Investigation of working memory representations bridging perception & action in the somatosensory domain

This dissertation comprises original experimental work exploring the intermediate stages of the perception-action loop in the somatosensory domain. The stages correspond to the maintenance of working memory (WM) content, the goal-directed manipulation of the content, and the formation of memory-based decisions. Concurrently, the thesis addresses ongoing debates in cognitive neuroscience, specifically, the localization of the respective WM- and decision-making content. For both debates, the central issue rests with the extent of influence that experimental design has on the localization of the resulting representations. By taking advantage of modifications of experimental paradigms, advanced whole-brain data analysis techniques, and the extensive literature in the somatosensory domain, the dissertation provides evidence in favour of the distributed representation of WM content. The distribution of WM representations is not limited to either frontal or sensory regions. Indeed, the fronto-parietal network - specifically the intraparietal sulcus, inferior frontal gyrus, and the premotor cortex - is necessary for the successful performance of the intermediate stages of the perception-action loop. Therefore, the maintenance of WM content, the manipulation and maintenance of the resulting content, and the computation of the decision variable, all take place in a network consisting primarily of frontal and parietal regions with the specific distribution of WM content depending on the experimental paradigm

Parametric Representation of Tactile Numerosity in Working Memory

Estimated numerosity perception is processed in an approximate number system (ANS) that resembles the perception of a continuous magnitude. The ANS consists of a right lateralized frontoparietal network comprising the lateral prefrontal cortex (LPFC) and the intraparietal sulcus. Although the ANS has been extensively investigated, only a few studies have focused on the mental representation of retained numerosity estimates. Specifically, the underlying mechanisms of estimated numerosity working memory (WM) is unclear. Besides numerosities, as another form of abstract quantity, vibrotactile WM studies provide initial evidence that the right LPFC takes a central role in maintaining magnitudes. In the present fMRI multivariate pattern analysis study, we designed a delayed match-to-numerosity paradigm to test what brain regions retain approximate numerosity memoranda. In line with parametric WM results, our study found numerosity-specific WM representations in the right LPFC as well as in the supplementary motor area and the left premotor cortex extending into the superior frontal gyrus, thus bridging the gap in abstract quantity WM literature

Regulation of Hepatic Drug Metabolizing Enzymes in Chronic Kidney Disease

Chronic kidney disease (CKD) occurs as a result of declining renal function for 3 or more months. CKD effects 1 in 10 Canadians and is associated with a number of co-morbidities including diabetes and cardiovascular disease. To manage CKD and associated co-morbidities, patients take an average of 12 medications with a median pill burden of 19. Indeed, renal drug elimination is compromised in CKD, as declining glomerular filtration reduces drug excretion into urine. More recently, studies have provided evidence of altered non-renal drug clearance in CKD. The majority of drug clearance occurs in the liver by CYP2C and CYP3A drug metabolizing enzymes. Hepatic CYP2C and CYP3A drug metabolizing enzymes are tightly regulated by nuclear receptors. The majority of CKD patients have mild to moderate degrees of CKD and the potential for altered hepatic drug metabolism at these earlier stages is unknown. As renal function declines, patients begin to experience the uremic condition, which consists of metabolic waste product accumulation in the blood. A number of studies suggest that these uremic toxins may mediate the downregulation of hepatic CYP2C and CYP3A; however, the mechanism by which this occurs remains to be determined. My overall hypothesis is that hepatic drug metabolism is altered in CKD. Herein, we evaluate the effects of moderate CKD on hepatic drug metabolism and determine a possible mechanism of CYP2C and CYP3A downregulation in rats with CKD. In a rat model of moderate CKD, hepatic CYP2C and CYP3A function and expression were significantly decreased demonstrating a negative exponential correlation with kidney function. Transcriptional activation in both the CYP2C and CYP3A promoters was reduced as a result of decreased nuclear receptor binding and histone acetylation. Untargeted metabolomics was utilized to identify potential uremic mediators of hepatic CYP2C and CYP3A altered expression and function. Gut-derived uremic toxins accounted for the most significant metabolic signatures defining plasma and liver tissue in CKD, leading to the evaluation of these toxin effects on hepatic CYP2C and CYP3A. Reduction of gut-derived uremic toxins did not recover CYP2C and CYP3A function and expression in CKD. In conclusion, these studies further our understanding of hepatic drug metabolizing enzyme downregulation in the setting of CKD

Response modality-dependent categorical choice representations for vibrotactile comparisons

Previous electrophysiological studies in monkeys and humans suggest that premotor regions are the primary loci for the encoding of perceptual choices during vibrotactile comparisons. However, these studies employed paradigms wherein choices were inextricably linked with the stimulus order and selection of manual movements. It remains largely unknown how vibrotactile choices are represented when they are decoupled from these sensorimotor components of the task. To address this question, we used fMRI-MVPA and a variant of the vibrotactile frequency discrimination task which enabled the isolation of choice-related signals from those related to stimulus order and selection of the manual decision reports. We identified the left contralateral dorsal premotor cortex (PMd) and intraparietal sulcus (IPS) as carrying information about vibrotactile choices. Our finding provides empirical evidence for an involvement of the PMd and IPS in vibrotactile decisions that goes above and beyond the coding of stimulus order and specific action selection. Considering findings from recent studies in animals, we speculate that the premotor region likely serves as a temporary storage site for information necessary for the specification of concrete manual movements, while the IPS might be more directly involved in the computation of choice. Moreover, this finding replicates results from our previous work using an oculomotor variant of the task, with the important difference that the informative premotor cluster identified in the previous work was centered in the bilateral frontal eye fields rather than in the PMd. Evidence from these two studies indicates that categorical choices in human vibrotactile comparisons are represented in a response modality-dependent manner

Intraparietal sulcus maintains working memory representations of somatosensory categories in an adaptive, context-dependent manner

Working memory (WM) representations are generally known to be influenced by task demands, but it is not clear whether this extends to the somatosensory domain. One way to investigate the influence of task demands is with categorization paradigms, wherein either a single stimulus or an associated category is maintained in WM. In the somatosensory modality, category representations have been identified in the premotor cortex (PMC) and the intraparietal sulcus (IPS). In this study we used multivariate-pattern-analysis with human fMRI data to investigate whether the WM representations in the PMC, IPS or other regions are influenced by changing task demands. We ensured the task-dependent, categorical WM information was decorrelated from stimulus features by (1) teaching participants arbitrary, non-rule based stimulus groupings and (2) contrasting identical pairs of stimuli across experimental conditions, where either a single stimulus or the associated group was maintained in WM. Importantly, we also decoupled the decision and motor output from the WM representations. With these experimental manipulations, we were able to pinpoint stimulus-specific WM information to the left frontal and parietal cortices and context-dependent, group-specific WM information to the left IPS. By showing that grouped stimuli are represented more similarly in the Group condition than in the Stimulus condition, free from stimulus and motor output confounds, we provide novel evidence for the adaptive nature of somatosensory WM representations in the IPS with changing task-demands

Color stabilization of apulian red wines through the sequential inoculation of starmerella bacillaris and saccharomyces cerevisiae

Mixed fermentation using Starmerella bacillaris and Saccharomyces cerevisiae has gained attention in recent years due to their ability to modulate the qualitative parameters of enological interest, such as the color intensity and stability of wine. In this study, three of the most important red Apulian varieties were fermented through two pure inoculations of Saccharomyces cerevisiae strains or the sequential inoculation of Saccharomyces cerevisiae after 48 h from Starmerella bacillaris. The evolution of anthocyanin profiles and chromatic characteristics were determined in the produced wines at draining off and after 18 months of bottle aging in order to assess the impact of the different fermentation protocols on the potential color stabilization and shelf-life. The chemical composition analysis showed titratable acidity and ethanol content exhibiting marked differences among wines after fermentation and aging. The 48 h inoculation delay produced wines with higher values of color intensity and color stability. This was ascribed to the increased presence of compounds, such as stable A-type vitisins and reddish/violet ethylidene-bridge flavonol-anthocyanin adducts, in the mixed fermentation. Our results proved that the sequential fermentation of Starmerella bacillaris and Saccharomyces cerevisiae could enhance the chromatic profile as well as the stability of the red wines, thus improving their organoleptic quality