Principal cells in lateral geniculate: Effects of metrazol on capacity to after-discharge

The effect of metrazol on the capacity of dorsal lateral geniculate nucleus (dLGN) principal (P) cells to repetitively burst (after-discharge) following visual system stimulation was examined in P cells which differed in terms of response patterns to visual stimulation (latency of initial spike, extent of repetitive bursting, and on- or off-type responding cells). Twenty-seven P cells were examined in as many subjects. Metrazol augmented repetitive bursting irrespective of the type of P cell as long as repetitive bursting was present in the pre-metrazol period. P cells that displayed only a single initial burst to photic stimulation did not exhibit after-discharge bursting during the metrazol challenge. In all but one cell metrazol enhanced baseline firing rate. These results are discussed in terms of the putative nature of inhibition in the rat dLGN.     

Spinal ventral root after-discharges as a pain index: involvement of NK-1 and NMDA receptors

Nociceptive signals are transmitted to the spinal dorsal horn via primary afferent fibers, and the signals induce withdrawal reflexes by activating spinal motoneurons in the ventral horn. Therefore, nociceptive stimuli increase motoneuronal firing and ventral root discharges. This study was aimed to develop a method for the study of pain mechanisms and analgesics by recording ventral root discharges. Spinalized rats were laminectomized in the lumbo-sacral region. The fifth lumbar ventral root was sectioned and placed on a pair of wire electrodes. Multi unit efferent discharges from the ventral root were increased by mechanical stimulation using a von Frey hair applied to the plantar surface of the hindpaw. The low-intensity mechanical stimuli increased the discharges during stimulation (during-discharges) without increasing the discharges after cessation of stimulation (after-discharges), and the high-intensity mechanical stimuli increased both during- and after-discharges. Pretreatment with resiniferatoxin, an ultrapotent analogue of capsaicin, halved during-discharges and eliminated after-discharges, suggesting that after-discharges are generated by heat- and mechanosensitive polymodal nociceptors. Ezlopitant, a neurokinin-1 (NK-1) receptor antagonist, but not its inactive enantiomer, selectively reduced the after-discharges. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, preferentially reduced the after-discharges, demonstrating that NK-1 and NMDA receptors mediate the after-discharges. Morphine reduced the after-discharges without affecting during-discharges. By contrast, mephenesin, a centrally acting muscle relaxant, reduced both during- and after-discharges. There results suggest that simultaneous recordings of during- and after-discharges are useful to study pain mechanisms and analgesics as well as to discriminate the analgesic effects from the side effects such as muscle relaxant effects.     

Unilateral subcutaneous bee venom but not formalin injection causes contralateral hypersensitized wind-up and after-discharge of the spinal withdrawal reflex in anesthetized spinal rats

This study aimed to investigate the effect of tonic nociception on spinal withdrawal reflexes including (1) long lasting spontaneous responses elicited by subcutaneous (s.c.) administration of formalin (2.5%, 50 microl) and bee venom (BV, 0.2 mg/50 microl) into the hind paw and (2) corresponding ipsilateral (primary) and contralateral (secondary) hypersensitivity to noxious pinch and repetitive supra-threshold (1.5 x T) electrical stimuli at different frequencies (3 Hz: wind-up; 20 Hz: after-discharge) in anesthetized spinal rats. Spinal withdrawal reflexes were studied by simultaneously assessing single motor units (SMUs) electromyographic (EMG) activities from the bilateral medial gastrocnemius (MG) muscles. Subcutaneous formalin-induced persistent spontaneous SMU EMG responses were in typical biphasic manner with an apparent silent period (about 13-18 min), but in contrast, BV elicited monophasic long lasting (about 1 h) SMU EMG responses without any resting state. The mechanically and electrically evoked responsiveness of SMUs were enhanced significantly by ipsilateral BV injection, whereas enhanced electrically, but not mechanically, evoked responses (including wind-up and after-discharge) were found at the non-injection site of the contralateral hind paw. However, s.c. administration of formalin was only able to establish ipsilateral hypersensitivity of the SMUs to repeated electrical, not mechanical, stimulation. Neither mechanically nor electrically evoked contralateral hypersensitivity of the SMUs was found during the ipsilateral formalin-induced nociception. For pharmacological intervention, intrathecal administration of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist CNQX (40 nmol/10 microl), but not the non-competitive NMDA receptor antagonist MK-801 (40 nmol/10 microl), significantly depressed BV-induced contralateral hypersensitivity of the SMUs to repeated 3 Hz (wind-up) and 20 Hz (after-discharge) frequencies of electrical stimulation. Using the extracellular SMU recording technique, we found that s.c. administration of formalin and BV shows a significant difference in long lasting spontaneous firing of SMUs. This is consistent with previous observations in animal behavioral studies. Additionally, contralateral electrically evoked hypersensitivity of the SMUs was found only following BV injection, not in the formalin test. The maintenance and development of BV-induced contralateral hypersensitivity of the spinal withdrawal reflex to noxious electrical stimulation indeed depend on different central pharmacological receptors. The spinal non-NMDA, but not the NMDA, receptors may play important role in BV-induced contralateral central hyperexcitability and sensitization.     

The novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 inhibits nociceptive responses, wind-up, and after-discharges in spinal neurons and withdrawal reflexes

Evidence shows that serotonin (5-HT) is involved in the transmission of nociception in the central nervous system. Using a new electrophysiological method of simultaneous recordings in rats we examined the actions of the novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 as well as those of the opioid receptor agonist fentanyl on simultaneously evoked responses of spinal dorsal horn (DH) wide-dynamic range (WDR) neurons and spinal withdrawal reflexes. Spinal withdrawal reflexes were studied by assessing the activity of single motor units (SMUs) electromyographically (EMG). Like that of 0.02 mg/kg fentanyl, intraperitoneal injection of 0.31 mg/kg of F 13640 markedly inhibited nociceptive pinch-evoked responses as well as C-fiber-mediated late responses including wind-up of both DH WDR neurons and SMUs to suprathreshold (1.5 x T) repeated (3 Hz) electrical stimulation. Specifically, in contrast to no significant depressive effects by fentanyl on 20 Hz electrically evoked after-discharge of DH WDR neurons, the after-discharges of DH WDR neurons and SMUs were significantly inhibited by F 13640 (P < 0.05 and P < 0.001, respectively). The inhibitory effects of F 13640 and fentanyl on responses of DH WDR neurons and SMUs were reversed by the specific antagonists WAY 100635 and naloxone, respectively, further indicating that this 5-HT1A receptor-modulated anti-nociception is mu-opioid receptor independent. For the first time, 5-HT1A receptors are clearly proved to be involved in the progressive wind-up to 3-Hz frequency of electrical stimulation as well as after-discharges of sensory input of DH WDR neurons, and simultaneously recorded motor output of spinal reflexes to 20-Hz frequency of electrical stimulation; this suggests that serotonin, through 5-HT1A receptors, exerts an inhibitory role in the control of obstinate pathological pain.     

Role of central NMDA versus non-NMDA receptor in spinal withdrawal reflex in spinal anesthetized rats under normal and hyperexcitable conditions

The present study aimed to investigate the role of central N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the spinal withdrawal reflex assessed by recording single motor unit (SMU) electromyogram (EMG) response to peripheral mechanical (pressure, pinch) stimuli and repeated electrical stimuli at 3 and 20 Hz. During normal conditions, intrathecal administration of MK-801 and CNQX apparently depressed mechanically and electrically (3 Hz) evoked EMG responses in a dose-dependent manner (10, 20 and 40 nmol in 10 microl). In contrast, the after-discharges to 20 Hz electrical stimuli were suppressed only by CNQX treatment, not by MK-801 treatment. This indicates that the central mechanisms underlying the different frequencies of electrically evoked withdrawal reflex may be different. During peripheral bee venom (BV, 0.2 mg/50 microl) induced inflammation and central sensitization, the enhanced SMU EMG responses including after-discharges to pinch stimuli and 3 Hz electrical stimuli were depressed significantly by treatments with both MK-801 and CNQX. However, the enhanced SMU activities to innocuous pressure stimuli were depressed only by treatment with CNQX. Likewise, enhanced long lasting after-discharges elicited by 20 Hz electrical stimuli were also only depressed by CNQX, indicating that different central mechanisms are involved in the persistent hyperexcitability during BV-induced inflammation. The data suggest that both central NMDA and non-NMDA receptors play important roles in the transmission of nociceptive information under normal conditions. In BV-induced inflammation, however, central non-NMDA receptors, but not NMDA receptors, play a pivotal role in the generation of persistent hyperexcitability to mechanical and electrical stimuli at different frequencies (3 Hz, 20 Hz).     

High-gamma modulation language mapping with stereo-EEG: A novel analytic approach and diagnostic validation

ObjectiveA novel analytic approach for task-related high-gamma modulation (HGM) in stereo-electroencephalography (SEEG) was developed and evaluated for language mapping.MethodsSEEG signals, acquired from drug-resistant epilepsy patients during a visual naming task, were analyzed to find clusters of 50–150 Hz power modulations in time–frequency domain. Classifier models to identify electrode contacts within the reference neuroanatomy and electrical stimulation mapping (ESM) speech/language sites were developed and validated.ResultsIn 21 patients (9 females), aged 4.8–21.2 years, SEEG HGM model predicted electrode locations within Neurosynth language parcels with high diagnostic odds ratio (DOR 10.9, p < 0.0001), high specificity (0.85), and fair sensitivity (0.66). Another SEEG HGM model classified ESM speech/language sites with significant DOR (5.0, p < 0.0001), high specificity (0.74), but insufficient sensitivity. Time to largest power change reliably localized electrodes within Neurosynth language parcels, while, time to center-of-mass power change identified ESM sites.ConclusionsSEEG HGM mapping can accurately localize neuroanatomic and ESM language sites.SignificancePredictive modelling incorporating time, frequency, and magnitude of power change is a useful methodology for task-related HGM, which offers insights into discrepancies between HGM language maps and neuroanatomy or ESM.     

Decreased epileptic susceptibility correlates with neuropeptide Y overexpression in a model of tolerance to excitotoxicity

Prior epileptic episodes have been shown to decrease markedly the neuronal damage induced by a second epileptic episode, similar to the tolerance following an episode of mild ischemia. Endogenous neuroprotective effects mediated by various mechanisms have been put forward. This study investigated whether neuroprotection against the excitotoxic damage induced by re-exposure to an epileptic challenge can reflect a change in epileptic susceptibility. Tolerance was elicited in rats by a preconditioning session using intrahippocampal kainic acid (KA) administration followed at 1, 7 and 15-day intervals by a subsequent intraventricular KA injection. The degree of pyramidal cell loss in the vulnerable CA3 subfield contralateral to the KA-injected hippocampus was extensively reduced in animals experiencing KA ventricular administration. This neuroprotection was highly significant 1 and 7 days after injection, but not 15 days after injection. In preconditioned animals, the after-discharge threshold was assessed as an index of epileptic susceptibility. It increased significantly from 1 to 15 days after intrahippocampal KA administration. Finally, an enhancement of neuropeptide Y expression in both non-principal cells and mossy fibers was detected, occurring at the same time as the decrease in epileptic susceptibility. These results provide further evidence of an 'epileptic tolerance' as shown by the substantial neuroprotective effect of a prior episode of epileptic activity upon subsequent epileptic insult and suggest that the prevention of excitotoxic damage after preconditioning results from an endogenous neuroprotective mechanism against hyperexcitability and seizures.     

Strain differences in the elicitation of electrocortical after-discharges

Two experiments were carried out. The first experiment compared four rat strains with respect to elicitation of photically evoked after-discharge (AD) and AD response to pentamethylenetetrazol (Metrazol). It was observed that in terms of AD elicitation the rat strains could be differentiated in the following order: albino > brown Norway > hooded Long-Evans > black Long-Evans. After discharges were essentially unelicitable from the black Long-Evans. Moreover, the black animals were unresponsive to Metrazol whereas the other strains had a reliable augmentation of AD following Metrazol injections. The second experiment was carried out to determine whether the general activity levels or open field mobility of the four rat strains would differentiate the strains in the same order indicated by AD responsivity. It was observed that open field mobility correlated negatively with the AD findings whereas general activity levels as measured with an activity platform and AD paramters had a small positive relationship.     

Detection of after-discharges during intraoperative functional brain mapping in awake brain tumor surgery using a novel high-density circular grid

ObjectiveTo evaluate intraoperative use of a novel high-density circular grid in detecting after-discharges (AD) on electrocorticography (ECoG) during functional brain mapping (FBM).MethodsFBM during glioma surgery (10/2016 to 5/2019) recorded ADs using a 22-channel circular grid compared to conventional strip electrodes. ADs were analyzed for detection, duration, amplitude, morphology, histology, direction, and clinical signs.ResultsThirty-two patients (mean age 54.2 years; r = 30–75) with glioma (WHO grade II-IV; 20 grade IV) had surgery. ADs during FBM were more likely in patients with wild-type as opposed to IDH-1 mutants (p < 0.0001) using more contacts compared with linear strip electrodes (p = 0.0001). More sensors tended to be involved in ADs detected by the circular grid vs strips (6.61 vs 3.43; p = 0.16) at lower stimulus intensity (3.14 mA vs 4.13 mA; p = 0.09). No difference in the number of cortical stimulations before resection was present (38.9 mA vs 47.9 mA; p = 0.26). ADs longer than 10 seconds were 32.5 seconds (circular grid) vs 58.4 (strips) (p = 0.12).ConclusionsHigh-density circular grids detect ADs in 360 degrees during FBM for glioma resection. Provocation of ADs was more likely in patients with wild-type than IDH-1 mutation.SignificanceCircular grids offer high-resolution ECoG during intraoperative FBM for detection of ADs.