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  • Fractionating the Neurocognitive Mechanisms Underlying Working Memory: Independent Effects of Dopamine and Parkinson's Disease.

    28 January 2018

    Deficits in working memory (WM) in Parkinson's disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter-resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time.

  • Apathy in rapid eye movement sleep behaviour disorder is common and under-recognized.

    21 February 2018

    BACKGROUND AND PURPOSE: Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population. METHODS: Eighty-eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated. RESULTS: A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy. CONCLUSIONS: Apathy is common in RBD and is underestimated by a single self-report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.

  • Fundamental bound on the persistence and capacity of short-term memory stored as graded persistent activity.

    5 February 2018

    It is widely believed that persistent neural activity underlies short-term memory. Yet, as we show, the degradation of information stored directly in such networks behaves differently from human short-term memory performance. We build a more general framework where memory is viewed as a problem of passing information through noisy channels whose degradation characteristics resemble those of persistent activity networks. If the brain first encoded the information appropriately before passing the information into such networks, the information can be stored substantially more faithfully. Within this framework, we derive a fundamental lower-bound on recall precision, which declines with storage duration and number of stored items. We show that human performance, though inconsistent with models involving direct (uncoded) storage in persistent activity networks, can be well-fit by the theoretical bound. This finding is consistent with the view that if the brain stores information in patterns of persistent activity, it might use codes that minimize the effects of noise, motivating the search for such codes in the brain.

  • Amiloride does not protect retinal nerve fibre layer thickness in optic neuritis in a phase 2 randomised controlled trial.

    20 December 2017

    BACKGROUND: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC). OBJECTIVE: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON). METHODS: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( , NCT 01802489). RESULTS: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer. CONCLUSION: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

  • Spin-history artifact during functional MRI: Potential for adaptive correction.

    17 November 2017

    PURPOSE: Functional magnetic resonance imaging (fMRI) is limited by sensitivity to millimetre-scale head motion. Adaptive correction is a strategy to adjust the imaging plane in response to measured head motion, thereby suppressing motion artifacts. This strategy should correct for motion in all six degrees of freedom and also holds promise for through-plane motion that creates "spin-history" artifact that cannot easily be removed by postprocessing methods. Improved quantitative understanding of the MRI signal behavior associated with spin-history artifact would be useful for implementing adaptive correction robustly. METHODS: A numerical simulation was developed to predict MRI artifact signal amplitude in a single-slice for simple motions, implemented with and without adaptive correction, and compared with experiment by imaging a phantom at 3.0 T. Functional MRI was also performed of a human volunteer to illustrate adaptive correction in the presence of spin-history artifact. RESULTS: Good agreement was achieved between simulation and experimental results. Although time-averaged artifact signal amplitude was observed to correlate linearly with motion speed, artifact time-courses were nonlinearly related to motion waveforms. In addition, experimental results demonstrated effective adaptive correction of spin-history artifact when the phantom underwent complex motions. Adaptive correction during human fMRI suppressed spin-history artifacts and spurious activations associated with task-correlated motion. CONCLUSIONS: Overall, this work suggests that adaptive correction, especially when implemented with minimal lag between motion measurement and scan plane update, may help to expand the populations for which fMRI can be performed robustly.

  • Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data.

    5 February 2018

    Converging evidence suggests that bipolar disorder (BD) is associated with white matter (WM) abnormalities. Meta-analyses of voxel based morphometry (VBM) data is commonly performed using published coordinates, however this method is limited since it ignores non-significant data. Obtaining statistical maps from studies (T-maps) as well as raw MRI datasets increases accuracy and allows for a comprehensive analysis of clinical variables. We obtained coordinate data (7-studies), T-Maps (12-studies, including unpublished data) and raw MRI datasets (5-studies) and analysed the 24 studies using Seed-based d Mapping (SDM). A VBM analysis was conducted to verify the results in an independent sample. The meta-analysis revealed decreased WM volume in the posterior corpus callosum extending to WM in the posterior cingulate cortex. This region was significantly reduced in volume in BD patients in the independent dataset (p=0.003) but there was no association with clinical variables. We identified a robust WM volume abnormality in BD patients that may represent a trait marker of the disease and used a novel methodology to validate the findings.

  • From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France.

    15 February 2018

    This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP.

  • The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial.

    21 February 2018

    BACKGROUND: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. METHODS/DESIGN: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. DISCUSSION: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. TRIAL REGISTRATION:, ID: NCT02790970 . Registered on 30 March 2016.

  • Depression and Violence in Adolescence and Young Adults: Findings From Three Longitudinal Cohorts.

    9 February 2018

    OBJECTIVE: Despite recent research demonstrating associations between violence and depression in adults, links in adolescents are uncertain. This study aims to assess the longitudinal associations between young people's depression and later violent outcomes. METHOD: We used data from three cohorts with different measurements of depression exposures and subsequent violent outcomes. In a Dutch community cohort Research on Adolescent Development And Relationships (RADAR; N = 623) and a population-based British birth cohort Avon Longitudinal Study of Parents and Children (ALSPAC; N = 4,030), we examined the longitudinal links between adolescent depressive symptoms and violent behaviors from age 13 to 17 years. In a total Finnish birth cohort (FBC 1987; N = 57,526), we estimated risk of violent convictions in individuals clinically diagnosed with depression from age 15 to 27 years. RESULTS: During a mean follow-up period of 4 years, the adjusted odds ratio (aOR) of violent behaviors per unit of increase in depressive symptoms was 1.7 (95% CI = 1.2-2.5) in the Dutch RADAR community sample and 1.8 (95% CI = 1.4-2.3) in the British ALSPAC birth cohort. In the FBC 1987 cohort, the aOR of violent convictions was 2.1 (95% CI = 1.7-2.7) among individuals with a depression diagnosis compared with general population controls without depression. All risk estimates were adjusted for family socioeconomic status and previous violence. CONCLUSION: Consistent findings across three longitudinal studies suggest that clinical guidelines should consider recommending risk assessment for violence in young people with depression. The benefits of targeting risk management in subgroups by gender need further investigation.