Clinical utility of implantable neurostimulation devices as adjunctive treatment of uncontrolled seizures

About one third of patients with epilepsy are refractory to medical treatment. For these patients, alternative treatment options include implantable neurostimulation devices such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation systems (RNS). We conducted a systematic literature review to assess the available evidence on the clinical efficacy of these devices in patients with refractory epilepsy across their lifespan. VNS has the largest evidence base, and numerous randomized controlled trials and open-label studies support its use in the treatment of refractory epilepsy. It was approved by the US Food and Drug Administration in 1997 for treatment of partial seizures, but has also shown significant benefit in the treatment of generalized seizures. Results in adult populations have been more encouraging than in pediatric populations, where more studies are required. VNS is considered a safe and well-tolerated treatment, and serious side effects are rare. DBS is a well-established treatment for several movement disorders, and has a small evidence base for treatment of refractory epilepsy. Stimulation of the anterior nucleus of the thalamus has shown the most encouraging results, where significant decreases in seizure frequency were reported. Other potential targets include the centromedian thalamic nucleus, hippocampus, cerebellum, and basal ganglia structures. Preliminary results on RNS, new-generation implantable neurostimulation devices which stimulate brain structures only when epileptic activity is detected, are encouraging. Overall, implantable neurostimulation devices appear to be a safe and beneficial treatment option for patients in whom medical treatment has failed to adequately control their epilepsy. Further large-scale randomized controlled trials are required to provide a sufficient evidence base for the inclusion of DBS and RNS in clinical guidelines

Functional MRI during hippocampal deep brain stimulation in the healthy rat brain

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS

Axonal Stimulations With a Higher Frequency Generate More Randomness in Neuronal Firing Rather Than Increase Firing Rates in Rat Hippocampus

Deep brain stimulation (DBS) has been used for treating many brain disorders. Clinical applications of DBS commonly require high-frequency stimulations (HFS, ∼100 Hz) of electrical pulses to obtain therapeutic efficacy. It is not clear whether the electrical energy of HFS functions other than generating firing of action potentials in neuronal elements. To address the question, we investigated the reactions of downstream neurons to pulse sequences with a frequency in the range 50–200 Hz at afferent axon fibers in the hippocampal CA1 region of anesthetized rats. The results show that the mean rates of neuronal firing induced by axonal HFS were similar even for an up to fourfold difference (200:50) in the number and thereby in the energy of electrical pulses delivered. However, HFS with a higher pulse frequency (100 or 200 Hz) generated more randomness in the firing pattern of neurons than a lower pulse frequency (50 Hz), which were quantitatively evaluated by the significant changes of two indexes, namely, the peak coefficients and the duty ratios of excitatory phase of neuronal firing, induced by different frequencies (50–200 Hz). The findings indicate that a large portion of the HFS energy might function to generate a desynchronization effect through a possible mechanism of intermittent depolarization block of neuronal membranes. The present study addresses the demand of high frequency for generating HFS-induced desynchronization in neuronal activity, which may play important roles in DBS therapy

A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy

Introduction : Over the last decade, deep brain stimulation (DBS) has emerged as a possible therapy for refractory epilepsy patients. Different intracerebral targets have been targeted, including remote network structures (e.g. the anterior thalamic nucleus, the centromedian thalamic nucleus, the subthalamic nucleus, the caudate nucleus and the cerebellum) and the ictal onset zone. The latter can be approached by either continuous or responsive stimulation. In this abstract we present our long-term results with continuous mesial temporal lobe (MTL) DBS for MTL epilepsy. Methods : Since 2001, 11 patients with refractory MTL complex partial seizures with or without secondary generalisation underwent uni-or bilateral MTL DBS depending on seizure onset localisation as determined by invasive video-EEG monitoring. When unilateral MTL DBS failed to decrease seizures with >90% after 3 years of stimulation, a switch to bilateral MTL DBS was proposed. Results : After a mean follow-up of 8.5 years, 3/11 patients are seizure free for > 36 months. 3/11 patient have a >90 % reduction in seizure frequency; 2/11 patients have a reduction in seizure frequency of 50-90 %; 1/11 patient has a reduction in seizure frequency of 30-50%; two patients are considered non-responders. Patients with a focal unilateral ictal onset (4/11), all of them experiencing a > 90% seizure frequency reduction, responded better than those with a regional unilateral (5/11) or bilateral ictal onset (2/11). None of the patients reported permanent symptomatic side effects. Regarding the chronic stimulation protocol, 4 relevant assessments were made. 1) Augmenting output voltage mostly did not affect seizure frequency, but in three cases it did. 2) In 5/6 patients in whom unilateral DBS failed to decrease seizure frequency with >90% after 2.5 to 3 years, bilateral DBS was started resulting in improved seizure control in 3/5 patients (> 90% reduction or seizure free). 3) In 4/5 patients in whom day-night cycling (DBS off between 0 and 6 am) was introduced after a stable frequency reduction had been reached, this did not affect seizure frequency. 4) In 7 patients, DBS was switched off during at least a month. This was associated with an immediate or delayed increased seizure frequency in 4/7 patients, did not affect seizure frequency in 2/7 patients and coincided with seizure freedom in 1/7 patient. Discussion : This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS in MTL structures for patients with refractory medial temporal lobe epilepsy. In >50% of patients, a seizure frequency reduction of at least 90% has been reached. Patients with unilateral focal ictal onset seem to respond best. After failure of unilateral DBS, bilateral stimulation can improve results and therefore should be considered. Weaknesses of this study include the open study design and – allthough until today no larger patient series has been published – the small number of patients

A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy

In this study, we present long-term results from patients with medial temporal lobe (MTL) epilepsy treated with deep brain stimulation (DBS). Since 2001, 11 patients (8M) with refractory MTL epilepsy underwent MTL DBS. When unilateral DBS failed to decrease seizures by > 90%, a switch to bilateral MTL DBS was proposed. After a mean follow-up of 8.5 years (range: 67-120 months), 6/11 patients had a >= 90% seizure frequency reduction with 3/6 seizure-free for > 3 years; three patients had a 40%-70% reduction and two had a < 30% reduction. In 3/5 patients switching to bilateral DBS further improved outcome. Uni-or bilateral MTL DBS did not affect neuropsychological functioning. This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS for MTL epilepsy. In more than half of the patients, a seizure frequency reduction of at least 90% was reached. Bilateral MTL DBS may herald superior efficacy in unilateral MTL epilepsy

Minimally invasive therapies for the brain using magnetic particles

Delivering a therapy with precision, while reducing off target effects is key to the success of any novel therapeutic intervention. This is of most relevance in the brain, where the preservation of surrounding healthy tissue is crucial in reducing the risk of cognitive impairment and improving patient prognosis. Our scientific understanding of the brain would also benefit from minimally invasive investigations of specific cell types so that they may be observed in their most natural physiological environment. Magnetic particles based techniques have the potential to deliver cellular precision in a minimally invasive manner. When inside the body, Magnetic particles can be actuated remotely using externally applied magnetic fields while their position can be detected non-invasively using MRI. The magnetic forces applied to the particles however, rapidly decline with increasing distance from the magnetic source. It is therefore critical to understand the amount of force needed for a particular application. The properties of the magnetic particle such as the size, shape and magnetic content, as well as the properties of the applied magnetic field, can then be tailored to that application. The aim of this thesis was to develop magnetic particle based techniques for precise manipulation of cells in the brain. Two different approaches were explored, utilising the versatile nature of magnetic actuation for two different applications. The first approach uses magnetic nanoparticles to mechanically stimulate a specific cell type. Magnetic particles conjugated with the antibody ACSA-1 would selectively bind to astrocytes to evoke the controlled release of ATP and induce a calcium flux which are used for communication with neighbouring cells. This approach allows for the investigation into the role of astrocytes in localised brain regions using a naturally occurring actuation process (mechanical force) without effecting their natural environment. The second approach uses a millimetre sized magnetic particle which can be navigated through the brain and ablate localised regions of cells using a magnetic resonance imaging system. The magnetic particle causes a distinct contrast in MRI images, allowing for precise detection of its location so that it may be iteratively guided along a pre-determined path to avoid eloquent brain regions. Once at the desired location, an alternating magnetic field can be applied causing the magnetic particle to heat and deliver controllable, well defined regions of cell death. The forces needed for cell stimulation are orders of magnitude less than the forces needed to guide particles through the brain. Chapters 4 and 5 use external magnets to deliver forces in the piconewton range. While stimulation was demonstrated in small animals, scaling up this technique to human proportions remains a challenge. Chapters 6 and 7 use a preclinical MRI system to generate forces in the millinewton range, allowing the particle to be moved several centimetres through the brain within a typical surgical timescale. When inside the scanner, an alternating magnetic field causes the particle to heat rapidly, enabling the potential for multiple ablations within a single surgery. For clinical translation of this technique, MRI scanners would require a dedicated propulsion gradient set and heating coil

MikroRNA-Regulation bei verschiedenen antikonvulsiven und antiepileptogenen elektrischen Hirnstimulationsparadigmen

Hintergrund: Weltweit leiden etwa 50 Millionen Menschen unter Epilepsie. Bis zu 80 % der Patienten mit der häufigen mesialer Temporallappenepilepsie (mTLE) sind resistent gegen pharmakologische Behandlung. Viele von ihnen können nicht durch einen resektiven epilepsiechirurgischen Eingriff geheilt werden. Für diese Patienten ist eine tiefe Hirnstimulation (deep brain stimulation; DBS) eine alternative Behandlungsmöglichkeit. Die Wirkmechanismen der DBS sind nur unzureichend verstanden. MikroRNAs (miRNAs) sind kleine, einzelsträngige RNAs, die die Proteinsynthese auf der Ebene der messenger RNA (mRNA) regulieren. Es wurde festgestellt, dass zahlreiche miRNAs bei experimenteller und menschlicher Epilepsie reguliert sind. DBS bei Parkinson-Patienten ist mit veränderter miRNA-Expression im Blut assoziiert. Wir haben verschiedene Ziele und Paradigmen der DBS in einem Rattenmodell der mTLE getestet, um Stimulationsparadigmen zu identifizieren, die die Epileptogenese inhibieren oder zu einer Anfallsreduktion bei manifester Epilepsie führen. Anschließend haben wir die miRNA-Expression im Hippokampus nach DBS mit dem effektivsten Paradigma untersucht. Methoden: Wir haben ein mTLE-Modell bei Ratten basierend auf elektrischer Stimulation des Tractus perforans (perforant pathway stimulation; PPS) verwendet. Stimulationselektroden wurden in den PP implantiert, und Ableitelektroden wurden in den Gyrus dentatus (DG) implantiert. Nach einer Woche wurde der PP an zwei aufeinanderfolgenden Tagen für 30 Minuten und am dritten Tag für 8 Stunden stimuliert. Die Tiere entwickelten innerhalb von 12 bis 34 Tagen nach der Stimulation spontane Anfälle. Die antiepileptogene und antikonvulsive Wirksamkeit der DBS vier verschiedener Ziele wurde untersucht: des PP, der Fimbria-Fornix-Formation (FF), des DG und der ventralen hippokampalen Kommissur (VHC). Die Stimulation wurde für eine oder zwei Wochen beginnend einen Tag nach dem letzten PPS angewendet, um einen antiepileptogenen Effekt zu untersuchen, oder nach dem ersten spontanen Anfall, um einen krankheitsmodifizierenden Effekt zu testen. Es wurden drei verschiedene Stimulationsparadigmen verwendet: 130 Hz und 0,1 V, 5 Hz und 2 V oder 1 Hz und 1 V. Wir haben die miRNA-Expression im Hippokampus unmittelbar nach DBS und nach 97 Tagen kontinuierlichem Video-EEG-Monitoring gemessen. Dafür wurde eine Sequenzierung inhibitions-kompetenter miRNAs im Hippokampus durchgeführt und mit Kontrollratten verglichen, die nicht mit DBS behandelt wurden. Ergebnisse: Kein DBS-Paradigma verringerte die Anfallsfrequenz bei Ratten, die bereits Epilepsie entwickelt hatten. Eine zweiwöchige DBS der VHC mit 1 Hz und 1 V verlängerte die Latenzzeit im PPS-Modell signifikant von 19 (± 11) auf 56 (± 23) Tage. Die Expression von 8 miRNAs war unmittelbar nach DBS signifikant reguliert. Fünf miRNAs (miRNA-129-5p, miRNA-379-3p, miRNA-410-3p, miRNA-431 und miRNA-433-3p) waren in der Kontrollgruppe nach 97 Tagen signifikant hochreguliert, zeigten jedoch keine Veränderungen in der mit DBS behandelten Gruppe. Schlussfolgerung: Keines der getesteten Paradigmen wirkte antikonvulsiv. Die LFS der VHC hatte eine antiepileptogene Wirkung. Die antiepileptogene VHC-Stimulation führte zu einer akuten Expressionsänderung von 8 miRNAs und hemmte die PPS-induzierte Langzeitveränderungen von 5 miRNAs. Diese miRNAs sind Kandidaten für eine in vivo-Manipulation zur Hemmung der Epileptogenese