Search

The marine flavobacterium Krokinobactereikastus light-driven sodium pump (KR2) generates an outward sodium ion current under 530 nm light stimulation, representing a promising optogenetic tool for seizure control. However, the specifics of KR2 application to suppress epileptic activity have not yet been addressed. In the present study, we investigated the possibility of KR2 photostimulation to suppress epileptiform activity in mouse brain slices using the 4-aminopyrindine (4-AP) model. We injected the adeno-associated viral vector (AAV-PHP.eB-hSyn-KR2-YFP) containing the KR2 sodium pump gene enhanced with appropriate trafficking tags. KR2 expression was observed in the lateral entorhinal cortex and CA1 hippocampus. Using whole-cell patch clamp in mouse brain slices, we show that KR2, when stimulated with LED light, induces a substantial hyperpolarization of entorhinal neurons. However, continuous photostimulation of KR2 does not interrupt ictal discharges in mouse entorhinal cortex slices induced by a solution containing 4-AP. KR2-induced hyperpolarization strongly activates neuronal HCN channels. Consequently, turning off photostimulation resulted in HCN channel-mediated rebound depolarization accompanied by a transient increase in spontaneous network activity. Using low-frequency pulsed photostimulation, we induced the generation of short HCN channel-mediated discharges that occurred in response to the light stimulus being turned off; these discharges reliably interrupt ictal activity. Thus, low-frequency pulsed photostimulation of KR2 can be considered as a potential tool for controlling epileptic seizures. [ABSTRACT FROM AUTHOR]

• Low frequency electrical stimulation of the peripheral nerve has concurrent and post-stimulation effects on cortical activity. • Source activity in the midcingulate and operculo-insular cortex decline linearly during low frequency stimulation. • Low frequency stimulation attenuates neural responses to noxious laser stimuli and enhances resting alpha and beta band power. Transcutaneous low-frequency stimulation (LFS) elicits long-term depression-like effects on human pain perception. However, the neural mechanisms underlying LFS are poorly understood. We investigated cortical activation changes occurring during LFS and if changes were associated with reduced nociceptive processing and increased amplitude of spontaneous cortical oscillations post-treatment. LFS was applied to the radial nerve of 25 healthy volunteers over two sessions using active (1 Hz) or sham (0.02 Hz) frequencies. Changes in resting electroencephalography (EEG) and laser-evoked potentials (LEPs) were investigated before and after LFS. Somatosensory-evoked potentials were recorded during LFS and source analysis was carried out. Ipsilateral midcingulate and operculo-insular cortex source activity declined linearly during LFS. Active LFS was associated with attenuated long-latency LEP amplitude in ipsilateral frontocentral electrodes and increased resting alpha (8–12 Hz) and beta (16–24 Hz) band power in electrodes overlying operculo-insular, sensorimotor and frontal cortical regions. Reduced ipsilateral operculo-insular cortex source activity during LFS correlated with a smaller post-treatment alpha-band power increase. LFS attenuated somatosensory processing both during and after stimulation. Results further our understanding of the attenuation of somatosensory processing both during and after LFS. [ABSTRACT FROM AUTHOR]

• Centromedian thalamic DBS can be considered as a "rescue" treatment of sRSE. • High frequency CMN-DBS can improve generalised seizures reducing intensive care time. • CMN-DBS could potentially help to avoid serious side effects of srSE medication. • Low frequency CMN-DBS can reduce severity and frequency of focal/multifocal seizures. [ABSTRACT FROM AUTHOR]

Background and Aim: Emotional disorders are prevalent in many epileptic patients. So, in this research, we have studied the efficacy of two treatment methods of seizure on anxiety-like behavior during kindling in adult male rat. Materials and Methods: 42 male rats were randomly divided into 6 groups: Control, Sham operation, saline-kindled and drug-kindled groups which have received saline or drug 15 minutes before kindling stimulations, and saline-kindled-LFS or drug-kindled-LFS group which have received saline or drug 15 minutes before kindling stimulations and LFS applied after termination of kindling stimulations. Anxiety-like behavior was assessed on the 6th day by using elevated plus maze and open field apparatus. Findings: kindling significantly increased open arms (OAs) entries percentage, OAs exploration percentage, increasing jumping from elevated plus maze (p

Objective: To investigate the effect of voluntary contraction at low frequency repetitive nerve stimulation (RNS) as a sign of presynaptic compensation in patients with Myasthenia Gravis (MG). Material and Method: Thirty-five patients with MG were included. RNS at 3 Hz, recorded from the abductor digiti minimi, trapezius, nasalis, and orbicularis oculi muscles were performed. In muscles with more than 10% decrement, RNS at 1 Hz with 20-90 stimuli was applied after 10-second maximal isometric voluntary muscle contraction (MIVMC). Progressive decremental pattern was considered when decrement values were increasing until the last response. Facilitation after MIVMC was determined by dividing the amplitude of motor response in resting state by the amplitude of the motor response recorded just after contraction. Results: Among 15 patients having RNS at 1 Hz, nine had facilitation after MIVMC. In the muscle with facilitation, there was a significant positive correlation between the increment ratio and the progressive decrement difference between responses 1-4 and 1-9 (correlation coefficient 0.730, p=0.026). Although not statistically significant, muscles showing facilitation following decrement tended to have a progressive decremental pattern. Conclusion: During RNS, facilitation after MIVMC followed by progressive decremental pattern may be related to presynaptic compensation of neuromuscular transmission failure in MG. [ABSTRACT FROM AUTHOR]

Epilepsy is the most common neurological disease with no definitive method in treatment. Notably, the main way to treat and control epileptic seizures is drug therapy. However, about 20-30% of patients with epilepsy are drug resistant and require other therapeutic manners. Deep brain stimulation is a new therapeutic strategy for these patients. Conspicuously, there are no clear answers for basic questions such as which brain area is a suitable target for stimulation, which pattern of stimulation exerts the best therapeutic effects and what is the probable mechanism of anticonvulsant effect of deep brain stimulation? Using laboratory models of epilepsy and seizure, it has been shown that low frequency electrical stimulation (LFS) is an effective pattern of deep brain stimulation to reduce the seizure severity. The mechanisms involved in LFS anticonvulsant effects are not completely determined. In this article, we reviewed the previous studies on the anticonvulsant effects of LFS and the possible mechanisms involved in it, as well as LFS-induced changes in the neuronal activities. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder that affects approximately 50 million people and about 30% of them have seizures despite antiepileptic-drug therapy. Even if 50% of these 600,000 or so patients benefit from surgical resection, many would still need new therapeutic approaches. Deep brain stimulation (DBS) has been suggested as an alternative to drug therapy. Low frequency stimulation (LFS) is an effective pattern of DBS that can decrease epileptic seizures. The incidence of epileptic seizures has been described by an imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission. This phenomenon may be affected by other neurotransmitter systems, including serotonin (5- hydroxytryptamine, 5-HT). The Serotonergic system undergoes many alterations in the epileptic brain. The link between LFS and serotonin release has been studied and it is documented that 5- HT1A receptor antagonist reduces the anti-convulsant effects of LFS. Thus, considering the effects of the serotonergic system in neuronal activities in the epileptic brain, it may be involved in the anti-convulsant mechanism(s) of LFS. In this review, we introduce the effects of low frequency stimulation on seizure and its possible mechanisms. The role of some neuromodulators in mediating the anticonvulsive effects of LFS and the probable signaling changes will be discussed. [ABSTRACT FROM AUTHOR]

Abstract Some studies have shown that low frequency stimulation (LFS, most commonly 60 Hz), compared to high frequency stimulation (HFS, most commonly 130 Hz), has beneficial effects, short-term or even long-term, on improving freezing of gait (FOG) and other axial symptoms, including speech and swallowing function, in Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN DBS). However, other studies failed to confirm this. It seems not clear what determines the difference in response to LFS. Differences in study design, such as presence or absence of FOG, exact LFS used (60 Hz versus 80 Hz), study size, open label versus randomized double blind assessment, retrospective versus prospective evaluation, medication On or Off state, total electric energy delivered maintained or not with the change in frequency, and the location of active contacts could all potentially affect the results. This mini-review goes over the literature with the aforementioned factors in mind, focusing on the effect of LFS versus HFS on FOG and other axial symptoms in PD with bilateral STN DBS, in an effort to extract the essential data to guide our clinical management of axial symptoms and explore the potential underlying mechanisms as well. Overall, LFS of 60 Hz seems to be consistently effective in patients with FOG at the usual HFS in regards to improving FOG, speech, swallowing function and other axial symptoms, though LFS could reduce tremor control in some patients. Whether LFS simply addresses the axial symptoms in the context of HFS or has other beneficial effects requires further studies, along with the mechanism.

Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced afterdischarges remain unclear. In the present study, we examined the effects of different brief-pulse stimulation frequencies (5, 50 and 100 Hz) on cortical electrical stimulation-induced afterdischarges in 10 patients with refractory epilepsy. Results demonstrated that brief-pulse stimulation could terminate cortical electrical stimulation-induced afterdischarges in refractory epilepsy patients. In conclusion, (1) a brief-pulse stimulation was more effective when the afterdischarge did not extend to the surrounding brain area. (2) A higher brief-pulse stimulation frequency (especially 100 Hz) was more likely to terminate an afterdischarge. (3) A low current intensity of brief-pulse stimulation was more likely to terminate an afterdischarge

Background: The long-term effect of subthalamic nucleus deep brain stimulation (STN-DBS) on dysarthria can be detrimental. A transient beneficial effect of low-frequency stimulation (LFS) has been reported.Objective: to investigate if the magnitude of dysarthria could predict the effect of LFS on speech in STN-DBS PD patients and to verify whether the benefit is maintained over time.Methods: a cohort study, comparing 10 PD patients with severe speech impairment (MDS-UPDRS item 3.1 ≥ 3) with 10 PD patients with mild speech impairment (MDS-UPDRS item 3.1 ≤ 2), all submitted to STN-DBS. Patients were tested in: MED OFF/STIM OFF, MED OFF/STIM ON (130 Hz, high frequency stimulation [HFS]), MED OFF/STIM ON (60 Hz - LFS) and MED ON with both HFS and LFS. The following was assessed in all conditions: voice (fundamental frequency and jitter), speech (articulatory diadochokinesis [DDK], pitch variability, rate and intelligibility) and motor performance (MDS-UPDRS-III).Results: LFS compared to no stimulation and HFS, in the absence of l-dopa effect, significantly improved DDK and speech intelligibility for sentence, among patients with severe speech impairment. During the l-dopa effect, comparing LFS vs. HFS, there was a significant improvement of speech intelligibility in both groups. Five patients with severe speech impairment opted to maintain LFS. After six months, speech benefit was maintained but treatment adjustments were required.Conclusions: LFS may offer both an immediate and long-lasting improvement of speech in a subgroup of STN-DBS patients with severe speech impairment during HFS. Nevertheless, its effect on motor symptoms may not be preserved over time. [ABSTRACT FROM AUTHOR]

Introduction: Experimental studies suggest that low-frequency (LF) (63 Hz) deep brain stimulation (DBS) of the substantia nigra pars reticulata (SNr) could be useful to regulate gait disorders refractory to medical treatment in Parkinson's disease (PD). The SNr neurons could act as high-frequency (HF) pacemakers within locomotor control systems. Currently, no specific therapies can treat gait disorders in PD with insufficient response to dopaminergic treatment.Objective: To investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone.Methods: Patients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson's Disease Rating.Results: We included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient.Conclusion: COMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option. [ABSTRACT FROM AUTHOR]

Highlights • Epileptiform activity (EA) was induced by high-K+ in hippocampal slices. • LFS had inhibitory effect on CA1 pyramidal neurons spikes during EA. • LFS with more pulse numbers and intensity had stronger inhibitory effect. • The inhibitory effect of LFS was greater when applied at the beginning of EA. • It may be proposed that the inhibitory effects of LFS rely on LTD. Abstract Low frequency stimulation (LFS) has inhibitory effect on hyperexcitability during epileptic states. However, knowledge is lacking about LFS patterns that can exert an optimal antiepileptic effect. In this study, the effect of different numbers of pulses and current intensities of 1 Hz LFS applied at various time points of epileptiform activity was evaluated in high-K+ model of epileptiform activity (EA). LFS was applied to the Schaffer collaterals, and changes in the excitability of CA1 pyramidal neurons were measured using whole-cell patch-clamp recording. Six hundred and 900 pulses of LFS at two current intensities (equal to and 1.5 times greater than the current intensity sufficient to elicit a 5 mV EPSP) administered at the beginning of EA revealed a stronger LFS inhibitory effect on EA-induced neuronal hyperexcitability when applied at higher pulse number and current intensity. LFS900 (high intensity) significantly hyperpolarized the membrane potential after a high-K+ ACSF washout, reduced the frequency of spontaneous action potentials during EA, and attenuated neuronal firing frequency after high-K+ ACSF washout. Moreover, applying LFS900 (high intensity) before EA induction and 8–10 min after EA initiation could not significantly affect neuronal hyperexcitability, compared to its application at the beginning of EA. This study's findings also offered long-term depression (LTD) as a probable mechanism for LFS' inhibitory role on EA-induced neuronal hyperexcitability. Therefore, the application of LFS (1 Hz) at 900 pulses and greater current intensity at the beginning of EA can exert a strong inhibitory effect on EA-induced neuronal hyperexcitability. [ABSTRACT FROM AUTHOR]

Background and Objective: Developing quantitative measures based on spectral analysis of electroencephalograph (EEG) recordings of neural activities plays an important role in developing efficient treatments for epilepsy. Such biomarkers can be used for developing open or closed loop approaches for seizure prediction or prevention. This study aims to quantitatively evaluate antiepileptogenic effects of low frequency stimulation (LFS) applied immediately before or after kindling stimulations using spectral power analysis of extracellular EEG in rat.Methods: Nineteen adult rats were used: seven for kindle, six for LFS+Kindle (LFSK) and six for Kindle+LFS (KLFS). Four packages of LFS (1Hz) were applied immediately before or after rapid kindling stimulations. The power spectral densities of afterdischarge (AD) sections of EEG corresponding to different stages of kindling for delta (0–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–28 Hz), gamma (28–40 Hz) sub-bands, and theta/alpha ratio were comparatively investigated. Moreover, correlation between AD duration (ADD) and its different frequency components was calculated.Results: Both LFSK and KLFS significantly increased delta and reduced beta and gamma oscillations, compared with kindle group. However, just the reduction in LFSK group was significant. Both protocols increased theta/alpha ratio, but just LFSK showed significant increase (p < 0.05). Although LFSK enhanced theta/alpha ratio more than KLFS, the difference was not statistically significant. Furthermore, strong correlation between each frequency sub band and ADD was not observed in kindle and LFS treated groups (both LFSK and KLFS).Conclusion: Although behavioral assessments showed relatively the same level of antiepileptogenic effects for KLFS and LFSK, quantitative assessments showed more significant differences in the quantitative measures between the two protocols. Developing more quantitative EEG based measures correlated with LFS-induced effects can facilitate developing open or closed loop seizure prevention modalities.

Numerous studies indicate that one of the bad effects of epilepsy is cognitive impairment. In this study we focused on the effect of LFS as a potential anticonvulsant agent, during epileptogenesis on cognitive impairments induced by amygdala kindling in rat. Twenty-one adult rats were divided into 3 groups including control (n = 7), kindled (n = 7), and Kindled+LFS (KLFS) (n = 7). Animals in the kindled group received kindling stimulation in a rapid kindling manner (a 3 s train of 50 Hz monophasic pulses of 1 ms duration, 12 times a day) in amygdala whereas control animals had no stimulation. Four packages of LFS (each package consisting of 200 monophasic square pulses, 0.1 ms pulse duration at 1 Hz) were applied daily after termination of kindling stimulation in KLFS group. Spatial memory of all animals was tested using radial arm maze after termination of stimulation on acquisition trial days and 14 days after the final acquisition trial test. Epileptogenesis process significantly increased working and reference memory error compared to control groups whereas application of LFS immediately after kindling stimulation prevented this impairment in 8 arm radial maze and there was no significant difference between KLS and control groups. Our results indicated that application of LFS during kindling acquisition suppresses memory impairment in epileptogenesis by kindling stimulation. [ABSTRACT FROM AUTHOR]

Introduction Administration of low-frequency electrical stimulation (LFS) at the kindling site has an antiepileptogenic effect. In the present study, we investigated the role of cannabinoid receptors type 1 (CB1) in mediating the inhibitory effects of LFS on the development of perforant path kindled seizures. Methods For seizure generation, rats were kindled by electrical stimulation of perforant path in semi-rapid kindling manner (12 stimulations per day at 10 min intervals at afterdischarge threshold intensity).To determine the effect of LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) on seizure generation, LFS was applied to the perforant path 5 min after the last kindling stimulation daily. AM281, a CB1 receptor antagonist, was microinjected into the lateral ventricle immediately after the last kindling stimulation (before LFS application) at the doses of 0.5 and 2 μg/μl during kindling procedure. The expression of cannabinoid receptors in the dentate gyrus was also investigated using immunohistochemistry. Results Application of LFS had inhibitory effect on development of kindled seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after the last kindling stimulation (before LFS application) reduced the inhibitory effect of LFS on the kindling rate and suppressed the effects of LFS on potentiation (increasing the magnitude) of both population spike amplitude and population excitatory postsynaptic potential slope during kindling acquisition. AM281 pretreatment also prevented the effects of LFS on kindling-induced increase in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl) failed to exert the effects observed with its lower dose (0.5 μg/μl). In addition, there was a decreased CB1 receptors immunostaining in kindled animals compared to control. However, application of LFS following kindling stimulations led to overexpression of CB1 receptors in the dentate gyrus. Conclusion Obtained results showed that activation of overexpressed cannabinoid CB1 receptors by endogenous cannabinoids may have a role in mediating the inhibitory effect of LFS on perforant path kindled seizures. [ABSTRACT FROM AUTHOR]

Background and Objective: Developing quantitative measures based on spectral analysis of electroencephalograph (EEG) recordings of neural activities plays an important role in developing efficient treatments for epilepsy. Such biomarkers can be used for developing open or closed loop approaches for seizure prediction or prevention. This study aims to quantitatively evaluate antiepileptogenic effects of low frequency stimulation (LFS) applied immediately before or after kindling stimulations using spectral power analysis of extracellular EEG in rat. Methods: Nineteen adult rats were used: seven for kindle, six for LFS+Kindle (LFSK) and six for Kindle+LFS (KLFS). Four packages of LFS (1Hz) were applied immediately before or after rapid kindling stimulations. The power spectral densities of afterdischarge (AD) sections of EEG corresponding to different stages of kindling for delta (0–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–28 Hz), gamma (28–40 Hz) sub-bands, and theta/alpha ratio were comparatively investigated. Moreover, correlation between AD duration (ADD) and its different frequency components was calculated. Results: Both LFSK and KLFS significantly increased delta and reduced beta and gamma oscillations, compared with kindle group. However, just the reduction in LFSK group was significant. Both protocols increased theta/alpha ratio, but just LFSK showed significant increase (p < 0.05). Although LFSK enhanced theta/alpha ratio more than KLFS, the difference was not statistically significant. Furthermore, strong correlation between each frequency sub band and ADD was not observed in kindle and LFS treated groups (both LFSK and KLFS). Conclusion: Although behavioral assessments showed relatively the same level of antiepileptogenic effects for KLFS and LFSK, quantitative assessments showed more significant differences in the quantitative measures between the two protocols. Developing more quantitative EEG based measures correlated with LFS-induced effects can facilitate developing open or closed loop seizure prevention modalities. [ABSTRACT FROM AUTHOR]

Subcallosal Brodmann's Area 25 (Cg25) Deep Brain Stimulation (DBS) is a new promising therapy for treatment resistant major depressive disorder (TR-MDD). While different DBS stimulating parameters may have an impact on the efficacy and safety of the therapy, there is no data to support a protocol for optimal stimulation parameters for depression. Here we present a prospective multi-center double-blind randomized crossed-over 13-month study that evaluated the effects of High (130 Hz) vs Low (20 Hz) frequency Cg25 stimulation for nine patients with TR-MDD. Four out of nine patients achieved response criteria (≥40% reduction of symptom score) compared to mean baseline values at the end of the study. The mean percent change of MADRS score showed a similar improvement in the high and low frequency stimulation groups after 6 months of stimulation (−15.4 ± 21.1 and −14.7 ± 21.1 respectively). The mean effect at the end of the second period (6 months after cross-over) was higher than the first period (first 6 months of stimulation) in all patients (−23.4 ± 19.9 (n = 6 periods) and −13.0 ± 22 (n = 9 periods) respectively). At the end of the second period, the mean percent change of the MADRS scores improved more in the high than low frequency groups (−31.3 ± 19.3 (n = 4 patients) and −7.7 ± 10.9 (n = 2 patients) respectively). Given the small numbers, detailed statistical analysis is challenging. Nonetheless the results of this study suggest that long term high frequency stimulation might confer the best results. Larger scale, randomized double blind trials are needed in order to evaluate the most effective stimulation parameters. [ABSTRACT FROM AUTHOR]

Application of low-frequency stimulation (LFS) can improve learning and memory in kindled animals (Ghafouri et al., 2016). Considering the important role of long-term potentiation (LTP) in learning and memory, in the present study the effectiveness of LFS on kindling-induced impairment in LTP induction was investigated in hippocampal CA1 area at different times post kindling stimulations. Animals were kindled via electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations per day). One group of animals received four trials of LFS at 30 s, 6 h, 24 h, and 30 h following the last kindling stimulation. Each LFS consisted of 4 packages at 5 min intervals; each package contained 200 monophasic square wave pulses of 0.1 ms duration at 1 Hz. The kindled, kindled + LFS and LFS groups were divided into four subgroups in which hippocampal slices were prepared at 48 h, 1 week, 2 weeks, and 1 month following the last kindling stimulation respectively. Extracellular evoked field excitatory postsynaptic potentials (fEPSPs) were recorded in the stratum radiatum of the CA1 area of the slice. Obtained results showed that LTP was not induced in kindled animals. However, application of LFS overcame the kindling-induced impairment in LTP generation in CA1 area of the hippocampus. This improving effect remained up to one week after the last kindling stimulation and extended to one month by increasing the number of applied LFS packages. [ABSTRACT FROM AUTHOR]

Objective: It has been suggested that low frequency stimulation (LFS) exerts itsinhibitory effect on epileptogenesis through adenosine receptors activation. In thepresent study, effect of different LFS frequencies on A1 and A2A receptors gene expressionwas investigated in perforant path kindled seizures.Materials and Methods: Animals were kindled by perforant path stimulation.Afterdischarges were recorded from the dentate gyrus. LFS (0.5, 1 and 5 Hz) wasapplied at the end of each kindling stimulation. On the 7th day, A1 and A2A receptorsgene expression were evaluated in the dentate gyrus.Results: Application of different LFS frequencies retarded the kindling acquisition.Also, it decreased the afterdischarge durations and behavioural seizure stages 4and 5 significantly. LFS application prevented the kindling induced decrease in theA1 receptor gene expression. On the other hand, LFS attenuated the level of A2Areceptor gene expression in the dentate gyrus. LFS had the most effect at thefrequency of 5 Hz.Conclusion: It may be suggested that antiepileptogenic effects of LFS is mediatedsomehow through changes in the gene expression of adenosine A1 (which hasinhibitory effects) and A2A (which has excitatory effects) receptors. These effectsmight be somehow frequency dependent.

Low frequency deep brain electrical stimulation (LFS) is a potential therapeutic strategy to control seizures in epilepsy patients. Given the functional connection of the olfactory bulb with the hippocampal formation, in this study the effect of applying LFS in the olfactory bulb on seizure severity, and learning and memory was investigated in hippocampal kindling. In male Wistar rats (250–300 g), a tripolar electrode was inserted in the CA1 region of the right hippocampus to apply kindling stimulations and record the afterdischarges (ADs). Two bipolar electrodes were also inserted bilaterally into the olfactory bulbs for applying LFS. In the kindled group, the animals received daily kindling stimulations to produce stage 5 seizures for three consecutive days. In one group of subjects, LFS was administered 2–3 min after the last kindling stimulation. Within this group, subjects were divided into two subgroups: one subgroup received two and the other subgroup received four packages of LFS protocol. Obtained data showed that bilateral LFS application to the left and right olfactory bulb reduced seizure severity. Among the protocols, applying four packages of LFS had a greater anticonvulsant effect compared to applying two packages LFS. Applying LFS in the olfactory bulb of kindled subject restored performance on measures that test short- and long-term memory – the Y maze and Morris water maze test – and applying four packages of LFS was more effective than two. These results indicated that applying LFS to the olfactory bulb had anticonvulsant effects and ameliorated the seizure-induced impairment of working and spatial memory. These effects appear to be depended on the number of applied LFS and were greater by increasing the number of LFS. [Display omitted] • The effect of applying LFS in olfactory bulb on seizure severity was investigated. • Animals received hippocampal electrical stimulations to achieve the fully kindled state. • Applying LFS to the olfactory bulb had anticonvulsant effect. • The olfactory bulb LFS ameliorated the seizure-induced impairment of memory. • These effects were greater by increasing the number of LFS. [ABSTRACT FROM AUTHOR]

Introduction Chronic pain is one of the most common non-motor symptoms of Parkinson's disease (PD) affecting up to 85% of patients. Previous studies have established that reduced mechanical and thermal thresholds occur in both idiopathic PD patients and animal models of PD, suggesting that changes may occur in sensory processing circuits. Improvements in sensory thresholds are achieved using subthalamic nucleus (STN) deep brain stimulation (DBS), however the mechanism by which this occurs remains unresolved. Materials and methods We examined unilateral medial forebrain bundle 6-hydroxydopamine (6OHDA) rat model of PD to determine whether STN DBS alters neuronal firing rates in brain areas involved in ascending and descending pain processing. Specifically, single unit in vivo recordings were conducted in the anterior cingulate cortex (ACC), the periaqueductal grey (PAG), and the ventral posteriolateral nucleus of the thalamus (VPL), before, during and after stimulation was applied to the STN at 50 or 150 Hz. Results Sham and 6OHDA lesioned animals have similar neuronal firing activity in the VPL, ACC and PAG before stimulation was applied (p > 0.05). In 6OHDA lesioned rats, both low frequency stimulation (LFS) (p < 0.01) and high frequency stimulation (HFS) (p < 0.05) attenuated firing frequency in the ACC. In shams, only LFS decreased firing frequency. A subset of neurons in the PAG was significantly attenuated in both sham and 6OHDA lesioned animals during HFS and LFS (p < 0.05), while another subset of PAG neuronal activity significantly increased in 6OHDA lesioned rats during HFS (p < 0.05). Finally, low or high frequency STN DBS did not alter neuronal firing frequencies in the VPL. Conclusions Our results suggest that STN DBS alters neuronal firing in descending pain circuits. We hypothesize that STN DBS attenuates excitatory projections from the ACC to the PAG in 6OHDA lesioned rats. Following this, neurons in the PAG respond by either increasing (during HFS only) or decreasing (during both LFS and HFS), which may modulate descending facilitation or inhibition at the level of the spinal cord. Future work should address specific neuronal changes in the ACC and PAG that occur in a freely moving parkinsonian animal during a pain stimulus treated with STN DBS. [ABSTRACT FROM AUTHOR]

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABA A receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital + LFS was investigated on GABA A -mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100 μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo . Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABA A currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital. [ABSTRACT FROM AUTHOR]

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is widely used to treat the symptoms of Parkinson’s disease but the mechanism of this therapy is unclear. Using a rat brain slice preparation maintaining the connectivity between the STN and one of its target nuclei, the globus pallidus (GP), we investigated the effects of high and low frequency stimulation (HFS 100 Hz, LFS 10 Hz) on activity of single neurons in the STN and GP. Both HFS and LFS caused changes in firing frequency and pattern of subthalamic and pallidal neurons. These changes were of synaptic origin, as they were abolished by glutamate and GABA antagonists. Both HFS and LFS also induced a long-lasting reduction in firing frequency in STN neurons possibly contending a direct causal link between HFS and the outcome DBS. In the GP both HFS and LFS induced either a long-lasting depression, or less frequently, a long-lasting excitation. Thus, in addition to the intrinsic activation of the stimulated neurons, long-lasting stimulation of the STN may trigger prolonged biochemical processes.

The pedunculopontine nucleus (PPN) has recently been introduced as an alternative target to the subthalamic nucleus (STN) or globus pallidus internus (GPi) for the treatment of advanced Parkinson's disease with severe and medically intractable axial symptoms such as gait and postural impairment. However, it is little known about how electrical stimulation of the PPN affects control of neuronal activities between the PPN and basal ganglia. We examined how low frequency stimulation of the pedunculopontine tegmental nucleus (PPTg) affects control of neuronal activities between the PPN and basal ganglia in 6-OHDA lesioned rats. In order to identify the effect of low frequency stimulation on the PPTg, neuronal activity in both the STN and substantia nigra par reticulata (SNr) were recorded and subjected to quantitative analysis, including analysis of firing rates and firing patterns. In this study, we found that the firing rates of the STN and SNr were suppressed during low frequency stimulation of the PPTg. However, the firing pattern, in contrast to the firing rate, did not exhibit significant changes in either the STN or SNr of 6-OHDA lesioned rats during low frequency stimulation of the PPTg. In addition, we also found that the firing rate of STN and SNr neurons displaying burst and random pattern were decreased by low frequency stimulation of PPTg, while the neurons displaying regular pattern were not affected. These results indicate that low frequency stimulation of the PPTg affects neuronal activity in both the STN and SNr, and may represent electrophysiological efficacy of low frequency PPN stimulation. [ABSTRACT FROM AUTHOR]

BACKGROUND: High frequency stimulation (HFS) of the subthalamic nucleus is one of the most effective treatments for advanced Parkinson's disease (PD). HFS has provided beneficial improvements in the cardinal features of PD, but has not been proven as effective for addressing the axial predominant levodopa resistant symptoms, such as speech disturbances, gait disturbances, and postural instability. Recent studies have suggested that changes in stimulation parameters may influence differing PD symptoms. OBJECTIVE: The purpose of this study was to compare the effects of low frequency stimulation (LFS) versus HFS on the Unified Parkinson's Disease Rating Scale (UPDRS), gait, balance, and verbal fluency. METHODS: Eight tremor dominant and nine non-tremor dominant participants with bilateral deep brain stimulation of the subthalamic nucleus were tested off stimulation, during LFS, and during HFS. RESULTS: Results revealed that HFS significantly reduced UPDRS tremor score in the tremor dominant group; however no differences emerged within the non-tremor dominant group. No differences between groups or stimulation conditions were found for gait, balance, and verbal fluency measures. CONCLUSION: These results may suggest that HFS is better than LFS for reducing tremor in tremor dominant patients. However, patients with mild or no tremor show no acute differences in benefit from LFS as compared to HFS. [ABSTRACT FROM AUTHOR]

Highlights: [•] 15 and 30min but not 1, 5min LFS inhibited seizures in kindling and kindled rats. [•] 15 and 30min LFS lowered power in delta band of amygdaloid EEG. [•] Discontinuous 15min LFS had no anti-epileptic effect. [•] Consecutive 15min may be necessary for LFS to inhibit kindling seizures in rats. [Copyright &y& Elsevier]

Abstract: Background: Deep brain stimulation (DBS) has emerged as a potential therapeutic strategy in the treatment of neurological disorders including epilepsy. However, the cellular mechanism responsible for the effects of DBS remains largely undefined. Therefore, using electrophysiological approach, we aimed to determine the antiepileptic effects and restorative potential of low frequency stimulation (LFS) on amygdala kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons. Methods: Animals were kindled by electrical stimulation of amygdala in a rapid kindling manner (12 times per day). In one group of animals, immediately after termination of daily 12 rapid kindling stimulations, the kindling site was subjected to 4 packages of LFS at intervals of 5 min (each package contained 200 monophasic square-wave pulses, 0.1 ms pulse duration at 1 Hz). Whole cell patch clamp recording under current clamp conditions was performed on visually identified pyramidal neurons in hippocampal slice preparations obtained from amygdala-kindled rats and the rats receiving LFS. Results: Kindling of the right basolateral amygdala profoundly affected spontaneous firing behavior and repetitive discharge characteristics of pyramidal neuronal electrophysiological properties. Application of LFS at the kindling site almost completely prevented the development of epilepsy and the disruptive effects of kindling on neuronal electrical activity through restoration of the normal electrophysiological characteristics. Conclusions: The results of this study implied that application of LFS during kindling acquisition prevents the kindling induced changes in functional electrical properties of CA1 pyramidal neurons, suggesting that this action may be involved in the antiepileptogenic mechanism of LFS. [Copyright &y& Elsevier]

Summary: Low frequency stimulation (LFS) may be considered as a new potential therapy for drug-resistant epilepsy. However, the relation between LFS parameters and its anticonvulsant effects is not completely determined. In this study, the effect of some LFS parameters on its anticonvulsant action was investigated in rats. In all animals, stimulating and recording electrodes were implanted into the perforant path and dentate gyrus, respectively. In one group of animals, kindling stimulations were applied until rats achieved a fully kindled state. In other groups, different patterns of LFS were applied at the end of kindling stimulations during twenty consecutive days. In the first experiment the effect of LFS pulse numbers was investigated on its anticonvulsant action. Animals were divided randomly into three groups and 1, 4, and 8 packages of LFS (each pack contains 200 pulses, 0.1ms pulse duration at 1Hz) were applied five minutes after termination of kindling stimulations. Obtained results showed that 4 packages of LFS had the strongest anticonvulsant effects. Therefore, this pattern (4 packages) was used in the next experiment. In the second experiment, 4 packages of LFS were applied at intervals of 30s and 30min after termination of kindling stimulations. The strongest anticonvulsant effect was observed in the group received LFS at the interval of 30s. Therefore, this pattern was selected for the third experiment. In the third experiment the effect of LFS at frequencies of 0.25Hz and 5Hz was investigated. The group of animals which received LFS at the frequency of 0.25Hz showed somehow stronger anticonvulsant effect. The results indicate that different parameters of LFS have important role in induction of LFS anticonvulsant effects. Regarding this view, it seems that the slower LFS frequency and the shorter interval between LFS and kindling stimulations, the stronger anticonvulsant effect will be observed. But there is no direct relation between number of pulses and the magnitude of anticonvulsant effect of LFS. [Copyright &y& Elsevier]

Summary: Low frequency stimulation (LFS) has an inhibitory effect on kindling acquisition. In the present study the effect of the perforant path LFS on induction of rapid perforant path kindled seizures and synaptic transmission in the dentate gyrus was investigated. Animals were kindled by perforant path stimulation in a rapid kindling manner (12 stimulations per day). In one group of animals LFS (0.1ms pulse duration at 1Hz, 200 pulses, and 50–150μA) was applied to perforant path, immediately after termination of each rapid kindling stimulation. Application of LFS significantly retarded the kindling acquisition and increased the number of stimulations to achieved different kindled seizure stages. LFS also prevented an increment in the slope of field excitatory postsynaptic potentials and population spike amplitude during kindling. In addition, LFS significantly reduced the marked increase in early (10–50ms intervals) and late (300–1000ms intervals) paired-pulse depression induced by kindling. According to obtained results, it may be suggested that LFS of perforant path has a significant antiepileptogenic effect through inhibition of synaptic transmission in dentate gyrus. Meanwhile, LFS prevents an increase in the paired-pulse depression during kindling acquisition. [Copyright &y& Elsevier]

Laboratory research on animals indicates that the potentiation of synapses in various areas of the limbic system is the primary step in fear memory formation. Depotentiation of these synapses can result in erasure or modification of these memories. The principal mechanism for depotentiation is induction of low frequency stimulation (LFS). This research has also shown that during memory recall, potentiated circuits within the limbic system become labile, and more vulnerable to depotentiation. The authors propose that LFS can be induced in the human brain during eye-movement desensitization and reprocessing therapy (EMDR), and that this can lead to quenching or modification of fear memory traces. Hence, the authors theorize that this process is the main biological basis for the therapeutic effects of EMDR. [ABSTRACT FROM PUBLISHER]

Abstract: Suppression of rapid eye movement sleep (REMS) in developing animals has both anatomical and physiological consequences. We have recently shown that initiating REMS deprivation (REMSD) prior to the end of the critical period in young rats delays termination of the critical period (CP) in visual cortex, and, consequently, the synaptic plasticity mechanisms that support a developmentally regulated form of long-term potentiation (LTP) are maintained in an immature state [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431–443]. In CP animals, high-frequency, theta burst stimulation (TBS) directed at the white matter (WM) below visual cortex produces LTP in the post-synaptic cells in layer II/III (LTPWM-III). However, LTPWM-III can be induced in cortical tissue taken from REMS-deprived animals for up to a week beyond the usual end of the CP [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431–443]. Further, in post-CP, adolescent animals (as late as postnatal day 60), REMSD appears to unmask synaptic plasticity mechanisms that allow for production of developmentally regulated LTPWM-III [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. It has been proposed that REMSD''s effects on production of LTPWM-III result from a reduction in efficiency of the inhibitory mechanisms thought to precipitate termination of the CP of brain development [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. In this study we tested the hypothesis that low-frequency stimulation (LFS) of the fibers of the WM, which usually produces the related form of synaptic plasticity, long-term depression (LTD), will also reflect the reduction in inhibitory tone. We report here that LFS protocols, which in normally sleeping, adolescent rats usually produce either LTD or no change in response magnitude, in REMS-deprived, adolescent rats are more likely to produce LTP. [Copyright &y& Elsevier]

Experiments were designed to reproduce the antiepileptic effects of low frequency stimulation (LFS) during the amygdala kindling process and to examine LFS-induced changes in receptor binding levels of different neurotransmitters in normal brain. Male Wistar rats were stereotactically implanted in the right amygdala with a bipolar electrode. Rats (n=14) received twice daily LFS (15 min train of 1 Hz, 0.1 ms at an intensity of 100 to 400 μA) immediately after amygdala kindling stimulation (1 s train of 60 Hz biphasic square waves, each 1 ms at amplitude of 200–500 μA) during 20 days. The LFS suppressed epileptogenesis (full attainment of stage V kindling) but not the presence of partial seizures (lower stages of kindling) in 85.7% of the rats. Thereafter, normal rats (n=7) received amygdala LFS twice daily for 40 trials. Animals were sacrificed 24 h after last stimulation and their brain used for labeling μ opioid, benzodiazepine (BZD), α1-adrenergic, and adenylyl cyclase binding. Autoradiography experiments revealed increased BZD receptor binding in basolateral amygdala (20.5%) and thalamus (29.3%) ipsilateral to the place of stimulation and in contralateral temporal cortex (18%) as well as decreased values in ipsilateral frontal cortex (24.2%). Concerning μ receptors, LFS decreased binding values in ipsilateral sensorimotor (7.2%) and temporal (5.6%) cortices, dentate gyrus (5.8% ipsi and 6.8% contralateral, respectively), and contralateral CA1 area of dorsal hippocampus (5.5%). LFS did not modify α1 receptor and adenylyl cyclase binding values. These findings suggest that the antiepileptic effects of LFS may involve activation of GABA–BZD and endogenous opioid systems. [Copyright &y& Elsevier]