Real-world human visual perception is superb, despite pervasive attentional capacity limitations that can severely impact behavioral performance. Long-term memory (LTM) is suggested to play a key role in efficiently deploying attentional resources; however, the nature of LTM-attention interactions remains poorly understood. Here, I present a series of behavioral and functional magnetic resonance imaging (fMRI) investigations of the mechanisms of LTM-guided visual attention in 139 healthy participants (18-34 years). In Experiment 1, I hypothesized that humans can use memory to guide spatial attention to multiple discrete locations that have been previously studied. Participants were able to simultaneously attend to more than one spatial location using an LTM cue in a novel change-detection behavioral paradigm also used in fMRI Experiments 2 and 4. Cortical networks associated with LTM and attention often interact competitively. In Experiment 2, I hypothesized that the cognitive control network supports cooperation between LTM and attention. Three posterior regions involved with cognitive control were more strongly recruited for LTM-guided attention than stimulus-guided attention: the posterior precuneus, posterior callosal sulcus, and lateral intraparietal sulcus. In Experiment 3, I hypothesized that regions identified in Experiment 2 are specifically activated for LTM-guided attention, not for LTM retrieval or stimulus-guided attention alone. This hypothesis was supported. Taken together, the results of Experiments 2 and 3 identify a cognitive control subnetwork specifically recruited for LTM-guided attention. Experiment 4 tested how LTM-guided attention affected spatial responsivity of maps within intraparietal sulcus. I hypothesized that left parietal maps would change their spatial responsivity due to the left lateralized effects of memory retrieval. During stimulus-guided attention, contralateral visuotopic maps in the right but not left intraparietal sulcus responded to the full visual field. In contrast, during LTM-guided attention, maps in both the left and right intraparietal sulcus responded to the full visual field, providing evidence for complementary forms of dynamic recruitment under different attentional conditions. Together, these results demonstrate that LTM-guided attention is supported by a parietal subnetwork within the cognitive control network and that internal attentional states influence the spatial specificity of visuotopically mapped regions in parietal cortex.

Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Moreover, potent postnatal brain plasticity engenders increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Recently, resting-state functional magnetic resonance imaging (fMRI) emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Its application has expanded to infant populations in the past decade, providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal/ disease states. However, rapid extension of the resting-state technique to infant populations leaves many methodological issues need to be resolved prior to standardization of the technique. The purpose of this thesis is to describe a protocol for intrinsic functional connectivity analysis, and extraction of resting-state networks in infants <12 months of age using the data-driven approach independent component analysis (ICA). To begin, we review the evolution of resting-state fMRI application in infant populations, including the biological premise for neural networks. Next, we present a protocol designed such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature. Presented protocol provides detailed, albeit basic framework for RSN analysis, with interwoven discussion of basic theory behind each technique, as well as the rationale behind selecting parameters. The overarching goal is to catalyze efforts towards development of robust, infant-specific acquisition and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used. Finally, we review the literature, current methodological challenges and potential future directions for the field of infant resting-state fMRI.

A percepção de esforço (PSE) e a fadiga tem grande participação do cérebro durante o exercício físico, no entanto, pouco se sabe quanto às áreas associadas a essas respostas. Dessa forma, o presente estudo teve como objetivo identificar e comparar as áreas cerebrais associadas à percepção de esforço durante exercício de ciclismo em diferentes intensidades e níveis de treinamento. Participaram do estudo 24 sujeitos adultos; 12 ciclistas (75,6 ± 8,4 kg; 175 ± 5,3 cm; 24,4 ± 7,1 anos; atividade física 5,4 ± 1,5 vezes por semana) e 12 não ciclistas (treinados) (79,7 ± 10,5 kg; 177 ± 9,1 cm; 27,4 ± 4,8 anos; atividade física 2,3 ± 1,3 vezes por semana). Os sujeitos foram posicionados ao ergômetro de ciclismo acoplado a ressonância magnética e realizaram um teste intervalado de carga incremental constituído por blocos de 30 s intervalados por 30 s de repouso. Ao término de cada bloco a percepção de esforço foi reportada. As análises comparativas das imagens foram todas geradas no Matlab através dos softwares SPM e NCA. Foi considerado para análise das imagens o período de 4 s imediatamente ao final de cada bloco de exercício com o objetivo de verificar as áreas relacionadas com o processamento da PSE. As seguintes áreas relacionadas à percepção de esforço foram ativadas: giro cingulado, giro pré-central, giro pós-central, giro frontal superior, giro frontal superior, lóbulo superior parietal, giro lingual, giro temporal médio, giro frontal médio, precuneus, cuneus e cerebelo. De forma complementar, as áreas inibidas foram: giro angular, giro temporal superior, giro temporal médio, giro pré-central, giro temporal superior, giro frontal médio, giro occipital médio, giro lingual, lóbulo paracentral, precuneus e tálamo. Essas áreas ativadas e inibidas estão associadas a uma resposta cognitiva, ou seja, o momento que o indivíduo reportava a percepção de esforço diante de um protocolo de exercício incremental, considerando todas as intensidades. Em intensidades baixas houve ativação do cerebelo e giro pós-central, e inibição do giro frontal médio e giro temporal superior. Em intensidades altas, houve uma ativação do giro cingulado e inibição do giro angular e precuneus. Na comparação entre as intensidades podemos destacar que em intensidades baixas houve maior ativação do lóbulo parietal superior. Por outro lado, em intensidades altas houve maior inibição do giro angular, cingulado posterior, lóbulo parietal inferior e precuneus. Quando comparados indivíduos ciclistas e saudáveis houve uma maior ativação do giro pré-central e maior inibição do giro pré-central, giro temporal inferior e cerebelo nos ciclistas considerando todas as intensidades. Por fim, na comparação entre ciclistas e treinados, nas intensidades altas houve maior inibição do giro temporal médio (giro fusiforme) nos ciclistas. As áreas cerebrais, ativadas e inibidas, associadas à percepção de esforço estão relacionadas à área motora, pré-motora, motor suplementar somatossensoriais, controle emocional, processamento de atenção, linguagem, auditivas, integração de informação, gerenciamento de memória, planejamento e resolução de problemas e cognitiva. Em intensidades baixas, áreas motoras e somatossensorias foram ativadas e houve inibição de área pré-frontal e auditiva. Por outro lado, em intensidades altas, foram ativadas áreas relacionadas com o controle de emoções e foram inibidas áreas relacionadas ao processamento de linguagem e memória episódica. Entre ciclistas e não ciclistas, houve maior ativação de área motora e maior inibição de área somatossensorial, processamento de atenção e motora / Perception of effort and fatigue are widely represented in the brain during exercise, however, the information is not clear about the areas associated with these responses. Thus, this study aimed to identify and compare the brain areas associated with perception of effort during cycling exercise at different intensities and levels of training. This study included 24 adult subjects; 12 cyclists (75.6 ± 8.4 kg, height 175 cm ± 5.3, 24.4 ± 7.1 years; physical activity 5.4 ± 1.5 times per week) and 12 non-cyclists (trained) (79.7 ± 10.5 kg; 177 cm ± 9.1, 27.4 ± 4.8 years; physical activity 2.3 ± 1.3 times per week). Subjects were positioned to cycling ergometer coupled to magnetic resonance equipment and performed an incremental load interval test comprising blocks 30 s intervals for 30 s rest. At the end of each block, the perception of effort was reported. Comparative analysis of the images was all generated in Matlab using the SPM and NCA software. The following areas related to perceived exertion were activated: cingulate gyrus, precentral gyrus, post-central gyrus, superior frontal gyrus, superior frontal gyrus, parietal upper lobe, gyrus lingual, middle temporal gyrus, middle frontal gyrus, precuneus, cuneus and cerebellum. Complementarily, these were inhibited areas: angular gyrus, superior temporal gyrus, middle temporal gyrus, precentral gyrus, superior temporal gyrus, middle frontal gyrus, middle occipital gyrus, gyrus lingual, paracentral lobule, precuneus and thalamus. These activated and inhibited areas are related to cognitive response, when the individual reported the perceived exertion on an incremental exercise protocol, considering all intensities. At low intensities, there was activation of the cerebellum and post-central gyrus, and inhibition of the middle frontal gyrus and superior temporal gyrus. At high intensities, there was an activation of the cingulate gyrus and inhibition of angular and precuneus spin. Comparing the intensities, there was greater activation in the superior parietal lobe at low intensities. On the other hand, high intensity demonstrated greater inhibition of the angular gyrus, posterior cingulate, inferior parietal lobule and precuneus. Compared trained and healthy individuals there was a greater activation of the precentral gyrus and greater inhibition of pre-central gyrus, inferior temporal gyrus and cerebellum in trained subjects considering all intensities. Finally, comparing trained healthy subjects at high intensities there was greater inhibition of medial temporal gyrus (fusiform gyrus) in trained individuals. The brain areas, activated and inhibited, associated with the perception of effort are related to motor, pre-motor, somatosensory supplemental motor, emotional control, attention processing, language, auditory, information integration, memory management, planning and resolution problems and cognitive. At low intensities, motor and somatosensory areas were activated and there was inhibition of the prefrontal and auditory area. On the other hand, at high intensities, areas related to the control of emotions were activated and areas related to language processing and episodic memory were inhibited. Between cyclists and non-cyclists, there was greater activation of motor area and greater inhibition of somatosensory area, attention and motor processing

Dynamic contrast enhanced (DCE) cardiac magnetic resonance imaging (MRI) is well-established as a non-invasive method for qualitatively detecting obstructive coronary artery disease (CAD) which can impair myocardial blood flow and may result in myocardial infarction. Mathematical modelling of cardiac DCE-MRI data can provide quantitative assessment of myocardial blood flow. Quantitative assessment of myocardial blood flow may have merit in further stratification of patients with obstructive CAD and to improve the diagnosis and prognostication of the disease in the clinical setting. This thesis investigates the development of a quantitative analysis protocol for cardiac DCE-MRI data. In the first study presented in this thesis, Fermi and distributed parameter (DP) modelling are compared in single bolus versus dual bolus analysis. For model-based myocardial blood flow quantification, the convolution of a model with the arterial input function (i.e. contrast agent concentration-time curve extracted from the left ventricular cavity) is fitted to the tissue contrast agent concentration-time curve. In contrast to dual bolus DCE-MRI protocols, single bolus protocols reduce patient discomfort and acquisition protocol duration/complexity but, are prone to arterial input function saturation caused in the left ventricular cavity by the high concentration of contrast agent during bolus passage. Saturation effects can degrade the accuracy of quantification using Fermi modelling. The analysis presented in this study showed that DP modelling is less dependent on arterial input function saturation than Fermi modelling in eight healthy volunteers. In a pilot cohort of five patients, DP modelling detected for the first time reduced myocardial blood flow in all stenotic vessels versus standard clinical assessments. In the second study, it was investigated whether first-pass DP modelling can give accurate myocardial blood flow, against ideal values generated by numerical simulations. Unlike Fermi modelling which is convolved with only the first-pass range of the arterial input function, DP modelling is convolved with the entire contrast agent concentration-time course. In noisy and/or dual bolus data, it can be particularly challenging to identify the end point of the first-pass in the arterial input function. This study demonstrated that contrary to Fermi modelling, myocardial blood flow analysis using DP modelling does not depend on the number of time points used for fitting. Furthermore, this data suggests that DP modelling can reduce the quantitative variability caused by subjectivity in selection of the first-pass range in cardiac MR data. This in turn may help to facilitate the development of more automated software algorithms for myocardial blood flow quantification. In the third study, Fermi and DP modelling were compared against invasive clinical assessments and visual MR estimates, to assess their diagnostic ability in detecting obstructive CAD. A single bolus DCE-MRI protocol was implemented in twentyfour patients. In per vessel analysis, DP modelling reached superior sensitivity and negative predictive value in detecting obstructive CAD compared to Fermi modelling and visual estimates. In per patient analysis, DP modelling reached the highest sensitivity and negative predictive value in detecting obstructive CAD. These studies show that DP modelling analysis of cardiac single bolus DCE-MRI data can provide important functional information and can establish haemodynamic biomarkers to non-invasively improve the diagnosis and prognostication of obstructive CAD.

Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating neuropathy caused by commonly used chemotherapeutics. Clinically, the problem of CIPN is compounded by difficulties with diagnosis and limited treatment options. The pathophysiology of CIPN remains elusive, with current mechanistic postulates focused mainly on the peripheral nervous system. However, animal and human models of non-CIPN neuropathic conditions have shown the brain to be central to the development and maintenance of painful neuropathy. Moreover, evidence suggests that aberrant activity in key regions of the brain and brainstem could denote individual vulnerability for chronic pain states. The impact of the brain on CIPN development is unknown. Assessment of drug efficacy using brain imaging can provide sensitive readouts and is increasingly used in clinical trials. Aims: Firstly, to prospectively explore the structure and function of the brain in cancer patients prior to chemotherapy administration, using functional magnetic resonance imaging (fMRI), in order to determine whether baseline differences exist between patients who progress to CIPN as compared to those who do not. Secondly, to develop a pilot study using fMRI to investigate a topical treatment for CIPN, in order to assess the feasibility of setting up a study with this kind of design. Methods: To address the first aim of this thesis a prospective cohort study (the CIPN fMRI Study) was developed. Cancer patients scheduled to receive neurotoxic chemotherapy treatment including oxaliplatin, carboplatin, carbotaxol, or cisplatin, were recruited from three NHS trusts in Scotland, to undergo a high resolution (3 tesla) functional MRI scan, at a single time point prior to commencement of chemotherapy. During the scan structural, resting state and functional data were collected. Functional data involved the presentation of punctate stimuli (using a 256mN von Frey filament), above the patients’ right medial malleolus. While receiving the punctate stimuli, patients viewed images that had neutral or positive emotional content or a baseline coloured image with no content. Sample size was based on previously successful pain fMRI studies and pragmatic estimates. Acute CIPN was defined clinically by common toxicity criteria as necessitating a chemotherapy dose reduction or cessation. Data were analysed using FMRIB’s Software Library (FSL) version 5, 2015. Standard data pre-processing (brain extraction, registration, B0 unwarping, motion correction, and denosiing with FIX) was carried out. Structural analysis was conducted using FIRST. Resting state analysis utilised FSL’s MELODIC tool, and a non-parametric group comparison was made following a dual regression approach. FEAT was used for both first and second level functional analyses. Group comparisons were made using a mixed effects analysis (z threshold 2·3 and 2, regions considered significant at p < 0·05, cluster corrected). The group was split by sex to explore known sex differences in pain processing. To address the second aim of this thesis, a pilot fMRI randomised controlled trial (MINT3 Study) was designed. Approvals from ethics and research and development were sought and obtained. Data collection forms were developed. An fMRI experiment was proposed and a single pilot scan was conducted and analysed. Results: 30 patients were recruited for the CIPN fMRI study (mean age 60·4 years, 95% Confidence Interval: 57.4-63.4, 17 women). Two patients had lung cancer, nine had gynecological malignancies and 18 had colorectal cancer. 17 patients developed acute CIPN. Structural analysis showed that patients who developed CIPN had a smaller volume of the Nucleus Accumbens (NAc). Resting state analysis did not show clear differences between those who developed CIPN and those who did not. Finally, functional analysis showed that patients who did not develop CIPN had greater activation in the superior frontal gyrus when viewing positive emotional images as compared to those who did progress to CIPN. Region of interest analysis showed that female patients who developed CIPN had greater activity in their mesencephalic pontine reticular formation (MPRF). Male patients who progressed to CIPN had decreased activity in their thalamus. Feasability of the MINT3 study set up and fMRI paradigm was assessed. Interpretation Differences in brain structure and function are evident between patients who developed CIPN and those who did not. Crucially, the regions identified, in particular the NAc, have been postulated to denote a vulnerability for progression to pain states. Although the findings need further confirmation they suggest a paradigm shift in terms of CIPN as a clinical problem. Specifically, it appears that certain individuals can be considered as having increased risk of CIPN development prior to chemotherapy administration. This risk relates to the baseline structure, and function of their brains. Finally, the set up of the MINT3 fMRI study showed that this kind of study design is acceptable in terms of ethical and R&D approvals and a single healthy volunteer pilot.

Temporal regularity and metrical organisation are important factors in beat and metre perception. The current thesis aims to investigate neural correlates of beat and metre perception in healthy non-musician volunteers, using functional magnetic resonance imaging (fMRI). In particular, the thesis focuses on determining the role of the Inferior Frontal Gyrus (IFG, in particular BA44/45) in beat and metre perception. The IFG has been proposed to be involved in higher order cognitive processes during various temporal sequencing, such as speech, movement, and music. Previous studies have shown that the temporal processing of rhythm activates auditory and sensorimotor areas, but the role of the IFG in rhythm perception has not yet been fully understood. Study 1 investigated beat perception in complex rhythms, in which the addition of volume accents either enhanced or weakened the beat perception, resulting in Unaccented, Beat Accented or Non-Beat Accented rhythms. Participants (N=14; 6 males) listened to rhythm pairs across all three conditions, and judged whether each rhythm pair was the same or different. Results showed that left IFG activation (BA44) was significantly greater during the Non-Beat Accented condition compared to Beat Accented condition, whereas the right IFG activation showed no significant difference between the two conditions. Study 2 investigated metre perception of a series of isochronous sequences, of which metrical organisation was grouped by 2/4 (C2), 3/4 (C3), or 4/4 (C4) using pitch accents, or remained without metrical grouping (or 1/4, C1). The same participants (N=15; 6 males) listened to the stimuli and indicated the perceived metrical grouping level. Results showed that the activation of bilateral IFG parametrically increased from C2 to C3 to C4. Interestingly, the activation was found to be significantly greater in C1 relative to C2, suggesting that involuntary subjective in C1 may increase the brain response. Converging results from both Study 1 and Study 2 demonstrated, firstly, that the bilateral IFG is involved in rhythm perception in addition to the auditory and sensorimotor areas, including primary and secondary auditory areas, supplementary motor areas, premotor areas, insula, and basal ganglia. Secondly, the left IFG (BA44) in particular was significantly modulated by the rhythmic complexity relating to both temporal regularity and metrical organisation, while showing the suppression during the Beat Accented rhythm condition of Study 1 and the binary pattern (C2) of Study 2. This thesis argues that the left IFG (BA44) may have the role the higher order cognitive processing, such as attention and prediction, in the perception of hierarchical structures in metric rhythms.

Self-concept is strongly influenced by beliefs about one’s personal psychological attributes, and these beliefs are held with varying degrees of confidence and consequence. Hence, it is investment in self-views of those attributes that helps to regulate and maintain stable self-concept. Self-view investment is relevant to numerous self-related functions, but high self-view investment can also contribute to maladaptive self-views. Theory suggests that mindfulness cultivates a less personal, more objective perception of one’s thoughts, emotions and behaviors, and training in mindfulness has been shown to alter self-referential processing. The current pilot study (N=21) investigates the possible role of dispositional mindfulness in two forms of self-view investment, epistemic certainty and emotive importance, as indicated by self-reported and neural (functional magnetic resonance imaging-based) indicators of investment. Results indicated that dispositional mindfulness was positively associated with self-reported epistemic certainty but not emotive importance. Trait mindfulness was associated with activity in the amygdala and parahippocampal gyrus during judgements of both epistemic certainty and emotive importance. Caudate activity was positively associated with trait mindfulness specifically for judgements of emotive importance.

Natural aging leads to substantial brain changes. These biological changes can, and often do, precede changes in affect, cognition, and behavior. Even subtle changes, for example in affective experience, can create problematic outcomes in day-to-day emotion regulation and decision-making. For example, poor emotion regulation may lead an individual to fall prey to an emotionally potent scam. Similarly, an overly positive individual may not fully attend to or consider potentially negative future outcomes when faced with a decision. This work characterizes changes in affect across the lifespan, and how affect corresponds to brain function, as indexed by the blood oxygen dependent signal, during tasks taxing emotion regulation and decision-making functions. I predicted that age would correlate with greater positive relative to negative emotions and with a more global (i.e., less specific and less complex) representation of emotions. The former predicted pattern indicates increased "affective optimization" and the latter indicates reduced "affective complexity." I predicted that affective optimization and complexity would correlate with brain function during emotion regulation and decision-making. I used time-based experience sampling, self-reported affect, implicit measures of affect, and performance based measures of affect to determine the associations between age and affective optimization and complexity. Results show that age negatively correlates with affective complexity. Specifically, older age was associated with less negative affect complexity, less positive emotion regulation, less affective awareness. Also, older age corresponded to lower levels of negative affect, as indexed by their experiences and an implicit measure of affect. Next, I examined emotion regulation using a cognitive reappraisal task. I found that older age was associated with less successful reappraisal of negative and positive affect. I also found individual differences in the ventromedial prefrontal cortex among older adults during emotion regulation. Lastly, I examined decision-making patterns using an intertemporal choice task. I found that younger adults’ experienced affect aligned more closely with their decision patterns. Among older adults, affective acceptance correlated with individual differences in the striatum and insula. Taken together, these results support the idea that lower levels of affective competence, rather than higher levels, characterize older age. Also, individual differences in affect parallel individual differences in brain function in the somatic marker circuitry. This suggests possible deficits in interpreting visceral information important to emotion regulation and decision-making. The findings from this work will be important for understanding why some older adults are more susceptible to scams, fraud, and decision-making problems.

Obsessive-compulsive disorder (OCD) is associated with diminished quality of life and cognitive control dysfunction. Conflict adaptation is a reflection of cognitive control, and consists of the ability to detect conflict in previous trials and adjust performance on current trials. Conflict adaptation is thought to rely on interplay between the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC) for detecting conflict and signaling for increases in control, respectively. We hypothesized that individuals with OCD would show reduced conflict adaptation effects in response times, error rates, ACC activation, and dlPFC activation when compared with healthy control subjects. We also expected diminished conflict adaptation to be associated with poorer quality of life in those with OCD. Nineteen individuals with OCD and twenty psychiatrically-healthy controls completed a Stroop task while response times, error rates, and fMRI data were recorded. 2-Group (OCD, control) x 2-Previous Trial Congruency (congruent, incongruent), x 2-Current Trial Congruency (congruent, incongruent) ANOVAs were conducted for both behavioral and fMRI data. Indices of conflict adaptation were correlated with quality of life scores. There was a significant response time conflict adaptation effect collapsed across groups; however, there were no between-groups interactions or main effects. No error rate conflict adaptation was observed at any level of the analysis. On fMRI analyses, the dlPFC showed increased activation on incongruent relative to congruent trials collapsed across groups; however, no ACC activation differences were observed between current incongruent and congruent trials. Conflict adaptation-related activation was noted in the ACC collapsed across groups. The between-groups ANOVA revealed a significant cluster in the ACC with control participants showing greater ACC, medial prefrontal cortex, and left orbitofrontal cortex conflict adaptation activation-related activation relative to individuals with OCD. No between-groups differences were seen in the dlPFC. Conflict adaptation was not significantly related to quality of life. Individuals with OCD may use different neural processes to achieve similar behavioral results to those of healthy controls. Alternative explanations of conflict adaptation effects such as temporal learning theory are also discussed. Our hypothesized model for the ACC and dlPFC functioning as the evaluative and regulative components of cognitive control was only partly supported. ACC and dlPFC activation appeared to highlight different roles, but these roles may be independent rather than existing in a feedback loop. Although quality of life is significantly diminished in individuals with OCD, this loss of quality of life does not appear to be mediated by conflict adaptation differences.

Functional brain images are extraordinarily rich data sets that reveal distributed brain networks engaged in a wide variety of cognitive operations. It is a substantial challenge both to create models of cognition that mimic behavior and underlying cognitive processes and to choose a suitable analytic method to identify underlying brain networks. Most of the contemporary techniques used in analyses of functional neuroimaging data are based on univariate approaches in which single image elements (i.e. voxels) are considered to be computationally independent measures. Beyond univariate methods (e.g. statistical parametric mapping), multivariate approaches, which identify a network across all regions of the brain rather than a tessellation of regions, are potentially well suited for analyses of brain imaging data. A multivariate method (e.g. partial least squares) is a computational strategy that determines time-varying distributed patterns of the brain (as a function of a cognitive task). Compared to its univariate counterparts, a multivariate approach provides greater levels of sensitivity and reflects cooperative interactions among brain regions. Thus, by considering information across more than one measuring point, additional information on brain function can be revealed. Similarly, by considering information across more than one measuring technique, the nature of underlying cognitive processes become well-understood. Cognitive processes have been investigated in conjunction with multiple neuroimaging modalities (e.g. fMRI, sMRI, EEG, DTI), whereas the typical method has been to analyze each modality separately. Accordingly, little work has been carried out to examine the relation between different modalities. Indeed, due to the interconnected nature of brain processing, it is plausible that changes in one modality locally or distally modulate changes in another modality. This thesis focuses on multivariate and multimodal methods of image analysis applied to various cognitive questions. These methods are used in order to extract features that are inaccessible using univariate / unimodal analytic approaches. To this end, I implemented multivariate partial least squares analysis in study I and II in order to identify neural commonalities and differences between the available and accessible information in memory (study I), and also between episodic encoding and episodic retrieval (study II). Study I provided evidence of a qualitative differences between availability and accessibility signals in memory by linking memory access to modality-independent brain regions, and availability in memory to elevated activity in modality-specific brain regions. Study II provided evidence in support of general and specific memory operations during encoding and retrieval by linking general processes to the joint demands on attentional, executive, and strategic processing, and a process-specific network to core episodic memory function. In study II, III, and IV, I explored whether the age-related changes/differences in one modality were driven by age-related changes/differences in another modality. To this end, study II investigated whether age-related functional differences in hippocampus during an episodic memory task could be accounted for by age-related structural differences. I found that age-related local structural deterioration could partially but not entirely account for age-related diminished hippocampal activation. In study III, I sought to explore whether age-related changes in the prefrontal and occipital cortex during a semantic memory task were driven by local and/or distal gray matter loss. I found that age-related diminished prefrontal activation was driven, at least in part, by local gray matter atrophy, whereas the age-related decline in occipital cortex was accounted for by distal gray matter atrophy. Finally, in study IV, I investigated whether white matter (WM) microstructural differences mediated age-related decline in different cognitive domains. The findings implicated WM as one source of age-related decline on tasks measuring processing speed, but they did not support the view that age-related differences in episodic memory, visuospatial ability, or fluency were strongly driven by age-related differences in white-matter pathways. Taken together, the architecture of different aspects of episodic memory (e.g. encoding vs. retrieval; availability vs. accessibility) was characterized using a multivariate partial least squares. This finding highlights usefulness of multivariate techniques in guiding cognitive theories of episodic memory. Additionally, competing theories of cognitive aging were investigated by multimodal integration of age-related changes in brain structure, function, and behavior. The structure-function relationships were specific to brain regions and cognitive domains. Finally, we urged that contemporary theories on cognitive aging need to be extended to longitudinal measures to be further validated.