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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.
The Role of Dependence in Alcohol Reinforcement: Neurobehavioral Mechanisms
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The motivation to consume alcohol is complex, though physiological dependence has long been implicated in alcohol reinforcement and alcoholism. The research presented here was conducted to examine the role of alcohol dependence on voluntary alcohol consumption and preference, the validity of the Lieber-DeCarli (LD) liquid diet as a procedure to induce dependence, and the effect of alcohol administration on dopamine and endocannabinoids. While the LD diet has been used extensively to induce alcohol toxicity and teratogenic effects, there has not been research that has examined its use in the development of dependence and alcohol reinforcement. This research utilized varying periods of chronic alcohol administration in three cohorts of C57 mice followed by two-bottle choice procedures to examine the role of dependence in alcohol consumption. Chronic oral intake of the alcohol containing LD diet produced moderate symptoms of physical dependence and increased motivation to consume alcohol. In all three cohorts, there were indications of greater alcohol intake or preference in mice that consumed the alcohol diet compared to the control diet. These differences were greatest in the cohort receiving chronic alcohol for 30 days in comparison to 21 and 52 days. Following behavioral data collection, analyses were performed to explore the role of dopamine and endocannabinoid brain systems in dependent mice. While significant differences were not found in the endocannabinoids, AEA or 2AG, there was a trend toward significance for experimental animals exhibiting lower levels of dopamine. These data indicate the value of orally administering alcohol chronically via a liquid diet. Utilizing equicaloric alcohol and non-alcohol LD diets permitted nutritional maintenance and caloric control while evaluating the effects chronic alcohol administration. Overall, animals in the experimental groups preferred alcohol to water on more occasions than the control animals. These findings confirm the role of dependence in motivating alcohol drinking and the validity of LD diet as a model for inducing alcohol dependence. Application of these methods will enhance our understanding of the role of dependence in alcohol drinking and in the development of novel treatments for alcohol use disorder.
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.
A Long-Term Follow-Up of Crossover Youth: Young Adult Outcomes for Maltreated Youth in the Juvenile Justice System
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Cathy Spatz Widom
Crossover youth, those with histories of childhood maltreatment and delinquency, may be at high risk for negative outcomes compared to other youth. However, very little is known about the long-term outcomes for this population. This dissertation compared four groups: youth with histories of child maltreatment and juvenile arrest (n = 180), youth with a history of maltreatment only (n = 428), youth with a history of juvenile arrest only (n = 91), and youth with no history of maltreatment or juvenile arrest (n = 496), on a range of outcomes, including mental health, education, employment, and criminal behavior. Data from a prospective cohort design study was used in which children with documented histories of physical and sexual abuse and neglect between the ages of 0 and 11, as well as matched controls, were subsequently interviewed at a mean age of 29 (N=1196). Analyses compared the four groups and examined potential differences by gender and race/ethnicity. Results indicated that crossover youth were at a significant disadvantage in likelihood for educational attainment, employment, and adult arrest when compared to other groups of youth, but were not necessarily at higher risk for lifetime psychiatric disorders. Overall, the impact of having both adversities was most salient for males and Black and Hispanic youth. Unexpectedly, crossover youth and arrested youth also had similar characteristics across many long-term outcomes. Furthermore, the similarities between crossover and arrested youth after accounting for self-reported delinquency, particularly when combined with the differences found between crossover and maltreated youth on psychosocial outcomes, strongly suggest that the juvenile justice system itself is associated with negative outcomes for crossover youth. This study yields information necessary for designing specialized treatment programs and interventions to improve and enhance the well-being of crossover youth.
Molecular-genetic and behavioral analysis of the functionality of patterning in the trigeminal neuraxis
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H. Philip Zeigler
A striking feature of the vibrissal representation in rodents is the presence; at brainstem (barrellettes), thalamic (barrelloids) and cortical levels (barrels) of a somatotopically organized pattern of neurons which is isomorphic, both morphologically and physiologically, to the pattern of vibrissae on the snout. The vibrissal system is required for several classes of behavior, including feeding and active vibrissal sensing, but the functional role of the patterning in these behaviors is unknown. We used two mutant animals lacking patterning in two areas of the vibrissal neuraxis to examine the functional role of patterning. We examined feeding behavior using a knockout of Prxxl, which abolishes somatotopic barrellette patterning in the lemniscal brainstem nucleus. Null animals were significantly smaller than littermates by postnatal day 5, but reached developmental landmarks at appropriate times, and survived to adulthood on liquid diet. A careful analysis of infant and adult ingestive behavior revealed subtle impairments in suckling, increases in time spent feeding and the duration of feeding bouts, feeding during inappropriate times of day, and difficulties in the mechanics of feeding. During liquid diet feeding, null mice displayed abnormal behaviors including extensive use of the paws to move food into the mouth, submerging the snout in the diet, changes in licking, and also had difficulty consuming solid chow pellets. We suggest that barrellette patterning is necessary for normal ingestive behavior. To examine the role of patterning in active sensing, we used the BRL mouse, an Adenylyl Cyclase 1 mutant in which TCAs enter the cortex but do not cluster into barrels. Prior studies lesioning or chemically silencing barrel cortex suggests that vibrissal active sensing tasks such as texture discrimination are barrel-cortex dependent. However, these studies confound the functional role of the somatotopic barrel patterning with the function of barrel cortex cell activity. Use of the BRL mouse allowed us to dissociate these two. We found that BRL mice are impaired in a texture discrimination task relative to wildtype mice, suggesting a functional role for cortical barrel patterning. We discuss the role of patterning versus topographical organization of afferents.
Attention shapes our expectations and perceptions: The neural mechanisms of top-down attention during adulthood and development
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Top-down attention is the focusing of attention at one's will through knowledge regarding a current task. There is evidence that top-down attention involves the modulation of sensory cortices by higher order regions. However, the mechanisms of top-down attention across sensory modalities, its influence on early sensory inputs, as well as interactions with motivational systems remain unclear. We performed the following set of electrophysiological experiments in typically developed adults and adolescents to examine these areas. 1) The supramodal attentional theory holds that parietally-based attentional mechanisms are shared across sensory modalities. We tested the supramodal theory by examining if lateralized parieto-occipital alpha-band activity, an established metric of top-down spatial attention, was observed in an audiospatial and visuospatial task. In support of the supramodal theory, we observed similar anticipatory alpha-band processes across auditory and visual tasks, but we also found an interaction of supramodal and sensory-specific attentional control processes. 2) There is evidence that top-down attention influences information immediately upon its arrival to sensory cortices, although there is debate in this area. In the current work, volitionally-driven top-down attention was engaged toward one of several overlapping surfaces in an illusion, in which the perceived brightness of the attended surface was enhanced. We observed the attentional enhancement of early visual evoked potentials, indicating that top-down attention shapes the earliest activations in visual cortices. 3) It is well known that motivation impacts attention, but the neural bases of these interactions remain unclear. We examined how level of interest in stimuli influenced top-down spatial attention mechanisms in typically-developing adolescents. Motivation enhanced established attentional processes during the anticipation of high vs. low interest stimuli, but also independently influenced frontal and parieto-occipital activations. These findings provide potential implications to inform clinical measures to improve impaired attentional processes in clinical populations (e.g. individuals with autism spectrum disorders). In sum, these studies revealed the powerful influence of top-down attentional control and its interacting systems on neural activations through several stages of anticipatory and post-stimulus processing during development and adulthood.
An Examination of Predictive Variables of Success in Mental Health Diversion Programs.
Virginia Barber Rioja
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Diversion programs were developed to ease the overrepresentation of individuals with psychiatric disorders in the criminal justice system. These programs divert individuals with mental illnesses out of jails into community treatment. Despite the increased popularity of these programs, little is known about the psychosocial, psychiatric and psychological characteristics of the diverted individuals. In addition, despite the importance of using standardized assessment instruments pre-diversion, no published study has attempted to evaluate the utility of risk assessment instruments or measures of malingering, personality or psychopathology in diverted offenders. This investigation attempted to address this gap in the literature through three different studies that (1) described a sample of 61 defendants released from jail in terms of demographical, clinical, and criminological characteristics; (2) determined the utility of the HCR-20 violence risk assessment scheme and the Psychopathy Checklist: Screening Version (PCL: SV) in the prediction of diversion non-compliance, and recidivism in a sample of 120 defendants, and (3) identified alternative factors that help defendants succeed in diversion through a multiple case-study design. Results revealed that this sample consisted primarily of minority male defendants with extensive histories of prior arrests, significant histories of physical abuse, homelessness and suicidality, and co-morbid substance abuse and psychiatric disorders. The findings provided preliminary validation of the predictive validity of the HCR-20 and PCL: SV with defendants diverted to community treatment. The HCR-20 was found to be superior to the PCL: SV in predicting both non-compliance and recidivism, and the PCL: SV proved to be more useful in predicting recidivism than non-compliance. Results of multiple case-studies found a pattern of characteristics shared by participants who failed diversion regardless of HCR-20 results. These variables included history of physical abuse, family history of substance abuse or criminal behavior, levels of social support, and level of responsibility taken for the instant offence.