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Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept. 22, 2008). Includes bibliographical references.

Electroconvulsive therapy (ECT) is used worldwide to treat severe mental disorders. The most common mental disorder, and the third leading cause of disease burden in the world is depression. The clinical efficacy of ECT for severe depression is well-established. However, both the pathophysiology of depression and the mechanism of action of ECT remain elusive. The main aims of this thesis are to address the following issues: 1) the use and practice of ECT in Sweden has not been systematically evaluated since 1975, 2) cognitive side-effects (memory disturbances) are a major concern with ECT and 3) the mechanism of action of ECT remain elusive. The neurobiological aspects of ECT focus on two hypotheses. First, the recent years´ preclinical studies that have provided evidence that ECT induces hippocampal cell proliferation, including neurogenesis. Second, that enhanced functional inhibition of neuronal activity is a key feature. Current use and practice of ECT in Sweden (paper I) is based on data from the national quality register for ECT, the mandatory patient register of the National Board of Health and Welfare and a survey. Treated person rate (TPR) in Sweden 2013 was found to be 41 individuals / 100 000, and thus unchanged since the latest systematic investigation in Sweden 1975. In more than 70% of treatment series the indication was a depressive episode. The selection of patients for ECT and treatment technique in Sweden was similar to that in other western countries, but the consent procedure and the involvement of nurses and nursing assistants in the delivery of ECT differ. Data also shows that there is room for improvement in both the specificity of use and availability of ECT. The second study in this thesis is a longitudinal observational trial where 12 (paper II and III) and 14 (paper IV) patients with depression referred for ECT were investigated. Patients underwent a 3 T MRI structural scanning and DSC-MRI perfusion, a neuropsychological test battery and clinical ratings before ECT, within one to two weeks after ECT and after 6 and 12 months.  In line with preclinical findings and the plasticity hypothesis of mechanism of action of ECT, the hippocampal volume increased after ECT in patients with depression. However, this increase was transient and returned to baseline levels within 6 months. No correlation was found between volumetric changes and clinical effect or cognitive outcome. Instead our results suggested an association to the number of treatments, without relation to the side of stimulation. A right-sided decrease in frontal blood flow distinguished remission from non-remission after ECT. There were significant impairments in verbal episodic memory and verbal fluency within one week after ending the ECT course, but these impairments were transient and no persistent cognitive impairments were seen during the follow-up. In summary, this thesis present the first update on the use and practice of ECT in Sweden in the last 40 years as well as a pioneering MRI-study on the hippocampal volume increase in the treatment of depression with ECT. Supportive to earlier findings we also found the cognitive side-effects that are measurable after ECT to be transient. Furthermore, we found that a decreased frontal blood flow is of importance for the anti-depressive response to ECT.

Theta activity is one of the most prominent rhythms in the brain and appears to be conserved among mammals.  These 4-12 Hz oscillations have been predominantly studied in the dorsal hippocampus where they are correlated with a broad range of voluntary and exploratory behaviors. Theta activity has been also implicated in a number of mnemonic processes, long-term potentiation (LTP) induction and even acting as a global synchronizing mechanism. Moving along the dorso-ventral axis theta activity is reduced in power and desynchronized from the dorsal part. However, theta activity can also be generated in the ventral hippocampus itself during anxiety- and fear-related behaviors. Until now it was unknown which hippocampal cell population was capable to generate theta activity and it was controversial if its origin was local, in the hippocampus, or driven by other brain regions. In this thesis I present compelling in vitro and in vivo  evidence that   a subpopulation of OLM interneurons (defined by the Chrna2-cre line)  distinctively enriched  in the CA1 region of  the ventral hippocampus is implicated in LTP function (paper I,II), information control (paper V) and the induction of theta activity that is under cholinergic  control (paper IV). Importantly, a concomitant effect of the optogenetically induced theta activity is reduction in anxiety (Paper IV). Another innovation of this work was the development of a methodological approach to avoid artefactual signals when combining electrophysiology with light activation during optogenetic experiments (Paper III). In summary, the work presented in this thesis elucidates the role of a morphologically and electrophysiologially identified cell population, OLMα2 interneurons, first on the cellular, then on the circuit and ultimately on the behavioral level.

Traumatic brain injury (TBI) is the leading cause of disability in individuals under 45 years of age, with mild TBI (mTBI) accounting for the majority of cases. The juvenile brain is in a period of robust synaptic reorganization and myelination, making adolescence a particularly vulnerable time to incur a TBI. Learning and memory deficits that involve the hippocampal formation are often observed following mTBI in adults. To examine this issue in the juvenile brain, we assessed changes in hippocampal synaptic plasticity following closed-head mTBI in male and female Long-Evans rats (25-28 days of age). Synaptic plasticity of field excitatory post-synaptic potentials (fEPSPs) was assessed using in vitro electrophysiology at either one hour, one day, seven days, or 28 days following mTBI in the dentate gyrus (DG) and the cornu ammonis area 1 (CA1) regions of the hippocampus. In female rats, the CA1 region ipsilateral to the impact showed a significant reduction in long-term potentiation (LTP) as early as one hour following mTBI. Similar LTP deficits were apparent at one day in the DG, and persisted to 28 days following injury. In male rats, a deficit in both DG- and CA1-LTP was maximal in the ipsilateral hemisphere by seven days following injury, but these deficits did not persist to 28 days post-injury. These data suggest that the juvenile brain is susceptible to mTBI-induced impairments in plasticity, and sex and regional differences are apparent in the expression and recovery of synaptic plasticity following mTBI. / Graduate

The hippocampus, in humans and rats, plays crucial roles in spatial tasks and nonspatial tasks involving episodic-type memory. This thesis presents a novel computational model of the hippocampus (CA1, CA3 and dentate gyrus) which creates a framework where spatial memory and episodic memory are explained together. This general model follows the approach where the memory function of the rodent hippocampus is seen as a “memory space” instead of a “spatial memory”. The innovations of this novel model are centred around the fact that it follows detailed hippocampal architecture constraints and uses spiking networks to represent all hippocampal subfields. This hippocampal model does not require stable attractor states to produce a robust memory system capable of pattern separation and pattern completion. In this hippocampal theory, information is represented and processed in the form of activity patterns. That is, instead of assuming firing-rate coding, this model assumes that information is coded in the activation of specific constellations of neurons. This coding mechanism, associated with the use of spiking neurons, raises many problems on how information is transferred, processed and stored in the different hippocampal subfields. This thesis explores which mechanisms are available in the hippocampus to achieve such control, and produces a detailed model which is biologically realistic and capable of explaining how several computational components can work together to produce the emergent functional properties of the hippocampus. In this hippocampal theory, precise explanations are given to why mossy fibres are important for storage but not recall, what is the functional role of the mossy cells (excitatory interneurons) in the dentate gyrus, why firing fields can be asymmetric with the firing peak closer to the end of the field, which features are used to produce “place fields”, among others. An important property of this hippocampal model is that the memory system provided by the CA3 is a palimpsest memory: after saturation, the number of patterns that can be recalled is independent of the number of patterns engraved in the recurrent network. In parallel with the development of the hippocampal computational model, a simulation environment was created. This simulation environment was tailored for the needs and assumptions of the hippocampal model and represents an important component of this thesis.

Hippocampus has an extended developmental trajectory, with refinements occurring in the trisynaptic circuit until adolescence. While structural change should suggest a protracted course in behavior, some studies find evidence of precocious hippocampal development in the first postnatal year and continuity in memory processes beyond. However, a number of memory functions, including binding and relational inference, can be cortically supported. Evidence from the animal literature suggests that tasks often associated with hippocampus (visual paired comparison, binding of a visuomotor response) can be mediated by structures external to hippocampus. Thus, a complete examination of memory development will have to rule out cortex as a source of early memory competency. We propose that early memory must show properties associated with full function of the trisynaptic circuit to reflect "adult-like" memory function, mainly (1) rapid encoding of contextual details of overlapping patterns, and (2) retention of these details over sleep-dependent delays. A wealth of evidence suggests that these functions are not apparent until 18-24 months, with behavioral discontinuities reflecting shifts in the neural structures subserving memory beginning approximately at this point in development. We discuss the implications of these observations for theories of memory and for identifying and measuring memory function in populations with typical and atypical hippocampal function. (C) 2015 The Authors. Published by Elsevier Ltd.

Previous research has investigated how the perirhinal cortex (PRC), hippocampus (HC) and temporal pole (TP) are involved in complex visual discrimination using a variety of stimuli. Results from these studies have shown that the PRC activates to a greater extent for object stimuli relative to scene stimuli and that familiar stimuli elicit greater activation than do novel stimuli. In contrast, the HC shows greater activation for scene stimuli relative to objects and has also been reported to show greater activation for familiar relative to novel stimuli. To our knowledge, however, no studies in humans have replicated the stimulus specificity findings reported for PRC and HC. Additionally, no studies have used a combination of perceptual difficulty and familiarity/novelty to investigate how varying these factors affects activation in PRC, HC and TP during visual discrimination tasks. Chapter 2 describes an fMRI study performed to investigate the PRC's and HC's involvement in object and scene visual discrimination. The results of this study showed that the PRC was activated similarly by scenes and objects and that the HC was activated similarly for objects and scenes. Chapter 3 describes an fMRI experiment that manipulated both familiarity and difficulty, measuring how this affected PRC, HC and TP activation. In PRC the results showed a significant interaction between novelty and level of difficulty, such that novel objects with high levels of overlapping features showed greater activation compared to all other conditions. In contrast, the HC only showed a main effect of difficulty, indicating that the stimuli with high, relative to low, levels of difficulty elicited greater activation regardless of familiarity. Cumulatively, the evidence above suggests that the involvement of the PRC and HC in visual discrimination is complex. We propose that PRC is engaged whenever visual discrimination is required for any stimuli with overlapping features not just objects, and is activated to a greater extent when stimuli are novel, while HC appears to respond to stimuli with overlapping features, regardless of familiarity.

Previous research has investigated intentional retrieval of contextual information and contextual influences on object identification and word recognition, yet few studies have systematically investigated context effects in episodic memory for objects. To address this issue, unique objects on a white background or embedded in a visually rich context were presented to participants. At test, the object was presented either in the original or a different context. Chapter 2 demonstrated that a context shift decrement (CSD)--decreased recognition performance when context is changed between encoding and retrieval--was observed. In four studies with young adults, the CSD was not attenuated by encoding or retrieval manipulations. Chapter 3 revealed that the CSD was resistant to aging and neuropsychological status. Importantly, older adults classified as high MTL performed better on the recognition task than those classified as low MTL, and as well as young adults, supporting the successful aging hypothesis. Chapter 4 focused on elucidating the neural correlates of the CSD using functional Magnetic Resonance Imaging. Right PHG activation during encoding was associated with subsequent recognition of objects in the context change condition. This same region was activated during recognition, suggesting it may automatically reinstate visual contextual information. Overall, the CSD is attributed to the automatic and obligatory binding of object and context information in episodic memory that results in an integrated representation, mediated by the hippocampal complex.

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