Anatol Kivi

The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease

Depth recordings in patients with Parkinsons disease (PD) have demonstrated prominent oscillatory activity in the beta frequency (13-35 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesized to contribute to bradykinesia, it is unclear to what extent the LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded both LFPs and multi-neuronal activity from microelectrodes inserted into STN in six PD patients (8 sides) during functional neurosurgery. As microelectrodes passed from above STN into STN, there was a pronounced increase in beta frequency band LFP activity. Furthermore, spike-triggered averages of LFP activity suggested that the discharges of neurons in STN were locked to beta oscillations in the LFP. The LFP is therefore likely to represent synchronous activity in populations of neurons in the STN of patients with PD.

Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mm) and whether the experimental activity differs according to the presence of aberrant mossy fibers. We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mm K+. They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250-300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mm K+. In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca2+]o. Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K+-induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.

Pallidal and thalamic deep brain stimulation in myoclonus-dystonia.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus‐dystonia (MD). We investigated short‐ and long‐term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi‐ and VIM‐DBS in MD. Ten MD‐patients (nine ε‐sarcoglycan‐mutation‐positive) were evaluated pre‐ and post‐surgically following continuous bilateral GPi‐ and VIM‐DBS at four time points: presurgical, 6, 12, and as a last follow‐up at a mean of 62.3 months postsurgically, and in OFF‐, GPi‐, VIM‐, and GPi‐VIM‐DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke‐Fahn‐Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL‐scores. MD‐symptoms significantly improved at 6 months post‐surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long‐term evaluation post‐surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long‐lasting stimulation‐related adverse events (AEs) were observed. Both GPi‐ and VIM‐DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation‐induced events of GPi‐DBS in comparison with VIM‐DBS, GPi‐DBS seems to be preferable. Combined GPi‐VIM‐DBS can be useful in cases of incapaciting myoclonus, refractory to GPi‐DBS alone.

Subthalamic gamma activity in patients with Parkinson's disease.

Depth recordings in patients with Parkinsons disease (PD) have demonstrated oscillatory activity in the gamma frequency (60-100 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesised to contribute to movement preparation, it is unclear to what extent these LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the STN in PD patients during functional neurosurgery. Eight sides in seven patients out of 15 sides in 12 patients were identified that had peaks in the gamma band in spectra of LFPs. As microelectrodes descended towards STN, there was a pronounced increase in gamma frequency band LFP activity 1 mm above the line joining the anterior and posterior commissures and 2 mm above the microelectrode defined dorsal border of the STN. Gamma activity dropped again 3 mm below the microelectrode defined dorsal border of the STN. Spike-triggered averages of LFP activity suggested that the discharges of neurons in this region were locked to gamma oscillations in the LFP. Gamma band oscillations in the LFP are therefore likely to represent synchronous activity in populations of neurons in the upper STN and bordering zona incerta of patients with PD.

Alterations of Neuronal Connectivity in Area CA1 of Hippocampal Slices from Temporal Lobe Epilepsy Patients and from Pilocarpine‐Treated Epileptic Rats

Summary: Purpose: Neuronal network reorganization might be involved in epileptogenesis in human and rat limbic epilepsy. Apart from aberrant mossy fiber sprouting, a more wide‐spread fiber rearrangement in the hippocampal formation might occur. Therefore, we studied sprouting in area CA1 because this region is most affected in human temporal lobe epilepsy.

Cellular and network properties of the subiculum in the pilocarpine model of temporal lobe epilepsy

The subiculum was recently shown to be crucially involved in the generation of interictal activity in human temporal lobe epilepsy. Using the pilocarpine model of epilepsy, this study examines the anatomical substrates for network hyperexcitability recorded in the subiculum. Regular‐ and burst‐spiking subicular pyramidal cells were stained with fluorescence dyes and reconstructed to analyze seizure‐induced alterations of the dendritic and axonal system. In control animals burst‐spiking cells outnumbered regular‐spiking cells by about two to one. Regular‐ and burst‐spiking cells were characterized by extensive axonal branching and autapse‐like contacts, suggesting a high intrinsic connectivity. In addition, subicular axons projecting to CA1 indicate a CA1‐subiculum‐CA1 circuit. In the subiculum of pilocarpine‐treated rats we found an enhanced network excitability characterized by spontaneous rhythmic activity, polysynaptic responses, and all‐or‐none evoked bursts of action potentials. In pilocarpine‐treated rats the subiculum showed cell loss of about 30%. The ratio of regular‐ and burst‐spiking cells was practically inverse as compared to control preparations. A reduced arborization and spine density in the proximal part of the apical dendrites suggests a partial deafferentiation from CA1. In pilocarpine‐treated rats no increased axonal outgrowth of pyramidal cells was observed. Hence, axonal sprouting of subicular pyramidal cells is not mandatory for the development of the pathological events. We suggest that pilocarpine‐induced seizures cause an unmasking or strengthening of synaptic contacts within the recurrent subicular network. J. Comp. Neurol. 483:476–488, 2005.

Deep brain stimulation in dystonia.

Abstract. Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinsons disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinsons disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Effects of barium on stimulus induced changes in extracellular potassium concentration in area CA1 of hippocampal slices from normal and pilocarpine-treated epileptic rats

Laminar profiles of rises in [K+]o and slow field potentials induced by alvear stimulation were recorded in area CA1 of hippocampal slices from control and pilocarpine-treated rats in absence and presence of Ba2+. In control animals, Ba2+ augmented rises in [K+]o in stratum pyramidale (SP) as well as in stratum radiatum (SR). In pilocarpine-treated animals an augmentation of rises in [K+]o was restricted to SP and its immediate vicinity. Moreover, the effect of Ba2+ in SP was small or missing in eight out of 15 slices of pilocarpine-treated animals. In these slices laminar profiles of rises in [K+]o were not affected by Ba2+. It is suggested that spatial K+-buffering is reduced in area CA1 of epileptic animals.

Effects of barium on stimulus-induced changes in [K+]o and field potentials in dentate gyrus and area CA1 of human epileptic hippocampus

The effects of barium on stimulus-induced rises in [K+]o were studied in the dentate gyrus (DG) and area CA1 of human hippocampal slices. Rises in [K+]o elicited by repetitive stimulation of the hilus, stratum moleculare, alveus, or stratum radiatum were dependent on stimulus intensity and frequency. Barium augmented rises in [K+]o in the DG by about 120% but failed to do so in area CA1. In both DG and area CA1 barium had no effects on population spikes whereas stimulus-induced slow field potentials were reduced. Since barium interferes with K+ uptake and redistribution by blocking leak conductances and inwardly-rectifying currents in astrocytes, our findings suggest that glial cells in the sclerotic hippocampal area CA1 may contribute less to K+ regulation.

Acute cell damage after low Mg2+-induced epileptiform activity in organotypic hippocampal slice cultures.

Upon perfusion with Mg2+-free artificial cerebrospinal fluid (ACSF) organotypic hippocampal slice cultures develop seizure-like events and tonic recurrent discharges in which areas CA3 and CA1 and, in contrast to acute slices, also the dentate gyrus (DG) participate. Using the fluorescent dye propidium iodide (PI) we show that sustained epileptic activity causes cell death in the DG and pyramidal cell layer particularly evident in the granule cell layer of the DG. This correlates with the decrease of the electrophysiological responses to hilar stimulation. Interestingly, perfusion with carbogenated serum-free ACSF also induces some cell death which is, however, mild compared with low magnesium treated slice cultures.