Modeling of a segmented electrode for desynchronizing deep brain stimulation.

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders like Parkinson's disease. The electrodes, implanted in the target area within the human brain, generate an electric field which activates nerve fibers and cell bodies in the vicinity. Even though the different target nuclei display considerable differences in their anatomical structure, only few types of electrodes are currently commercially available. It is desirable to adjust the electric field and in particular the volume of tissue activated around the electrode with respect to the corresponding target nucleus in a such way that side effects can be reduced. Furthermore, a more selective and partial activation of the target structure is desirable for an optimal application of novel stimulation strategies, e.g., coordinated reset neuromodulation. Hence we designed a DBS electrode with a segmented design allowing a more selective activation of the target structure. We created a finite element model (FEM) of the electrode and analyzed the volume of tissue activated for this electrode design. The segmented electrode activated an area in a targeted manner, of which the dimension and position relative to the electrode could be controlled by adjusting the stimulation parameters for each electrode contact. According to our computational analysis, this directed stimulation might be superior with respect to the occurrence of side effects and it enables the application of coordinated reset neuromodulation under optimal conditions.

External trial deep brain stimulation device for the application of desynchronizing stimulation techniques.

In the past decade deep brain stimulation (DBS)-the application of electrical stimulation to specific target structures via implanted depth electrodes-has become the standard treatment for medically refractory Parkinson's disease and essential tremor. These diseases are characterized by pathological synchronized neuronal activity in particular brain areas. We present an external trial DBS device capable of administering effectively desynchronizing stimulation techniques developed with methods from nonlinear dynamics and statistical physics according to a model-based approach. These techniques exploit either stochastic phase resetting principles or complex delayed-feedback mechanisms. We explain how these methods are implemented into a safe and user-friendly device.

Long-lasting desynchronization in rat hippocampal slice induced by coordinated reset stimulation.

In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with a widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude.

Cumulative and after-effects of short and weak coordinated reset stimulation: a modeling study.

We show that the dynamical multistability of a network of bursting subthalamic neurons, caused by synaptic plasticity has a strong impact on the stimulus-response properties when exposed to weak and short desynchronizing stimuli. Intriguingly, such stimuli can reliably shift the network from a stable state with pathological synchrony and connectivity to a stable desynchronized state with down-regulated connectivity. However, unlike in the case of stronger coordinated reset stimulation, after termination of weaker stimulation the network may undergo a transient rebound of synchrony. When the coordinated reset stimulation is even weaker and/or shorter, so that a single stimulation epoch is not effective, the network dynamics and connectivity can still be reshaped in a cumulative manner by repetitive stimulation delivery.

Anti-kindling achieved by stimulation targeting slow synaptic dynamics.

PURPOSE: Different stimulation techniques are introduced which specifically modulate the slow synaptic dynamics in a neuronal network model of the subthalamic nucleus with activity dependent synaptic plasticity. METHODS: A modeling approach is utilized to investigate the effects of the different stimulation techniques. In particular, the short-term and long-term outcome is studied in a mathematical model for a population of bursting STN neurons subject to synaptic plasticity with symmetric spike timing characteristics. In our mathematical model in the absence of stimulation synchronized network states with strong connectivity (modeling disease states) as well as desynchronized states with weak connectivity (modeling healthy states) are stable. RESULTS: We demonstrate that different stimulation techniques induce an anti-kindling by shifting the target population to a weakly connected, desynchronized state. Intriguingly, long-term anti-kindling can even be achieved although during stimulus delivery the neuronal synchrony hardly decreases or even slightly increases. The therapeutic index and the impact of inhibition, calculated to compare the different stimulation techniques, indicate that coordinated rest stimulation might be particularly robust and reliable. CONCLUSIONS: The presented stimulation strategies and the results of our modeling study might have strong implications in the context of deep brain stimulation.

Pneumococcal meningitis during antiviral treatment with interferon and ribavirin in a splenectomized patient with chronic hepatitis C - do not miss vaccination before starting therapy.

We report on a 35-year-old man who developed pneumococcal meningitis while receiving antiviral therapy with interferon (consensus interferon, CIFN) and ribavirin for chronic hepatitis C. Antibiotic therapy was started four days after the onset of symptoms. Unfortunately, the patient developed a persisting right-sided cochlear hearing impairment. Antiviral therapy led to sustained viral response of hepatitis C. At the age of 14 years he had experienced a hemorrhagic shock after a traffic accident, received multiple blood transfusions and undergone a splenectomy. He had not received vaccination against Streptococcus pneumoniae. This case report reminds us that splenectomized patients without previous pneumococcal vaccination should receive such vaccination before immunomodulatory treatment.

Control of spatially patterned synchrony with multisite delayed feedback.

We present an analytical study describing a method for the control of spatiotemporal patterns of synchrony in networks of coupled oscillators. Delayed feedback applied through a small number of electrodes effectively induces spatiotemporal dynamics at minimal stimulation intensities. Different arrangements of the delays cause different spatial patterns of synchrony, comparable to central pattern generators (CPGs), i.e., interacting clusters of oscillatory neurons producing patterned output, e.g., for motor control. Multisite delayed feedback stimulation might be used to restore CPG activity in patients with incomplete spinal cord injury or gait ignition disorders.

Effectively desynchronizing deep brain stimulation based on a coordinated delayed feedback stimulation via several sites: a computational study.

In detailed simulations we present a coordinated delayed feedback stimulation as a particularly robust and mild technique for desynchronization. We feed back the measured and band-pass filtered local filed potential via several or multiple sites with different delays, respectively. This yields a resounding desynchronization in a naturally demand-controlled way. Our novel approach is superior to previously developed techniques: It is robust against variations of system parameters, e.g., the mean firing rate. It does not require time-consuming calibration. It also prevents intermittent resynchronization typically caused by all methods employing repetitive administration of shocks. We suggest our novel technique to be used for deep brain stimulation in patients suffering from neurological diseases with pathological synchronization, such as Parkinsonian tremor, essential tremor or epilepsy.

Stimulus-dependent onset latency of inhibitory recurrent activity.

This paper gives an explanation for the experimentally observed onset latencies of the inhibitory responses that vary from a few milliseconds to hundreds of milliseconds in systems where the conduction delays are only several milliseconds in the feedback pathways. To do this we use a simple mathematical model. The model consists of two delay differential equations (DDE) where the nonlinear relation between the postsynaptic potential and the firing frequency of the neuron population arises from the stoichiometry of the transmitter-receptor kinetics. The parameters of the model refer to the hippocampal feedback system, and the modeling results are compared with corresponding experiments.

Information capacity and pattern formation in a tent map network featuring statistical periodicity.

We provide quantitative support to the observation that lattices of coupled maps are "efficient" information coding devices. It has been suggested recently that lattices of coupled maps may provide a model of information coding in the nervous system because of their ability to create structured and stimulus-dependent activity patterns which have the potential to be used for storing information. In this paper, we give an upper bound to the effective number of patterns that can be used to store information in the lattice by evaluating numerically its information capacity or information rate as a function of the coupling strength between the maps. We also estimate the time taken by the lattice to establish a limiting activity pattern.

Epileptiform activity in a neocortical network: a mathematical model.

A simple mathematical model describing the generation and propagation of epileptiform activity in a cerebral cortical network is presented. The model consists of a system of nonlinear delay differential equations. Physiological properties are taken into account as nonlinear transmission of signals at the synapse, temporal and spatial summation of incoming signals at the soma, active membrane characteristics, and dendritic and axonal propagation times. The influence of the connectivity and the temporal parameters on the oscillatory properties of the model is studied. The computer simulations are in agreement with experimental observations in cortical networks: whereas a weak excitatory or strong inhibitory synaptic connection strength produces a stationary status with short-lasting responses to external stimuli, increases in excitation or decreases in inhibition induce spontaneous and stimulus-evoked rhythmic discharges. Synaptic burst-like activity is observed only for an intermediate range of excitatory and inhibitory connection strengths and external inputs. The form and duration of the bursts can also be controlled by the temporal parameters. The results demonstrate that relatively simple mathematical equations are sufficient to model some of the network properties underlying the generation and propagation of epileptiform activity.

[Procollagen III propeptide. Values in the course of pediatric celiac disease]. / Prokollagen-III-Propeptid. Messungen im Verlauf der kindlichen Zöliakie.

OBJECTIVES: An explanation for an incomplete catch-up growth in children with coeliac disease has not yet been found. The marker of growth procollagen-III-propeptide could possible provide a better understanding of the actual regulation of growth in the situation. METHODS: The investigation was made in children with established coeliac disease (n = 30). A commercial radioimmunoassay was used for the measurement of PC-III-P. RESULTS: A close relationship (r = 0.75; P < 0.0001) was found between height velocity and PC-III-P in serum of coeliac children. There was also a good correlation (r = 0.54; P < 0.001; n = 72) with serum levels of alcaline phosphatase. Only weak correlations were found to insulin-like growth factor I (r = 0.33; P < 0.05; n = 62), to urinary calcium (r = 0.27; P < 0.05; n = 62), and to the maturation of bones (r = 0.25; P < 0.05; n = 54). In accordance with the good correlation between height velocity and PC-III-P normal results were found in normal growing children with coeliac disease. Reduced serum levels of PC-III-P were found in coeliac children who failed to show a complete catch-up growth while on a gluten-free diet. CONCLUSIONS: Gluen challenge, as required for the confirmation of the diagnosis, led to a significant further decrease of the values of PC-III-P. Parallel investigations for IgA endomysium antibodies in serum suggest that besides dietary errors additional factors may impede growth, or in other words that disorders of growth regulation persist in some patients with coeliac disease even under treatment. This assumption will have to be tested by further investigations.

[The ultrastructure of human pituitary adenomas (author's transl)]. / Zur Ultrastruktur menschlicher Hypophysenadenome

34 pituitary adenomas were examined by light and electron microscopical methods. Slices of tumor tissue fixed in formaldehyde or Bouin's solution, respectively, and embeded in paraffin were stained by hematoxylin-eosin, Goldner's method (including Orang G), periodic acid Schiff (PAS) reaction, and in some cases by Herlant's tetrachrom. The ultrastructure was studied using tumor tissue fixed in glutaraldehyde within 1 hour after removal. The adenomas were classified by their light microscopical characteristics as chromophilic or chromophobe tumors. Employing the PAS reaction and Goldner's staining method, 27 adenomas were found to give intense or weak staining reactions. By electron microscopical investigation , all the adenomas studied were seen to contain secretory granules more or less densely packed within the cytoplasm. The number of these granules was strongly correlated with the intensity of the tinctorial properties of the tumor tissue. Out of 11 acidophilic adenomas, 10 were observed consisting of typical STH cells. 4 acromegalic patients were found to possess heavily or poorly granulated STH cell adenomas (two patients in each of these groups). One patient with a clinical history of liver cirrhosis and gynecomastia was observed bearing an acidophilic (and erythrosinophilic) adenomatous hyperplasia of prolactin cells, 13 tumors consisted of cells exhibiting almost weak amphophilic staining properties and secretory granules of 100-250nm diameter, thus resembling cells which have been reported to produced ACTH. One of the patients suffering from these adenomas, showed the clinical signs of M. Cushing. By ultrastructural criterions, 3 adenomas with PAS-positive tumor cells were considered to be composed of gonadotropic cells. Only 7 adenomas were observed which did not give any chromophilic reaction. These tumors consisted of extreme poorly granulated cells which could not be significantly associated with one of the pituitary hormones by their morphological properties. In respect of the abundance of mitochondria, 4 out of the adenomas were designated as oncocytic tumors.