Modulation of temporal summation threshold of the nociceptive withdrawal reflex by transcutaneous spinal direct current stimulation in humans.

OBJECTIVE: Transcutaneous spinal direct current stimulation (tsDCS) modulates spinal cord pain pathways. The study is aimed to clarify the neurophysiology of the tsDCS-induced modulation of the spinal cord pain processing by evaluating the effect of the tsDCS on temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR). METHODS: In a randomized, double-blind, crossover study the effects of anodal, cathodal and sham tsDCS (2 mA, 15 min) applied on the skin overlying the thoracic spinal cord were investigated in 10 healthy subjects. RESULTS: Anodal tsDCS induced a long-lasting (up to 60 min) increase in TST of the NWR as well as a parallel decrease in related psychophysical temporal summation of pain, while cathodal and sham tsDCS resulted ineffective. CONCLUSIONS: Anodal tsDCS represents a non-invasive tool able to induce an early and long-lasting depression of the transitory facilitation of the wide dynamic range neurons activity at the basis of both the temporal summation of the NWR and the related temporal summation of pain sensation. SIGNIFICANCE: The modulation of the temporal processing of nociceptive stimuli could be effective in treating clinical pain conditions in which pain is generated by spinal cord structures.

Dynamic changes in thalamic microstructure of migraine without aura patients: a diffusion tensor magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The thalamus seems to be profoundly involved in the cyclical recurrence of migraine clinical and neurophysiological features. Here possible structural changes in the thalamus of migraineurs were searched for by means of diffusion tensor (DT) magnetic resonance imaging (MRI). This MRI technique provides quantitative data on water molecule motion as a marker of tissue microstructure. METHODS: Twenty-four untreated migraine without aura (MO) patients underwent DT-MRI scans (3-T Siemens Gyroscan) during (n = 10) and between attacks (n = 14) and were compared with a group of 15 healthy volunteers (HVs). Fractional anisotropy (FA) and mean diffusivity (MD) were examined. RESULTS: During the interictal phase MO patients had a significantly higher FA and slightly lower MD values in bilateral thalami compared with HVs. During attacks, all MRI quantitative measurements in migraineurs were similar to those found in HVs. Right thalamic FA was positively correlated with the number of days since the last migraine attack in pooled patient data (r = 0.626, P = 0.003). CONCLUSIONS: These higher thalamic FA values noted during the interictal period which normalized during an attack are probably related to plastic peri-ictal modifications in regional branching and crossing of fibres. Whether these changes could be considered as the anatomical counterpart of the cyclical functional fluctuations previously observed in the neurophysiology of migraine remains to be determined.

Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs.

OBJECTIVES: In migraine, an interictal reduction of mitochondrial energy metabolism and a preventive effect of high-dose riboflavin were reported. To explore the relation between the two, we tested if the therapeutic response to riboflavin is associated with specific mitochondrial DNA (mtDNA) haplogroups. We focused our attention on haplogroup H, which is known to differ from others in terms of energy metabolism. METHODS: Sixty-four migraineurs completed a 4-month open trial with riboflavin (400 mg QD) and were genotyped blindly for mtDNA haplogroups. RESULTS: Forty patients responded to riboflavin treatment and 24 were nonresponders. The mtDNA haplogroup H was found in 29 subjects (20 migraine without aura, 9 migraine with aura). Riboflavin responders were more numerous in the non-H group (67.5%). Conversely, nonresponders were mostly H (66.7%). The difference between the two groups was significant (chi(2) = 7.07; p = 0.01). The presence of aura had no influence on riboflavin's effectiveness (chi(2) = 0.113; p = 0.74) and was not associated with a particular haplogroup (chi(2) = 0.55; p = 0.46). CONCLUSIONS: In this pharmacogenetic study, riboflavin appears to be more effective in patients with migraine with non-H mitochondrial DNA haplotypes. The underlying mechanisms are unknown, but could be related to the association of haplogroup H with increased activity in complex I, which is a major target for riboflavin. Our results may have ethnic implications, since haplogroup H is chiefly found in the European population.

Reduced habituation of trigeminal reflexes in patients with episodic cluster headache during cluster period.

A growing body of evidence supports the pivotal role of the hypothalamus in the pathophysiology of cluster headache (CH). On the basis of animal studies, it has been suggested that a hypothalamic dysfunction can lead to a habituation deficit of brainstem reflex responses, as result of a stress-like condition. Taking into account these findings, we tested the hypothesis that habituation of brainstem reflexes may be impaired in CH patients. The habituation phenomenon of the late components (R2 and R3) of the blink reflex was studied in 27 CH patients during the cluster period, in 22 migraine patients interictally and in 20 control subjects. A significant habituation deficit in the R2 and R3 components was found in CH compared with both controls and migraineurs. The lack of habituation in CH, more pronounced than in migraine, points to abnormal processing of sensory stimuli at the trigeminal level that could be driven by hypothalamic dysfunction during the cluster period.

Interictal abnormalities of gamma band activity in visual evoked responses in migraine: an indication of thalamocortical dysrhythmia?

Between attacks, migraineurs lack habituation in standard visual evoked potentials (VEPs). Visual stimuli also evoke high-frequency oscillations in the gamma band range (GBOs, 20-35 Hz) assumed to be generated both at subcortical (early GBOs) and cortical levels (late GBOs). The consecutive peaks of GBOs were analysed regarding amplitude and habituation in six successive blocks of 100 averaged pattern reversal (PR)-VEPs in healthy volunteers and interictally in migraine with (MA) or without aura patients. Amplitude of the two early GBO components in the first PR-VEP block was significantly increased in MA patients. There was a significant habituation deficit of the late GBO peaks in migraineurs. The increased amplitude of early GBOs could be related to the increased interictal visual discomfort reported by patients. We hypothesize that the hypofunctioning serotonergic pathways may cause, in line with the thalamocortical dysrhythmia theory, a functional disconnection of the thalamus leading to decreased intracortical lateral inhibition, which can induce dishabituation.

Lack of habituation causes high intensity dependence of auditory evoked cortical potentials in migraine.

Migraineurs are characterized interictally by lack of habituation, or even potentiation, of cortical evoked potentials during repetitive stimulation and by a strong intensity dependence of auditory evoked potentials (IDAP). To determine whether these two features of sensory processing are interrelated, we have studied them simultaneously on the same recordings of auditory evoked potentials (AEPs). AEPs were obtained at four different stimulation intensities in 14 patients suffering from migraine without aura (MO) and 14 healthy volunteers (HV). For each intensity, 120 trials were averaged off-line globally and over four sequential blocks of 30 trials. IDAP was expressed by the amplitude/stimulus intensity function (ASF slope) for global and block averages. Habituation was calculated as the percentage amplitude variation between the first and fourth blocks for each stimulus intensity. The IDAP slope for global averages was higher in MO (1.05 +/- 0.27 microV/10 dB) than in HV (0.64 +/- 0.45 microV/10 dB) (P = 0.008), but IDAP slopes for block averages were greater in MO only at the fourth block (P = 0.048). First block amplitudes tended to be lower in MO, except at 80 dB. There was a potentiation of AEP amplitudes at every stimulus intensity in MO, contrasting with habituation in HV. IDAP slopes were negatively correlated with mean habituation percentages in pooled data from patients and controls (r = -0.610; P = 0.0006). This study confirms that IDAP is higher in migraineurs than in healthy controls. It also shows that the AEP habituation is replaced by potentiation at all stimulus intensities. The negative correlation found between IDAP and habituation suggests that the latter is able to have a strong influence on the former and perhaps even lead to it. In migraine, the habituation deficit amplifies the IDAP and may thus be the causal functional abnormality. We propose that it is due to a decreased pre-activation level of sensory cortices, a hypothesis also supported in this study by the lower amplitude of first AEP blocks in patients.

Antiepileptic effects of a calcium antagonist (nimodipine) on cefazolin-induced epileptogenic foci in rabbits.

The epileptogenic properties of cefazolin (CFZ) were utilized to induce an electrophysiological pattern of epilepsy in the rabbit. CFZ, cortically applied in different concentrations (2 or 4%), produced epileptic activity in a degree proportional to the concentration of the substance. In this experimental epilepsy model, we evaluated the effects of increasing doses (0.025, 0.05, and 0.1 mg/kg i.v.) of the calcium antagonist nimodipine (Bay e 9736). In the evaluation of nimodipine effects, the spike-and-wave burst frequency per minute was taken into account. These data were compared with those of placebo-treated (Bay e 9736 control test) control groups and statistically evaluated by two-tailed t test. In 2% CFZ-induced epilepsy, nimodipine at the 0.025- and 0.05-mg/kg doses did not produce significant changes in the EEG pattern. A statistically significant reduction (p less than 0.001) in epileptic activity was observed at the 0.1-mg/kg nimodipine dose. This reduction was seen first in the contralateral focus leads and persisted for the entire time of observation. In the more intense epileptic form (4% CFZ), nimodipine at the doses employed did not induce noteworthy EEG modifications. These data indicate that nimodipine exerts an antiepileptic effect. The possible mechanisms involved in this activity of a calcium antagonist are discussed.

Brain slow potentials and hypnosis.

Contingent negative variation behavior was studied in 12 voluntary normal subjects in basal conditions and in the hypnotic trance state under different emotional suggestions. A CNV voltage decrease and the appearance of a PINV were observed in the hypnotic state. Furthermore 12 nonhypnotizable control subjects were tested under the same experimental conditions and no CNV modification was found.