What information is represented in the human hippocampus?

The hippocampus plays a critical role in supporting memories of our personal past experiences (episodic memories). However, it is not known how individual episodic memories are represented by neuronal populations within the hippocampus. The aim of my thesis was to explore the nature of the information represented in the human hippocampus, with a particular focus on episodic memories. I conducted five experiments using high-resolution and standard functional MRI (fMRI). In four of these projects I used and further developed a method known as multi-voxel pattern analysis (MVPA). This enabled me to interrogate the fMRI data to look for functionally-relevant patterns of information encoded across multiple voxels. My findings revealed that episodic memories were represented in the hippocampus more so than in neighbouring brain regions, that this was true even of memories that were highly overlapping in terms of content and context, and for recently-formed and very remote memories. Furthermore, I found that the episodic information within individual hippocampal subfields was consistent with computational models of episodic memory. One important contribution to the representation of an episodic memory is scene construction - the mental construction of a complex spatially coherent scene into which event details are bound. In order to explore the role of the hippocampus in scene construction, I used fMRI to study boundary extension – a scene-related phenomenon whereby people extrapolate beyond the edges of a given view. This revealed that hippocampal activity tracked the emergence of boundary extension, suggesting that scene construction can be rapid, automatic, and implicit. Overall, my findings shed new light on the nature of episodic representations within the human hippocampus, and offer an empirical link between episodic memory and computational theory. Moreover, they provide further evidence regarding scene construction, which is a key component of episodic representations within the hippocampus

A goal direction signal in the human entorhinal/subicular region

Being able to navigate to a safe place, such as a home or nest, is a fundamental behaviour for all complex animals. Determining the direction to such goals is a crucial first step in navigation. Surprisingly, little is known about how, or where in the brain, this 'goal direction signal' is represented. In mammals 'head-direction cells' are thought to support this process, but despite 30 years of research no evidence for a goal direction representation has been reported [1, 2]. Here we used functional magnetic resonance imaging to record neural activity while participants made goal directions judgments based on a previously learned virtual environment. We applied multivoxel pattern analysis [3-5] to this data, and found that the human entorhinal/subicular region contains a neural representation of intended goal direction. Furthermore, the neural pattern expressed for a given goal direction matched the pattern expressed when simply facing that same direction. This suggests the existence of a shared neural representation of both goal and facing direction. We argue that this reflects a mechanism based on head-direction populations that simulate future goal directions during route planning [6]. Our data further revealed that the strength of direction information predicts performance. Finally, we found a dissociation between this geocentric information in the entorhinal/subicular region and egocentric direction information in the precuneus

Semantic representations in the temporal pole predict false memories

Recent advances in neuroscience have given us unprecedented insight into the neural mechanisms of false memory, showing that artificial memories can be inserted into the memory cells of the hippocampus in a way that is indistinguishable from true memories. However, this alone is not enough to explain how false memories can arise naturally in the course of our daily lives. Cognitive psychology has demonstrated that many instances of false memory, both in the laboratory and the real world, can be attributed to semantic interference. Whereas previous studies have found that a diverse set of regions show some involvement in semantic false memory, none have revealed the nature of the semantic representations underpinning the phenomenon. Here we use fMRI with representational similarity analysis to search for a neural code consistent with semantic false memory. We find clear evidence that false memories emerge from a similarity-based neural code in the temporal pole, a region that has been called the "semantic hub" of the brain. We further show that each individual has a partially unique semantic code within the temporal pole, and this unique code can predict idiosyncratic patterns of memory errors. Finally, we show that the same neural code can also predict variation in true-memory performance, consistent with an adaptive perspective on false memory. Taken together, our findings reveal the underlying structure of neural representations of semantic knowledge, and how this semantic structure can both enhance and distort our memories

Big-Loop Recurrence within the Hippocampal System Supports Integration of Information across Episodes

Recent evidence challenges the widely held view that the hippocampus is specialized for episodic memory, by demonstrating that it also underpins the integration of information across experiences. Contemporary computational theories propose that these two contrasting functions can be accomplished by big-loop recurrence, whereby the output of the system is recirculated back into the hippocampus. We use ultra-high-resolution fMRI to provide support for this hypothesis, by showing that retrieved information is presented as a new input on the superficial entorhinal cortex—driven by functional connectivity between the deep and superficial entorhinal layers. Further, the magnitude of this laminar connectivity correlated with inferential performance, demonstrating its importance for behavior. Our findings offer a novel perspective on information processing within the hippocampus and support a unifying framework in which the hippocampus captures higher-order structure across experiences, by creating a dynamic memory space from separate episodic codes for individual experiences

Carbamazepine-Induced Tics

A variety of movement disorders are known to occur in association with carbamazepine (CBZ) therapy in adults and children, but development of tics has been described infrequently and only in patients with underlying Tourette's syndrome or other movement disorders. We report 3 children with epilepsy who developed facial motor tics after initiation of CBZ for complex partial seizures. All 3 had documented CBZ blood levels in the therapeutic range at the time, and none had other symptoms or signs of clinical intoxication. Neurologic examinations were normal in 2 and showed developmental de lay of expressive language in the third. Brain imaging was normal in all. After development of the tics in 2, CBZ was continued at the same or higher dose, and the tics abated and then ceased spontaneously ≤6 months. In the third child, the tics ceased after CBZ discontinuation. These cases demonstrate that CBZ can induce simple motor tics in children. These idiosyncratic reactions may be transient and do not always necessitate drug discontinuation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66313/1/j.1528-1157.1993.tb02119.x.pd

Managing fertiliser nitrogen to reduce nitrous oxide emissions and emission intensities from a cultivated Cambisol in Scotland

Emissions of nitrous oxide (N2O) were measured from an arable site in south east Scotland for twelve months during 2011–2012 using an intensive sampling strategy. This fully replicated and blocked field experiment aimed to provide accurate measurements of N2O emissions from one of the UK's principle geoclimatic zones supporting agricultural production and to produce robust N2O emission factors (EFs). Calculated EFs were compared to the IPCC's default Tier 1 EF of 1.25%, and the new value of 1%, to assess their suitability for use in locations throughout the UK. Emissions from ten treatments fertilised with either ammonium nitrate or urea at rates of 0 kgNha−1 to 200 kgN ha−1, and sownwith spring barley,were measured using the static closed chamber technique. Potential N2O mitigation options were investigated; these included the use of a nitrification inhibitor (NI), split fertiliser applications and variations in the formand quantity of fertiliser applied. Crop yieldswere measured to enable calculation of N2O emission intensities for each treatment; this is an important factor to consider when assessing N2O mitigation options due to the need to maintain crop yields. Cumulative N2O emissions varied between 1.32 kg N2O-N ha−1 and 3.82 kg N2O-N ha−1 with a mean 42% decrease in emissions associated with the use of the NI. Increases in crop yield were associatedwith increases inN fertiliser application, and the amendment of treatmentswith a NI and the use of a split fertiliser application significantly decreased crop yields by approximately 10% and 5% respectively. Annual EFs ranged between −0.28% to 1.35%. Emission intensities decreasedwith increasing fertiliser application at low N application rates, and the optimumfertiliser application rate to obtain minimum emissions but maximum crop yield was 160 kg N ha−1. © 2014 Published by Elsevier B.V

Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acid A (GABA A ) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABA A -receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65554/1/j.1528-1157.1994.tb05955.x.pd

Pavlovian Fear Conditioning Activates a Common Pattern of Neurons in the Lateral Amygdala of Individual Brains

Understanding the physical encoding of a memory (the engram) is a fundamental question in neuroscience. Although it has been established that the lateral amygdala is a key site for encoding associative fear memory, it is currently unclear whether the spatial distribution of neurons encoding a given memory is random or stable. Here we used spatial principal components analysis to quantify the topography of activated neurons, in a select region of the lateral amygdala, from rat brains encoding a Pavlovian conditioned fear memory. Our results demonstrate a stable, spatially patterned organization of amygdala neurons are activated during the formation of a Pavlovian conditioned fear memory. We suggest that this stable neuronal assembly constitutes a spatial dimension of the engram