Reward Processing and High-Risk Behaviour in Adolescents with a History of Childhood Abuse

Funding for this study was provided by a Young Investigator Award from the Brain and Behaviour Research Foundation (NARSAD – Grant Number: 18774) awarded to Pia Pechtel. Pia Pechtel reports no biomedical financial interests or potential conflicts of interest.Systematic Literature Review: Abstract Objective: Childhood abuse (CA) is commonly associated with increased frequency of high-risk behaviours (HRB) in adolescence. Similarly, research has highlighted links between CA and blunted responses to reward. To date, little attention has been devoted to examine if altered reward processes may also be linked to increased engagement in HRB. To explore this hypothesis, this systematic review collated research that investigated the relationship among CA, reward processes and HRB. Specifically, the review addressed the question: Are HRB associated with altered reward processes in children and adults with a history of CA? Method: Behavioural and neurobiological studies on CA, reward processing and HRB in children and adults were selected from multidisciplinary and subject-specific databases published prior to the 1st of March 2016. The systematic literature search yielded 271 records with 198 non-duplicated results. Screening of 14 full-text publications led to five eligible studies synthesized in this review. Results: Results confirmed impaired reward learning and increased HRB in those with a history of CA. Associations of blunted anticipatory or consummatory reward processing and HRB in individuals with CA remained inconclusive. Conclusions: Reward learning appears to be associated with CA. Further research is required to explore the relationship between reward processes and HRB. Understanding CA from a neurodevelopment perspective is a critical step to developing effective intervention strategies to reduce HRB. Empirical Paper: Abstract Objective: Following childhood abuse (CA), adolescence often sees the onset of depression and high-risk behaviour (HRB). Despite the prevalence, little is known about underlying neurobiological factors linking CA and HRB. To address this gap, I examined if anticipatory and consummatory reward processing in adolescents with CA predict frequency of HRB, irrespective of depressive symptoms. Methods: Thirty-seven adolescents (M=17.08 years; SD = 1.86) participated in the study: 13 females with CA and current major depressive disorder (MDD), eight females with MDD and no CA, and 16 individuals with no CA and no MDD for comparison (control group). Adolescents completed the Card-Guessing paradigm to assess reward processing, while undergoing a magnetic resonance imaging scan. Neural region-of-interest responses in the striatum and pallidum were assessed during anticipatory and consummatory reward phases. Hierarchical regression models investigated if neural responses to reward were altered based on exposure to CA and if altered neural responses predicted higher use of HRB. Results: Data showed that (1) depressed adolescents engaged more frequently in HRB irrespective of history of CA, (2) anticipatory and consummatory reward processes were not altered based on a history of CA, and (3) blunted activation in right pallidum in anticipation of rewards predicted HRB irrespective of depressive symptoms. Conclusion: Although the current study did not confirm changes in reward processing following CA, blunted reward ‘wanting’ was linked to more frequent HRB. Findings are relevant to theories highlighting the critical role of the pallidum in perceiving cues as rewarding and in initiating goal-directed actions to obtain rewards.Young Investigator Award from the Brain and Behaviour Research Foundation (NARSAD

Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1-mRNA expression in patients with AML and MDS

OBJECTIVE As peripheral blood (PB) Wilm's Tumor 1 (WT1)-mRNA expression is established as MRD-marker during conventional AML chemotherapy, impact of pretransplant WT1 expression remains unclear. Therefore, we aimed to assess prognostic impact of pretransplant WT1 expression on post-transplant outcome in patients with AML/MDS. METHODS In 64 AML/MDS patients, pretransplant WT1 expression was retrospectively analyzed using a standardized assay offering high sensitivity, specificity, and a validated cut-off. Patients were divided into three groups determined by pretransplant remission and WT1 expression. Post-transplant outcome of these groups was compared regarding cumulative incidence of relapse (CIR), relapse-free (RFS), and overall survival (OS). RESULTS Pretransplant forty-six patients (72%) showed hematologic remission, including 21 (46%) MRD-negative and 25 (54%) MRD-positive patients indicated by WT1 expression, while 18 refractory patients (28%) showed active disease. Two-year estimates of post-transplant CIR, RFS, and OS were similar in MRD-positive (61%, 37%, 54%) and refractory patients (70%, 26%, 56%), but significantly inferior compared with MRD-negative patients (10%, 89%, 90%). After multivariable adjustment, pretransplant MRD negativity measured by WT1 expression retained its prognostic impact on CIR (P~=~.008), RFS (P~=~.005), and OS (P~=~.049). CONCLUSIONS PB WT1 expression represents a useful method to estimate pretransplant MRD, which is highly predictable for post-transplant outcome and may help improving peri-transplant management in AML/MDS patients

Emerging ecophenotype: reward anticipation is linked to high-risk behaviours after sexual abuse.

This is the final version. Available from Oxford University Press via the DOI in this record. Adolescents frequently engage in high-risk behaviours (HRB) following childhood sexual abuse (CSA). Aberrant reward processes are implicated in HRB, and their underlying fronto-striatal networks are vulnerable to neurodevelopmental changes during adversity representing a promising candidate for understanding links between CSA and HRB. We examined whether fronto-striatal responses during reward anticipation and feedback (i) are altered in depressed adolescents with CSA compared to depressed, non-abused peers and (ii) moderate the relationship between CSA and HRB irrespective of depression. Forty-eight female adolescents {14 with CSA and depression [CSA +  major depressive disorder (MDD)]; 17 with MDD but no CSA (MDD); 17 healthy, non-abused controls} completed a monetary reward task during functional magnetic resonance imaging. No differences in fronto-striatal response to reward emerged between CSA + MDD and MDD. Critically, high left nucleus accumbens activation during reward anticipation was associated with greater HRB in CSA + MDD compared to MDD and controls. Low left putamen activation during reward feedback was associated with the absence of HRB in CSA + MDD compared to MDD. Striatal reward responses appear to play a key role in HRB for adolescents with CSA irrespective of depression, providing initial support for a CSA ecophenotype. Such information is pivotal to identify at-risk youth and prevent HRB in adolescents after CSA.Brain and Behaviour Research FoundationWellcome TrustNational Institute of Mental HealthNational Institute of Mental Healt

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognised in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine. Since this pathway – the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress it also stands in an unique position to mediate the effects of environmental factors on cognition and behaviour. Targetting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures

Demonstrating test‐retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test‐retest reliability for the three electrophysiological measures selected for a multisite project—Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty‐nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes‐open and eyes‐closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60–100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference‐free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low‐resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test‐retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good‐to‐excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/1/psyp12758_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/2/psyp12758.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/3/psyp12758-sup-0001-suppinfo1.pd

Impact of childhood experience and adult well-being on eating preferences and behaviours

Objectives: To examine the relative contribution of childhood experience, measured by childhood violence and childhood happiness, and adult well-being on adult eating preferences and behaviours, independent of proximal factors such as current deprivation. Design: A cross-sectional, stratified, randomised sample survey using retrospective measures of childhood violence and happiness and self-reported measures of current well-being. Setting: The North West Region of England between September 2012 and March 2013. Participants: Individuals aged 18–95-year-olds from randomly selected households (participation was successful for 90% of eligible households and 78% of the total visited addresses; n=11 243). Outcomes: Dichotomised measures for preference of healthy foods or ‘feel good’ foods and low or high daily fruit and vegetable consumption. Results: After correcting for demographics, combined categories for childhood experience and dichotomised measures of adult well-being were found to be significantly related to adult food preferences and eating behaviours. Participants with unhappy and violent childhoods compared to those with happy and non-violent childhoods had adjusted ORs (95% CI, significance) of 2.67 (2.15 to 3.06, p<0.001) of having low daily fruit and vegetable intake (two or less portions) and 1.53 (1.29 to 1.81, p<0.001) of choosing ‘feel good’ foods over foods which were good for their long term health. Conclusions: Daily intake of fruit and vegetables, linked to non-communicable diseases, and preference for ‘feel good’ foods, linked to obesity, are affected by childhood experience and adult well-being independent of demographic factors. Preventative interventions which support parent–child relationships and improve childhood experience are likely to reduce the development of poor dietary and other health-risk behaviours

A cellular defense memory imprinted by early life toxic stress

Stress exposure early in life is implicated in various behavioural and somatic diseases. Experiences during the critical perinatal period form permanent, imprinted memories promoting adult survival. Although imprinting is widely recognized to dictate behaviour, whether it actuates specific transcriptional responses at the cellular level is unknown. Here we report that in response to early life stresses, Caenorhabditis elegans nematodes form an imprinted cellular defense memory. We show that exposing newly-born worms to toxic antimycin A and paraquat, respectively, stimulates the expression of toxin-specific cytoprotective reporters. Toxin exposure also induces avoidance of the toxin-containing bacterial lawn. In contrast, adult worms do not exhibit aversive behaviour towards stress-associated bacterial sensory cues. However, the mere re-encounter with the same cues reactivates the previously induced cytoprotective reporters. Learned adult defenses require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. Thus, exposure of C. elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses, which do not form imprinted aversive behaviour, but imprint a cytoprotective memory. Our findings identify a novel form of imprinting and suggest that imprinted molecular defenses might underlie various pathophysiological alterations related to early life stress. © 2019, The Author(s)

The effects of juvenile stress on anxiety, cognitive bias and decision making in adulthood:a rat model

Stress experienced in childhood is associated with an increased risk of developing psychiatric disorders in adulthood. These disorders are particularly characterized by disturbances to emotional and cognitive processes, which are not currently fully modeled in animals. Assays of cognitive bias have recently been used with animals to give an indication of their emotional/cognitive state. We used a cognitive bias test, alongside a traditional measure of anxiety (elevated plus maze), to investigate the effects of juvenile stress (JS) on adulthood behaviour using a rodent model. During the cognitive bias test, animals were trained to discriminate between two reward bowls based on a stimulus (rough/smooth sandpaper) encountered before they reached the bowls. One stimulus (e.g. rough) was associated with a lower value reward than the other (e.g. smooth). Once rats were trained, their cognitive bias was explored through the presentation of an ambiguous stimulus (intermediate grade sandpaper): a rat was classed as optimistic if it chose the bowl ordinarily associated with the high value reward. JS animals were lighter than controls, exhibited increased anxiety-like behaviour in the elevated plus maze and were more optimistic in the cognitive bias test. This increased optimism may represent an optimal foraging strategy for these underweight animals. JS animals were also faster than controls to make a decision when presented with an ambiguous stimulus, suggesting altered decision making. These results demonstrate that stress in the juvenile phase can increase anxiety-like behaviour and alter cognitive bias and decision making in adulthood in a rat model