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- Creators: Arizona State University
- Creators: Nichols, Joshua
Description
Following a traumatic brain injury (TBI) 5-50% of patients will develop post traumatic epilepsy (PTE). Pediatric patients are most susceptible with the highest incidence of PTE. Currently, we cannot prevent the development of PTE and knowledge of basic mechanisms are unknown. This has led to several shortcomings to the treatment of PTE, one of which is the use of anticonvulsant medication to the population of TBI patients that are not likely to develop PTE. The complication of identifying the two populations has been hindered by the ability to find a marker to the pathogenesis of PTE. The central hypothesis of this dissertation is that following TBI, the cortex undergoes distinct cellular and synaptic reorganization that facilitates cortical excitability and promotes seizure development. Chapter 2 of this dissertation details excitatory and inhibitory changes in the rat cortex after severe TBI. This dissertation aims to identify cortical changes to a single cell level after severe TBI using whole cell patch clamp and electroencephalogram electrophysiology. The work of this dissertation concluded that excitatory and inhibitory synaptic activity in cortical controlled impact (CCI) animals showed the development of distinct burst discharges that were not present in control animals. The results suggest that CCI induces early "silent" seizures that are detectable on EEG and correlate with changes to the synaptic excitability in the cortex. The synaptic changes and development of burst discharges may play an important role in synchronizing the network and promoting the development of PTE.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2014
Description
Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers. Although cigarette smoking is highly addictive, nicotine is a relatively weak primary reinforcer, spurring research on other potential targets that may maintain smoking, including the potential benefits of nicotine on attention, inhibition, and reinforcer efficacy. The present study employs the most prevalent rodent model of ADHD, the spontaneously hypertensive rat (SHR) and its control comparison Wistar Kyoto (WKY) to examine the effects of acute and chronic subcutaneous nicotine injections on performance in three operant response inhibition paradigms. Functional activation in select regions of the prefrontal cortex and striatum was also explored. Acute (0.1, 0.3, 0.6 mg/kg) and chronic (0.3 mg/kg) nicotine increased impulsive responding regardless of strain, dose, or operant schedule. Dose-dependent decreases in latency to initiate the task were also observed. SHR receiving daily nicotine injections showed less activation in the nucleus accumbens shell compared to saline controls. Despite close similarities, one of the three operant tasks did not detect response inhibition deficits in SHR relative to WKY. A closer examination of these tasks may highlight critical components involved in the amelioration of response inhibition deficits.
ContributorsMazur, Gabriel Joseph (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter R (Committee member) / Neisewander, Janet L (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2014
Description
The failure to withhold inappropriate behavior is a central component of most impulse control disorders, including Attention Deficit Hyperactivity Disorder (ADHD). The present study examined the effects of housing environment and methylphenidate (a drug often prescribed for ADHD) on the performance of rats in two response inhibition tasks: differential reinforcement of low rate (DRL) and fixed minimum interval (FMI). Both tasks required rats to wait a fixed amount of time (6 s) before emitting a reinforced response. The capacity to withhold the target response (volitional inhibition) and timing precision were estimated on the basis of performance in each of the tasks. Paradoxically, rats housed in a mildly enriched environment that included a conspecific displayed less volitional inhibition in both tasks compared to rats housed in an isolated environment. Enriched housing, however, increased timing precision. Acute administration of methylphenidate partially reversed the effects of enriched housing. Implications of these results in the assessment and treatment of ADHD-related impulsivity are discussed.
ContributorsHill, Jade C (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2011
Description
Dopamine (DA) is a neurotransmitter involved in attention, goal oriented behavior, movement, reward learning, and short term and working memory. For the past four decades, mathematical and computational modeling approaches have been useful in DA research, and although every modeling approach has limitations, a model is an efficient way to generate and explore hypotheses. This work develops a model of DA dynamics in a representative, single DA neuron by integrating previous experimental, theoretical and computational research. The model consists of three compartments: the cytosol, the vesicles, and the extracellular space and forms the basis of a new mathematical paradigm for examining the dynamics of DA synthesis, storage, release and reuptake. The model can be driven by action potentials generated by any model of excitable membrane potential or even from experimentally induced depolarization voltage recordings. Here the model is forced by a previously published model of the excitable membrane of a mesencephalic DA neuron in order to study the biochemical processes involved in extracellular DA production. After demonstrating that the model exhibits realistic dynamics resembling those observed experimentally, the model is used to examine the functional changes in presynaptic mechanisms due to application of cocaine. Sensitivity analysis and numerical studies that focus on various possible mechanisms for the inhibition of DAT by cocaine provide insight for the complex interactions involved in DA dynamics. In particular, comparing numerical results for a mixed inhibition mechanism to those for competitive, non-competitive and uncompetitive inhibition mechanisms reveals many behavioral similarities for these different types of inhibition that depend on inhibition parameters and levels of cocaine. Placing experimental results within this context of mixed inhibition provides a possible explanation for the conflicting views of uptake inhibition mechanisms found in experimental neuroscience literature.
ContributorsTello-Bravo, David (Author) / Crook, Sharon M (Thesis advisor) / Greenwood, Priscilla E (Thesis advisor) / Baer, Steven M. (Committee member) / Castaneda, Edward (Committee member) / Castillo-Chavez, Carlos (Committee member) / Arizona State University (Publisher)
Created2012
Description
The purpose of this study, originally, was to contribute to the completion of a meta-analysis conducted by Mara Wierstra from the University of Virginia. Wierstra had requested individual participant data from two separate studies conducted in our lab: "Acute bouts of assisted cycling improves cognitive and upper extremity movement functions in adolescents with Down syndrome" and "Assisted Cycling Therapy (ACT) improves inhibition in adolescents with autism spectrum disorder." From the data requested, the participants were required to complete three separate tests (i.e., Tower of London, Trail Making Task and the Stroop Test). After compiling the data and sending it to her, we decided to conduct a small meta-analysis of our own, drawing connecting conclusions from the data from the two studies. We concluded that observationally our data suggest an advantage for ACT over voluntary cycling and no cycling across two separate populations (i.e., Autism Spectrum Disorder and Down syndrome), and across different measures of executive function (i.e., Stroop Test, Trail Making Test, and Tower of London). The data suggest that the ACT interventions may promote the upregulation of neurotropic factors leading to neurogenesis in the prefrontal cortex of the brain.
ContributorsParker, Cade Joseph (Author) / Ringenbach, Shannon (Thesis director) / Holzapfel, Simon (Committee member) / School of Nutrition and Health Promotion (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
In this study, the oppositional processes theory was proposed to suggest that reliance on semantic and episodic memory systems hinder originality during idea generation for divergent thinking tasks that are generally used to assess creative potential. In order to investigate the proposed oppositional processes theory, three experiments that manipulated the memory accessibility in participants during the alternative uses tasks were conducted. Experiment 1 directly instructed participants to either generate usages based on memory or not from memory; Experiment 2 provided participants with object cues that were either very common or very rare in daily life (i.e., bottle vs. canteen); Experiment 3 replicated the same manipulation from Experiment 2 with much longer generation time (10 minutes in Experiment 2 vs. 30 minutes in Experiment 3). The oppositional processes theory predicted that participants who had less access to direct and unaltered usages (i.e., told to not use memory, were given rare cues, or were outputting items later in the generation period) during the task would be more creative. Results generally supported the predictions in Experiments 1 and 2 where participants from conditions which limited their access to memory generated more novel usages that were considered more creative by independent coders. Such effects were less prominent in Experiment 3 with extended generation time but the trends remained the same.
ContributorsXu, Dongchen (Author) / Brewer, Gene (Thesis advisor) / Glenberg, Arthur (Committee member) / Homa, Donald (Committee member) / Goldinger, Stephen (Committee member) / Arizona State University (Publisher)
Created2017
Description
It has been suggested that directed forgetting (DF) in the item-method paradigm results from selective rehearsal of R items and passive decay of F items. However, recent evidence suggested that the passive decay explanation is insufficient. The current experiments examined two theories of DF that assume an active forgetting process: (1) attentional inhibition and (2) tagging and selective search (TSS). Across three experiments, the central tenets of these theories were evaluated. Experiment 1 included encoding manipulations in an attempt to distinguish between these competing theories, but the results were inconclusive. Experiments 2 and 3 examined the theories separately. The results from Experiment 2 supported a representation suppression account of attentional inhibition, while the evidence from Experiment 3 suggested that TSS was not a viable mechanism for DF. Overall, the results provide additional evidence that forgetting is due to an active process, and suggest this process may act to suppress the representations of F items.
ContributorsHansen, Whitney Anne (Author) / Goldinger, Stephen D. (Thesis advisor) / Azuma, Tamiko (Committee member) / Brewer, Gene (Committee member) / Homa, Donald (Committee member) / Arizona State University (Publisher)
Created2011
Description
Retrieving an item from memory can cause subsequent suppression of related items. This phenomenon, involving a procedure where participants retrieve category-exemplar pairs (e.g. FRUIT-orange), is known as Retrieval Induced Forgetting (RIF). Individuals who demonstrate greater amounts of RIF also exhibit greater working memory capacity (WMC). Reasoning ability is highly related to WMC, which may suggest that a similar relation exists between RIF and Reasoning ability. The goal of the present investigation was to examine this possibility. Rotation Span and a Letter Number task were used as indicators of WMC and a Cognitive Reflection Test was used to measure Reasoning ability. A significant RIF effect was found, but it did not significantly correlate with WMC or Reasoning ability. These results demonstrate the importance of designing a RIF task appropriately, selecting measures of Reasoning ability, and the theoretical accounts of the RIF effect. One possibility is that by not controlling for output interference, the obtained RIF effect cannot be reasoned to come from the executive control process as suggested by the inhibition account. Although this account is the chief explanation of the RIF effect, it has been challenged by alternative accounts and it remains unclear how the underlying mechanism of RIF is related to higher cognitive abilities.
ContributorsMaxwell, Joshua (Author) / Duran, Nicholas (Thesis advisor) / Hall, Deborah (Committee member) / Robles-Sotelo, Elias (Committee member) / Arizona State University (Publisher)
Created2016
Description
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. When TBI occurs in children it often results in severe cognitive and behavioral deficits. Post-injury, the pediatric brain may be sensitive to the effects of TBI while undergoing a number of age-dependent physiological and neurobiological changes. Due to the nature of the developing cortex, it is important to understand how a pediatric brain recovers from a severe TBI (sTBI) compared to an adult. Investigating major cortical and cellular changes after sTBI in a pediatric model can elucidate why pediatrics go on to suffer more neurological damage than an adult after head trauma. To model pediatric sTBI, I use controlled cortical impact (CCI) in juvenile mice (P22). First, I show that by 14 days after injury, animals begin to show recurrent, non-injury induced, electrographic seizures. Also, using whole-cell patch clamp, layer V pyramidal neurons in the peri-injury area show no changes except single-cell excitatory and inhibitory synaptic bursts. These results demonstrate that CCI induces epileptiform activity and distinct synaptic bursting within 14 days of injury without altering the intrinsic properties of layer V pyramidal neurons. Second, I characterized changes to the cortical inhibitory network and how fast-spiking (FS) interneurons in the peri-injury region function after CCI. I found that there is no loss of interneurons in the injury zone, but a 70% loss of parvalbumin immunoreactivity (PV-IR). FS neurons received less inhibitory input and greater excitatory input. Finally, I show that the cortical interneuron network is also affected in the contralateral motor cortex. The contralateral motor cortex shows a loss of interneurons and loss of PV-IR. Contralateral FS neurons in the motor cortex synaptically showed greater excitatory input and less inhibitory input 14 days after injury. In summary, this work demonstrates that by 14 days after injury, the pediatric cortex develops epileptiform activity likely due to cortical inhibitory network dysfunction. These findings provide novel insight into how pediatric cortical networks function in the injured brain and suggest potential circuit level mechanisms that may contribute to neurological disorders as a result of TBI.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Qiu, Shenfeng (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2015