Local Dynamic Stability of Trunk During Gait is Responsive to Rehabilitation in Subjects with Primary Degenerative Cerebellar Ataxia.

This study aimed to assess the responsiveness to the rehabilitation of three trunk acceleration-derived gait indexes, namely the harmonic ratio (HR), the short-term longest Lyapunov's exponent (sLLE), and the step-to-step coefficient of variation (CV), in a sample of subjects with primary degenerative cerebellar ataxia (swCA), and investigate the correlations between their improvements (∆), clinical characteristics, and spatio-temporal and kinematic gait features. The trunk acceleration patterns in the antero-posterior (AP), medio-lateral (ML), and vertical (V) directions during gait of 21 swCA were recorded using a magneto-inertial measurement unit placed at the lower back before (T0) and after (T1) a period of inpatient rehabilitation. For comparison, a sample of 21 age- and gait speed-matched healthy subjects (HSmatched) was also included. At T1, sLLE in the AP (sLLEAP) and ML (sLLEML) directions significantly improved with moderate to large effect sizes, as well as SARA scores, stride length, and pelvic rotation. sLLEML and pelvic rotation also approached the HSmatched values at T1, suggesting a normalization of the parameter. HRs and CV did not significantly modify after rehabilitation. ∆sLLEML correlated with ∆ of the gait subscore of the SARA scale (SARAGAIT) and ∆stride length and ∆sLLEAP correlated with ∆pelvic rotation and ∆SARAGAIT. The minimal clinically important differences for sLLEML and sLLEAP were ≥ 36.16% and ≥ 28.19%, respectively, as the minimal score reflects a clinical improvement in SARA scores. When using inertial measurement units, sLLEAP and sLLEML can be considered responsive outcome measures for assessing the effectiveness of rehabilitation on trunk stability during walking in swCA.

Can the ketogenic diet improve our dreams? Effect of very low-calorie ketogenic diet (VLCKD) on sleep quality.

BACKGROUND: Obesity is a condition that is often associated with sleep disorders, including reduced sleep quality (SQ). Very low calorie ketogenic diet (VLCKD) has proven to be effective in the management of obesity and associated metabolic disorders. However, little is still known about the effects of this promising nutritional protocol on SQ. Thus, the purpose of this study was to investigate the short-term effect of VLCKD on SQ in women with overweight/obesity and if any changes, to identify the predictive factor that through VLCKD modified SQ. METHODS: Were consecutively enrolled a total of 324 subjects, who met the inclusion criteria and accepted to adhere to VLCKD. Assessment of nutritional status, including anthropometric measurements (height, weight, and waist circumference), bioelectrical impedance analysis (phase-sensitive system, 50 kHz BIA 101 RJL, Akern Bioresearch, Florence, Italy Akern), high sensitivity C reactive protein levels (hs-CRP), and SQ were carried out at baseline and after 31 days of active stage of VLCKD. SQ was evaluated using the validated questionnaire Pittsburgh Sleep Quality Index (PSQI). RESULTS: In addition to the expected general improvement of anthropometric parameters and body composition, VLCKD improved significantly SQ, as demonstrated by the improvement of all parameters included in the PSQI questionnaire (p < 0.001). Both at baseline and after 31 days of active stage of VLCKD, the PSQI score was significantly associated with BMI, waist circumference, fat mass, fat free mass (p < 0.001 for all) and hs-CRP (p = 0.023). PhA was negatively associated with PSQI score only at baseline (p < 0.001). ∆% PSQI positively correlated with ∆% BMI, ∆% fat mass, ∆% hs-CRP (p < 0.001 for all) and negatively correlated with ∆% fat free mass (p < 0.001), and ∆% PhA (p = 0.031). In the multiple regression analysis ∆% fat mass represented the only predictor of changes in SQ after VLCKD. Finally, in the ROC analysis, a threshold value of ∆% fat mass > - 8.4% predicted improvement in SQ (p < 0.001). CONCLUSION: In conclusion, VLCKD determines an improvement of SQ in women with overweight and obesity, that was mostly mediated by the reduction of fat mass related to this nutritional protocol.

2:1 ketogenic diet and low-glycemic-index diet for the treatment of chronic and episodic migraine: a single-center real-life retrospective study.

AIMS: The evidence supporting the efficacy of dietary preventive therapy in migraine is rising, particularly regarding the ketogenic diet. However, less evidence exists for the Low-Glycemic Index Diet and the 2:1 KD. This retrospective single-center real-life study aims to evaluate the efficacy of a 2:1 ketogenic diet and a Low-Glycemic-index Diet in chronic and high-frequency episodic migraine. METHODS: Sixty patients with high-frequency episodic and chronic migraine were treated with either a Low-Glycemic-index diet (39 patients) or a 2:1 (21 patients) ketogenic diet for three months. We collected data on the migraine frequency and intensity and the MIDAS and HIT-6 scores through the headache diary. Anthropometric measurements (BMI, fat mass, free fat mass, and weight) were also collected and analyzed similarly. Data obtained at the baseline and after three months of each diet were compared. RESULTS: Migraine intensity, frequency, MIDAS and HIT-6 scores, fat mass, weight, and BMI improved in both diet groups. CONCLUSIONS: Both diets are effective in reducing migraine symptoms and migraine-related disability.

The monoclonal CGRP-receptor blocking antibody erenumab has different effects on brainstem and cortical sensory-evoked responses.

OBJECTIVES: It is unclear whether the electrophysiological effects of erenumab, a monoclonal antibody against the calcitonin gene-related peptide receptor, occur only at the periphery of the trigeminal system or centrally and at the cortical level. METHODS: We prospectively enrolled 20 patients with migraine who had failed at least two preventative treatments. We measured the nociceptive blink reflex and non-noxious somatosensory evoked potentials in all participants. The area under the curve and habituation of the second polysynaptic nociceptive blink reflex component (R2) as well as the amplitude and habituation of somatosensory evoked potentials N20-P25 were measured. Electrophysiological data were collected at baseline (T0), 28 days (T1), and 56 days (T2) before each injection of erenumab (70 mg). RESULTS: Erenumab reduced the patients' mean monthly headache days, headache intensity, and acute medication intake considerably at T1 and T2 (all p < 0.05). The nociceptive blink reflex area under the curve was considerably lower at T1 and T2 than at baseline without changing the habituation slope. At T2, there was a significant increase in the delayed somatosensory evoked potentials amplitude reduction (habituation) but not in the initial cortical activation. CONCLUSION: Our findings showed that erenumab, in addition to its well-known peripheral effects, can induce central effects earlier in the brainstem and later in the cortex. We cannot rule out whether these results are due to a direct effect of erenumab on the central nervous system or an indirect effect secondary to peripheral drug modulation.

Bimodal sensory integration in migraine: A study of the effect of visual stimulation on somatosensory evoked cortical responses.

BACKGROUND: Merging of sensory information is a crucial process for adapting the behaviour to the environment in all species. It is not known if this multisensory integration might be dysfunctioning interictally in migraine without aura, where sensory stimuli of various modalities are processed abnormally when delivered separately. To investigate this question, we compared the effects of a concomitant visual stimulation on conventional low-frequency somatosensory evoked potentials and embedded high-frequency oscillations between migraine patients and healthy volunteers. METHODS: We recorded somatosensory evoked potentials in 19 healthy volunteers and in 19 interictal migraine without aura patients before, during, and 5 min after (T2) simultaneous synchronous pattern-reversal visual stimulation. At each time point, we measured amplitude and habituation of the N20-P25 low-frequency-somatosensory evoked potentials component and maximal peak-to-peak amplitude of early and late bursts of high-frequency oscillations. RESULTS: In healthy volunteers, the bimodal stimulation significantly reduced low-frequency-somatosensory evoked potentials habituation and tended to reduce early high-frequency oscillations that reflect thalamocortical activity. By contrast, in migraine without aura patients, bimodal stimulation significantly increased low-frequency-somatosensory evoked potentials habituation and early high-frequency oscillations. At T2, all visual stimulation-induced changes of somatosensory processing had vanished. CONCLUSION: These results suggest a malfunctioning multisensory integration process, which could be favoured by an abnormal excitability level of thalamo-cortical loops.

Neuromodulation for Chronic Daily Headache.

PURPOSE OF REVIEW: We reviewed the literature that explored the use of central and peripheral neuromodulation techniques for chronic daily headache (CDH) treatment. RECENT FINDINGS: Although the more invasive deep brain stimulation (DBS) is effective in chronic cluster headache (CCH), it should be reserved for extremely difficult-to-treat patients. Percutaneous occipital nerve stimulation has shown similar efficacy to DBS and is less risky in both CCH and chronic migraine (CM). Non-invasive transcutaneous vagus nerve stimulation is a promising add-on treatment for CCH but not for CM. Transcutaneous external trigeminal nerve stimulation may be effective in treating CM; however, it has not yet been tested for cluster headache. Transcranial magnetic and electric stimulations have promising preventive effects against CM and CCH. Although the precise mode of action of non-invasive neuromodulation techniques remains largely unknown and there is a paucity of controlled trials, they should be preferred to more invasive techniques for treating CDH.

A Hypothalamic Mechanism Regulates the Duration of a Migraine Attack: Insights from Microstructural and Temporal Complexity of Cortical Functional Networks Analysis.

The role of the hypothalamus and the limbic system at the onset of a migraine attack has recently received significant interest. We analyzed diffusion tensor imaging (DTI) parameters of the entire hypothalamus and its subregions in 15 patients during a spontaneous migraine attack and in 20 control subjects. We also estimated the non-linear measure resting-state functional MRI BOLD signal's complexity using Higuchi fractal dimension (FD) and correlated DTI/fMRI findings with patients' clinical characteristics. In comparison with healthy controls, patients had significantly altered diffusivity metrics within the hypothalamus, mainly in posterior ROIs, and higher FD values in the salience network (SN). We observed a positive correlation of the hypothalamic axial diffusivity with migraine severity and FD of SN. DTI metrics of bilateral anterior hypothalamus positively correlated with the mean attack duration. Our results show plastic structural changes in the hypothalamus related to the attacks severity and the functional connectivity of the SN involved in the multidimensional neurocognitive processing of pain. Plastic changes to the hypothalamus may play a role in modulating the duration of the attack.

Inositols Depletion and Resistance: Principal Mechanisms and Therapeutic Strategies.

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

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

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.

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

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.

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

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.

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

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).

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

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.

Clinical neurophysiology of migraine with aura.

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.

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

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.

Resting state connectivity between default mode network and insula encodes acute migraine headache.

Background Previous functional MRI studies have revealed that ongoing clinical pain in different chronic pain syndromes is directly correlated to the connectivity strength of the resting default mode network (DMN) with the insula. Here, we investigated seed-based resting state DMN-insula connectivity during acute migraine headaches. Methods Thirteen migraine without aura patients (MI) underwent 3 T MRI scans during the initial six hours of a spontaneous migraine attack, and were compared to a group of 19 healthy volunteers (HV). We evaluated headache intensity with a visual analogue scale and collected seed-based MRI resting state data in the four core regions of the DMN: Medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and left and right inferior parietal lobules (IPLs), as well as in bilateral insula. Results Compared to HV, MI patients showed stronger functional connectivity between MPFC and PCC, and between MPFC and bilateral insula. During migraine attacks, the strength of MPFC-to-insula connectivity was negatively correlated with pain intensity. Conclusion We show that greater subjective intensity of pain during a migraine attack is associated with proportionally weaker DMN-insula connectivity. This is at variance with other chronic extra-cephalic pain disorders where the opposite was found, and may thus be a hallmark of acute migraine head pain.

Anodal transcranial direct current stimulation over the left temporal pole restores normal visual evoked potential habituation in interictal migraineurs.

BACKGROUND: Neuroimaging data has implicated the temporal pole (TP) in migraine pathophysiology; the density and functional activity of the TP were reported to fluctuate in accordance with the migraine cycle. Yet, the exact link between TP morpho-functional abnormalities and migraine is unknown. Here, we examined whether non-invasive anodal transcranial direct current stimulation (tDCS) ameliorates abnormal interictal multimodal sensory processing in patients with migraine. METHODS: We examined the habituation of visual evoked potentials and median nerve somatosensory evoked potentials (SSEP) before and immediately after 20-min anodal tDCS (2 mA) or sham stimulation delivered over the left TP in interictal migraineurs. RESULTS: Prior to tDCS, interictal migraineurs did not exhibit habituation in response to repetitive visual or somatosensory stimulation. After anodal tDCS but not sham stimulation, migraineurs exhibited normal habituation responses to visual stimulation; however, tDCS had no effect on SSEP habituation in migraineurs. CONCLUSION: Our study shows for the first time that enhancing excitability of the TP with anodal tDCS normalizes abnormal interictal visual information processing in migraineurs. This finding has implications for the role of the TP in migraine, and specifically highlights the ventral stream of the visual pathway as a pathophysiological neural substrate for abnormal visual processing in migraine.

Excitability of the motor cortex in patients with migraine changes with the time elapsed from the last attack.

BACKGROUND: Motor-evoked potentials (MEPs) produced by single-pulse transcranial magnetic stimulation (TMS) of the motor cortex can be an objective measure of cortical excitability. Previously, MEP thresholds were found to be normal, increased, or even reduced in patients with migraine. In the present study, we determined whether the level of cortical excitability changes with the time interval from the last migraine attack, thereby accounting for the inconsistencies in previous reports. METHODS: Twenty-six patients with untreated migraine without aura (MO) underwent a MEP study between attacks. Their data were then compared to the MEP data collected from a group of 24 healthy volunteers (HVs). During the experiment, the TMS figure-of-eight coil was positioned over the left motor area. After identifying the resting motor threshold (RMT), we delivered 10 single TMS pulses (rate: 0.1 Hz, intensity: 120% of the RMT) and averaged the resulting MEP amplitudes. RESULTS: The mean RMTs and MEP amplitudes were not significantly different between the MO and HV groups. In patients with MO, the RMTs were negatively correlated with the number of days elapsed since the last migraine attack (rho = -0.404, p = 0.04). CONCLUSION: Our results suggest that the threshold for evoking MEPs is influenced by the proximity of an attack; specifically, the threshold is lower when a long time interval has passed after an attack, and is higher (within the range of normative values) when measured close to an attack. These dynamic RMT variations resemble those we reported previously for visual and somatosensory evoked potentials and may represent time-dependent plastic changes in brain excitability in relation to the migraine cycle.

Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features.

BACKGROUND: To date, few MRI studies have been performed in patients affected by chronic migraine (CM), especially in those without medication overuse. Here, we performed magnetic resonance imaging (MRI) voxel-based morphometry (VBM) analyses to investigate the gray matter (GM) volume of the whole brain in patients affected by CM. Our aim was to investigate whether fluctuations in the GM volumes were related to the clinical features of CM. METHODS: Twenty untreated patients with CM without a past medical history of medication overuse underwent 3-Tesla MRI scans and were compared to a group of 20 healthy controls (HCs). We used SPM12 and the CAT12 toolbox to process the MRI data and to perform VBM analyses of the structural T1-weighted MRI scans. The GM volume of patients was compared to that of HCs with various corrected and uncorrected thresholds. To check for possible correlations, patients' clinical features and GM maps were regressed. RESULTS: Initially, we did not find significant differences in the GM volume between patients with CM and HCs (p < 0.05 corrected for multiple comparisons). However, using more-liberal uncorrected statistical thresholds, we noted that compared to HCs, patients with CM exhibited clusters of regions with lower GM volumes including the cerebellum, left middle temporal gyrus, left temporal pole/amygdala/hippocampus/pallidum/orbitofrontal cortex, and left occipital areas (Brodmann areas 17/18). The GM volume of the cerebellar hemispheres was negatively correlated with the disease duration and positively correlated with the number of tablets taken per month. CONCLUSION: No gross morphometric changes were observed in patients with CM when compared with HCs. However, using more-liberal uncorrected statistical thresholds, we observed that CM is associated with subtle GM volume changes in several brain areas known to be involved in nociception/antinociception, multisensory integration, and analgesic dependence. We speculate that these slight morphometric impairments could lead, at least in a subgroup of patients, to the development and continuation of maladaptive acute medication usage.