The studies in this dissertation investigate multisensory integration in a sample of patients with schizophrenia using three different paradigms. Chapter 2 evaluates the integrity of visual-tactile integration in this population using the size-weight illusion (SWI), in which the smaller of two objects of identical mass feels substantially heavier compared to a larger object. The result show a reduced SWI in schizophrenia patients which cannot be explained by observed differences in weight discrimination sensitivity. These results support the idea of reduced multisensory integration, as well as dysfunctional efference copy mechanisms, in this population. These integration deficits are correlated with reduced sensorimotor gating, as assessed by prepulse inhibition (PPI). Chapter 3 investigates auditory and visual integration of congruent cues for target detection using an intersensory facilitation of reaction time (RT) paradigm, on which non-psychiatric individuals are known to be faster to detect bimodal targets, with cues from two sensory modalities, compared to detection times for unimodal targets. Though patients with schizophrenia do show some RT speeding when detecting bimodal targets, it is not to the same extent as non-psychiatric individuals, indicating reduced automatic multisensory integration of these cues. The amount of RT facilitation is related to the symptoms of schizophrenia, as well as the modality of the patient's hallucinations. Finally, Chapter 4 presents a version of the McGurk illusion, in which auditory speech perception is biased by the presentation of an incongruent visual speech cues. This McGurk paradigm has yielded inconsistent patterns of results in previous studies with schizophrenia patients, and this study design includes many experimental conditions designed to address methodological differences between these earlier investigations. This study finds no evidence of a difference between schizophrenia patients and non- psychiatric participants on the incidence of the McGurk illusion; however, there is evidence for impaired lip- reading ability in this population. Generally, these results support the idea of a specific impairment in multisensory integration in patients with schizophrenia, above any beyond deficits within individual sensory modalities. As these integration deficits correlate with the symptoms and characteristics of schizophrenia, this is an important area for future research.

The last decade has witnessed intense interest in how people perceive the minds of other entities (humans, non-human animals, and non-living objects and forces) and how this perception impacts behavior. Despite the attention paid to the topic, the psychological structure of mind perception-that is, the underlying properties that account for variance across judgements of entities-is not clear and extant reports conflict in terms of how to understand the structure. In the present research, we evaluated the psychological structure of mind perception by having participants evaluate a wide array of human, non-human animal, and non-animal entities. Using an entirely within-participants design, varied measurement approaches, and data-driven analyses, four studies demonstrated that mind perception is best conceptualized along a single dimension.

PURPOSE:The aims of this study were (1) to assess the utility of the Quality of Life in Neurological Disorder (Neuro-QoL) questionnaire in patients with carpal tunnel syndrome by comparing the validated patient-reported outcome (PRO) measure Neuro-QoL to the validated Carpal Tunnel Syndrome Assessment Questionnaire (CTSAQ) before and following carpal tunnel release, (2) to compare the measurements of the median nerve cross-sectional area (CSA) using high-resolution ultrasound (HRUS) before and after surgery, and (3) to determine a correlation between HRUS and PRO. METHODS:Individuals diagnosed with carpal tunnel syndrome were evaluated using the CTSAQ, Neuro-QoL, and HRUS before surgery and at 3 months after surgery. RESULTS:Twenty patients completed the study. Overwhelmingly, there was an improvement in symptoms and function assessed by patients on both the Neuro-QoL and the CTSAQ at 3 months after surgery. The Neuro-QoL Physical Function and Upper Extremity scores had strong correlation with the CTSAQ activity score but had low to moderate correlation with the CTSAQ symptoms score, before and after surgery. The HRUS measurements of the median nerve at the carpal tunnel inlet demonstrated a decrease in CSA whereas no noticeable changes were observed at mid tunnel and at the outlet (hook of hamate). The correlations between the ultrasound findings and PRO measures ranged from weak to strong. CONCLUSIONS:Patients had resolution of symptoms and higher physical function following carpal tunnel release measured by both the CTSAQ and the Neuro-QoL scores. The Neuro-QoL self-assessment questionnaire, a measurement of quality of life, correlated well with the CTSAQ. Therefore, it could be used as a self-assessment outcomes tool in patients undergoing carpal tunnel release. At 3 months after surgery, HRUS measurements of the median nerve CSA showed a noticeable decrease of CSA only at the inlet of carpal tunnel. This objective improvement correlated with the improvement in CTSAQ and Neuro-QoL scores. TYPE OF STUDY/LEVEL OF EVIDENCE:Diagnosis II.

Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an 'uncertain' cue elicited increased amygdala activation, as compared with the same faces following a 'certain' cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs.

Objective

Anxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders.

Methods

FA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects.

Results

Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts.

Conclusions

These findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD₁₇). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD₁₇≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD₁₇). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

A challenge facing metabolomics in the analysis of large human cohorts is the cross-laboratory comparability of quantitative metabolomics measurements. In this study, 14 laboratories analyzed various blood specimens using a common experimental protocol provided with the Biocrates AbsoluteIDQ p400HR kit, to quantify up to 408 metabolites. The specimens included human plasma and serum from male and female donors, mouse and rat plasma, as well as NIST SRM 1950 reference plasma. The metabolite classes covered range from polar (e.g., amino acids and biogenic amines) to nonpolar (e.g., diacyl- and triacyl-glycerols), and they span 11 common metabolite classes. The manuscript describes a strict system suitability testing (SST) criteria used to evaluate each laboratory's readiness to perform the assay, and provides the SST Skyline documents for public dissemination. The study found approximately 250 metabolites were routinely quantified in the sample types tested, using Orbitrap instruments. Interlaboratory variance for the NIST SRM-1950 has a median of 10% for amino acids, 24% for biogenic amines, 38% for acylcarnitines, 25% for glycerolipids, 23% for glycerophospholipids, 16% for cholesteryl esters, 15% for sphingolipids, and 9% for hexoses. Comparing to consensus values for NIST SRM-1950, nearly 80% of comparable analytes demonstrated bias of <50% from the reference value. The findings of this study result in recommendations of best practices for system suitability, quality control, and calibration. We demonstrate that with appropriate controls, high-resolution metabolomics can provide accurate results with good precision across laboratories, and the p400HR therefore is a reliable approach for generating consistent and comparable metabolomics data.

Introduction

The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.

Methods

Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.

Results

Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ_1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.

Discussion

Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.