High Frequency Electrical Stimulation Research Articles

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor 1. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials 2. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation 3. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity 4,5. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Neural Correlates of Heterotopic Facilitation Induced after High Frequency Electrical Stimulation of Nociceptive Pathways

BackgroundHigh frequency electrical stimulation (HFS) of primary nociceptive afferents in humans induce a heightened sensitivity in the surrounding non-stimulated skin area. Several studies suggest that this heterotopic effect is the result of central (spinal) plasticity. The aim of this study is to investigate HFS-induced central plasticity of sensory processing at the level of the brain using the electroencephalogram (EEG). To this end we measured evoked potentials in response to noxious electrical pinprick-like stimuli applied in the heterotopic skin area before, directly after and 30 minutes after HFS.ResultsWe observed potential cortical electrophysiological correlates of heterotopic facilitation. Two different cortical correlates were found; the first one was a lateralized effect, i.e. a larger N100 amplitude on the conditioned arm than the control arm 30 minutes after end of HFS. This was comparable with the observed lateralized effect of visual analogue scale (VAS) scores as response to the mechanical punctate stimuli. The second correlate seems to be a more general (non-lateralized) effect, because the result affects both arms. On average for both arms the P200 amplitude increased significantly 30 minutes after end of HFS with respect to baseline.ConclusionsWe suggest that for studying heterotopic nociceptive facilitation the evoked brain response is suitable and relevant for investigating plasticity at the level of the brain and is perhaps a more sensitive and reliable marker than the perceived pain intensity (e.g. VAS).

High-frequency electrical stimulation in the nucleus accumbens of morphine-treated rats suppresses neuronal firing in reward-related brain regions

SummaryBackgroundPrevious studies have reported that high-frequency stimulation (HFS) in the nucleus accumbens (NAc) is a potential treatment modality for drug craving and relapse. We aimed to explore the electrophysiological changes in reward-related brain regions during NAc stimulation and reveal the effects of stimulation frequency and target changes on NAc neuronal activities.Material/MethodsTwenty-eight rats were randomized into saline (n=8) and morphine (n=20) groups. The morphine group was further divided into core (n=10, only the core of the NAc was stimulated) and shell (n=10, only the shell of the NAc was stimulated) subgroups. Conditioned place preference (CPP) behavior of the rats was evaluated to confirm morphine preference after morphine injection and CPP training for 10 days. We recorded NAc neuronal responses to NAc core stimulation at different frequencies, as well as changes in VP and VTA neuronal firing during NAc core stimulation, and changes in NAc neuronal firing during NAc shell stimulation.ResultsThe results indicate that high frequency stimulation was more effective in suppressing NAc neuronal activities than low frequency stimulation and that core stimulation was more effective than shell stimulation. Most VP neurons were inhibited by NAc core stimulation, while VTA neurons were not.ConclusionsThe results suggest that electrical stimulation in the NAc can suppress neuronal firing in reward-related brain regions. The stimulation might be frequency- dependent in suppressing neuronal firing. The core and shell of the NAc play different roles in suppressing NAc neuronal firing as 2 stimulating targets.

The involvement of potassium ion channels in memory

Hippocampal long-term potentiation (LTP), an increase in the efficacy of synaptic transmission, has been considered a powerful candidate for the physiological basis of memory. Although hippocampal LTP has been induced by high frequency electrical stimulation of the presynaptic fiber in most studies, it has been reported that pharmacological blockade of potassium ion channels also induces synaptic plasticity. Furthermore, several studies have recently used a newly developed selective blocker and opener to demonstrate that potassium ion channels play an important role in memory and learning. This article reviews studies that have shown the possible involvement of potassium ion channels in memory function and hippocampal synaptic plasticity.

The Subthalamic Nucleus becomes a Generator of Bursts in the Dopamine-Depleted State. Its High Frequency Stimulation Dramatically Weakens Transmission to the Globus Pallidus

Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.

Associative Stimulation of the Supraorbital Nerve Fails to Induce Timing-Specific Plasticity in the Human Blink Reflex

BackgroundAssociative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger, 2001). HFS given at the onset of the R2 component of the blink reflex (HFSLTP) produced a lasting facilitation of the R2, whereas HFS given shortly before R2 (HFSLTD) caused a lasting suppression of the R2. In patients with benign essential blepharospasm (BEB), a focal dystonia affecting the orbicularis oculi muscles, HFSLTP induced excessive LTP-like associative plasticity relative to healthy controls, which was normalized after botulinum toxin (BTX) injections (Quartarone et al, 2006).Methodology/Principal FindingsWe used HFS conditioning of the supraorbital nerve to study homeostatic metaplasticity of the blink reflex circuit in healthy subjects and dystonic patients. On separate days, we tested the conditioning effects on the R2 response and paired-pulse R2 inhibition after (i) HFSLTP, (ii) HFSLTP followed by HFSLTP, and (iii) HFSLTP followed by HFSLTD. Controls also received (iv) HFSLTD alone and (v) a non-intervention protocol. In BEB patients, HFSLTP followed by HFSLTD was given before and after BTX treatment. We were not able to replicate the bidirectional timing-dependent effects of HFSLTP and HFSLTD alone. All HFS protocols produced a non-specific reduction of the R2 response and a relative decrease in paired-pulse inhibition. These R2 changes also occurred in controls when no HFS was applied. There was also no trace of a homeostatic response pattern in BEB patients before or after BTX treatment.Conclusion/SignificanceOur data challenge the efficacy of associative HFS to produce bidirectional plasticity in the human blink reflex circuit. The non-specific decrease of the R2 response might indicate habituation of the blink reflex following repeated electrical supraorbital stimulation. The increase of inhibition after paired pulse stimulation might reflect homeostatic behaviour to prevent further down regulation of the R2 response to preserve the protection of this adverse-effects reflex.

Metaplasticity of the human trigeminal blink reflex

Although synaptic plasticity in the human cerebral cortex is governed by metaplasticity, whether a similar mechanism operates at brainstem level is unknown. In this study in healthy humans we examined the effects and interactions induced by pairing supraorbital nerve high-frequency electrical stimulation (HFS) protocols on the R2 component of the trigeminal blink reflex [Mao, J.B. & Evinger, C (2001) J Neurosci., 21:RC151(1-4)]. Changes in the R2 component were tested by pairing three different priming stimulation protocols inducing long-term potentiation (LTP)-like or long-term depression (LTD)-like effects (LTP-HFS and LTD-HFS), or no change (CONTROL-HFS) with a subsequent test LTP-HFS. Additionally, to examine changes in the R2 component induced by nonspecific factors, two CONTROL-HFS sessions were paired. Priming LTP-, LTD- or CONTROL-HFS potentiated, inhibited or left unchanged the area of the R2 component. Regardless of the type of priming LTP-, LTD- or CONTROL-HFS, the test LTP-HFS induced negligible differences in the R2 component. When two CONTROL-HFS sessions were paired, the test CONTROL-HFS increased the latency and markedly reduced the duration and area of the R2 component. The analysis of the normalized data across the first three experimental sessions, corrected for the inhibitory effects found in the fourth experiment, showed that the test LTP-HFS potentiated the R2 component area of the trigeminal blink reflex only when preceded by a priming LTD-HFS. We propose that homosynaptic metaplasticity might operate in the brainstem circuitry of the blink reflex.

P16-9 Change in cortical fast activities after high frequency electric cortical stimulation in a patient with cortical dysplasia and intractable epilepsy

P16-9 Change in cortical fast activities after high frequency electric cortical stimulation in a patient with cortical dysplasia and intractable epilepsy

P3-12 Cooling enhances the masking effects of conditioining high frequency electrical stimulation on sensory nerve action potential in human

P3-12 Cooling enhances the masking effects of conditioining high frequency electrical stimulation on sensory nerve action potential in human

Effects of hippocampal high‐frequency electrical stimulation in memory formation and their association with amino acid tissue content and release in normal rats

Hippocampal high frequency electrical stimulation (HFS) at 130 Hz has been proposed as a therapeutical strategy to control neurological disorders such as intractable temporal lobe epilepsy (TLE). This study was carried out to determine the effects of hippocampal HFS on the memory process and the probable involvement of amino acids. Using the autoshaping task, we found that animals receiving hippocampal HFS showed augmented short-term, but not long-term memory formation, an effect blocked by bicuculline pretreatment and associated with enhanced tissue levels of amino acids in hippocampus. In addition, microdialysis experiments revealed high extracellular levels of glutamate, aspartate, glycine, taurine, and alanine during the application of hippocampal HFS. In contrast, GABA release augmented during HFS and remained elevated for more than 1 h after the stimulation was ended. HFS had minimal effects on glutamine release. The present results suggest that HFS has an activating effect on specific amino acids in normal hippocampus that may be involved in the enhanced short-term memory formation. These data further provide experimental support for the concept that hippocampus may be a promising target for focal stimulation to treat intractable seizures in humans.

Ictal asomatognosia due to dominant superior parietal cortical dysplasia

We report a 23-year-old man with left dominant parietal cortical dysplasia manifesting as ictal asomatognosia. The man had experienced seizures, during which he underwent ictal asomatognosia as a feeling of loss of his right extremities. Scalp electroencephalography (EEG) showed interictal discharges in the left parietal region of his brain. Magnetic resonance fluid-attenuated inversion recovery (FLAIR) imaging revealed a hyperintense lesion in the left superior parietal lobule. A [ 123I]-iomazenil (IMZ) single-photon-emission CT scan demonstrated an area of low IMZ binding coincident with the lesion observed in the MRI scan. Invasive EEG monitoring showed ictal discharges in the cortex posterior to the postcentral sulcus. High-frequency electrical stimulation of the same area of the cortex also induced asomatognosia of the patient’s right forearm. We performed a corticectomy of the anterior part of the superior parietal lobule, which resulted in no new neurological deficits. The seizures disappeared after surgery with the maintenance of preoperative medication. Therefore, the anterior part of the superior parietal lobule may be a symptomatogenic zone for ictal asomatognosia.

Nerve conduction block using combined thermoelectric cooling and high frequency electrical stimulation

Conduction block of peripheral nerves is an important technique for many basic and applied neurophysiology studies. To date, there has not been a technique which provides a quickly initiated and reversible “on-demand” conduction block which is both sustainable for long periods of time and does not generate activity in the nerve at the onset of the conduction block. In this study we evaluated the feasibility of a combined method of nerve block which utilizes two well established nerve blocking techniques in a rat and cat model: nerve cooling and electrical block using high frequency alternating currents (HFAC). This combined method effectively makes use of the contrasting features of both nerve cooling and electrical block using HFAC. The conduction block was initiated using nerve cooling, a technique which does not produce nerve “onset response” firing, a prohibitive drawback of HFAC electrical block. The conduction block was then readily transitioned into an electrical block. A long-term electrical block is likely preferential to a long-term nerve cooling block because nerve cooling block generates large amounts of exhaust heat, does not allow for fiber diameter selectivity and is known to be unsafe for prolonged delivery.

Sympathetic Neurons Express and Secrete MMP-2 and MT1-MMP to Control Nerve Sprouting via Pro-NGF Conversion

Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

48. Change in cortical fast activities after high frequency electric cortical stimulation in a patient with cortical dysplasia and intractable epilepsy

48. Change in cortical fast activities after high frequency electric cortical stimulation in a patient with cortical dysplasia and intractable epilepsy

Toward a quantitative multivariate analysis of the efficacy of antiseizure therapies

Seizure frequency is the only variable used for assessing therapeutic efficacy. Advances in quantitative analyses allow measurement of intensity, duration, spread, and time between seizures (TBS). These variables are used here to investigate the efficacy of brain electrical stimulation in humans with pharmacoresistant seizures.The results of a trial of contingent high-frequency electrical stimulation (HFES) for abatement of clinical and subclinical seizures are examined using principal component analysis (PCA) and regression models. HFES significantly: (1) Decreased seizure severity in two of eight and increased TBS in one of eight subjects; (2) decreased seizure severity in the primary epileptogenic zone of one subject but increased it in the secondary zones; (3) had both a beneficial and detrimental effect on severity and/or TBS (increase). These effects were immediate and also outlasted the duration of stimulation (“carryover”). Contingent HFES has multifarious and complex effects, intra- and interindividually, on seizure severity and TBS. Two inferences, at once promising and sobering may be drawn from these results: one, that contingent electrical stimulation deserves a place in the armamentarium of therapies for pharmacoresistant seizures, and the other, that its apparently narrow therapeutic ratio calls for careful implementation and multivariate quantification of its effects.

Expression of the immediate-early gene egr-1 and substance P in the spinal cord following locomotor training in adult rats

The immediate-early gene egr-1 has been shown to have an increased expression during long-term potentiation (LTP). High frequency electrical stimulation induces an increase in such expression in the dorsal horn of the spinal cord. However, evidence demonstrating the activation of this gene in the spinal cord and its relationship with LTP is still scarce. The substance P (SP) has also been associated with LTP in the dorsal horn of the spinal cord following high frequency stimulation. Here we evaluated the expression of both Egr-1 and SP in the sacrolumbar area of the spinal cord after locomotor training in adult rats. Increased neuronal Egr-1 expression was found in the spinal cord sections in rats that underwent locomotor training, especially in laminae IV and X across L3–S4 levels ( p < 0.05). Conversely, SP expression in synaptic terminals was not altered in the abovementioned regions. Our results suggest that locomotor training activates mechanisms in a similar way to LTP, and is involved in the synaptic plasticity in the spinal cord. The results also indicate that variations in the training protocol influence Egr-1 expression. Such events appear not to be directly influenced by SP, which suggests a plastic process that differs from those triggered by nociceptive stimuli.

High‐Frequency Electrical Stimulation (HES) of Vagus Nerves Reduces Airway Resistance (RL) in Response to Methacholine (MCh) in Anesthetized Guinea Pigs

Asthmatic patients are characterized by cholinergic‐mediated airway hyperreactivity and bronchoconstriction. Tachyphylaxis and safety‐related side effects of the drugs used to treat asthma are clinical challenges. Because vagotomy blunts the RL response to MCh and HES blocks nerve conduction, we hypothesized that HES of the cervical vagus nerve would reduce the RL responses to MCh, especially in ovalbumin (Ova)‐sensitized guinea pigs, an established animal model of asthma. Both saline (Sal)‐ and Ova‐treated animals were anesthetized, paralyzed, and ventilated. RL and its responses to 10 s of low frequency electrical stimulation (LES, 50 Hz) and HES (≥1 KHz, 0.5 V; 0.2‐ms pulse duration) were recorded before and after MCh (100 μg/ml/min for 2 min) inhalation. Only LES significantly increased RL in both groups of animals before MCh. After MCh, the RL was increased 2.5‐fold higher in the Ova‐ than Sal‐treated animals and LES still enhanced RL, but HES suppressed the RL response more greatly in the Ova‐ (49%) than the Sal‐treated animals (35%). These evoked RL responses completely followed the electrical stimulation in an on‐and‐off manner with little effect on cardiovascular activity. Our data suggest that HES is a potentially useful approach in alleviating asthmatic bronchoconstriction.

Neurophysiological Correlates of Nociceptive Heterosynaptic Long-Term Potentiation in Humans

Long-term potentiation (LTP) is a cellular model of synaptic plasticity and reflects an increase of synaptic strength. LTP is also present in the nociceptive system and is believed to be one of the key mechanisms involved in the manifestations of chronic pain. LTP manifested as an increased response in pain perception can be induced in humans using high-frequency electrical stimulation (HFS). The aim of this study was to induce spinal heterosynaptic LTP using HFS and investigate its heterotopic effects on event-related potentials (ERPs) to repeated nonpainful cutaneous stimuli as a possible electrophysiological cortical correlate of sensitization. Twenty-two healthy subjects were randomly assigned to one of the two experimental conditions: HFS and control stimulation. Before and after the stimulation, both conditions received heterotopic mechanical (pinprick) and paired nonpainful electrical test stimuli to quantify and confirm the effects of HFS on the behavioral level. ERPs to paired nonpainful electrical stimulation were measured simultaneously. Conditioning HFS resulted in significant heterotopic effects after 30 min, including increased perceived intensity in response to (pinprick) mechanical and paired nonpainful electrical stimulation compared with control. The paired nonpainful electrical stimuli were accompanied by significantly enhanced responses regarding the ERP N1-P2 peak-to-peak and P300 amplitude compared with control. These findings suggest that HFS is capable of producing heterosynaptic spinal LTP that can be measured not only behaviorally but also using ERPs.