeneration: A randomized pilot study.

PLoS One 2019 26;14(7):e0220435. Epub 2019 Jul 26.

IRCCS-Fondazione Bietti, Rome, Italy.

Purpose: To evaluate whether treatment with Citicoline in oral solution (OS-Citicoline) would increase visual function, retinal ganglion cells (RGCs) function, and neural conduction along visual pathways (neuroenhancement), and/or induce preservation of RGCs fibers' loss (neuroprotection) in non-arteritic ischemic optic neuropathy (NAION), a human model of neurodegeneration.

Methods: Thirty-six patients with NAION and 20 age-matched controls were enrolled. Nineteen NAION patients received 500 mg/day of OS-Citicoline for a 6-month period followed by 3-month of wash-out (NC Group); 17 NAION patients were not treated (NN Group) from baseline to 9 months. In all subjects at baseline, and in NC and NN eyes at 6 and 9 months of follow-up, we assessed Visual Acuity (VA), Pattern Electroretinogram (PERG), Visual Evoked Potentials (VEP), retinal nerve fiber layer thickness (RNFL-T), and Humphrey 24-2 visual field mean deviation (HFA MD). Mean differences were statistically evaluated with ANOVA between Groups, and linear correlations were analysed with Pearson's test.

Results: At 6 months, significant differences between groups for all parameters were observed (ANOVA, p<0.01). In NC eyes, VA increased, PERG responses increased, VEP recordings improved and were significantly correlated with increases in HFA MD (p<0.01), and RNFL-T was unmodified or improved. In contrast, in NN eyes, VA, PERG, VEP responses, RNFL-T, and HFA MD were further worsened. Significant differences were still present at 9-month follow-up in the NN Group and after 3 months of OS-Citicoline wash-out in NC eyes.

Conclusions: OS-Citicoline treatment induced neuroenhancement (improvement in RGCs function and neural conduction along visual pathways related to improvement of visual field defects) and neuroprotection (unmodified or improved RNFL morphological condition) in a human model of NAION involving fast RGCs degeneration.

Trial Registration: ClinicalTrials.gov NCT03758118.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220435PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660126PMC
February 2020

A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs.

BMC Neurol 2019 Jun 22;19(1):136. Epub 2019 Jun 22.

Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University Rof Rome Polo Pontino, Latina, Italy.

Background: A short ketogenic diet (KD) treatment can prevent migraine attacks and correct excessive cortical response. Here, we aim to prove if the KD-related changes of cortical excitability are primarily due to cerebral cortex activity or are modulated by the brainstem.

Methods: Through the stimulation of the right supraorbital division of the trigeminal nerve, we concurrently interictally recorded the nociceptive blink reflex (nBR) and the pain-related evoked potentials (PREP) in 18 migraineurs patients without aura before and after 1-month on KD, while in metabolic ketosis. nBR and PREP reflect distinct brain structures activation: the brainstem and the cerebral cortex respectively. We estimated nBR R2 component area-under-the-curve as well as PREP amplitude habituation as the slope pof the linear regression between the 1st and the 2nd block of 5 averaged responses.

Results: Following 1-month on KD, the mean number of attacks and headache duration reduced significantly. Moreover, KD significantly normalized the interictal PREP habituation (pre: + 1.8, post: - 9.1, p = 0.012), while nBR deficit of habituation did not change.

Conclusions: The positive clinical effects we observed in a population of migraineurs by a 1-month KD treatment coexists with a normalization at the cortical level, not in the brainstem, of the typical interictal deficit of habituation. These findings suggest that the cerebral cortex may be the primary site of KD-related modulation.

Trial Registration: ClinicalTrials.gov NCT03775252 (retrospectively registered, December 09, 2018).
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http://dx.doi.org/10.1186/s12883-019-1351-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588932PMC
June 2019

Aberrant interactions of cortical networks in chronic migraine: A resting-state fMRI study.

Neurology 2019 05 3;92(22):e2550-e2558. Epub 2019 May 3.

From the Department of Medico-Surgical Sciences and Biotechnologies (G. Coppola, M.S., F.P.), Sapienza University of Rome Polo Pontino, Latina; Research Unit of Neurophysiology of Vision and Neuroophthalmology (A.D.R., V.P.), IRCCS-Fondazione Bietti; Department of Human Neurosciences (B.P., E.T., V.C., S.T., G. Cartocci, F.C., V.D.P.), Sapienza University of Rome; Don Carlo Gnocchi Onlus Foundation (C.D.L.), Milan, Italy; Headache Research Unit, University Department of Neurology CHR (J.S.), Citadelle Hospital, University of Liège, Belgium; and IRCCS-Neuromed (F.P.), Pozzilli, Italy.

Objective: We investigated resting-state (RS)-fMRI using independent component analysis (ICA) to determine the functional connectivity (FC) between networks in chronic migraine (CM) patients and their correlation with clinical features.

Methods: Twenty CM patients without preventive therapy or acute medication overuse underwent 3T MRI scans and were compared to a group of 20 healthy controls (HC). We used MRI to collect RS data in 3 selected networks, identified using group ICA: the default mode network (DMN), the executive control network (ECN), and the dorsal attention system (DAS).

Results: Compared to HC, CM patients had significantly reduced functional connectivity between the DMN and the ECN. Moreover, in patients, the DAS showed significantly stronger FC with the DMN and weaker FC with the ECN. The higher the severity of headache, the increased the strength of DAS connectivity, and the lower the strength of ECN connectivity.

Conclusion: These results provide evidence for large-scale reorganization of functional cortical networks in chronic migraine. They suggest that the severity of headache is associated with opposite connectivity patterns in frontal executive and dorsal attentional networks.
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http://dx.doi.org/10.1212/WNL.0000000000007577DOI Listing
May 2019

Clinical neurophysiology of migraine with aura.

J Headache Pain 2019 Apr 29;20(1):42. Epub 2019 Apr 29.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Corso della Repubblica, 79-04100, Latina, Italy.

Background: The purpose of this review is to provide a comprehensive overview of the findings of clinical electrophysiology studies aimed to investigate changes in information processing of migraine with aura patients.

Main Body: Abnormalities in alpha rhythm power and symmetry, the presence of slowing, and increased information flow in a wide range of frequency bands often characterize the spontaneous EEG activity of MA. Higher grand-average cortical response amplitudes, an increased interhemispheric response asymmetry, and lack of amplitude habituation were less consistently demonstrated in response to any kind of sensory stimulation in MA patients. Studies with single-pulse and repetitive transcranial magnetic stimulation (TMS) have reported abnormal cortical responsivity manifesting as greater motor evoked potential (MEP) amplitude, lower threshold for phosphenes production, and paradoxical effects in response to both depressing or enhancing repetitive TMS methodologies. Studies of the trigeminal system in MA are sparse and the few available showed lack of blink reflex habituation and abnormal findings on SFEMG reflecting subclinical, probably inherited, dysfunctions of neuromuscular transmission. The limited studies that were able to investigate patients during the aura revealed suppression of evoked potentials, desynchronization in extrastriate areas and in the temporal lobe, and large variations in direct current potentials with magnetoelectroencephalography. Contrary to what has been observed in the most common forms of migraine, patients with familial hemiplegic migraine show greater habituation in response to visual and trigeminal stimuli, as well as a higher motor threshold and a lower MEP amplitude than healthy subjects.

Conclusion: Since most of the electrophysiological abnormalities mentioned above were more frequently present and had a greater amplitude in migraine with aura than in migraine without aura, neurophysiological techniques have been shown to be of great help in the search for the pathophysiological basis of migraine aura.
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http://dx.doi.org/10.1186/s10194-019-0997-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734510PMC
April 2019

Migraine classification using somatosensory evoked potentials.

Cephalalgia 2019 Aug 26;39(9):1143-1155. Epub 2019 Mar 26.

1 School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA.

Objective: The automatic detection of migraine states using electrophysiological recordings may play a key role in migraine diagnosis and early treatment. Migraineurs are characterized by a deficit of habituation in cortical information processing, causing abnormal changes of somatosensory evoked potentials. Here, we propose a machine learning approach to utilize somatosensory evoked potential-based biomarkers for migraine classification in a noninvasive setting.

Methods: Forty-two migraine patients, including 29 interictal and 13 ictal, were recruited and compared with 15 healthy volunteers of similar age and gender distribution. The right median nerve somatosensory evoked potentials were collected from all subjects. State-of-the-art machine learning algorithms including random forest, extreme gradient-boosting trees, support vector machines, K-nearest neighbors, multilayer perceptron, linear discriminant analysis, and logistic regression were used for classification and were built upon somatosensory evoked potential features in time and frequency domains. A feature selection method was employed to assess the contribution of features and compare it with previous clinical findings, and to build an optimal feature set by removing redundant features.

Results: Using a set of relevant features and different machine learning models, accuracies ranging from 51.2% to 72.4% were achieved for the healthy volunteers-ictal-interictal classification task. Following model and feature selection, we successfully separated the three groups of subjects with an accuracy of 89.7% for the healthy volunteers-ictal, 88.7% for healthy volunteers-interictal, 80.2% for ictal-interictal, and 73.3% for healthy volunteers-ictal-interictal classification tasks, respectively.

Conclusion: Our proposed model suggests the potential use of somatosensory evoked potentials as a prominent and reliable signal in migraine classification. This non-invasive somatosensory evoked potential-based classification system offers the potential to reliably separate migraine patients in ictal and interictal states from healthy controls.
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http://dx.doi.org/10.1177/0333102419839975DOI Listing
August 2019

Effect of phobic visual stimulation on spinal nociception.

Physiol Behav 2019 07 19;206:22-27. Epub 2019 Mar 19.

"Sapienza" University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechonologies, Latina, Italy.

To explore the role of strong negative emotions in spinal nociception, we evaluated the effect of fear-relevant videos of small animals on the nociceptive withdrawal reflex (NWR) and reflex-related pain perception in healthy subjects with a specific phobia of small animals. Twenty healthy subjects with a specific phobia of small animals diagnosed according to DSM-V criteria were included in this study. The NWR was evoked in the lower limb by stimulating the sural nerve and recording EMG activity in the biceps femoris. NWR pain-related perception was quantified on an 11-point numerical rating scale (NRS). Subjects were examined during 4 recording sessions. In the baseline session, no images were projected. In the other sessions, the subjects were invited to watch a video containing either neutral or phobic content. To evaluate neurovegetative responses, we measured heart rate using a pulse oximeter during each recording session. A series of clinical rating scales were administered to subjects to evaluate disgust, fear, and anxiety. The NWR amplitude was significantly increased during the phobic video session and was associated with the fear inventory scale scores. Women showed higher NWR amplitude values during the phobic video session and a lower recovery rate during the after-effect video session than did men. The NWR amplitude and related pain perception were dissociated from each other during the phobic video session, as the NRS score remained unchanged while the NWR increased in amplitude. Emotions induced by the viewing of phobic videos seem to enhance the activation of the spinal circuitries involved in nociception and the withdrawal reaction without interfering with pain processing pathways or dissociating the reflex response from related pain perception. This effect appears to differ by sex, as it was more intense and longer lasting in women than in men. Emotions induced by phobic video viewing increase the alertness devoted to the defensive reaction by emphasizing nociceptive responses independently from pain perception. The NWR may represent an interesting tool for exploring the interaction between strong negative emotions and spinal nociception. A better understanding of this mechanism may be a theoretical prerequisite for the optimization of pain management in several chronic pain syndromes.
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http://dx.doi.org/10.1016/j.physbeh.2019.03.021DOI Listing
July 2019

Evidence for associative plasticity in the human visual cortex.

Brain Stimul 2019 May - Jun;12(3):705-713. Epub 2019 Feb 1.

Research Unit of Neurology, Neurophysiology and Neurobiology, Università Campus Bio-Medico, Roma, Italy; Fondazione Alberto Sordi-Research Institute for Aging, Roma, Italy.

Background: Repetitive convergent inputs to a single post-synaptic neuron can induce long-term potentiation (LTP) or depression (LTD) of synaptic activity in a spike timing-dependent manner.

Objective: Here we set a protocol of visual paired associative stimulation (vPAS) of the primary visual cortex (V1) in humans to induce persistent changes in the excitatory properties of V1 with a spike timing rule.

Methods: We provided convergent inputs to V1 by coupling transcranial magnetic stimulation (TMS) pulses of the occipital cortex with peripheral visual inputs, at four interstimulus intervals of -50/-25/+25/+50 ms relative to the visual evoked potential (VEP) P1 latency. We analysed VEP amplitude and delayed habituation before and up to 10 min after each vPAS protocol.

Results: VEP amplitude was reduced after vPAS+25. Delayed VEP habituation was increased after vPAS-25 while it was reduced after vPAS+25.

Conclusions: We provide evidence that associative bidirectional synaptic plasticity is a feature not only of the sensorimotor but also of the human visual system.
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http://dx.doi.org/10.1016/j.brs.2019.01.021DOI Listing
July 2019

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine.

J Headache Pain 2019 Feb 13;20(1):15. Epub 2019 Feb 13.

Department of Clinical and Molecular Medicine, Regional Referral Headache Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy.

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting.

Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version.

Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity.

Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.
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http://dx.doi.org/10.1186/s10194-019-0966-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734365PMC
February 2019

Age related metabolic modifications in the migraine brain.

Cephalalgia 2019 Jul 11;39(8):978-987. Epub 2019 Feb 11.

5 Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Neurology, Brussels, Belgium.

Purpose: The aim of this study was to evaluate the possibility that migraine patients exhibit specific age-related metabolic changes in the brain, which occur regardless of disease duration or the frequency of attacks.

Methods: We analysed the relation between brain glucose (F-fluorodeoxyglucose) uptake and age in healthy volunteers (n = 20) and episodic migraine patients (n = 19). In the latter, we additionally compared the correlation between F-fluorodeoxyglucose uptake and disease duration and monthly migraine days.

Results: In contrast to controls, in migraine patients advancing age was positively correlated to increased metabolism in the brainstem (especially the posterior pons), hippocampus, fusiform gyrus and parahippocampus. Conversely, no significant correlations between cerebral metabolism and disease duration or migraine days were observed.

Conclusions: Findings of this cross-sectional study show that episodic migraine patients exhibit specific metabolic brain modifications while ageing. As such, age is correlated with metabolic changes in key regions of the brain previously associated with migraine's pathophysiology to a better extent than disease duration or the number of monthly migraine days. More than the repeated headache attacks, the continuous interaction with the environment seemingly models the brain of migraine sufferers in an adaptive manner. A positive control (e.g. chronic pain) is missing in this study and therefore findings cannot be proven to be migraine-specific.
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http://dx.doi.org/10.1177/0333102419828984DOI Listing
July 2019

Withdrawal from acute medication normalises short-term cortical synaptic potentiation in medication overuse headache.

Neurol Sci 2019 May 1;40(5):963-969. Epub 2019 Feb 1.

Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome Polo Pontino, Corso della Repubblica 79, 04100, Latina, Italy.

Objectives: To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH).

Methods: Thirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication withdrawal program. Ten trains of 10 stimuli each (120% resting motor threshold) were delivered at 1 Hz or 5 Hz in two separate sessions in a randomised order. Motor evoked potential (MEP) amplitudes were measured from the right first dorsal interosseous muscle and the slope of the linear regression line from the first to the tenth stimuli was calculated for each participant.

Results: All subjects exhibited MEP amplitude inhibition in response to 1 Hz rTMS. Alternatively, the 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in patients with MOH. The physiological potentiating effect of 5 Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH.

Conclusions: The results suggest that acute medication withdrawal normalises brain responses in patients with MOH. Clinical improvements after medication withdrawal may reflect the reversal of neurophysiological dysfunction. Accordingly, medication withdrawal should be offered to patients with MOH as early as possible in order to prevent the development of more pronounced alterations in brain plasticity.
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http://dx.doi.org/10.1007/s10072-019-03735-4DOI Listing
May 2019

Pain Perception and Migraine.

Front Neurol 2018 2;9:576. Epub 2018 Aug 2.

Department of Medical, Surgical, Neurological, Metabolic, and Aging Sciences, Headache Center, University of Campania "Luigi Vanvitelli, ", Naples, Italy.

It is well-known that both inter- and intra-individual differences exist in the perception of pain; this is especially true in migraine, an elusive pain disorder of the head. Although electrophysiology and neuroimaging techniques have greatly contributed to a better understanding of the mechanisms involved in migraine during recent decades, the exact characteristics of pain threshold and pain intensity perception remain to be determined, and continue to be a matter of debate. The aim of this review is to provide a comprehensive overview of clinical, electrophysiological, and functional neuroimaging studies investigating changes during various phases of the so-called "migraine cycle" and in different migraine phenotypes, using pain threshold and pain intensity perception assessments. A systematic search for qualitative studies was conducted using search terms "migraine," "pain," "headache," "temporal summation," "quantitative sensory testing," and "threshold," alone and in combination (subject headings and keywords). The literature search was updated using the additional keywords "pain intensity," and "neuroimaging" to identify full-text papers written in English and published in peer-reviewed journals, using PubMed and Google Scholar databases. In addition, we manually searched the reference lists of all research articles and review articles. Consistent data indicate that pain threshold is lower during the ictal phase than during the interictal phase of migraine or healthy controls in response to pressure, cold and heat stimuli. There is evidence for preictal sub-allodynia, whereas interictal results are conflicting due to either reduced or no observed difference in pain threshold. On the other hand, despite methodological limitations, converging observations support the concept that migraine attacks may be characterized by an increased pain intensity perception, which normalizes between episodes. Nevertheless, future studies are required to longitudinally evaluate a large group of patients before and after pharmacological and non-pharmacological interventions to investigate phases of the migraine cycle, clinical parameters of disease severity and chronic medication usage.
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http://dx.doi.org/10.3389/fneur.2018.00576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082953PMC
August 2018

Evidence of an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients: a study comparing FDG-PET and visual evoked potentials.

J Headache Pain 2018 Jul 5;19(1):49. Epub 2018 Jul 5.

Headache Research Unit, University Department of Neurology CHR, CHU de Liège, Boulevard du 12eme de Ligne 1, 4000, Liege, Belgium.

Background: Migraine attacks might be triggered by a disruption of cerebral homeostasis. During the interictal period migraine patients are characterized by abnormal sensory information processing, but this functional abnormality may not be sufficient to disrupt the physiological equilibrium of the cortex unless it is accompanied by additional pathological mechanisms, like a reduction in energetic reserves. The aim of this study was to compare resting cerebral glucose uptake (using positron emission tomography (fluorodeoxyglucose-PET)), and visual cortex activation (using visual evoked potentials (VEP)), between episodic migraine without aura patients in the interictal period and healthy volunteers.

Methods: Twenty episodic migraine without aura patients and twenty healthy volunteers were studied. FDG-PET and VEP recordings were performed on separate days. The overall glucose uptake in the visual cortex-to-VEP response ratio was calculated and compared between the groups. Additionally, PET scan comparisons adding area under the VEP curve as a covariate were performed. For case-wise analysis, eigenvalues from a specific region exhibiting significantly different FDG-PET signal in the visual cortex were extracted. Standardized glucose uptake values from this region and VEP values from each subject were then coupled and compared between the groups.

Results: The mean area under the curve of VEP was greater in migraine patients compared to healthy controls. In the same line, patients had an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex. Statistical parametric mapping analysis revealed that cortical FDG-PET signal in relation to VEP area under the curve was significantly reduced in migraineurs in a cluster extending throughout the left visual cortex, from Brodmann's areas 19 and 18 to area 7. Within this region, case-wise analyses showed that a visual neuronal activation exceeding glucose uptake was present in 90% of migraine patients, but in only 15% of healthy volunteers.

Conclusion: This study identifies an area of increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients between attacks. Such observation supports the concept that an activity-induced rupture of cerebral metabolic homeostasis may be a cornerstone of migraine pathophysiology. This article has been selected as the winner of the 2018 Enrico Greppi Award. The Enrico Greppi Award is made to an unpublished paper dealing with clinical, epidemiological, genetic, pathophysiological or therapeutic aspects of headache. Italian Society for the Study of Headaches (SISC) sponsors this award, and the award is supported through an educational grant from Teva Neuroscience. This article did not undergo the standard peer review process for The Journal of Headache and Pain. The members of the 2018 Enrico Greppi Award Selection Committee were: Francesco Pierelli, Paolo Martelletti, Lyn Griffiths, Simona Sacco, Andreas Straube and Cenk Ayata.
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http://dx.doi.org/10.1186/s10194-018-0877-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033847PMC
July 2018

Short-term cortical synaptic depression/potentiation mechanisms in chronic migraine patients with or without medication overuse.

Cephalalgia 2019 02 19;39(2):237-244. Epub 2018 Jun 19.

5 G. B. Bietti Foundation IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy.

Objective: To study the effects of trains of repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in patients with chronic migraine (CM) with or without medication overuse (MOH).

Subjects And Methods: Thirty-two patients (CM [n = 16]; MOH [n = 16]) and 16 healthy volunteers (HVs) underwent rTMS recording. Ten trains of 10 stimuli each (120% resting motor threshold) were applied over the left motor cortex at 1 Hz or 5 Hz in random order. The amplitude of motor evoked potential (MEP) was evaluated from electromyographic recording in the first dorsal interosseous muscle. The slope of the linear regression line for the 10 stimuli for each participant was calculated using normalized data.

Results: rTMS-1 Hz had a normal depressive effect on MEP amplitude in all groups. rTMS-5 Hz depressed instead of potentiating MEP amplitudes in MOH patients, with a significantly different response from that in HVs and CM patients. The slope of the linear regression of MEP amplitudes was negatively correlated with pain intensity in CM patients, and with the duration of overuse headache in MOH patients.

Conclusions: This different plastic behaviour suggests that MOH and CM, despite exhibiting a similar clinical phenotype, have different neurophysiological learning processes, probably related to different pathophysiological mechanisms of migraine chronification.
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http://dx.doi.org/10.1177/0333102418784747DOI Listing
February 2019