Matching Items (156)

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Young Adult and Middle-Age Rats Display Unique Working Memory Impairment and Differential Neurobiological Profiles following Hysterectomy

Description

Hysterectomy is the second most common gynecological surgery performed in women. Half of these surgeries involve removal of the uterus alone, and half involve concomitant removal of the ovaries. While

Hysterectomy is the second most common gynecological surgery performed in women. Half of these surgeries involve removal of the uterus alone, and half involve concomitant removal of the ovaries. While the field has retained the notion that the nonpregnant uterus is dormant, more recent findings suggest that hysterectomy is associated with cognitive detriment. Of note, the clinical literature suggests that an earlier age at hysterectomy, with or without concomitant ovarian removal, increases dementia risk, implicating age at surgery as a variable of interest. While preclinical work in a rodent model of hysterectomy has demonstrated spatial working memory impairments, the role of age at surgery has yet to be addressed. The current experiment utilized a rodent model of hysterectomy to investigate the importance of age at surgery in post- surgical cognitive outcomes and to evaluate relative protein expression related to brain activity, FosB and ∆FosB, in regions critical to spatial learning processes. Young adult and middle-aged female rats underwent sham surgery, hysterectomy, or hysterectomy with ovariectomy, and were tested on a behavioral battery that evaluated spatial working and reference memory. Following the behavioral battery, animals were sacrificed and brain tissues from the Dorsal Hippocampus and Entorhinal Cortex were processed via Western Blot for relative FosB and ∆FosB expression. Behavioral analyses demonstrated that animals receiving hysterectomy, regardless of age or ovarian status, were generally impaired in learning a complex spatial working memory task. However, rats that received hysterectomy in middle-age uniquely demonstrated persistent working memory impairment, particularly with a high working memory demand. Subsequent neurobiological analyses revealed young rats that underwent hysterectomy had reduced relative FosB expression in the Entorhinal Cortex compared to sham controls, where no significant effects were observed for rats that received surgery in middle-age. Finally, unique relationships between neurobiological and behavioral outcomes were observed largely for sham rats, suggesting that such surgical manipulations might modulate these relationships. Taken together, these findings suggest that age at surgery plays an important role in learning and memory outcomes following hysterectomy, and demonstrate the need for further research into the role of the uterus in communications between the reproductive tract and brain.

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  • 2020

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Understanding Cortical Neuron Dynamics through Simulation-Based Applications of Machine Learning

Description

It is increasingly common to see machine learning techniques applied in conjunction with computational modeling for data-driven research in neuroscience. Such applications include using machine learning for model development, particularly

It is increasingly common to see machine learning techniques applied in conjunction with computational modeling for data-driven research in neuroscience. Such applications include using machine learning for model development, particularly for optimization of parameters based on electrophysiological constraints. Alternatively, machine learning can be used to validate and enhance techniques for experimental data analysis or to analyze model simulation data in large-scale modeling studies, which is the approach I apply here. I use simulations of biophysically-realistic cortical neuron models to supplement a common feature-based technique for analysis of electrophysiological signals. I leverage these simulated electrophysiological signals to perform feature selection that provides an improved method for neuron-type classification. Additionally, I validate an unsupervised approach that extends this improved feature selection to discover signatures associated with neuron morphologies - performing in vivo histology in effect. The result is a simulation-based discovery of the underlying synaptic conditions responsible for patterns of extracellular signatures that can be applied to understand both simulation and experimental data. I also use unsupervised learning techniques to identify common channel mechanisms underlying electrophysiological behaviors of cortical neuron models. This work relies on an open-source database containing a large number of computational models for cortical neurons. I perform a quantitative data-driven analysis of these previously published ion channel and neuron models that uses information shared across models as opposed to information limited to individual models. The result is simulation-based discovery of model sub-types at two spatial scales which map functional relationships between activation/inactivation properties of channel family model sub-types to electrophysiological properties of cortical neuron model sub-types. Further, the combination of unsupervised learning techniques and parameter visualizations serve to integrate characterizations of model electrophysiological behavior across scales.

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Date Created
  • 2020

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Transcranial Focused Ultrasound for Modulation of Attention Networks in Humans

Description

Transcranial focused ultrasound (tFUS) is a unique neurostimulation modality with potential to develop into a highly sophisticated and effective tool. Unlike any other noninvasive neurostimulation technique, tFUS has a high

Transcranial focused ultrasound (tFUS) is a unique neurostimulation modality with potential to develop into a highly sophisticated and effective tool. Unlike any other noninvasive neurostimulation technique, tFUS has a high spatial resolution (on the order of millimeters) and can penetrate across the skull, deep into the brain. Sub-thermal tFUS has been shown to induce changes in EEG and fMRI, as well as perception and mood. This study investigates the possibility of using tFUS to modulate brain networks involved in attention and cognitive control.Three different brain areas linked to saliency, cognitive control, and emotion within the cingulo-opercular network were stimulated with tFUS while subjects performed behavioral paradigms. The first study targeted the dorsal anterior cingulate cortex (dACC), which is associated with performance on cognitive attention tasks, conflict, error, and, emotion. Subjects performed a variant of the Erikson Flanker task in which emotional faces (fear, neutral or scrambled) were displayed in the background as distractors. tFUS significantly reduced the reaction time (RT) delay induced by faces; there were significant differences between tFUS and Sham groups in event related potentials (ERP), event related spectral perturbation (ERSP), conflict and error processing, and heart rate variability (HRV).
The second study used the same behavioral paradigm, but targeted tFUS to the right anterior insula/frontal operculum (aIns/fO). The aIns/fO is implicated in saliency, cognitive control, interoceptive awareness, autonomic function, and emotion. tFUS was found to significantly alter ERP, ERSP, conflict and error processing, and HRV responses.
The third study targeted tFUS to the right inferior frontal gyrus (rIFG), employing the Stop Signal task to study inhibition. tFUS affected ERPs and improved stopping speed. Using network modeling, causal evidence is presented for rIFG influence on subcortical nodes in stopping.
This work provides preliminarily evidence that tFUS can be used to modulate broader network function through a single node, affecting neurophysiological processing, physiologic responses, and behavioral performance. Additionally it can be used as a tool to elucidate network function. These studies suggest tFUS has the potential to affect cognitive function as a clinical tool, and perhaps even enhance wellbeing and expand conscious awareness.

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  • 2020

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Neuronal Deep Fakes Data Driven Optimization of Reduced Neuronal Model

Description

Neuron models that behave like their biological counterparts are essential for computational neuroscience.Reduced neuron models, which abstract away biological mechanisms in the interest of speed and interpretability, have received much

Neuron models that behave like their biological counterparts are essential for computational neuroscience.Reduced neuron models, which abstract away biological mechanisms in the interest of speed and interpretability, have received much attention due to their utility in large scale simulations of the brain, but little care has been taken to ensure that these models exhibit behaviors that closely resemble real neurons.
In order to improve the verisimilitude of these reduced neuron models, I developed an optimizer that uses genetic algorithms to align model behaviors with those observed in experiments.
I verified that this optimizer was able to recover model parameters given only observed physiological data; however, I also found that reduced models nonetheless had limited ability to reproduce all observed behaviors, and that this varied by cell type and desired behavior.
These challenges can partly be surmounted by carefully designing the set of physiological features that guide the optimization. In summary, we found evidence that reduced neuron model optimization had the potential to produce reduced neuron models for only a limited range of neuron types.

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  • 2020

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Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Description

Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases,

Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases, yet its neuropathophysiology is still poorly understood. While a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (post-natal day 20) to repeat weight drop impact. Animals were anesthetized and subjected to sham or rmTBI once per day for 5 days. At 14 days post injury (PID), magnetic resonance imaging (MRI) revealed that rmTBI animals displayed marked cortical atrophy and ventriculomegaly. Specifically, the thickness of the cortex was reduced up to 46% beneath and the ventricles increased up to 970% beneath the impact zone. Immunostaining with the neuron specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker, 4-Aminophyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents.

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Date Created
  • 2014

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Understanding the processing of degraded speech: electroencephalographic measures as a surrogate for recovery from concussion

Description

The recent spotlight on concussion has illuminated deficits in the current standard of care with regard to addressing acute and persistent cognitive signs and symptoms of mild brain injury. This

The recent spotlight on concussion has illuminated deficits in the current standard of care with regard to addressing acute and persistent cognitive signs and symptoms of mild brain injury. This stems, in part, from the diffuse nature of the injury, which tends not to produce focal cognitive or behavioral deficits that are easily identified or tracked. Indeed it has been shown that patients with enduring symptoms have difficulty describing their problems; therefore, there is an urgent need for a sensitive measure of brain activity that corresponds with higher order cognitive processing. The development of a neurophysiological metric that maps to clinical resolution would inform decisions about diagnosis and prognosis, including the need for clinical intervention to address cognitive deficits. The literature suggests the need for assessment of concussion under cognitively demanding tasks. Here, a joint behavioral- high-density electroencephalography (EEG) paradigm was employed. This allows for the examination of cortical activity patterns during speech comprehension at various levels of degradation in a sentence verification task, imposing the need for higher-order cognitive processes. Eight participants with concussion listened to true-false sentences produced with either moderately to highly intelligible noise-vocoders. Behavioral data were simultaneously collected. The analysis of cortical activation patterns included 1) the examination of event-related potentials, including latency and source localization, and 2) measures of frequency spectra and associated power. Individual performance patterns were assessed during acute injury and a return visit several months following injury. Results demonstrate a combination of task-related electrophysiology measures correspond to changes in task performance during the course of recovery. Further, a discriminant function analysis suggests EEG measures are more sensitive than behavioral measures in distinguishing between individuals with concussion and healthy controls at both injury and recovery, suggesting the robustness of neurophysiological measures during a cognitively demanding task to both injury and persisting pathophysiology.

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Date Created
  • 2014

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The role of tactile information in transfer of learned manipulation following changes in degrees of freedom

Description

Humans are capable of transferring learning for anticipatory control of dexterous object manipulation despite changes in degrees-of-freedom (DoF), i.e., switching from lifting an object with two fingers to lifting the

Humans are capable of transferring learning for anticipatory control of dexterous object manipulation despite changes in degrees-of-freedom (DoF), i.e., switching from lifting an object with two fingers to lifting the same object with three fingers. However, the role that tactile information plays in this transfer of learning is unknown. In this study, subjects lifted an L-shaped object with two fingers (2-DoF), and then lifted the object with three fingers (3-DoF). The subjects were divided into two groups--one group performed the task wearing a glove (to reduce tactile sensibility) upon the switch to 3-DoF (glove group), while the other group did not wear the glove (control group). Compensatory moment (torque) was used as a measure to determine how well the subject could minimize the tilt of the object following the switch from 2-DoF to 3-DoF. Upon the switch to 3-DoF, subjects wearing the glove generated a compensatory moment (Mcom) that had a significantly higher error than the average of the last five trials at the end of the 3-DoF block (p = 0.012), while the control subjects did not demonstrate a significant difference in Mcom. Additional effects of the reduction in tactile sensibility were: (1) the grip force for the group of subjects wearing the glove was significantly higher in the 3-DoF trials compared to the 2-DoF trials (p = 0.014), while the grip force of the control subjects was not significantly different; (2) the difference in centers of pressure between the thumb and fingers (ΔCoP) significantly increased in the 3-DoF block for the group of subjects wearing the glove, while the ΔCoP of the control subjects was not significantly different; (3) lastly, the control subjects demonstrated a greater increase in lift force than the group of subjects wearing the glove (though results were not significant). Combined together, these results suggest different force modulation strategies are used depending on the amount of tactile feedback that is available to the subject. Therefore, reduction of tactile sensibility has important effects on subjects' ability to transfer learned manipulation across different DoF contexts.

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  • 2014

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Surgical Freedom in Endoscopic Skull Base Surgery: Quantitative Analysis for Endoscopic Approaches

Description

During the past five decades neurosurgery has made great progress, with marked improvements in patient outcomes. These noticeable improvements of morbidity and mortality can be attributed to the advances in

During the past five decades neurosurgery has made great progress, with marked improvements in patient outcomes. These noticeable improvements of morbidity and mortality can be attributed to the advances in innovative technologies used in neurosurgery. Cutting-edge technologies are essential in most neurosurgical procedures, and there is no doubt that neurosurgery has become heavily technology dependent. With the introduction of any new modalities, surgeons must adapt, train, and become thoroughly familiar with the capabilities and the extent of application of these new innovations. Within the past decade, endoscopy has become more widely used in neurosurgery, and this newly adopted technology is being recognized as the new minimally invasive future of neurosurgery. The use of endoscopy has allowed neurosurgeons to overcome common challenges, such as limited illumination and visualization in a very narrow surgical corridor; however, it introduces other challenges, such as instrument "sword fighting" and limited maneuverability (surgical freedom). The newly introduced concept of surgical freedom is very essential in surgical planning and approach selection and can play a role in determining outcome of the procedure, since limited surgical freedom can cause fatigue or limit the extent of lesion resection. In my thesis, we develop a consistent objective methodology to quantify and evaluate surgical freedom, which has been previously evaluated subjectively, and apply this model to the analysis of various endoscopic techniques. This model is crucial for evaluating different endoscopic surgical approaches before they are applied in a clinical setting, for identifying surgical maneuvers that can improve surgical freedom, and for developing endoscopic training simulators that accurately model the surgical freedom of various approaches. Quantifying the extent of endoscopic surgical freedom will also provide developers with valuable data that will help them design improved endoscopes and endoscopic instrumentation.

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Date Created
  • 2014

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Optimization of menopausal hormone therapies for cognitive and brain aging using a rat model

Description

Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels

Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive decline, and other symptoms that reduce quality of life. To ameliorate these negative consequences, estrogen-containing hormone therapy is prescribed. Findings from clinical and pre-clinical research studies suggest that menopausal hormone therapies can benefit memory and associated neural substrates. However, findings are variable, with some studies reporting null or even detrimental cognitive and neurobiological effects of these therapies. Thus, at present, treatment options for optimal cognitive and brain health outcomes in menopausal women are limited. As such, elucidating factors that influence the cognitive and neurobiological effects of menopausal hormone therapy represents an important need relevant to every aging woman. To this end, work in this dissertation has supported the hypothesis that multiple factors, including post-treatment circulating estrogen levels, experimental handling, type of estrogen treatment, and estrogen receptor activity, can impact the realization of cognitive benefits with Premarin hormone therapy. We found that the dose-dependent working memory benefits of subcutaneous Premarin administration were potentially regulated by the ratios of circulating estrogens present following treatment (Chapter 2). When we administered Premarin orally, it impaired memory (Chapter 3). Follow-up studies revealed that this impairment was likely due to the handling associated with treatment administration and the task difficulty of the memory measurement used (Chapters 3 and 4). Further, we demonstrated that the unique cognitive impacts of estrogens that become increased in circulation following Premarin treatments, such as estrone (Chapter 5), and their interactions with the estrogen receptors (Chapter 6), may influence the realization of hormone therapy-induced cognitive benefits. Future directions include assessing the mnemonic effects of: 1) individual biologically relevant estrogens and 2) clinically-used bioidentical hormone therapy combinations of estrogens. Taken together, information gathered from these studies can inform the development of novel hormone therapies in which these parameters are optimized.

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Date Created
  • 2013

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Evaluating and controlling glioblastoma infiltration

Description

Glioblastoma (GBM) is the most common primary brain tumor with an incidence of approximately 11,000 Americans. Despite decades of research, average survival for GBM patients is a modest 15 months.

Glioblastoma (GBM) is the most common primary brain tumor with an incidence of approximately 11,000 Americans. Despite decades of research, average survival for GBM patients is a modest 15 months. Increasing the extent of GBM resection increases patient survival. However, extending neurosurgical margins also threatens the removal of eloquent brain. For this reason, the infiltrative nature of GBM is an obstacle to its complete resection. We hypothesize that targeting genes and proteins that regulate GBM motility, and developing techniques that safely enhance extent of surgical resection, will improve GBM patient survival by decreasing infiltration into eloquent brain regions and enhancing tumor cytoreduction during surgery. Chapter 2 of this dissertation describes a gene and protein we identified; aquaporin-1 (aqp1) that enhances infiltration of GBM. In chapter 3, we describe a method for enhancing the diagnostic yield of GBM patient biopsies which will assist in identifying future molecular targets for GBM therapies. In chapter 4 we develop an intraoperative optical imaging technique that will assist identifying GBM and its infiltrative margins during surgical resection. The topic of this dissertation aims to target glioblastoma infiltration from molecular and cellular biology and neurosurgical disciplines. In the introduction we; 1. Provide a background of GBM and current therapies. 2. Discuss a protein we found that decreases GBM survival. 3. Describe an imaging modality we utilized for improving the quality of accrued patient GBM samples. 4. We provide an overview of intraoperative contrast agents available for neurosurgical resection of GBM, and discuss a new agent we studied for intraoperative visualization of GBM.

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Date Created
  • 2014