Publications by authors named "Vincenzo Parisi"

119 Publications

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

-Related Retinitis Pigmentosa: Staging of Disease Severity and Morpho-Functional Studies.

Diagnostics (Basel) 2021 Feb 1;11(2). Epub 2021 Feb 1.

Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Usher syndrome type 2A () is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients' age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = -0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease.
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http://dx.doi.org/10.3390/diagnostics11020213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912870PMC
February 2021

Correlations between visual morphological, electrophysiological, and acuity changes in chronic non-arteritic ischemic optic neuropathy.

Graefes Arch Clin Exp Ophthalmol 2021 Jan 7. Epub 2021 Jan 7.

Visual Neurophysiology and Neurophthalmology Unit, IRCCS - Fondazione Bietti, Via Livenza 1, 00198, Rome, Italy.

Purpose: To study whether there is a correlation between the macular and optic nerve morphological condition and the retinal ganglion cells (RGCs) and visual pathways' function, and to investigate whether visual acuity (VA) changes might be related to the morpho-functional findings in chronic non-arteritic ischemic optic neuropathy (NAION).

Methods: In this retrospective study, 22 patients (mean age 62.12 ± 6.87) with chronic unilateral NAION providing 22 affected and 22 fellow eyes without NAION (NAION-FE), and 20 (mean age 61.20 ± 7.32) healthy control subjects were studied by spectral domain optical coherence tomography (Sd-OCT) for investigating macular thickness (MT) and volume (MV) of the whole (WR), inner (IR) and outer retina (OR), and the peripapillary retinal nerve fiber layer thickness (RNFL-T) measured overall and for all quadrants. Also, simultaneous 60' and 15' pattern electroretinogram (PERG) and visual evoked potentials (VEP) and VA were assessed. Differences of MT and MV of WR, IR, OR, and RNFL-T overall and for all quadrants, PERG amplitude (A), VEP implicit time (IT), and A and VA values between NAION eyes and controls were assessed by one-way analysis of variance. Pearson's test was used for regression analysis. A p value < 0.01 was considered as significant.

Results: In NAION eyes as compared to NAION-FE eyes and controls, significant (p < 0.01) changes of MT, MV of WR and IR, RNFL-T, 60' and 15' PERG A, VEP IT and A, and VA were found. No significant (p > 0.01) OR changes were observed between groups. In NAION eyes, significant (p < 0.01) correlations between MV of WR and IR and 15' PERG A were found. Overall, RNFL-T values were significantly correlated (p < 0.01) with those of 60' PERG A and VEP IT and A; temporal RNFL-T values were correlated (p < 0.01) with 15' PERG A and VEP IT and A ones. Temporal RNFL-T, MV-IR, and 15' PERG A as well as VEP IT were significantly (p < 0.01) correlated with VA. Significant (p < 0.01) linear correlations between 60' and 15' PERG A findings and the corresponding values of 60' and 15' VEP A were also found.

Conclusion: Our findings suggest that in chronic NAION, there is a morpho-functional impairment of the IR, with OR structural sparing. VA changes are related to the impaired morphology and function of IR, to the temporal RNFL-T reduction and to the dysfunction of both large and small axons forming the visual pathway.
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http://dx.doi.org/10.1007/s00417-020-05023-wDOI Listing
January 2021

Functional Assessment of Outer and Middle Macular Layers in Multiple Sclerosis.

J Clin Med 2020 Nov 22;9(11). Epub 2020 Nov 22.

IRCCS-Fondazione Bietti, Via Livenza 1, 00198 Rome, Italy.

The involvement of macular preganglionic elements' function, during the neurodegenerative process of multiple sclerosis (MS), is controversial. In this case-control observational and retrospective study, we assessed multifocal electroretinogram (mfERG) responses from 41 healthy Controls, 41 relapsing-remitting MS patients without optic neuritis (ON) (MS-noON Group) and 47 MS patients with ON: 27 with full recovery of high-contrast best corrected visual acuity (BCVA) (MS-ON-G Group) and 20 with poor recovery (between 0.2 and 1 LogMAR) of BCVA, (MS-ON-P Group). In the latter Group, Sd-OCT macular volumes and thicknesses of whole and inner and outer retina were measured. MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs), were measured from concentric rings (R) with increasing foveal eccentricity: 0-5° (R1), 5-10° (R2), 10-15° (R3), 15-20° (R4), 20-25° (R5), and from retinal sectors (superior, nasal, inferior and temporal) between 0-15° and 0-25°. In the MS-ON-P Group, mean mfERG RADs detected from R1 (0-5°) and from the central nasal sector (0-15°) were significantly reduced ( < 0.01) with respect to those of the Control, MS-noON and MS-ON-G Groups. No other significant differences between Groups for any mfERG parameters were found. All Sd-OCT measurements, apart from the inner retina macular volume in the central 1 mm, were significantly reduced in MS-ON-P patients compared to Controls. The functional impairment in the MS-ON-P Group was associated but not correlated with structural changes of the outer and inner retinal layers in corresponding retinal Areas and Sectors. Our results suggest that in MS, exclusively after ON with poor recovery of BCVA, the neurodegenerative process can induce dysfunctional mechanisms involving photoreceptors and bipolar cells of the fovea and of the more central nasal macular area.
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http://dx.doi.org/10.3390/jcm9113766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700336PMC
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

Visual Evoked Potentials in Joubert Syndrome: A Suggested Useful Method for Evaluating Future Approaches Targeted to Improve Visual Pathways' Function.

Adv Ther 2021 01 24;38(1):278-289. Epub 2020 Oct 24.

Department of Surgical and Clinical, Diagnostic and Pediatric Sciences, Section of Ophthalmology, University of Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Introduction: Joubert syndrome (JS) is a recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including optic nerve morphologic abnormalities. The function of the visual pathways, including the optic nerve, can be objectively evaluated by visual evoked potential (VEP) recordings. Our work aims to employ VEP to evaluate the neural conduction along the visual pathways in JS patients with or without optic nerve morphologic abnormalities (ONMA).

Methods: In this observational and prospective study, 18 children with genetic diagnosis of JS (mean age 8.78 ± 5.87 years) and 17 healthy age-similar control subjects (control group, 9.05 ± 6.02 years) were enrolled. Based on presence/absence of ONMA at fundus examination, JS patients were divided into two groups: the JS-A group (eight patients with ONMA) and JS-N group (ten patients without ONMA). Following the ISCEV standards, pattern VEPs were recorded in patients and controls in response to 60' and 15' checks to obtain a prevalent activation of large or small axons, respectively.

Results: Compared to controls, both the JS-A and JS-N groups showed significant abnormalities in 60' and 15' VEP implicit time and amplitude. Only in the JS-N group were values of 15' VEP implicit significantly correlated with the corresponding values of visual acuity.

Conclusions: Our results suggest that a visual pathways dysfunction (of both large and small axons) detectable by VEP may occur in JS patients regardless of the presence of ONMA. Since clinical trials are envisaged in the near future to address JS-related ocular problems, our results might provide information about the potential usefulness of VEP recordings to assess the efficacy of treatments targeted to improve the visual pathways' function.
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http://dx.doi.org/10.1007/s12325-020-01534-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854410PMC
January 2021

Morphological Outer Retina Findings in Multiple Sclerosis Patients With or Without Optic Neuritis.

Front Neurol 2020 15;11:858. Epub 2020 Sep 15.

Istituto di Ricovero e Cura a Carattere Scientifico - Fondazione Bietti, Rome, Italy.

To investigate on the morphology of the macular inner (IR) and outer (OR) layers in multiple sclerosis (MS) patients with and without history of optic neuritis (ON), followed by good or poor recovery of best corrected visual acuity (BCVA). Thirty-five normal control subjects and 93 relapsing remitting MS patients were enrolled. Of this, 40 MS patients without ON (MS-noON, 40 eyes), 27 with history of ON and good BCVA recovery (MS-ON-G, 27 eyes), and 26 with history of ON and poor BCVA recovery (MS-ON-P, 26 eyes) were studied. Controls and MS patients underwent an extensive ophthalmological examination including spectral-domain optical coherence tomography evaluating in 3 localized macular areas (0-1 mm, Area 1; 1-3 mm, Area 2; 3- 6 mm, Area 3), volumes (MV), and thicknesses (MT) of the whole retina (WR), further segmented in IR and OR. The differences of MV and MT between the groups were tested by ANOVA. In the MS-ON-P group, the correlations between MV and MT and BCVA were evaluated by Pearson's test. When compared to controls, the MS-noON group showed not significantly ( > 0.01) different MVs, whereas MTs were significantly ( < 0.01) reduced in the evaluation of WR and IR. In the MS-ON-G group, a significant ( < 0.01) reduction of WR and IR MVs and MTs was found in Areas 2 and 3; OR MVs and MTs were similar ( > 0.01) to controls. In the MS-ON-P group a significant ( < 0.01) reduction of WR, IR, and OR MVs and MTs was detected in all areas; the BCVA reduction was significantly ( < 0.01) correlated with WR and IR MVs and MTs. In MS without history of ON or when ON is followed by a good BCVA recovery, the neurodegenerative process is limited to IR macular layers; in the presence of ON, with a poor BCVA recovery, a morphological impairment of both IR and OR macular layers occurs.
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http://dx.doi.org/10.3389/fneur.2020.00858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522220PMC
September 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

Electroretinographic Assessment in Joubert Syndrome: A Suggested Objective Method to Evaluate the Effectiveness of Future Targeted Treatment.

Adv Ther 2020 09 15;37(9):3827-3838. Epub 2020 Jul 15.

Department of Surgical and Clinical, Diagnostic and Pediatric Sciences, Section of Ophthalmology, IRCCS Fondazione Policlinico San Matteo, University of Pavia, Pavia, Italy.

Introduction: Joubert syndrome (JS) is an autosomal recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including congenital retinal dystrophy. The function of different retinal elements (rod, cone, bipolar cells) can be objectively evaluated by electroretinogram (ERG) recordings. Our work aims to evaluate the retinal function (by ERG recordings) in patients with JS with or without congenital retinal dystrophy. In addition, since clinical trials should be performed in the near future in JS, our results could provide information about the possible usefulness of ERG recordings in the assessment of the efficacy of treatments targeted to improve the retinal involvement.

Methods: In this observational and prospective study, 24 children with genetic identification for JS (mean age 10.75 ± 6.59 years) and 25 healthy age-similar normal control subjects (control group, mean age 10.55 ± 3.76 years) were enrolled. On the basis of the presence/absence of retinal dystrophy at fundus examination, patients with JS were divided into two groups: patients with JS with retinal dystrophy (16 children, mean age 11.00 ± 6.74 years, providing 16 eyes; JS-RD group) and patients with JS without retinal dystrophy (8 children, mean age 10.50 ± 6.45 years, providing 8 eyes; JS-NRD group). In patients with JS and controls, visual acuity (VA), dark-adapted, light-adapted, and 30-Hz flicker ERGs were performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols.

Results: When compared to controls, patients in the JS-RD and JS-NRD groups showed significant abnormalities of the values of dark-adapted, light-adapted, and 30-Hz flicker ERG parameters. The ERG and VA changes were not significantly correlated.

Conclusions: Our results suggest that a dysfunction of photoreceptors and bipolar cells occurs in patients with JS with or without retinal dystrophy. The retinal impairment can be detected by ERG recordings and this method should be proposed to evaluate the effectiveness of adequate treatment targeted to improve the retinal impairment in patients with JS.
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http://dx.doi.org/10.1007/s12325-020-01432-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444391PMC
September 2020

Macular Functional and Morphological Changes in Intermediate Age-Related Maculopathy.

Invest Ophthalmol Vis Sci 2020 05;61(5):11

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Purpose: The purpose of this study was to evaluate macular preganglionic function and to verify its relationship with retinal and choroidal morphology in patients with intermediate age-related macular degeneration (iAMD) patients.

Methods: All included patients performed multifocal electroretinogram (mfERG) for investigating on macular function from the central 15° of foveal eccentricity, spectral domain optical coherence tomography (SD-OCT) for studying retinal structure, enhanced depth imaging OCT (EDI-OCT) for the measure of choroidal vascularity index (CVI), and OCT-angiography (OCTA) for the evaluation of vessel density (VD) in the superficial and deep capillary plexus, and choriocapillaris (CC) layer.

Results: Twenty-seven patients with iAMD and 20 age-matched control eyes were analyzed. Significantly (P < 0.01) delayed and reduced mfERG responses in the central 0 to 2.5°, paracentral 2.5 to 5°, and overall 0 to 5° areas, as well as increased CVI values in both foveal (1 mm centered to the fovea) and fovea + parafovea areas (3 mm centered to the fovea), increased foveal and parafoveal (annular area of 1-3 mm centered to the fovea) retinal pigment epithelium thickness, and volume and parafoveal outer retinal volume were found in iAMD eyes as compared to controls. Moreover, iAMD eyes showed significantly (P < 0.01) reduced foveal and parafoveal OCTA-VD values in the CC layer when compared to controls. In the iAMD group, not significant (P > 0.01) correlations were found between morphological and functional parameters.

Conclusions: Our findings support a dysfunction of photoreceptors and bipolar cells in both foveal and parafoveal areas in the presence of outer retina, CC, and choroidal structural changes, however, not significantly correlated. The observed enlargement of luminal choroidal area (measured by CVI) is possibly compensatory to CC vascular insufficiency.
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http://dx.doi.org/10.1167/iovs.61.5.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405611PMC
May 2020

Choriocapillaris Integrity in Relapsed Central Serous Chorioretinopathy in a Patient Treated With Fingolimod for Multiple Sclerosis: New Insights From Optical Coherence Tomography Angiography.

J Neuroophthalmol 2021 Mar;41(1):e51-e53

Neurophysiology of Vision and Neuroophthalmology Unit (LZ, LB, VP), IRCCS-Fondazione Bietti, Rome, Italy; Medical Retina Unit (DDG, PG, MP), IRCCS-Fondazione Bietti, Rome, Italy; and Multiple Sclerosis Clinical and Research Unit (DL, GAM, MA), Department of Systems Medicine, Tor Vergata University, Rome, Italy.

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http://dx.doi.org/10.1097/WNO.0000000000000937DOI Listing
March 2021

The Role of Autophagy in Glaucomatous Optic Neuropathy.

Front Cell Dev Biol 2020 4;8:121. Epub 2020 Mar 4.

Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, Rende, Italy.

Autophagy is a conserved lysosomal-dependent pathway responsible for the degradation of cytoplasmic macromolecules. Based on the mechanism of cargo delivery to lysosomes, mammalian cells can undergo micro, macro, and chaperone-mediated autophagy. Other than physiological turnover of proteins and organelles, autophagy regulates cellular adaptation to different metabolic states and stressful conditions by allowing cellular survival or, when overactivated, participating to cell death. Due to their structure and function, neurons are highly dependent on autophagy efficiency and dysfunction of the pathway has been associated with neurodegenerative disorders. Glaucomatous optic neuropathies, a leading cause of blindness, are characterized by the progressive loss of a selective population of retinal neurons, i.e., the retinal ganglion cells (RGCs). Here we review the current literature on the role of autophagy in the pathogenic process that leads to the degeneration of RGC in various experimental models of glaucoma exploring the modulation of the pathway as a potential therapeutic intervention.
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http://dx.doi.org/10.3389/fcell.2020.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066980PMC
March 2020

Citicoline and Vitamin B Eye Drops in Type 1 Diabetes: Results of a 3-year Pilot Study Evaluating Morpho-Functional Retinal Changes.

Adv Ther 2020 04 16;37(4):1646-1663. Epub 2020 Mar 16.

IRCCS Fondazione Bietti, Rome, Italy.

Introduction: This study aimed to evaluate the effect of treatment with eye drops containing citicoline and vitamin B on changes in function of the inner retina, morphology of the inner and outer retina, and microvascular condition in patients with type 1 diabetes (DM1) with mild signs of non-proliferative diabetic retinopathy (NPDR) during 3 years of follow-up.

Methods: A pilot study with prospective, randomized, and double-masked design was conducted to address the aims. Twenty patients with DM1 were enrolled and randomly divided into two groups: the DC group comprising patients treated with citicoline and vitamin B eye drops (10 patients; mean age ± standard deviation, 46.86 ± 8.78 years) and the DP group comprising those treated with placebo (10 patients; mean age ± standard deviation, 47.89 ± 7.74 years). In the DC group, one eye of each patient was treated with citicoline and vitamin B eye drops (OMK2, Omikron Italia srl, Italy, 3 drops/day), while in the DP group, it was treated with placebo (eye drops containing hypromellose 0.3%, 3 drops/day) for a 3-year period. In both groups, Humphrey Matrix frequency doubling technology (FDT), spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA), and adaptive optics (AO) were applied at baseline and 12, 24, and 36 months of the follow-up period.

Results: In the results of follow-up evaluation, the DC and DP groups were significantly different: Significant reduction in function in terms of 10-2 FDT mean sensitivity and in morphology reflected by an increase in inner nuclear layer thickness and decrease in other plexiform layer thickness and foveal vessel density were observed in the DP group, while no such significant changes were observed in the DC group in the long term.

Conclusions: This pilot study indicated that patients with DM1 with mild signs of diabetic retinopathy (DR) who underwent treatment with citicoline and vitamin B eye drops for a 3-year duration achieved stabilization or decreased rate of functional impairment, neuroretinal degeneration, and microvascular damage.

Trial Registration: ClinicalTrials.gov identifier, NCT04009980.
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http://dx.doi.org/10.1007/s12325-020-01284-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140741PMC
April 2020

Surgery for Idiopathic Epimacular Membrane: Morpho-Functional Outcomes Based on the Preoperative Macular Integrity of the Photoreceptoral Junction. A Prospective Pilot Study.

Adv Ther 2020 01 11;37(1):566-577. Epub 2019 Dec 11.

Department of Surgical & Clinical, Diagnostic and Pediatric Sciences, Section of Ophthalmology, University of Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Introduction: This study aimed to evaluate whether the preoperative integrity of the inner segment (IS) and outer segment (OS) photoreceptoral junction may influence the postoperative visual acuity, the macular morphology [assessed by spectral domain optical coherence tomography (SD-OCT)], and macular function (evaluated by multifocal electroretinogram, mfERG) in patients with idiopathic epimacular membrane (EMM) followed up for 6 months.

Methods: In this observational prospective study, 18 patients with EMM (mean age 72.5 ± 6.87 years) were enrolled. They were divided into two groups according to the preoperative integrity of the SD-OCT IS/OS junction: the EMM-I group with an intact IS/OS junction (11 patients, mean age 72.75 ± 3.49 years, providing 11 eyes) and the EMM-D group with a disrupted IS/OS junction (7 patients, mean age 70.86 ± 10.79 years, providing 7 eyes). For each enrolled patient, visual acuity (VA), mfERG, and SD-OCT were assessed at baseline (preoperative) and after 1, 3, and 6 months of follow-up after surgical treatment for EMM (pars plana vitrectomy with EMM removal and internal limiting membrane peeling).

Results: During the whole follow-up, VA was significantly increased in EMM-I eyes and unmodified in EMM-D eyes. In both groups, mfERG responses were not significantly different and not related to VA differences. In EMM-I eyes a significant reduction of central retinal thickness (CRT) was observed; however, it was not correlated with VA changes. In EMM-D eyes CTR was not significantly reduced, whereas macular volume was significantly reduced. These changes were significantly related to the corresponding differences in VA.

Conclusions: Our results suggest that the preoperative evaluation of the integrity of the IS/OS junction is relevant for postoperative outcomes. The recovery in VA was higher in EMM-I eyes than in EMM-D eyes. Postoperative recovery was not associated with morphology of the outer retina (photoreceptor and outer nuclear layer) and the function of preganglionic elements.
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http://dx.doi.org/10.1007/s12325-019-01165-4DOI 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

Correction to: Effects of Macuprev Supplementation in Age-Related Macular Degeneration: A Double-Blind Randomized Morpho-Functional Study Along 6 Months of Follow-Up.

Adv Ther 2019 Nov;36(11):3288

IRCCS Fondazione Bietti, Rome, Italy.

The article ''Effects of Macuprev Supplementation in Age-Related Macular Degeneration: A Double-Blind Randomized Morpho-Functional Study Along 6 Months of FollowUp'', written by Mariacristina Parravano, Massimiliano Tedeschi, Daniela Manca, Eliana Costanzo, Antonio Di Renzo, Paola Giorno, Lucilla Barbano, Lucia Ziccardi, Monica Varano, Vincenzo Parisi was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 25, 2019 without Open Access. The article has now been made Open Access.
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http://dx.doi.org/10.1007/s12325-019-01094-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822796PMC
November 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

Effects of Macuprev Supplementation in Age-Related Macular Degeneration: A Double-Blind Randomized Morpho-Functional Study Along 6 Months of Follow-Up.

Adv Ther 2019 09 25;36(9):2493-2505. Epub 2019 Jun 25.

IRCCS Fondazione Bietti, Rome, Italy.

Background: To evaluate the effects of Macuprev supplementation on macular function and structure in intermediate age-related macular degeneration (AMD) along 6 months of follow-up.

Methods: In this double-blind, monocentric, randomized, and prospective study, 30 patients with intermediate AMD were enrolled and randomly divided into two age-similar groups: 15 patients (AMD-M group; mean age 68.50 ± 8.79 years) received 6-month oral daily supplementation with Macuprev (Farmaplus Italia s.r.l., Italy, two tablets/day on an empty stomach, before meals; contained in total lutein 20 mg, zeaxanthin 4 mg, N-acetylcysteine 140 mg, bromelain 2500GDU 80 mg, vitamin D 800 IU, vitamin B 18 mg, alpha-lipoic acid 140 mg, rutin 157 mg, vitamin C 160 mg, zinc oxide 16 mg, Vaccinium myrtillus 36% anthocyanosides 90 mg, Ganoderma lucidum 600 mg) and 15 patients (AMD-P group; mean age 70.14 ± 9.87) received two tablets of placebo daily on an empty stomach, before meals. A total of 28 eyes, 14 from each AMD group, completed the study. Multifocal electroretinogram (mfERG) and spectral domain-optical coherence tomography (SD-OCT) were assessed at baseline and after 6 months.

Results: At 6-month follow-up, AMD-M eyes showed a significant increase of mfERG response amplitude density (RAD) recorded from the central macular areas (ring 1, 0-2.5°; ring 2, 2.5-5°), whereas non-significant changes of retinal and choroidal SD-OCT parameters were found when values were compared to baseline. Non-significant correlations between functional and structural changes were found. In AMD-P eyes, non-significant differences for each mfERG and SD-OCT parameters were observed at 6 months.

Conclusions: In intermediate AMD, Macuprev supplementation increases the function of the macular pre-ganglionic elements, with no associated retinal and choroidal ultra-structural changes.

Trial Registration: ClinicalTrials.gov identifier, NCT03919019.

Funding: Research for this study was financially supported by the Italian Ministry of Health and Fondazione Roma. Article processing charges were funded by Farmaplus Italia s.r.l., Italy.
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http://dx.doi.org/10.1007/s12325-019-01016-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822854PMC
September 2019

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

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber's Hereditary Optic Neuropathy during One Year of Follow-up.

Ophthalmology 2019 07 26;126(7):1033-1044. Epub 2019 Feb 26.

Studio Oculistico d'Azeglio, Bologna, Italy; IRCCS Istituto Scientifico San Raffaele, Milan, Italy.

Purpose: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase.

Design: Retrospective case series.

Participants: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls.

Methods: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60' and 15' checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test-retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA.

Main Outcome Measures: Changes of individual and mean absolute values of 60' and 15' PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group.

Results: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values.

Conclusions: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.
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http://dx.doi.org/10.1016/j.ophtha.2019.02.018DOI Listing
July 2019

Enhancement of Retinal Function and of Neural Conduction Along the Visual Pathway Induced by Treatment with Citicoline Eye Drops in Liposomal Formulation in Open Angle Glaucoma: A Pilot Electrofunctional Study.

Adv Ther 2019 04 21;36(4):987-996. Epub 2019 Feb 21.

DSCMT, University of Rome Tor Vergata, Rome, Italy.

Introduction: To evaluate the retinal function and the relative neural conduction along the visual pathway after treatment with citicoline in liposomal formulation (CLF) eye drops in patients with open angle glaucoma (OAG).

Methods: Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure < 18 mmHg under topical hypotensive treatment, Humphrey field analyzer mean deviation - 4.49 ± 2.46 dB) were enrolled. Only one eye of studied patients was treated with CLF eye drops (OMK1-LF, Omikron Italia, 3 drops/day) (CLF group, 12 eyes) over a period of 4 months. In CLF eyes, pattern electroretinogram (PERG), visual evoked potentials (VEP), and visual field test were assessed at baseline and at the end of treatment (month 4).

Results: After treatment with CLF eye drops, a significant increase of PERG P50-N95 amplitude and a significant shortening of VEP P100 implicit time were found. In CLF eyes, the shortening of VEP P100 implicit time was significantly correlated with the increase of PERG P50-N95 amplitude.

Conclusion: Data from this pilot study suggest that treatment with CLF eye drops induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening of VEP implicit time).

Funding: Omikron Italia S.r.l. and Opko Health Europe.
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http://dx.doi.org/10.1007/s12325-019-0897-zDOI Listing
April 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

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