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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.

Human development is a dynamic, protracted process influenced by genetics, the environment, experience, and many other factors. During development, an individual develops an entirely unique neural architecture along with a unique set of cognitive skills and abilities. Through recent large-scale pediatric neuroimaging initiatives, we now have a better understanding of the protracted structural changes occurring in the developing brain. We are also beginning to map out relationships between developing brain structure and domain-specific cognition, although we haven’t fully characterized these relationships and their variability throughout typical development. The goal of this work is to assess how individual differences in regional cortical and subcortical brain structure are related to behavioral and cognitive variability in different domains during childhood and adolescence, which is a period of rapid dynamic change. This work also aims to investigate overlapping as well as distinguishing characteristics of the relationships between developing neural systems and domain-specific cognition. In this dissertation, I focus on three cognitive domains: phonological awareness, spatial working memory, and response inhibition. These three cognitive domains are thought to involve relatively distinct brain regions and networks, allowing us to investigate the specificity of associations between structure and function in the developing brain. In addition, these three domains have been well studied in pediatric, clinical, and adult populations in behavioral and functional neuroimaging studies, leading to relatively well-defined region-specific hypotheses. Utilizing three distinct cognitive domains also supports the investigation of domain-general aspects of cognitive development, such as latent factors or skills supporting multiple areas of cognitive development. In addition, studying multiple cognitive domains allows me to study the reflection of any shared features in the neural architecture. I will first address the region-specific associations between cortical and white matter regions thought to be principally related to each cognitive domain. Following that, I will carry out a more data-driven analysis aimed at exploring possible latent factors underlying the associations between these cognitive domains and structural regions. These results may provide insight into the neurobiological correlates of cognitive development and the nature of individual difference variability during development.

Degenerative cervical myelopathy (DCM) is a chronic, progressive disorder characterized by the age-related degeneration of osseocartilaginous structures within the cervical spine resulting in narrowing of the spinal canal and chronic compression of the spinal cord. Chronic spinal cord compression can result in persisting neck pain and neurological deficits including loss of fine motor skills, weakness or numbness in the upper limbs, and gait abnormalities and imbalance, ultimately requiring surgical intervention to relieve cord compression. DCM is the most common form of spinal cord injury in adults and as the elderly population continues to grow, incidence of DCM will rise alongside an increased demand on healthcare resources. Further investigation into the neural response to chronic spinal cord compression may not only inform disease progression and prognosis but may benefit patient monitoring and treatment planning.This dissertation aims to elucidate how symptom presentation, degree of spinal compression, microstructural and cellular integrity of the affected cord, and sex impact supraspinal structure and function in patients with DCM. To address the goals of the dissertation, we implemented a multimodal neuroimaging approach including anatomical, functional, and diffusion imaging of the brain and T2-weighted, diffusion, and metabolic imaging of the spine. First, we characterized and compared spinal cord compression induced alterations in cerebral morphometry and functional connectivity between symptomatic DCM and asymptomatic spinal cord compression (ASCC) patients to further uncover potential compensatory neural mechanisms driving symptom presentation and disease progression. Because the degree of cervical cord compression is not strongly linked to symptom severity, we investigated whether macrostructural, microstructural, and metabolic properties of the cervical spinal cord result in conventional anatomical and functional alterations within the brains of patients with DCM. Lastly, we identified sex-specific differences on cerebral structure and functional connectivity in patients with DCM. In summary, the dissertation revealed unique cerebral signatures between symptomatic and asymptomatic patients, novel insights into the interrelationship between spinal and supraspinal alterations, and sex-specific supraspinal reorganization in patients with DCM. Findings from this work contribute to our knowledge of disease characteristics and compensatory neural mechanisms; and may benefit future development of non-invasive imaging biomarkers, more precise predicative models to inform disease progression, and novel pharmacological strategies to enhance neuroprotective mechanisms and functional recovery in patients with DCM.

Maternal exposure to infection can lead to an increased risk of children developing neurodevelopmental or neuropsychiatric disorders. This effect is defined as “Maternal Immune Activation” (MIA), as it is present regardless of the type of infectious agent. MIA researchers have begun to understand the relationship between an increase in maternal cytokine levels and changes in their offspring’s brain and behavioral development. Progress on uncovering the mechanism of MIA is slowed by the inherent variability in the model. It is critical to address variability in MIA protocols to enhance reproducibility and begin work on translational therapies. In these studies, we quantified the effects of changing MIA protocols within a Sprague Dawley rat model. Initial pilot studies revealed that LPS is better suited as an immunogen for MIA models in rats compared to poly(I:C), due to its robust immune activation without unintended litter loss. Further studies found that, of the viable LPS dosages tested, a lower dose (50µg/kg) of MIA created a different trajectory of behavioral development in than higher dose (100µg/kg) of MIA. An unsupervised clustering model sorted the dosages into significantly different distributions, implying that rats from different dosages developed different sets of behaviors. While all MIA rat offspring showed differences in brain cytokines, 50µg/kg MIA increased several cytokines compared to saline controls, while the direction of cytokine levels was sex-specific in 100µg/kg rats, implying a sex-specific compensatory effect. This body of work will assist researchers in identifying effective protocols, which will enhance our ability to understand MIA mechanism.

Mapping presents a compelling way to demystify complex data and concepts into useful visual information that most people can understand regardless of language, level of literacy, or culture. These maps can also be shared instantaneously with the world via the Internet. Interactive community mapping (ICM) is one method of information and communication technology (ICT)-enabled participatory mapping. In the development context, ICM can be a useful approach in helping community members, members of civil society organizations (CSOs), governments, and development partners to better picture and assess the needs and concerns of the mapped communities and adjust development plans, activities, and policies accordingly. This note is aimed at providing step-by-step guidance on the design and implementation of the ICM process to achieve an evidence-based and increasingly participatory decision-making approach for development projects. Relying on good practice examples from Kenya and Tanzania, this note seeks to provide a better understanding of how the potential benefits of ICM can be translated into tangible results. The note outlines some of the available ICM technology, delineate the enabling environment for ICM, and provide step-by-step guidance on how to effectively design and implement ICM in projects.

Drugs developed to slow, halt or reverse the progression of Alzheimer’s Disease (AD) have failed to alter the course of the disease in clinical trials. One possible explanation is that drugs need to be administered earlier, before the onset of clinical symptoms. AD-related pathological processes that occur before clinical symptoms emerge define the preclinical phase of the disease. Neuroimaging biomarkers and genetics together present a powerful system for characterizing potential preclinical changes in the brain. The work presented in this volume is predicated on the need for a better understanding of genetic risk and neuroimaging biomarkers for AD in healthy adults. In Chapter 1, a thorough review of neuroimaging genetics in AD is presented. The studies described in Chapters 2 and 3 explore the relationship between functional connectivity and the apolioprotein E (APOE) risk allele, APOEε4. In the first study a pattern of context-dependent connectivity was uncovered that indicates APOEε4 carriers disengage key cortical regions from the hippocampus during a memory task. These findings support the growing consensus that functional connectivity changes may be among the earliest preclinical markers of AD-related changes in the brain. The second study utilized resting state fMRI scans from 570 healthy college-age adults. Young carriers of APOEε4 showed decreased connectivity between key regions involved in AD and increased segregation of task-positive and task-negative regions. This work is a crucial reminder that genetic risk for AD has important implications across the lifespan and that gene-biomarker associations must be tracked over time to identify changes that might be signs of imminent clinical decline. In Chapter 4, the focus expands to include additional genetic risk factors for AD beyond APOE. This study is the first to show that a genetic risk score for AD is significantly associated with hippocampal thinning over two years in a cohort of older, cognitively healthy adults. Finally, Chapter 5 is a call for the further development of polygenic approaches to studying neuroimaging markers of genetic risk for AD. Together, this volume represents steps toward understanding how genetic risk for AD and neuroimaging can be used to identify individuals at greatest risk for decline.

Cognitive control is an important framework for understanding the neuropsychological processes that underlie and enable the successful completion of everyday tasks. Only recently has research in this area investigated motivational contributions to control allocation. An important gap in our understanding is the way in which intrinsic rewards associated with a task motivate the sustained allocation of cognitive control. In three behavioral and one functional magnetic resonance imaging studies, we use a naturalistic and open-sourced simulator to show that changes in the balance between task difficulty and an individual’s ability to perform the task result in different levels of intrinsic reward, which motivates dynamic shifts between networked brain states. Specifically, high levels of intrinsic reward associated with a balance between task difficulty and individual ability are associated with increased connectivity between cognitive control and reward networks. By comparison, a mismatch between task difficulty and individual ability is associated with lower levels of intrinsic reward and corresponds to increased activity within the default mode network. Insular activation suggests that motivational salience, as defined by the level of intrinsic reward, drives shifts between networked brain states associated with task engagement or disengagement. These results implicate reward processing as a critical component of cognitive control.

There are divergent claims concerning the broad cortical organization of speechrecognition. One model holds that speech perception and comprehension is governed by a left lateralized anterior temporal lobe (ATL) pathway. Another model argues that bilateral superior temporal regions are critically important, and, in fact, represent a lower level of processing that drives ATL activation in a bottom up fashion. These models were tested in a series of auditory fMRI experiments that gradually investigated lower levels of speech analysis. The experiments contrasted listening to clear monosyllabic words, pseudowords, sentences, and word lists with unintelligible spectrally rotated and time-reversed speech. In the first experiment, posterior temporal regions did not respond differentially to sentence versus word list stimuli, consistent with the idea that bilateral regions of the superior temporal plane support speech recognition at a lower (perhaps phonological) level. An area of the ATL centered around the superior temporal sulcus (STS) was activated more for sentences than word lists, indicating that the region may be involved in sentence-level operations. In the second experiment, this same region in the left hemisphere was activated more by monosyllabic words than rotated words. This suggests that the anterior focus is not exclusively attributable to sentence-level operations. In the third experiment, lexical status was found to differentially modulate anterior and posterior STS regions. There was more activation in the aSTS bilaterally for words than pseudowords, but these conditions did not lead to activation differences in the posterior region. It appears that anterior temporal speech-selective regions respond to lexical-semantic aspects of speech, whereas posterior temporal speech-selective areas are coding lower level phonemic information.

Timing is an essential component of human actions, and is the foundation of any sort of sequential behavior, from picking up a glass to playing an instrument or dancing. Because of this, our understanding of how we represent time in the brain (i.e., the human timing system) critically relies on basic research on simple behaviors. Perception of temporal regularities is central to a wide range of basic actions, but also underpins abilities unique to humans such as the creation of complex musical scores. This dissertation is an in-depth examination of endogenously and exogenously guided timing behavior, and how context is a critical component of understanding rhythmic entrainment in humans. We previously validated “gold standard” functional magnetic resonance imaging (fMRI) findings on action-based timing behavior using functional near infrared spectroscopy (fNIRS) (Rahimpour et al., 2020). In particular, we observed significant hemodynamic responses in cortical areas in direct relation to the complexity of the behavior being performed. To do so, we probed multiple levels of contextual influence on action-based timing behavior and patterns of cortical activation as measured using fNIRS. Our findings highlighted several distinct, context-dependent parameters of specific timing behaviors. Here we further interrogate human timing abilities by introducing variations of our original experimental design, observing that subtle contextual variations have a significant impact on the degree of rhythmic entrainment given the presence/absence of metronomic input. We used electroencephalogram (EEG) to further validate our fNIRS findings, demonstrating that single trial neurobiological activity can be used to predict whether behavior is exogenously or endogenously guided. We also found that patterns of neural activity correspond to differential use of the internal timing system, and that specific differences in neural activity correlate with accuracy of action-based timing behavior. These findings emerged from our use of a novel deep learning approach to extract person-specific, neural-based features as predictors of behavioral performance. Finally, we examined whether fNIRS and EEG produced similar localization information, finding that the influence of training factors on cortical localization must be accounted for to make such comparisons.

In daily life, moral judgments are embedded in dynamic, complex, and contextualized environments. As we reason about morally right or wrong behaviors, our personal history shapes how we judge who did what to whom, where, when, and why. Yet, surprisingly little is known about how individual differences in moral dispositions modulate shared neural response patterns when processing increasingly complex moral scenarios. Consequently, we herein examine brain-behavior-trait coherence in moral cognition across three datasets of increasing naturalistic complexity. Applying intersubject representational similarity analysis, we demonstrate how between-subject variability in moral dispositions modulates similarity in neural responses when processing decontextualized moral vignettes, auditory movie summaries, political attack advertisement, soap opera clips, and full-length movies. Our approach highlights how brain-behavior-trait relationships during moral cognition are shaped by paradigm choice, and provides a reference for conducting research at the intersection of socio-moral cognition, communication science, and naturalistic neuroimaging.