Behavioural and neuroimaging investigations of the relationship between visual attention, affordance and action

In this thesis the relationship between visual attention, affordance and action was investigated using a combination of neuroimaging and behavioural studies. Neuronal activity and movement construction were assessed when individuals passively viewed or produced action towards stimuli varying in their affordance and/or attentional attributes. The main findings were: (i) the passive perception of both object and abstract visual patterns was associated with decreased alpha and/or beta activity in sensori-motor cortex, occipito-temporal cortex and cerebellum. These are brain regions associated with the planning and production of visually guided action; (ii) for object patterns, decreased alpha and beta activity was also observed in regions of superior parietal and premotor cortex. These regions contain neurons argued to be essential for matching hand kinematics with manipulate objects; and (iii) in both control participants and a deafferented individual, studies of planned and unplanned pointing manoeuvres revealed that the attentional bias of a stimulus was critical for fast, efficient action production whereas the affordance bias was critical in determining end-point accuracy. Taken together, these findings demonstrate that affordance is not a necessary prerequisite for the potential of motor codes. Rather, affordance enables the construction of motor responses that reflect object functionality and/or manipulability. They further demonstrate that visual attention is associated with the potentiation of motor codes. Indeed, directed visual attention would appear critical for speeded responses. These findings provide new insights into the roles of directed visual attention and affordance upon action.

The investigation of oscillatory changes in the visual cortex using synthetic aperture magnetometry

This thesis is an exploration of the oscillatory changes occurring in the visual cortex as measured by a functional imaging technique known as Synthetic Aperture Magnetometry (SAM), and how these compare to the BOLD response, across a number of different experimental paradigms. In chapter one the anatomy and physiology of the visual pathways and cortex are outlined, introducing the reader to structures and terms used throughout the thesis whilst chapter two introduces both the technology and analysis techniques required to record MEG and fMRI and also outlines the theory behind SAM. In chapter three the temporal frequency tuning of both striate and extrastriate cortex is investigated, showing fundamental differences in both tuning characteristics and oscillatory power changes between the two areas. Chapter four introduces the concept of implied-motion and investigates the role of area V5 / MT in the perception of such stimuli and shows, for the first time, the temporal evolution of the response in this area. Similarly a close link is shown between the early evoked potential, produced by the stimulus, and previous BOLD responses. Chapter five investigates the modulation of cortical oscillations to both shifts in attention and varying stimulus contrast. It shows that there are both induced and evoked modulation changes with attention, consistent with areas previously known to show BOLD responses. Chapter six involves a direct comparison of cortical oscillatory changes with those of the BOLD response in relation to the parametric variation of a motion coherence stimulus. It is shown that various cortical areas show a linear BOLD response to motion coherence and, for the first time, that both induced oscillatory and evoked activity also vary linearly in areas coincidental with the BOLD response. The final chapter is a summary of the main conclusions and suggests further work.

Beta-amyloid (beta/A4) deposition in the medial temporal lobe in Down's syndrome: effects of brain region and patient age

The density of diffuse, primitive, classic and compact beta-amyloid (beta/A4) deposits was studied in the medial temporal lobe in 12 cases of Down's syndrome (DS) from 38 to 67 years of age. Total beta/A4 deposit density was greater in the adjacent cortex compared with regions of the hippocampus, and these differences were similar within each age group of patients. The ratio of the primitive to diffuse deposits was greater in the hippocampus than in the adjacent cortex. Total beta/A4 density did not vary significantly with patient age. However, the density of the diffuse deposits exhibited a parabolic, and the primitive, classic and compact deposits an inverted parabolic, response with age. Hence, in DS, (1) beta/A4 density remains relatively constant with age, (2) differences in beta/A4 density between the hippocampus and adjacent cortex are established at an early age, and (3) mature beta/A4 subtype formation depends on brain region and patient age.

Moderate relationships between NAA and cognitive ability in healthy adults:implications for cognitive spectroscopy

Background: Proton Magnetic Resonance Spectroscopy (H-MRS) is a non-invasive imaging technique that enables quantification of neurochemistry in vivo and thereby facilitates investigation of the biochemical underpinnings of human cognitive variability. Studies in the field of cognitive spectroscopy have commonly focused on relationships between measures of N-acetyl aspartate (NAA), a surrogate marker of neuronal health and function, and broad measures of cognitive performance, such as IQ. Methodology/Principal Findings: In this study, we used H-MRS to interrogate single-voxels in occipitoparietal and frontal cortex, in parallel with assessments of psychometric intelligence, in a sample of 40 healthy adult participants. We found correlations between NAA and IQ that were within the range reported in previous studies. However, the magnitude of these effects was significantly modulated by the stringency of data screening and the extent to which outlying values contributed to statistical analyses. Conclusions/Significance: H-MRS offers a sensitive tool for assessing neurochemistry non-invasively, yet the relationships between brain metabolites and broad aspects of human behavior such as IQ are subtle. We highlight the need to develop an increasingly rigorous analytical and interpretive framework for collecting and reporting data obtained from cognitive spectroscopy studies of this kind. © 2014 Patel, Blyth, Griffiths, Kelly and Talcott.

Oculo-visual changes and clinical considerations affecting older patients with dementia

Purpose: Dementia is associated with various alterations of the eye and visual function. Over 60% of cases are attributable to Alzheimer's disease, a significant proportion of the remainder to vascular dementia or dementia with Lewy bodies, while frontotemporal dementia, and Parkinson's disease dementia are less common. This review describes the oculo-visual problems of these five dementias and the pathological changes which may explain these symptoms. It further discusses clinical considerations to help the clinician care for older patients affected by dementia. Recent findings: Visual problems in dementia include loss of visual acuity, defects in colour vision and visual masking tests, changes in pupillary response to mydriatics, defects in fixation and smooth and saccadic eye movements, changes in contrast sensitivity function and visual evoked potentials, and disturbance of complex visual functions such as in reading ability, visuospatial function, and the naming and identification of objects. Pathological changes have also been reported affecting the crystalline lens, retina, optic nerve, and visual cortex. Clinically, issues such as cataract surgery, correcting the refractive error, quality of life, falls, visual impairment and eye care for dementia have been addressed. Summary: Many visual changes occur across dementias, are controversial, often based on limited patient numbers, and no single feature can be regarded as diagnostic of any specific dementia. Nevertheless, visual hallucinations may be more characteristic of dementia with Lewy bodies and Parkinson's disease dementia than Alzheimer's disease or frontotemporal dementia. Differences in saccadic eye movement dysfunction may also help to distinguish Alzheimer's disease from frontotemporal dementia and Parkinson's disease dementia from dementia with Lewy bodies. Eye care professionals need to keep informed of the growing literature in vision/dementia, be attentive to signs and symptoms suggestive of cognitive impairment, and be able to adapt their practice and clinical interventions to best serve patients with dementia.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

Neural activity during object perception in schizophrenia patients is associated with illness duration and affective symptoms

Background - Abnormalities in visual processes have been observed in schizophrenia patients and have been associated with alteration of the lateral occipital complex and visual cortex. However, the relationship of these abnormalities with clinical symptomatology is largely unknown. Methods - We investigated the brain activity associated with object perception in schizophrenia. Pictures of common objects were presented to 26 healthy participants (age = 36.9; 11 females) and 20 schizophrenia patients (age = 39.9; 8 females) in an fMRI study. Results - In the healthy sample the presentation of pictures yielded significant activation (pFWE (cluster) < 0.001) of the bilateral fusiform gyrus, bilateral lingual gyrus, and bilateral middle occipital gyrus. In patients, the bilateral fusiform gyrus and bilateral lingual gyrus were significantly activated (pFWE (cluster) < 0.001), but not so the middle occipital gyrus. However, significant bilateral activation of the middle occipital gyrus (pFWE (cluster) < 0.05) was revealed when illness duration was controlled for. Depression was significantly associated with increased activation, and anxiety with decreased activation, of the right middle occipital gyrus and several other brain areas in the patient group. No association with positive or negative symptoms was revealed. Conclusions - Illness duration accounts for the weak activation of the middle occipital gyrus in patients during picture presentation. Affective symptoms, but not positive or negative symptoms, influence the activation of the right middle occipital gyrus and other brain areas.

EFFECTS OF AGING ON MIDBRAIN AND CORTICAL SPEECH-IN-NOISE PROCESSING

Older adults frequently report that they can hear what they have been told but cannot understand the meaning. This is particularly true in noisy conditions, where the additional challenge of suppressing irrelevant noise (i.e. a competing talker) adds another layer of difficulty to their speech understanding. Hearing aids improve speech perception in quiet, but their success in noisy environments has been modest, suggesting that peripheral hearing loss may not be the only factor in the older adult’s perceptual difficulties. Recent animal studies have shown that auditory synapses and cells undergo significant age-related changes that could impact the integrity of temporal processing in the central auditory system. Psychoacoustic studies carried out in humans have also shown that hearing loss can explain the decline in older adults’ performance in quiet compared to younger adults, but these psychoacoustic measurements are not accurate in describing auditory deficits in noisy conditions. These results would suggest that temporal auditory processing deficits could play an important role in explaining the reduced ability of older adults to process speech in noisy environments. The goals of this dissertation were to understand how age affects neural auditory mechanisms and at which level in the auditory system these changes are particularly relevant for explaining speech-in-noise problems. Specifically, we used non-invasive neuroimaging techniques to tap into the midbrain and the cortex in order to analyze how auditory stimuli are processed in younger (our standard) and older adults. We will also attempt to investigate a possible interaction between processing carried out in the midbrain and cortex.

The role of Proteasome in the development, maintenance and management of Chronic Pain

In chronic pain, opioids represent the gold standard analgesics, but their use is hampered by the development of several side effects, as development of analgesic tolerance and opioid-induced hyperalgesia. Evidence showed that many molecular mechanisms (changes in opioid receptors, neurotransmitter release, and glia/microglia activation) are involved in their appearance, as well as in chronic pain. Recently, a crucial role has been proposed for oxidative stress and proteasome in chronic pain and in treatment-related side effects. To better elucidate these aspects, the aim of this PhD thesis was to investigate the effects of opioids on cell oxidative stress, antioxidant enzymatic machinery and proteasome expression and activity in vitro. Also, the involvement of proteasome in the development of chronic pain conditions was investigated utilizing an experimental model of oxaliplatin-induced neuropathy (OXAIN), in vivo. Data showed that morphine, fentanyl, buprenorphine and tapentadol alter differently ROS production. The ROS increasing effect of morphine is not shared by the other opioids, suggesting that the different pharmacological profile could influence this parameter. Moreover, these drugs produced different alterations of β2trypsin-like and β5chymotrypsin-like activities. In fact, while morphine and fentanyl increased the proteolytic activity after prolonged exposure, a different picture was observed for buprenorphine and tapentadol, suggesting that the level of MOR agonism could be strongly related with proteasome activation. In vivo studies revealed that rats treated with oxaliplatin showed a significant increase in β5, in the thalamus (TH) and somatosensory cortex (SSCx). Moreover, a selective up-regulation of β5 and LMP7 subunit gene expression was assessed in the SSCx. Furthermore, our study revealed that oprozomib, a selective β5 inhibitor normalized the spinal prodynorphin gene expression upregulation induced by oxaliplatin, and reverted mechanical/thermal allodynia and mechanical hyperalgesia in oxaliplatin-treated rats. These results underline the role of proteasome in the OXAIN and suggest new pharmacological targets to counteract it.

New approaches to underground systems in Brazilian Smilax species (Smilacaceae)

MARTINS, A. R. (Institute of Biology, State University of Campinas - UNICAMP, 13083-970, Campinas, SP, Brazil), N. PUT, (Division of Biology and Education, University of Vechta, 49377 Vechta, Germany), A. N. SOARES, A.B BOMB, and B. APPEZZATO DA GLORIA (Biological Science Department, Escola Superior de Agricultura `Luiz de Queiroz`, University of Sao Paulo, 13418-900, Piracicaba, SP, Brazil). J. Torrey Bot. Soc. 137: 220-235. 2010.-New approaches to underground systems in Brazilian Smilax species (Smilacaceae). Scientific studies show that the watery extract of the thickened underground stem and its adventitious roots of the genus Smilax can act as a therapeutic agent in immunoinflammatory disorders, such as rheumatic arthritis. Brazilians have used this genus of plants in folk medicine, however it is very hard to identify these species, since the morphology of the underground systems is very similar in this group. For better identification of those systems, we studied six species of Smilax L. (S. brasiliensis, S. campestris, S. cissoides, S. goyazana, S. oblongifolia and S. rufescens), collected in different regions of Brazil with different physiognomies and soil characteristics. The main purpose is to describe the morpho-anatomy of the underground systems and to analyze if their structure depends on environmental conditions. The underground stem (rhizophore) is of brown color and it is knotty, massive, slender (S. rufescens) or tuberous (S. brasiliensis, S. campestris, S. cissoides, S. goyazana and S. oblongifolia). The tuberization is a result of primary thickened meristem (PTM) activity. The color and thickness of the adventitious roots change during development because the epidermis and outer cortex are disposed of, so the inner cortex becomes the new covering tissue with lignified and dark color cells. There are differences in starch grain shapes in mature roots. The chemical attributes of the soil are very similar in all studied environments and, even when soil characteristics varied, all the species` underground system was distributed close to the soil surface (10 to 15 cm deep). The species exhibited clonal growth hence their underground system functions as storage structures and the axillary buds can sprout into new stems. Only Smilax rufescens, collected in sandy soil of Restinga, has vegetative dispersal due to the runners.

Effect of Cu Toxicity on Growth of Cowpea (Vigna unguiculata)

Accurate determination of the rhizotoxicity of Cu in dilute nutrient solutions is hindered by the difficulty of maintaining constant, pre-determined concentrations of Cu (micromolar) in solution. The critical Cu2+ activity associated with a reduction in the growth of solution-grown cowpea (Vigna unguiculata (L.) Walp. cv Caloona) was determined in a system in which Cu was maintained constant through the use of a cation exchange resin. The growth of roots and shoots was found to be reduced at solution Cu2+ activities ≥ 1.7 µM (corresponding to 90 % maximum growth). Although root growth was most likely reduced due to a direct Cu2+ toxicity, it is considered that the shoot growth reduction is attributable to a decrease in tissue concentrations of K, Ca, Mg, and Fe and the formation of interveinal chlorosis. At high Cu2+ activities, roots were brown in color, short and thick, had bent root tips with cracking of the epidermis and outer cortex, and had local swellings behind the roots tips due to a reduction in cell elongation. Root hair growth was reduced at concentrations lower than that which caused a significant reduction in overall root fresh weight.

Response selection deficits in melancholic but not nonmelancholic unipolar major depression

One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.

Mathematically gifted male adolescents activate a unique brain network during mental rotation

Mental rotation involves the creation and manipulation of internal images, with the later being particularly useful cognitive capacities when applied to high-level mathematical thinking and reasoning. Many neuroimaging studies have demonstrated mental rotation to be mediated primarily by the parietal lobes, particularly on the right side. Here, we use fMRI to show for the first time that when performing 3-dimensional mental rotations, mathematically gifted male adolescents engage a qualitatively different brain network than those of average math ability, one that involves bilateral activation of the parietal lobes and frontal cortex, along with heightened activation of the anterior cingulate. Reliance on the processing characteristics of this uniquely bilateral system and the interplay of these anterior/posterior regions may be contributors to their mathematical precocity.

Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia

Obstetric complications play a role in the pathophysiology of schizophrenia. However, the biological consequences during neurodevelopment until adulthood are unknown. Microarrays have been used for expression profiling in four brain regions of a rat model of neonatal hypoxia as a common factor of obstetric complications. Animals were repeatedly exposed to chronic hypoxia from postnatal (PD) day 4 through day 8 and killed at the age of 150 days. Additional groups of rats were treated with clozapine from PD 120-150. Self-spotted chips containing 340 cDNAs related to the glutamate system (""glutamate chips"") were used. The data show differential (up and down) regulations of numerous genes in frontal (FR), temporal (TE) and parietal cortex (PAR), and in caudate putamen (CPU), but evidently many more genes are upregulated in frontal and temporal cortex, whereas in parietal cortex the majority of genes are downregulated. Because of their primary presynaptic occurrence, five differentially expressed genes (CPX1, NPY, NRXN1, SNAP-25, and STX1A) have been selected for comparisons with clozapine-treated animals by qRT-PCR. Complexin 1 is upregulated in FR and TE cortex but unchanged in PAR by hypoxic treatment. Clozapine downregulates it in FR but upregulates it in PAR cortex. Similarly, syntaxin 1A was upregulated in FR, but downregulated in TE and unchanged in PAR cortex, whereas clozapine downregulated it in FR but upregulated it in PAR cortex. Hence, hypoxia alters gene expression regionally specific, which is in agreement with reports on differentially expressed presynaptic genes in schizophrenia. Chronic clozapine treatment may contribute to normalize synaptic connectivity.

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder

Objective: Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD. Methods: Sixty-three BD patients were studied (mean +/- SD age = 38.2 +/- 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions. Results: Left rostral ACC GM volume was inversely correlated with the BIS total score (t = 3.95, p(corrected) = 0.003) and the BIS motor score (t = 5.22, p(corrected) < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance. Conclusions: Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.