Identification of Gait Unbalance and Fallers Among Subjects with Cerebellar Ataxia by a Set of Trunk Acceleration-Derived Indices of Gait.

This study aimed to assess the ability of 25 gait indices to characterize gait instability and recurrent fallers among persons with primary degenerative cerebellar ataxia (pwCA), regardless of gait speed, and investigate their correlation with clinical and kinematic variables. Trunk acceleration patterns were acquired during the gait of 34 pwCA, and 34 age- and speed-matched healthy subjects (HSmatched) using an inertial measurement unit. We calculated harmonic ratios (HR), percent recurrence, percent determinism, step length coefficient of variation, short-time largest Lyapunov exponent (sLLE), normalized jerk score, log-dimensionless jerk (LDLJ-A), root mean square (RMS), and root mean square ratio of accelerations (RMSR) in each spatial direction for each participant. Unpaired t-tests or Mann-Whitney tests were performed to identify significant differences between the pwCA and HSmatched groups. Receiver operating characteristics were plotted to assess the ability to characterize gait alterations in pwCA and fallers. Optimal cutoff points were identified, and post-test probabilities were calculated. The HRs showed to characterize gait instability and pwCA fallers with high probabilities. They were correlated with disease severity and stance, swing, and double support duration, regardless of gait speed. sLLEs, RMSs, RMSRs, and LDLJ-A were slightly able to characterize the gait of pwCA but failed to characterize fallers.

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.

Ability of a Set of Trunk Inertial Indexes of Gait to Identify Gait Instability and Recurrent Fallers in Parkinson's Disease.

The aims of this study were to assess the ability of 16 gait indices to identify gait instability and recurrent fallers in persons with Parkinson's disease (pwPD), regardless of age and gait speed, and to investigate their correlation with clinical and kinematic variables. The trunk acceleration patterns were acquired during the gait of 55 pwPD and 55 age-and-speed matched healthy subjects using an inertial measurement unit. We calculated the harmonic ratios (HR), percent recurrence, and percent determinism (RQAdet), coefficient of variation, normalized jerk score, and the largest Lyapunov exponent for each participant. A value of ≤1.50 for the HR in the antero-posterior direction discriminated between pwPD at Hoehn and Yahr (HY) stage 3 and healthy subjects with a 67% probability, between pwPD at HY 3 and pwPD at lower HY stages with a 73% probability, and it characterized recurrent fallers with a 77% probability. Additionally, HR in the antero-posterior direction was correlated with pelvic obliquity and rotation. RQAdet in the antero-posterior direction discriminated between pwPD and healthy subjects with 67% probability, regardless of the HY stage, and was correlated with stride duration and cadence. Therefore, HR and RQAdet in the antero-posterior direction can both be used as age- and-speed-independent markers of gait instability.

Medication overuse and drug addiction: a narrative review from addiction perspective.

Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH). MOH is a secondary headache caused by overuse of analgesics or other medications such as triptans to abort acute migraine attacks. The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected. MO patients may also develop certain behaviors such as ritualized drug administration, psychological drug attachment, and withdrawal symptoms that have been suggested to correlate with drug addiction. Although several reviews have been performed on this topic, to the authors best knowledge none of them have examined this topic from the addiction point of view. Therefore, we aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications that can cause MOH and those with high risk to produce MO. We further compare differences between sensitization resulting from MO and from drug addiction, the neuronal pathways that may be involved, and the genetic susceptibility that may overlap between the two conditions. Finally, ICHD recommendations to treat MOH will be provided herein.

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.

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).

The association between migraine and physical exercise.

BACKGROUND: There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain conditions, including. However, what exact role exercise plays in migraine prevention is unclear. Here, we review the associations between physical exercise and migraine from an epidemiological, therapeutical and pathophysiological perspective. METHODS: The review was based on a primary literature search on the PubMed using the search terms "migraine and exercise". RESULTS: Low levels of physical exercise and high frequency of migraine has been reported in several large population-based studies. In experimental studies exercise has been reported as a trigger factor for migraine as well as migraine prophylaxis. Possible mechanisms for how exercise may trigger migraine attacks, include acute release of neuropeptides such as calcitonin gene-related peptide or alternation of hypocretin or lactate metabolism. Mechanisms for migraine prevention by exercise may include increased beta-endorphin, endocannabinoid and brain-derived neurotrophic factor levers in plasma after exercise. CONCLUSION: In conclusion, it seems that although exercise can trigger migraine attacks, regular exercise may have prophylactic effect on migraine frequency. This is most likely due to an altered migraine triggering threshold in persons who exercise regularly. However, the frequency and intensity of exercise that is required is still an open question, which should be addressed in future studies to delineate an evidence-based exercise program to prevent migraine in sufferers.

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.

Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: Correlations with thalamocortical activity and clinical features.

BACKGROUND: We studied lateral inhibition in the somatosensory cortex of migraineurs during and between attacks, and searched for correlations with thalamocortical activity and clinical features. PARTICIPANTS AND METHODS: Somatosensory evoked potentials (SSEP) were obtained by electrical stimulation of the right median (M) or ulnar (U) nerves at the wrist or by simultaneous stimulation of both nerves (MU) in 41 migraine without aura patients, 24 between (MO), 17 during attacks, and in 17 healthy volunteers (HVs). We determined the percentage of lateral inhibition of the N20-P25 component by using the formula [(100)-MU/(M + U)*100]. We also studied high-frequency oscillations (HFOs) reflecting thalamocortical activation. RESULTS: In migraine, both lateral inhibition (MO 27.9% vs HVs 40.2%; p = 0.009) and thalamocortical activity (MO 0.5 vs HVs 0.7; p = 0.02) were reduced between attacks, but not during. In MO patients, the percentage of lateral inhibition negatively correlated with days elapsed since the last migraine attack (r = -0.510, p = 0.01), monthly attack duration (r = -0.469, p = 0.02) and severity (r = -0.443, p = 0.03), but positively with thalamocortical activity (r = -0.463, p = 0.02). CONCLUSIONS: We hypothesize that abnormal migraine cycle-dependent dynamics of connectivity between subcortical and cortical excitation/inhibition networks may contribute to clinical features of MO and recurrence of attacks.

Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study.

BACKGROUND: Here, we aim to identify cortical electrofunctional correlates of responsiveness to short-lasting preventiveintervention with ketogenic diet (KD) in migraine. METHODS: Eighteen interictal migraineurs underwent visual (VEPs) and median nerve somatosensory (SSEPs) evokedpotentials before and after 1 month of KD during ketogenesis. We measured VEPs N1-P1 and SSEPs N20-P25 amplitudes respectively in six and in two sequential blocks of 100 sweeps as well as habituation as theslope of the linear regression between block 1 to 6 for VEPs or between 1 to 2 for SSEPs. RESULTS: After 1-month of KD, a significant reduction in the mean attack frequency and duration was observed (all P< 0.001). The KD did not change the 1st SSEP and VEP block of responses, but significantly inducednormalization of the interictally reduced VEPs and SSEPs (all p < 0.01) habituation during the subsequentblocks. CONCLUSIONS: KD could restore normal EPs habituation curves during stimulus repetition without significantly changing theearly amplitude responses. Thus, we hypothesize that KD acts on habituation regulating the balancebetween excitation and inhibition at the cortical level.

Lateralized nociceptive blink reflex habituation deficit in episodic cluster headache: Correlations with clinical features.

BACKGROUND: We previously observed impaired habituation mechanisms of the conventional blink reflex (BR) in patients with episodic cluster headache (ECH) during the bout, studying only the affected side. Here, we have studied the nociceptive-specific BR (nBR) both on the affected and non-affected sides, and in relation to clinical features. PARTICIPANTS AND METHODS: We recorded nBR in 18 ECH patients during the bout, and in 18 healthy volunteers (HVs). We compared pain threshold, area, and habituation of the nBR, recorded both for the affected and non-affected sides. RESULTS: In patients, the pain threshold on the affected side was lower than that of the non-affected side (p = 0.009), and lower than in HVs (p = 0.038). Reflex area was decreased on both sides (p < 0.05) compared with HVs, whereas habituation was significantly impaired only on the affected side (p = 0.025 vs. HVs; p = 0.003 vs. non-affected). The habituation slope was positively correlated with the number of days since the onset of the bout and the daily attack frequency. CONCLUSIONS: Our data reflect lateralized pathological variations in craniofacial nociception in ECH patients over the course of the cluster period. We hypothesized that this is due to malfunctioning of mechanisms that regulate hypothalamic activity and descending aminergic controls.

Evidence for brain morphometric changes during the migraine cycle: a magnetic resonance-based morphometry study.

Neurophysiological investigations have demonstrated that there are unique fluctuations in the migraine brain functional activity between the ictal and interictal periods. Here we investigated the possibility that there are fluctuations over time also in whole brain morphometry of patients affected by episodic migraine without aura (MO).Twenty-four patients with untreated MO underwent 3T MRI scans during (n = 10) or between attacks (n = 14) and were compared to a group of 15 healthy volunteers (HVs). We then performed voxel-based-morphometry (VBM) analysis of structural T1-weighted MRI scans to determine if changes in brain structure were observed over the course of the migraine cycle.Interictally, MO patients had a significantly lower gray matter (GM) density within the right inferior parietal lobule, right temporal inferior gyrus, right superior temporal gyrus, and left temporal pole than did HVs. Ictally, GM density increased within the left temporal pole, bilateral insula, and right lenticular nuclei, but no areas exhibited decreased GM density.These morphometric GM changes between ictal and interictal phases suggest that abnormal structural plasticity may be an important mechanism of migraine pathology. Given the functional neuroanatomy of these areas, our findings suggest that migraine is a condition associated with global dysfunction of multisensory integration and memory processing.

Visual evoked potentials in subgroups of migraine with aura patients.

BACKGROUND: Patients suffering from migraine with aura can have either pure visual auras or complex auras with sensory disturbances and dysphasia, or both. Few studies have searched for possible pathophysiological differences between these two subgroups of patients. METHODS: Methods - Forty-seven migraine with aura patients were subdivided in a subgroup with exclusively visual auras (MA, N = 27) and another with complex neurological auras (MA+, N = 20). We recorded pattern-reversal visual evoked potentials (VEP: 15 min of arc cheques, 3.1 reversal per second, 600 sweeps) and measured amplitude and habituation (slope of the linear regression line of amplitude changes from the 1st to 6th block of 100 sweeps) for the N1-P1 and P1-N2 components in patients and, for comparison, in 30 healthy volunteers (HV) of similar age and gender distribution. RESULTS: VEP N1-P1 habituation, i.e. amplitude decrement between 1st and 6th block, which was obvious in most HV (mean slope -0.50), was deficient in both MA (slope +0.01, p = 0.0001) and MA+ (-0.0049, p = 0.001) patients. However, VEP N1-P1 amplitudes across blocks were normal in MA patients, while they were significantly greater in MA+ patients than in HVs. CONCLUSIONS: Our findings suggest that in migraine with aura patients different aura phenotypes may be underpinned by different pathophysiological mechanisms. Pre-activation cortical excitability could be higher in patients with complex neurological auras than in those having pure visual auras or in healthy volunteers.

Visual Evoked Potential Responses after Photostress in Migraine Patients and Their Correlations with Clinical Features.

In the past few years, researchers have detected subtle macular vision abnormalities using different psychophysical experimental tasks in patients with migraine. Recording of visual evoked potential (VEP) after photostress (PS) represents an objective way to verify the integrity of the dynamic properties of macular performance after exposure to intense light. VEPs were recorded before and after PS in 51 patients with migraine (19 with aura (MA) and 22 without aura (MO) between attacks, and 10 recorded during an attack (MI)) and 14 healthy volunteers. All study participants were exposed to 30 s of PS through the use of a 200-watt bulb lamp. The P100 implicit time and N75-P100 amplitude of the baseline VEP were compared with those collected every 20 s up to 200 s after PS. VEP parameters recorded at baseline did not differ between groups. In all groups, the VEP recordings exhibited a significant increase in implicit times and a reduction in amplitude at 20 s after the PS. In migraine, the percentage decrease in amplitudes observed at 20 s after photostress was significantly lower than in healthy volunteers, in both MO and MA patients, but not in MI patients. When data for MO and MA patients were combined, the percentage of amplitude change at 20 s was negatively correlated with the number of days that had elapsed since the last migraine attack, and positive correlated with attack frequency. We showed dynamic changes of recovery of VEP after PS depending on the migraine cycle. This finding, in conjunction with those previously attained with other neuromodulatory interventions using VEPs, leads us to argue that migraine-disease-related dysrhythmic thalamocortical activity precludes amplitude suppression by PS.

Efficacy of Modified Atkins Ketogenic Diet in Chronic Cluster Headache: An Open-Label, Single-Arm, Clinical Trial.

INTRODUCTION: Drug-resistant cluster headache (CH) is still an open clinical challenge. Recently, our group observed the clinical efficacy of a ketogenic diet (KD), usually adopted to treat drug-resistant epilepsies, on migraine. AIM: Here, we aim to detect the effect of KD in a group of drug-resistant chronic CH (CCH) patients. MATERIALS AND METHODS: Eighteen drug-resistant CCH patients underwent a 12-week KD (Modified Atkins Diet, MAD), and the clinical response was evaluated in terms of response (≥50% attack reduction). RESULTS: Of the 18 CCH patients, 15 were considered responders to the diet (11 experienced a full resolution of headache, and 4 had a headache reduction of at least 50% in terms of mean monthly number of attacks during the diet). The mean monthly number of attacks for each patient at the baseline was 108.71 (SD = 81.71); at the end of the third month of diet, it was reduced to 31.44 (SD = 84.61). CONCLUSION: We observed for the first time that a 3-month ketogenesis ameliorates clinical features of CCH. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03244735.