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. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.

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. Remarkably, the phase differences between structures were close to zero, corresponding to <1 ms delays. Likely, this hypersynchrony has major effects on the integration of information across neuronal systems and we propose that it is a key contributor to changes in perception and cognition during psychedelic drug use. Potentially, similar mechanisms could induce hallucinations and delusions in psychotic disorders and would constitute promising targets for new antipsychotic treatments.

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. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

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. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70-110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

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. Different categories of Be-rich particles were found: co-deposits peeled-off from plasma-facing components (PFC), complex multi-element spherical objects, and solid metal splashes and regular spherical droplets. The fuel content on the two latter categories was at the level of 1 × 1016 at/cm-2 indicating that Be melting and splashing occurred in the very last phase of the second experimental campaign. The splashes adhere firmly to the substrate thus not posing risk of Be dust mobilisation. No tungsten droplets were detected. The only W-containing particles were fragments of tungsten coatings from the divertor tiles.

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. RESULTS: Testing the technical limitations of the developed method, we found that the choice of scanning angle influences the achievable spatial resolution due to shadowing effects caused by the electrodes. However, under optimal acquisition conditions, individual electrode tip locations within arrays with 250 µm inter-electrode spacing were possible to reliably determine. COMPARISON TO EXISTING METHODS: Comparison to a histological verification method suggested that, under conditions where individual wires are possible to track in slices, a 90% correspondence could be achieved in terms of the number of electrodes groups that could be reliably assigned to the same anatomical structure. CONCLUSIONS: The herein reported semi-automated procedure to verify anatomical targeting of brain structures in the rodent brain could help increasing the quality and reproducibility of acquired neurophysiological data by reducing the risk of assigning recorded brain activity to incorrectly identified anatomical locations. DATA AVAILABILITY: The tools developed in this study are freely available as a software package at: https://github.com/NRC-Lund/ct-tools.

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. Importantly, the inertia sensor technology needed exists in any standard smartphone, making the procedure widely accessible. Applying this procedure, we have characterized detailed features of tremor patterns displayed by both Parkinson's disease and essential tremor patients and directly compared measured data against both clinical ratings (Fahn-Tolosa-Marin) and finger-attached inertia sensors. Our results suggest that smartphone accelerometry, when used in a standardized testing procedure, can provide tremor descriptors that are sufficiently detailed and reliable to be used for closed-loop control of DBS.

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. Our data show that the representation of tactile stimuli in terms of both temporal and spatial response patterns changes as a consequence of the training and that spatial changes particularly involve the primary motor cortex. Based on the observed reorganization, we propose that reshaping of the spatiotemporal representation of the tactile afference to motor circuits is an integral component of the learning process that underlies skill acquisition in reaching and grasping.NEW & NOTEWORTHY Sensorimotor transformations are fundamental to the function of the nervous system and determine how patterns of sensory input are converted into appropriate movements. We here investigated the extent to which experience-dependent processes can reshape the organization of somatosensory input feeding into cortico-basal ganglia motor structures. Our data point to a particularly important role for the primary motor cortex in the functional adaptions associated with skilled motor learning.

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. Our data suggest that longer action sequences in rodent grooming behavior emerge from stepwise control of individual behavioral transitions, where future actions are encoded differently depending on current motor state. This state-dependent motor coding was found to differentiate between rare behavioral transitions and as opposed to more habitual sequencing of actions.

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. those related to a subject's motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)-a measure based on the physical acceleration of the head of rats-to the local field potential (LFP) oscillatory power in the 1-80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0-26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0-79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25-40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.

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. We here briefly review the various manifestations of basal ganglia oscillations observed in human subjects and in animal models of PD. In this context, we also review the evidence supporting a pathophysiological role of different oscillations for the suppression of voluntary movements as well as for the induction of excessive motor activity. In light of these findings, it is discussed how oscillations could be used to guide a more precise targeting of dysfunctional circuits to obtain improved symptomatic treatment of PD.

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. We here review the experimental support for this hypothesis primarily in relation to Parkinson's disease but also in relation to dystonia, essential tremor, epilepsy, and psychosis/schizophrenia.

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. Here we focus on faster oscillatory phenomena that have been reported in association with a diverse range of motor states. We review the occurrence of different types of fast oscillations and the evidence supporting their pathophysiological role. We also provide a general discussion on the definition, possible mechanisms, and translational value of synchronized oscillations of different frequencies in cortico-basal ganglia structures. Revealing how oscillatory phenomena are caused and spread in cortico-basal ganglia-thalamocortical networks will offer a key to unlock the neural codes of both motor and non-motor symptoms in PD. In preclinical therapeutic research, recording of oscillatory neural activities holds the promise to unravel mechanisms of action of current and future treatments.

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. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.

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 3He 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. The particles found are composed of a mix of codeposited species up to 120 µm in size with a thickness of 30-40 µm. The main constituents are D from the fusion fuel, Be and W from the main plasma-facing components, and Ni and Cr from the Inconel grills of the antennas for auxiliary plasma heating. Elemental concentrations were estimated by iterative NRA-PIXE analysis. Two types of dust particles were found: (i) larger Be-rich particles with Be concentrations above 90 at% with a deuterium presence of up to 3.4 at% and containing Ni (1-3 at%), Cr (0.4-0.8 at%), W (0.2-0.9 at%), Fe (0.3-0.6 at%), and Cu and Ti in lower concentrations and (ii) small particles rich in Al and/or Si that were in some cases accompanied by other elements, such as Fe, Cu, or Ti or W and Mo.

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. We demonstrate that our architecture can simultaneously handle data from more than one million neurons and provide, in real time (< 25 ms), feedback based on analysis of previously recorded data. In addition to managing recordings from very large numbers of neurons in real time, it also has the capacity to handle the extensive periods of recording time necessary in certain scientific and clinical applications. Furthermore, the bit-encoding proposed has the additional advantage of allowing an extremely fast analysis of spatiotemporal spike patterns in a large number of neurons. Thus, we conclude that this architecture is well suited to support current and near-future Brain Machine Interface requirements.

Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT1A receptor biased agonists.

Recently, the biased and highly selective 5-HT1A 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-HT1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms.

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. Synchronized and rhythmic activities were detected in the form of betaband oscillations in local field potentials and as cortical entrainment of action potentials in several basal ganglia structures. Analyses of the temporal development of synchronized oscillations revealed a spread from cortex to gradually also include deeper structures. In addition, firing rate changes involving neurons in all parts of the network were observed. These changes were typically relatively balanced within each structure, resulting in negligible net rate changes. Animals treated with D1 receptor antagonist showed a rapid onset of hypokinesia that preceded most of the neurophysiological changes, with the exception of these balanced rate changes. Parallel rate changes in functionally coupled ensembles of neurons in different structures may therefore be the first step in a cascade of neurophysiological changes underlying motor symptoms in the parkinsonian state. We suggest that balanced rate changes in distributed networks are possible mechanism of disease that should be further investigated in conditions involving dopaminergic dysfunction.

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. Using the relatively simple locomotion pattern of 10 days old zebrafish larvae we have here characterized the basic organizational principles governing the swimming behavior. Our results show that transitions between different behavioral states can be described by a model combining a stochastic component with a control signal. By dividing swimming bouts into a limited number of categories, we show that similar types of swimming behavior as well as stand-stills between bouts were temporally clustered, indicating a basic level of action sequencing. Finally, we show that pharmacological manipulations known to induce alterations in the organization of motor behavior in mammals, mainly through basal ganglia interactions, have related effects in zebrafish larvae. This latter finding may be of specific relevance to the field of drug development given the growing importance of zebrafish larvae in phenotypic screening for novel drug candidates acting on central nervous system targets.