Low-intensity Stimulation Research Articles

Cortical excitability in patients after loading doses of lamotrigine: a study with magnetic brain stimulation.

Transcranial magnetic stimulation (TMS) of the brain allows the pharmacologic effects of anti-convulsant drugs (AEDs) on the excitability of motor corticospinal pathways to be evaluated in patients with epilepsy and normal subjects. However, no study has yet documented the changes in motor excitability in patients treated with lamotrigine (LTG). We aimed to study the effects of loading doses of LTG on TMS recordings in patients with epilepsy at the beginning of their treatment. We investigated single-pulse TMS in six patients with complex partial seizures. The TMS recordings were performed in five sessions before and during 5 weeks of treatment. Motor threshold, motor-evoked potential (MEP) amplitude, cortical silent period, and peripheral conduction velocity were used as parameters of evaluation. LTG was started with a dosage of 25 mg/day until a daily maintenance dosage of 200 mg/day was reached. The motor threshold activation of thenar muscles was significantly increased by LTG after 2 weeks of treatment and was increased in a parallel way to the loading dose of the drug at week 3 and 5 of treatment. The MEP size recorded from the thenar muscles did not show significant changes at high- or low-intensity stimulation. The cortical silent period remained unchanged at low- and high-intensity stimulation. The absolute latency of MEPs after cortical and cervical stimulation was unchanged, as was the central motor conduction time. Our study documents that loading doses of LTG, administered as monotherapy, progressively increases patients' motor thresholds over short periods.

Heteronymous H-reflex in temporal muscle motor units.

An electric stimulation of the masseteric nerve elicits a heteronymous H-reflex in the temporal muscle. The characteristics of this reflex response were investigated by analysis of the firing probability changes of single motor units. Eleven healthy subjects participated in the experiments. The heteronymous H-reflex of the temporal muscle was electrically elicited by stimulation of the masseteric nerve at 120% of the intensity needed for the maximal masseteric M-wave. From 8 to 24 motor units were sampled from the temporal muscle of each subject. Peri-stimulus time histograms of motor unit recordings were built with a 0.5-ms bin width. The mean firing probability was calculated for the 20 ms preceding the stimulus. The firing probability was considered increased when it exceeded the mean by 3 standard deviations. Of 104 sampled motor units, 40 motor units showed a significant increase of the firing probability, which lasted 1 ms or less in 29 of them. In 12 out of 16 motor units, a significant increase of firing probability also persisted at a lower stimulation intensity (120% of the threshold needed to elicit a masseteric M wave). These data indicate that: (1) some temporal muscle motor units are modulated by afferents from the masseter muscle, (2) the heteronymous H-reflex has a monosynaptic component, and (3) there might be a more complex than just monosynaptic organization serving the heteronymous temporal H-reflex. For the latter conclusion regarding synaptic wiring, however, PSTH studies like the present one can offer only indirect evidence, and this question could be better studied in animals.

Long-term potentiation in the neocortex of the adult, freely moving rat.

Neocortical preparations have proven highly resistant to the induction of long-term potentiation (LTP), and we have only recently determined the conditions sufficient for the induction of neocortical LTP in the adult, freely moving rat. The stimulation trains must be spaced and repeated over a period of days in order to reach asymptotic levels of potentiation. Here we show that, within these constraints, the neocortex is actually highly responsive. LTP could be induced with as few as one brief high frequency train per day or with extremely low-intensity stimulation trains. We also provide evidence for a critical role for N-methyl-D-aspartate (NMDA) receptor activation in LTP induction in this preparation, and demonstrate that this LTP is input-specific. Control pathways showed no potentiation effects. LTP was found in a monosynaptic and two polysynaptic components (average latencies to peak: 8.1, 15.2 and 20.0 ms) and in the superimposed population spikes. Although LTP could be induced with one train per day or with low-intensity trains, larger and longer-lasting potentiation effects could be induced by increasing the number of trains delivered per session, the number of sessions over which trains were delivered, or the pulse intensity of the trains. The LTP decayed slowly and was still evident 5 weeks later. Administration of the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid blocked the induction of LTP in a dose-dependent fashion and appeared to unmask a depression of both the population spikes and a polysynaptic component. These results indicate that the neocortex is highly sensitive to LTP induction procedures, as long as the stimulation trains are spaced and applied over a period of days. They are also consistent with the view that the neocortex must operate with a slow learning rate to reduce interference effects in memory.

Excitability changes and glucose metabolism in experimentally induced focal cortical dysplasias.

Malformations of cortical development are increasingly recognized in association with severe epileptic syndromes, neuropsychological disorders and mental retardation. Several clinical and experimental studies suggest that functional consequences of cortical dysplasias are not restricted to the area of the dysplastic lesion but also involve remote brain regions. In the present study cortical malformations were induced in newborn rats at day of birth by intracerebral injection of the glutamatergic agonist ibotenate. The resulting cytoarchitectonic lesion associates neuronal depopulation of deep cortical layers, ectopic neurons in superficial layers and sulcus formation, mimicking human polymicrogyria and migration disorders. Electrophysiological recordings of evoked field potentials in slice preparations of adult animals reveal hyperexcitability in widespread cortical regions surrounding the dysplasia. Low-intensity stimulation induced epileptiform activity consisting of long-lasting, multiphasic and N-methyl-D-aspartate-dependent field responses. They appeared with high variability as all-or-none events. These widespread changes in excitability were not observed in sham-operated animals with small superficial ectopias but intact deep cortical layers, indicating that focal loss of these layers induces extended alterations in cortical connectivity and imbalance of excitation and inhibition. Restricted zones of increased excitability were also found in the forelimb and hindlimb representation cortex in sham-operated and control animals, demonstrating that this activity has to be considered as an intrinsic property of specific cortical areas. Deoxyglucose autoradiography showed that the widespread hyperexcitability in ibotenate-injected animals was not accompanied by alterations in glucose metabolism, although in the area of structural abnormality a typical metabolic pattern was found, revealing an increased glucose uptake in layer I. Hypometabolism as described for many types of human dysplastic lesions was not observed. This difference between the experimental and clinical data may be due to the absence of behavioral seizures in this model. However, it can be hypothesized that in patients with developmental malformations, additional pathogenic factors contribute to the manifestation of seizure disorders.

Dynamics of heart rate response to sympathetic nerve stimulation.

Electrical stimulation of the right cardiac sympathetic nerve was used to achieve a step increase of norepinephrine concentration at the sinus node. The heart rate (HR) response to sympathetic stimulation was characterized by a first-order process with a time delay. For moderate to high intensities of stimulation the mean delay and time constant were 0.7 and 2.1 s, respectively, and for low intensities of stimulation they were 0.4 and 1.1 s, respectively. From the analysis of the HR response to different patterns of nerve stimulation, in vivo neurotransmitter kinetics were estimated. The time constant of norepinephrine dissipation averaged approximately 9 s. These results combined with computer simulations revealed two facets of sympathetic neural control of HR: 1) negligible role of the sympathetic system in beat-to-beat regulation of HR under stationary conditions and 2) ability of HR to react relatively quickly (within a few seconds) to sharp increases in sympathetic nerve traffic.

NMDA EPSCs at Glutamatergic Synapses in the Spinal Cord Dorsal Horn of the Postnatal Rat

In rat dorsal horn, little is known about the properties of synaptic NMDA receptors during the first two postnatal weeks, a period of intense synaptogenesis. Using transverse spinal cord slices from postnatal day 0-15 rats, we show that 20% of glutamatergic synapses tested at low-stimulation intensity in spinal cord laminae I and II were mediated exclusively by NMDA receptors. Essentially all of the remaining glutamatergic EPSCs studied were attributable to the activation of both NMDA and AMPA receptors. Synaptic NMDA receptors at pure and mixed synapses showed similar sensitivity to membrane potential, independent of age, indicating similar Mg2+ sensitivity. Kinetic properties of NMDA EPSCs from pure and mixed synapses were measured at +50 mV. The 10-90% rise times of the pure NMDA EPSCs were slower (16 vs 10 msec), and the decay tau values were faster (tau1, 24 vs 42 msec; tau2, 267 vs 357 msec) than NMDA EPSCs at mixed synapses. Our results indicate that NMDA receptors are expressed at glutamatergic synapses at a high frequency, either alone or together with AMPA receptors, consistent with the prominent role of NMDA receptors in central sensitization (McMahon et al., 1993).

Differential frequency-dependent reflex integration of myelinated and nonmyelinated rat aortic baroreceptors.

Electrical activation of myelinated (A type) and nonmyelinated (C type) baroreceptor axons (BR) in aortic depressor nerve (ADN) evoked baroreflex changes in mean arterial pressure (MAP) in chloralose-urethan-anesthetized rats. Low stimulation intensities (<3 V) activated only A-type BR electroneurograms (ENG). A-type selective stimulus trains required minimum frequencies >10 Hz to evoke reflex MAP decreases, and the largest MAP responses occurred at 50 Hz and higher. In contrast, high stimulation intensities (18-20 V) maximally activated two volleys in ADN ENG corresponding to A- and C-type BR volleys. High-intensity trains decreased MAP at low frequency (1 Hz) and largest reflex responses at >/=5 Hz. Capsaicin (Cap) applied periaxonally to ADN selectively blocked C-type ENG volleys but not A-type volleys. Reflex curves with supramaximal intensity during Cap were indistinguishable from the pre-Cap, low-intensity baroreflexes. In comparison, vagus ENG showed graded Cap block of the C-fiber volley (ED50 = 200 nM) without significant attenuation of the A-type volley below 1 microM. However, 100 microM Cap blocked conduction in all myelinated vagal axons as well as C-type axons. Thus Cap is selective for sensory C-type axons only at low micromolar concentrations. Myelinated and nonmyelinated arterial BR evoke characteristically different frequency-response reflex relations that suggest distinct differences in sensory information processing mechanisms.

Electrophysiological and pharmacological characterization of the direct perforant path input to hippocampal area CA3.

Monosynaptic perforant path responses evoked by subicular stimulation were recorded from CA3 pyramidal cells of rat hippocampal slices. These monosynaptic responses were isolated by using low intensities of stimulation and by placing a cut through the mossy fibers. Perforant path-evoked responses consisted of both excitatory and inhibitory components. Excitatory postsynaptic currents (EPSCs) were mediated by both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptors (AMPAR) and N-methyl--aspartate receptors (NMDAR). Inhibitory postsynaptic currents consisted of gamma-aminobutyric acid-A (GABAA-) and -B (GABAB)-receptor-mediated components. At membrane potentials more positive than -60 mV and at physiological [Ca2+]/[Mg2+] ratios, >30% of perforant path evoked EPSC was mediated by NMDARs. This value varied as a function of the membrane voltage and external [Mg2+]. Two types of responses were observed after low-intensity stimulation of the perforant path. The first type of response showed paired-pulse facilitation and was reduced by 2-amino-4-phosphonobutyric acid (AP4). The second type of response showed paired-pulse depression and was reduced by baclofen. Electrophysiological and pharmacological characteristics of these two types of responses are similar to the properties of lateral and medial perforant path-evoked EPSPs in the dentate gyrus.

Spatiotemporal distribution of a late synchronized activity in olfactory pathways following stimulation of the olfactory bulb in rats.

The evoked potential recorded in the rat piriform cortex in response to electrical stimulation of the olfactory bulb is composed of an early component occasionally followed by a late component (60-70 ms). We previously showed that the late component occurrence was enhanced following an olfactory learning. In the present study carried out in naive rats, we investigated the precise conditions of induction of this late component, and its spatiotemporal distribution along the olfactory pathways. In the anaesthetized rat, a stimulating electrode was implanted in the olfactory bulb. Four recording electrodes were positioned, respectively, in the olfactory bulb, the anterior and posterior parts of the piriform cortex, and the entorhinal cortex. Simultaneous recording of signals evoked in the four sampled structures in response to stimulation of the olfactory bulb revealed that the late component was detected in anterior and posterior piriform cortex as well as in entorhinal cortex, but not in the olfactory bulb. The late component occurred reliably for a narrow range of low intensities of stimulation delivered at frequencies not exceeding 1 Hz. Comparison of late component amplitude and latency across the different recorded sites showed that this component appeared first and with the greatest amplitude in the posterior piriform cortex. In addition to showing a functional dissociation between anterior and posterior parts of the piriform cortex, these data suggest that the posterior piriform cortex could be the locus of generation of this late high amplitude synchronized activity, which would then propagate to the neighbouring regions.

Evaluation of Neuromuscular Electrical Stimulation in the Treatment of Genuine Stress Incontinence

Summary Objectives The purpose of this clinical trial was to evaluate the effectiveness of acute maximal clinic-based and chronic low-intensity home-based neuromuscular electrical stimulation in the treatment of genuine stress incontinence in women. For the purpose of this article these will be referred to as clinic and home treatments. As these treatments are often applied in combination with pelvic floor exercises and biofeedback, the two types of electrotherapy were evaluated within a combination therapy programme. Study design A prospective randomised controlled clinical trial was conducted, with 70 women aged 24–68, who had urodynamically proven genuine stress incontinence, referred for treatment in the department of urotherapy. The control group received a six-month treatment programme of pelvic floor exercises and biofeedback. The two treatment groups received, in addition, either home or clinic vaginal electrical stimulation. The primary outcome measures were the amount of urine loss determined by pad-testing, and the patients' subjective appraisal of their condition. Results A total of 57 women completed the trial and these sets of data were used for analysis to evaluate the effect of electrotherapy on subjects who received that treatment. Results were also evaluated on an intent-to-treat basis; 61% were subjectively greatly improved or cured, and 64% had a reduction in urine loss of 75% or more at pad-testing. There were no statistically significant differences in outcome measures between the three groups. However, the greatest percentage of subjects greatly improved or cured subjectively (80%) and by pad-test (80%), were in the maximal stimulation group (n = 20). Subjects who received home stimulation had a lower success rate than either the clinic treatment or the control group. Conclusions Pelvic floor exercises and biofeedback alone are an effective treatment for genuine stress incontinence. Women with a long history of symptoms or previous ineffective incontinence surgery, may benefit from the addition of maximal vaginal stimulation. The addition of low intensity stimulation to a pelvic floor exercise programme appeared to have a detrimental influence on the women's progress.

Functional Properties of Perigeniculate Inhibition of Dorsal Lateral Geniculate Nucleus Thalamocortical NeuronsIn Vitro

The properties of the inhibitory influence of neurons in the perigeniculate (PGN) nucleus on thalamocortical cells were examined with intracellular recordings in the ferret geniculate slice maintained in vitro. Activation of PGN neurons with the local application of glutamate caused IPSPs in thalamocortical neurons that were mediated by both GABAA and GABAB receptors, as well as the activation of spindle waves. With low intensity stimulation of the PGN, local application of bicuculline to the dorsal lateral geniculate nucleus (LGNd) strongly inhibited evoked and spindle-associated IPSPs, indicating that these are largely mediated by GABAA receptors. The generation of GABAB receptor-mediated IPSPs in thalamocortical cells that were large enough to generate rebound low threshold Ca2+ spikes required substantially increased activation of the PGN with glutamate. The activation of synchronous bicuculline-induced slowed oscillations in thalamocortical neurons required the block of GABAA receptors in the LGNd as well as in the PGN. These results indicate that bursts of action potentials in PGN neurons can result in the activation of both GABAA and GABAB receptors in thalamocortical neurons, with the strong activation of GABAB receptors requiring an intense, simultaneous discharge of a number of PGN neurons. Functionally, these results suggest that PGN neurons inhibit thalamocortical cells preferentially through the activation of GABAA receptors, although the strong activation of GABAB receptors may occur under pathological conditions and contribute to the generation of abnormal, synchronous slow oscillations.

Facilitation and inhibition of the urethrogenital reflex in spinal cord-transected rats

It was evaluated in the spinal cord-transected rats whether the urethrogenital (UG) reflex shows some of the features that are present during ejaculation in intact animals. It was found that the UG reflex was facilitated after its first elicitation: the latency of the reflex was shorter than the previous one and low intensity of stimulation was needed to produce the reflex. In addition, a change in the latency of the reflex was found that was correlated with the number of stimulation trials. The latency change showed a J-shaped curve that is similar to that found for the ejaculation latency in a copulatory series. An inhibition of the reflex appeared after several trials: the reflex could not be elicited after three continuous trials. The reflex could be elicited again if the intensity of stimulation was increased. The UG reflex also showed `exhaustion': it could not be elicited, even with high intensities of stimulation, after 3 h of rest. All these findings were present when the UG reflex was elicited by applying pressure to the urethra or when it was evoked by the electrical stimulation to the pudendal nerve. According to these findings, it can be concluded that the UG reflex maintains some of the features that are found during ejaculation in intact animals. According to this view, it can be speculated that some of the mechanisms that control ejaculation in intact animals can be localized at a spinal level.

Characterization of long-term potentiation of C-fiber-evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors.

Impulses in afferent C fibers, e.g., during peripheral trauma, may induce plastic changes in the spinal dorsal horn that are believed to contribute to some forms of hyperalgesia. The nature of lasting changes in spinal nociception are still not well understood. Here we characterized the long-term potentiation (LTP) of spinal field potentials with a negative focus in superficial spinal dorsal horn evoked by supramaximal electrical stimulation of the sciatic nerve in urethan-anesthetized adult rats. The field potentials studied in this work had high thresholds (>/=7 V, 0.5 ms), long latencies (90-130 ms), and long chronaxy (1.1 ms) and were not abolished by muscle relaxation and spinalization. Thus they were evoked by afferent C fibers. In response to 1-Hz stimulation of afferent C fibers, amplitudes of C-fiber-evoked field potentials remained constant, whereas number of action potentials of some dorsal horn neurons increased progressively (wind-up). In all 25 rats tested, high-frequency, high-intensity stimulation (100 Hz, 30-40 V, 0.5 ms, 400 pulses given in 4 trains of 1-s duration at 10-s intervals) always induced LTP (to approximately 200% of control), which consistently lasted until the end of recording periods (4-9 h). This tetanic stimulation also significantly decreased mean threshold of C-fiber-evoked field potentials. The C-fiber volley, which was recorded simultaneously in sural nerve, was, however, not affected by the same tetanic stimulation. High-frequency, low-intensity stimulation (100 Hz, 3 V, 0.5 ms) never induced LTP in six rats tested. At an intermediate frequency, high-intensity stimulation (20 Hz, 40 V, 0.5 ms, 400 pulses given in 4 trains of 5 s at 10-s intervals) induced LTP in four out of six rats, which lasted until end of recording periods (3-6 h). In the remaining two rats, no LTP was induced. Low-frequency, high-intensity stimulation (2 Hz, 30-40 V, 0.5 ms, 400 pulses) induced LTP that lasted for 2-8 h in four out of five rats. Intravenous application of neurokinin 1 (NK1) or neurokinin 2 (NK2) receptor antagonist RP 67580 (2 mg/kg, n = 5) or SR 48968 (0.3 mg/kg, n = 5) 30 min before high-frequency, high-intensity stimulation blocked the induction of LTP in all rats tested. In contrast, the same dose of their inactive enantiomers RP 68651 (n = 5) or SR 48965 (n = 5) did not affect the induction of LTP. Spinal superfusion with RP 67580 (1 microM) from 30 min before to 30 min after high-frequency, high-intensity stimulation blocked induction of LTP in all five rats tested. Spinal application of SR 48968 (10 nM) prevented LTP in five out of seven rats. However, when spinal superfusions with RP 67580 (1 microM, n = 3) or SR 48968 (10 nM, n = 3) were started 1 h after high-frequency, high-intensity stimulation, established LTP was not affected. Thus the activation of neurokinin receptors is necessary for the induction but not for the maintenance of LTP of C-fiber-evoked field potentials in spinal dorsal horn. This model may be useful to study plastic changes in spinal cord induced by peripheral C-fiber stimulation. The LTP of C-fiber-evoked field potentials may be a mechanism underlying some forms of hyperalgesia.

Spontaneous excitatory currents and kappa-opioid receptor inhibition in dentate gyrus are increased in the rat pilocarpine model of temporal lobe epilepsy.

Temporal lobe epilepsy is associated with a characteristic pattern of synaptic reorganization in the hippocampal formation, consisting of neuronal loss and aberrant growth of mossy fiber collaterals into the dentate gyrus inner molecular layer. We have used the rat pilocarpine model of temporal lobe epilepsy to study the functional consequences of mossy fiber sprouting on excitatory activity and kappa-opioid receptor-mediated inhibition. Using the whole cell voltage-clamp technique, we found that abnormal excitatory activity was evident in granule cells of the dentate gyrus from pilocarpine-treated rats. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) was increased greatly in cells from tissue in which significant mossy fiber sprouting had developed. In the presence of bicuculline, giant spontaneous EPSCs, with large amplitudes and long durations, were seen only in association with mossy fiber sprouting. Giant EPSCs also could be evoked by low-intensity stimulation of the perforant path. Mossy fibers release not only excitatory amino acids, but also opioid peptides. kappa-Opioid receptor-mediated inhibition in normal Sprague-Dawley rats was seen only in hippocampal sections from the ventral pole. In pilocarpine-treated rats, however, kappa receptor-mediated effects were seen in both ventral and more dorsal sections. Thus in this model of temporal lobe epilepsy, several types of abnormal excitatory activity were observed, thereby supporting the idea that mossy fiber sprouting leads to recurrent excitatory connections. At the same time, inhibition of excitatory activity by kappa-opioid receptors was increased, perhaps representing an endogenous anticonvulsant mechanism.

Reversal of fusimotor reflex responses during locomotion in the decerebrate cat.

The effect of brief trains of electrical stimulation, at 2, 3 and 20 x threshold (T), of cutaneous afferents in the medial plantar nerve on the discharges of single medial gastrocnemius static and dynamic gamma-efferents has been investigated at rest and during locomotion in a decerebrate cat preparation. The units were classified as dynamic (10 units) or static (10 units) indirectly on the basis of their resting and locomotor discharge characteristics. Responses were assessed by calculating the change in mean gamma-rate during the 100 ms after stimulus onset compared with a control period. At rest, most dynamic neurones were inhibited by stimulation at 2T (9 of 10 units) and above. In contrast, the resting responses of most static neurones were excitatory at 2T (9 of 10 units) and 3T, while 20T produced static gamma-effects that varied in sign. During locomotion the responses of both types of gamma-efferent were phase related. Two patterns were observed with dynamic units. For seven dynamic neurones, at stimulus levels of 2T (7 units) and above, responses during electromyogram (EMG) bursts were inhibitory while those between bursts were not significantly different from zero. However, for three other dynamic units, a phase-related reversal of reflex responses was observed at some stimulus intensities (always 2T, 3 units) comprising inhibition during, and excitation between, EMG bursts. For static neurones, inhibitory (never excitatory) responses occurred during walking at stimulus intensities of 2T (10 units) and above. The locomotor responses of static units were maximum during (3 units) or between (7 units) EMG bursts and were minimum in the opposite phase of EMG activity. A task-related reversal of reflex responses was thus generally apparent (9 of 10 units) to low intensity stimulation (2T) for static gamma-efferents during locomotion (inhibition) compared with rest (excitation). During locomotion there was a significant linear relation between the magnitude of response and the background gamma-rate for static units and those dynamic units that did not exhibit phase-related reflex reversal (total, 17 units). For dynamic gamma-efferents, inhibition at rest and during locomotion occurred at short (spinal) latencies which were not significantly different and are consistent with the involvement of the same interneuronal pathway. We conclude that pathways of opposite sign may dominate the responses of fusimotor neurones to low threshold cutaneous afferents from the plantar surface of the foot depending on behavioural context. Furthermore, the cutaneous reflex responses of both types of gamma-motoneurones during locomotion appear to vary with the source of the afferent input and do not constitute a general excitatory drive. The results are discussed in relation to the role and reflex control of the fusimotor system.

Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat.

The modulatory effects of electrical and chemical (glutamate) stimulation in the rostral ventromedial medulla (RVM) on spinal nociceptive transmission and a spinal nociceptive reflex were studied in rats. Electrical stimulation at a total 86 sites in the RVM in the medial raphe nuclei (n = 54) and adjacent gigantocellular areas (n = 32) produced biphasic (facilitatory and inhibitory, n = 43) or only inhibitory (n = 43) modulation of the tail-flick (TF) reflex. At these 43 biphasic sites in the RVM, facilitation of the TF reflex was produced at low intensities of stimulation (5-25 microA) and inhibition was produced at greater intensities of stimulation (50-200 microA). At 43 sites in the RVM, electrical stimulation only produced intensity-dependent inhibition of the TF reflex. Activation of cell bodies in the RVM by glutamate microinjection reproduced the biphasic modulatory effects of electrical stimulation. At biphasic sites previously characterized by electrical stimulation, glutamate at a low concentration (5 nmol) produced facilitation of the TF reflex; a greater concentration (50 nmol) only inhibited the TF reflex. In electrophysiological experiments, electrical stimulation at 62 sites in the RVM produced biphasic (n = 26), only inhibitory (n = 26), or only facilitatory (n = 10) modulation of responses of lumbar spinal dorsal horn neurons to noxious cutaneous thermal (50 degrees C) or mechanical (75.9 g) stimulation. Facilitatory effects were produced at lesser intensities of stimulation and inhibitory effects were produced at greater intensities of stimulation. The apparent latencies to stimulation-produced facilitation and inhibition, determined with the use of a cumulative sum method and bin-by-bin analysis of spinal neuron responses to noxious thermal stimulation of the skin, were 231 and 90 ms, respectively. The spinal pathways conveying descending facilitatory and inhibitory influences were found to be different. Descending facilitatory influences on the TF reflex were conveyed in ventral/ventrolateral funiculi, whereas inhibitory influences were conveyed in dorsolateral funiculi. The results indicate that descending inhibitory and facilitatory influences can be simultaneously engaged throughout the RVM, including nucleus raphe magnus, and that such influences are conveyed in different spinal funiculi.

Learning-induced changes in rat piriform cortex activity mapped using multisite recording with voltage sensitive dye.

The piriform cortex (PCx) has a potential role in storage and recall of olfactory information. This study is a first extensive investigation of the spatiotemporal distribution of activity in the PCx induced by learned sensory inputs following conditioning. In a conditioned group, rats chronically implanted with four electrodes in the olfactory bulb were trained to associate the electrical stimulation of a given bulbar electrode with a positive reinforcement, while stimulation of a different electrode predicted a negative reinforcement. In a familiarized group, rats received the same protocol of daily electrical stimulation with no associated reinforcement. At the end of the conditioning or familiarization episode, activity evoked in the PCx was optically mapped using a 144 photodiode array. In the anaesthetized rats, PCx maps were recorded in response to stimulation of each of the four bulbar electrodes using either high (0.5-1 mA) or low (0.1 mA) test current intensities. Low intensity stimulation revealed that conditioning selectively enhanced the probability of occurrence of a signal composed of a single late (56-73 ms) component which occurred almost simultaneously on a large PCx area. In the conditioned group, high intensity stimulation through either of the four electrodes revealed a potentiation of the early (17-30 ms) disynaptic component of the PCx response in the most posterior part of the PCx as well as a homogeneous increase of the late (39-52 ms) component spread over the PCx areas. These data suggest that learning induces synaptic changes at different nodes of the PCx circuitry.

Low-intensity repetitive transcranial magnetic stimulation of the motor cortex affects accuracy of drawing movements but not the underlying motor program

Low-intensity repetitive transcranial magnetic stimulation of the motor cortex affects accuracy of drawing movements but not the underlying motor program

Increased amplitude of distortion product emissions in the human caused by contralateral low intensity acoustic stimulation

Distortion product otoacoustic emissions (DPOAEs) are probably based on the motile properties of the cochlear outer hair cells (OHCs), which are richly innervated by medial olivo-cochlear efferent nerves (MOCs). DPOAEs provide a stimulating model for functional exploration of the efferent system. The influences of contralateral acoustic stimulation were studied on the amplitude of ipsilateral DPOAEs at the frequency 2f1-f2. Fifteen ears of adults with normal hearing (7 women, 8 men, mean age; 23.1 +/- 4.2 years) were examined. Sound stimulation consisted of exposure to 6 successive series of contralateral pure tones at frequencies between 0.5 and 4.0 kHz and low intensities of 30 dB HL. DP grams were registered with f2 ranging from 708 to 6165 Hz. Contralateral pure tones in the frequency range above 750 Hz and with intensities of 30 dB HL increased the ipsilaterally registered DPOAE amplitudes. The results showed that this increase was frequency specific, at least for frequencies at 1 and 2 kHz. The frequency specificity was especially marked when ipsilateral f2 was near 1 kHz. Contralateral frequencies of 3 and 4 kHz induced a significant, increasing effect, including ipsilateral frequencies around f2 = 3 kHz (or 4 kHz) and also lower frequencies around f2 = 1 kHz. Our results support the concept that the observed increase in DPOAE amplitudes is mediated by the medial olivo-cochlear efferent system. The rule of OHCs as a cochlear amplifier in the presence of contralateral low-intensity sound stimulation is discussed.

Suppression of task-related saccades by electrical stimulation in the primate's frontal eye field.

Patients with frontal lobe damage have difficulty suppressing reflexive saccades to salient visual stimuli, indicating that frontal lobe neocortex helps to suppress saccades as well as to produce them. In the present study, a role for the frontal eye field (FEF) in suppressing saccades was demonstrated in macaque monkeys by application of intracortical microstimulation during the performance of a visually guided saccade task, a memory prosaccade task, and a memory antisaccade task. A train of low-intensity (20-50 microA) electrical pulses was applied simultaneously with the disappearance of a central fixation target, which was always the cue to initiate a saccade. Trials with and without stimulation were compared, and significantly longer saccade latencies on stimulation trials were considered evidence of suppression. Low-intensity stimulation suppressed task-related saccades at 30 of 77 sites tested. In many cases saccades were suppressed throughout the microstimulation period (usually 450 ms) and then executed shortly after the train ended. Memory-guided saccades were most dramatically suppressed and were often rendered hypometric, whereas visually guided saccades were less severely suppressed by stimulation. At 18 FEF sites, the suppression of saccades was the only observable effect of electrical stimulation. Contraversive saccades were usually more strongly suppressed than ipsiversive ones, and cells recorded at such purely suppressive sites commonly had either foveal receptive fields or postsaccadic responses. At 12 other FEF sites at which saccadic eye movements were elicited at low thresholds, task-related saccades whose vectors differed from that of the electrically elicited saccade were suppressed by electrical stimulation. Such suppression at saccade sites was observed even with currents below the threshold for eliciting saccades. Pure suppression sites tended to be located near or in the fundus, deeper in the anterior bank of the arcuate than elicited saccade sites. Stimulation in the prefrontal association cortex anterior to FEF did not suppress saccades, nor did stimulation in premotor cortex posterior to FEF. These findings indicate that the primate FEF can help orchestrate saccadic eye movements by suppressing inappropriate saccade vectors as well as by selecting, specifying, and triggering appropriate saccades. We hypothesize that saccades could be suppressed both through local FEF interactions and through FEF projections to subcortical regions involved in maintaining fixation.