Stuttering is a developmental speech disorder characterized by interruptions of fluency. A large body of research suggests that stuttering occurs due to a reduced ability to generate timing signals in order to sequence speech sounds. One piece of supporting evidence for this is that when speaking along with an external timing source like a metronome, disfluencies suddenly and significantly decrease. The aim of this dissertation was to characterize the effects of using auditory cues to time speech on neural activation and auditory feedback processing, and how these effects may contribute to fluency in adults who stutter (AWS). Two studies were carried out to examine these effects. In the first study, functional magnetic resonance imaging was used to measure brain activity while AWS and adults who do not stutter (ANS) read sentences aloud either using natural speech timing or aligning each syllable to the beat of a metronome. Consistent with previous literature, AWS produced fewer disfluent trials in the externally paced condition than in the normal condition. Collapsing across the AWS and ANS groups, participants had greater activation in the metronome-timed condition in regions associated with speech sequencing, sensory feedback control, and timing perception. AWS also demonstrated increased functional connectivity among cerebellar regions during externally paced speech. In the second study, responses to online spectral and timing perturbations of auditory feedback were measured while AWS and ANS read sentences with and without metronome pacing. Results indicated that AWS showed no responses to spectral perturbations during the non-paced condition and significant compensatory responses during the paced condition along with fewer disfluencies, while responses in ANS showed the opposite effect. For the timing perturbation, no significant differences were found between groups in either condition. Together, these studies indicate that the deficit in stuttering is related to spectral processing rather than purely temporal processing, and that externally paced speech recruits compensatory neural regions that may help resolve this deficit.

In adult humans, the aging process is marked by gradual declines in most bodily functions. Such decline is thought to begin sometime in early middle age. Declines in cognition and other functions have been well studied primarily in those over the age of 65. Cerebrovascular factors, amyloid deposition, and tau deposition have all been linked to declines in the brain’s ability to function in this older aged group. Less is known about the impact of these factors in a relatively younger group of aged adults. The series of studies in my dissertation were designed to fill this gap in our knowledge. I was fortunate in my doctoral work to have been given access to data that was being collected by the Framingham Heart Study. This is a single-site, longitudinal community-based cohort study that was initiated in 1948 with a recruitment of 5209 participants. Since the inception of the study, three generations of participants have been enrolled. The Offspring cohort, recruited between 1971 and 1975, is comprised of a total of 5,124 participants. The generation 3 cohort recruited between 2002 and 2005 consists of 4,095 participants. They have been evaluated approximately every 4 years since, for a variety of factors including cardiovascular, socio-demographic, and cognition. For the purposes of this investigation, I was able to work with data from the Offspring and the generation 3 cohort participants who attended the 9th examination cycle (2011-2014), and the third examination cycle (2016-2019) respectively. Participants underwent an MRI scan, C-Pittsburgh Compound-B (PiB)-PET scan and F-Flortaucipir PET scan between 2016 and 2019. They were free of stroke, dementia and other neurological condition at the time of assessment. All the participants included in my work were cognitively normal. To assess brain function, we examined functional connectivity with a focus on the default mode network (DMN). The goal of our first study was to determine whether vascular factors, expressed as the Framingham Stroke Risk Profile (FSRP), impact brain connectivity within and between various functional brain networks i.e. the default mode, frontoparietal, dorsal attention, ventral attention, somatomotor, limbic, and visual networks. Both T1 and resting state fMRI scans were acquired and processed using Freesurfer version 6.0 and FSL. Functional brain networks were constructed using the Yeo 7 network atlas. The FSRP score is a composite based on cardiovascular risk factors which were developed to quantify stroke risk. The FSRP is comprised of measures of systolic blood pressure, antihypertensive therapy, diabetes, cigarette smoking status, history of cardiovascular disease, and atrial fibrillation. In addition to FSRP, we examined the isolated effects of age, sex, total cholesterol to hdl cholesterol ratio, hypertention, and body mass index (BMI). In our first study of 388 participants, we examined whether isolated vascular factors expressed separately or as a composite score using FSRP age, sex, total cholesterol to hdl cholesterol ratio, hypertention, body mass index (BMI), and/or ApoE status are associated with functional brain network connectivity with a primary focus on the DMN and a secondary focus on frontoparietal, dorsal attention, and ventral attention networks. We found that FSRP and ApoE status were not associated with functional connectivity within or between any of the functional brain networks. However, individual factors such as age, sex, total cholesterol to hdl cholesterol ratio, hypertention, and BMI had an effect on functional connectivity. In our second study, we examined the relationship between global amyloid deposition and functional connectivity. This study included 305 out of the 388 individuals who participated in study one above and underwent PET imaging with the PiB compound. The primary analysis was focused on functional connectivity within the DMN as components of this network have been described as having a susceptiblety to amyloid plaque deposition. Secondary analyses were focused on functional connectivity within the remaining functional networks such as frontoparietal, dorsal attention, ventral attention, somatomotor, limbic, and visual networks. Interestingly, global amyloid deposition and ApoE status were not related to functional connectivity within any of the networks. Rather, connectivity within the DMN, frontoparietal and limbic networks were related to age and sex. Connectivity within the visual network was only related to age. No relationships were found for functional connectivity within the dorsal attention, ventral attention or somatosensory networks. In our third study, we investigated the relationship between regional tau (hippocampus, parahippocampal gyrus, entorhinal cortex, precuneus, inferior temporal gyrus and rhinal cortex) and functional connectivity. This study included 247 out of the 388 individuals who participated in study one above and underwent PET imaging with the F-Flortaucipir (FTP) compound. The primary analyses here were focused on functional connectivity within the DMN and limbic networks. As with amyloid deposition, we did not find any relationship between regional tau or APOE status and functional connectivity in any of the functional networks. Age and sex were related to functional connectivity within the DMN, frontoparietal and limbic networks. Age alone was related to functional connectivity within the visual network. No relationships were found with functional connectivity within the dorsal attention, ventral attention or somatosensory networks. The findings from our studies differ from what has been reported in an older populations (>65 years) where amyloid and tau accumulation along with vascular factors have a significant effect on functional network connectivity especially in the DMN in healthy older adults.

In the mammalian neocortex, GABAergic interneurons play a variety of roles in higher-order brain functions as key components of brain circuits. Many studies have revealed properties of pyramidal neurons, but the functions of interneurons are relatively poorly understood. Focusing on inter-species differences, previous work in our lab (Gilman et al, 2017) revealed pyramidal neuron differences in monkey and mouse primary visual (V1) and frontal (FC) cortices. Here, we designed a comparative study in a similar context to reveal knowledge of Calretinin (CR)-expressing interneurons in monkey and mouse V1 and area FA of the mouse, prefrontal cortical area 46, and V1 of the monkey. Monkey and mouse brain tissues were immuno-stained, scanned with a confocal microscope and 3D reconstructed using NeuroLucida 360. Semi-automated analyses revealed that mouse CR interneurons on both brain regions were larger and showed more dendritic branching. Cell type sorting following the previous classification method by Cauli et al (2014) showed distinctive cell type distribution Monkey V1. CR interneurons in V1 regions in both species showed features that differentiate them from FC interneurons, including more node counts than those in FC. Also, a sudden increase in average V1 dendritic diameter after its 75% length progression was shown between species. These findings have provided gap-filling knowledge about CR+ interneuron species-specific differences in V1 and PFC, which gives a foundation for inter-species data comparison.

Music therapy is the evidence-based and clinical use of music interventions to accomplish the specific goals of an individual within a therapeutic relationship with a certified music therapist that has completed an approved music therapy program. Neurologic Music Therapy (NMT), and evidence-based music therapy treatment model, centers specifically around music and rhythm’s physical effect on the brain and neuropathways. This is accomplished through specific NMT interventions which are applied in a consistent manner based on the goal of individuals (Hoemberg & Thaut, 2014). Of particular interest to the current study are gait training goals of individuals with neurologic conditions and the use of Rhythmic Auditory Stimulation (RAS) within a rehabilitative setting. The purpose of this analysis was to identify and discuss the use of RAS for individuals with neurologic conditions focusing on velocity, stride length, and cadence in gait training interventions. The intention of this content analysis is to reach a more comprehensive understanding of effective auditory production methods in interventions and populations that may benefit from RAS. Five of the six studies (83.33%) in this content analysis show in increase in the measured gait training functions. Live feedback as the primary auditory production method was used in two of the six (33.33%) studies found. Research using live feedback as the primary auditory production method within rehabilitation was limited, however, delivered positive results. Results may provide a starting point for further, more in-depth research on the therapeutic benefits of RAS gait training with neurologic disorders and the use of live feedback as the primary auditory production method within rehabilitative populations. / A Thesis submitted to the College of Music in partial fulfillment of the requirements for the degree of Master of Music. / 2019 / November 12, 2019. / music therapy, neurologic disability, neurologic disorders, neurologic music therapy, RAS, Rhythmic Auditory Stimulation / Includes bibliographical references. / Kimberly VanWeelden, Professor Directing Thesis; Lori Gooding, Committee Member; Alice-Ann Darrow, Committee Member.

Have you ever noticed when you are hungry and looking for something to eat, you can smell the freshly salted fries of McDonalds before seeing the golden arches? That is because our sense of smell, olfaction, is intimately linked with metabolic state and feeding behavior. In fact, many of the circulating hormones and gut peptides that regulate feeding behaviors have receptors located in the olfactory bulb (OB), and thus, have been reported to influence olfactory functioning; increasing sensitivity while hungry and decreasing odor perception once satiated. If metabolic state becomes disrupted, as observed in metabolic disorders such as obesity and Type 2 Diabetes, this can negatively impact one’s sense of smell, which is why many obese and/or diabetic patients also display symptoms of anosmia, or loss of smell. My laboratory has pinpointed the OB as an internal metabolic sensor, in particular, the mitral cells (MCs) within the OB, which are the major output neurons of the OB and are responsible for sending signals to higher-order processing regions in the brain. Gut peptides and important metabolic factors such as insulin and glucose can increase MC firing frequency via modulation of the voltage-gated potassium channel, Kv1.3. Kv1.3 channels are widely distributed across the body, but are highly expressed in the OB and predominantly located on MCs; Kv1.3 channel carries 60 – 80% of the outward current of these cells. The central theme of my dissertation involves understanding how excess energy substrates can perturb the operation of the brain to effect behavior of the organism. My research involves specifically targeting Kv1.3, that is modulated by circulating neuropeptides and hormones. Our laboratory has demonstrated gut peptides and important metabolic factors such as insulin, glucose, and glucagon-like peptide -1 (GLP-1) can increase MC firing frequency via modulation of Kv1.3, and ultimately modify olfactory and metabolic behaviors. This dissertation examines two aspects in which energy substrates modulate Kv1.3 activity, behaviorally and physiologically. Results from these experiments revealed that 1. Long-term intranasal delivery of insulin does not affect olfactory or metabolic behaviors, but changes meal bout and dampens Kv1.3 phosphorylation. 2. Intranasal delivery of the specific Kv1.3 inhibitor, stichodactyla (ShK) 186 toxin, partially improves metabolism in obese animals. 3. GLP-1 modulates Kv1.3 activity via serine phosphorylation. This work will further expand upon how feeding-related hormones can shape olfactory ability and bring forth new insight into using sensory systems to control food intake and overconsumption, a leading cause of obesity in America. / A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2018. / June 21, 2018. / Includes bibliographical references. / Debra Ann Fadool, Professor Directing Dissertation; Christopher Schatschneider, University Representative; Pradeep G. Bhide, Committee Member; Frank Johnson, Committee Member; Laura R. Keller, Committee Member.

The endocannabinoid system plays an important role in regulating energy balance. Administration of D9-tetrahydrocannabinol (THC), the main constituent of the Cannabis sativa plant, increases food intake and decreases energy expenditure by acting on cannabinoid receptor 1 (CB1R). Despite these well-documented effects, THC treatment has had mixed success in alleviating symptoms and reducing weight loss in anorexia nervosa (AN) patients and in the pre-clinical activity-based anorexia (ABA) rodent model of AN. To maximize medicinal benefits while minimizing potential side effects, the novel cannabinoid AM11101 was developed with the goal of having better efficacy than THC in treating AN symptoms. The goal of this dissertation was to provide the first examination of AM11101’s ability to increase food intake in healthy animals, attenuate weight loss in the pre-clinical ABA model, and identify brain areas that are activated by acute AM11101 treatment. In the first study, the orexigenic effects of AM11101 and THC were compared in pre-fed and free-fed female rats. Acute administration of AM11101 increased food intake for up to 4 h in pre-fed rats with no compensatory decrease in subsequent feeding. Although THC increased food intake in pre-fed rats, it was less reliable than AM11101 in increasing food intake in free-fed rats following both acute and chronic administration. Similar to THC, AM11101’s orexigenic effect was mediated by an increase in meal size. The second study examined whether daily treatment with AM11101 or THC would attenuate weight loss in female rats exposed to the ABA paradigm. We found that AM11101-treated rats displayed greater resilience to ABA than THC-treated rats. AM11101 attenuated ABA-induced weight loss and helped to preserve adipose tissue through a reduction in energy expenditure rather than an increase in food intake. Despite the well-characterized orexigenic effects of cannabinoids, the underlying neuronal mechanisms remain poorly understood. In the third study, we used the immunohistochemical detection of cFos, a marker of neuronal activity, to examine the effect of AM11101 treatment on cFos expression in brain areas that control food intake. We also examined whether AM11101 modulates feeding-induced changes in cFos expression. Acute administration of AM11101 produced a robust increase in cFos expression in multiple brain areas that control food intake. AM11101 was also found to increase feeding-induced cFos expression in one of these areas, the arcuate nucleus of the hypothalamus (ARC). These findings identify multiple brain areas where AM1101 could act to increase meal size. Taken together, these studies demonstrate for the first time that AM11101 increases food intake by a selective increase in meal size, attenuates the development of ABA with improved efficacy over THC, and increases feeding-induced neuronal activation in the ARC, a brain area that plays a critical role in controlling meal size. As such, AM11101 offers a promising new treatment to improve appetite in conditions that are characterized by undernutrition including AN. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / 2019 / November 1, 2019. / activity-based anorexia, cannabinoid, cannabinoid receptor 1, endocannabinoid system, feeding, neuronal activity / Includes bibliographical references. / Lisa Eckel, Professor Directing Dissertation; David Kirby, University Representative; Thomas Houpt, Committee Member; Thomas Joiner, Committee Member; Zuoxin Wang, Committee Member.

Despite early combination antiretroviral therapy (cART) administration, children born with human immunodeficiency virus (HIV) continue to demonstrate neurodevelopmental abnormalities. Often, there is a link between structural and functional abnormalities. Previously, we found HIV-associated changes in white matter and functional networks in a cohort of 7-year-old HIV infected (HIV+) children who intiatied early cART compared to uninfected controls. To explore possible relationships between these alterations, we used tractography to identify HIV-related abnormalities within structural connections located in functional resting state networks. Within HIV+ children (n=61), we identified white matter (WM) tracts with lower mean fractional anisotropy (FA) and/or higher mean diffusivity (MD) located in several functional networks, including the somatosensory, auditory, salience, default mode network (DMN), motor and basal ganglia networks compared to uninfected controls (n=46). Among the uninfected controls, children born to HIV+ mothers (exposed uninfected, HEU) (n=19) showed WM alterations (higher FA) compared to HIV unexposed uninfected children (HUU) (n=27) within tracts in the posterior DMN, visual (occipital lobe and lingual gyrus), salience and motor networks. The observed WM alterations in HIV+ children point to demyelination/dysmyelination within six networks. Four of these networks – the basal ganglia, default mode, salience and somatosensory – were all found to have altered functional connectivity in a previous study; therefore, these results point to damage or developmental delay in white matter may be related to or responsible for the HIV-associated functional abnormalities. The observed WM alterations in the HEU children suggest that even exposure to HIV and/or antiretroviral therapy (ART) also has long-term effects on axonal integrity in the developing brain.

A central question in the study of cortical development is how neural progenitors generate the many types of neurons that organize into distinct functional areas and layers. Using in vivo genetic fate-mapping, we previously showed that separate progenitor lineages specify distinct properties of layer 2/3 pyramidal neurons in the frontal cortex of the mouse. Here we interrogate whether this constitutes a general rule of cortical development by examining a different layer and area of the brain using the same approach. We show that neuronal diversity is also specified by progenitor type of origin in the earlier developing layer 4 of the barrel cortex, but that the differences in progeny are distinct from those specified for layer 2/3 in the frontal cortex. This elucidates a dynamic temporal program in progenitor classes, which fine-tunes the properties of their progeny according to the lamina of destination. Our results also demonstrate that distinct lineages contribute unique features of the barrel cortex topography, specifying daughter cell allocation, electrophysiological properties and synaptic contacts with the thalamus. / 2018-07-01T00:00:00Z

Exposure to repetitive closed-head impact injuries are associated with later development of chronic traumatic encephalopathy (CTE), a progressive tau protein neurodegenerative disease. Increased cumulative exposure to closed-head impact injuries correlates with greater risk of developing CTE. No treatments or validated diagnostic biomarkers for CTE currently exist due to a lack of understanding the mechanistic pathways that underlie the progression of aberrant neuropathology after closed-head injury. Animal models with biological endpoints that match the human neuropathology of closed-head injury could help to understand the biological mechanisms underpinning the development of CTE. To address this issue, we created a novel model of closed-head impact injury. We hypothesized that closed-head impact injury creates focal damage in the ipsilateral cortex and retina. The retina is an optically accessible tissue and shares developmental origins with the brain. The optical accessibility of the retina allows for the observation of pathological changes and functional deficits after closed-head injury. We found that closed-head injury resulted in acute and transient neurobehavioral deficits similar to signs of concussion in humans. After closed-head injury, we observed focal damage to the ipsilateral cortex which included microvascular disruption, neuroinflammation, axonopathy, and tauopathy. We also observed bilateral electrophysiological deficits. In the retina, we observed focal ipsilateral microgliosis and ipsilateral electroretinography deficits. The pathology and functionality of the cortex and retina were normal in sham mice. Given the identification of pathological and functional deficits, we selected several in vivo biomarkers of traumatic brain injury (TBI) for study. Closed-head injured mice could be distinguished from sham mice using a peripheral blood biomarker, by magnetic resonance imaging assessment of the blood-brain barrier, and with fluorescent adaptive optics scanning laser ophthalmoscopy observation of retinal microglia. Our novel animal model of closed-head injury produces traumatic brain injury pathology consistent with human case studies. The results of this work identify components of the acute-subacute response to closed-head injury and potential biomarkers for assessing TBI.

Little is known regarding the brain regions responsible for the perception of 3 dimensional (3D) versus 2 dimensional (2D) images. Thus, functional magnetic resonance imaging (fMRI) was used to determine activation patterns in the human brain under stereoscopic or monoscopic stimuli (e.g. 3D or 2D). To examine whether these regions differ as a function of subject matter, stimuli were separated based on the image themes: locations, objects, and plants and animals. A block design was used to collect data from subjects who were asked to view images in 2 and 3 dimensions in 6 runs. The goal of this study was to determine whether the activation pattern using passive 3D viewing is similar to what has been previously demonstrated using other 3D viewing techniques. A secondary aim was to determine if the stimulus thematic content altered the brain regions involved. The results revealed that in addition to lateral occipital complex (LOC), which has been previously discussed in literature, the supramarginal gyrus and parietal operculum cortex are involved in 3D image perception.