Indiana University-Purdue University Indianapolis (IUPUI) / Neuroimaging biomarkers play a crucial role in our understanding of Alzheimer’s disease. Beyond providing a fast and accurate in vivo picture of the neuronal structure and biochemistry, these biomarkers make up a research framework, defined in a 2018 as the A(amyloid)/T(tau)/N(neurodegeneration) framework after three of the hallmarks of Alzheimer’s disease. I first used imaging measures of amyloid, tau and neurodegeneration to study clinically diagnosed Alzheimer’s disease. After dividing subjects into early (onset younger than 65) and late-onset (onset of 65 and older) amyloid-positive (AD) and amyloid-negative (nonAD) groups, I saw radically differing topographical distribution of tau and neurodegeneration. AD subjects with an early disease onset had a much more severe amyloid, tau and neurodegeneration than lateonset AD. In the nonAD group, neurodegeneration was found only in early-onset FDG PET data and in a nonAlzheimer’s-like MRI and FDG pattern for late-onset. The late-onset nonAD resembled that of limbic-predominant age-related TDP-43 encephalopathy. I next utilized an imaging genetics approach to associate genome-wide significant Alzheimer’s risk variants to structural (MRI), metabolic (FDG PET) and tau (tau PET) imaging biomarkers. Linear regression was used to select variants for each of the models and included a pooled sample, cognitively normal, mild cognitive impairment and dementia groups in order to fully capture the cognitive spectrum from normal cognition to the most severely impaired. Model selected variants were replicated using voxelwise regression in an exploratory analysis of spatial associations for each modality. For each imaging type, I replicated some associations to the biomarkers previously seen, as well as identified several novel associations. Several variants identified with crucial Alzheimer’s biomarkers may be potential future targets for drug interventions.

Compassion is an affective state and comprises recognition of the suffering of others and a motivation to help them. Studies have indicated that compassion is trainable and compassion training based on contemplative practice has beneficial effects on well-being. The primary aim of this thesis was to conduct a systematic review on the functional and structural neural effects of compassion training in healthy adults. The secondary aim was to review the psychological or behavioral changes after compassion training in the reviewed articles. Eight articles employing compassion meditation or loving-kindness meditation, and applying the same definition of compassion, were reviewed. The neural effects of compassion training were diverse, but changes in the activity of the medial orbitofrontal cortex (mOFC), the amygdala, and reward-related areas were the most consistent outcomes. Also, compassion training resulted in increased positive affect and feelings of compassion, decreased depression scores, and more charitable donations (i.e., prosociality). The findings of this systematic review suggest that compassion training engages a broader neural network than previous studies have indicated and is a strategy that may lead to improved well-being andprosocial behavior.

The goal of this study is to advance the utility of functional brain imaging as a tool for the diagnosis and treatment of neurological disorders by creating a statistical database of functional MRI (fMRI) brain activation patterns collected from neurologically and psychiatrically unimpaired subjects. Continuous fMRI scans have been obtained from each subject while s/he performed a variety of cognitive tasks that are commonly found in standard neurological and cognitive assessment batteries. The collected fMRI data has been processed, analyzed, and converted into database which can be used as a reference of reliable indices of normal brain activity patterns for a wide range of cognitive functions.

This paper examined the claims postulated by the somatic marker hypothesis and compares those claims to the current evidence surrounding the neural basis of alexithymia. The results were then compared to see if they contradict or have a distinct localisation in the brain separate from those behavioural brain regions hypothesized by the somatic marker hypothesis. It was concluded that the somatic marker hypothesis and the neural basis for alexithymia share certain regions of interest, primarily the amygdala and insula, but also potentially the anterior cingulate cortex.

The conscious or unconscious acquirement of knowledge in implicit category learning was examined in accordance with predictions made by the COVIS theory of categorization (Ashby & Maddox, 2011). COVIS assumes separate category learning systems. The explicit system relies on easily verbalized rules while the implicit system requires integration of more than one stimulus dimension. Participants in this experiment categorized lines varying in length and orientation as belonging to one of two categories; in the rule-based (RB) condition only length was relevant, while participants in the information integration (II) condition needed to integrate both dimensions. Corrective feedback was provided during training. In test phases, participants were asked to attribute their responses to one of four criteria (guess, intuition, memory, or rule), a measure adapted from Dienes and Scott (2005). Neural activity in dorsolateral prefrontal cortex (DLPFC) was recorded with a 20-optode fNIRS system. We found that in the implicit (II) learning condition, participants who reported guessing less than half the time were learning but were unconscious to the structures driving that learning, reflected by accuracy, attribution self-report and neural activation. Our results substantiate the claim that implicit category learning is mediated unconsciously and evidence the dual-system model of categorization postulated by COVIS, furthering our understanding of category learning and thus, the ways in which to improve it.

It is well known that music can influence our emotions. Research on mind-wandering has revealed that our emotional state can influence the valence of thought content and the prevalence of mind-wandering. Recent behavioural studies have suggested that music can modulate mind-wandering. However, the neural mechanisms to support the claims are unknown. This thesis aim was to explore how music can modulate mind-wandering by reviewing functional neuroimaging studies on the topic. The findings suggest that music induces mind-wandering as it engages the default mode network in a similar fashion that resting does. Music-induced activity from the orbitofrontal cortex and the posterior cingulate cortex seems to be a good neural indicator for mind-wandering content that has a negative valence.

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are chronic, debilitating illnesses. Impairments in cognitive processes such as social cognition, episodic simulation, and neuropsychological performance have been documented separately in both disorders. Despite our increasing knowledge of these impairments, the potential underlying transdiagnostic mechanisms remain relatively unexplored. This thesis examines correlates of these processes in persons with a primary diagnosis of MDD with a history of trauma exposure, and in persons with PTSD. The first study examined the association between the social cognitive domain of empathy and parental bonding in women with PTSD associated with childhood abuse. Participants with PTSD reported altered levels of cognitive and affective empathy, compared to controls. Paternal care during childhood was the only predictor of cognitive empathy (i.e., perspective taking). The second study investigated the specificity of episodic simulation of future positive, negative, and neutral events in relation to parental bonding and neuropsychological functioning among participants with MDD. Optimal parental bonding and higher scores on measures of neuropsychological functioning were associated with increased specificity of episodic simulation. In the third study, we examined the relation between dissociative symptoms and neuropsychological functioning in participants with MDD. Patients with MDD report significantly higher levels of dissociation as compared to controls, and more severe dissociation was related to poorer neuropsychological performance among this patient group. Lastly, using independent component analysis of resting-state fMRI data, the fourth study examined the association between intrinsic connectivity networks and neuropsychological performance among participants with MDD. Connectivity within the default mode, salience, and central executive networks was associated with neuropsychological and clinical (i.e., depression, dissociation, PTSD) variables. Overall, this thesis demonstrates that variables such as parental attachment, dissociation, and intrinsic connectivity networks may underlie some of the alterations in cognitive processes seen in MDD and trauma-related disorders. / Dissertation / Doctor of Philosophy (PhD) / Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) negatively affect quality of life and day-to-day functioning. These populations show difficulties in domains related to cognitive processing, such as empathy, imagining future events, and neuropsychological functioning (e.g., memory and attention). This thesis focuses on examining variables that may be related to these difficulties. In particular, we study developmental variables, such as parental bonding, clinical symptoms, such as dissociation, and neuroimaging data. Our findings suggest that these variables are all related to impairments in different areas of cognitive processing. By understanding what may be contributing to these cognitive difficulties, we may be able to design treatment strategies that target the underlying causes of these difficulties.

Emotion processing and regulatory deficits have been well established in individuals diagnosed with bipolar disorder (BD). Both structural and functional neural deficits have been associated with the presence of psychiatric symptoms in BD. In Chapter 2, we reviewed cortical thickness deficits found in patients with BD. It is unclear however, how early these deficits appear; whether they contribute to risk, or whether these deficits develop as a consequence of the onset of symptoms. To address this, many researchers have turned to high-risk offspring populations. These high-risk offspring are at much greater risk of developing BD by virtue of having a parent diagnosed with BD. Moreover, the presence of anxiety, depression or ADHD related symptoms in this population suggest these children are at even greater risk to develop BD. By comparing high-risk offspring with and without the symptoms can help to elicudate neural correlates associated with risk and resilience for BD. It was the aim of this thesis research to investigate the behavioural, structural and functional correlates of risk. Specifically, presented in this thesis, we compared the gray matter integrity, through volume (Chapter 3) and cortical thickness (Chapter 4) techniques, in symptomatic and asymptomatic high-risk offspring to healthy children of healthy parents. We also compared the ability of these offspring to perform an emotion-labelling task (Chapter 5) and engage in emotional conflict monitoring and conflict adaptation during an fMRI scan (Chapter 6). Altogether, our results provide evidence for the presence of gray matter volume, emotion labelling, and conflict monitoring and conflict adaptation functional deficits in high-risk offspring compared to healthy children of healthy parents. With the exception of cortical thickness, we found that the deficits between symptomatic and asymptomatic high-risk offspring were comparable. This suggests that behavioural, structural and functional deficits may reflect neural correlates of risk and are not associated with the presence of symptoms. / Thesis / Doctor of Philosophy (PhD)

Yes / This article discusses the current evidence for the short- and long-term effects of concussion in sport and how occurrences of concussion should be managed. The article also considers the potential role of medical imaging in terms of assessing both acute and chronic head injuries. Greater awareness of when medical imaging could be used will aid the practitioner's understanding of its potential contribution while still maintaining the fundamental importance of clinical judgement.

A worldwide demographic shift is currently occurring, with rapidly increasing numbers of elderly individuals. Since the incidence of neurodegenerative disease generally increases with age, this entails an increase in dementia prevalence. There are several strong incentives for establishing robust and widely available imaging methods for the early diagnosis of these diseases. Atrophy patterns are evident only late in the disease process, and the distinction from healthy ageing can often be elusive. For early diagnosis, physiologic parameters such as perfusion or metabolism must be assessed. The available modalities all have restricted clinical usefulness. The main aim of this thesis was to advance the clinical usefulness of perfusion and metabolism imaging in patients with neurodegenerative dementia, with a focus on visual assessment. A cohort of patients with neurodegenerative dementia was included, along with an age-matched control group. All subjects underwent MRI, including a pseudocontinuous ASL sequence and FDG-PET. In papers II and III, a subgroup containing both patients and controls underwent a second FDG-PET with reduced dose. In paper IV, the material was combined with a similar cohort from Amsterdam. Paper I showed that spatial smoothing increased the correlation between visually assessed perfusion and metabolism levels as displayed with FDG-PET. However, the distinction between patients and healthy controls was less satisfactory due to false positives. Paper II showed that differences in regional standard uptake value ratios between normal- and low-dose FDG-PET were small and without clinically significant bias. Paper III showed that the diagnostic performance of Z-score maps showing regions of significant deficits in metabolism was highly similar in normal- and low-dose FDG-PET images.  Paper IV showed that ASL perfusion-based Z-score maps can be used for diagnostic purposes with high specificity, but inferior sensitivity, compared to FDG-PET. In conclusion, the included studies address aspects of the visual assessment of perfusion and metabolism neuroimaging, with a focus on clinical usefulness in diagnosing neurodegenerative dementia.