The medial temporal lobe and prefrontal cortex are known to play a critical role in tasks involving learned associations, such as between an object and a location. However, the exact neural mechanisms underlying the learning and retrieval of high-fidelity spatial associations are unknown. To address this gap, we tested presurgical epilepsy patients with bilateral depth electrodes implanted in the medial temporal lobe and prefrontal cortex on two variants of an object-location spatial learning task. In the first version of this task, subjects were shown a series of objects at random positions along the circumference of an invisible circle. At test, the same objects were shown at the top of the circle, and subjects used a dial to move the object to the location shown during encoding. Angular error between the correct location and the indicated location was recorded as a continuous measure of performance. By registering pre- and post-implantation MRI scans, we were able to localize electrodes to specific hippocampal subfields. We found a correlation between increased high-frequency gamma power (40-100 Hz), thought to reflect local excitatory activity, and the precision of spatial memory retrieval in hippocampal CA1 and dorsolateral prefrontal electrodes. Additionally, we found a directional relationship between these regions, suggesting that the dorsolateral prefrontal cortex is involved in post-retrieval processing. In order to examine the neural activity underlying spatial learning, we then tested presurgical epilepsy patients on a variant of this task in which subjects attempted to learn object-location associations over the course of three training blocks with feedback. At retrieval, we found increased medial temporal and dorsolateral prefrontal gamma power for low error trials, consistent with the results described above. At feedback, we found the opposite pattern of activity, with increased medial temporal and dorsolateral prefrontal gamma power for high error trials. Increased medial temporal gamma activity at feedback also predicted greater decreases in error from one training block the next, indicating that these error signals are involved in updating memory representations or modifying incorrect associations during learning. Finally, we examined the contributions of low frequency oscillatory power to performance on this spatial learning task as well as the relationship between the 1/f aperiodic slope and spatial memory retrieval and learning. We found that the aperiodic slope, thought to reflect the ratio of excitation to inhibition, decreased across training blocks, but did not predict error within training blocks, suggesting that decreased excitation and/or increased inhibition is associated with increased familiarity and/or decreased novelty. Low frequency oscillatory power did not predict error within blocks and did not change across blocks. Overall, these data suggest putative mechanisms for the learning and retrieval of high-fidelity spatial associations.

An estimated 6.1 million Americans currently suffer with Alzheimer’s disease (AD) and in the absence of effective treatment or a cure, this number could increase to 13.8 million by 2060. One of the most common changes that occurs in aging and Alzheimer’s disease is decline in memory for everyday experiences (episodic memory). Computational models suggest that the brain uses a neural computation known as pattern separation to distinguish among highly similar inputs during memory recall. Furthermore, episodic memory has several components: what happened, where it happened, and when it happened. The posteromedial cortices are regions that are thought to be involved in spatial memory and are early sites that are affected by AD pathology. Neuropathological hallmarks of AD include the presence of beta-amyloid (Aβ) plaques, and the formation of neurofibrillary tangles (NFT) and neuropil threads. Eventually, this is followed by neurodegeneration. In vivo candidate biomarkers for AD include pathological aggregations of misfolded proteins (e.g. amyloid plaques, [A], and hyperphosphorylated tau tangles, as measured by CSF assays, and PET imaging), neuronal dysfunction or atrophy (as measured by functional or structural MRI, and total tau levels as measured by CSF assays), and cognitive impairment (as measured by neuropsychological tests). However, the relationship between the pathological, neuroimaging, behavioral, and cognitive markers in the aging brain and in AD remains unclear. The goal of this dissertation was to understand how regions of the brain that support memory for where events occur (spatial memory) are altered in the context of Alzheimer’s disease. We gave participants a spatial pattern separation task, in which we showed participants a series of objects on different locations on a screen and tested participants on their ability to remember the spatial location of the objects after a delay. We found that cortical regions known as the posteromedial network may support spatial pattern separation. Spatial pattern separation task performance was associated with word list delayed recall test commonly used in a clinical setting, a relationship that is conditional upon the level of amyloid burden. Spatial pattern separation task performance was also associated with AD pathology, and cognitive decline. These findings suggest that the pattern separation framework may provide an account for understanding mechanistic changes that occur in the progression of AD. Future studies of spatial memory should investigate associations between regionally specific effects of AD pathology, vascular and immune contributions to AD, and include community-based samples of ethnically diverse populations.

The medial temporal lobes (MTL) comprise a set of brain regions known to be critical for the formation of memories. Different regions of the MTL support distinct aspects of experience, with the perirhinal and lateral entorhinal cortices comprising a “what” information pathway supporting local features (such as objects), and the parahippocampal and medial entorhinal cortices comprising a “where” pathway supporting configurational features (such as space or context). Importantly, both pathways converge on the hippocampus, where domain-general pattern separation has been hypothesized to occur.. These regions – chiefly perirhinal and lateral entorhinal cortices – are known to be susceptible to the earliest stages of age-related neuropathology. An understanding the distinct contributions of the regions of the MTL will help to elucidate their function in the service of memory, as well as their roles in age-related cognitive decline. However, evidence for functional subdivisions of the human entorhinal cortex, their contributions to hippocampal computations such as pattern separation, and their roles in neurocognitive aging is severely lacking.

In a series of behavioral and functional magnetic resonance imaging (MRI) experience, we sought to fill these gaps in knowledge. First, in a behavioral experiment, we developed a spatial mnemonic discrimination paradigm, modeled after work in rodents studying pattern separation. This complemented prior object discrimination paradigms studying human memory, and showed age-related deficits consistent with a decline in pattern separation ability. Next, in a high-resolution functional MRI study, we used an object vs. spatial mnemonic discrimination paradigm to show dissociable functional roles of lateral and medial entorhinal cortex in human subjects. We next used the object vs. spatial paradigm to investigate whether cognitively normal aging asymmetrically affected performance on the two tasks. We found that older adults are relatively more impaired at object than spatial discrimination, consistent with selective vulnerability of perirhinal and/or lateral entorhinal cortices. Finally, in a high-resolution functional MRI study, we replicated the aforementioned selective object discrimination deficits, and furthermore demonstrated associated hypoactivity in the lateral entorhinal cortex. We additionally replicated prior reports of hyperactivity in the dentate/CA3 subfields of the hippocampus, and furthermore found that the ratio of relative activity between dentate/CA3 and lateral entorhinal cortex predicted the extent of object discrimination impairment. In sum, the studies presented here provide novel evidence for dissociable functional roles of lateral and medial entorhinal cortex in humans, and suggest that the lateral entorhinal cortex-dentate/CA3 circuit is selectively disrupted in aging.

The hippocampus’s role in memory was first recognized in 1957 after the bilateral resection of patient HM’s medial temporal lobes left him with profound amnesia; HM’s case study supported hypotheses that the brain possesses multiple memory systems, and suggested the hippocampus is critical for memories of experience. Subsequent lesion cases bolstered additional support, but initially, experimental progress was limited by a lack of technology that could ethically probe hippocampal function in humans, and in animals, was confounded by flawed experimental design and sidetracked by a competing theory about the hippocampus’s role in spatial navigation. Nevertheless, research on navigation became complementary, offering new experimental paradigms also suitable for probing hippocampal memory function and revealing many noteworthy features of hippocampal function like the theta rhythm. Today these research trajectories have begun to coalesce, and now prominent theories presume a more general role of the hippocampus as an index linking arbitrary cortical activation patterns; furthermore, these index representations are thought to relate to the ability of generalizing over or discriminating between similar stimuli via pattern separation/completion processes.Brain electrophysiology is composed of a geometric progression of distinct rhythms, and the theta rhythm (3-8 Hz) has been elegantly linked to navigation processes in the hippocampus of various mammalian species. Additionally, this activity has been associated with memory in mammals, including humans, albeit, primarily with non-invasive methods incapable of attributing this activity to the hippocampus; notably, several studies have also demonstrated that pre-stimulus theta activity is correlated with recognition memory strength. Nevertheless, in the last couple of decades, direct recordings of human hippocampi have been conducted in patients implanted with intracranial EEG (iEEG) prior to brain surgery, but these studies related to memory have provided conflicting results, casting some doubt on the function of hippocampal theta. In this dissertation, I analyze iEEG data collected from human epilepsy patients while engaged in a recollection memory task. I demonstrate that post-stimulus theta during encoding is indeed associated with successful recollection memory. While the first result runs counter to the several iEEG studies on memory, it is consistent with long-standing theories about theta’s role in hippocampal memory processes. Additionally, I provide evidence that pre-stimulus theta activity at encoding is associated with poor recollection memory in the presence of mnemonic interference. Although this result also seems to be in contradiction with all prior accounts of pre-stimulus theta’s effect on memory, it might be reconciled by interpreting the role of pre-stimulus theta as facilitating generalization of memory, rather than memory in general.

Many studies have provided evidence that the medial temporal lobes of the brain are involved in memory for everyday life experiences (episodic memory). Episodic memory has several components: the event itself (what), where the event took place, and when the event took place. The goal of this dissertation was to understand how the brain supports memory for when events occur (temporal memory). We showed participants an episode of Curb Your Enthusiasm inside of the MRI scanner, to monitor task-related changes in relevant brain regions. Then, we tested participants’ memory for when events in the episode occurred. We found that a network of brain regions, including the hippocampus, lateral entorhinal cortex (LEC), and perirhinal cortex (PRC) were preferentially activated when participants were closest to the correct answer. This suggests that memory for time may have different neurobiological correlates than memory for spatial information. Cortical regions, such as medial prefrontal cortex, angular gyrus, and posterior cingulate cortex were also activated when participants responded most precisely, indicating that they may also support temporal memory precision. We found no evidence that scene changes (event boundaries) had an effect on temporal memory performance in this task. A cluster in the superior temporal gyrus was preferentially activated at event boundaries while participants watched the episode, which could reflect changes occurring at boundaries, music during the episode, or both. We also tested older adults on this task and their performance correlated with a neuropsychological test of memory involving remembering words over a delay. Future studies of memory for time involving more naturalistic stimuli will provide additional information on brain-behavior relationships critical for remembering when events occurred.

Decades of research have investigated the impact of the quantity and quality of maternal care on the development of healthy cognitive and emotional function in both human and rodent offspring. Emerging from this literature is the notion that the (un)predictability of maternal signals in early infancy is an important factor influencing the development of these systems. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes, including impaired memory performance and anhedonia (the loss of pleasure or lack of reactivity to pleasurable stimuli). However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In Chapter 2 of this Dissertation, in mother–child dyads, we tested the hypothesis that exposure to unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe–prefrontal cortex circuit. Using high angular resolution diffusion imaging, we discovered that higher maternal unpredictability during infancy was associated with greater uncinate fasciculus generalized fractional anisotropy (a correlate of fractional anisotropy with distinct advantages). In a separate experiment, Chapter 3 of this Dissertation tested the hypothesized role of the uncinate fasciculus in adjudicating between competing memory representations at retrieval. Using multimodal imaging, we discovered that greater uncinate fasciculus integrity is associated with reduced hippocampal dentate and CA3 activity during correct discrimination of similar emotional stimuli. Together, this work yields novel insight into neurobiological mechanisms of vulnerability to cognitive deficits and advances our knowledge of the function of medial prefrontal white matter connectivity with the temporal lobe.