David Prvulovic

Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest

Cortical functional connectivity, as indicated by the concurrent spontaneous activity of spatially segregated regions, is being studied increasingly because it may determine the reaction of the brain to external stimuli and task requirements and it is reportedly altered in many neurological and psychiatric disorders. In functional magnetic resonance imaging (fMRI), such functional connectivity is investigated commonly by correlating the time course of a chosen “seed voxel” with the remaining voxel time courses in a voxel‐by‐voxel manner. This approach is biased by the actual choice of the seed voxel, however, because it only shows functional connectivity for the chosen brain region while ignoring other potentially interesting patterns of coactivation. We used spatial independent component analysis (sICA) to assess cortical functional connectivity maps from resting state data. SICA does not depend on any chosen temporal profile of local brain activity. We hypothesized that sICA would be able to find functionally connected brain regions within sensory and motor regions in the absence of task‐related brain activity. We also investigated functional connectivity patterns of several parietal regions including the superior parietal cortex and the posterior cingulate gyrus. The components of interest were selected in an automated fashion using predefined anatomical volumes of interest. SICA yielded connectivity maps of bilateral auditory, motor and visual cortices. Moreover, it showed that prefrontal and parietal areas are also functionally connected within and between hemispheres during the resting state. These connectivity maps showed an extremely high degree of consistency in spatial, temporal, and frequency parameters within and between subjects. These results are discussed in the context of the recent debate on the functional relevance of fluctuations of neural activity in the resting state. Hum. Brain Mapp. 22:165–178, 2004.

Localizing P300 Generators in Visual Target and Distractor Processing: A Combined Event-Related Potential and Functional Magnetic Resonance Imaging Study

Constraints from functional magnetic resonance imaging (fMRI) were used to identify the sources of the visual P300 event-related potential (ERP). Healthy subjects performed a visual three-stimulus oddball paradigm with a difficult discrimination task while fMRI and high-density ERP data were acquired in separate sessions. This paradigm allowed us to differentiate the P3b component of the P300, which has been implicated in the detection of rare events in general (target and distractor), from the P3a component, which is mainly evoked by distractor events. The fMRI-constrained source model explained >99% of the variance of the scalp ERP for both components. The P3b was mainly produced by parietal and inferior temporal areas, whereas frontal areas and the insula contributed mainly to the P3a. This source model reveals that both higher visual and supramodal association areas contribute to the visual P3b and that the P3a has a strong frontal contribution, which is compatible with its more anterior distribution on the scalp. The results point to the involvement of distinct attentional subsystems in target and distractor processing.

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

Functional imaging of visuospatial processing in Alzheimer's disease

Alzheimers disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.

Facial affect recognition training in autism: can we animate the fusiform gyrus?

One of the most consistent findings in the neuroscience of autism is hypoactivation of the fusiform gyrus (FG) during face processing. In this study the authors examined whether successful facial affect recognition training is associated with an increased activation of the FG in autism. The effect of a computer-based program to teach facial affect identification was examined in 10 individuals with high-functioning autism. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) changes in the FG and other regions of interest, as well as behavioral facial affect recognition measures, were assessed pre- and posttraining. No significant activation changes in the FG were observed. Trained participants showed behavioral improvements, which were accompanied by higher BOLD fMRI signals in the superior parietal lobule and maintained activation in the right medial occipital gyrus.

The spatiotemporal pattern of auditory cortical responses during verbal hallucinations.

Functional magnetic resonance imaging (fMRI) studies can provide insight into the neural correlates of hallucinations. Commonly, such studies require self-reports about the timing of the hallucination events. While many studies have found activity in higher-order sensory cortical areas, only a few have demonstrated activity of the primary auditory cortex during auditory verbal hallucinations. In this case, using self-reports as a model of brain activity may not be sensitive enough to capture all neurophysiological signals related to hallucinations. We used spatial independent component analysis (sICA) to extract the activity patterns associated with auditory verbal hallucinations in six schizophrenia patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. The resulting activity patterns from auditory and sensorimotor components were further analyzed in a single-subject fashion using a visualization tool that allows for easy inspection of the variability of regional brain responses. We found bilateral auditory cortex activity, including Heschls gyrus, during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. However, the average of the time courses during hallucinations showed a clear association with this clinical phenomenon. We suggest that detection of this activity may be facilitated by examining hallucination epochs of sufficient length, in combination with a data-driven approach.

Neuronal Correlates of Colour-Graphemic Synaesthesia: Afmri Study

Synaesthesia is a perceptual phenomenon in which specific events in one sensory modality induce experiences in another. In colour-graphemic synaesthesia, subjects report colour experiences induced by written letters. Our subjects displayed this type of synaesthesia, as verified by a test of the consistency of the perceptual associations over time, and had no history of neurological or psychiatric disorders. We investigated the hypothesis that the synaesthetic colour experience is accompanied by an activation of the human colour area (V4/V8) using functional magnetic resonance imaging (fMRI). With retinotopic and colour mapping we could confirm that colour stimuli specifically activate area V4/V8. For the study of colour-graphemic synaesthesia we used an AB boxcar design with blocks of letters that elicited a synaesthetic colour experience (condition A) alternating with blocks of letters that did not (condition B). In both hemispheres condition A led to a significantly higher activation of V4/V8 than condition B. These findings support the hypothesis that the grapheme-induced colour perception in synaesthesia is caused by an activation of the colour areas of the human visual cortex.

Biomarkers for Alzheimer's disease therapeutic trials

The development of disease-modifying treatments for Alzheimers disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimers disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimers disease therapy trials and to propose practical recommendations for the planning of future AD trials.

Cognitive and behavioural effects of physical exercise in psychiatric patients

The current review outlines the under-appreciated effects of physical exercise on the course of psychiatric disorders, focussing on recent findings from animal and human research. Several studies have shown that regular physical exercise is significantly beneficial for psychiatric patients both on a biological and a psychological level. Positive effects of controlled exercise include improved metabolic responses, neuro-protection, increased quality of life, and reduced psychopathological symptoms. Studies investigating the effectiveness of various physical training interventions in alleviating severe mental diseases, such as Alzheimers dementia (AD), schizophrenia (SZ) or major depressive disorder (MDD) indicate that physical exercise can relieve symptoms of depression, psychosis and dementia and more importantly can curtail further progression of these diseases. This review assesses the most effective methods of physical training for specific psychiatric symptoms. Introducing physical exercise in therapeutic regimes would be an innovative approach that could significantly reduce the severity of psychopathological and cognitive symptoms in patients. The positive biological and molecular outcomes associated with physical exercise render it a concrete therapeutic strategy for improving the quality of live and reducing physical illness in psychiatric patients. Therefore, integrating physical activity into a patients social life may be an effective treatment strategy. Furthermore, exercise might have the potential to be a preventative treatment within the context of multi-modal therapeutic programs.

Functional activation imaging in aging and dementia

With life expectancy increasing continuously, the effects of neurodegeneration on brain function are a topic of ever increasing importance. Thus there is a need for tools and models that probe both the functional consequences of neurodegenerative processes and compensatory mechanisms that might occur. As neurodegenerative burden and compensatory mechanisms may change over time, these tools will ideally be applied multiple times over the lifespan. Specifically, in order to elucidate whether brain-activation patterns in Alzheimers disease (AD) and in healthy aging follow general rules in the context of degeneration and compensation, it is necessary to compare functional brain-activation patterns during different states of neurodegeneration. This article integrates the findings of functional activation studies at different stages of neurodegeneration: in healthy aging, in subjects at high risk of developing dementia, in subjects with mild cognitive impairment (MCI), and in patients suffering from AD. We review existing theoretical models that aim to explain the underlying mechanisms of functional activation changes in aging and dementia, and we propose an integrative account, which allows for different neural response patterns depending on the amount of neuronal damage and the recruitment of compensatory pathways.