Regulation of redox forms of plasma thiols by albumin in multiple sclerosis after fasting and methionine loading test.

Increases in plasma concentrations of total homocysteine (tHcy) have recently been reported in multiple sclerosis (MS) as the alteration of the methionine cycle for the onset of autoimmune diseases. Homocysteine (Hcy) and cysteine (Cys) are generated by the methionine cycle and transsulfuration reactions. Their plasma levels are subjected to complex redox changes by oxidation and thiol/disulfide (SH/SS) exchange reactions regulated by albumin. The methionine loading test (MLT) is a useful in vivo test to assay the functionality of the methionine cycle and transsulfuration reactions. Time courses of redox species of Cys, cysteinylglycine (CGly), Hcy, and glutathione have been investigated in plasma of MS patients versus healthy subjects after an overnight fasting, and 2, 4, and 6 h after an oral MLT (100 mg/kg body weight), to detect possible dysfunctions of the methionine cycle, transsulfuration reactions and alterations in plasma distribution of redox species. After fasting, the MS group showed a significant increase in cysteine-protein mixed disulfides (bCys) and total Cys (tCys). While plasma bCys and tCys in MS group remained elevated after methionine administration when compared to control, cystine (oxCys) increased significantly with respect to control. Although increased plasma concentrations of bCys and tCys at fasting might reflect an enhance of transsulfuration reactions in MS patients, this was not confirmed by the analysis of redox changes of thiols and total thiols after MLT. This study has also demonstrated that albumin-dependent SH/SS exchange reactions are a potent regulation system of thiol redox species in plasma.

Dysfunctions of cortical excitability in drug-naïve posttraumatic stress disorder patients.

BACKGROUND: The investigation of a wide set of transcranial magnetic stimulation (TMS)-related variables in both hemispheres might help to identify a pattern of cortical excitability changes in posttraumatic stress disorder (PTSD) patients, reflecting gamma-amino-butiric acid (GABA)/glutamate balance and dysfunction, and to determine whether some of these variables are related to clinical features. METHODS: In 20 drug-naive PTSD patients without comorbidity and 16 matched healthy control subjects we tested bilaterally with standard TMS procedures: resting motor threshold (RMT) to single-pulse TMS (reflecting ion channel function), paired-pulse short-latency intracortical inhibition (SICI; mainly reflecting GABA(A) function) and intracortical facilitation (ICF; mainly reflecting glutamatergic function), single-pulse cortical silent period (CSP; mainly reflecting GABA(B)-ergic function), and paired-pulse short-latency afferent inhibition (SAI; reflecting cholinergic mechanisms and their presynaptic GABA(A)-mediated modulation). RESULTS: The PTSD patients showed widespread impairment of GABA(A)-ergic SICI, which was reversed toward facilitation in both hemispheres in one-half of the patients, marked increase of glutamatergic ICF in the right hemisphere, and right-sided impairment of SAI. Illness duration and avoidance symptoms but not anxiety correlated with right-lateralized dysfunctions of cortical excitability. CONCLUSIONS: Although the neurobiological complexity of each TMS variable makes current results theoretical, the pattern of cortical excitability accompanying PTSD symptoms suggests a bilateral decrease of the GABA(A)-ergic function. This prevails in the right hemisphere, in association with a relative prevalence of the glutamatergic tone, a new finding that current neuroimaging investigations cannot provide due to the lack of reliable glutamate tracers. Results might help to disclose new pathophysiological aspects of PTSD symptoms, providing a rationale for future neuromodulatory strategies of treatment.

Distinct olfactory cross-modal effects on the human motor system.

BACKGROUND: Converging evidence indicates that action observation and action-related sounds activate cross-modally the human motor system. Since olfaction, the most ancestral sense, may have behavioural consequences on human activities, we causally investigated by transcranial magnetic stimulation (TMS) whether food odour could additionally facilitate the human motor system during the observation of grasping objects with alimentary valence, and the degree of specificity of these effects. METHODOLOGY/PRINCIPAL FINDINGS: In a repeated-measure block design, carried out on 24 healthy individuals participating to three different experiments, we show that sniffing alimentary odorants immediately increases the motor potentials evoked in hand muscles by TMS of the motor cortex. This effect was odorant-specific and was absent when subjects were presented with odorants including a potentially noxious trigeminal component. The smell-induced corticospinal facilitation of hand muscles during observation of grasping was an additive effect which superimposed to that induced by the mere observation of grasping actions for food or non-food objects. The odour-induced motor facilitation took place only in case of congruence between the sniffed odour and the observed grasped food, and specifically involved the muscle acting as prime mover for hand/fingers shaping in the observed action. CONCLUSIONS/SIGNIFICANCE: Complex olfactory cross-modal effects on the human corticospinal system are physiologically demonstrable. They are odorant-specific and, depending on the experimental context, muscle- and action-specific as well. This finding implies potential new diagnostic and rehabilitative applications.

Natural history of vertebrobasilar dolichoectasia.

OBJECTIVE: The long-term prognosis of patients with vertebrobasilar dolichoectasia (VBD) is unknown. The purpose of this study was to explore the natural history of VBD, evaluate its progression, and examine factors that may influence the clinical course of this condition. METHODS: We conducted a prospective clinical and imaging follow-up study of 156 consecutive patients with VDB followed for an average of 11.7 years. Predictors of events were evaluated by multivariate analysis. Survival analysis was used to evaluate rates of incidence. RESULTS: During follow-up, 93 patients (60%) experienced at least one event: 75 patients had stroke (59 ischemic and 21 hemorrhagic), 31 patients had new compressive symptoms, and 2 patients had hydrocephalus. Events were significantly associated with the severity of VBD, i.e., diameter, height of bifurcation, and lateral displacement of the basilar artery. During follow-up VBD progressed in 43% of patients. Progression of VBD was associated with a higher morbidity and mortality. The cumulative proportion of survivors free of adverse health event was 54.1 at 5 years, 39.5 at 10 years, and 23.5 at 15 years. During follow-up, 62 patients died and stroke was the most common cause of death. CONCLUSIONS: The long-term prognosis of patients with vertebrobasilar dolichoectasia (VBD) depended mainly on the severity of the condition at diagnosis and on its evolutionary characteristics. Progression of VBD exposed patients to high risk of adverse events, especially stroke.

Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study.

BACKGROUND: Chronic tinnitus is a disabling, almost untreatable, condition, usually accompanied by psychiatric distress. In patients with complex neuropsychiatric diseases, such as chronic pain, with which tinnitus shares pathophysiological similarities, placebo effects may be pronounced. Moreover, it may be difficult to distinguish actual repetitive transcranial magnetic stimulation (rTMS) induced clinical benefits beyond placebo effects in neuropsychiatric patients. METHODS: 16 patients with chronic tinnitus underwent a randomised, double blind, crossover, placebo controlled trial of 1 Hz rTMS (120% of motor threshold; 1200 stimuli/day for 5 days) of the left temporoparietal region. Patients were screened for psychiatric comorbidity; additionally, anxiety and depression were monitored throughout the study. Moreover, an original placebo rTMS procedure produced the same activation of ipsilateral face muscles (a condition which may per se change the subjective rating of tinnitus) as the real rTMS. RESULTS: There were 8 out of 14 responders. Two patients dropped out for transient worsening of tinnitus. Active rTMS induced an overall significant, but transient, improvement (35% of the basal score) of subjective tinnitus perception that was independent of either tinnitus laterality or mood or anxiety changes. No correlations were found between response to rTMS and tinnitus duration, initial subjective score or patient age. When asked after the study was over, 71.4% of patients failed to identify the temporal sequence of the real or sham rTMS interventions. CONCLUSION: The beneficial effects of rTMS on tinnitus are independent of mood changes. Moreover, they appear in the context of an original placebo stimulation designed to more closely replicate the somatic sensation of active stimulation. Because of the limited temporal duration of the clinical benefit, these neuromodulatory effects could be mediated by transient functional changes taking place in the neural circuits underlying tinnitus processing.

A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS).

OBJECTIVE: There is growing interest in neuropsychiatry for repetitive transcranial magnetic stimulation (rTMS) as a neuromodulatory treatment. However, there are limitations in interpreting rTMS effects as a real consequence of physiological brain changes or as placebo-mediated unspecific effects, which may be particularly strong in psychiatric patients. This is due to the fact that existing sham rTMS procedures are less than optimal. A new placebo tool is introduced here, called real electro-magnetic placebo (REMP) device, which can simulate the scalp sensation induced by the real TMS, while leaving both the visual impact and acoustic sensation of real TMS unaltered. METHODS: Physical, neurophysiological and behavioural variables of monophasic and biphasic single-pulse TMS and biphasic 1Hz and 20Hz rTMS procedures (at different intensities) were tested in subjects who were expert or naïve of TMS. Results of the real TMS were compared with those induced by the REMP device and with two other currently used sham procedures, namely the commercially available Magstim sham coil and tilting the real coil by 90 degrees . RESULTS: The REMP device, besides producing scalp sensations similar to the real TMS, attenuated the TMS-induced electric field (as measured by a dipole probe) to a biologically inactive level. Behaviourally, neither expert nor naïve TMS subjects identified the "coil at 90 degrees " or the "Magstim sham coil" as a real TMS intervention, whilst naïve subjects were significantly more likely to identify the REMP-attenuated TMS as real. CONCLUSIONS: The "goodness of sham" of the REMP device is demonstrated by physical, neurophysiological, and behavioural results. SIGNIFICANCE: Such placebo TMS is superior to the available sham procedures when applied on subjects naïve to TMS, as in case of patients undergoing a clinical rTMS trial.

Intracranial bleeding in patients with vertebrobasilar dolichoectasia.

BACKGROUND AND PURPOSE: Intracranial bleeding in patients with vertebrobasilar dolichoectasia (VBD) is considered uncommon, but there are no precise data to support this opinion. The purpose of this study was to examine the incidence and characteristics of intracranial hemorrhage in patients with VBD and to evaluate factors that may promote bleeding. METHODS: We conducted a prospective study of 156 consecutive VDB patients followed-up for an average 9.35 years. The association of demographic, clinical, and imaging features with occurrence of intracranial bleeding was evaluated by multivariate analysis. Survival analysis was used to evaluate rates of incidence. RESULTS: 32 hemorrhagic strokes were observed in 28 patients either as a diagnostic event (n=10) or during follow-up (n=22). Of the 32 hemorrhagic events, 6 were subarachnoid hemorrhage and 26 intraparenchymal hemorrhage. Multivariate analysis found an association between intracranial bleeding and maximum diameter of the basilar artery (OR, 4.29; P=0.009), degree of lateral displacement of the basilar artery (OR, 4.53; P=0.004), hypertension (OR, 4.74; P=0.024), use of antiplatelet or anticoagulant agents (OR, 3.07; P=0.033), and female sex (OR 6.33; P=0.001). The cumulative proportion of survivors free of hemorrhagic stroke was 88.6 at 5 years and 84.4 at 10 years. CONCLUSIONS: Our study showed that intracranial bleeding in patients with VBD is not as uncommon as usually believed. Its occurrence is associated with the degree of ectasia and elongation of the basilar artery and may be favored by hypertension and use of antiplatelet or anticoagulant agents.

Hypofunctioning of sensory gating mechanisms in patients with obsessive-compulsive disorder.

BACKGROUND: In obsessive-compulsive disorder (OCD) patients, functional abnormalities in basal ganglia/precentral circuitries cause cortical hyperexcitability and lack of inhibitory control. These loops can be partly explored by median-nerve somatosensory evoked potentials (SEPs), which functionally reflect the brain responsiveness to somatosensory stimuli. In healthy humans, SEPs' amplitude during voluntary finger movements is lower than during muscular relaxation (i.e., sensory gating). Cortical hyperexcitability in OCD could be eventually responsible for a reduction of sensory gating. This might have pathophysiologic implications for motor compulsions. METHODS: Median-nerve SEPs were recorded in 11 OCD patients and 9 healthy volunteers during muscle relaxation ("Relax") or finger movements of the stimulated hand ("Move"). Latencies and amplitudes of pre- and postcentral SEP components were compared between groups during "Relax" and "Move" conditions. RESULTS: In OCD patients, the responsiveness to sensory stimuli was enhanced for precentral SEPs. Sensory gating ("Relax" vs. "Move") in control subjects involved both pre- and postcentral SEPs, the former being reduced in amplitude by approximately 60%. In OCD patients, sensory gating was spatially restricted to precentral SEP components and was significantly reduced compared with control subjects (approximately 30%). CONCLUSIONS: Enhanced precentral SEPs and hypofunctioning of centrifugal sensory gating in OCD might reflect the inability to modulate sensory information due to a "tonic" high level of cortical excitability of motor and related areas, likely resulting from basal ganglia dysfunction. This might offer new insights into the pathophysiology of OCD.

Abnormal fronto-parietal coupling of brain rhythms in mild Alzheimer's disease: a multicentric EEG study.

Cholinergic deafferentation/recovery in rats mainly impinges on the fronto-parietal coupling of brain rhythms [D. P. Holschneider et al. (1999) Exp. Brain Res., 126, 270-280]. Is this reflected by the functional coupling of fronto-parietal cortical rhythms at an early stage of Alzheimer's disease (mild AD)? Resting electroencephalographic (EEG) rhythms were studied in 82 patients with mild AD and in control subjects, such as 41 normal elderly (Nold) subjects and 25 patients with vascular dementia (VaD). Patients with AD and VaD had similar mini-mental state evaluation scores of 17-24. The functional coupling was estimated by means of the synchronization likelihood (SL) of the EEG data at electrode pairs, accounting for linear and non-linear components of that coupling. Cortical rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha (1 8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz) and gamma (30-40 Hz). A preliminary data analysis (Nold) showed that surface Laplacian transformation of the EEG data reduced the values of SL, possibly because of the reduction of influences due to head volume conduction. Therefore, the final analysis was performed on Laplacian-transformed EEG data. The SL was dominant at alpha 1 band in all groups. Compared with the Nold subjects, patients with VaD and mild AD presented a marked reduction of SL at both fronto-parietal (delta-alpha) and inter-hemispherical (delta-beta) electrode pairs. The feature distinguishing the patients with mild AD with respect to patients with VaD groups was a more prominent reduction of fronto-parietal alpha 1 SL. These results suggest that mild AD is characterized by an abnormal fronto-parietal coupling of the dominant human cortical rhythm at 8-10.5 Hz.

Uncommon findings in idiopathic hypertrophic cranial pachymeningitis.

BACKGROUND: Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare, poorly understood, inflammatory disease, usually involving the dura mater of skull base, tentorium, and falx, and presenting with headache, progressive cranial nerve palsies, and cerebellar dysfunction. PATIENTS AND METHODS: In four patients, the diagnosis of IHCP has been made on the basis of extensive clinical, and radiological investigation, and confirmed by dural biopsy in three patients. The clinical follow-up ranges from 24 to 120 months. RESULTS: At diagnosis, all the patients complained of severe, progressively increasing headache, two had simple or complex partial seizures, but none had cranial nerve palsies. Two patients had electrophysiological evidence of axonal peripheral neuropathy, biopsy-proved in one of them. In all the patients, MRI showed linear or focal thickening of the dura mater of the tentorium and/or of the convexity, sparing the skull base. In one patient, MRI findings resembled chronic subdural hematoma. Dural biopsy demonstrated fibrosis and prominent CD4+ T-cells inflammatory infiltrate. Pachymeningitis was highly responsive to steroid therapy, as was the peripheral neuropathy. In three patients, temporary steroids withdrawal led to dramatic clinical worsening including status epilepticus in one. CONCLUSIONS: In the patients here reported, absence of cranial nerve impairment, seizures, MRI findings resembling chronic subdural hematoma, and association with polineuropathy were unusual findings of IHCP. Moreover, the type of inflammatory infiltrate, lacking in previous reported cases, suggests a probable pathogenetic role for cell-mediated immunity of unknown origin.

Reduction of cortical myoclonus-related epileptic activity following slow-frequency rTMS.

In a drug-resistant epilepsy patient with continuous forearm/hand positive myoclonia due to a focal cortical dysplasia of the right motor cortex, cortical jerk-related and electromyographic activity were recorded for 15 min before and after 1 Hz rTMS (15 min, 10% below the resting excitability threshold) of the right motor cortex. A stable negative cortical spike, time-locked with contralateral muscle jerks (60 > 100 microV), was detected only at perirolandic electrodes (maximal amplitudes: block 1 = 21.3 microV, block 2 = 22 microV, block 3 = 25.9 microV). After rTMS, only 20 muscle jerks accomplished the criterion of > 100 microV; blind back-averaging of these disclosed a topographically similar cortical spike, but with amplitude reduced by at least 50% (11.2 microV). This represents in vivo evidence of the possibility to selectively modulate the activity of an epileptic focus by intervening with local low-frequency rTMS.

The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage.

OBJECTIVE: To determine whether diabetes and admission hyperglycemia in nondiabetic patients influence outcome and the occurrence of cerebral and medical complications after intracerebral hemorrhage (ICH). METHODS: The study sample included 764 patients with ICH. The effects of diabetes and admission hyperglycemia were examined in relation to 30-day and 3-month mortality using Cox regression models controlling for potential confounders. The analysis was conducted for the entire sample of patients and repeated in comatose and noncomatose patients. RESULTS: Among comatose patients, neither diabetes nor admission hyperglycemia contributed significant predictive information, as nearly all patients died. In noncomatose patients, diabetes was an independent predictor of 30-day (odds ratio [OR] 1.31; 95% CI 1.08 to 1.58) and 3-month (OR 1.30; 95% CI 1.08 to 1.56) mortality and was associated with a greater incidence of infectious (OR 1.24; 95% CI 1.03 to 1.49) and cerebral (OR 1.42; 95% CI 1.10 to 1.83) complications. Among nondiabetic patients with Glasgow Coma Scale score of >8, hyperglycemia was an independent predictor of 30-day (OR 1.29; 95% CI 1.05 to 1.58) and 3-month (OR 1.27; 95% CI 1.05 to 1.53) mortality and was associated with a greater incidence of cerebral complications (OR 1.47; 95% CI 1.12 to 2.94). CONCLUSIONS: Both diabetes and admission hyperglycemia in nondiabetic patients are predictors of poor outcome after supratentorial ICH. This may be related to the greater incidence of cerebral and infectious complications in diabetic patients and of cerebral complications in hyperglycemic nondiabetic patients.

Seizures after spontaneous supratentorial intracerebral hemorrhage.

PURPOSE: To characterize seizures after intracerebral hemorrhage (ICH), evaluating the risk of occurrence and relapse, predisposing factors, and prognostic significance, and to assess the utility of antiepileptic drug (AED) therapy as used in clinical practice. METHODS: The study sample consisted of 761 patients with spontaneous, nonaneurysmal, supratentorial ICH. Seizures were classified as immediate (within 24 h of ICH) and early (within 30 days of ICH). Baseline variables and clinical events were compared in the seizure and nonseizure group by using a multivariate regression model of failure time data. RESULTS: Fifty-seven patients had one or more seizures. The 30-day actuarial risk of a post-ICH seizure was 8.1%. Lobar location and small volume of ICH were independent predictors of immediate seizures. Early seizures were associated with lobar location and neurologic complications, mainly rebleeding. In patients with lobar ICH, the risk of early seizures was reduced by prophylactic AED therapy. Among seizure patients, history of alcohol abuse increased the risk of status epilepticus. Immediate and early seizures were not independent predictors of in-hospital mortality. CONCLUSIONS: Patients with ICH are exposed to a substantial risk of seizures; however, short-term mortality was not affected, and the risk of epilepsy was lower than previously thought. The likelihood of immediate seizures is influenced by factors that are inherent characteristics of ICH, whereas the chance of developing early seizures is influenced not only by certain characteristics of ICH, but also by unpredictable events. A brief period of therapy soon after ICH onset may reduce the risk of early seizures in patients with lobar hemorrhage.