Near infrared imaging of intrinsic signals in cortical spreading depression observed through the intact scalp in hairless mice.

Brain cooling was inevitable in both thinned and intact skull windows in neuroimaging in vivo of mice. Thus we proposed the novel imaging method leaving intact scalp on the skull using the light at 670, 785, and 975 nm. In this study, we used hairless mice (Hos:HR-1) since the deterioration of image quality was resulted from the hair. Cortical spreading depression was induced by KCl application through small incision and burr hole on the frontal bone. Intrinsic optical signals through the intact scalp in the observation area were detected. Time course of the signal showed a triphasic feature which was consistent with the intrinsic optical signals through the intact skull. In three pairs of signal amplitudes at the different wavelengths, no significant differences were observed. Although the intact scalp weakened the amplitudes significantly, e.g., 4.0 from 6.9 at 975 nm, the signals during cortical spreading depression were sufficient to be detected.

Abnormal response of motor cortex to photic stimulation in idiopathic generalized epilepsy.

BACKGROUND: Intermittent photic stimulation (IPS) shortens the cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) over the primary motor hand area (M1(HAND)). This response is absent in healthy individuals with a photoparoxysmal response (PPR). Here we combined TMS of the M1(HAND) with IPS to examine whether patients with idiopathic generalized epilepsy (IGE) exhibit an abnormal cortical response pattern to IPS. METHODS: In 13 PPR-positive and 12 PPR-negative patients with IGE and in 13 PPR-negative healthy controls, we used focal TMS to the M1(HAND) to study how cortical excitability is changed by concurrent IPS at 50 Hz. RESULTS: IPS at 50 Hz reduced the duration of the CSP in healthy PPR-negative individuals, whereas IPS had no effect on the CSP in PPR-positive and PPR-negative patients with generalized epilepsy. The failure of IPS to shorten the CSP was independent of antiepileptic medication. Single-pulse or paired-pulse TMS only without concurrent IPS showed a higher motor threshold in PPR-positive patients with epilepsy, presumably caused by antiepileptic medication. No additional differences in cortical excitability were found among groups. CONCLUSIONS: Because the CSP is mediated by intracortical GABAergic mechanisms, our results indicate that IGEs are associated with an altered responsiveness of GABAergic inhibitory circuits in the M1(HAND). This electrophysiological trait is independent of photosensitivity. Excitability changes at the cortical or thalamic level may mediate this abnormal cortical response pattern in patients with IGE.

Sulfhydryl oxidation: a potential strategy to achieve neuroprotection during severe hypoxia?

Previously we reported that sulfhydryl (SH) modulation affects the susceptibility of rat hippocampal slices to severe hypoxia. SH-oxidation by DTNB (5,5'-dithiobis 2-nitrobenzoic acid) or H2O2 postponed the onset of hypoxia-induced spreading depression (HSD), thereby delaying the loss of neuronal function, whereas SH-reduction by DTT (1,4-dithio-dl-threitol) hastened HSD onset. To judge the neuroprotective merit that might arise from a postponement of HSD by oxidants, we have extended our earlier observations by multiparametric recordings and screened for changes in the extracellular K+ accumulation, HSD propagation velocity, and its maximum spread. As parameters for neuronal network function, the failure of synapses during hypoxia and their posthypoxic recovery were analyzed. DTNB (2 mM) or H2O2 (5 mM) postponed HSD but did not attenuate the rise in extracellular K+ concentration ([K+](o)), HSD propagation velocity or its maximum spread. H2O2 slightly postponed the synaptic failure during hypoxia; the posthypoxic recovery of synapses was, however, incomplete. DTNB slowed the synaptic recovery upon reoxygenation. DTT (2 mM) hastened HSD onset, but HSD propagation velocity and tissue invasion were not affected. Upon reoxygenation, however, normalization of [K+](o) was disturbed and synaptic recovery failed. Therefore, SH-reducing conditions at the onset of HSD proved to be devastating for the hippocampal network. In conclusion, the only merit of DTNB or H2O2 treatment is a delayed HSD onset, i.e. some extra time before neuronal function is lost during severe hypoxia. Attenuation of the severe changes during HSD or an improved outcome was not observed. Nevertheless, combination of SH-oxidants with established neuroprotectants might be a potential therapeutic approach.

Focal transcranial magnetic stimulation of motor cortex evokes bilateral and symmetrical silent periods in human masseter muscles.

OBJECTIVE: To determine whether a single hemisphere exerts distinct inhibitory influences over masseter muscles on each side, and to compare features of the masseter cortical silent period (CSP) evoked by transcranial magnetic stimulation (TMS) with previous reports from limb and other cranial muscles. METHODS: Focal TMS was applied over the motor cortex jaw area in 14 normal subjects. In one experiment, TMS intensity was constant (1.1 or 1.3x active motor threshold, T) and masseter muscle activation varied from 10% to 100% of maximal. In another experiment, muscle activation was constant (20% maximal) and TMS intensity varied from 0.7 to 1.3T. RESULTS: In all subjects, TMS evoked a silent period of similar duration in masseter muscles on both sides. Masseter CSP duration increased at higher TMS intensities, but was not affected by muscle activation level or the size of the excitatory response evoked by TMS. Weak TMS produced a bilateral CSP without short-latency excitation. The masseter CSP was short ( approximately 100ms at 1.3T), yet this was not due to maintenance of excitatory drive from the unstimulated hemisphere, as the masseter CSP was not prolonged with dual-hemisphere TMS. CONCLUSIONS: Intracortical inhibitory circuits activated by TMS have a relatively weak effect on corticotrigeminal neurons supplying masseter, and effects are equivalent for corticobulbar efferents directed to contralateral and ipsilateral masseter motoneuron pools. SIGNIFICANCE: Trigeminally innervated masseter muscles exhibit weak, bilaterally symmetric inhibition following focal TMS. This method can be used to investigate abnormalities of intracortical inhibition in movement disorders or focal lesions affecting the masticatory muscles in humans.

Suppression of cortical spreading depression in migraine prophylaxis.

OBJECTIVE: Topiramate, valproate, propranolol, amitriptyline, and methysergide have been widely prescribed for migraine prophylaxis, but their mechanism or site of action is uncertain. Cortical spreading depression (CSD) has been implicated in migraine and as a headache trigger and can be evoked in experimental animals by electrical or chemical stimulation. We hypothesized that migraine prophylactic agents suppress CSD as a common mechanism of action. METHODS: Rats were treated either acutely or chronically over weeks and months, with one of the above migraine prophylactic drugs, vehicle, or D-propranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD. RESULTS: Chronic daily administration of migraine prophylactic drugs dose-dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold, whereas acute treatment was ineffective. Longer treatment durations produced stronger CSD suppression. Chronic D-propranolol treatment did not differ from saline control. INTERPRETATION: Our data suggest that CSD provides a common therapeutic target for widely prescribed migraine prophylactic drugs. Assessing CSD threshold may prove useful for developing new prophylactic drugs and improving upon existing ones.

Changes of neuronal activity in areas CA1 and CA3 during anoxia and normoxic or hyperoxic reoxygenation in juvenile rat organotypic hippocampal slice cultures.

In neonates, asphyxia is usually followed by hyperoxic treatment. In order to study whether hyperoxic reoxygenation might cause additional impairment of neuronal function, we subjected organotypic hippocampal slice cultures of juvenile rats (7 DIV, P6-8) to 30 min anoxia followed by 60 min hyperoxic or normoxic reoxygenation (95% or 19% O2, respectively). Spontaneous and evoked field potentials as well as [Ca2+]o were recorded in the pyramidal layer of area CA1 or area CA3. In area CA1, 30 min of anoxia led to decline of evoked field potential amplitudes by on average 67% and to profound changes in field potential characteristics and Ca2+ homeostasis which were not related to outcome after reoxygenation. Hyperoxic reoxygenation resulted first in a fast recovery of the field potential amplitude to 82% of the control value and then, in 75% of slice cultures, in a large negative field potential shift accompanied by a prolonged decrease of [Ca2+]o and loss of excitability outlasting the experiment. Recovery of field potential amplitude under normoxic conditions stayed poor, with a first increase to 51% and a second decrease to 22%. In contrast, field potential amplitude in area CA3 recovered to 80% of the initial amplitude, irrespective of the reoxygenation mode. The selective loss of function during hyperoxic reoxygenation in area CA1 might be a first sign of neuronal injury that we observed 1 h after end of hyperoxic reoxygenation in a previous study. Whether the poor outcome after normoxic reoxygenation would favour long-term recovery remains to be determined.

WIN 55,212-2 decreases the spatial spread of neocortical excitation in vitro.

The 'intrinsic optical signal' was used to monitor neuronal network excitability. The cannabinoid receptor type 1 agonist WIN 55,212-2 reduced the intensity and the spatial spread of the intrinsic optical signal and prolonged its kinetics in the rat neocortex in vitro. These effects were antagonized by the cannabinoid receptor antagonist SR141716A. Thus, our results suggest that neocortical network activity is modulated via the activation of cannabinoid receptors. The decrease of neocortical network excitability in the present study is probably due to a decreased excitability of glutamatergic neurons.

Lasting accelerative effects of 1 Hz and 20 Hz electrical stimulation on cortical spreading depression: relevance for clinical applications of brain stimulation.

Clinical applications of brain stimulation have been increasing during the last decade; however, the mechanisms of action remain unknown. One proposed mechanism of action is that repetitive stimulation modulates cortical excitability. Herein, we explore the question of whether repetitive electric stimulation increases cortical excitability as indexed by the cortical spreading depression. Twenty-four Wistar rats were divided into three groups according to the treatment: sham, 1-Hz and 20-Hz stimulation. Stimulation was applied to the left frontal cortex through a pair of epidurally implanted silver-wire electrodes. The cortical spreading depression-features were analysed at three time points (one day before, one day after and 2 weeks after treatment) in both the stimulated and unstimulated hemisphere. A 3 x 2 x 3 factorial anova with repeated measures showed significant differences in the main effect of time (P < 0.0001), hemisphere (P = 0.0002) and stimulation group (P = 0.008). The interaction between time vs. hemisphere vs. stimulation group was also significant (P < 0.0001). Posthoc analysis demonstrated that 1-Hz and 20-Hz repetitive electrical stimulation significantly increased the velocity of cortical spreading depression in the stimulated hemisphere. Furthermore, 20-Hz stimulation showed a greater effect on cortical spreading depression compared to 1-Hz stimulation. The results show that 1-Hz and 20-Hz repetitive electrical stimulation results in an increase in cortical spreading depression velocity that is associated with the frequency and the hemisphere of stimulation. Furthermore, the effects are found to be long lasting. We believe that these findings have strong relevance to support the clinical application of therapies involving electrical stimulation for diseases of reduced cortical excitability.

"Rapid regeneration" in the cat retina: a case for spreading depression.

Fundus reflectometry of the cat retina showed that under certain circumstances a rapid increase in density may follow intense bleaching exposures. The spectral characteristics of the density changes indicated that neither rhodopsin nor its bleach products could be responsible for this effect. The poor condition of the animals in which the phenomenon was observed and its conspicuous absence in the majority of the experimental runs suggested that the effect was associated with a process other than the resynthesis of rhodopsin. It was shown that an extrareceptoral event, spreading depression (SD) of the retina, is the most likely source of the rapid spectral change. The well-known tissue alterations associated with SD were induced in the retina independently of pigment density change. The resultant difference spectra resembled those produced when the rapid density increase occurred spontaneously. It seems likely that the abnormal physiological condition of those cats in which the phenomenon is more frequently observed primes the retina for the light-induced generation of spreading depression.