Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis.

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions.

5-HT2AR and NMDAR psychedelics induce similar hyper-synchronous states in the rat cognitive-limbic cortex-basal ganglia system.

The profound changes in perception and cognition induced by psychedelic drugs are thought to act on several levels, including increased glutamatergic activity, altered functional connectivity and an aberrant increase in high-frequency oscillations. To bridge these different levels of observation, we have here performed large-scale multi-structure recordings in freely behaving rats treated with 5-HT2AR psychedelics (LSD, DOI) and NMDAR psychedelics (ketamine, PCP). While interneurons and principal cells showed disparate firing rate modulations for the two classes of psychedelics, the local field potentials revealed a shared pattern of synchronized high-frequency oscillations in the ventral striatum and several cortical areas.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state.

Dust Monitors in JET with ITER-like Wall for Diagnosis of Mobilized Particles and Co-Deposited Layers.

Silicon plates were installed above the inner and outer divertor of the JET with the ITER-like wall (ILW) after the second and third ILW campaigns to monitor dust generation and deposition with the aim to determine the morphology and content of individual particles and co-deposits, including deuterium content. Particular interest was in metal-based particles: Be, W, steel, Cu. Ex-situ examination after two ILW campaigns was performed by a set of microscopy and ion beam methods including micro-beam nuclear reaction analysis and particle-induced X-ray emission.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia.

L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata.

Verification of multi-structure targeting in chronic microelectrode brain recordings from CT scans.

Background: Large-scale microelectrode recordings offer a unique opportunity to study neurophysiological processes at the network level with single cell resolution. However, in the small brains of many experimental animals, it is often technically challenging to verify the correct targeting of the intended structures, which inherently limits the reproducibility of acquired data.

New Method: To mitigate this problem, we have developed a method to programmatically segment the trajectory of electrodes arranged in larger arrays from acquired CT-images and thereby determine the position of individual recording tips with high spatial resolution, while also allowing for coregistration with an anatomical atlas, without pre-processing of the animal samples or post-imaging histological analyses.

Tremor evaluation using smartphone accelerometry in standardized settings.

Tremor can be highly incapacitating in everyday life and typically fluctuates depending on motor state, medication status as well as external factors. For tremor patients being treated with deep-brain stimulation (DBS), adapting the intensity and pattern of stimulation according the current needs therefore has the potential to generate better symptomatic relief. We here describe a procedure for how patients independently could perform self-tests in their home to generate sensor data for on-line adjustments of DBS parameters.

Differential effects of skilled reaching training on the temporal and spatial organization of somatosensory input to cortical and striatal motor circuits.

It has been hypothesized that to perform sensorimotor transformations efficiently, somatosensory information being fed back to a particular motor circuit is organized in accordance with the mechanical loading patterns of the skin that result from the motor activity generated by that circuit. Rearrangements of sensory information to different motor circuits could in this respect constitute a key component of sensorimotor learning. We here explored whether the organization of tactile input from the plantar forepaw of the rat to cortical and striatal circuits is affected by a period of extensive sensorimotor training in a skilled reaching and grasping task.

Cortical and striatal circuits together encode transitions in natural behavior.

In natural behavior, we fluidly change from one type of activity to another in a sequence of motor actions. Corticostriatal circuits are thought to have a particularly important role in the construction of action sequences, but neuronal coding of a sequential behavior consisting of different motor programs has not been investigated at the circuit level in corticostriatal networks, making the exact nature of this involvement elusive. Here, we show, by analyzing spontaneous self-grooming in rats, that neuronal modulation in motor cortex and dorsal striatum is strongly related to transitions between behaviors.

Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions.

Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson's disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs.

Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease.

Oscillations are a naturally occurring phenomenon in highly interconnected dynamical systems. However, it is thought that excessive synchronized oscillations in brain circuits can be detrimental for many brain functions by disrupting neuronal information processing. Because synchronized basal ganglia oscillations are a hallmark of Parkinson's disease (PD), it has been suggested that aberrant rhythmic activity associated with symptoms of the disease could be used as a physiological biomarker to guide pharmacological and electrical neuromodulatory interventions.

Oscillations in cortico-basal ganglia circuits: implications for Parkinson's disease and other neurologic and psychiatric conditions.

Cortico-basal ganglia circuits are thought to play a crucial role in the selection and control of motor behaviors and have also been implicated in the processing of motivational content and in higher cognitive functions. During the last two decades, electrophysiological recordings in basal ganglia circuits have shown that several disease conditions are associated with specific changes in the temporal patterns of neuronal activity. In particular, synchronized oscillations have been a frequent finding suggesting that excessive synchronization of neuronal activity may be a pathophysiological mechanism involved in a wide range of neurologic and psychiatric conditions.

Significance and Translational Value of High-Frequency Cortico-Basal Ganglia Oscillations in Parkinson's Disease.

The mechanisms and significance of basal ganglia oscillations is a fundamental research question engaging both clinical and basic investigators. In Parkinson's disease (PD), neural activity in basal ganglia nuclei is characterized by oscillatory patterns that are believed to disrupt the dynamic processing of movement-related information and thus generate motor symptoms. Beta-band oscillations associated with hypokinetic states have been reviewed in several excellent previous articles.

On the neuronal circuitry mediating L-DOPA-induced dyskinesia.

With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID.

Ion Microbeam Analyses of Dust Particles and Codeposits from JET with the ITER-Like Wall.

Generation of metal dust in the JET tokamak with the ITER-like wall (ILW) is a topic of vital interest to next-step fusion devices because of safety issues with plasma operation. Simultaneous Nuclear Reaction Analysis (NRA) and Particle-Induced X-ray Emission (PIXE) with a focused four MeV He microbeam was used to determine the composition of dust particles related to the JET operation with the ILW. The focus was on "Be-rich particles" collected from the deposition zone on the inner divertor tile.

A Bit-Encoding Based New Data Structure for Time and Memory Efficient Handling of Spike Times in an Electrophysiological Setup.

Recent neuroscientific and technical developments of brain machine interfaces have put increasing demands on neuroinformatic databases and data handling software, especially when managing data in real time from large numbers of neurons. Extrapolating these developments we here set out to construct a scalable software architecture that would enable near-future massive parallel recording, organization and analysis of neurophysiological data on a standard computer. To this end we combined, for the first time in the present context, bit-encoding of spike data with a specific communication format for real time transfer and storage of neuronal data, synchronized by a common time base across all unit sources.

Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT receptor biased agonists.

Recently, the biased and highly selective 5-HT agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT agonists and reappeared upon co-administration of the antagonist, WAY100635.

Changes in neuronal activity of cortico-basal ganglia-thalamic networks induced by acute dopaminergic manipulations in rats.

The basal ganglia are thought to be particularly sensitive to changes in dopaminergic tone, and the realization that reduced dopaminergic signaling causes pronounced motor dysfunction is the rationale behind dopamine replacement therapy in Parkinson's disease. It has, however, proven difficult to identify which neurophysiological changes that ultimately lead to motor dysfunctions. To clarify this, we have here recorded neuronal activity throughout the cortico-basal ganglia-thalamic circuits in freely behaving rats during periods of immobility following acute dopaminergic manipulations, involving both vesicular dopamine depletion and antagonism of D1 and D2 type dopamine receptors.

Action sequencing in the spontaneous swimming behavior of zebrafish larvae - implications for drug development.

All motile organisms need to organize their motor output to obtain functional goals. In vertebrates, natural behaviors are generally composed of a relatively large set of motor components which in turn are combined into a rich repertoire of complex actions. It is therefore an experimental challenge to investigate the organizational principles of natural behaviors.

A combined segmented anode gas ionization chamber and time-of-flight detector for heavy ion elastic recoil detection analysis.

A dedicated detector system for heavy ion elastic recoil detection analysis at the Tandem Laboratory of Uppsala University is presented. Benefits of combining a time-of-flight measurement with a segmented anode gas ionization chamber are demonstrated. The capability of ion species identification is improved with the present system, compared to that obtained when using a single solid state silicon detector for the full ion energy signal.

Untangling Cortico-Striatal Connectivity and Cross-Frequency Coupling in L-DOPA-Induced Dyskinesia.

We simultaneously recorded local field potentials (LFPs) in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analyzed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex.

Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled.

Systems-level neurophysiological state characteristics for drug evaluation in an animal model of levodopa-induced dyskinesia.

Disorders affecting the central nervous system have proven particularly hard to treat, and disappointingly few novel therapies have reached the clinics in recent decades. A better understanding of the physiological processes in the brain underlying various symptoms could therefore greatly improve the rate of progress in this field. We here show how systems-level descriptions of different brain states reliably can be obtained through a newly developed method based on large-scale recordings in distributed neural networks encompassing several different brain structures.

Design of a high-density multi-channel electrode for multi-structure parallel recordings in rodents.

In neurophysiology, investigating brain connectivity within and between different brain structures is of fundamental importance for understanding nervous system function and its relation to behavior. Yet, parallel recordings in multiple brain structures is highly challenging, especially in rodents, which are most commonly employed in neurophysiological research but rather small in size. In this study, the design and manufacturing of a high-density multi-channel electrode for chronic, multi-structure parallel recordings in rats is presented and exemplified with functional neuronal recordings from 128 recording channels, placed bilaterally in eight different brain structures, in an awake, freely moving animal.