Ulrich G. Hofmann

In vivo monitoring of glial scar proliferation on chronically implanted neural electrodes by fiber optical coherence tomography.

In neural prosthetics and stereotactic neurosurgery, intracortical electrodes are often utilized for delivering therapeutic electrical pulses, and recording neural electrophysiological signals. Unfortunately, neuroinflammation impairs the neuron-electrode-interface by developing a compact glial encapsulation around the implants in long term. At present, analyzing this immune reaction is only feasible with post-mortem histology; currently no means for specific in vivo monitoring exist and most applicable imaging modalities can not provide information in deep brain regions. Optical coherence tomography (OCT) is a well established imaging modality for in vivo studies, providing cellular resolution and up to 1.2 mm imaging depth in brain tissue. A fiber based spectral domain OCT was shown to be capable of minimally invasive brain imaging. In the present study, we propose to use a fiber based spectral domain OCT to monitor the progression of the tissues immune response through scar encapsulation progress in a rat animal model. A fine fiber catheter was implanted in rat brain together with a flexible polyimide microelectrode in sight both of which acts as a foreign body and induces the brain tissue immune reaction. OCT signals were collected from animals up to 12 weeks after implantation and thus gliotic scarring in vivo monitored for that time. Preliminary data showed a significant enhancement of the OCT backscattering signal during the first 3 weeks after implantation, and increased attenuation factor of the sampled tissue due to the glial scar formation.

High-frequency electrical stimulation suppresses cholinergic accumbens interneurons in acute rat brain slices through GABAB receptors

The nucleus accumbens is selected as a surgical target in deep brain stimulation for treating refractory obsessive‐compulsive disorder (OCD). One of the therapeutic benefits of this procedure is that the abnormal hyper‐functioning prefrontal cortex of patients with OCD is restored during stimulation. One hypothesis regarding the mechanism of deep brain stimulation is that the neuronal electrophysiological properties are directly altered by electrical stimulation; another hypothesis assumes that the stimulation induces selective neuron transmitter release, such as γ‐aminobutyric acid (GABA). In this study, we used multi‐electrode arrays with electrode size of 40 × 40 μm to record electrophysiological signals from the large nucleus accumbens neurons in acute rat brain slices while applying electrical stimulation simultaneously. We revealed that high‐frequency stimulation (HFS, 140 Hz) suppressed the spontaneous neuronal firing rate significantly, whereas low‐frequency stimulation (LFS, 10 Hz) did not. Both HFS and LFS have no effect on neuronal firing pattern or on neuronal oscillation synchrony. GABAB receptor antagonism reversed the HFS‐provoked neuronal inhibition, whereas GABAA receptor blockade failed to affect it. The recorded neurons were pharmacologically identified to be cholinergic interneurons. We propose that HFS has a direct suppressive effect on the identified accumbal acetylcholine (ACh) interneurons by enhancing GABA release in the stimulated region. Potentially, suppressed ACh interneurons decrease the disinhibiting function of medium‐sized spiny neurons in the striato‐thalamo‐cortical circuit. This finding might give an indication of the mechanism of the therapeutic effect of HFS in nucleus accumbens on restoring the abnormal hyperactive prefrontal cortex status in OCD.

A robotic assistant for stereotactic neurosurgery on small animals.

This work presents the development and performance analysis of a robotic system for stereotactic neurosurgery on small animals. The system is dedicated to the precise placement of probes in the small animal brain, thus providing an improved framework for brain research.

Cellular Modulation of Polymeric Device Surfaces: Promise of Adult Stem Cells for Neuro-Prosthetics

Minimizing the foreign body response is seen as one critical research strategy for implants especially when designed for immune-privileged organs like the brain. The context of this work is to improve deep brain stimulating devices used in a consistently growing spectrum of psychomotor and psychiatric diseases mainly in form of stiff electrodes. Based on the compliance match hypothesis of biocompatibility we present another step forward using flexible implant materials covered with brain cell-mimicking layers. We covered two types of flexible polyimide films with glandular stem cells derived from pancreatic acini. Using real time-PCR and fluorescent immunocytochemistry we analyzed markers representing various cell types of all three germ layers and stemness. The results demonstrate an unchanged differentiation potential of the polyimide fixated cells as measured by mRNA and protein level. Additionally we developed a fibrinous hydrogel coating to protect them against shear forces upon eventual implantation. By repeating previous analysis and additional metabolism tests for all stages we corroborate the validity of this improvement. Consequently we assume that a stem cell-containing cover may provide a native, fully and actively integrating brain-mimicking interface to the neuropil.

MARS — Motor assisted robotic stereotaxy system

We report on the design, setup and first results of a robotized system for stereotactic neurosurgery. It features three translational and two rotational axes, as well as a motorized MicroDrive, thereby resembling the Zamorano-Duchovny (ZD) design of stereotactic frames (inomed Medizintechnik GmbH). Both rotational axes intersect in one point, the Center of the Arc, facilitating trajectory planning. We used carbon fiber-reinforced plastic to reduce the weight of the system. The robot can be mounted to standard operating tables side rails and can be transported on an operation theatre (OT) instrument table. We discuss the design paradigms, the resulting design and the actual robot. Kinematic calculations for the robot based on the Denavit-Hartenberg (DH) rules are presented. Positioning accuracy of our system is determined using two perpendicular cameras mounted on an industrial robot. The results are compared to a manual ZD system. We found that the robots mean position deviation is 0.231 mm with a standard deviation of 0.076 mm.

Spherical assistant for stereotactic surgery

This contribution reports the development of a novel robotic manipulator for stereotactic surgery on small animals, the spherical assistant for stereotactic surgery (SAS- SU). A kinematic design is deduced based on the surgical task requirements. Forward and inverse kinematics are derived analytically. As the system is required to position medical probes of varying size and shape, details on the calibration for different probe configurations are provided. The kinematic design of the novel manipulator is compared to an existing stereotactic instrument in terms of kinematic accuracy. Results show that the SASSU systems is less sensitive to translational positioning errors induced by changes in the joint variables.

The Double-H Maze: A Robust Behavioral Test for Learning and Memory in Rodents

Spatial cognition research in rodents typically employs the use of maze tasks, whose attributes vary from one maze to the next. These tasks vary by their behavioral flexibility and required memory duration, the number of goals and pathways, and also the overall task complexity. A confounding feature in many of these tasks is the lack of control over the strategy employed by the rodents to reach the goal, e.g., allocentric (declarative-like) or egocentric (procedural) based strategies. The double-H maze is a novel water-escape memory task that addresses this issue, by allowing the experimenter to direct the type of strategy learned during the training period. The double-H maze is a transparent device, which consists of a central alleyway with three arms protruding on both sides, along with an escape platform submerged at the extremity of one of these arms. Rats can be trained using an allocentric strategy by alternating the start position in the maze in an unpredictable manner (see protocol 1; §4.7), thus requiring them to learn the location of the platform based on the available allothetic cues. Alternatively, an egocentric learning strategy (protocol 2; §4.8) can be employed by releasing the rats from the same position during each trial, until they learn the procedural pattern required to reach the goal. This task has been proven to allow for the formation of stable memory traces. Memory can be probed following the training period in a misleading probe trial, in which the starting position for the rats alternates. Following an egocentric learning paradigm, rats typically resort to an allocentric-based strategy, but only when their initial view on the extra-maze cues differs markedly from their original position. This task is ideally suited to explore the effects of drugs/perturbations on allocentric/egocentric memory performance, as well as the interactions between these two memory systems.

Dynamically adjusted, scalable electrical stimulator for exciteable tissue

A scalable current stimulation system is designed to cover a wide range of electrical stimulation paradigms such as those used for deep brain stimulation (DBS) and functional electrical stimulation (FES) with a maximum current requirement of +/-2 mA and +/-15 mA respectively. An improved Howland current source configuration is used for its high output impedance range and also its capability of working with grounded loads. The systems output range can be changed with a GUI based software anytime during the stimulation process. Most mono/bi-phasic waveforms such as rectangular, sawtooth, triangle and sine waves can be chosen with their respective parameter settings like pulse width, interphase time and frequency. The system is also equipped with a bias current regulator for safe stimulation of exciteable tissue.

Modulation of Extracellular Levels of 5-HT in the Caudate Putamen of Freely Moving Rats by High Frequency Stimulation of the Subthalamic Nucleus

Electrical high frequency stimulation (HFS) in the subthalamic nucleus (STN) has been shown to have a thera- peutic effect in several movement disorders. But, debilitating psychiatric effects like depression and suicidality are occa- sionally seen and might be caused by the changes in the serotoninergic activity. Previous studies could show that HFS of the STN results in inhibition of the serotonergic neurons originating in the dorsal raphe nucleus. The aim of this study was to characterize the effect of HFS (124 Hz, 0.5 mA) in the STN, on the extracellular levels of serotonin, dopamine and their metabolites HIAA, DOPAC and HVA in the caudate-putamen (CPu) in conscious and freely moving rats. Extracellular levels of the neurotransmitters and their metabolites were quantified using high performance liquid chromatography with electrochemical detection. Under HFS conditions, a significant reduction in the extracellular levels of serotonin was ob- served. Cessation of HFS showed a recovery back to basal levels. Dopamine levels were not affected, although significant increase of its metabolites DOPAC and HVA were measured. In the case of low frequency stimulation (LFS), levels of se- rotonin and its metabolite HIAA remained unchanged, while the levels of dopamine metabolites, DOPAC and HVA, showed a significant decline. These results demonstrate evidence for a strong linkage between HFS in the STN and reduc- tion of the levels of serotonin in the caudate-putamen, which is likely responsible for psychiatric side effects seen in Park- insonian patients who are treated with STN stimulation.