Sub-anesthetic doses of ketamine increase single cell entrainment in the rat auditory cortex during auditory steady-state response.

BACKGROUND: Understanding the effects of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine on brain function is of considerable interest due to the discovery of its fast-acting antidepressant properties. It is well known that gamma oscillations are increased when ketamine is administered to rodents and humans, and increases in the auditory steady-state response (ASSR) have also been observed. AIMS: To elucidate the cellular substrate of the increase in network activity and synchrony observed by sub-anesthetic doses of ketamine, the aim was to investigate spike timing and regularity and determine how this is affected by the animal's motor state. METHODS: Single unit activity and local field potentials from the auditory cortex of awake, freely moving rats were recorded with microelectrode arrays during an ASSR paradigm. RESULTS: Ketamine administration yielded a significant increase in ASSR power and phase locking, both significantly modulated by motor activity. Before drug administration, putative fast-spiking interneurons (FSIs) were significantly more entrained to the stimulus than putative pyramidal neurons (PYRs). The degree of entrainment significantly increased at lower doses of ketamine (3 and 10 mg/kg for FSIs, 10 mg/kg for PYRs). At the highest dose (30 mg/kg), a strong increase in tonic firing of PYRs was observed. CONCLUSIONS: These findings suggest an involvement of FSIs in the increased network synchrony and provide a possible cellular explanation for the well-documented effects of ketamine-induced increase in power and synchronicity during ASSR. The results support the importance to evaluate different motor states separately for more translational preclinical research.

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model.

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer's Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.

Activity-State Dependent Reversal of Ketamine-Induced Resting State EEG Effects by Clozapine and Naltrexone in the Freely Moving Rat.

Ketamine is a non-competitive N-Methyl-D-aspartate receptor (NMDAR) antagonist used in the clinic to initiate and maintain anaesthesia; it induces dissociative states and has emerged as a breakthrough therapy for major depressive disorder. Using local field potential recordings in freely moving rats, we studied resting state EEG profiles induced by co-administering ketamine with either: clozapine, a highly efficacious antipsychotic; or naltrexone, an opioid receptor antagonist reported to block the acute antidepressant effects of ketamine. As human electroencephalography (EEG) is predominantly recorded in a passive state, head-mounted accelerometers were used with rats to determine active and passive states at a high temporal resolution to offer the highest translatability. In general, pharmacological effects for the three drugs were more pronounced in (or restricted to) the passive state. Specifically, during inactive periods clozapine induced increases in delta (0.1-4 Hz), gamma (30-60 Hz) and higher frequencies (>100 Hz). Importantly, it reversed the ketamine-induced reduction in low beta power (10-20 Hz) and potentiated ketamine-induced increases in gamma and high frequency oscillations (130-160 Hz). Naltrexone inhibited frequencies above 50 Hz and significantly reduced the ketamine-induced increase in high frequency oscillations. However, some frequency band changes, such as clozapine-induced decreases in delta power, were only seen in locomoting rats. These results emphasise the potential in differentiating between activity states to capture drug effects and translate to human resting state EEG. Furthermore, the differential reversal of ketamine-induced EEG effects by clozapine and naltrexone may have implications for the understanding of psychotomimetic as well as rapid antidepressant effects of ketamine.

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.

Effects of a tailored multidisciplinary counselling intervention to support the adjustment process after a traumatic injury: a randomized controlled trial.

PURPOSE: To investigate the efficacy of a tailored counselling intervention for injured workers regarding different aspects of subjective well-being. MATERIALS AND METHODS: Prospective randomized controlled trial with 192 mildly-to-moderately injured workers who were on sick leave for at least 18 weeks and showed a high-risk profile for a complicated rehabilitation process in a screening. Patients were assessed at baseline, 12 and 18 months post-injury. The outcome variables concerned five aspects of subjective well-being (negative feelings, life and job satisfaction, satisfaction related to family and health). Both the control and the experimental group received conventional case management. Participants in the intervention group additionally received tailored workplace interventions and/or mental health counselling sessions. RESULTS: Participants in the intervention group received an average of 2.23 (SD = 6.94) counselling sessions. Both groups showed a significant reduction (mean (95% CI) of negative feelings control group 2.6 (2.3-3.4), intervention group 2.4 (1.6-3.4)), with a significant difference in negative feelings between the groups (p = 0.01). CONCLUSIONS: Our results suggest that a tailored counselling intervention has a modest long-term effect (d = 0.74) on negative feelings for mildly-to-moderately injured workers. However, future studies should evaluate the feasibility of this study's treatment approach.Implications for rehabilitationAccidents and the resulting injuries often cause a wide range of burdens including psychosocial and emotional distress as well as long-time sick leaves.Tailored counselling led to significant reductions of negative feelings in mildly-to-moderately injured workers over time.By showing that even conventional case management can have a beneficial effect on subjective wellbeing, the results of this study reaffirm the holistic biopsychosocial nature of injury rehabilitation.

Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat.

Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

The reproducibility of psychiatric evaluations of work disability: two reliability and agreement studies.

BACKGROUND: Expert psychiatrists conducting work disability evaluations often disagree on work capacity (WC) when assessing the same patient. More structured and standardised evaluations focusing on function could improve agreement. The RELY studies aimed to establish the inter-rater reproducibility (reliability and agreement) of 'functional evaluations' in patients with mental disorders applying for disability benefits and to compare the effect of limited versus intensive expert training on reproducibility. METHODS: We performed two multi-centre reproducibility studies on standardised functional WC evaluation (RELY 1 and 2). Trained psychiatrists interviewed 30 and 40 patients respectively and determined WC using the Instrument for Functional Assessment in Psychiatry (IFAP). Three psychiatrists per patient estimated WC from videotaped evaluations. We analysed reliability (intraclass correlation coefficients [ICC]) and agreement ('standard error of measurement' [SEM] and proportions of comparisons within prespecified limits) between expert evaluations of WC. Our primary outcome was WC in alternative work (WCalternative.work), 100-0%. Secondary outcomes were WC in last job (WClast.job), 100-0%; patients' perceived fairness of the evaluation, 10-0, higher is better; usefulness to psychiatrists. RESULTS: Inter-rater reliability for WCalternative.work was fair in RELY 1 (ICC 0.43; 95%CI 0.22-0.60) and RELY 2 (ICC 0.44; 0.25-0.59). Agreement was low in both studies, the 'standard error of measurement' for WCalternative.work was 24.6 percentage points (20.9-28.4) and 19.4 (16.9-22.0) respectively. Using a 'maximum acceptable difference' of 25 percentage points WCalternative.work between two experts, 61.6% of comparisons in RELY 1, and 73.6% of comparisons in RELY 2 fell within these limits. Post-hoc secondary analysis for RELY 2 versus RELY 1 showed a significant change in SEMalternative.work (- 5.2 percentage points WCalternative.work [95%CI - 9.7 to - 0.6]), and in the proportions on the differences ≤ 25 percentage points WCalternative.work between two experts (p = 0.008). Patients perceived the functional evaluation as fair (RELY 1: mean 8.0; RELY 2: 9.4), psychiatrists as useful. CONCLUSIONS: Evidence from non-randomised studies suggests that intensive training in functional evaluation may increase agreement on WC between experts, but fell short to reach stakeholders' expectations. It did not alter reliability. Isolated efforts in training psychiatrists may not suffice to reach the expected level of agreement. A societal discussion about achievable goals and readiness to consider procedural changes in WC evaluations may deserve considerations.

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.

Work and Health Questionnaire (WHQ): A Screening Tool for Identifying Injured Workers at Risk for a Complicated Rehabilitation.

Purpose Unintentional injuries occur frequently and many of the accident survivors suffer from temporary or permanent disabilities. Although most accident victims recover quickly, a significant fraction of them shows a complicated recovery process and accounts for the majority of disability costs. Thus, early identification of vulnerable persons may be beneficial for compensation schemes, government bodies, as well as for the worker themselves. Here we present the Work and Health Questionnaire (WHQ), a screening tool that is already implemented in the case management process of the Swiss Accident Insurance Fund (Suva). Moreover, we demonstrate its prognostic value for identifying workers at risk of a complicated recovery process. Methods A total of 1963 injured workers answered the WHQ within the first 3 months after their accident. All of them had minor to moderate accidental injuries; severely injured workers were excluded from the analyses. The anonymized individual-level data were extracted from insurance databases. We examined construct validity by factorial analyses, and prognostic validity by hierarchical multiple regression analyses on days of work disability. Further, we evaluated well-being and job satisfaction 18 months post-injury in a subsample of 192 injured workers (9.8 %) Results Factor analyses supported five underlying factors (Job Design, Work Support, Job Strain, Somatic Condition/Pain, and Anxiety/Worries). These subscales were moderately correlated, thus indicating that different subscales measured different aspects of work and health-related risk factors of injured workers. Item analysis and reliability analysis showed accurate psychometric properties. Each subscale was predictive at least for one of the evaluated outcomes 18 months post-injury. Conclusion The WHQ shows good psychometric qualities with high clinical utility to identify injured persons with multiple psychosocial risk factors. Thus, the questionnaire appears to be suitable for exploring different rehabilitation needs among minor to moderate injured workers.

Use of a structured functional evaluation process for independent medical evaluations of claimants presenting with disabling mental illness: rationale and design for a multi-center reliability study.

BACKGROUND: Work capacity evaluations by independent medical experts are widely used to inform insurers whether injured or ill workers are capable of engaging in competitive employment. In many countries, evaluation processes lack a clearly structured approach, standardized instruments, and an explicit focus on claimants' functional abilities. Evaluation of subjective complaints, such as mental illness, present additional challenges in the determination of work capacity. We have therefore developed a process for functional evaluation of claimants with mental disorders which complements usual psychiatric evaluation. Here we report the design of a study to measure the reliability of our approach in determining work capacity among patients with mental illness applying for disability benefits. METHODS/DESIGN: We will conduct a multi-center reliability study, in which 20 psychiatrists trained in our functional evaluation process will assess 30 claimants presenting with mental illness for eligibility to receive disability benefits [Reliability of Functional Evaluation in Psychiatry, RELY-study]. The functional evaluation process entails a five-step structured interview and a reporting instrument (Instrument of Functional Assessment in Psychiatry [IFAP]) to document the severity of work-related functional limitations. We will videotape all evaluations which will be viewed by three psychiatrists who will independently rate claimants' functional limitations. Our primary outcome measure is the evaluation of claimant's work capacity as a percentage (0 to 100 %), and our secondary outcomes are the 12 mental functions and 13 functional capacities assessed by the IFAP-instrument. Inter-rater reliability of four psychiatric experts will be explored using multilevel models to estimate the intraclass correlation coefficient (ICC). Additional analyses include subgroups according to mental disorder, the typicality of claimants, and claimant perceived fairness of the assessment process. DISCUSSION: We hypothesize that a structured functional approach will show moderate reliability (ICC ≥ 0.6) of psychiatric evaluation of work capacity. Enrollment of actual claimants with mental disorders referred for evaluation by disability/accident insurers will increase the external validity of our findings. Finding moderate levels of reliability, we will continue with a randomized trial to test the reliability of a structured functional approach versus evaluation-as-usual.

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.

Attitudes towards evaluation of psychiatric disability claims: a survey of Swiss stakeholders.

QUESTIONS: In Switzerland, evaluation of work capacity in individuals with mental disorders has come under criticism. We surveyed stakeholders about their concerns and expectations of the current claim process. METHODS: We conducted a nationwide online survey among five stakeholder groups. We asked 37 questions addressing the claim process and the evaluation of work capacity, the maximum acceptable disagreement in judgments on work capacity, and its documentation. RESULTS: Response rate among 704 stakeholders (95 plaintiff lawyers, 285 treating psychiatrists, 129 expert psychiatrists evaluating work capacity, 64 social judges, 131 insurers) varied between 71% and 29%. Of the lawyers, 92% were dissatisfied with the current claim process, as were psychiatrists (73%) and experts (64%), whereas the majority of judges (72%) and insurers (81%) were satisfied. Stakeholders agreed in their concerns, such as the lack of a transparent relationship between the experts' findings and their conclusions regarding work capacity, medical evaluations inappropriately addressing legal issues, and the experts' delay in finalising the report. Findings mirror the characteristics that stakeholders consider important for an optimal work capacity evaluation. For a scenario where two experts evaluate the same claimant, stakeholders considered an inter-rater difference of 10%‒20% in work capacity at maximum acceptable. CONCLUSIONS: Plaintiff lawyers, treating psychiatrists and experts perceive major problems in work capacity evaluation of psychiatric claims whereas judges and insurers see the process more positively. Efforts to improve the process should include clarifying the basis on which judgments are made, restricting judgments to areas of expertise, and ensuring prompt submission of evaluations.

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.

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.

Predictors of depressed mood 12 months after injury. Contribution of self-efficacy and social support.

PURPOSE: There is evidence that depressed mood and perception of pain are related in patients with chronic illness. However, how individual resources such as self-efficacy and social support play a role in this association remains unclear. The aim of this study was to investigate the influence of both variables as either moderator or mediator. METHOD: In a longitudinal study, 274 injured workers (M = 43.24 years) were investigated. Data were collected on sociodemographics, depressed mood, pain, social support, and self-efficacy at three months post-injury, and depressed mood one year post-injury. RESULTS: Hierarchical multiple linear regression analyses revealed that pain (ß = 0.14; p < 0.01) and social support (ß = -0.18; p < 0.001) were significant predictors of depressed mood. Self-efficacy moderated the relationship of pain (ß = -0.12; p < 0.05) and depressed mood after one year. Lower self-efficacy in combination with pain had a stronger impact than higher self-efficacy and pain on depressed mood. Social support did not moderate the association. CONCLUSIONS: Self-efficacy for managing pain is important in the development of depressed mood. According to the results of this study, we suggest that the detection of low social support and low self-efficacy might be important in long-term rehabilitation process. IMPLICATIONS FOR REHABILITATION: Risk for depressed mood one year after an accident is high: One in five workers report depressed mood. Protective factors for depressed mood in injured workers needs to be considered in the rehabilitation. Focusing on resources like social support and self-efficacy could be protective against depressed mood. The early detection of low social support and low self-efficacy might be important in long-term rehabilitation processes.

Evaluation of work capacity in Switzerland: a survey among psychiatrists about practice and problems.

QUESTIONS UNDER STUDY: In Switzerland, psychiatric evaluations of work capacity for determining a person's eligibility for disability benefits are being criticised for a lack of transparency and high inter-rater variability. The aims of this study were to learn about the current practice of psychiatrists, to explore possible sources for lack of transparency and variability, and to contrast practice with current professional guidance. METHODS: A national online-survey among psychiatrists who performed five or more evaluations of work capacity per year. Based on discussions with experts and a literature review, we structured questions focusing on reporting on work capacity, the description of a claimant's previous job, and measures of quality assurance. RESULTS: A total of 129 psychiatrists responded (31% of estimated 412 eligible psychiatrists). The majority reported using instructions of the insurers (77%), peer consulting (65%) and process guidelines (51%). They expressed a claimant's work capacity as free text and percentage work capacity (49%), percentage only (23%), or free text only (14%). A total of 13% used instruments to document work capacity. Psychiatrists considered three different interpretations of percentage work capacity as equally applicable. A job description was regarded as mandatory to determine work capacity by 90% but only 26% received it and found it mostly deficient. CONCLUSIONS: The transparency and reliability of Swiss psychiatrists' conclusions on a claimant's work capacity may be reduced by unsystematic reporting, variable interpretation of the percentage work capacity, lack of a detailed job description and insufficient quality control. Education, engagement of insurers and new guidelines might be effective means of implementing improvements.

A structural basis for BRD2/4-mediated host chromatin interaction and oligomer assembly of Kaposi sarcoma-associated herpesvirus and murine gammaherpesvirus LANA proteins.

Kaposi sarcoma-associated herpesvirus (KSHV) establishes a lifelong latent infection and causes several malignancies in humans. Murine herpesvirus 68 (MHV-68) is a related γ2-herpesvirus frequently used as a model to study the biology of γ-herpesviruses in vivo. The KSHV latency-associated nuclear antigen (kLANA) and the MHV68 mLANA (orf73) protein are required for latent viral replication and persistence. Latent episomal KSHV genomes and kLANA form nuclear microdomains, termed 'LANA speckles', which also contain cellular chromatin proteins, including BRD2 and BRD4, members of the BRD/BET family of chromatin modulators. We solved the X-ray crystal structure of the C-terminal DNA binding domains (CTD) of kLANA and MHV-68 mLANA. While these structures share the overall fold with the EBNA1 protein of Epstein-Barr virus, they differ substantially in their surface characteristics. Opposite to the DNA binding site, both kLANA and mLANA CTD contain a characteristic lysine-rich positively charged surface patch, which appears to be a unique feature of γ2-herpesviral LANA proteins. Importantly, kLANA and mLANA CTD dimers undergo higher order oligomerization. Using NMR spectroscopy we identified a specific binding site for the ET domains of BRD2/4 on kLANA. Functional studies employing multiple kLANA mutants indicate that the oligomerization of native kLANA CTD dimers, the characteristic basic patch and the ET binding site on the kLANA surface are required for the formation of kLANA 'nuclear speckles' and latent replication. Similarly, the basic patch on mLANA contributes to the establishment of MHV-68 latency in spleen cells in vivo. In summary, our data provide a structural basis for the formation of higher order LANA oligomers, which is required for nuclear speckle formation, latent replication and viral persistence.

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.