Quantification of neural substrates of vergence system via fMRI

Vergence eye movement is one of the oculomotor systems which allow depth perception via disconjugate movement of the eyes. Neuroimaging methods such as functional magnetic resonance imaging (fMRI) measure neural activity changes activity in the brain while subjects perform experimental tasks. A rich body of primate investigations on vergence is already established in the neurophysiology literature; on the other hand, there are a limited number of fMRI studies on neural mechanisms behind the vergence system. The results demonstrated that vergence system shares neural sources and also shows differentiation within the boundaries of frontal eye fields (FEF) and midbrain of the brainstem in comparison to saccadic, rapid conjugate eye movements, system with application of simple tracking experiment. Functional activity within the FEF was located anterior to the saccadic functional activity (z \u3e 2.3; p \u3c 0.03). Functional activity within the midbrain was observed as a result of application of vergence task, but not for the saccade data set. The novel memory-guided vergence experiment also showed a relationship between posterior parahippocampal area and memory where two other experiments were implemented for comparison of memory load in this region. Significant percent change in the functional activity was observed for the posterior parahippocampal area. Furthermore, an increase in the interconnectivity was observed for vergence tasks via utilization of Granger-Causality Analysis. When prediction was involved the increase in the number of causal interactions was statistically significant (p\u3c 0.05). The comparison of the number of influences between prediction-evoked vergence task and simple tracking vergence task was also statistically significant for these two experimental paradigms, p \u3c 0.0001. Another result observed in this dissertation was the application of hierarchical independent component analysis from to the fronto-parietal and cerebellar components within saccade and vergence tasks. Interestingly, cerebellar component showed delayed latency in the group level signal in comparison to fronto-parietal group level signals, which was evaluated to determine why segregation existed between the components acquired from the implementation of independent component analysis. Lastly, region of interet (ROI) based analysis in comparison to global (whole) brain analysis indicated more sensitive results on frontal, parietal, brainstem and occipital areas at both individual and group levels. Overall, the purpose of this dissertation was to investigate neural control of vergence movements by 1-spatial mapping of vergence induced functional activity, 2- applying different signal processing methods to quantify neural correlates of the vergence system at causal functional connectivity, underlying sources and region of interests (ROI) based levels. It was concluded that quantification of vergence movements via fMRI can build a synergy with behavioral investigations and may also shed light on neural differentiation between healthy individuals and patients with neural dysfunctions and injuries by serving as a biomarker

Developmental changes in effective connectivity associated with relational reasoning

Rostrolateral prefrontal cortex (RLPFC) is part of a frontoparietal network of regions involved in relational reasoning, the mental process of working with relationships between multiple mental representations. RLPFC has shown functional and structural changes with age, with increasing specificity of left RLPFC activation for relational integration during development. Here, we used dynamic causal modeling (DCM) to investigate changes in effective connectivity during a relational reasoning task through the transition from adolescence into adulthood. We examined fMRI data of 37 healthy female participants (11–30 years old) performing a relational reasoning paradigm. Comparing relational integration to the manipulation of single relations revealed activation in five regions: the RLPFC, anterior insula, dorsolateral PFC, inferior parietal lobe, and medial superior frontal gyrus. We used a new exhaustive search approach and identified a full DCM model, which included all reciprocal connections between the five clusters in the left hemisphere, as the optimal model. In line with previous resting state fMRI results, we showed distinct developmental effects on the strength of long-range frontoparietal versus frontoinsular short-range fixed connections. The modulatory connections associated with relational integration increased with age. Gray matter volume in left RLPFC, which decreased with age, partly accounted for changes in fixed PFC connectivity. Finally, improvements in relational integration performance were associated with greater modulatory and weaker fixed PFC connectivity. This pattern provides further evidence of increasing specificity of left PFC function for relational integration compared to the manipulation of single relations, and demonstrates an association between effective connectivity and performance during development. Hum Brain Mapp, 2013

Multimodal imaging : functional, structural, and molecular brain correlates of cognitive aging

Aging is associated with a decline in many (but not all) cognitive abilities. Although it remains largely unknown how changes in brain integrity relate to cognitive deficits, these changes are likely expressed across interrelated functional, structural, and molecular layers. This complexity calls for a multimodal imaging approach in age-related mind-brain research. Hence, in this thesis, different imaging modalities were combined in order to study the neural basis of cognitive aging. Study I investigated functional connectivity patterns among three large-scale functional brain networks (i.e., default mode [DMN], frontoparietal control [FPN], and dorsal attention [DAN] networks) during rest and task in younger and older adults. The FPN was flexible in its affiliation to other networks, given that it was more functionally connected to the DMN during rest and to the DAN during task performance. Age-related differences were stable across states for the FPN, but were only present for connectivity between the DMN and DAN during the task. Taken together, these results suggest that resting-state is not sufficient to uncover the entire functional connectome of the human brain. Study II identified brain iron as a potential source of age-related differences in connectivity. Greater striatal iron content was associated with lower intrinsic functional connectivity of the caudate and putamen. Additionally, more iron was associated with less connectivity between the putamen and the rest of the brain. Functional connectivity within the putamen was also linked to motor ability, indicating that iron-related connectivity features are behaviorally meaningful. Study III explored the relationship between functional and structural connectivity, and showed that increased homotopic functional connectivity in the prefrontal cortex was associated with worse microstructural degeneration of the corpus callosum, and exacerbated working memory decline. However, given that the association between function and structure was weak, results also suggest that homotopic functional connectivity can be resilient to change in the integrity of its structural paths. Study IV found that dopamine and iron in the putamen were positively associated, but only up until middle age. Together with the fact that dopamine requires iron for its synthesis, these results indicate that, for individuals without excessive iron accumulation, more iron is associated with higher dopaminergic activity. Higher iron load in the putamen was also linked to better processing speed for those in middle age. Collectively, the studies show that functional connectivity is influenced by mental state, white-matter changes, and molecular properties, with the latter also being interrelated among themselves. These different features are associated with performance and interact with each other, suggesting that cognitive decline is linked to a multitude of changes in brain integrity, and that age-related alterations in the human brain are complex and multifaceted

The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study

The use and public knowledge of noninvasive neurostimulation is rapidly increasing. Transcranial direct current stimulation (tDCS) is a noninvasive technique in which small amounts of current are passed through the cortex in order to change the resting state of underlying neurons. This technique has wide use in rehabilitation and research settings. Here we studied the use of tDCS in healthy younger adults. Our previous findings demonstrated that tDCS can improve working memory (WM) performance in some individuals. We learned that individual differences in education level and WM capacity modulate tDCS effects. In Experiment 1 and 2 we investigated why low WM capacity participants do not benefit or have reduced performance after tDCS. We also explored how tDCS affects cortical blood flow using functional near infrared spectroscopy (fNIRS). In Experiment 1 we examined how strategy use influences tDCS effects. The results demonstrated that active strategy use does not facilitate tDCS effects in low WM capacity participants. Conversely, the high WM capacity participants continued to improve. Furthermore, we found that only the high WM capacity participants had an increase in oxygenated blood flow following anodal tDCS regardless of strategy use. In Experiment 2 we investigated how motivation level modified tDCS effects. We found that motivation level promoted enhanced performance across tDCS conditions for both WM capacity groups. Interestingly, only the low WM capacity participants had an increase in oxygenated blood flow across all motivation and tDCS conditions. The results from all four experiences have important implications for future successful use of neurostimulation in both clinical and healthy populations

Modafinil modulation of the default mode network

RationaleThe default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.ObjectivesIn the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.MethodsEighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.ResultsThere was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.ConclusionsModafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil

Magnetoencephalography as a tool in psychiatric research: current status and perspective

The application of neuroimaging to provide mechanistic insights into circuit dysfunctions in major psychiatric conditions and the development of biomarkers are core challenges in current psychiatric research. In this review, we propose that recent technological and analytic advances in Magnetoencephalography (MEG), a technique which allows the measurement of neuronal events directly and non-invasively with millisecond resolution, provides novel opportunities to address these fundamental questions. Because of its potential in delineating normal and abnormal brain dynamics, we propose that MEG provides a crucial tool to advance our understanding of pathophysiological mechanisms of major neuropsychiatric conditions, such as Schizophrenia, Autism Spectrum Disorders, and the dementias. In our paper, we summarize the mechanisms underlying the generation of MEG signals and the tools available to reconstruct generators and underlying networks using advanced source-reconstruction techniques. We then survey recent studies that have utilized MEG to examine aberrant rhythmic activity in neuropsychiatric disorders. This is followed by links with preclinical research, which have highlighted possible neurobiological mechanisms, such as disturbances in excitation/inhibition parameters, which could account for measured changes in neural oscillations. In the final section of the paper, challenges as well as novel methodological developments are discussed which could pave the way for a widespread application of MEG in translational research with the aim of developing biomarkers for early detection and diagnosis

Effects of cholinesterase inhibition on brain function

Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work - both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmine-induced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section

Age-differential relationships among dopamine D1 binding potential, fusiform BOLD signal, and face-recognition performance

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during facerecognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults