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.

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.

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.

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.

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.

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. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80-Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the control state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ~10 Hz) across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ~80 Hz.

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. Using this technology, we characterize the neurophysiological states associated with parkinsonism and levodopa-induced dyskinesia in a rodent model of Parkinson's disease together with pharmacological interventions aimed at reducing dyskinetic symptoms. Our results show that the obtained electrophysiological data add significant information to conventional behavioral evaluations and hereby elucidate the underlying effects of treatments in greater detail. Taken together, these results potentially open up for studies of neurophysiological mechanisms underlying symptoms in a wide range of neurological and psychiatric conditions that until now have been very hard to investigate in animal models of disease.

Inferior frontal oscillations reveal visuo-motor matching for actions and speech: evidence from human intracranial recordings.

The neural correspondence between the systems responsible for the execution and recognition of actions has been suggested both in humans and non-human primates. Apart from being a key region of this visuo-motor observation-execution matching (OEM) system, the human inferior frontal gyrus (IFG) is also important for speech production. The functional overlap of visuo-motor OEM and speech, together with the phylogenetic history of the IFG as a motor area, has led to the idea that speech function has evolved from pre-existing motor systems and to the hypothesis that an OEM system may exist also for speech. However, visuo-motor OEM and speech OEM have never been compared directly. We used electrocorticography to analyze oscillations recorded from intracranial electrodes in human fronto-parieto-temporal cortex during visuo-motor (executing or visually observing an action) and speech OEM tasks (verbally describing an action using the first or third person pronoun). The results show that neural activity related to visuo-motor OEM is widespread in the frontal, parietal, and temporal regions. Speech OEM also elicited widespread responses partly overlapping with visuo-motor OEM sites (bilaterally), including frontal, parietal, and temporal regions. Interestingly a more focal region, the inferior frontal gyrus (bilaterally), showed both visuo-motor OEM and speech OEM properties independent of orolingual speech-unrelated movements. Building on the methodological advantages in human invasive electrocorticography, the present findings provide highly precise spatial and temporal information to support the existence of a modality-independent action representation system in the human brain that is shared between systems for performing, interpreting and describing actions.

Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease.

Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method--epidural spinal cord stimulation (SCS)--has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD.

Neural generators of psychogenic seizures: evidence from intracranial and extracranial brain recordings.

Psychogenic seizures (PSs) convincingly mimic seizure phenomena but with no underlying epileptic activity. However, not much is known about their neurophysiological basis. We had the rare opportunity to analyze intracranial brain recordings of PSs occurring besides epileptic seizures (ESs), which identified distinct frequency changes over the parietal cortex. For further validation, we applied topographic frequency analysis to two other patients who presented PSs and ESs during long-term monitoring. The analysis revealed a power decrease in the theta band at the posterior parietal cortex in all three patients during PSs but not during ESs. These changes may reflect disturbed self-referential processing associated with some PSs.

Mechanisms underlying cortical resonant states: implications for levodopa-induced dyskinesia.

A common observation in recordings of neuronal activity from the cerebral cortex is that populations of neurons show patterns of synchronized oscillatory activity. However, it has been suggested that neuronal synchronization can, in certain pathological conditions, become excessive and possibly have a pathogenic role. In particular, aberrant oscillatory activation patterns have been implicated in conditions involving cortical dysfunction. We here review the mechanisms thought to be involved in the generation of cortical oscillations and discuss their relevance in relation to a recent finding indicating that high-frequency oscillations in the cerebral cortex have an important role in the generation of levodopa-induced dyskinesia. On the basis of these insights, it is suggested that the identification of physiological changes associated with symptoms of disease is a particularly important first step toward a more rapid development of novel treatment strategies.

Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations.

The standard pharmacological treatment for Parkinson's disease using the dopamine precursor levodopa is unfortunately limited by gradual development of disabling involuntary movements for which the underlying causes are poorly understood. Here we show that levodopa-induced dyskinesia in hemiparkinsonian rats is strongly associated with pronounced 80 Hz local field potential oscillations in the primary motor cortex following levodopa treatment. When this oscillation is interrupted by application of a dopamine antagonist onto the cortical surface the dyskinetic symptoms disappear. The finding that abnormal cortical oscillations are a key pathophysiological mechanism calls for a revision of the prevailing hypothesis that links levodopa-induced dyskinesia to an altered sensitivity to dopamine only in the striatum. Apart from having important implications for the treatment of Parkinson's disease, the discovered pathophysiological mechanism may also play a role in several other psychiatric and neurological conditions involving cortical dysfunction.

A system for automated tracking of motor components in neurophysiological research.

In the study of motor systems it is often necessary to track the movements of an experimental animal in great detail to allow for interpretation of recorded brain signals corresponding to different control signals. This task becomes increasingly difficult when analyzing complex compound movements in freely moving animals. One example of a complex motor behavior that can be studied in rodents is the skilled reaching test where animals are trained to use their forepaws to grasp small food objects, in many ways similar to human hand use. To fully exploit this model in neurophysiological research it is desirable to describe the kinematics at the level of movements around individual joints in 3D space since this permits analyses of how neuronal control signals relate to complex movement patterns. To this end, we have developed an automated system that estimates the paw pose using an anatomical paw model and recorded video images from six different image planes in rats chronically implanted with recording electrodes in neuronal circuits involved in selection and execution of forelimb movements. The kinematic description provided by the system allowed for a decomposition of reaching movements into a subset of motor components. Interestingly, firing rates of individual neurons were found to be modulated in relation to the actuation of these motor components suggesting that sets of motor primitives may constitute building blocks for the encoding of movement commands in motor circuits. The designed system will, thus, enable a more detailed analytical approach in neurophysiological studies of motor systems.

Alpha band oscillations correlate with illusory self-location induced by virtual reality.

Neuroscience of the self has focused on high-level mechanisms related to language, memory or imagery of the self. However, recent evidence suggests that low-level mechanisms such as multisensory and sensorimotor integration may play a fundamental role in self-related processing. Here we used virtual reality technology and visuo-tactile conflict to study such low-level mechanisms and manipulate where participants experienced their self to be localized (self-location). Frequency analysis and electrical neuroimaging of co-recorded high-resolution electroencephalography revealed body-specific alpha band power modulations in bilateral sensorimotor cortices. Furthermore, alpha power in the medial prefrontal cortex (mPFC) was correlated with the degree of experimentally manipulated self-location. We argue that these alpha oscillations in sensorimotor cortex and mPFC reflect self-location as manipulated through multisensory conflict.

Feeling in control of your footsteps: Conscious gait monitoring and the auditory consequences of footsteps.

A fundamental aspect of the "I" of conscious experience is that the self is experienced as a single coherent representation of the entire, spatially situated body. The purpose of the present study was to investigate agency for the entire body. We provided participants with performance-related auditory cues and induced online sensorimotor conflicts in free walking conditions investigating the limits of human consciousness in moving agents. We show that the control of full-body locomotion and the building of a conscious experience of it are at least partially distinct brain processes. The comparable effects on agency using audio-motor and visuo-motor cues as found in the present and previous agency work may reflect common supramodal mechanisms in conscious action monitoring. Our data may help to refine the scientific criteria of selfhood and are of relevance for the investigation of neurological and psychiatric patients with disturbance of selfhood.