The FBS (Lees-Haley, 1992) is a relatively new validity scale for the MMPI-2 designed specifically to detect feigned neurocognitive deficit. The aim of the present study was to examine the FBSs efficacy in differentiating psychiatric and neurocognitive feigners using a known-groups design. Malingering tests were administered to 180 individuals undergoing forensic neuropsychiatric evaluations. Based on the malingering test results, participants were classified as honest responders, psychiatric feigners, neurocognitive feigners, or feigning both psychiatric and neurocognitive deficits. The FBS significantly differentiated the 3 feigning groups from the honest group, but it did not discriminate effectively between neurocognitive and psychiatric feigners.

Detection of malingering is a significant concern in forensic psychological assessments. The best-validated tests currently available are time-intensive for both test-takers and mental health professionals. Thus, well-validated, brief screening measures for malingering would be useful in a forensic environment. The Structured Inventory of Malingered Symptomatology (SIMS; Smith andamp; Burger, 1997) has demonstrated potential in this role. The present study attempts replication of previous studies while extending validation from analogue and male criminal forensic samples to both men and women in a civil forensic setting. The SIMS accuracy in the detection of both neurocognitive and psychiatric symptom feigning is evaluated by comparing its performance to stringent multi-scale criterion measures in a large forensic sample. Cut scores suggested by previous studies yield high sensitivity and negative predictive power in this sample when the SIMS is used to detect psychiatric symptom malingering; however, these cut scores perform inadequately here when screening for the feigning of neurocognitive impairment, and no alternative cut score functions well in this capacity. The results lend support to the utility of the SIMS as a screen for psychiatric symptom malingering by men and women in a civil forensic setting.

The goal of this thesis was to investigate the hypothesis whether symptomatic remission for patents with schizophrenia spectrum syndrome would provide practical and qualitative benefits for patients and for society. The first work (Paper I) examines the relationship between cross-sectional remission and the patients’ practical resources. The patients’ adaptations to society as well as their employments, living situations and social networks were studied. Their activity of daily living resources are described in terms of the extent to which they could pursue various undertakings autonomously. Their need for care was also studied. The results showed that the patient group that had achieved remission scored better on all of the variables studied, had better resources and less need for medical care and sheltered housing. The second work (Paper II) analysed the relationship between cross-sectional remission and quality of life, burden placed on patients by the illness, and the patients’ satisfaction with care received and with their medication, and also their capacity for understanding their symptoms and their illness. Even the results of this study showed that the patients in the remission group had a better quality of life, bore a lesser burden, were more satisfied with their care and had better insight into their illness. The third work (Paper III) studied the patients’ neurocognitive capacity to see if a higher capacity resulted in a higher percentage of patients achieving remission. The results showed unequivocally that the patients in remission consistently performed better in the cognitive tests. They also showed that they even had a larger vocabulary indicating a higher premorbid capacity. The fourth work (Paper IV) followed the patients over an average time of 65 months. In this study, the patients’ needs for medical care and for housing were investigated. Patients who were not in cross-sectional remission at baseline had for all the measured variables a higher consumption than those in remission even if the differences were not significant, except for patients who lived in sheltered housing and who had greater need for medical care. Taking all these findings together, the result of this thesis shows that the attainment of remission provides practical and qualitative advantages to the patients and to society.

Chronic Traumatic Encephalopathy (CTE) has been linked to contact sports, most notably boxing and American football, due to their propensity for repetitive head impacts. Concerns in the community for the safety of athletes in all contact sports has driven a significant amount of research into concussions, their long term effects, and strategies for treatment and prevention. Knowledge of long term brain health in response to neurotrauma is limited, a gap especially noticeable in the literature on non-catastrophic brain injuries sustained as a child. Concussion is a common injury that is often self-resolving with no lasting neurologic or cognitive deficits. Although repetitive brain trauma is hypothesized to be necessary and sufficient to lead to CTE, no human or animal models have definitively demonstrated the pathophysiologic connection or confirmed the mechanism of symptoms. The research to date has been case based, lacking prospective cohorts, with data complicated by convenience sampling. These factors limit the generalizability of conclusions. CTE is neuropathologically defined with variable symptoms; however, it is only diagnosable at postmortem autopsy making the etiology and prevalence difficult to understand. As more research is published to understand if there is an association between a neurocognitive degenerative disease and contact sports, the concentration is on professional athletes. Yet professional athletes do not represent the overwhelming majority of all contact sport participants. The proposed study will compare adults who participated in youth football, but not beyond the high school level, to a control group of adults who did not play contact sports. Evaluating their cognitive function with an online assessment, the Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A), data will be analyzed for signs of clinical cognitive impairment. The objective is to measure adults who represent the high percentage of youth football players who do not continue to the advanced levels. Data obtained from this study will help communities make informed decisions, and create the foundation for future studies on long term benefits and risks of contact sports for children.

Preterm birth (defined as birth before 37 weeks) is a leading cause of neurocognitive impairment in childhood, including difficulties in social cognition and executive function. Microstructural divergence from typical brain development in the preterm brain can be quantified using diffusion magnetic resonance imaging (dMRI) tractography during the neonatal period. The relationship between dMRI tractography metrics and later cognitive difficulties remains inconclusive. A general measure of white matter microstructure (gWM) offers a neural basis for cognitive processes in adults, however it remains unclear when gWM is first detectable in the developmental trajectory. Eye-tracking is a technique which assesses eye-gaze behaviour in response to visual stimuli, which permits inference about underlying cognitive processes, such as social cognition and executive function in infancy. The primary aims of this thesis were to test the hypotheses: dMRI tractography reveals significant differences in tract-average fractional anisotropy (FA) and mean diffusivity (MD) between preterm and term infants, and variance in tract-average FA and MD is shared across major tracts. Secondly, infants born preterm have altered social cognition and executive function compared to term born peers, assessed by eye-tracking and finally, neonatal MRI gWM is associated with cognitive function in infancy. Preterm (birth weight ≤ 1500g) and term infants (born ≥ 37 weeks’ post-menstrual age [PMA]) were recruited and underwent a MRI scan at term equivalent age (between 38 - 42 weeks’ PMA) and an eye-tracking assessment six to nine months later. Preterm infants were assessed at two years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). dMRI tractography metrics were generated using probabilistic neighbourhood tractography (PNT) in eight pre-defined tracts-of-interest. Principal component analyses (PCA) were used to determine the correlations between the eight tracts-of-interest for four tract-averaged water diffusion parameters. dMRI metrics were compared to the eye-tracking performance and two year outcome data. Quantitative microstructural changes were identifiable within the preterm brain when compared to infants born at term. PCA revealed a single variable that accounts for nearly 50% of shared variance between tracts-of-interest, and all tracts showed positive loadings. Eye-tracking revealed group-wise differences in infant social cognition, attributable to preterm birth, but executive functions inferred from eye-tracking did not differ between groups. dMRI tractography metrics within the neonatal period did not relate to later outcome measures. This thesis shows that variance in dMRI parameters is substantially shared across white matter tracts of the developing brain and suggests that anatomical foundations of later intelligence are present by term equivalent age. Social cognition is altered by preterm birth, however social cognitive ability in infancy is independent of gWM.

Background. Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. Right Superior Longitudinal Fasciculus II (SLF II) WMI has been associated with visual attention. These relationships have held true for neurotypical controls and brain tumor survivors. The current study examined the relationships between RC-LF WMI and processing speed, attention, and working memory. SLF II WMI and visual attention were included as a control tract and task to demonstrate a correlational double dissociation. This study also examined the relationship between the volume of brain regions within the RC-LF network and RC-LF WMI. Methods. Adult survivors of childhood brain tumors (n= 29, age: M=22 years (SD= 5), 45% female) were treated with neurosurgery, and combinations of radiation therapy and chemotherapy. Age- and gender-matched controls (n=29) were also included. Tests of auditory attention span, working memory, visual attention, and processing speed served as cognitive measures. Participants completed a 3T MRI diffusion imaging scan. WMI (FA, RD) and volume served as neuroimaging measures. In the survivor group, partial correlations between WMI and cognitive scores included controlling for type of treatment. Results. A correlational double dissociation was found. RC-LF WMI was associated with auditory attention span (FA: r=.42, p=.03; RD: r=-.50, p=.01), and was not associated with visual attention (FA: r=-.11, p=.59; RD: r=-.11, p=.57). SLF II FA WMI was associated with visual attention (FA: r=.44, p=.02; RD: r=-.17, p=.40), and was not associated with auditory attention span (FA: r=.24, p=.22; RD: r=-.10, p=.62). The relationship between RC-LF WMI and auditory attention span robustly dissociated from working memory and visual attention. In the radiation group, thalamic-frontal segment of RC-LF WMI associated with the volumetric measures of each structure of the RC-LF pathway, whereas in the no radiation group cerebellar-rubral segment of RC-LF WMI associated with the volumetric measures. Conclusions. The current study advances the understanding of structural brain changes following cerebellar tumor resection and treatment because the results show that RC-LF WMI is associated with auditory attention span rather that working memory, provide evidence for a correlational double dissociation, and suggest distinct relationships between WMI and volume based on treatment.

The prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) is rising despite combination antiretroviral therapy (cART). Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, but causes neurological symptoms that may interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HAND in patients on cART. Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production (Chapter 3). Treatment with EFV or the EFV containing regimen generated significantly increased soluble Aβ, and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide. Further (Chapter 4), there is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor EFV has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6 mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV. 1 Portions of this abstract have been previously published (Brown LAM, et al., 2014; Jin, J, et al, 2016) and are utilized with permission of the publisher.1

Among people living with HIV (PLWH), adherence to antiretroviral therapy (ART) can be affected by problems of neurocognitive (NC) impairment, stress, alcohol and other drug (AOD) abuse, and other barriers. The aims of this research were to: (1) examine factors associated with NC impairment, (2) explore relationships between psychosocial variables with ART adherence and viral load (VL), and (3) evaluate the efficacy of an evidence-based intervention in improving ART adherence, increasing service utilization, and decreasing VL. The first study (n=370) was cross sectional and used structural equation modeling to test whether AOD use, years living with HIV, and time from HIV diagnosis to seeking care were associated with poorer NC functioning. The second study (n=246) used similar methods to test the hypothesis that stress, barriers to adherence, NC impairment, poor social support, and AOD use were related to lower VL mediated by ART adherence. The third study (n=243) evaluated an evidence-based, eight-session program to improve ART adherence, reduce VL, and increase service utilization in a randomized controlled trial. Study participants were PLWH living in South Florida, 18 to 60 years old, with a history of alcohol abuse enrolled from January 2009 through November 2012. Secondary analysis of available data showed: (1) scores on interference with executive functioning increased by 0.32 for each day of marijuana use and 1.18 for each year living with HIV, but no association was found between alcohol use and NC functioning; (2) each barrier to adherence was associated with a 10% decrease in adherence to ART and a 0.42 unit increase in VL (log10) and the relationship between barriers and VL was partially mediated by ART adherence; (3) participants in the evidence-based program were more likely than the comparison group to report an undetectable VL (OR=2.25, p Psychosocial factors affect VL, but ART adherence is essential in achieving an undetectable VL in PLWH.

Nearly half of all HIV-positive individuals present with some form of HIV-associated neurocognitive disorder (HAND). The experiments described in this thesis examined the structural changes that occur in the brain as a result of HIV infection. While previous work has established that HIV targets the basal ganglia and fronto-striatal systems and impacts cortical and white matter pathways, it was unknown whether these changes occur in the absence of HAND. The studies described here focused on cognitively asymptomatic HIV+ individuals (CAHIV+) without HAND as determined by widely accepted neuropsychological performance guidelines. Experiment 1 utilized diffusion tensor imaging (DTI) to examine HIV-associated alterations in white matter (WM) fractional anisotropy (FA) in the absence of HAND in 23 HIV+ individuals and 17 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would show lower FA values than HIV- in the corpus callosum, frontotemporal, and parietal regions of interest (ROIs). CAHIV+ individuals demonstrated higher FA in the frontotemporal region and posterior corpus callosum, but lower FA in parietal WM relative to HIV- individuals. Experiment 2 utilized structural MRI to compare cortical thickness in 22 CAHIV+ individuals and 19 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would have thinner frontal, temporal, and parietal regions than HIV- participants. Reduced cortical thickness measures were identified in the cingulate and superior temporal gyri, with increased cortical thickness measures in the inferior occipital gyrus, for HIV+ participants compared to HIV-. Experiment 3 examined the relationship between the structural alterations identified in Experiments 1 and 2, neuropsychological performance on tests sensitive to HAND identification, and immunological characteristics in 30 HIV+ participants and 28 HIV- control participants. As hypothesized, regional FA values, cortical thickness, and viral load were related to neuropsychological composite scores for CAHIV+, but not HIV-. Together, results from these three studies suggest that regional FA and cortical alterations identified in CAHIV+ patients may contribute to the cognitive deficits often seen in later stages of HIV disease.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13372号 / 論医博第2209号 / 新制||医||1047(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 髙橋 良輔, 教授 小柳 義夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM