Biomedical subjects

Steven C R Williams

Publications and source records attributed to Steven C R Williams.

At least 19 recordsLinked to original sources

PubMed2006

A fMRI investigation of startle gating deficits in schizophrenia patients treated with typical or atypical antipsychotics.

A key feature of schizophrenia is the inability to screen out irrelevant sensory input. Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable opportunity to study this feature. PPI is reliably impaired in schizophrenia. Animal models of disrupted PPI have proved valuable for the evaluation of antipsychotic substances. The cortico-striato-pallido-thalamic circuitry is primarily responsible for modulation of PPI in animals. We examined PPI and its brain correlates, using functional magnetic resonance imaging (fMRI), in men with schizophrenia treated with typical or atypical antipsychotics. Thirty men with schizophrenia on stable doses of typical antipsychotics (n=10), risperidone (n=10) or olanzapine (n=10; 9 with usable fMRI data) and 12 healthy men underwent psychophysiological testing and fMRI during a tactile PPI paradigm. The results showed reduced PPI of the eye-blink startle response in patients compared with healthy controls. Within the patient group, those on typical antipsychotics showed significantly impaired PPI but risperidone- or olanzapine-treated patients showed a milder (non-significant) deficit. Increased activity in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal and inferior parietal regions occurred in association with PPI in controls. Patients treated with risperidone or olanzapine, but not with typical antipsychotics, showed significant activation in PPI-relevant regions. Our findings provide preliminary evidence that atypical antipsychotics positively influence PPI and partially restore associated brain functions in schizophrenia. Imaging data buttress the validity of PPI as a useful animal model of schizophrenia.

Acoustic Stimulation↗

PubMed2006

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat.

RATIONALE: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. OBJECTIVES: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. METHOD: Responses to 25 mg kg-1S(+) isomer, R(-) isomer and racemic ketamine in independent groups of Sprague-Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. RESULTS: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(-) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(-) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. CONCLUSIONS: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(-) isomer comparative to the racemate offers significant differences of interest.

Anesthetics, Dissociative↗

PubMed2006

Neural dysfunction and violence in schizophrenia: an fMRI investigation.

Contemporary theories and evidence implicate frontal lobe dysfunction in violent behaviour as well as in schizophrenia. We applied functional magnetic resonance imaging (fMRI) to investigate and compare brain activation during an 'n-back' working memory task in groups of men with (i) schizophrenia and a history of serious physical violence (VS; n=13), (ii) schizophrenia without a history of violence (NVS: n=12), (iii) antisocial personality disorder (APD) and a history of serious physical violence (n=10), and (iv) no history of violence or a mental disorder (n=13). We observed comparable performance in all four groups during the control (0-back) condition. Subtle working memory deficits were seen in the NVS and APD groups but severe deficits emerged in the VS group relative to the healthy group. The VS group showed activation deficit bilaterally in the frontal lobe and precuneus when compared to the healthy group, and in the right inferior parietal region when compared to the NVS group during the working memory load condition. Frontal (bilateral) as well as right inferior parietal activity was negatively associated with the ratings of violence across all schizophrenia patients, with the right parietal region showing this association most strongly. APD patients, relative to healthy subjects, showed activation deficit in the left frontal gyrus, anterior cingulate and precuneus. It is concluded that reduced functional response in the frontal and inferior parietal regions leads to serious violence in schizophrenia perhaps via impaired executive functioning.

Antisocial Personality Disorder↗

PubMed2006

Mapping the central effects of ketamine in the rat using pharmacological MRI.

RATIONALE: Ketamine induces, in both humans and rodents, behaviours analogous to some of the symptoms of schizophrenia. OBJECTIVES: To utilise pharmacological magnetic resonance imaging (phMRI) techniques that identify changes in blood-oxygenation-level-dependent (BOLD) contrast to determine the temporal and spatial neuronal activation profile of ketamine in the rat brain. METHOD: To obtain a pharmacodynamic profile of the drug, we assessed changes in locomotor activity after vehicle and 10 and 25 mg/kg ketamine. Separate animals were then anaesthetised and placed in a 4.7-T magnetic resonance (MR) system before receiving the same doses of ketamine during serial MR image acquisition. Subsequent statistical parametric mapping of the main effect of the drug was then undertaken to identify changes in BOLD contrast. Levels of gamma-aminobutyric acid (GABA) and dopamine (DA) in brain areas showing localised changes in BOLD contrast were then assessed via microdialysis. RESULTS: Both doses of ketamine produced increases in BOLD image contrast in frontal, hippocampal, cortical and limbic areas. A further investigation of the release of DA and its metabolites in the nucleus accumbens, both in anaesthesised and freely moving rats, corroborated these findings. However, an investigation of GABA and DA levels in the ventral pallidum gave no indication of changes in activity. CONCLUSIONS: Ketamine produced localised dose-dependent alterations in BOLD MR signal, which correlate with the pharmacodynamic profile of the drug. These results can be, at least, partially substantiated with complementary techniques but consideration must be given to the input function applied to the MR signal and the use of anaesthesia during phMRI experimentation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia.

RATIONALE: Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. OBJECTIVES: To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. MATERIALS AND METHODS: In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 microg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. RESULTS: Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups. CONCLUSIONS: Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity.

Adult↗

PubMed2006

Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia.

Diffusion tensor magnetic resonance imaging (DT-MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results. The aim of the study was to use a novel method for tract-specific measurements of fronto-temporal fasciculi in early-onset schizophrenia. We hypothesized that by making tract-specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia. Measurements of diffusion anisotropy and mean diffusivity were localized within fronto-temporal fasciculi by forming 3-D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto-occipital fasciculi using diffusion tensor tractography. We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT-MRI-based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus. The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age-matched comparison subjects, but this difference diminished with increasing age. The main conclusion of this study was that direct comparisons of absolute DT-MRI-based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age-related differences in brain maturation between groups.

Adult↗

PubMed2006

Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures.

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.

Adult↗

PubMed2006

In vivo estimation of the flow-driven adiabatic inversion efficiency for continuous arterial spin labeling: a method using phase contrast magnetic resonance angiography.

The accurate quantification of perfusion with arterial spin labeling (ASL) requires consideration of a number of factors, including the efficiency of the inversion and control pulses used for spin labeling. In this study the effects of spin velocity on continuous ASL efficiency when using the amplitude modulated control strategy were investigated using simulations of the Bloch equations. The inversion efficiency was determined in vivo by combining the simulations with phase-contrast velocity mapping data acquired at the level of the tagging plane. Using this novel method, an average inversion efficiency of 69% was calculated for a group of 28 subjects, in good agreement with experimental data reported previously. There was, however, a large range in inversion efficiency measured across the subject group (50-76%), indicating that the velocity dependence of the amplitude modulated control efficiency may introduce additional variability into the perfusion calculations if not properly taken into account.

Algorithms↗

PubMed2005

Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind fMRI study.

Facilitation of central cholinergic activity may form a potential treatment strategy for cognitive impairment in schizophrenia. In a randomized, placebo-controlled, double-blind, parallel-group design, we investigated the neural correlates of cognitive effects of rivastigmine, an acetylcholinesterase inhibitor, given as an add-on therapy to antipsychotic-treated schizophrenia patients. Thirty-six chronic schizophrenia patients with mild cognitive impairment took part. After 1 week on placebo (baseline), all patients entered a double-blind protocol; 18 were allocated to receive rivastigmine and 18 placebo for the next 12 weeks (final sample with usable imaging data: 11 patients on rivastigmine, 10 on placebo). All patients underwent functional magnetic resonance imaging during a parametric 'n-back' task, involving monitoring of dots in particular locations on a screen at a given delay from the original occurrence, twice: at baseline and 12 weeks post-rivastigmine/placebo treatment. Compared to placebo, rivastigmine produced only a small and non-significant improvement in task accuracy across all conditions with no change in response latency, and increased activity in the extrastriate visual cortex in areas associated with visual and spatial attention but not in any region within the working memory network. Our observations suggest that cholinergic enhancement with rivastigmine at doses known to be effective in Alzheimer's disease does not produce strong and clinically meaningful cognitive and neural changes in schizophrenia patients treated with atypical antipsychotics although the neural effects in terms of enhanced neuronal activity in regions associated with visual and spatial attention are consistent with those reported previously with cholinergic enhancement in healthy subjects.

Adult↗

PubMed2005

Functional neuroanatomy of body shape perception in healthy and eating-disordered women.

BACKGROUND: Abnormalities in perception and evaluation of body shape are a hallmark of eating disorders. METHODS: Brain responses to line drawings of underweight, normal weight, and overweight female bodies were measured with functional magnetic resonance imaging in 9 women with bulimia nervosa, 13 with anorexia nervosa, and 18 healthy women. Participants rated the stimuli for fear and disgust. RESULTS: In the three groups, the lateral fusiform gyrus, inferior parietal cortex, and lateral prefrontal cortex were activated in response to body shapes compared with the control condition (drawings of houses). The responses in the lateral fusiform gyrus and in the parietal cortex were less strong in patients with eating disorders compared with healthy control subjects. Patients with eating disorders rated the body shapes in all weight categories as more aversive than did healthy women. In the group with eating disorders, the aversion ratings correlated positively with activity in the right medial apical prefrontal cortex. CONCLUSIONS: Processing of female body shapes engages a distributed neural network, parts of which are underactive in women with eating disorders. The considerable variability in subjective emotional reaction to body shapes in patients with eating disorders is associated with differential activity in the prefrontal cortex.

Adult↗

PubMed2005

The neural correlates of anhedonia in major depressive disorder.

BACKGROUND: Anhedonia is a relative lack of pleasure in response to formerly rewarding stimuli. It is an important diagnostic feature of major depressive disorder (MDD), and predicts antidepressant efficacy. Understanding its neurobiological basis may help to target new treatments and predict treatment outcomes. Using a novel paradigm, we aimed to explore the correlations between anhedonia severity and magnitude of neural responses to happy and sad stimuli in regions previously implicated in studies of human reward processing and depressive anhedonia. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical prompts and mood congruent facial expressions) were measured using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in twelve MDD individuals with varying degrees of anhedonia. RESULTS: In response to happy stimuli, anhedonia, but not depression severity per se, was positively and negatively correlated with ventromedial prefrontal cortex (VMPFC) and amygdala/ventral striatal activity, respectively. State anxiety independently contributed to a VMPFC-subcortical dissociation of response to happy (but not sad) stimuli, which was similar, but different, to anhedonia. CONCLUSIONS: These findings suggest that anhedonia and state anxiety are associated with dysfunction within neural systems underlying the response to, and assessment of, the rewarding potential of emotive stimuli in MDD, and highlight the importance of employing a symptom-dimension-based approach in the examination of the neurobiology of depression.

Adult↗

PubMed2005

A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals.

BACKGROUND: The ventromedial prefrontal cortex (VMPFC) is a region implicated in the assessment of the rewarding potential of stimuli and may be dysfunctional in major depressive disorder (MDD). The few studies examining prefrontal cortical responses to emotive stimuli in MDD have indicated increased VMPFC responses to pleasant images but decreased responses to sad mood provocation when compared with healthy individuals. We wished to corroborate these results by examining neural responses to personally relevant happy and sad stimuli in MDD and healthy individuals within the same paradigm. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical memory prompts and congruent facial expressions) were measured using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in MDD (n = 12) and healthy (n = 12) individuals. RESULTS: Increased and decreased responses in VMPFC were observed in MDD and healthy individuals, respectively, to happy stimuli, whereas the pattern was reversed for MDD and healthy individual responses to sad stimuli. These findings were not explained by medication effects in depressed individuals. CONCLUSIONS: These findings indicate a double dissociation of the pattern of VMPFC response to happy and sad stimuli in depressed and healthy individuals and suggest abnormal reward processing in MDD.

Adult↗

PubMed2005

A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder.

BACKGROUND: Accurate recognition of facial expressions is crucial for social functioning. In depressed individuals, implicit and explicit attentional biases away from happy and toward sad stimuli have been demonstrated. These may be associated with the negative cognitions in these individuals. METHODS: Using event-related functional magnetic resonance imaging (fMRI), neural responses to happy and sad facial expressions were measured in 14 healthy individuals and 16 individuals with major depressive disorder. RESULTS: Healthy but not depressed individuals demonstrated linear increases in response in bilateral fusiform gyri and right putamen to expressions of increasing happiness, while depressed individuals demonstrated linear increases in response in left putamen, left parahippocampal gyrus/amygdala, and right fusiform gyrus to expressions of increasing sadness. There was a negative correlation in depressed individuals between depression severity and magnitude of neural response within right fusiform gyrus to happy expressions. CONCLUSIONS: Our findings indicate preferential increases in neural response to sad but not happy facial expressions in neural regions involved in the processing of emotional stimuli in depressed individuals. These findings may be associated with the above pattern of implicit and explicit attentional biases in these individuals and suggest a potential neural basis for the negative cognitions and social dysfunction in major depression.

Adult↗

PubMed2005

Neural correlates of the misattribution of self-generated speech.

Auditory hallucinations are thought to arise through the misidentification of self-generated verbal material as alien. The neural mechanisms that normally mediate the differentiation of self-generated from nonself speech are unclear. We investigated this in healthy volunteers using functional MRI. Eleven healthy volunteers were scanned whilst listening to a series of prerecorded words. The source (self/nonself) and acoustic quality (undistorted/distorted) of the speech was varied across trials. Participants indicated whether the words were spoken in their own or another person's voice via a button press. Listening to self-generated words was associated with more activation in the left inferior frontal and right anterior cingulate cortex than words in another person's voice, which was associated with greater engagement of the lateral temporal cortex bilaterally. Listening to distorted speech was associated with activation in the inferior frontal and anterior cingulate cortex. There was an interaction between the effects of source of speech and distortion on activation in the left temporal cortex. In the presence of distortion participants were more likely to misidentify their voice as that of another. This misattribution of self-generated speech was associated with reduced engagement of the cingulate and prefrontal cortices. The evaluation of auditory speech involves a network including the inferior frontal, anterior cingulate, and lateral temporal cortex. The degree to which different areas within this network are engaged varies with the source and acoustic quality of the speech. Accurate identification of one's own speech appears to depend on cingulate and prefrontal activity.

Acoustic Stimulation↗

PubMed2005

Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study.

BACKGROUND & AIMS: Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. METHODS: Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. RESULTS: Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. CONCLUSIONS: We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.

Adult↗

PubMed2005

A diffusion tensor magnetic resonance imaging study of frontal cortex connections in very-late-onset schizophrenia-like psychosis.

OBJECTIVE: Onset of psychosis after the age of 60 may be associated with structural abnormalities within cerebral white matter. The authors looked within white-matter tracts, which mediate connectivity of the frontal lobes, in psychotic patients for evidence of loss of fiber integrity consistent with degenerative damage. METHODS: Fourteen patients with very-late-onset schizophrenia-like psychosis and an age-matched control group underwent diffusion tensor magnetic resonance imaging. Tract maps were constructed for each subject from the imaging data, and measurements of fractional anisotropy and mean diffusivity were made within the uncinate, superior longitudinal, and inferior occipito-frontal fasciculi, and the cingulum. RESULTS: There were no significant differences in fractional anisotropy, a measure of the ordering of axons within fiber tracts, nor in mean diffusivity, an orientationally-averaged measure of the bulk diffusivity within each voxel, between patients and control subjects. CONCLUSION: The lack of difference in fractional anisotropy and mean diffusivity measures between patients and controls argues against the presence of structural abnormalities within these tracts and the notion that a focal white-matter abnormality within the tracts investigated underpins the onset of psychosis.

Age of Onset↗

PubMed2005

Functional neuroanatomy of successful paired associate learning in Alzheimer's disease.

OBJECTIVE: The purpose of the study was to develop a strategy for functional imaging of neurodegenerative disorders that overcomes confounds associated with differential performance between patient and comparison groups. METHOD: Functional magnetic resonance imaging was used to examine responses to increasing difficulty of visuospatial paired associate learning in 12 patients with mild probable Alzheimer's disease and 12 age-matched healthy comparison subjects. Performance was matched across groups by only examining successful encoding and retrieval attempts. Adjustment for task difficulty was made on an individual basis so that the patients with Alzheimer's disease and the comparison subjects performed at the same relative levels of difficulty. RESULTS: A network of lateral and medial frontoparietal and occipital regions was engaged in all subjects during successful associative learning. As task difficulty increased, blood-oxygen-level-dependent responses increased linearly in occipitoparietal regions during encoding and retrieval. Differential activations in patients with Alzheimer's disease and comparison subjects were small and were found only when an uncorrected statistical threshold was used. CONCLUSIONS: By controlling for confounds of varying task difficulty and subsequent performance, remarkably similar brain activations were identified during successful paired associate learning in patients with Alzheimer's disease and in healthy comparison subjects. The study methods provide a useful model for further applications of functional imaging involving cognitive activation paradigms in the study of neuropsychiatric disorders.

Aged↗

PubMed2004

Personality predicts brain responses to cognitive demands.

Eysenck (1981) proposed that the personality dimension of introversion- extraversion (E) reflects individual differences in a cortical arousal system modulated by reticulothalamic- cortical pathways: it is chronically more active in introverts relative to extraverts and influences cognitive performance in interaction with task parameters. A circuit with connections to this system, including the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate (AC) cortex, has been identified in studies applying functional magnetic resonance imaging (fMRI) to a broad range of cognitive tasks. We examined the influence of E, assessed with the Eysenck Personality Questionnaire-Revised (Eysenck and Eysenck, 1991), in fMRI activity during an "n-back" task involving four memory loads (0-, 1-, 2-, and 3-back) and a rest condition in healthy men. To confirm the specificity of E effects, we also examined the effects of neuroticism and psychoticism (P) scores. We observed that, as predicted by Eysenck's model, the higher the E score, the greater the change in fMRI signal from rest to the 3-back condition in the DLPFC and AC. In addition, E scores were negatively associated with resting fMRI signals in the thalamus and Broca's area extending to Wernicke's area, supporting the hypothesized (negative) relationship between E and resting arousal. P scores negatively correlated with resting fMRI signal in the globus pallidus-putamen, extending previous findings of a negative relationship of schizotypy to striatal activity seen with older neuroimaging modalities to fMRI. These observations suggest that individual differences affect brain responses during cognitive activity and at rest and provide evidence for the hypothesized neurobiological basis of personality.

Adult↗