Abstract: BACKGROUND: Verbal declarative memory is a core deficit in schizophrenia patients, seen to a lesser extent in unaffected biological relatives. Neuroimaging studies suggest volumetric differences and aberrant function in prefrontal and temporal regions in schizophrenia patients compared to controls. These deficits are also reflected in the small number of similar investigations in unaffected biological relatives. However, it is unclear the extent to which dysfunction is genetically mediated or a feature of the established illness. METHOD: Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation in 68 biological relatives of schizophrenia patients (of whom 27 experienced transient or isolated psychotic symptoms) and 21 controls during verbal classification and recognition. RESULTS: During word classification, the high-risk group showed a greater response relative to controls in the right inferior frontal gyrus. During correct recognition (relative to correct rejection), the high-risk group showed significantly greater response relative to controls in the right cerebellum. When the high-risk group was split into those with (HR+) and without (HR-) psychotic symptoms, the increased response in the right inferior frontal gyrus was only seen when the HR+ were compared to controls. The greater cerebellar response was seen when both HR groups were compared to controls. CONCLUSIONS: Activation increases in the right inferior frontal gyrus and cerebellum in high-risk subjects compared to controls during a relatively low-load memory task are likely to represent compensation for genetically mediated abnormalities. This is consistent with a leftward shift of the inverted 'U' load-response model of cognitive function in schizophrenia.
Abstract: BACKGROUND: Prospective studies of young individuals at high risk of schizophrenia allow the investigation of whether neural abnormalities predate development of illness and, if present, have the potential to identify those who may become ill. METHODS: We studied young individuals with at least two relatives with the disorder. At baseline functional magnetic resonance imaging (fMRI) scan, none met criteria for any psychiatric disorder, but four subjects subsequently developed schizophrenia. We report the baseline functional imaging findings in these subjects performing a sentence completion task compared with normal control subjects (n = 21) and those at high risk with (n = 21) and without (n = 41) psychotic symptoms who have not developed the disorder. RESULTS: High-risk subjects who became ill demonstrated increased activation of the parietal lobe, decreased activation of the anterior cingulate, and smaller increases in activation with increasing task difficulty in the right lingual gyrus and bilateral temporal regions. The hypothesized predictive power of parietal activation was supported only in combination with lingual gyrus activity, which gave a positive predictive value in this sample of .80. CONCLUSIONS: Although these findings should be considered cautiously, as only four subjects who had an fMRI scan subsequently became ill, they suggest functional abnormalities are present in high-risk subjects who later became ill, which distinguish them not only from normal control subjects but also those at high risk who had not developed the disorder. These differences are detectable with fMRI and may have clinical utility.
Abstract: Schizophrenia is a highly heritable psychotic disorder. It has been suggested that deficits of the established state arise from abnormal interactions between brain regions. We sought to examine whether such connectivity abnormalities would be present in subjects at high genetic risk for the disorder. Functional connectivity analysis was carried out on functional MRI images from 21 controls and 69 high risk subjects performing the Hayling sentence completion task; 27 high risk subjects reported isolated psychotic symptoms, the remaining high risk subjects and controls did not. There were no significant differences in task performance between the groups. Based on previous findings we hypothesized: (i) state-related differences in connectivity between dorsolateral prefrontal cortex and lateral temporal lobe; (ii) genetically mediated reductions in a medial prefrontal-thalamic-cerebellar network; and (iii) increased prefrontal-parietal connectivity in high risk subjects (to a greater extent in those with isolated psychotic symptoms). Connectivity analysis was performed in two ways: with and without variance associated with task effects modelled and removed from the data. We did not find evidence to support our first hypothesis with either analysis method. However, consistent with hypothesis (ii), decreased connectivity between right medial prefrontal regions and contralateral cerebellum was found. This was only statistically significant in the analysis with task effects modelled and removed from the data. Finally, consistent with hypothesis (iii), increased connectivity between the left parietal and left prefrontal regions in high risk subjects was found in both analyses. These results, all in a situation uncontaminated by the effects of anti-psychotic medication, performance differences and prolonged illness, suggest there are abnormalities in functional connectivity over and above those attributable to task effects in high risk subjects. These connectivity abnormalities may underlie the diverse deficits seen in the established condition and the more subtle deficits seen in close relatives of those with the disorder.
Abstract: OBJECTIVE: To compare brain activity identified by fMRI in subjects with Alzheimer disease (AD) and older healthy controls (HCs) performing an episodic/working memory (EWM) and semantic memory (SM) task. METHODS: Nine AD (mean age 73.6) and 10 HC (mean age 71.8) subjects underwent an fMRI memory paradigm. Tasks comprised 1) baseline (recognizing a single digit presented for 1 second), 2) SM (addition of two single digits, always producing a single digit answer), and 3) EWM (recall of the previous single digit on the stimulus of the next digit). Each condition was presented in 2-minute blocks with a shorter and longer time interval for the first and second minute within blocks. RESULTS: Comparing AD and HC subjects, there were no activated brain regions in common for EWM > SM, but left anterior cingulate (Brodmann area [BA] 24, 0, 31, 4) and left medial frontal lobe gyrus (BA 25, -6, 23, -15) were activated by both groups for SM > EWM. Key differences were that for EWM > SM, HC subjects activated the right parahippocampal gyrus, whereas subjects with AD activated the right superior frontal gyrus and left uncus. CONCLUSIONS: Subjects with Alzheimer disease (AD) recruited brain regions for easier episodic/working memory (EWM) tasks used by healthy controls (HCs) for more difficult EWM tasks. AD subjects recruited brain regions for semantic memory tasks used by HCs for more difficult EWM tasks. The authors propose a functional "memory reserve" model of compensatory recruitment according to task difficulty and underlying neuropathology.
Abstract: Schizophrenia is a highly heritable disorder that typically develops in early adult life. Structural imaging studies have indicated that patients with the illness, and to some extent their unaffected relatives, have subtle deficits in several brain regions, including prefrontal and temporal lobes. It is, however, not known how this inherited vulnerability leads to psychosis. This study used a covert verbal initiation fMRI task previously shown to elicit frontal and temporal activity (the Hayling sentence completion task) to examine this issue. A large (n = 69) number of young participants at high risk of developing schizophrenia for genetic reasons took part, together with a matched group of healthy controls (n = 21). At the time of investigation, none had any psychotic disorder, but on detailed interview some of the high-risk participants (n = 27) reported isolated psychotic symptoms. The study aimed to determine: (i) whether there were activation differences that occurred in all subjects with a genetic risk of schizophrenia (i.e. 'trait' effects); and (ii) whether there were activation differences that only occurred in those at high risk who had isolated psychotic symptoms ('state' effects). No activation differences were found in regions commonly reported to be abnormal in the established illness, namely the dorsolateral prefrontal cortex or in the temporal lobes, but group differences of apparent genetic cause were evident in medial prefrontal, thalamic and cerebellar regions. In addition, differences in activation in those with symptoms were found in the intraparietal sulcus. No significant differences in performance were found between the groups, and all subjects were antipsychotic naïve. These findings therefore suggest that vulnerability to schizophrenia may be inherited as a disruption in a fronto-thalamic-cerebellar network, and the earliest changes specific to the psychotic state may be related to hyperactivation in the parietal lobe.
Abstract: PURPOSE: To prospectively determine the repeatability of functional magnetic resonance (MR) imaging brain activation tasks in a group of healthy older male volunteers. MATERIALS AND METHODS: Local research ethics committee approval and informed consent were obtained. Sixteen men with a mean age of 69 years +/- 3 (standard deviation) performed finger-tapping and N-back (number of screens back) working-memory tasks. Each subject underwent MR imaging three times in weekly intervals. Within-subject task repeatability was analyzed in terms of the number of voxels classified as activated (activation extent), the mean activation amplitude, and (for finger tapping) the center of the mass of the activated region. A repeatability index was calculated to compare test-retest repeatability between subjects and between functional MR imaging tasks. Within-session, between-session, and between-subject variability was assessed by using analysis of variance testing of activation amplitude and extent. RESULTS: Nine of the 16 subjects generated useful data at all three MR imaging-functional task sessions. At single-subject, single-session analysis, cortical activation was identified in most subjects and at most sessions. The centers of the masses of motor cortex activation were highly reproducible (within 3 mm). Patterns of activation were qualitatively repeatable, but there was substantial variability in the amplitudes and extents of activated regions. Within-session coefficients of variation (CVs) for left- versus right-hand and right- versus left-hand finger tapping were, respectively, 65% and 43% for activation amplitude and 75% and 121% for activation extent. The between-session CVs for activation amplitude were similar to the within-session values, whereas between-session CVs for activation extent were much greater than within-session values, up to 206%. CONCLUSION: The generally poor quantitative task repeatability highlights the need for further methodologic developments before much reliance can be placed on functional MR imaging results of single-session experiments.
Abstract: Twenty healthy young adults underwent functional magnetic resonance imaging (fMRI) of the brain while performing a visual inspection time task. Inspection time is a forced-choice, two-alternative visual backward-masking task in which the subject is briefly shown two parallel vertical lines of markedly different lengths and must decide which is longer. As stimulus duration decreases, performance declines to chance levels. Individual differences in inspection time correlate with higher cognitive functions. An event-related design was used. The hemodynamic (blood oxygenation level-dependent; BOLD) response was computed as both a function of the eight levels of stimulus duration, from 6 ms (where performance is almost at chance) to 150 ms (where performance is nearly perfect), and a function of the behavioral responses. Random effects analysis showed that the difficulty of the visual discrimination was related to bilateral activation in the inferior fronto-opercular cortex, superior/medial frontal gyrus, and anterior cingulate gyrus, and bilateral deactivation in the posterior cingulate gyrus and precuneus. Examination of the time courses of BOLD responses showed that activation was related specifically to the more difficult, briefer stimuli and that deactivation was found across most stimulus levels. Functional connectivity suggested the existence of two networks. One comprised the fronto-opercular area, intrasylvian area, medial frontal gyrus, and the anterior cingulate cortex (ACC), possibly associated with processing of visually degraded percepts. A posterior network of sensory-related and associative regions might subserve processing of a visual discrimination task that has high processing demands and combines several fundamental cognitive domains. fMRI can thus reveal information about the neural correlates of mental events which occur over very short durations.
Abstract: Many areas of biological research generate large volumes of very diverse data. Managing this data can be a difficult and time-consuming process, particularly in an academic environment where there are very limited resources for IT support staff such as database administrators. The most economical and efficient solutions are those that enable scientists with minimal IT expertise to control and operate their own desktop systems. Axiope provides one such solution, Catalyzer, which acts as flexible cataloging system for creating structured records describing digital resources. The user is able specify both the content and structure of the information included in the catalog. Information and resources can be shared by a variety of means, including automatically generated sets of web pages. Federation and integration of this information, where needed, is handled by Axiope's Mercat server. Where there is a need for standardization or compatibility of the structures usedby different researchers this canbe achieved later by applying user-defined mappings in Mercat. In this way, large-scale data sharing can be achieved without imposing unnecessary constraints or interfering with the way in which individual scientists choose to record and catalog their work. We summarize the key technical issues involved in scientific data management and data sharing, describe the main features and functionality of Axiope Catalyzer and Axiope Mercat, and discuss future directions and requirements for an information infrastructure to support large-scale data sharing and scientific collaboration.
Abstract: There is significant interest amongst neuroscientists in sharing neuroscience data and analytical tools. The exchange of neuroscience data and tools between groups affords the opportunity to differently re-analyze previously collected data, encourage new neuroscience interpretations and foster otherwise uninitiated collaborations, and provide a framework for the further development of theoretically based models of brain function. Data sharing will ultimately reduce experimental and analytical error. Many small Internet accessible database initiatives have been developed and specialized analytical software and modeling tools are distributed within different fields of neuroscience. However, in addition large-scale international collaborations are required which involve new mechanisms of coordination and funding. Provided sufficient government support is given to such international initiatives, sharing of neuroscience data and tools can play a pivotal role in human brain research and lead to innovations in neuroscience, informatics and treatment of brain disorders. These innovations will enable application of theoretical modeling techniques to enhance our understanding of the integrative aspects of neuroscience. This article, authored by a multinational working group on neuroinformatics established by the Organization for Economic Co-operation and Development (OECD), articulates some of the challenges and lessons learned to date in efforts to achieve international collaborative neuroscience.
Abstract: Neuroscience is generating vast amounts of highly diverse data which is of potential interest to researchers beyond the laboratories in which it is collected. In particular, quantitative neuroanatomical data is relevant to a wide variety of areas, including studies of development, aging, pathology and in biophysically oriented computational modelling. Moreover, the relatively discrete and well-defined nature of the data make it an ideal application for developing systems designed to facilitate data archiving, sharing and reuse. At present, the only widely used forms of dissemination are figures and tables in published papers which suffer from inaccessibility and the loss of machine readability. They may also present only an averaged or otherwise selected subset of the available data. Numerous database projects are in progress to address these shortcomings. They employ a variety of architectures and philosophies, each with its own merits and disadvantages. One axis on which they may be distinguished is the degree of top-down control, or curation, involved in data entry. Here we consider one extreme of this scale in which there is no curation, minimal standardization and a wide degree of freedom in the form of records used to document data. Such a scheme has advantages in the ease of database creation and in the equitable assignment of perceived intellectual property by keeping the control of data in the hands of the experts who collected it. It does, however, require a more sophisticated infrastructure than conventional databases since the software must be capable of organizing diverse and differently documented data sets in an effective way. Several components of a software system to provide this infrastructure are now in place. Examples are presented, showing how these tools can be used to archive and publish neuronal morphology data, and how they can give an integrated view of data stored at many different sites.
Abstract: Biological nervous systems and the mechanisms underlying their operation exhibit astonishing complexity. Computational models of these systems have been correspondingly complex. As these models become ever more sophisticated, they become increasingly difficult to define, comprehend, manage and communicate. Consequently, for scientific understanding of biological nervous systems to progress, it is crucial for modellers to have software tools that support discussion, development and exchange of computational models. We describe methodologies that focus on these tasks, improving the ability of neuroscientists to engage in the modelling process. We report our findings on the requirements for these tools and discuss the use of declarative forms of model description--equivalent to object-oriented classes and database schema--which we call templates. We introduce NeuroML, a mark-up language for the neurosciences which is defined syntactically using templates, and its specific component intended as a common format for communication between modelling-related tools. Finally, we propose a template hierarchy for this modelling component of NeuroML, sufficient for describing models ranging in structural levels from neuron cell membranes to neural networks. These templates support both a framework for user-level interaction with models, and a high-performance framework for efficient simulation of the models.
Abstract: We discuss a framework for the organization of learning systems in the mammalian brain, in which the hippocampus and related areas form a memory system complementary to learning mechanisms in neocortex and other areas. The hippocampal system stores new episodes and "replays" them to the neocortical system, interleaved with ongoing experience, allowing generalization as cortical memories form. The data to account for include: 1) neurophysiological findings concerning representations in hippocampal areas, 2) behavioral evidence demonstrating a spatial role for hippocampus, 3) and effects of surgical and pharmacological manipulations on neuronal firing in hippocampal regions in behaving animals. We hypothesize that the hippocampal memory system consists of three major modules: 1) an invertible encoder subsystem supported by the pathways between neocortex and entorhinal cortex, which provides a stable, compressed, invertible encoding in entorhinal cortex (EC) of cortical activity patterns, 2) a memory separation, storage, and retrieval subsystem, supported by pathways between EC, dentate gyrus and area CA3, including the CA3 recurrent collaterals, which facilitates encoding and storage in CA3 of individual EC patterns, and retrieval of those CA3 encodings, in a manner that minimizes interference, and 3) a memory decoding subsystem, supported by the Shaffer collaterals from area CA1 to area CA3 and the bi-directional pathways between EC and CA3, which provides the means by which a retrieved CA3 coding of an EC pattern can reinstate that pattern on EC. This model has shown that 1) there is a trade-off between the need for information-preserving, structure-extracting encoding of cortical traces and the need for effective storage and recall of arbitrary traces, 2) long-term depression of synaptic strength in the pathways subject to long-term potentiation is crucial in preserving information, 3) area CA1 must be able to exploit correlations in EC patterns in the direct perforant path synapses.
