Biomedical subjects

Steve C R Williams

Publications and source records attributed to Steve C R Williams.

At least 19 recordsLinked to original sources

PubMed2007

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry.

The in vivo monitoring of cell survival and migration will be essential to the translation of cell-based therapies from the laboratory to clinical studies. The pre-labeling of cells with magnetic resonance imaging (MRI) contrast agents renders them visible in vivo for serial cellular imaging. However, little is known about the impact of the presence of these metal particles inside transplanted cells. The use of the bimodal contrast agent GRID made it possible to demonstrate by means of fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS) that, after 16 h of incubation (without the use of a transfection agent), neural stem cells (NSCs) were saturated and no longer incorporated particles. With this maximal uptake, no significant effect on cell viability was observed. However, a significant decrease in proliferation was evident in cells that underwent 24 h of labeling. A significant increase in reactive oxygen species was observed for all GRID labeling, with a very significant increase with 24 h of labeling. GRID labeling did not affect cell motility in comparison with PKH26-labeled NSCs in a glioma-based migration assay and also allowed differentiation into all major cell types of the brain. GRID-labeled cells induced a signal change of 47% on T(2) measurements and allows a detection of cell clusters of approximately 220 cells/microl. Further in vivo testing will be required to ensure that cell labeling with gadolinium-based MRI contrast agents does not impair their ability to repair.

Animals↗

PubMed2006

Applications of functional magnetic resonance imaging in psychiatry.

While the use of MRI techniques has become a cornerstone of the neurology clinic, the application of such methods in psychiatry was rather limited until the advent of functional magnetic resonance imaging (fMRI). Over the past decade fMRI has superseded radionuclide-imaging techniques and blossomed into a widely used psychiatric research tool. This review focuses on the neurobiological findings from fMRI research in three less well-documented psychiatric disorders: attention deficit hyperactivity disorder (ADHD), depression, and obsessive-compulsive disorder (OCD). Although there was some disparity in early findings, greater standardization of image acquisition, analysis, and paradigms, and improved clinical classification are leading to a greater convergence of observations from different laboratories. fMRI is also beginning to realize its potential as an important mediator between genes and phenotypes, and may thus contribute to a better understanding of the pathophysiology of major neuropsychiatric diseases. The role of fMRI in the objective assessment of therapeutic intervention and early prediction of response to treatment is also discussed.

Brain↗

PubMed2006

Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortex.

OBJECTIVES: Bipolar patients are impaired in Stroop task performance, a measure of selective attention. Structural and functional abnormalities in task-associated regions, in particular the prefrontal cortex (PFC), have been reported in this population. We aimed to examine the relationship between functional abnormalities, impaired task performance and the severity of depressive symptoms in bipolar patients. METHODS: Remitted bipolar patients (n = 10; all medicated), either euthymic or with subsyndromal depression, and age-matched control subjects (n = 11) viewed 10 alternating blocks of incongruent Stroop and control stimuli, naming the colour of the ink. Neural response was measured using functional magnetic resonance imaging. We computed between-group differences in neural response and within-group correlations with mood and anxiety. RESULTS: There were no significant between-group differences in task performance. During the Stroop condition, controls demonstrated greater activation of visual and dorsolateral and ventrolateral prefrontal cortical areas; bipolar patients demonstrated relative deactivation within orbital and medial prefrontal cortices. Depression scores showed a trend towards a negative correlation with the magnitude of orbitofrontal cortex deactivation in bipolar patients, whereas state anxiety correlated positively with activation of dorsolateral PFC and precuneus in controls. CONCLUSIONS: Our findings confirm previous reports of decreased ventral prefrontal activity during Stroop task performance in bipolar patients, and suggest a possible negative correlation between this and depression severity in bipolar patients. These findings further highlight the ventromedial PFC as a potential candidate for illness related dysfunction in bipolar disorder.

Adult↗

PubMed2005

Modulation of effective connectivity by cognitive demand in phonological verbal fluency.

Verbal fluency is a classic neuropsychological measure of language production. Phonological verbal fluency involves the generation of words beginning with a specified letter, and its functional neuroanatomy is comprised of a distributed network of regions which is modulated by cognitive load. In order to investigate the functional relationship of these regions, the effective connectivity was analyzed with covariance structural equation modeling under conditions of varying cognitive load. Significant path coefficients were evident between the anterior cingulate, left middle frontal gyrus, and precuneus. The left middle frontal gyrus showed a facilitory projection to the precuneus which had a suppressive influence on anterior cingulate activation. With increasing cognitive demand, the left middle frontal projection to the precuneus became suppressive, and the path coefficient from the precuneus to the anterior cingulate showed a marked diminution in strength. The path analysis suggests that the lead-in process for letter verbal fluency may primarily involve an orthographic visual strategy. The marked changes in path coefficients with the increased cognitive load may reflect the greater demands placed on executive function. The significant changes in path coefficient values with increased cognitive demand indicate the importance of accounting for task difficulty not only in the interpretation of brain activation maps but also for effective connectivity measurements.

Adult↗

PubMed2005

Effects of ketamine on prefrontal and striatal regions in an overt verbal fluency task: a functional magnetic resonance imaging study.

RATIONALE: Glutamatergic dysfunction at N-methyl-D: -aspartate (NMDA) receptors has been proposed as a neurochemical model for schizophrenia. A key feature of this disorder is impairments in cognitive function. OBJECTIVE: The present study sought to investigate the effects of ketamine, an NMDA antagonist, on the performance and neural correlates of verbal fluency, a task that engages executive function. METHODS: Ten healthy dextral male volunteers received intravenous placebo normal saline or ketamine (bolus of 0.23 mg/kg and infusion of 0.65 mg/kg), administered in a double-blind, randomized order, during two functional magnetic resonance imaging sessions. During scanning, subjects performed a verbal fluency task. Two levels of cognitive load were examined in the task, and overt responses were acquired in order to measure subject performance on-line. RESULTS: Ketamine induced symptoms in the healthy individuals comparable to an acute psychotic state. Although ketamine did not significantly impair task performance relative to placebo, an interaction of task demand with ketamine was observed in the anterior cingulate, prefrontal, and striatal regions. CONCLUSIONS: The behavioural and functional effects of ketamine during verbal fluency in healthy individuals were comparable to those evident in patients with schizophrenia. The findings support a role for glutamatergic dysfunction in the pathophysiology of schizophrenia.

Corpus Striatum↗

PubMed2005

An fMRI study of verbal self-monitoring: neural correlates of auditory verbal feedback.

The ability to recognize one's own inner speech is essential for a sense of self. The verbal self-monitoring model proposes that this process entails a communication from neural regions involved in speech production to areas of speech perception. According to the model, if the expected verbal feedback matches the perceived feedback, then there would be no change in activation in the lateral temporal cortices. We investigated the neural correlates of verbal self-monitoring in a functional magnetic resonance (fMRI) study. Thirteen healthy male volunteers read aloud presented adjectives and heard their auditory feedback which was experimentally modified. Decisions about the source of the feedback were made with a button-press response. We used a 'clustered' fMRI acquisition sequence, consisting of periods of relative silence in which subjects could speak aloud and hear the feedback in the absence of scanner noise, and an event-related design which allowed separate analysis of trials associated with correct attributions and misattributions. Subjects made more misattribution responses when the feedback was a distorted version of their voice. This condition showed increased superior temporal activation relative to the conditions of hearing their own voice undistorted and hearing another person's voice. Furthermore, correct attributions during this condition were associated with greater temporal activation than misattributions. These findings support the self-monitoring model as mismatches between expected and actual auditory feedback were associated with greater temporal activation.

Adult↗

PubMed2005

Examining the neural targets of the AMPA receptor potentiator LY404187 in the rat brain using pharmacological magnetic resonance imaging.

RATIONALE: Drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor-mediated glutamatergic transmission, such as the AMPA receptor potentiator LY404187, may form treatment strategies for disorders of cognition, learning and memory. OBJECTIVES: Pharmacological magnetic resonance imaging (phMRI) uses blood oxygenation level dependent (BOLD) contrast as a marker of neuronal activity and allows dynamic non-invasive in vivo imaging of the effects of CNS-active compounds. This study used phMRI to examine the effects of LY404187 in the rat brain. METHOD: Groups of Sprague Dawley rats (n=7) were anaesthetised and placed in a 4.7 Tesla superconducting magnet before receiving an acute dose of LY404187 (0.5 mg/kg s.c.), either alone or after pretreatment with the selective AMPA/kainate antagonist LY293558 (15 mg/kg s.c.), or LY293558 alone (15 mg/kg s.c.). Brain images were acquired for each subject every minute for 180 min. These volumes were extensively pre-processed before being analysed for changes in BOLD contrast. RESULTS: LY404187 produced significant increases in BOLD contrast in brain regions including the hippocampus, lateral and medial habenulae and superior and inferior colliculi. These changes were blocked by LY293558. When administered alone, LY293558 caused widespread decreases in BOLD contrast. CONCLUSIONS: The known actions of LY404187 suggest the observed BOLD signal increases reflect increases in excitatory neurotransmission. The decreases in signal following LY293558 alone are harder to interpret and are discussed in terms of the negative BOLD response. This study provides the first evidence that the effects of AMPA receptor-mediating compounds can be observed using phMRI.

Animals↗

PubMed2005

Frontotemporal white matter changes in amyotrophic lateral sclerosis.

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

Adult↗

PubMed2005

Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency.

OBJECTIVE: Impaired prefrontal cortical function is regarded as a central feature of schizophrenia. Although many neuroimaging studies have found evidence of abnormal prefrontal activation when patients with schizophrenia perform cognitive tasks, the extent to which this abnormality depends on the presence of active psychotic symptoms and on the demands of the task is unclear. The authors tested the hypothesis that prefrontal functional abnormalities in schizophrenia would be more evident in patients with active psychosis than in patients who were in remission and would become more apparent in the face of increasing task demands. METHOD: The authors used functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity during a paced letter verbal fluency task in three groups of subjects: acutely psychotic patients with schizophrenia, schizophrenia patients in remission, and healthy volunteers. Online subject performance was measured by utilizing a clustered fMRI acquisition sequence that allowed overt verbal responses to be made in the relative absence of scanner noise. RESULTS: Patients with schizophrenia showed less activation than the healthy comparison subjects in the anterior cingulate and the inferior frontal and right middle frontal cortices, independent of psychotic state and task demand. Acutely psychotic patients showed less activation than the healthy comparison subjects, but these differences were less marked than the differences between the patients in remission and the healthy comparison subjects. Acutely psychotic patients had less activation than the comparison subjects in the anterior cingulate but no significant difference in lateral prefrontal activation. Increasing task demand led to greater anterior cingulate and middle frontal activation in patients with active psychosis than in patients in remission. CONCLUSIONS: Schizophrenia is associated with impaired prefrontal function, but its manifestation depends on the severity of psychotic symptoms and the level of task difficulty.

Adult↗

PubMed2004

Imaging localised dynamic changes in the nucleus accumbens following nicotine withdrawal in rats.

This study utilises pharmacological functional magnetic resonance imaging (fMRI) to examine the neurobiological mechanisms through which nicotine produces dependence. Using an established regime to induce physical dependence to nicotine in rats (osmotic minipumps delivering 3.16 mg/kg/day nicotine for 7 days SC), animals were subsequently anaesthetised under urethane and positioned in a stereotaxic frame to allow collection of gradient echo whole brain images with a 4.7-T MRI spectrometer. Rats were initially scanned for 34 min (40 baseline image volumes, 1 volume per 51 s) then challenged with mecamylamine (1.0 mg/kg SC) or saline (1 ml/kg) and scanned for a further 68 min (80 image volumes). Mecamylamine precipitated highly significant positive changes in fMRI blood oxygen level dependent (BOLD) contrast that were predominantly localised to the NAc of nicotine-dependent rats. Saline-treated rats challenged with the same dose of mecamylamine exhibited similar but smaller increases in BOLD contrast although such changes were less defined around the NAc. Precipitated withdrawal also elicited statistically significant negative BOLD contrast changes in widespread cortical regions. These findings are consistent with previous neurochemical reports on decreases in dopamine in the NAc during nicotine withdrawal. This fMRI study further highlights the potential and power to image the neurobiological events during nicotine dependence.

Analysis of Variance↗

PubMed2004

A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction.

OBJECTIVES: Even when euthymic bipolar disorder patients can have persistent deficits in working memory, but the neural basis of this deficit remains unclear. We undertook an functional magnetic resonance imaging investigation of euthymic bipolar disorder patients performing two working memory paradigms; the two-back and Sternberg tasks, selected to examine the central executive and the phonological loop respectively. We hypothesized that neuronal dysfunction would be specific to the network underlying the executive rather than the phonological loop component of working memory. METHODS: Twelve right-handed euthymic bipolar I males receiving lithium carbonate monotherapy were matched with 12 controls. The two-back task comprised a single working memory load contrasted with baseline vigilance condition. The Sternberg paradigm used a parametric design incorporating variable working memory load with fixed delay between presentation of an array of items to be remembered and a target item. Functional activation data were acquired during performance of the tasks and were analysed to produce brain activation maps representing significant group differences in activation (ANOVA). Load-response curves were derived from the Sternberg task data set. RESULTS: There were no significant between-group differences (t-test) in performance of the two-back task, or in 2 x 5 group by memory load ANOVA for the performance data from Sternberg task. In the two-back task, compared with controls bipolar disorder patients showed reductions in bilateral frontal, temporal and parietal activation, and increased activations with the left precentral, right medial frontal and left supramarginal gyri. No between-group differences were observed in the Sternberg task at any working memory load. CONCLUSIONS: Our findings support the notion that, in euthymic bipolar disorder, failure to engage fronto-executive function underpins the core neuropsychological deficits.

Bipolar Disorder↗

PubMed2004

Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family.

Recent progress in developmental neurobiology and neuroimaging can be drawn together to provide new insight into the links between genetically specified processes of embryonic brain development and adult human brain structure and function. We used magnetic resonance imaging (MRI) to show that individuals with aniridia and deficits in executive and social cognition, due to heterozygous mutation of the neurodevelopmental control gene PAX6, have structural abnormalities of grey matter in anterior cingulate cortex, cerebellum and medial temporal lobe, as well as white matter deficits in corpus callosum. Functional MRI demonstrated reduced activation of fronto-striato-thalamic systems during performance of overt verbal fluency and nonsense sentence completion; the most consistent abnormality of verbal executive activation was located in the thalamus. These results provide the first evidence for brain functional differences in humans with PAX6 mutation that are compatible both with anatomical abnormalities in the same subjects and, more circumstantially, with the known roles of murine Pax6 in regional differentiation, axonal guidance and other aspects of early forebrain development. Highly conserved homeobox genes may be critical for normal ontogenesis of large-scale neurocognitive networks supporting phylogenetically advanced mental functions.

Adolescent↗

PubMed2004

Temporal course of auditory hallucinations.

We used functional magnetic resonance imaging to examine how brain activity associated with auditory verbal hallucinations in schizophrenia changed during hallucinatory events. Activation in the left inferior frontal and right middle temporal gyri was evident 6-9 s before the person signalled the onset of the hallucination, whereas activation in the bilateral temporal gyri and the left insula coincided with the perception of the hallucination. This supports the hypothesis that during hallucinations activation in cortical regions mediating the generation of inner speech may precede the engagement of areas implicated in the perception of auditory verbal material.

Adult↗

PubMed2004

In vivo monitoring of cellular transplants by magnetic resonance imaging and positron emission tomography.

Cellular loss is a common pathological observation in many disease conditions. Recent evidence that these cells can be replaced has generated huge excitement over possible clinical applications. The use of stem or progenitor cells, which can differentiate into site-appropriate phenotypes required to "repair" the damaged tissue, has already demonstrated potential in animal models, but many aspects of this novel treatment strategy require further elucidation. Most importantly, the monitoring of the safety of cellular transplants in patients remains a challenge. Traditional histological methods do not address the dynamic nature of transplant-induced recovery and highlight the necessity of in vivo imaging to probe the survival, migration and functional consequences of transplanted cells. This paper reviews how non-invasive imaging technology can be used to serially assess intact living organisms in order to visualise and monitor cellular transplants.

Animals↗

PubMed2003

Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects.

Prepulse inhibition (PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibit the response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number of psychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neural correlates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of (i) healthy subjects and (ii) schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120 ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increased activation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateral inferior parietal lobe/supramarginal gyrus, and with decreased activation in the right cerebellum and left medial occipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenic patients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlie observations of reduced PPI in schizophrenia.

Adult↗

PubMed2003

Functional magnetic resonance imaging of verbal fluency and confrontation naming using compressed image acquisition to permit overt responses.

Verbal fluency and confrontation naming, two tests of word retrieval, are of great utility in the field of cognitive neuroscience. However, in the context of functional magnetic resonance imaging (fMRI), movement artefact has necessitated the use of covert paradigms, which has limited clinical application. We developed two overt fMRI paradigms that allowed for performance measurement and hence were appropriate for use with patient groups. The paradigms incorporated a blocked-design and compressed-acquisition methodology where cues were presented and responses made in a "silent" period allowing for performance measurement. The slow response pace was specifically designed for older and potentially cognitively impaired participants. Verbal fluency was associated with activation in the middle frontal gyrus (Brodmann areas 46 and 9), anterior cingulate gyrus and inferior frontal gyrus (area 44 and 45). Confrontation naming activated areas of the temporo-occipital cortices (areas 18, 19, and 37) and the inferior frontal gyrus. The two paradigms successfully activated regions involved in executive and word retrieval processes and overcame the potential artefacts resulting from overt speech during image acquisition, providing useful neuropsychological tools to investigate cognitive deficits in clinical populations.

Acoustic Stimulation↗

PubMed2003

Practice and difficulty evoke anatomically and pharmacologically dissociable brain activation dynamics.

Brain activation is adaptive to task difficulty and practice. We used functional MRI to map brain systems activated by an object-location learning task in 24 healthy elderly volunteers each scanned following placebo and two of four active drugs studied. We distinguished a fronto-striatal system adaptive to difficulty from a posterior system adaptive to practice. Fronto-striatal response to increased cognitive load was significantly attenuated by scopolamine, sulpiride and methylphenidate; practice effects were not modulated by these drugs but were enhanced by diazepam. We also found enhancement by methylphenidate, and attenuation by sulpiride, of load response in premotor, cingulate and parietal regions comprising a spatial attention network. Difficulty and practice evoke anatomically and pharmacologically dissociable brain activation dynamics, which are probably mediated by different neurotransmitter systems in humans.

Adrenergic Uptake Inhibitors↗

PubMed2002

Acoustic noise and functional magnetic resonance imaging: current strategies and future prospects.

Functional magnetic resonance imaging (fMRI) has become the method of choice for studying the neural correlates of cognitive tasks. Nevertheless, the scanner produces acoustic noise during the image acquisition process, which is a problem in the study of auditory pathway and language generally. The scanner acoustic noise not only produces activation in brain regions involved in auditory processing, but also interferes with the stimulus presentation. Several strategies can be used to address this problem, including modifications of hardware and software. Although reduction of the source of the acoustic noise would be ideal, substantial hardware modifications to the current base of installed MRI systems would be required. Therefore, the most common strategy employed to minimize the problem involves software modifications. In this work we consider three main types of acquisitions: compressed, partially silent, and silent. For each implementation, paradigms using block and event-related designs are assessed. We also provide new data, using a silent event-related (SER) design, which demonstrate higher blood oxygen level-dependent (BOLD) response to a simple auditory cue when compared to a conventional image acquisition.

Auditory Pathways↗