Range Of Stimulation Intensities Research Articles

Fentanyl self-administration is accelerated by methamphetamine co-use and results in worsened hypodopaminergia in male, but not female rats.

Combined use of fentanyl and methamphetamine (FENT + METH) has increased in recent years and has been documented in a growing number overdose deaths each year. The impact of FENT + METH on behavior and neurobiology is not well understood. In this study, male and female Long Evans rats were tested on a limited access, fixed ratio 1 self-administration schedule for increasing doses (1.25-5 μg/kg/infusion; iv) of fentanyl, with and without a single dose (0.1 mg/kg/infusion; iv) of methamphetamine, for 15 days. FENT + METH abolished dose responsiveness to fentanyl in all rats and accelerated intake in males, resulting in patterns of responding that may be more likely to result in adverse effects. Ex vivo slice voltammetry in the nucleus accumbens core showed decreases in dopamine release and reuptake (Vmax) following FENT + METH exposure, compared with saline, fentanyl, and methamphetamine alone groups at baseline parameters. Further, significant decreases in dopamine release were observed across a range of stimulation intensities following FENT + METH exposure. Overall, male and female rats displayed sex-specific behavioral and neurobiological responses to FENT + METH exposure, with males displaying increased vulnerability.

Neural mechanisms responsible for vagus nerve stimulation-dependent enhancement of somatosensory recovery

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

Two-photon imaging of excitatory and inhibitory neural response to infrared neural stimulation.

Pulsed infrared neural stimulation (INS, 1875nm) is an emerging neurostimulation technology that delivers focal pulsed heat to activate functionally specific mesoscale networks and holds promise for clinical application. However, little is known about its effect on excitatory and inhibitory cell types in cerebral cortex. Estimates of summed population neuronal response time courses provide a potential basis for neural and hemodynamic signals described in other studies. Using two-photon calcium imaging in mouse somatosensory cortex, we have examined the effect of INS pulse train application on hSyn neurons and mDlx neurons tagged with GCaMP6s. We find that, in anesthetized mice, each INS pulse train reliably induces robust response in hSyn neurons exhibiting positive going responses. Surprisingly, mDlx neurons exhibit negative going responses. Quantification using the index of correlation illustrates responses are reproducible, intensity-dependent, and focal. Also, a contralateral activation is observed when INS applied. In sum, the population of neurons stimulated by INS includes both hSyn and mDlx neurons; within a range of stimulation intensities, this leads to overall excitation in the stimulated population, leading to the previously observed activations at distant post-synaptic sites.

Analysis of electrical stimulation and voluntary muscle contraction on skeletal muscle oxygen uptake and mitochondrial recovery using near-infrared spectroscopy.

This investigation was to compare differences in skeletal muscle oxygen consumption ([Formula: see text]) and mitochondrial recovery between voluntary (VOL) and electrically stimulated (ES) plantarflexion contractions. Twelve men and women (26 ± 4.0years; 171.8 ± 5.1cm; 74.0 ± 13.7kg) were seated in a chair with their right knee fully extended and right foot secured to a force transducer. ES electrodes and a near-infrared spectroscopy device were placed on the gastrocnemius. Participants performed ES plantarflexion contractions across a range of stimulation intensities at frequencies of 1 and 2Hz and similar VOL contractions. Cuff occlusion occurred immediately following each series of contractions to measure [Formula: see text]. A standardized mitochondrial function assessment protocol was also performed to calculate K-constants between work-matched ES and VOL contractions. For mitochondrial assessments, there were no significant differences between ES and VOL rate constants (2.03 ± 0.98 vs. 1.25 ± 1.35min-1, p = 0.266). ES resulted in a significantly greater workrate-[Formula: see text] slope at 1Hz (0.007 ± 0.007 vs. 0.001 ± 0.002% [Formula: see text]/s/N, p = 0.014) and 2Hz (0.010 ± 0.010 vs. 0.001 ± 0.001% [Formula: see text]/s/N, p = 0.012), as well as a significantly greater workrate-[Formula: see text] Y-intercept at 2Hz (1.603 ± 1.513 vs. 0.556 ± 0.564% [Formula: see text]/s, p = 0.035) but not 1Hz (0.579 ± 0.448 vs. 0.442 ± 0.357% mV̇O2/s, p = 0.535) when compared to VOL. ES results in a significantly greater [Formula: see text] at similar work rates compared to VOL, however, the mitochondrial recovery rate constants were similar. The greater mVO2 with ES may partially contribute to the increased rate of fatigue during ES exercise in individuals with muscle paralysis.

A novel method for quantitative evaluation of motor evoked potential monitoring during cerebrovascular surgeries

Transcranial motor evoked potential (MEP) monitoring, intended to assess cerebral cortical ischemia, may produce false negative results when the stimulation inadvertently activates the deep, subcortical motor pathways. This study examined hand MEP onset latency as a potential means to differentiate superficial versus deep stimulus penetration in surgical patients monitored for cerebral ischemia.Intraoperative MEP data were prospectively collected from 40 patients treated for intracranial aneurysm or carotid stenosis. Onset latencies of hand MEP responses were measured over a range of stimulation intensities from both the contralateral and ipsilateral hand (crossover responses). At the threshold for superficial, cortical stimulation of the contralateral hand, the MEP latency was 26.9 ± 0.4 ms. MEP onset latencies measurements became shorter as stimulation intensities were increased. At the maximum intensity (when crossover response was usually generated), the contralateral hand MEP latency of 22.5 ± 0.3 ms was significantly shorter than at threshold stimulation (p < 0.001). Latency-stimulus intensity plots best fit a 3 parameter hyperbolic decay function (r2 = 0.85 ± 0.02) and revealed a narrow window of acceptable MEP stimuli to obtain superficial cortical activation. Our analysis refutes the utility of the crossover response in reliably gauging depth of activation. Additionally, we found that differentiation between long and short MEP onset latency times may serve as a dependable marker for depth of stimulation. Attention to hand MEP onset latency may reduce inadvertent stimulation of the deep corticospinal tract pathways and avoid false negative MEP recordings during cerebrovascular surgeries.

The Impact of Stimulation Intensity on Spatial Discrimination with Multi-Pad Finger Electrode

Multi-pad electrotactile stimulation can be used to provide tactile feedback in different applications. The electrotactile interface needs to be calibrated before each use, which entails adjusting the intensity to obtain clear sensations while allowing the subjects to differentiate between active pads. The present study investigated how the stimulation intensity affects the localization of sensations using a multi-pad electrode placed on a fingertip and proximal phalange. First, the sensation, localization, smearing and discomfort thresholds were determined in 11 subjects. Then, the same subjects performed a spatial discrimination test across a range of stimulation intensities. The results have shown that all thresholds were significantly different, while there was no difference in the threshold values between the pads and phalanges. Despite the subjective feeling of spreading of sensations, the success rates in spatial discrimination were not significantly different across the tested stimulation intensities. However, the performance was better for distal compared to proximal phalange. Presented results indicate that spatial discrimination is robust to changes in the stimulation intensity. Considering the lack of significant difference in the thresholds between the pads, these results imply that more coarse adjustment of stimulation amplitude (faster calibration) might be enough for practical applications of a multi-pad electrotactile interface.

Speech comprehension across multiple CI processor generations: Scene dependent signal processing.

ObjectivesIn clinical practice, characterization of speech comprehension for cochlear implant (CI) patients is typically administered by a set of suprathreshold measurements in quiet and in noise. This study investigates speech comprehension of the three most recent cochlear implant sound processors; CP810, CP910, and CP1000 (Cochlear Limited). To compare sound processor performance across generations and input dynamic range changes, the state‐of‐the art signal processing technologies available in each sound processor were enabled. Outcomes will be assessed across a range of stimulation intensities, and finally analyzed with respect to normal hearing listeners.MethodsIn a prospective study, 20 experienced postlingually deafened CI patients who received a Nucleus CI in the ENT department of the University Hospital of SH in Kiel were recruited. Speech comprehension was measured in quiet at 40, 50, and 65 dBSPL with monosyllabic words as well as by speech reception threshold for two‐digit numbers. In noise, speech reception thresholds were measured with the adaptive German matrix test with speech and noise in front.ResultsWe found that high levels of open‐set speech comprehension are achieved at suprathreshold presentation levels in quiet. However, results at lower test levels have remained mostly unchanged for tested sound processors with default dynamic range. Expanding the lower limit of the acoustic input dynamic range yields better speech comprehension at lower presentation levels. In noise the application of ForwardFocus improves the speech reception. Overall, a continuous improvement for speech perception across three generations of CI sound processors was found.ConclusionsFindings motivate further development of signal pre‐processing, an additional focus of clinical work on lower stimulation levels, and automation of ForwardFocus.Level of evidence2.

Sensitivity to haptic sound-localisation cues

Hearing aid and cochlear implant (CI) users often struggle to locate and segregate sounds. The dominant sound-localisation cues are time and intensity differences across the ears. A recent study showed that CI users locate sounds substantially better when these cues are provided through haptic stimulation on each wrist. However, the sensitivity of the wrists to these cues and the robustness of this sensitivity to aging is unknown. The current study showed that time difference sensitivity is much poorer across the wrists than across the ears and declines with age. In contrast, high sensitivity to across-wrist intensity differences was found that was robust to aging. This high sensitivity was observed across a range of stimulation intensities for both amplitude modulated and unmodulated sinusoids and matched across-ear intensity difference sensitivity for normal-hearing individuals. Furthermore, the usable dynamic range for haptic stimulation on the wrists was found to be around four times larger than for CIs. These findings suggest that high-precision haptic sound-localisation can be achieved, which could aid many hearing-impaired listeners. Furthermore, the finding that high-fidelity across-wrist intensity information can be transferred could be exploited in human–machine interfaces to enhance virtual reality and improve remote control of military, medical, or research robots.

Cellular and Synaptic Mechanisms That Differentiate Mitral Cells and Superficial Tufted Cells Into Parallel Output Channels in the Olfactory Bulb.

A common feature of the primary processing structures of sensory systems is the presence of parallel output “channels” that convey different information about a stimulus. In the mammalian olfactory bulb, this is reflected in the mitral cells (MCs) and tufted cells (TCs) that have differing sensitivities to odors, with TCs being more sensitive than MCs. In this study, we examined potential mechanisms underlying the different responses of MCs vs. TCs. For TCs, we focused on superficial TCs (sTCs), which are a population of output TCs that reside in the superficial-most portion of the external plexiform layer, along with external tufted cells (eTCs), which are glutamatergic interneurons in the glomerular layer. Using whole-cell patch-clamp recordings in mouse bulb slices, we first measured excitatory currents in MCs, sTCs, and eTCs following olfactory sensory neuron (OSN) stimulation, separating the responses into a fast, monosynaptic component reflecting direct inputs from OSNs and a prolonged component partially reflecting eTC-mediated feedforward excitation. Responses were measured to a wide range of OSN stimulation intensities, simulating the different levels of OSN activity that would be expected to be produced by varying odor concentrations in vivo. Over a range of stimulation intensities, we found that the monosynaptic current varied significantly between the cell types, in the order of eTC > sTC > MC. The prolonged component was smaller in sTCs vs. both MCs and eTCs. sTCs also had much higher whole-cell input resistances than MCs, reflecting their smaller size and greater membrane resistivity. To evaluate how these different electrophysiological aspects contributed to spiking of the output MCs and sTCs, we used computational modeling. By exchanging the different cell properties in our modeled MCs and sTCs, we could evaluate each property's contribution to spiking differences between these cell types. This analysis suggested that the higher sensitivity of spiking in sTCs vs. MCs reflected both their larger monosynaptic OSN signal as well as their higher input resistance, while their smaller prolonged currents had a modest opposing effect. Taken together, our results indicate that both synaptic and intrinsic cellular features contribute to the production of parallel output channels in the olfactory bulb.

TMS excitability study in essential tremor: Absence of gabaergic changes assessed by silent period recordings

Essential tremor (ET) is thought to emerge from activity in a distributed cerebello-thalamo-cortical network. It has been proposed that the network goes into oscillation because of abnormal GABAergic inhibitory transmission. To test this idea by investigating GABAergic circuitry in motor cortex using transcranial magnetic stimulation (TMS). Motor cortex excitability was examined using TMS in 21 patients with essential tremor and in 20 control subjects. Resting and active motor threshold (RMT, AMT) and input-output curves examined corticospinal excitability. Contralateral silent period (cSP) at a different range of stimulation intensities, and the ipsilateral silent period (iSP) using a stimulus intensity of 150% RMT were used as measures of GABAergic function. RMT and AMT were significantly lower in patients than controls and patients had a steeper I/O curve. However, there were no significant differences in either cSP at different intensities or in iSP. We found no evidence in favour of the GABA hypothesis in ET.

Is hippocampal theta frequency related to individual and sex differences in anxiety-like behaviour? An analysis in male and female Long-Evans rats

Hippocampal theta activity is a prominent slow (4–12 Hz) oscillatory activity pattern generated in the mammalian hippocampal formation. Based on evidence that anxiolytic drugs consistently decrease the frequency of hippocampal theta activity in rodents, hippocampal theta has been linked to anxiety states, leading to the influential theta suppression model of anxiolysis. Surprisingly, very few studies have examined whether hippocampal theta frequency relates to individual or sex differences in anxiety-like behaviour. Here, male and female rats were tested on the elevated plus maze (EPM) to quantify levels of defensive, anxiety-like behaviours. Females exhibited higher levels of open arm exploration (open arm entries and open arm time) compared to males, suggestive of reduced anxiety in females. Subsequently, reticular-elicited hippocampal theta activity was characterized in the same rats under deep urethane anesthesia. There was no sex difference in theta frequency over a range of stimulation intensities. Further, there were no significant correlations between behavioural measures of anxiety in the EPM and theta frequency among individual animals. Theta frequency did, however, decrease following systemic administration of the clinically-used anxiolytic agent buspirone (10 mg/kg). Together, these results suggest that theta frequency does not relate to levels of anxiety-like behaviours in the EPM in male and female rats, challenging the predictive validity of hippocampal theta activity as an index of anxiety in rodents.

Changes in recruitment of motor cortex excitation and inhibition in patients with drug-induced tardive syndromes

It has recently been suggested that drug-induced tardive syndromes (TS) might be due to maladaptive plasticity, which increases motor excitability in cerebral cortex and basal ganglia. In order to test this hypothesis, we performed the first measurements of cortical excitability in TS. Motor cortex excitability was examined using transcranial magnetic stimulation (TMS) in 22 TS patients and compared with that in 20 age and sex-matched healthy individuals. Resting and active motor threshold (RMT, AMT) and input-output curves (I/O curves) assessed corticospinal excitability. The duration of the contralateral silent period (cSP) at a range of stimulation intensities and ipsilateral silent period (iSP) were used as measures of inhibition. There were no significant differences in RMT and AMT between patients and controls, although the input-output curves were significantly steeper in patients. The cSP (at different stimulus intensities) and iSP were both longer in the patients compared to the control group. However, most of this difference could be accounted for by increased recruitment of motor evoked potentials (MEPs) in patients. TS is characterized by hyperexcitability of corticospinal output that might contribute to the lack of selectivity in muscle recruitment and contribute to excess involuntary movement. The findings are opposite to those in naturally-occurring hyperkinesia such as Sydenham's and Huntington's chorea, suggesting a fundamental difference in the pathophysiology.

A New Mathematical Force Model that Predicts the Force-pulse Amplitude Relationship of Human Skeletal Muscle.

Current functional electrical stimulation (FES) systems vary the stimulation intensity to control the muscle force in order to produce precise functional movements. However, mathematical model that predicts the intensity effect on the muscle force is required for model-based controller design. The most previous force model designed by Ding et al was validated only for a standardized stimulation pulse amplitude (intensity). Thus, the purpose of this study was to adapt the Ding et al model to be able to predict the force-pulse amplitude relationship. The experimental results tested on quadriceps femoris muscles of healthy subjects (N=5) show that our adapted model accurately predicts the force response for trains of a wide range of stimulation intensities (30-100 mA). The accurate predictions indicate that our adapted model could be used for designing model-based control strategies to control the muscle force through FES.

Intense Focused Ultrasound Stimulation of the Rotator Cuff: Evaluation of the Source of Pain in Rotator Cuff Tears and Tendinopathy

The objective of this preliminary study was to evaluate the ability of individual 0.1-s long pulses of intense focused ultrasound (iFU) emitted with a carrier frequency of 2 MHz to evoke diagnostic sensations when applied to patients whose shoulders have rotator cuff tears or tendinopathy. Patients were adults with painful shoulders and clinical and imaging findings consistent with rotator cuff disease. iFU stimulation of the shoulder was performed using B-mode ultrasound coupled with a focused ultrasound transducer that allowed image-guided delivery of precisely localized pulses of energy to different anatomic areas around the rotator cuff. The main outcome measure was iFU spatial average–temporal average intensity (I_SATA), and location required to elicit sensation. In control patients, iFU produced no sensation throughout the range of stimulation intensities (≤2000 W/cm2 I_SATA). In patients with rotator cuff disease, iFU was able to induce sensation in the tendons of the rotator cuff, the subacromial bursa, and the subchondral bone in patients with chronic shoulder pain and rotator cuff disease, with an average ± standard deviation intensity equaling 680 ± 281 W/cm2 I_SATA. This result suggests a primary role for these tissues in the pathogenesis of shoulder pain related to rotator cuff tendinopathy.

P 19. Threshold for neurodegeneration and microstructural changes in different cell types induced by anodal transcranial direct current stimulation

Introduction Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and to improve motor learning (Nitsche and Paulus, 2000; Reis et al., 2009; Fritsch et al., 2010). To date there is no data available on the safety aspects of tDCS covering a broad range of stimulation intensities, thus limitations for dosages applied to humans are still based empirically on other types of electrical brain stimulation (Agnew and McCreery, 1987). Objectives The aim of this study was to investigate lesion threshold, accompanying neurodegeneration and possible microstructural changes in glial cells in an animal model of tDCS. Methods The tDCS electrode was placed in a screw tube surgically fixed on the skull above the left primary motor cortex of 47 Male Sprague Dawley rats. Anodal tDCS was applied in different intensities (254.8, 127.4, 63.7, 31.8, 15.9 and 8A/sqm) or as sham stimulation for 20min under slight isoflurane anesthesia. For each intensity animals were sacrificed either 24h (acute effects) or 7days (chronic effects) after intervention. Histological analyses of neurodegeneration (HE-staining, Fluoro-Jade C), astrocyte (anti-GFAP) and microglial (anti-CD11b [OX-42]) cell counts/density and/or morphological changes were evaluated. Results Macroscopical lesions could be observed at tDCS intensity of 127A/sqm and above whereas the lesion dose 50 (LD 50) for microscopical neurodegeneration was determined at 60A/sqm. Threshold for damage in neuronal and glial cells and change in morphology (activation) was identical. These changes could be detected both in the acute and chronic group. Notably, signs of still ongoing neurodegeneration, though to a slighter extent, were seen 7days after stimulation. Brain swelling, which was seen underneath the stimulation electrode 24h following the highest intensity used, was not present one week after stimulation. Conclusions Our results demonstrate that the LD 50 intensity of anodal tDCS for unwanted structural effects is 75 times higher than the intensities applied to humans to date. Additional safety derives from the fact that structures between brain and stimulation electrode, which lead to energy absorbtion, are thicker in humans compared to rats. Cell death, as a trigger for glial reaction, continues even 7days after the intervention. Based on our results we conclude that higher tDCS intensities in human studies can be applied without risking structural damage.

Characterizing Changes in the Excitability of Corticospinal Projections to Proximal Muscles of the Upper Limb

BackgroundThere has been an explosion of interest in methods of exogenous brain stimulation that induce changes in the excitability of human cerebral cortex. The expectation is that these methods may promote recovery of function following brain injury. To assess their effects on motor output, it is typical to assess the state of corticospinal projections from primary motor cortex to muscles of the hand, via electromyographic responses to transcranial magnetic stimulation. If a range of stimulation intensities is employed, the recruitment curves (RCs) obtained can, at least for intrinsic hand muscles, be fitted by a sigmoid function. Objective/hypothesisTo establish whether sigmoid fits provide a reliable basis upon which to characterize the input–output properties of the corticospinal pathway for muscles proximal to the hand, and to assess as an alternative the area under the (recruitment) curve (AURC). MethodsA comparison of the reliability of these measures, using RCs obtained for muscles that are frequently the targets of rehabilitation. ResultsThe AURC is an extremely reliable measure of the state of corticospinal projections to hand and forearm muscles, which has both face and concurrent validity. Construct validity is demonstrated by detection of widely distributed (across muscles) changes in corticospinal excitability induced by paired associative stimulation (PAS). Conclusion(s)The parameters derived from sigmoid fits are unlikely to provide an adequate means to assess the effectiveness of therapeutic regimes. The AURC can be employed to characterize corticospinal projections to a range of muscles, and gauge the efficacy of longitudinal interventions in clinical rehabilitation.

Muscle enhancement using closed-loop electrical stimulation: Volitional versus induced torque

In cases of partial deficiency of muscle activation capacity, force augmentation can be achieved by hybrid activation, i.e., by combining electrical stimulation (ES) with volitional activation. In this activation modality the shares of the volitional and induced torques within the overall hybrid torque are unknown. The purpose of this study was to suggest a computational approach to parcel out the volitional and stimulation induced components of joint torque generated during combined voluntary and electrical activation of the Tibialis Anterior muscle (TA). For this purpose, isometric contraction of the TA was studied on 5 healthy subjects, using an activation protocol involving ES alone, volitional activation alone and hybrid activation. Ankle torque and TA EMG were measured. A computational algorithm was developed to dissociate the volitional from the overall torque, based on EMG filtering and on pre-measured calibration curves of volitional torque versus EMG. The results indicated that for a certain hybrid torque there is a linear decaying relationship between the induced torque and the volitional torque shares. Moreover, based on a defined enhancement ratio, the results indicate that within the range of stimulation intensities, there exist regions of increased facilitation, in which the stimulation efficiency is higher under combined compared to isolated conditions.

Cysteamine pre-treatment reduces pentylenetetrazol-induced plasticity and epileptiform discharge in the CA1 region of rat hippocampal slices

The effects of prior treatment of cysteamine, a somatostatin inhibitor, on pentylenetetrazol (PTZ) induced epileptic and plastic changes in CA1 excitability were examined. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. Changes in the population spike and epileptiform amplitudes were used as indices to quantify the effects of PTZ exposure in the control and cysteamine pre-treated slices. Cysteamine pre-treatment decreased baseline CA1 population spike amplitude following high intensity stimulation of Schaffer collaterals. Following PTZ application directly to the slices, cysteamine diminished the increased population spike and epileptiform amplitudes which were normally observed following collateral stimulation. Magnesium-free medium induced epileptiform activity was also significantly reduced with cysteamine pre-treatment. It is concluded that somatostatin may be involved in PTZ-induced epileptic and plastic changes in CA1 excitability.

Corticostriatal paired-pulse potentiation produced by voltage-dependent activation of NMDA receptors and L-type Ca(2+) channels.

AMPA and N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses expressed differential paired-pulse plasticity when examined in the same cell using intracellular or whole cell voltage-clamp recordings. Electrical stimulation of corticostriatal afferents in brain slices bathed in artificial cerebrospinal fluid containing bicuculline produces excitatory postsynaptic potentials and excitatory postsynaptic currents (EPSCs) mediated primarily by AMPA receptors. Cell-to-cell variation existed in AMPA receptor paired-pulse plasticity, but within-cell plasticity was stable over a range of stimulation intensities. Addition of 6-cyano-7-nitroquinoxalene-2,3-dione blocked most of the synaptic response leaving behind a small AP-5-sensitive component. Increasing the stimulation intensity produced large, long-lasting NMDA receptor-mediated responses. In contrast to AMPA receptor-mediated responses, NMDA receptor responses consistently showed an increase in paired-pulse potentiation with increasing stimulation intensity. This relationship was restricted to interstimulus intervals shorter than 100 ms. Paired-pulse potentiation of NMDA receptor responses was voltage-dependent and reduced by removal of extracellular Mg(2+). Block of postsynaptic L-type Ca(2+) channels with nifedipine produced a voltage-dependent reduction of NMDA receptor excitatory postsynaptic currents (EPSCs) and a voltage-dependent reduction of NMDA receptor paired-pulse potentiation. These data indicate depolarization during the first NMDA receptor response causes facilitation of the second by removing voltage-dependent block of NMDA receptors by Mg(2+) and by activating voltage-dependent Ca(2+) channels.

Primed-burst potentiation occludes the potentiation phenomenon and enhances the epileptiform activity induced by transient pentylenetetrazol in the CA1 region of rat hippocampal slices

The effects of pentylenetetrazol (PTZ) following induction of long-term potentiation (LTP) on population spikes in CA1 of hippocampal slices were investigated. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. LTP was induced using θ-pattern primed burst tetanic stimulation. Changes in the population spike amplitude and number of population spikes were used as indices to quantify the effects of PTZ exposure in the control (non-tetanized) and LTP (tetanized) conditions. The amplitude of population spike was measured 20 min before, during 20 min chemical application (3 mM), and also after 30 or 60 min washout period. In non-tetanized slices, the population spike input-output curve was significantly increased 20 min after PTZ application and persisted at least for 60 min. Multiple population spikes or after potentials also appeared, but did not persist. When PTZ was applied on tetanized slices, 60 min after LTP induction, the amplitude increase produced by PTZ was smaller than the increase seen in the control condition. Also LTP induction preceding PTZ exposure increased the number of population spikes evoked by stimulation of Schaffer collaterals. It is concluded that a transient PTZ application produces a long-lasting increase in population spike amplitude. Primed burst LTP occludes PTZ-induced potentiation while also increasing the epileptogenic effect of PTZ.