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Influences of the Female Reproductive Cycle on Inflammatory Induced Pain Resonses
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Abstract Influences of the Female Reproductive Cycle on Inflammatory Induced Pain Responses by Nicole J. Amador Advisor: Professor Vanya Quiñones-Jenab Clinical and preclinical studies have demonstrated significant sex differences in the perception of inflammatory pain; females display higher nociceptive responses to inflammatory stimuli than male rats. Additionally, the complex endocrinological profile of females has been shown to impact their nociceptive responses. For example, estradiol reduces Phase II behavioral-nociceptive responses after formalin administration. However, little is known about the specific biological pathway(s) and/or mechanisms in which cycling endogenous female sex hormones affect inflammatory pain responses. Current literature has established that cyclooxygenases and prostanoids are major pro-inflammatory mediators directly linked to inflammatory responses. Additionally, glucocorticoids, (i.e. corticosterone) negatively regulate inflammatory induced COX-2, resulting in attenuation of inflammatory responses. The objective of this study was to further understand how fluctuations of endogenous female sex hormones alter inflammatory-induced responses by examining two physiological pathways (i.e. NO/COX-2 regulation of the prostanoid biosynthetic pathway and corticosterone regulation of the NO/COX pathway) which may in part be responsible for these effects. Endogenous peaks of estrogen and progesterone during proestrus, were shown to significantly attenuate behavioral responses after formalin administration. This attenuation of behavioral responding was accompanied by a significant increase in PGD2 serum levels. Cortiscosterone serum levels were unaffected after formalin administration suggesting that regulation of behavioral responses by endogenous hormones may be occurring through a pathway independent of the corticosterone biosynthetic pathway. COX-2 and nNOS levels in the spinal cord were not significantly affected by the estrous cycle, suggesting that regulation of behavioral responses by endogenous hormonal fluctuations may be occurring through a pathway independent of the NO/COX biosynthetic pathway. Furthermore, although no estrous cycle effects were seen in paw withdrawal latency after carrageenan administration, we observed estrous cycle effects in the contralateral paw at baseline and one hour post-injection. Rats in proestrus showed a significant reduction in thermal- induced hyperalgesia as measured by increased paw withdrawal latency. Although no significant differences were seen in PGD2 serum levels, rats in estrus had significantly higher PGE2 serum levels after carrageenan administration. A significant decrease in PWL was observed in rats during estrus, a time of the lowest levels of fluctuating hormones. These results suggest that hormonal troughs during the cycle may affect inflammation through the PG biosynthetic pathway. Finally, during ages when animals are considered "middle aged" attenuation in inflammatory induced behavior was observed. This finding was accompanied by significant decreases in PGE2 and PGD2 levels and a significant increase in corticosterone serum levels. Taken together these results suggest a relationship between endogenous hormonal fluctuations, corticosterone release and PG activity. In summary, our results suggest that endogenous hormonal peaks and troughs effects on inflammation may be mediated through the regulation of the NO/COX-2/prostanoid biosynthetic pathway.
Object Relations, Internal Resources, and HIV/AIDS Risk: A Rorschach Study
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Abstract The purpose of this study was to explore the quality of Rorschach scores of a population who self-reported sexual risk-taking behaviors that place them at increased risk for contracting HIV. It was hypothesized that this group would produce scores indicative of fewer internal resources available for impulse inhibition, specifically capacity for affect regulation and stress tolerance. It was further predicted that a measure of object relations would indicate that study participants would generally experience interpersonal interactions as imbalanced and possibly threatening. This group produced significantly lower scores with regard to affect regulation, but did not differ from the normed, non-clinical sample with regard to stress tolerance. Further, study participants produced scores in the healthy range on the measure of object relational development. The potential theoretical and clinical implications of this finding are discussed.
DISSOCIATION AND POTENTIAL SPACE ON THE RORSCHACH AS PREDICTORS OF CONCURRENT PTSD AND SUBSTANCE DEPENDENCE TREATMENT OUTCOMES
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Both posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are ongoing public health crises. Dissociative experiences are considered core processes within both of these conditions (van der Kolk & van der Hart, 1989; Briere & Runtz, 1987; Schafer et al., 2010). Dissociation, which involves the compartmentalization of psychic experience, also exerts a significant influence over psychotherapies that aim to address both PTSD and SUD (Davidson & Foa, 1991; Spitzer, Barnow, Freyberger, & Grabe, 2007). However, dissociation is a wide concept that encompasses several perceptual, cognitive, affective, memory, and self-state processes (Bernstein & Putnam, 1986; Briere, Weathers, & Runtz, 2005). Through separate self-reports and projective measures that operationalize dissociation in distinct ways, this study investigated the quality and intensity of dissociative experiences in a sample of treatment-seeking individuals with comorbid PTSD and SUD. Additionally, this dissertation explored whether these measures of dissociation had significant relationships with treatment outcome. Results: Cross-sectional correlation analysis identified convergence between certain measures of dissociation, but not others. Within hierarchical regression analysis, specific subscales of dissociation demonstrated discrepant relationships with response-to-treatment variables. Altogether, this study further evidenced the multidimensional nature of dissociative processes and, subsequently, the value of multi-method assessment. In addition, separate types of dissociation appeared to differentially influence treatment, indicating a pathway through which to improve customization of treatment planning.
Increasing the Variability of Verbal Responding in Children and Adolescents with Autism Using a Conjunctive-Differential Reinforcement Schedule
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A procedure intended to teach variation in appropriate verbal responding to an antecedent stimulus was systematically manipulated for 5 individuals with autism. Four antecedent stimuli that include the clause, "else do you like to do" were presented in a varying order. Five responses that were appropriate to any of the antecedent stimuli were taught using a script-fading procedure. Percentage of varied verbal responses was studied under a conjunctive-differential reinforcement procedure using a multiple-baseline-across-subjects experimental design. Under a modified percentile requirement of the conjunctive schedule, responses were ranked according to their frequency of emission after every session and reinforcement was omitted for the 2 most frequent responses on the subsequent session. Under a lag-1 schedule requirement, reinforcement was omitted for consecutive occurrences of a given response within a given session. Data showed that the percentage of responses meeting the conjunctive schedule requirement increased with the systematic implementation of the schedule. A variability measure showed that responses were more stereotyped during baseline sessions in comparison to treatment sessions. Comparisons between the numbers of different statements emitted by individuals with autism versus those of their typically developing peers suggest that further research is necessary to increase responding to a typical level. Nevertheless, responses by teachers and parents to a social validity questionnaire suggest that the procedure could be applied in clinical and home settings and used to increase varied verbal responding.
Construction of a Forced-Choice Task for the Assessment of Factual Understanding and Feigning in Competency to Stand Trial Evaluations
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Psychologists are commonly called upon to conduct evaluations of a defendant's competency to stand trial. Under Dusky v. United States (1960) the legal criteria for competency to stand trial were enumerated and since then, a number of standardized assessment instruments that aim to assess those criteria have been developed, each with its own noted strengths and weaknesses. Although there are several instruments available to aid clinicians in these types of evaluations, only three include screens for feigning, and only one assesses for feigned cognitive impairment. In the current research an instrument was constructed to assess for competence related knowledge, while also incorporating several logical and statistical methods to assess for a feigned lack of knowledge of the legal system, including forced-choice testing, floor effect strategies, and completion time methodologies. The Factual Understanding Instrument (FUI) was constructed over five studies. Studies 1-3 involved instrument construction and included a review of the literature, a critical incidents phase with experts in the field, and item construction. Studies 4-5 focused on item evaluation and included an expert review of the constructed items and the pilot testing of the FUI in a simulation study with unimpaired college students. In study 5, multiple statistical analyses were conducted to evaluate the FUI items and the various feigning detection strategies. In this sample reliability of the FUI was high. Items were relatively easy for honest responding participants, with many scoring near perfect. Feigning participants did not score as low as would be predicted by symptom validity testing, as responses varied from less than 50% correct to values seen in honest responders. Intelligence level, item difficulty, and response condition were found to be significant predictors in responses to FUI items. Completion time was not supported as a feigning detection method as hypothesized, however, alternative interpretations of the theory are offered. Further research on the FUI with a known-groups sample in forensic settings is needed to establish a floor value, to further evaluate item performance, and to improve the external validity of the current research. Research methodologies and future directions are offered.
SUPRASPINAL AND SPINAL MECHANISMS OF MORPHINE-INDUCED HYPERALGESIA
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Morphine is the most prominent pharmacological treatment for moderate to severe pain in both acute and chronic paradigms. However, morphine notoriously elicits a paradoxical state of increased pain sensitivity known as hyperalgesia that complicates its use in clinical application. Research over the past three decades has reported that morphine-induced hyperalgesia is dose- and sex-dependent, and likely involves the synchronous activity of several neural networks beyond the opioid system. Whereas systemic, supraspinal, and spinal administration of morphine all cause hyperalgesia that is differentially reversible by N-methyl-D-aspartate receptor (NMDAR) antagonists or melanocortin-1 receptor (MC1R) antagonists, it is unknown as to whether or not these non-opioid systems that contribute to this state are located supraspinally or spinally. The current studies were performed with the goal of elucidating the precise location of regulatory action of this sex- and dose- dependent state of morphine hyperalgesia. In all studies, outbred CD-1 male and female mice were pretreated with the general opioid receptor antagonist, naltrexone (NTX) 24 hours prior to morphine treatment. All mice were subsequently implanted with osmotic pumps, continuously dispensing a low (1.6mg/kg/24h) or high dose of morphine (40mg/kg/24h). As noted previously, mice of both sexes were hyperalgesic by Day 4 of continuous infusion of either morphine dose, a state that persisted through Day 6 of infusion. The first series demonstrated that NMDAR and MC1R systems that mediate this morphine-induced hyperalgesic state are located supraspinally, as intracerebroventricular injections of MK-801 and MSG606, respectively successfully reversed hyperalgesia during a one-hour testing period. A second series of studies investigated possible involvement of spinal systems. Whereas intrathecal MK-801 significantly reversed hyperalgesia in males at both doses, and females at the low morphine infusion dose, spinal administration of MSG606 significantly reduced hyperalgesia in females following continuous high dose morphine infusion. This indicates that the sex-dependent mechanism involved in morphine-induced hyperalgesia is located supraspinally and spinally, and either locus can independently modulate female-typical hyperalgesia. A third series of studies investigated hormonally-regulated mechanisms involved in morphine-induced hyperalgesia. Ovariectomized females displayed male-typical patterns of hyperalgesia after i.c.v. and i.t. antagonist injection paradigms following continuous infusion of either dose of morphine on Day 4. On Day 6, NMDAR and MC1R antagonist injections were preceded by an acute systemic progesterone injection in ovariectomized female mice, and intact male mice. Following continuous morphine infusion, ovariectomized females displayed male-typical patterns of hyperalgesic reversal. However, following progesterone administration, hyperalgesia elicited by high doses of morphine was reversed by i.c.v. injection of MK-801 and MSG606 in both males and ovariectomized females. Conversely, following i.t. injections the data show that ovariectomized females are able to recruit the NMDAR or MC1R system, while males exclusively used the NMDAR system to mediate hyperalgesia. The current studies indicate that in terms of modulating morphine-induced hyperalgesia, there are both supraspinally- and spinally-regulated sex-dependent effects that mediate morphine-induced hyperalgesia.
Cerebrospinal Fluid Biomarkers for the Differential Diagnosis of Normal Pressure Hydrocephalus and Alzheimers Disease
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Differential diagnosis of Idiopathic Normal Pressure Hydrocephalus (NPH) is complicated by symptomatic overlap with neurodegenerative conditions such as Alzheimers Disease (AD). Efforts to improve diagnosis through the use of cerebrospinal fluid (CSF) biomarkers have led to the identification of more than a dozen potential diagnostic markers for NPH. However, no single biomarker has proven sufficient for differential diagnosis in clinical practice. The current study uses proteomic analysis of CSF to identify sets of protein markers that are expressed differentially in NPH and AD. Two-dimensional gel electrophoresis was used to analyze the CSF of 8 probable NPH and 8 probable AD patients. Gels were stained with SYPRO Ruby and the percentage volume of over 1339 spots was determined. The Random Forest statistical method was used to identify proteins that optimally segregated NPH cases from AD. Protein identification was achieved by the use of a previously published CSF map and mass spectrometry. Eleven protein spots were found to optimally distinguish the groups, correctly classifying 100% of all NPH and AD samples. Of the 11 proteins of interest, six were identified and include the following: beta-trace, serum albumin A, serum albumin B, apolipoprotein A-IV precursor, pigment epithelium-derived factor, and complement component 3 precursor. The current study identifies CSF biomarkers that differentiate between NPH and AD cases. The highly successful separation of cases obtained in this study suggests that multiplexed CSF markers have the potential to improve the differential diagnosis of NPH from one of its most common competing diagnoses.
INTERPERSONAL RHYTHMS DISRUPTED BY A HISTORY OF TRAUMA: AN IN-DEPTH CASE STUDY OF ANALYTICAL MUSIC THERAPY
Tanja Auf der Heyde
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Abstract INTERPERSONAL RHYTHMS DISRUPTED BY A HISTORY OF TRAUMA: AN IN-DEPTH CASE STUDY OF ANALYTICAL MUSIC THERAPY by Tanja Maud Christine Auf der Heyde Advisor: Steven Tuber, Ph.D. This dissertation project is a phenomenological study of interpersonal rhythms within the music therapy treatment of a client with a history of cumulative trauma. An attempt was made to explore whether and how rhythmic interactions within musical improvisations facilitate the repair of ruptures in such rhythms. Towards this aim, the rhythmic interactions between the two participants were analyzed to find evidence for bi-directional rhythmic co-regulation and loose mid-range coordination. Furthermore, this study tracked shifts in the client's mental state by applying a moment-to-moment analysis of the music with four Improvisation Assessment Profiles (IAPs). It was found that musical improvisation allows for ample opportunities for bi-directional co-regulation and loose mid-range coordination. Most of the mental state ratings were within the "optimal arousal state," suggesting that music does, in fact, facilitate regulation on both intrapsychic and interpersonal levels. However, this study also uncovered the importance of spontaneous and planned disruptions in rhythmic interaction, which find their musical expression in syncopations, polyrhythms, and a-rhythmic sections. These experiences are deeply embedded in the body. Thus, they provide the opportunity not only for reconnecting with one's own rhythms, and for reconstructing a disrupted expectation system within an improvisation, but also for finding agency in the playful thwarting of expectations, and for exploring the continuum of separation and connectedness in a musical relationship. In this sense, music acts as a transitional phenomenon, creating an intermediate space between inner and outer worlds. In this "third" area of experiencing, both participants align with patterns that go beyond the sum of their contributions; when this state of flow is reached, one can feel that one is played by the music as much as one is playing it. The results of this study indicate that a close rhythmic analysis of improvised interactions can help music therapists to assess the client's level of trauma as well as to tailor interventions to move them out of the repetitious rhythms of hyper- and hypoarousal. For verbal psychotherapists and psychoanalysts, the implication is that rhythmically aware, embodied listening can open up new dimensions of transference and countertransference phenomena. To this end, clinicians should pay special attention to rhythmic shifts in affect, speech, and bodily gestures.
EVALUATING THE INFLUENCE OF DAUBERT'S CROSS-EXAMINATION SAFEGUARD ON ATTORNEYS' AND JURORS' JUDGMENTS ABOUT SCIENTIFIC EVIDENCE
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The Supreme Court's decision in Daubert v. Merrell Dow Pharmaceuticals, Inc clarified that federal trial judges were to serve as evidentiary gatekeepers for scientific evidence, evaluating scientific reliability when determining admissibility. When judges fail at gatekeeping and admit unreliable expert testimony, the Court expresses faith in the ability of cross-examination to reveal the reliability of testimony for jurors. For cross-examination to function as the Court intends, attorneys must recognize scientific flaws and craft cross-examination questions that expose scientific threats. Moreover, these scientifically informed cross-examinations must act as a form of scientific training for jurors. I conducted two studies to empirically examine the Court's assumptions regarding cross-examination. In Study One, 95 attorneys read a trial summary that contained expert testimony regarding an intelligence test. I varied the validity (presence v. absence of experimenter bias threat) and reliability (moderate v. high reliability indices on test-retest, inter-observer, and internal consistency scores) of the intelligence test. Attorneys provided lower ratings of scientific quality when the test was unreliable but did not craft cross-examination questions designed to expose the low reliability indices of the scientific test. Attorneys did not provide lower ratings of scientific quality when the intelligence test was invalid; however, a proportion of attorneys did craft cross-examination questions to expose the validity threat. In Study Two, I again varied the reliability and validity of the intelligence test and whether the cross-examination educated jurors about the study's flaws (scientifically informed vs. naïve). Either a judge or an attorney conducted the scientifically informed cross-examinations. Scientifically informed cross-examinations did not assist jurors with evaluating scientific reliability or validity. These studies suggest that cross-examinations may not function as a safeguard against flawed scientific evidence. Although some attorneys may be able to meet the Court's expectations, cross-examination may be an ineffective method of providing methodological training for jurors.
Perspective-taking Based Insights into Theory of Mind: An ERP Study
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Theory of Mind (ToM) is defined as the ability to make inferences about another person's mental state. One account of ToM, Simulation Theory, posits that this ability is accomplished by using one's own mental processes as a model for the other person's mind. This is accomplished in a serial manner by first accessing the processes related to the self before switching to taking the perspective of the other. Hemodynamic imaging studies of ToM have provided evidence that self and perspective-taking processes depend on different brain circuits but cannot identify the temporal aspects of the processes. To determine if these processes occur in the posited serial manner, event-related potentials (ERPs) were recorded while participants made evaluations either from their own perspective or from the perspective of another person (i.e., Task: Evaluation, Perspective-taking). The relatedness of the person (target) of the evaluations (i.e., Relatedness: Self, Close Other, CO, Non-Close Other, NCO) was also varied to determine if the brain areas posited to be involved in the processing of the self would be activated differentially. Thus, a three-stage, serial process was hypothesized, suggesting that the perspective-taking process requires an initial anchoring in the self, a decoupling of different perspectives (i.e., self and other) and then a late stage in which the other's perspective is maintained in order to make a decision. The results showed that RTs were similar across conditions. Recordings from 83 scalp sites revealed differential patterns of activation as a function of both Task (Evaluation, Perspective-taking) and Relatedness (Self, CO, NCO). Consistent with the "serial hypothesis," the ERP results provided evidence of three temporally distinct stages during the decision process when the various evaluation and perspective-taking tasks were compared in the electrodes corresponding to TPJ. When Evaluation and Perspective-taking judgments were compared, a first stage (i.e., 200 - 350 ms) was found in which there were no ERP differences as a function of Task, in accord with the idea that perspective-taking processes require an initial grounding in the self. In contrast, during this first stage, effects were seen as a function of Relatedness in which judgments about Self were more negative-going than judgments of CO or NCO. A second stage (400 - 600 ms) became apparent in which the lack of ERP differences between Evaluation and Perspective-taking tasks continued but now the Relatedness effects disappeared. That is, during this middle stage, the ERP activity from all conditions was similar. As a result of its timing, being interposed between the early and late stages, this middle stage may reflect the hypothesized decoupling process (i.e., shift from self to other) that was posited to occur between the self and perspective-taking stages In the third stage (700 - 850 ms) the ERP activity elicited during perspective-taking differed from that in evaluation tasks due to the addition of a negative slow potential over the temporal-parietal junction (TPJ). Relatedness effects returned in this later stage, although in this time period judgments about the self elicited more positive-going ERPs than judgments of CO or NCO. In addition, the results revealed that self-referential evaluations were marked by greater ERP activity over occipital and mid-frontal scalp very early after stimulus onset (i.e., 70 - 360 ms). Increased activity at these locations has previously been shown to reflect the level of attention devoted to stimuli indicating that self-referential evaluation engendered the highest levels of overall attention. Finally, although not addressed in models of ToM processes, the results revealed that the differences in use of control processes varied as a function of both task and the object of the decision. Specifically, compared to evaluation tasks, perspective-taking tasks elicited a larger pre-response negativity (PRN), which has been linked to the use of goal-oriented, strategic monitoring processes. Moreover, within each of these tasks, there were graded effects on the relatedness dimension in which judgments about the self required the least strategic monitoring, followed by the close other, with non-close other requiring the most. In addition, the amplitude of the medial frontal negativity (MFN), which follows the response and has been shown to reflect the residual conflict following a response, also varied as a function of both task and the object of the decision. That is, perspective taking judgments elicited larger MFNs (i.e., greater residual conflict) than evaluations and judgments about the self elicited the smallest MFN with larger MFNs for close other judgments and the largest MFNs for non-close other judgments. In sum, the ERP results from scalp sites overlying the TPJ appear to confirm the role of that brain area in ToM. More important, it was shown that the activity there is not constant during the ToM judgments but rather follows three distinct stages. Hence this supports previous hypotheses stating that the perspective-taking process involves an initial anchoring in Self before a decoupling process begins, followed by the shift to the other's perspective and suggests that the TPJ plays a role in all three of these stages. Further, we extended previous hemodynamic results by showing that the executive processes related to strategic and tactical monitoring play an important role in ToM. Taken together, the results from the present study demonstrate the value of using the ERP as a tool for studying the nature and timing of the processes used when one engages in Theory of Mind operations.