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.

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.

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.

Infectious risk in multiple sclerosis patients treated with disease-modifying therapies: A three-year observational cohort study.

BACKGROUND: The disease-modifying therapies (DMTs) largely used in multiple sclerosis (MS) may result in higher infectious risk. OBJECTIVE: We aimed to investigate the infectious risk in DMT-treated MS patients. METHODS: MS patients were evaluated for infectious risk before starting, switching or during DMT. RESULTS: In this three-year observational cohort study 174 MS patients were enrolled. Among them, 18 patients were anti-HBc + and 19 patients were QuantiFERON®-TB Gold In-Tube (QFT) + . No patients with anti-HBc + showed a detectable HBV-DNA and all started DMT. Among QTB + patients, 17 latent TB infections (LTBIs) and 2 active TB infections (TBIs) were identified. After one month of LTBI prophylaxis or TB treatment, respectively, all patients started DMTs.Overall, 149 started DMTs. During DMTs, one ocrelizumab-treated patient with anti-HBc + developed HBV reactivation and six patients (3 on natalizumab, 2 on ocrelizumab and 1 on IFN-ß) showed reactivation of HSV-1, with detectable plasma DNA. Finally, 1 cladribine-treated patient experienced VZV reactivation. All the reactivations of latent infections have been successfully treated. CONCLUSION: Screening of infectious diseases in DMT candidate MS patients helps to mitigate the infectious risk. During DMTs, a regular assessment of infectious risk allows to avoid discontinuing MS therapy and guarantees a higher degree of safety.

Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers.

BACKGROUND AND AIMS: Most patients with multiple sclerosis presenting with a relapsing-remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1-2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis. METHODS: We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement. RESULTS: From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers. CONCLUSION: To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

Post-stroke plastic reorganisation in the adult brain.

Recovery of function after a stroke is attributable to several factors, including events in the first few days (eg, reabsorption of perilesional oedema, tissue reperfusion). However, consistent reorganisation and recovery after a stroke takes weeks or months. In the early stages, recovery from stroke can vary greatly among patients with identical clinical symptoms. Neuroimaging techniques that enable us to assess baseline and task-related functions, and neurophysiological techniques that measure brain function in "real time", can be used to study the recovery of brain lesions after a stroke. In this review, we discuss important neuroimaging and neurophysiological studies of post-stroke brain reorganisation.

Copper perturbation in 2 monozygotic twins discordant for degree of cognitive impairment.

BACKGROUND: Recent evidence indicates that peripheral tissue markers can provide information regarding changes affecting cellular metabolism in Alzheimer disease (AD). We previously reported that serum copper levels can discriminate subjects with AD from normal control subjects (with 60% sensitivity and 95% specificity) and from patients with vascular dementia (with 63% sensitivity and 85% specificity). OBJECTIVE: To study the correlation between AD and serum levels of transition metals and markers of peripheral oxidative stress. DESIGN: Case study. SETTING: General hospital inpatient wards and outpatient clinics. Patients A pair of elderly monozygotic female twins discordant for AD. MAIN OUTCOME MEASURES: Biochemical analyses of peripheral-blood transition metals and indicators of oxidative stress and neurologic and neuropsychological assessments of clinical status for presence of cognitive impairment and AD. RESULTS: Serum copper and total peroxide levels were both 44% higher in the twin with greater cognitive impairment and a diagnosis of AD. CONCLUSIONS: The cases reported support the hypothesis of a major involvement of copper and oxidative abnormalities in AD.

Reduction of transcallosal inhibition upon awakening from REM sleep in humans as assessed by transcranial magnetic stimulation.

STUDY OBJECTIVES: The aim of the study is to assess, in humans, transcallosal inhibition upon awakening from rapid eye movement (REM) and non-REM sleep, by paired-pulse transcranial magnetic stimulation (TMS). DESIGN: During the daytime, a baseline session of motor evoked potentials (MEPs) was recorded. During the nighttime, the TMS sessions were administered just before sleep onset and upon awakenings from REM and stage 2 sleep, both in the early and final part of night. SETTING: The sleep research laboratory at the University of Rome "La Sapienza." PARTICIPANTS: Ten right-handed subjects participated in the experiment for 4 consecutive sleep-recording nights. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: During the daytime, a robust transcallosal inhibition was found; the MEP amplitude reduction ranged from 35% to 40%. During the nighttime, a decrease of transcallosal inhibition from right-to-left motor cortex, as compared to that from left-to-right motor cortex, was observed. The direct assessment of MEP changes, as a function of sleep stage and of the time of night, pointed to a drop of transcallosal inhibition after awakening from REM sleep. Therefore, the inhibitory activity of transcallosal fibers observed after non-REM awakening almost disappeared after REM sleep awakenings. CONCLUSIONS: The drastic drop of transcallosal inhibition after awakenings from REM sleep represents the first evidence in humans of a change of interhemispheric connectivity mediated by the corpus callosum during this sleep stage and may open new avenues for a better understanding of some aspects of sleep mechanisms (ie, dreaming function and dream mentation).

Callosal effects of transcranial magnetic stimulation (TMS): the influence of gender and stimulus parameters.

Transcranial magnetic stimulation (TMS) of the motor cortex of one hemisphere (conditioning stimulus, CS) inhibits EMG responses evoked in distal hand muscles by a magnetic stimulus given at appropriate interval later over the opposite hemisphere (test stimulus, TS). The common interpretation attributes this effect to an inhibition produced at cortical level via a transcallosal route. The variability of cortical excitability as measured by the interhemispheric paired-pulse (PP) technique has been assessed in healthy subjects in order to compare sub- and supra-threshold intensity of CS (80% versus 120% of individual motor threshold, MT). Within- and between-subject variability relating, respectively, to interhemispheric and gender differences were also assessed. Results point to an efficacy of a magnetic CS on one hemisphere in inhibiting EMG responses of the abductor digiti minimi (ADM) stimulated by a TS delivered over the opposite hemisphere in a range of intervals centered at 12ms. These reductions were produced by the 120% suprathreshold CS, while the 80% subthreshold CS did not affect EMG responses. Females showed a higher transcallosal inhibition than males, suggesting gender differences in interhemispheric connectivity that concern the anterior half of the trunk of the corpus callosum.

Reproducibility of callosal effects of transcranial magnetic stimulation (TMS) with interhemispheric paired pulses.

Transcranial magnetic stimulation (TMS) of the motor cortex of one hemisphere (conditioning stimulus (CS)) inhibits EMG responses evoked in distal hand muscles by a later magnetic stimulus given at an appropriate interval, over the opposite hemisphere (test stimulus (TS)). This effect is commonly attributed to an inhibition produced at cortical level via a transcallosal route. The present study assessed the reproducibility of the transcallosal inhibition effects in different sessions in healthy subjects. Within- and between-subject variability, relating to interhemispheric differences was also evaluated. A magnetic CS on one hemisphere effectively inhibited EMG responses of the abductor digiti minimi stimulated by a TS delivered over the opposite hemisphere in a range of intervals centered at 12 ms. Even though group effects were reproduced in separate sessions, the high between- and within-subject variability yielded low test-retest correlations. This differentiation forces the definition of reproducibility (or repeatability), as the replication of the same mean curves of EMG reduction, and of reliability, as the between- or within-subject correlations between values of specific EMG measures.

Visualization of evolving status epilepticus with diffusion and perfusion MR imaging.

Since Kojewnikoff's first description of epilepsia partialis continua, isolated case reports and small case series have elucidated the disease. However, few imaging studies have been performed. We report a case in which serial diffusion and perfusion MR imaging allowed monitoring of the changes in hemodynamic and cell membrane permeability until the resolution of clinical and electrical epileptic activity.

Recurrent leukoencephalopathy in a cocaine abuser.

We report the case of a cocaine abuser who presented two consecutive episodes of acute leukoencephalopathy, documented by serial MRI, with favourable outcome. Clinical findings and brain imaging led to the diagnosis of cocaine-induced toxic leukoencephalopathy and other possible mimickers have been excluded on the basis of clinical assessment. The patient's unexpected recovery on neurological and neuropsychological examination, despite initially severe neurological symptoms, is striking and differs from more common reports of a rapid progression to death. Of note, case presented in the peculiar form of recurrent episodes of acute leukoencephalopathy, with favourable outcome, which, to our knowledge, has not been described yet. We speculate about the aetiology of this condition, which is still poorly understood.

An atypical case of neuro-Whipple: Clinical presentation, magnetic resonance spectroscopy and follow-up.

We report a case of a 53-year-old man with a 2-year history of progressive gait and balance disturbance, supranuclear ophthalmoparesis, mild dysarthria and dysmetria. EMG revealed a lower limb axonal sensory-motor neuropathy, while MR imaging demonstrated a small focal lesion in the right frontal lobe, mild diffuse hyperintensity of the periventricular white matter and diffuse brain atrophy. Magnetic resonance spectroscopy revealed a mild decrease in N-acetyl-aspartate peak and an increase in the choline peak in the small right frontal lesion and within 6 voxels of interest in normal appearing cerebral tissue. According to the clinical picture the diagnosis of WD was made by the positivity of PCR for T. whipplei DNA on CSF. After treatment the patient showed a mild clinical improvement although MR images and laboratory test remained unchanged. The MRS findings suggest that the pathological process of the disease diffusely involves the brain. Despite the absence of gastrointestinal involvement WD should be suspected in all complex and atypical neurological pictures, even in presence of peripheral involvement, in order to be able to start treatment promptly.

Muscles in "concert": study of primary motor cortex upper limb functional topography.

BACKGROUND: Previous studies with Transcranial Magnetic Stimulation (TMS) have focused on the cortical representation of limited group of muscles. No attempts have been carried out so far to get simultaneous recordings from hand, forearm and arm with TMS in order to disentangle a 'functional' map providing information on the rules orchestrating muscle coupling and overlap. The aim of the present study is to disentangle functional associations between 12 upper limb muscles using two measures: cortical overlapping and cortical covariation of each pair of muscles. Interhemispheric differences and the influence of posture were evaluated as well. METHODOLOGY/PRINCIPAL FINDINGS: TMS mapping studies of 12 muscles belonging to hand, forearm and arm were performed. Findings demonstrate significant differences between the 66 pairs of muscles in terms of cortical overlapping: extremely high for hand-forearm muscles and very low for arm vs hand/forearm muscles. When right and left hemispheres were compared, overlapping between all possible pairs of muscles in the left hemisphere (62.5%) was significantly higher than in the right one (53.5% ). The arm/hand posture influenced both measures of cortical association, the effect of Position being significant [p = .021] on overlapping, resulting in 59.5% with prone vs 53.2% with supine hand, but only for pairs of muscles belonging to hand and forearm, while no changes occurred in the overlapping of proximal muscles with those of more distal districts. CONCLUSIONS/SIGNIFICANCE: Larger overlapping in the left hemisphere could be related to its lifetime higher training of all twelve muscles studied with respect to the right hemisphere, resulting in larger intra-cortical connectivity within primary motor cortex. Altogether, findings with prone hand might be ascribed to mechanisms facilitating coupling of muscles for object grasping and lifting -with more proximal involvement for joint stabilization- compared to supine hand facilitating actions like catching. TMS multiple-muscle mapping studies permit a better understanding of motor control and 'plastic' reorganization of motor system.

Shortened cortical silent period in facial muscles of patients with migraine.

Despite intensive neurophysiological research, evidence is lacking to show whether abnormal cortical excitability in migraine reflects a primary cortical disturbance or reduced control by thalamo-cortical loops. One way to contribute to the scientific discussion on this topic is to deliver transcranial magnetic stimulation (TMS) and test the cortical silent period (SP) recorded in facial muscles. The facial-muscle SP is a purely cortical phenomenon that reflects the excitability of inhibitory interneurons, and can disclose changes in cortical inhibition even in patients without documented primary lesions of the motor cortices. To test the interictal excitability of cortical motor inhibitory interneurons in migraine, we investigated the facial-SP in patients with migraine with and without aura between attacks. In 26 patients and 15 age-matched controls, high-intensity magnetic stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction. Electromyographic responses were recorded from surface electrodes placed over the subjects' perioral muscles. Facial SPs were significantly shorter in patients than in controls. The SP shortening provides neurophysiological evidence showing hypoexcitability of cortical inhibitory neurons in patients with migraine between attacks. Despite a possible primary deficit of cortical inhibitory interneurons in migraine, we favor the interpretation of a secondary disfacilitation by hypoactive thalamo-cortical loops. Based on this interpretation, the interictal reduced cortical inhibition documented by the shortened SP could be considered the motor counterpart of the reduced preactivation excitability level in the sensory cortices purported to explain why cortical evoked responses habituate poorly in patients with migraine.

Somatosensory evoked potentials of inferior alveolar nerve.

PURPOSE: The use of inferior alveolar nerve somatosensory evoked potentials may represent an objective means of evaluating sensory nerve function in the maxillofacial region. The aim of this work was to confirm the existence of a standard sequence of prominent events in the trigeminal somatosensory evoked potentials (TSEPs) of inferior alveolar nerve (IAN) waveform, examine those components and their normal variability by statistical analysis, and discuss TSEPs' nervous origin and some patterns of TSEPs' abnormalities due to dysfunctional nerves. MATERIALS AND METHODS: TSEPs were obtained following electrical stimulation (square wave pulses 0.2 millisecond [ms] in duration, 4 to 6.5 mA, 0.7/second repetition rate, 200 averages) of the gum at the mental foramen level via intraoral surface electrodes and recorded from the contralateral central scalp sites. RESULTS: We successfully recognized steady waveforms of sufficient quality and consistently recorded a "W"-shaped response: latency onset and peak of the initial deflection of positive polarity were approximately 12 ms and 20 ms, respectively. Negative and positive deflections followed with respective peak latencies at around 26 ms and 36 ms. One side of the lower lip can be compared with the contralateral side and patients may serve as their own control in cases of unilateral nerve injury. The anaesthetic block showed the total abolition of responses. Reproducible TSEP waveform was only obtained during nerve stimulation and not during masseter muscle stimulation. CONCLUSIONS: TSEPs, obtained with the present technique, may represent an objective, low-invasive, and reliable way of testing sensory nerve function in the maxillofacial region.

Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity.

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.

Enhanced trigemino-cervical-spinal reflex recovery cycle in pain-free migraineurs.

OBJECTIVE: To evaluate trigemino-cervical-spinal reflexes (TCSRs) in a group of migraine patients during the pain-free period. BACKGROUND: TCRSs are part of a complex nocifensive response involving the cervical and the upper limb muscles, and are modulated by supraspinal inhibitory pathways; it may, thus, be possible to use TCRSs to explore the trigeminal system in migraineurs. METHODS: A total of 43 migraine patients without aura (MWoA, 32 patients) or with typical aura (MWA, 11 patients) and 30 age- and sex-matched healthy subjects took part in the study. TCRSs were obtained by stimulating the supraorbital nerve and recorded from the semispinalis capitis muscle and the biceps brachii. The latency (L, msec), area (A, mVms) and recovery cycle of the reflexes were recorded. The effects of heterotopic painful stimulation on the neurophysiological parameters were studied by a validated cold pressor test (CPT). RESULTS: No significant changes were found between either migraine patients and controls or MWoA and MWA patients in the mean values in the L and A of TCRSs (t-test, P > .05). The recovery curve of the trigemino-cervical reflexes (TCRs) was significantly faster in migraine patients than in controls, while no differences were found in the trigemino-spinal reflexes (TSRs) (t-test, P < .01). Activation of the diffuse inhibitory controls through the CPT induced a significant reduction in the TCRs and TSRs area in both migraine patients and controls (paired t-test, P < .01), though the extent of this reduction did not differ significantly between migraineurs and controls (t-test, P > .05). COMMENTS: Our data suggest that the pain-free period in migraine patients is characterized by a hyperexcitability of the trigeminal pathways and of their anatomical and functional connections with the upper cervical cord neurons, and that this abnormal hyperexcitability does not appear to be due to a lack of a supraspinal inhibitory modulation.