Effects Of High-frequency Stimulation Research Articles

Local field potential activity dynamics in response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease

Local field potentials (LFPs) may afford insight into the mechanisms of action of deep brain stimulation (DBS) and potential feedback signals for adaptive DBS. In Parkinson's disease (PD) DBS of the subthalamic nucleus (STN) suppresses spontaneous activity in the beta band and drives evoked resonant neural activity (ERNA). Here, we investigate how STN LFP activities change over time following the onset and offset of DBS. To this end we recorded LFPs from the STN in 14 PD patients during long (mean: 181.2 s) and short (14.2 s) blocks of continuous stimulation at 130 Hz. LFP activities were evaluated in the temporal and spectral domains. During long stimulation blocks, the frequency and amplitude of the ERNA decreased before reaching a steady state after ~70 s. Maximal ERNA amplitudes diminished over repeated stimulation blocks. Upon DBS cessation, the ERNA was revealed as an under-damped oscillation, and was more marked and lasted longer after short duration stimulation blocks. In contrast, activity in the beta band suppressed within 0.5 s of continuous DBS onset and drifted less over time. Spontaneous activity was also suppressed in the low gamma band, suggesting that the effects of high frequency stimulation on spontaneous oscillations may not be selective for pathological beta activity. High frequency oscillations were present in only six STN recordings before stimulation onset and their frequency was depressed by stimulation. The different dynamics of the ERNA and beta activity with stimulation imply different DBS mechanisms and may impact how these activities may be used in adaptive feedback.

Inhibition of Experimental Tinnitus With High Frequency Stimulation of the Rat Medial Geniculate Body

BackgroundNeuromodulation is a promising treatment modality for tinnitus, especially in chronic and severe cases. The auditory thalamus plays a key role in the pathophysiology of tinnitus, as it integrates and processes auditory and limbic information.ObjectiveThe effect of high frequency stimulation and low frequency stimulation of the medial geniculate bodies on tinnitus in a noise‐induced tinnitus rat model is assessed.Materials and MethodsPresence of tinnitus was verified using the gap‐induced prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma with auditory brainstem responses. Anxiety‐related side‐effects were evaluated in the elevated zero maze and open field.ResultsResults show tinnitus development after noise exposure and preserved hearing thresholds of the ear that was protected from noise trauma. We found that high frequency stimulation of the medial geniculate bodies suppressed tinnitus. This effect maintained directly after stimulation when the stimulator was turned off. Low frequency stimulation did not have any effects on the gap:no‐gap ratio of the acoustic startle response.ConclusionHigh frequency stimulation of the MGB has a direct and residual suppressing effect on tinnitus in this animal model. Low frequency stimulation of the MGB did not inhibit tinnitus.

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

P108 Remediation of cognitive impairment due to sleep deprivation: A rTMS pilot study

Introduction The lack of sleep is associated with diminished cognitive performance. rTMS has been applied in sleep deprived subjects, showing a decrease in response times (upper middle occipital gyrus); but this effect is no longer found after recovery ( Luber et al., 2008 ). Objectives To explore the effects of high frequency stimulation in different areas. Patients & methods 6 healthy right-handed subjects were randomly assigned to one stimulation group: medial frontal gyrus, medial occipital gyrus or SHAM. Subjects completed one initial fMRI session and another final session (post 24 h sleep deprivation & stimulation). Letters were presented for 500 ms in 5 min blocks (300 letters & 60 targets). Stimulation consisted of a 20-min session at 5 Hz in the left hemisphere at 100% of the MT. Mood (VAS) and sensation (1:10) were measured. For 1-back, accuracy increased for MFG (3.33%) and for 2-back increased in MOG (25%). MOG group showed shorter response times in 1-back (5.05%) and 2-back (18.32%). Sensation scale measure was 3(±1.9), subjects were not able to distinguish whether it was true or false stimulation. VAS results are shown in Fig. 1 Download : Download high-res image (455KB) Download : Download full-size image (0: minimum value and 10: maximum value). MFG group: activation increased was found for both contrasts (1 & 2-back) especially in areas related to frontal lobes. MOG group: activation decreased in frontal lobes (1-back). SHAM group: increment at parietal lobe, prefrontal cortex, cingulate gyrus and temporal lobe for both contrasts (Fig. 2 Download : Download high-res image (618KB) Download : Download full-size image ). Conclusion Stimulation has a positive effect in the perception of symptoms related to SD. In MOG group, subjects showed better accuracy and response times. These findings may be caused by the stimulation of parietal-temporal-occipital association area (in charge of focusing specific objects and rejecting others, attention in spatial loctralization and plays an important role in verbal memory); located near MOG ( Rhoades, 2009 ). Results indicate that there are differences between the different sites of stimulation, so it will be interesting to further explore these areas with a larger size population.

Deep brain stimulation: increasing efficiency by alternative waveforms

Abstract Deep brain stimulation (DBS) is based on the effect of high frequency stimulation (HFS) in neuronal tissue. As a therapy option for patients suffering from e.g. Parkinson’s disease, DBS has been used for decades. Despite the widespread use, the effect of HFS on neurons is not fully investigated. Improving the stimulation efficiency und specificity could increase the efficiency of the INS (internal neuronal stimulator) as well as potentially reduce unwanted side effects. The effect of HFS on the GABAergic system was quantified using whole cell patch clamp electrophysiology during HFS stimulation in cortical human brain slices in vitro. Rectangular, sine, sawtooth and triangular waveforms were applied extracellularly. Since HFS has been hypothesized to increase the activity of the axons of GABAergic interneurons, a decrease in activity can be observed in the pyramidal cells that the interneurons project to. By isolating the incoming non- GABAergic events, we can filter out only the GABAA currents which can be verified using a GABAA antagonist. The results show that all the waveforms effectively increase the GABAA currents. The triangle waveform causes the highest significant increase in the activity which further increases over time after the stimulation was turned off.

FREQUENCY ESTIMATION FOR ATRIAL FIBRILLATION FROM HUMAN STUDIES

Atrial Fibrillation (AF) is the most common disorder of the heart rhythms. There are about 2.3 million people in United States and 4.5 million people in the European Union with AF [1]. It is also one of the factors that may contribute to mortality and morbidity. Researchers who apply spectral techniques show that certain areas of the atria can have higher activation frequencies than other areas. Frequency analysis is used to measure changes in Dominant Frequency (DF). We access the electrical propagation inside the atria by spectrogram plotting and examining the effect of high frequency stimulation on human.

Non-Human Primate: An Essential Building Brick in the Discovery of the Subthalamic Deep Brain Stimulation Therapy.

Non-Human Primate: An Essential Building Brick in the Discovery of the Subthalamic Deep Brain Stimulation Therapy.

Abstract 19312: Multiplexed Images of the Heart Provide Novel Functional Information to Guide Invasive Procedures: A Review of the Initial Case Series

Introduction: The novel, high sensitivity and dedicated cardiac camera (D-SPECT, Spectrum Dynamics) allows single or dual tracer studies to add functional information to 3D DICOM image information from CT or CMR. Information consists of either perfusion information (from (technetium-99m (Tc-99m) methoxyisobutylisonitrile (MIBI, for perfusion) and/or sympathetic nnervation information using meta-iodobenzylguanidine (mIBG). Merging these 3D images with invasive 3D electroanatomical maps (EAM) offers image integration on a function rather than geometrical level alone. These fused 3D images can be combined with EAM to guide ablation procedures for either atrial or ventricular arrhythmias. Methods: A total of 23 patients (15 male, mean age 59.9 yrs) underwent either single iodine-123 mIBG (n=10, for sympathetic innervation) or dual tracer (n= 13, mIBG+MIBI, for perfusion) imaging and the acquired information was fused with the 3D cCT or CMR using a custom-made software. Results: Twenty out of 23 patients underwent invasive electrophysiology studies which targeted either atrial or ventricular arrhythmias. During the atrial arrhythmia procedures, high uptake sites for mIBG was correlated to positive effect of high frequency stimulation (=transient prolongation of AV nodal conduction) and thereby confirming ganglionated plexi which were targeted in addition to the standard ablation. Patients with ventricular arrhythmia, low amplitude voltage mapping showed good correlation to the perfusion scar imaging, thereby serving as a substrate map even in patients with implantable devices. Interestingly, regions of mismatch where identified which proved to be pro-arrhythmogenic during EP study in the 4/6 patients who underwent ventricular tachycardia (VT) ablation. Conclusion: The combination of innervation (by mIBG) and perfusion (by MIBI) nuclear imaging in addition to the 3D cCT or CMR imaging provides a novel type of “road map” information for complex arrhythmia ablation by providing a region of mismatch of innervation and perfusion. This provides a novel substrate information even in the presence of implantable devices.

Electrical high frequency stimulation modulates GABAergic activity in the nucleus accumbens of freely moving rats

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective treatment option for those affected by obsessive compulsive disorder, who do not respond to pharmacological treatment strategies. Yet, little is known about the mechanism by which DBS achieve its therapeutic effects. Previous studies have shown an increase in GABA levels due to high frequency stimulation (HFS) in the rat caudate putamen. Here, the effect of high frequency stimulation in the nucleus accumbens of conscious and freely moving rats was characterized using unilateral but simultaneous microdialysis and HFS with a frequency of 124 Hz and 0.5 mA current. Extracellular levels of neurotransmitters – GABA, glutamate, dopamine, serotonin and their metabolites were quantified by means of HPLC with electrochemical detection. Basal levels of GABA were significantly increased in animals of the stimulation group compared to the control group without HFS. The levels of other neurotransmitters were unaffected. The influence of NMDA receptor antagonist, memantine (5 mg/kg) on the effect of HFS was investigated by subcutaneous administration of memantine on the day of the experiment. Memantine (without stimulation) enhanced basal GABA and dopamine levels. However, under the influence of both memantine and HFS, GABA levels were not affected by HFS whereas dopamine levels decreased during the stimulation period. The results of our study demonstrate that HFS in the nucleus accumbens of freely moving rats induces selective increase in GABA outflow and show a possible involvement of NMDA receptors in the mechanistic action of HFS.

The Effect of High-Frequency Stimulation on Sensory Thresholds in Chronic Pain Patients

Background: High-frequency stimulation (HFS) has recently gained attention as an alternative to parameters used in traditional spinal cord stimulation (SCS). Because HFS is paresthesia free, the gate theory of pain control as a basis of SCS has been called into question. The mechanism of action of HFS remains unclear. Objective: We compare the effects of HFS and traditional SCS on quantitative sensory testing parameters to provide insight into how HFS modulates the nervous system. Methods: Using quantitative sensory testing, we measured thermal detection and pain thresholds and mechanical detection and pressure pain thresholds, as well as vibratory detection, in 20 SCS patients off stimulation (OFF), on traditional stimulation (ON) and on HFS in a randomized order. Results: HFS significantly increased the mechanical detection threshold compared to OFF stimulation (p < 0.001) and traditional SCS (p = 0.01). Pressure pain detection and vibratory detection thresholds also significantly increased with HFS compared to ON states (p = 0.04 and p = 0.01, respectively). In addition, HFS significantly decreased 10- and 40-gram pinprick detection compared to OFF states (both p = 0.01). No significant differences between OFF, ON and HFS states were seen in thermal and thermal pain detection. Conclusion: HFS is a new means of modulating chronic pain. The mechanism by which HFS works seems to differ from that of traditional SCS, offering a new platform for innovative advancements in treatment and a greater potential to treat patients by customizing waveforms.

Varying time-course of effects of high frequency stimulation of sub-regions of the globus pallidus in patients with parkinson's disease.

Deep brain stimulation of the globus pallidus can be a highly effective treatment for patients with Parkinson's disease (PD), experiencing Levodopa-induced-dyskinesia (LID). Stimulation programming can focus simply on eliminating dyskinesia, or can also attempt to relieve the rigidity, tremor or akinesia of PD itself. In this study, we explored whether additional benefit on the "off" symptoms and signs of PD, could be achieved in post-operative PD patients with good LID control, by making further adjustment to existing stimulation parameters directed towards the more superior electrode contacts, located in the Globus Pallidus pars externa (GPe). Acutely, GPe-DBS led to clear improvement in the akinesia, rigidity and tremor of PD in the off-medication state compared with Globus Pallidus pars interna (GPi) DBS (p=0.003), however this was accompanied by the development of off-medication dyskinesia. Combined GPi-GPe DBS allowed maintained improvement but without dyskinesia. Follow up of patients over the subsequent 6-12 weeks showed gradual loss of this initial improvement. Switching back to GPi-DBS alone provided greater improvement in off medication symptoms than had been observed using the same GPi-DBS setting, 6-12 weeks previously. Benefits on the off-medication symptoms of PD obtained acutely with GPe-DBS are in general not sustained. Similarly, the effects of GPi-DBS on the off medication symptoms of PD, can evolve over short periods of time presumably as a result of changes in network-wide neuronal plasticity. These clinical observations provide further insight into DBS mechanism of action, and can also help inform optimal methods of GPi-DBS programming.

Effects of high frequency stimulation of nucleus accumbens shell subregion on food intake in obesity rats and regulation of appetite-related hormones

Objective To explore the effects of chronic high frequency deep brain stimulation (DBS) of nucleus accumbens shell subregion on food intake and regulation of appetite-related hormones. Methods High-fat diet induced obesity rats were randomly divided into two groups, namely DBS group and sham-DBS group.Stimulating electrodes were implanted in the bilateral shell subregion of nucleus accumbens. The amount of food intake was measured before and during stimulation.Peripheral concentrations of ghrelin, NPY, and leptin were tested before and after DBS or sham-DBS. Results The amount of food intake began to significantly decrease once stimulation was on. After 7 days'continuous stimulation, peripheral concentrations of NPY and leptin decreased significantly (Leptin: pre-DBS: 32±10 vs.post-DBS: 20±10pg/ml, P<0.05; NPY: pre-DBS: 1 302±287 vs. post-DBS: 926±299 pg/ml, P<0.05), and ghrelin increased significantly (Pre-DBS: 1066±310 vs. Post-DBS: 1603±848 pg/ml, P<0.05). Conclusions NAc shell subregion is an effective DBS target to decrease food intake in obesity rats. NAc-shell DBS seems to temporarily inhibit the hypothalamic secretion of NPY. Increase of ghrelin levels maybe a second result of decreased food intake caused by NAc-shell stimulation. Key words: Deep brain stimulation; Nucleus accumbens; Obesity; Ghrelin; Leptin; Neuropeptide Y; Rats

Effect of high-frequency stimulation of the perforant path on previously acquired spatial memory in rats: influence of memory strength and reactivation.

If memory depends on changes in synaptic strength, then manipulation of synaptic strength after learning should alter memory for what was learned. Here, we examined whether high frequency stimulation of the perforant path in vivo disrupts memory for a previously-learned hidden platform location in the Morris water task as well as whether this effect is modulated by memory strength or memory reactivation. We found that high frequency stimulation affected probe test performance regardless of memory strength or state of memory activation, although the precise nature of this effect differed depending on whether rats received minimal or extensive training prior to high frequency stimulation. These findings suggest that artificial manipulation of synaptic strength between the entorhinal cortex and hippocampus may destabilize memory for a previously-learned spatial location.

High frequency stimulation of subthalamic nucleus results in behavioral recovery by increasing striatal dopamine release in 6-hydroxydopamine lesioned rat

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective medical therapy in alleviating motor symptoms in moderate to severe Parkinson's disease (PD) patients. However, there are still remaining questions regarding the mechanisms of this action. In this experiment, using 6-hydroxydopamine (6-OHDA) PD rat model we investigated the effect of high frequency stimulation (HFS)-STN on improvement of the motor symptoms, DA release in the striatum and to elucidate the underlying mechanisms. Our results showed that HFS-STN improved the motor symptoms of 6-OHDA lesioned rat model of PD via inducing a significant increase in the extracellular dopamine levels and directly evoked dopamine release in the striatum of normal and partially 6-OHDA lesioned rats. In addition, we found the tyrosine hydroxylase (TH) positive cells in the substantia nigra pars compacta (SNpc) did not increase after HFS-STN, while the expression of TH in the substantia nigra increased significantly compared to the 6-OHDA lesioned group. This suggested that STN-HFS could reverse motor deficits against 6-OHDA-induced lesion through increasing striatal dopamine release by modulating the expression of TH, without rescuing dopaminergic neurons in the SNpc.

Effects of high frequency stimulation of nucleus accumbens on food intake in obesity rats and its mechanism

Objective To explore the effects of chronic high frequency deep brain stimulation (DBS) of accumben nucleus on food intake and expression of dopamine D1 and D2 receptors and provide evidence for the central mechanism of the effects.Methods 40 rats received high-fat diet to induce obesity and 36 reached the standard of obesity.These rats were randomly even divided in two groups,namely core group and shell group.Stimulating electrode was implanted in the corresponding target.Thirty-two rats survived and were further evenly divided into DBS subgroup and sham DBS subgroup.Rats in the DBS subgroup received continuous high frequency DBS for 7 days.The amount of food and water intake was measured during the period.Seven days later,the rats of all groups were sacrificed to obtain the brain tissue in accumbens nucleus shell and core subregion.The levels of D1 and D2 cDNA were measured using quantitative real time PCR to observe the effect of accumbens nucleus chronic high frequency stimulation on the D1 and D2 receptors expression.Results The amount of food intake began to show significant difference between the NAc shell DBS and sham DBS subgroups from the 5th day (P ＜0.05).D2 receptor expression was downregulated after 7 days of DBS in the NAc shell group.However,no difference was shown between the NAc core DBS and sham DBS subgroups.The amount of water intake showed no significant difference among the four subgroups.Conclusion The effective target region of high frequency stimulation to decrease the amount of food intake is the NAc shell subregion rather than core subregion.The mechanism involved might be due to upregulation of D2 receptor in the NAc shell subregion. Key words: Deep brain stimulation; Nucleus accumbens; Obesity; Dopamine receptor; Consumption behavior

Characterization of the Left Atrial Neural Network and its Impact on Autonomic Modification Procedures

Left atrial (LA) ganglionated plexi (GP) are part of the intrinsic cardiac autonomic nervous system and implicated in the pathogenesis of atrial fibrillation. High frequency stimulation is used to identify GP sites in humans. The effect of ablation on neural pathways connecting GPs in humans is unknown. Thirty patients undergoing LA ablation with autonomic modification were recruited. In patients with persistent atrial fibrillation, endocardial continuous high frequency stimulation identified GP sites producing AV block. After right lower GP ablation (N=5), 2 of 15 sites remained positive, whereas after ablation of other GPs (N=5), leaving right lower GP intact, all 19 sites remained positive (right lower GP versus other GP, P<0.005), indicating that neural pathways between LAGPs and the AV node are via the right lower GP. In 20 patients with paroxysmal atrial fibrillation, synchronized high frequency stimulation identified sites initiating pulmonary vein (PV) ectopy. After PV isolation (N=8), no sites remained positive. After local GP ablation (N=9), 3 of 14 sites remained positive, suggesting neural connections to the PV were disrupted by both PV isolation and GP ablation. Heart rate variability indices reduced significantly after right upper GP ablation alone, suggesting that neural pathways from the LA to the SA node travel via the right upper GP. We have demonstrated neural pathways connecting LA GPs with the PVs, AV node, and SA node. The effects of high frequency stimulation at GP sites can be prevented by ablating the GP site or the neural pathway. This further delineates the mechanism via which PV isolation prevents atrial fibrillation and highlights important caveats for autonomic modification end points.

Mode-dependent effect of high-frequency electrical stimulation of the anterior thalamic nucleus on amygdala-kindled seizures in rats

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. The present study aimed to investigate the effects of high frequency stimulation (HFS) targeting the ANT on amygdala-kindled seizures in Wistar rats in two different stimulation modes i.e. pre-treatment and post-treatment stimulations, mimicking the scheduled and responsive stimulations in clinical use respectively. When fully-kindled seizures were achieved by daily amygdala kindling (1s train of 1ms pulses at 60Hz), HFS (15min train of 100μs pulses at 150Hz and 450–800μA) was applied in two modes for 10days. Bilateral post-treatment with HFS reduced the incidence of generalized seizures and the mean behavioral seizure stage and shortened average afterdischarge duration (ADD) and generalized seizure duration (GSD), while bilateral pre-treatment with HFS resulted in a similar but much weaker inhibition of seizures. On the other hand, we also found the two stimulation modes both increased the afterdischarge threshold (ADT) and the differences of current intensity between ADT and generalized seizure threshold (GST) i.e. Δ(GST−ADT). However, Δ(GST−ADT) increased by at least 20μA in bilateral post-treatment group, while less in bilateral pre-treatment group. Additionally, unilateral post-treatment with HFS failed to inhibit seizures. Our data show that anti-epileptic effect of bilateral post-treatment with HFS of ANT is much stronger than that of bilateral pre-treatment HFS, indicating bilateral responsive stimulation might be more appropriate for clinical anti-epileptic treatment of ANT HFS.

Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

BackgroundWe previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC.ResultsHFS induced long lasting suppression (LLS) of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA) receptor antagonists (2-amino-5-phosphonovaleric acid (APV), dizocilpine (MK-801)) and also metabotropic glutamate receptor (mGluR) group antagonists (α-methyl-4-carboxyphenylglycine (MCPG), and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495)), prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA) on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA) injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride) and D4 (3-{[4-(4-chlorophenyl) piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870)), microinjected into the PFC, inhibited LLS of nociceptive responses.ConclusionsOur results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

High frequency stimulation abolishes thalamic network oscillations: an electrophysiological and computational analysis

Deep brain stimulation (DBS) of the thalamus has been demonstrated to be effective for the treatment of epilepsy. To investigate the mechanism of action of thalamic DBS, we examined the effects of high frequency stimulation (HFS) on spindle oscillations in thalamic brain slices from ferrets. We recorded intracellular and extracellular electrophysiological activity in the nucleus reticularis thalami (nRt) and in thalamocortical relay (TC) neurons in the lateral geniculate nucleus, stimulated the slice using a concentric bipolar electrode, and recorded the level of glutamate within the slice. HFS (100 Hz) of TC neurons generated excitatory post-synaptic potentials, increased the number of action potentials in both TC and nRt neurons, reduced the input resistance, increased the extracellular glutamate concentration, and abolished spindle wave oscillations. HFS of the nRt also suppressed spindle oscillations. In both locations, HFS was associated with significant and persistent elevation in extracellular glutamate levels and suppressed spindle oscillations for many seconds after the cessation of stimulation. We simulated HFS within a computational model of the thalamic network, and HFS also disrupted spindle wave activity, but the suppression of spindle activity was short-lived. Simulated HFS disrupted spindle activity for prolonged periods of time only after glutamate release and glutamate-mediated activation of a hyperpolarization-activated current (Ih) was incorporated into the model. Our results suggest that the mechanism of action of thalamic DBS as used in epilepsy may involve the prolonged release of glutamate, which in turn modulates specific ion channels such as Ih, decreases neuronal input resistance, and abolishes thalamic network oscillatory activity.

Long-term potentiation of synaptic response and intrinsic excitability in neurons of the rat medial vestibular nuclei

Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type-B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals.