Altered hippocampal function in major depression despite intact structure and resting perfusion

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation. Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed. Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow. Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression

Allocentric memory and hippocampal function

PhD ThesisApproximately one-third of trauma patients are coagulopathic on arrival to the emergency department. Acute traumatic coagulopathy and systemic inflammatory responses are serious secondary consequences of severe trauma and are linked to increased morbidity and mortality. Early tissue hypoxia is a major component in the aetiology of both complications. New resuscitation strategies are aimed at improving tissue oxygenation in the pre-hospital phase, and may attenuate coagulopathy and inflammatory sequelae. This is of particular importance in military personnel who suffer complex injuries, often from blast exposure, and may have extended evacuation times. This thesis evaluates the effect of a novel hybrid (NH) resuscitation strategy on coagulation and inflammation. Terminally anaesthetised pigs were randomised to one of two injury strands of haemorrhage +/- blast injury; initially resuscitated with 0.9% Saline to a hypotensive systolic blood pressure of 80mmHg for one hour. This was followed by either a return to a normotensive pressure (110mmHg) (NH) or a continuation at the hypotensive level. Over both injury strands NH significantly reduced Prothrombin Time, PT (mean proportion of baseline: 1.40±0.05 vs. 1.80±0.09; p=0.001) and interleukin-6 (IL6) levels (mean 1106±153 vs. 429±79 pg/ml; p=0.001) compared to the hypotensive groups. PT was positively correlated with IL6 (p=0.002) and base deficit (p=0.0004). These findings indicate that improving tissue oxygenation reduces the coagulation derangement and the pro-inflammatory response. No difference in coagulopathy was found between injury strands although blast did cause greater inflammation. Early identification of coagulopathic casualties is essential and a separate feasibility field study was preformed to assess the use of thromboelastometry in a deployed military hospital, evaluating the degree of coagulopathy in battlefield casualties and to monitor the coagulation status during the resuscitation process. In conclusion, NH attenuated the acute traumatic coagulopathy and inflammatory responses and therefore should be considered when an extended casualty evacuation is enforced

The link between learning performance, immobility in the forced swim test, and hippocampal glia

Aim: To obtain maximal translational insights from animal models of depression, we need to know the meaning of behavioral parameters of animal models. The extent of construct and face validities of behavioral despair in the form of behavioral immobility in forced swim test (FST) is disputed. In this study, learning performance in a dual solution T-Maze and immobility on the 2nd day of FST was compared to shed light on this debate. Furthermore, we aimed to inspect the relationship between hippocampal glial densities and behaviors observed. Method: Twelve adult male Sprague Dawley rats were tested in the dual-solution T-Maze and in FST. Subsequently, hippocampal slices were obtained, astrocyte and microglia cells were stained, and the densities were calculated for each subject. Results: The rats utilized different learning strategies to solve the T-Maze. But irrespective of strategy, the rats that exhibited an overall efficiency in their learning performance, remained immobile for longer durations on the 2nd day of the FST. No significant relationship was detected between hippocampal microglia and behavioral indices in T-Maze and FST. However, we detected a significant positive correlation with CA1 astrocyte density and T-Maze learning and dentate gyrus CA1 astrocyte density and headshake behavior in FST. Conclusions: The subjects showing a better cognitive performance in the T-Maze were immobile longer in the FST. This observation raises doubts about immobility as depression index and posits that it might reflect better learning. Our results also suggest that hippocampal glia cell types are differentially involved in cognition and affect

Allocentric spatial memory performance predicts intrusive memory severity in posttraumatic stress disorder

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterised by distressing trauma-related memories. According to the dual representation theory, intrusive memories arise from strengthened egocentric encoding and a poor contextual encoding, with spatial context requiring allocentric processing. Contextualization of mental imagery is proposed to be formed hierarchically through the ventral visual stream (VVS) to the hippocampal formation. Here, we tested this notion by investigating whether neuronal aberrations in structures of the VVS or in the hippocampus, as well as allocentric memory performance are associated with intrusive memory severity. METHODS: The sample comprised 33 women with PTSD due to childhood trauma. Allocentric memory performance was measured with the virtual Town Square Task and T1-weighted images acquired on a 3T Siemens Scanner. Intrusive memories were evoked by presenting an audio script describing parts of their trauma (script-driven imagery). RESULTS: Using hierarchical linear regression analysis, we found a significant association between lower intrusive memory severity and higher allocentric spatial memory, controlling for age, working memory, and general visuospatial ability. No significant association was found between cortical thickness of VVS structures, hippocampal volume and intrusive memory severity. Post hoc exploratory analyses revealed a negative correlation between years since index trauma and left hippocampal volume. LIMITATIONS: Our results are based on correlational analyses, causality cannot be inferred. CONCLUSION: This study supports the dual representation theory, which emphasizes the role of allocentric spatial memory for the contextualization of mental imagery in PTSD. Clinical implications are discussed

Tree shrews (Tupaia belangeri) exhibit novelty preference in the novel location memory task with 24-h retention periods

Novelty preference is pervasive in mammalian species, and describes an inherent tendency to preferentially explore novelty. The novel location memory task studied here assesses the ability of animals to form accurate memories of a spatial configuration, consisting of several identical objects placed within an arena. Tree shrews were first familiarized with a particular object configuration during several sessions, and then an object was displaced during a test session. Tree shrews exhibited enhanced exploration when confronted with this novel configuration. The most reliable indicator associated with novelty preference was an enhancement in directed exploration towards the novel object, although we also observed a non-specific overall increase in exploration in one experiment. During the test session, we also observed an exploration of the location, which had previously been occupied by the displaced object, an effect termed empty quadrant. Our behavioral findings suggest multiple stages of spatial memory formation in tree shrews that are associated with various forms of behavioral responses to novelty. Reduced novelty preference has been linked to major depressive disorder in human patients. Given the established social conflict depression model in tree shrews, we anticipate that the study of the neural circuits of novelty preference and their malfunction during depression may have implications for understanding or treating depression in humans

Neurobiological Underpinnings of Trauma-related Psychopathology

The understanding and treatment of trauma-related psychopathology is a crucial challenge in the field of global mental health today. The etiology and mechanisms of two common trauma-related symptoms – intrusive re-experiencing and dissociative symptomatology – are still not well understood. The present work aims to advance the understanding of these phenomena by investigating their neurobiological underpinnings in two disorders: depersonalization/derealization disorder (DPD), in which dissociation depicts the core feature, and the dissociative subtype of posttraumatic stress disorder (PTSD-D), in which dissociative symptomatology and intrusive re-experiencing co-occur and correlate in regard to their severity. Alterations in fiber tract networks in white matter, which are crucial for communicating between brain regions, have not yet been investigated in DPD or PTSD-D. In Study I, white matter network alterations were explored in 23 patients with DPD compared to 23 matched healthy controls. Results yielded relatively lower structural connectivity in left and right temporal regions in DPD, which have previously been associated with dissociative symptomatology in DPD and in other disorders. Furthermore, a trend indicated alterations in a fronto-limbic circuit, which a neurobiological model proposes underlies dissociation in DPD as well as PTSD-D. In Study II, we tested whether fronto-limbic circuits are also altered in PTSD-D (n=23) compared to ‘classic’ PTSD patients (n=19) using the same analysis pipeline as in Study I. No respective white matter changes were detected on a network level in PTSD-D. However, subsequent exploratory analyses revealed alterations in two subcortical networks comprising a limbic-thalamic circuit and low-level motor regions, respectively. The limbic-thalamic network is crucial for declarative and spatial mnemonic processes, which according to dual memory models play a crucial role for the development of intrusive memories. We tested the respective memory model in Study III and confirmed for the first time empirically, that spatial-contextual (allocentric) memory ability is negatively associated with severity of intrusive memories in 33 patients with PTSD. The findings of the present work indicate that (1) dissociation in DPD is underpinned by different alterations in structural connectivity than in PTSD-D and (2) dissociative and intrusive memories are associated with aberrations in similar sub-cortical circuits, supporting the notion that in PTSD-D, a lower state of consciousness exacerbates de-contextualization of the traumatic content, resulting in heightened intrusive symptomatology. Clinical implications of our findings are discussed

Effect of valenced stimuli on hippocampus-dependent spatial memory in depression

This thesis focused on neurobiological changes in depression. Part 1 reviewed research investigating the relationship between trauma in childhood, depression in adulthood and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The reviewed studies provided some evidence for associated changes to the HPA axis, however, there was inconsistency in findings as to whether this was linked to childhood trauma or depression in adulthood independently, or an interaction of the two. The studies provided tentative evidence for a specific sub-type of depression, associated with a history of childhood trauma, but study heterogeneity and lack of replication mean further research is needed. Part 2 reported an investigation into the effects on hippocampus-dependent spatial memory of using valenced stimuli (neutral, negative) for both people with depression and healthy controls. No influence of valence on memory performance was found, counter to the hypotheses. However, some interesting effects of sex were found, warranting further investigation. Potential reasons for the null results were explored, along with suggestions for further research to allow these reasons to be examined. This investigation formed part of a joint study with Line Sagfors (trainee clinical psychologist, UCL; Sagfors, 2017). Part 3 reflected on some of the methodological issues and learnings from the major research project, including adapting an existing spatial memory test and working with a mental health service and clinical population. It explored the advantages of conducting joint DClinPsy research, both practical and emotional, and ended with some brief reflections on the challenges of the literature review

The Impact of the Brain-Derived Neurotrophic Factor Gene on Trauma and Spatial Processing.

The influence of genes and the environment on the development of Post-Traumatic Stress Disorder (PTSD) continues to motivate neuropsychological research, with one consistent focus being the Brain-Derived Neurotrophic Factor (BDNF) gene, given its impact on the integrity of the hippocampal memory system. Research into human navigation also considers the BDNF gene in relation to hippocampal dependent spatial processing. This speculative paper brings together trauma and spatial processing for the first time and presents exploratory research into their interactions with BDNF. We propose that quantifying the impact of BDNF on trauma and spatial processing is critical and may well explain individual differences in clinical trauma treatment outcomes and in navigation performance. Research has already shown that the BDNF gene influences PTSD severity and prevalence as well as navigation behaviour. However, more data are required to demonstrate the precise hippocampal dependent processing mechanisms behind these influences in different populations and environmental conditions. This paper provides insight from recent studies and calls for further research into the relationship between allocentric processing, trauma processing and BDNF. We argue that research into these neural mechanisms could transform PTSD clinical practice and professional support for individuals in trauma-exposing occupations such as emergency response, law enforcement and the military

Autobiographical and hippocampus-dependent spatial memory in depression

Depression is associated with deficits in the recollection of specific autobiographical memories, a phenomenon referred to as overgeneral memory. Neither the modifiability nor the neural correlates of overgeneral memory are currently well understood. The aim of this thesis was to increase the understanding of autobiographical memory specificity and overgeneral memory in depression. Part one of the thesis is a literature review investigating whether interventions for treating and preventing depression are effective in improving autobiographical memory specificity. Nineteen studies of varying methodological strength were identified and included in the review. There is evidence that memory specificity improves over the course of treatment for depression, but further research is required to establish the causal effects of different interventions and the effectiveness of prevention strategies. Part two of the thesis presents an empirical study aimed at establishing the association between overgeneral memory and allocentric spatial memory as a measure of hippocampal function in depression. Depressed and non-depressed adults completed measures of autobiographical memory and allocentric spatial memory. The depression group showed impairment in autobiographical memory, but not in allocentric spatial memory, and there was no association between performance on the two memory tasks. The data was collected in the context of a joint project (Williams, 2017). Part three of the thesis is a critical appraisal of the research. It offers reflections on study design and recruitment, benefits of a joint project, exclusion criteria and generalizability, challenges in measuring autobiographical memory, and the role of a clinical researcher in the National Health Service

Mental imagery of positive and neutral memories : a fMRI study comparing field perspective imagery to observer perspective imagery

Imagery perspective can influence what information is recalled, processing style, and emotionality; however, the understanding of possible mechanisms mediating these observed differences is still limited. We aimed to examine differences between memory recall from a field perspective and observer perspective at the neurobiological level, in order to improve our understanding of what is underlying the observed differences at the behavioral level. We conducted a fMRI study in healthy individuals, comparing imagery perspectives during recall of neutral and positive autobiographical memories. Behavioral results revealed field perspective imagery of positive memories, as compared to observer perspective, to be associated with more positive feelings afterwards. At the neurobiological level, contrasting observer perspective to field perspective imagery was associated with greater activity, or less decrease relative to the control visual search task, in the right precuneus and in the right temporoparietal junction (TPJ). Greater activity in the right TPJ during an observer perspective as compared to field perspective could reflect performing a greater shift of perspective and mental state during observer perspective imagery than field perspective imagery. Differential activity in the precuneus may reflect that during observer perspective imagery individuals are more likely to engage in (self-) evaluative processing and visuospatial processing. Our findings contribute to a growing understanding of how imagery perspective can influence the type of information that is recalled and the intensity of the emotional response. Observer perspective imagery may not automatically reduce emotional intensity but this could depend on how the imagined situation is evaluated in relation to the self-concept. (C) 2016 Elsevier Inc. All rights reserved