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  • Benefits of flexible prioritization in working memory can arise without costs.

    21 May 2018

    Most recent models conceptualize working memory (WM) as a continuous resource, divided up according to task demands. When an increasing number of items need to be remembered, each item receives a smaller chunk of the memory resource. These models predict that the allocation of attention to high-priority WM items during the retention interval should be a zero-sum game: improvements in remembering cued items come at the expense of uncued items because resources are dynamically transferred from uncued to cued representations. The current study provides empirical data challenging this model. Four precision retrocueing WM experiments assessed cued and uncued items on every trial. This permitted a test for trade-off of the memory resource. We found no evidence for trade-offs in memory across trials. Moreover, robust improvements in WM performance for cued items came at little or no cost to uncued items that were probed afterward, thereby increasing the net capacity of WM relative to neutral cueing conditions. An alternative mechanism of prioritization proposes that cued items are transferred into a privileged state within a response-gating bottleneck, in which an item uniquely controls upcoming behavior. We found evidence consistent with this alternative. When an uncued item was probed first, report of its orientation was biased away from the cued orientation to be subsequently reported. We interpret this bias as competition for behavioral control in the output-driving bottleneck. Other items in WM did not bias each other, making this result difficult to explain with a shared resource model. (PsycINFO Database Record

  • Prioritizing Information during Working Memory: Beyond Sustained Internal Attention.

    14 May 2018

    Working memory (WM) has limited capacity. This leaves attention with the important role of allowing into storage only the most relevant information. It is increasingly evident that attention is equally crucial for prioritizing representations within WM as the importance of individual items changes. Retrospective prioritization has been proposed to result from a focus of internal attention highlighting one of several representations. Here, we suggest an updated model, in which prioritization acts in multiple steps: first orienting towards and selecting a memory, and then reconfiguring its representational state in the service of upcoming task demands. Reconfiguration sets up an optimized perception-action mapping, obviating the need for sustained attention. This view is consistent with recent literature, makes testable predictions, and links WM with task switching and action preparation.

  • Feature-based attentional weighting and spreading in visual working memory.

    28 January 2018

    Attention can be directed at features and feature dimensions to facilitate perception. Here, we investigated whether feature-based-attention (FBA) can also dynamically weight feature-specific representations within multi-feature objects held in visual working memory (VWM). Across three experiments, participants retained coloured arrows in working memory and, during the delay, were cued to either the colour or the orientation dimension. We show that directing attention towards a feature dimension (1) improves the performance in the cued feature dimension at the expense of the uncued dimension, (2) is more efficient if directed to the same rather than to different dimensions for different objects, and (3) at least for colour, automatically spreads to the colour representation of non-attended objects in VWM. We conclude that FBA also continues to operate on VWM representations (with similar principles that govern FBA in the perceptual domain) and challenge the classical view that VWM representations are stored solely as integrated objects.

  • Early behavioural facilitation by temporal expectations in complex visual-motor sequences.

    9 May 2018

    In daily life, temporal expectations may derive from incidental learning of recurring patterns of intervals. We investigated the incidental acquisition and utilisation of combined temporal-ordinal (spatial/effector) structure in complex visual-motor sequences using a modified version of a serial reaction time (SRT) task. In this task, not only the series of targets/responses, but also the series of intervals between subsequent targets was repeated across multiple presentations of the same sequence. Each participant completed three sessions. In the first session, only the repeating sequence was presented. During the second and third session, occasional probe blocks were presented, where a new (unlearned) spatial-temporal sequence was introduced. We first confirm that participants not only got faster over time, but that they were slower and less accurate during probe blocks, indicating that they incidentally learned the sequence structure. Having established a robust behavioural benefit induced by the repeating spatial-temporal sequence, we next addressed our central hypothesis that implicit temporal orienting (evoked by the learned temporal structure) would have the largest influence on performance for targets following short (as opposed to longer) intervals between temporally structured sequence elements, paralleling classical observations in tasks using explicit temporal cues. We found that indeed, reaction time differences between new and repeated sequences were largest for the short interval, compared to the medium and long intervals, and that this was the case, even when comparing late blocks (where the repeated sequence had been incidentally learned), to early blocks (where this sequence was still unfamiliar). We conclude that incidentally acquired temporal expectations that follow a sequential structure can have a robust facilitatory influence on visually-guided behavioural responses and that, like more explicit forms of temporal orienting, this effect is most pronounced for sequence elements that are expected at short inter-element intervals.

  • The Cumulative Effects of Predictability on Synaptic Gain in the Auditory Processing Stream.

    30 April 2018

    Stimulus predictability can lead to substantial modulations of brain activity, such as shifts in sustained magnetic field amplitude, measured with magnetoencephalography (MEG). Here, we provide a mechanistic explanation of these effects using MEG data acquired from healthy human volunteers (N = 13, 7 female). In a source-level analysis of induced responses, we established the effects of orthogonal predictability manipulations of rapid tone-pip sequences (namely, sequence regularity and alphabet size) along the auditory processing stream. In auditory cortex, regular sequences with smaller alphabets induced greater gamma activity. Furthermore, sequence regularity shifted induced activity in frontal regions toward higher frequencies. To model these effects in terms of the underlying neurophysiology, we used dynamic causal modeling for cross-spectral density and estimated slow fluctuations in neural (postsynaptic) gain. Using the model-based parameters, we accurately explain the sensor-level sustained field amplitude, demonstrating that slow changes in synaptic efficacy, combined with sustained sensory input, can result in profound and sustained effects on neural responses to predictable sensory streams.SIGNIFICANCE STATEMENT Brain activity can be strongly modulated by the predictability of stimuli it is currently processing. An example of such a modulation is a shift in sustained magnetic field amplitude, measured with magnetoencephalography. Here, we provide a mechanistic explanation of these effects. First, we establish the oscillatory neural correlates of independent predictability manipulations in hierarchically distinct areas of the auditory processing stream. Next, we use a biophysically realistic computational model to explain these effects in terms of the underlying neurophysiology. Finally, using the model-based parameters describing neural gain modulation, we can explain the previously unexplained effects observed at the sensor level. This demonstrates that slow modulations of synaptic gain can result in profound and sustained effects on neural activity.

  • Sleep homeostasis, habits and habituation.

    16 May 2018

    The importance of sleep for behavioural performance during waking is long-established, but the underlying reasons and mechanisms remain elusive. Waking and sleep are associated with changes in the levels of GluA1 AMPAR subunit in synaptic membranes, while studies using genetically-modified mice have identified an important role for GluA1-dependent synaptic plasticity in a non-associative form of memory that underlies short-term habituation to recently experienced stimuli. Here we posit that sleep may play a role in dishabituation, which restores attentional capacity and maximises the readiness of the animal for learning and goal-directed behaviour during subsequent wakefulness. Furthermore we suggest that sleep disturbance may fundamentally change the nature of behaviour, making it more model-free and habitual as a result of reduced attentional capacity.

  • Measuring Sleep in the Intensive Care Unit: A Critical Appraisal of the Use of Subjective Methods.

    15 March 2018

    OBJECTIVES: To collate and appraise the use of subjective measures to assess sleep in the intensive care unit (ICU). DESIGN: A systematic search and critical review of the published literature. DATA SOURCES: Medline, Scopus, and Cumulative Index to Nursing and Allied Health Literature were searched using combinations of the key words "Sleep," "Critical Care," "Intensive Care," and "Sleep Disorders," and this was complemented by hand searching the most recent systematic reviews on related topics. STUDY ELIGIBILITY CRITERIA: Papers were limited to non-gray English-language studies of the adult population, published in the last 10 years. OUTCOME MEASURES: Primary outcomes were the number and categorization of quantitative studies reporting measures of sleep, the number of participants for each data collection method, and a synthesis of related material to appraise the use of survey tools commonly used for sleep measurement in the ICU. RESULTS: Thirty-eight papers reported quantitative empirical data collection on sleep, 17 of which used a primary method of subjective assessment of sleep by the patient or nurse. Thirteen methods of subjective sleep assessment were identified. Many of these tools lacked validity and reliability testing. CONCLUSIONS: Research using questionnaires to assess sleep is commonplace in light of practical barriers to polysomnography or other measures of sleep. A methodologically sound approach to tool development and testing is crucial to gather meaningful data, and this robust approach was lacking in many cases. Further research measuring sleep subjectively in ICU should use the Richards Campbell Sleep Questionnaire, and researchers should maintain a commitment to transparency in describing methods.

  • Investigations into within- and between-subject resting-state amplitude variations.

    15 May 2018

    The amplitudes of spontaneous fluctuations in brain activity may be a significant source of within-subject and between-subject variability, and this variability is likely to be carried through into functional connectivity (FC) estimates (whether directly or indirectly). Therefore, improving our understanding of amplitude fluctuations over the course of a resting state scan and variation in amplitude across individuals is of great relevance to the interpretation of FC findings. We investigate resting state amplitudes in two large-scale studies (HCP and UK Biobank), with the aim of determining between-subject and within-subject variability. Between-subject clustering distinguished between two groups of brain networks whose amplitude variation across subjects were highly correlated with each other, revealing a clear distinction between primary sensory and motor regions ('primary sensory/motor cluster') and cognitive networks. Within subjects, all networks in the primary sensory/motor cluster showed a consistent increase in amplitudes from the start to the end of the scan. In addition to the strong increases in primary sensory/motor amplitude, a large number of changes in FC were found when comparing the two scans acquired on the same day (HCP data). Additive signal change analysis confirmed that all of the observed FC changes could be fully explained by changes in amplitude. Between-subject correlations in UK Biobank data showed a negative correlation between primary sensory/motor amplitude and average sleep duration, suggesting a role of arousal. Our findings additionally reveal complex relationships between amplitude and head motion. These results suggest that network amplitude is a source of significant variability both across subjects, and within subjects on a within-session timescale. Future rfMRI studies may benefit from obtaining arousal-related (self report) measures, and may wish to consider the influence of amplitude changes on measures of (dynamic) functional connectivity.

  • Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.

    17 May 2018

    Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V-VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15-52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.

  • Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

    21 May 2018

    OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.