Anastasia K. Kalpakidou

Functional Neuroanatomy of Executive Function after Neonatal Brain Injury in Adults Who Were Born Very Preterm

Individuals who were born very preterm (VPT; <33 gestational weeks) are at risk of experiencing deficits in tasks involving executive function in childhood and beyond. In addition, the type and severity of neonatal brain injury associated with very preterm birth may exert differential effects on executive functioning by altering its neuroanatomical substrates. Here we addressed this question by investigating with functional magnetic resonance imaging (fMRI) the haemodynamic response during executive-type processing using a phonological verbal fluency and a working memory task in VPT-born young adults who had experienced differing degrees of neonatal brain injury. 12 VPT individuals with a history of periventricular haemorrhage and ventricular dilatation (PVH+VD), 17 VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH), 13 VPT individuals with no history of neonatal brain injury and 17 controls received an MRI scan whilst completing a verbal fluency task with two cognitive loads (‘easy’ and ‘hard’ letters). Two groups of VPT individuals (PVH+VD; n = 10, UPVH; n = 8) performed an n-back task with three cognitive loads (1-, 2-, 3-back). Results demonstrated that VPT individuals displayed hyperactivation in frontal, temporal, and parietal cortices and in caudate nucleus, insula and thalamus compared to controls, as demands of the verbal fluency task increased, regardless of type of neonatal brain injury. On the other hand, during the n-back task and as working memory load increased, the PVH+VD group showed less engagement of the frontal cortex than the UPVH group. In conclusion, this study suggests that the functional neuroanatomy of different executive-type processes is altered following VPT birth and that neural activation associated with specific aspects of executive function (i.e., working memory) may be particularly sensitive to the extent of neonatal brain injury.

Modafinil combined with cognitive training: Pharmacological augmentation of cognitive training in schizophrenia

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

The effects of a single dose of oxytocin on working memory in schizophrenia

Fig. 1. Effects of oxytocin on Digits Backward score. Oxytocin significantly increasedmean Digits Backward score. *Denotes significant difference fromplacebo at p b 0.016. Error bars represent ±1 standard error. Cognitive impairment associated with schizophrenia (CIAS) is related to the functional outcome of the illness. Oxytocin (OT), a “social” neuropeptide, has recently been linked with “non-social” cognition, such as cognitive flexibility, spatial and episodic memory (Chini et al., 2014) and with immediate and short-term verbal memory in schizophrenia (Feifel et al., 2012). Working memory (WM) is a central cognitive deficit of schizophrenia and a target domain for the development of new CIAS treatments (Barch and Smith, 2008). In the present study, we investigated the effects of a single OT dose on WM. We included the Digit Span (DS) as secondary outcomemeasure in a study implemented in our laboratory (Averbeck et al., 2012). DSmeasures twoWM components: a) information storage and maintenance (Digits Forward — DF) and b) information maintenance plus manipulation, i.e. the “executive component” of WM (Digits Backward — DB), which is more sensitive to WM deficits in schizophrenia (Kim et al., 2004). We also included Digit Symbol Coding (DSC), a processing speed test. The design details can be found elsewhere (Averbeck et al., 2012). Briefly, we conducted a double-blind placebo-controlled, crossover study. Twenty-one participants who met DSM-IV criteria for schizophrenia (mean illness duration 15.57 ± 6.61 years, NART IQ 100.79 ± 9.59, education years 12.19 ± 2.7) and were male, 18–50 years old (mean age 38.19 ± 8.04), clinically stable for one year prior to study entry (PANSS total score 58.86 ± 15.13), on atypical (n = 19) or lowdoses of typical (n = 2) antipsychotics (daily mean chlorpromazine equivalent 469.81 ± 351.44) were included in the study and were randomly allocated to a single intranasal dose of 24 IU OT (Syntocinon, Novartis) or saline placebo [n1 = 11 received placebo and n2 = 10 OT during the first visit — 7 or 8 days between the two visits (mean= 7.33 ± 0.48)]. There were no significant differences in demographic and clinical measures between n1 and n2 groups. Testing began 50 min after OT/placebo administration. No adverse events occurred. We used repeated measures ANOVA with drug as the within and order of drug administration as the between subject factor (alpha level = 0.05). Effect sizes were measured using Cohens formula for one sample comparisons (Cohens dz). We found a significant main effect of drug on DB [F (1, 19) = 7.354, p = 0.014] (DB under placebo = 5.38 ± 2.42 and under OT = 5.90 ± 2.55). Post-hoc analysis (paired t-tests, p after Bonferroni correction = 0.016) showed significant DB improvement under OT, irrespective of the visit OT was taken [t (20) =−2.75, p = 0.012, Cohens dz = 0.6] (Fig. 1). No significant order effect [F (1, 19)= 0.814, p= 0.378] or drug × order interaction [F (1, 19) = 1.272, p = 0.273] was found. No significant main effect of drug [F (1, 19) = 0.188, p = 0.669], order [F (1, 19) = 0.968, p = 0.338] or drug × order interaction [F (1, 19) = 1.340, p = 0.066] was

Neural compensation in adulthood following very preterm birth demonstrated during a visual paired associates learning task.

Very preterm birth (VPT; < 33 weeks of gestation) is associated with an increased risk of learning disability, which contributes to more VPT-born children repeating grades and underachieving in school. Learning problems associated with VPT birth may be caused by pathophysiological alterations in neurodevelopment resulting from perinatal brain insult; however, adaptive neuroplastic processes may subsequently occur in the developing preterm brain which ameliorate, to an extent, the potential sequelae of altered neurophysiology. Here, we used functional magnetic resonance imaging (fMRI) to compare neuronal activation in 24 VPT individuals and 22 controls (CT) in young adulthood during a learning task consisting of the encoding and subsequent recognition of repeated visual paired associates. Structural MRI data were also collected and analysed in order to explore possible structure-function associations. Whilst the two groups did not differ in their learning ability, as demonstrated by their capacity to recognize previously-seen and previously–unseen visual pairs, between-group differences in linear patterns of Blood Oxygenation Level Dependant (BOLD) activity were observed across the four repeated blocks of the task for both the encoding and recognition conditions, suggesting that the way learning takes place differs between the two groups. During encoding, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the cerebellum, the anterior cingulate gyrus, the midbrain/substantia nigra, medial temporal (including parahippocampal) gyrus and inferior and superior frontal gyri. During the recognition condition, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the claustrum and the posterior cerebellum. Structural analysis revealed smaller grey matter volume in right middle temporal gyrus in VPT individuals compared to controls, however volume in this region was not significantly associated with functional activation. These results demonstrate that although cognitive task performance between VPT individuals and controls may be comparable on certain measures, differences in BOLD signal may also be evident, some of which could represent compensatory neural processes following VPT-related brain insult.

The Prognosis in Palliative care Study II (PiPS2): study protocol for a multi-centre, prospective, observational, cohort study

BackgroundMore accurate methods of prognostication are likely to lead to improvements in the quality of care of patients approaching the ends of their lives. The Prognosis in Palliative care Scales (PiPS) are prognostic models of survival. The scores are calculated using simple clinical data and observations. There are two separate PiPS models; PiPS-A for patients without blood test results and PiPS-B for patients with blood test results. Both models predict whether a patient is likely to live for “days”, “weeks” or “months” and have been shown to perform as well as clinicians’ estimates of survival. PiPS-B has also been found to be significantly better than doctors’ estimates of survival. We report here a protocol for the validation of PiPS and for the evaluation of the accuracy of other prognostic tools in a new, larger cohort of patients with advanced cancer.MethodsThis is a national, multi-centre, prospective, observational cohort study, aiming to recruit 1778 patients via palliative care services across England and Wales. Eligible patients have advanced, incurable cancer and have recently been referred to palliative care services. Patients with or without capacity are included in the study.The primary outcome is the accuracy of PiPS predictions and the difference in accuracy between these predictions and the clinicians’ estimates of survival; with PiPS-B being the main model of interest. The secondary outcomes include the accuracy of predictions by the Palliative Prognostic Index (PPI), Palliative Performance Scale (PPS), Palliative Prognostic score (PaP) and the Feliu Prognostic Nomogram (FPN) compared with actual patient survival and clinicians’ estimates of survival.A nested qualitative sub-study using face-to-face interviews with patients, carers and clinicians is also being undertaken to assess the acceptability of the prognostic models and to identify barriers and facilitators to clinical use.DiscussionThe study closed to recruitment at the end of April 2018 having exceeded the required sample size of 1778 patients. The qualitative sub-study is nearing completion. This demonstrates the feasibility of recruiting large numbers of participants to a prospective palliative care study.Trial registrationISRCTN13688211 (registration date: 28/06/2016).

26 The prognosis in palliative care ii (PIPS2): recruitment data collected during the first year of a multi-centre, prospective, observational cohort study

Introduction More accurate methods of prognostication are likely to lead to improvements in the quality of care of patients approaching the ends of their lives. The Prognosis in Palliative care Scales (PiPS) predict survival in terms of ‘days’, ‘weeks’ or ‘months’ and have been shown to perform as well as, or better than Clinician Estimates of Survival (CES).1 Aims a) To validate PiPS in a new cohort of patients and b) to evaluate the accuracy of other prognostic tools.2,3 Methods This is a national, multi-centre, prospective, observational cohort study, aiming to recruit 1780 patients via palliative care services (PCS). Eligible patients have advanced, incurable cancer who have recently been referred to PCS. Patients with or without capacity are included in the study. The primary outcome is the accuracy of PiPS predictions and the difference in accuracy between these predictions and the CES. The secondary outcomes include the accuracy of predictions by the Palliative Prognostic Score, Palliative Prognostic Index, Palliative Performance Scale, and the Feliu Prognostic Nomogram compared with actual patient survival and CES. Results Within 10 months of recruitment, 5699 patients were screened across 27 recruiting sites. Of those, 1608 were approached to participate in the study and 940 were recruited (812 patients with and 128 patients without capacity). Updated recruitment figures and a breakdown of the reasons for ineligibility, inability to approach patients and refusal to consent will be presented. Conclusion This study demonstrates the feasibility of recruiting large numbers of participants to a prospective palliative care study. References . Gwilliam B, Keeley V, Todd C, Roberts C, Gittins M, Kelly L, Barclay S, Stone P. Prognosticating in patients with advanced cancer-observational study comparing the accuracy of clinicians’ and patients‘ estimates of survival. Ann Oncol2013;24(2):482–488available from: PM:23028038. . Kim ES, Lee JK, Kim MH, Noh HM, Jin YH.Validation of the prognosis in palliative care study predictor models in terminal cancer patients. Korean J Fam Med2014;35(6):283–294available from: PM:25426276 . Stone PC, Lund S. Predicting prognosis in patients with advanced cancer. AnnOncol2007;18(6):971–976available from: PM:17043092

The Effects of a Combined Intervention for Cognition in Schizophrenia On Cogstate Schizophrenia Battery

Background Cognitive impairment in schizophrenia is a strong predictor of the functional outcome and no effective treatments are available. MATRICS Consensus Cognitive Battery (MCCB) is approved by the FDA as outcome measure for trials of cognitive-enhancing drugs in schizophrenia. CogState Schizophrenia Battery (CSB) provides a briefer cognition assessment with minimal practice effects and a strong correlation between the CSB and MCCB composite scores. We tested the sensitivity of CSB as a cognitive outcome measure in a clinical trial in schizophrenia, where a cognitive-enhancing drug and cognitive training were combined. Methods 49 participants with schizophrenia were enrolled in a double-blind, placebo-controlled study. Participants were randomised to modafinil (200mg/day) or placebo and underwent a cognitive training program for 10 weekdays. CSB was administered twice at baseline to minimise practice effects, at the last day of the intervention and two weeks after the completion of the intervention. Results There was a significant time effect at the end of the intervention on the CSB composite score (p=0.042). There was no significant treatment effect on CSB composite score at the end of the intervention (p=0.686) or at follow up (p=0.120). Conclusions Multiple administrations of CSB were well tolerated by participants. The significant time effects on the composite score may suggest the operation of practice effects. Several factors could have contributed to the lack of treatment effects on CSB, such as the burden of multiple neuropsychological testing in a relatively brief study, the duration of modafinil treatment and also the intensive nature of cognitive training.