The experiential and neurological underpinnings of spatial working memory representations

It remains contentious how information is stored in visual working memory (vWM), even though it is well established that its capacity is limited. Most models have assumed that information is stored in representations that generalise over features. Distinct features have also been assumed to be stored independent of each other. I will present evidence in this thesis that the precision of spatial recall is not only influenced by the number of objects held in memory, but also their location. Moreover, the configuration of the sample array affects recall of single items, suggesting that vWM depends on both, high-resolution local maps and coarse global, representations. Various strategies may be available to overcome the limited capacity of vWM, for example, by utilizing in long-term memory (LTM). I will demonstrate that recall is improved when spatial data are encoding. On the other hand, statistical regularities in the distribution of the memorised objects' locations do not seem to affect recall. Sleep, known to consolidate LTM, has recently been suggested to improve vWM capacity as well. I will present evidence to show that immediate post-learning sleep plays a crutial role in improvingvWM recall by consolidating landmarks in LTM, without improving overall vWM capacity. vWM depends on a distributed cortical network including Visual, Parietal, Frontal and medial Occipito-Temporal areas, though the precise functional role of each area is yet to be established. I will show that binding spatial to visual features, e.g. location and colour, but not binding non-spatial features, is impaired in a patient with bilateral Lingual gyrus and Parahippocampal cortical lesions. Moreover, these lesions disproportionately affect the maintenance of high-resolution spatial data, but not the binding errors, in vWM over longer delays

Spatial Binding Impairments in Visual Working Memory following Temporal Lobectomy

Disorders of the medial temporal lobe (MTL) adversely affect visual working memory (vWM) performance, including feature binding. It is unclear whether these impairments generalize across visual dimensions or are specifically spatial. To address this issue, we compared performance in two tasks of 13 epilepsy patients, who had undergone a temporal lobectomy, and 15 healthy controls. In the vWM task, participants recalled the color of one of two polygons, previously displayed side by side. At recall, a location or shape probe identified the target. In the perceptual task, participants estimated the centroid of three visible disks. Patients recalled the target color less accurately than healthy controls because they frequently swapped the nontarget with the target color. Moreover, healthy controls and right temporal lobectomy patients made more swap errors following shape than space probes. Left temporal lobectomy patients, showed the opposite pattern of errors instead. Patients and controls performed similarly in the perceptual task. We conclude that left MTL damage impairs spatial binding in vWM, and that this impairment does not reflect a perceptual or attentional deficit

Measurement of brain glutathione with magnetic resonance spectroscopy in Schizophrenia-Spectrum disorders — A systematic review and Meta-Analysis

Oxidative stress may contribute to declining course and poor outcomes in psychosis. However, in vivo Magnetic Resonance Spectroscopy studies yield disparate results due to clinical stage, sample demographics, neuroanatomical focus, sample size, and acquisition method variations. We investigated glutathione in brain regions from participants with psychosis, and the relation of glutathione to clinical features and spectroscopy protocols. Meta-analysis comprised 21 studies. Glutathione levels did not differ between total psychosis patients (N = 639) and controls (N = 704) in the Medial Prefrontal region (k = 21, d = -0.09, CI = -0.28 to 0.10, p = 0.37). Patients with stable schizophrenia exhibited a small but significant glutathione reduction compared to controls (k = 14, d = -0.20, CI = -0.40 to -0.00, p = 0.05). Meta-regression showed older studies had greater glutathione reductions, possibly reflecting greater accuracy related to spectroscopy advancements in more recent studies. No significant effects of methodological variables, such as voxel size or echo time were found. Reduced glutathione in patients with stable established schizophrenia may provide novel targets for precision medicine. Standardizing MRS acquisition methods in future studies may help address discrepancies in glutathione levels. [Abstract copyright: Copyright © 2023 The Author(s)

Quantifying the core deficit in classical schizophrenia

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognised disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role-function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganisation, mental impoverishment, impaired cognition and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from three commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit.Persisting brain disorders are associated with a reduction in Post Motor Beta Rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score.While the symptoms constituting impoverished and disorganised mental activity are dissociable in schizophrenia, nonetheless, the variance that these two symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia

Implementing and Evaluating a National Integrated Digital Registry and Clinical Decision Support System in Early Intervention in Psychosis Services (Early Psychosis Informatics Into Care): Co-Designed Protocol

BACKGROUND: Early intervention in psychosis (EIP) services are nationally mandated in England to provide multidisciplinary care to people experiencing first-episode psychosis, which disproportionately affects deprived and ethnic minority youth. Quality of service provision varies by region, and people from historically underserved populations have unequal access. In other disease areas, including stroke and dementia, national digital registries coupled with clinical decision support systems (CDSSs) have revolutionized the delivery of equitable, evidence-based interventions to transform patient outcomes and reduce population-level disparities in care. Given psychosis is ranked the third most burdensome mental health condition by the World Health Organization, it is essential that we achieve the same parity of health improvements. OBJECTIVE: This paper reports the protocol for the program development phase of this study, in which we aimed to co-design and produce an evidence-based, stakeholder-informed framework for the building, implementation, piloting, and evaluation of a national integrated digital registry and CDSS for psychosis, known as EPICare (Early Psychosis Informatics into Care). METHODS: We conducted 3 concurrent work packages, with reciprocal knowledge exchange between each. In work package 1, using a participatory co-design framework, key stakeholders (clinicians, academics, policy makers, and patient and public contributors) engaged in 4 workshops to review, refine, and identify a core set of essential and desirable measures and features of the EPICare registry and CDSS. Using a modified Delphi approach, we then developed a consensus of data priorities. In work package 2, we collaborated with National Health Service (NHS) informatics teams to identify relevant data currently captured in electronic health records, understand data retrieval methods, and design the software architecture and data model to inform future implementation. In work package 3, observations of stakeholder workshops and individual interviews with representative stakeholders (n=10) were subject to interpretative qualitative analysis, guided by normalization process theory, to identify factors likely to influence the adoption and implementation of EPICare into routine practice. RESULTS: Stage 1 of the EPICare study took place between December 2021 and September 2022. The next steps include stage 2 building, piloting, implementation, and evaluation of EPICare in 5 demonstrator NHS Trusts serving underserved and diverse populations with substantial need for EIP care in England. If successful, this will be followed by stage 3, in which we will seek NHS adoption of EPICare for rollout to all EIP services in England. CONCLUSIONS: By establishing a multistakeholder network and engaging them in an iterative co-design process, we have identified essential and desirable elements of the EPICare registry and CDSS; proactively identified and minimized potential challenges and barriers to uptake and implementation; and addressed key questions related to informatics architecture, infrastructure, governance, and integration in diverse NHS Trusts, enabling us to proceed with the building, piloting, implementation, and evaluation of EPICare. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50177

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial

Background: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. Methods: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. Discussion: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. Trial registration: ISRCTN12682719 registration date 24/11/2020

Fine-Grained, Local Maps and Coarse, Global Representations Support Human Spatial Working Memory

<div><p>While sensory processes are tuned to particular features, such as an object's specific location, color or orientation, visual working memory (vWM) is assumed to store information using representations, which generalize over a feature dimension. Additionally, current vWM models presume that different features or objects are stored independently. On the other hand, configurational effects, when observed, are supposed to mainly reflect encoding strategies. We show that the location of the target, relative to the display center and boundaries, and overall memory load influenced recall precision, indicating that, like sensory processes, capacity limited vWM resources are spatially tuned. When recalling one of three memory items the target distance from the display center was overestimated, similar to the error when only one item was memorized, but its distance from the memory items' average position was underestimated, showing that not only individual memory items' position, but also the global configuration of the memory array may be stored. Finally, presenting the non-target items at recall, consequently providing landmarks and configurational information, improved precision and accuracy of target recall. Similarly, when the non-target items were translated at recall, relative to their position in the initial display, a parallel displacement of the recalled target was observed. These findings suggest that fine-grained spatial information in vWM is represented in local maps whose resolution varies with distance from landmarks, such as the display center, while coarse representations are used to store the memory array configuration. Both these representations are updated at the time of recall.</p></div

Location-probe diminishes the effects of memory load on recall.

<p>(A) Trial structure. When the memory load was three, the target to be recalled was identified by highlighting the location of the two non-target items. When the memory load was one the appearance of the cursor indicated the beginning of the recall period. (B) The error standard deviation is shown as a function of target azimuth, when the memory load is one (in blue) and three (in red), and (C) as a function of target elevation. Along azimuth, the variable error increases monotonically with target eccentricity. Along elevation, however, the variable error shows a peak at eccentricities intermediate between the display center and its boundaries. (D) Recalled targets were systematically displaced outward and downward (in blue) relative to their location in the sample display (in black) when the memory load was one, (E) while they were displaced toward the center of the display when the memory load was three (in red). (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107969#pone.0107969.s001" target="_blank">Figures S1A-C</a>).</p