Biomedical subjects

Philip B Ward

Publications and source records attributed to Philip B Ward.

15 recordsLinked to original sources

PubMed2006

Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression.

BACKGROUND: Although the short allele of the serotonin transporter promoter polymorphism (5-HTT) has been linked to increased risk of major depression in early adult life, its relationships with late-life depression and to changes in subcortical nuclei remain unclear. METHODS: 5-HTT genotypes (SS, SL, LL) were determined for 45 older persons with major depression (mean age=52.0, sd=12.8) and 16 healthy controls (mean age=55.8, sd=10.3). MRI-derived volumes of the amygdala, hippocampus, caudate and putamen were determined by reliable tracing techniques. RESULTS: In those with depression, the short allele of 5-HTT was associated with smaller caudate nucleus volumes. Although hippocampal and amygdala volumes were smaller in those with depression as compared with control subjects, 5-HTT gene status did not predict this reduction in size. LIMITATIONS: The findings are limited by the number of clinical and control participants. CONCLUSIONS: Reduced caudate nucleus volume in older patients with major depression was associated with the short allele of the 5-HTT gene. This regional brain change may be a consequence of early developmental expression as well as later vascular or degenerative effects of this genotype.

Aged↗

PubMed2006

Empathetic perspective-taking is impaired in schizophrenia: evidence from a study of emotion attribution and theory of mind.

INTRODUCTION: Schizophrenia and autism are clinically distinct yet both disorders are characterised by theory of mind (ToM) deficits. Autistic individuals fail to appreciate false beliefs, yet understand the causal connections between behavioural events and simple emotions. Findings of this type have promoted the view that ToM deficits in autism reflect a domain-specific difficulty with appreciating the representational nature of epistemic mental states (i.e., beliefs and intentions and not emotions). This study examines whether the same holds true for schizophrenia. METHODS: A picture-sequencing task assessed capacity to infer false beliefs in patients with schizophrenia and healthy controls. To assess emotion attribution, participants were shown cartoon strips of events likely to elicit strong emotional reactions in story characters. Characters' faces were blanked out. Participants were instructed to think about how the characters would be feeling in order to match up the cards depicting facial affect appropriately. Participants later named emotions depicted in facial affect cards. RESULTS: Patients were as capable as controls of identifying cartoon facial expressions, yet had greater difficulties with: (a) attributing emotions based on circumstances; and (b) inferring false beliefs. CONCLUSIONS: Schizophrenia patients, unlike autistic individuals, suffer a domain-general difficulty with empathetic perspective-taking that affects equally their appreciation of other people's beliefs, percepts, and emotions.

Adult↗

PubMed2005

Impaired implicit sequence learning in depression: a probe for frontostriatal dysfunction?

BACKGROUND: Implicit learning through motor sequencing tasks is sensitive to basal ganglia dysfunction. Consequently, it is ideally suited for testing elements of the frontostriatal model of major depression and performance can be related to key clinical, neuropsychological, vascular and biochemical data. METHOD: Twenty-one subjects with moderate to severe unipolar depression and 21 age-, sex- and education-matched controls were recruited. Clinical, vascular and biochemical data were recorded. Subjects were administered a battery of neuropsychological tests that assessed speed of processing, working memory, learning, memory, language, perceptual organization and executive functioning. Additionally, subjects were administered a motor sequencing implicit learning task. Implicit learning is assumed when reaction times improve during the sequenced condition as compared to the pseudo-random baseline condition. RESULTS: The rate of implicit learning in persons with depression was only half that of control subjects (3.6% v. 7.3%). Lower rates of implicit learning in patients were associated with poorer performance on neuropsychological tests of visuomotor speed and mental flexibility, longer duration of depressive episode and severity of acute stress. In a small number of subjects, poorer performance was also related to past suicide attempt. CONCLUSIONS: Impaired implicit learning in persons with depression is consistent with frontostriatal dysfunction. Performance is related to some clinical characteristics and to neuropsychological functioning on tests of visuomotor speed and mental flexibility.

Adult↗

PubMed2005

Externalizing and personalizing biases in persecutory delusions: the relationship with poor insight and theory-of-mind.

The presence of externalizing bias (EB) for negative events together with personalizing bias (PB) (a bias to blame others rather than circumstances) may jointly constitute a vulnerability to develop persecutory delusions (PDs). Whereas EB purportedly serves to defend a vulnerable self-concept by avoiding negative self-attributions and might therefore exacerbate poor insight, PB may reflect cognitive deficits, including theory-of-mind impairment. We investigated these proposals in 34 schizophrenic patients with a history of PDs and 21 healthy controls. Patients with moderate- to severe-PDs and patients without a current PD showed excessive EB which was, surprisingly, absent in patients with mild persecutory delusions (mild-PDs). That EB might wax and wane with fluctuating delusional intensity was interpreted in accord with a new dynamic model of attribution self-representation cycles. As predicted, EB exacerbated poor insight. However, counter to predictions, theory-of-mind impairment did not increase PB, which was marked in all participants, whether clinical or non-clinical; instead, theory-of-mind impairment was also correlated with poor insight. Our findings indicate multiple pathways to poor insight, one of which is a theory-of-mind difficulty, impairing the capacity to simulate other perspectives for the purpose of critically evaluating one's own beliefs and circumstances.

Adult↗

PubMed2005

Attentional orienting triggered by gaze in schizophrenia.

The ability to detect the direction of another person's gaze and to shift our own attention reflexively in the same direction facilitates the sharing of attention with other people. Such sharing of attention would seem critical for the maintenance of normal social cognition. Social cognition is severely impaired in people with schizophrenia. So, we used spatial cuing paradigms to investigate reflexive (Experiment 1) and controlled (Experiment 2) attentional orienting triggered by gaze in schizophrenia. In Experiment 1, 30 patients and 24 controls detected targets appearing right or left of a central image of a head turned right, left, or straight-ahead. These gaze-cues were non-predictive. Patients, but not controls, showed a significant congruency advantage at 100 ms SOA. The congruency advantage was similar in patients and controls at 300-800 ms SOA. In Experiment 2, 20 patients and 24 controls detected targets 300-800 ms after a central gaze-cue that pointed away from the target on 80% of trials. Controls, but not patients, were able to reverse the reflexive congruency advantage at 800 ms SOA. This study provides the first evidence that people with schizophrenia show abnormally sensitive gaze-triggered reflexive orienting. Findings are discussed in light of recent neuroimaging work investigating the neural basis of social orienting and social cognition.

Adult↗

PubMed2005

Auditory recovery cycle dysfunction in schizophrenia: a study using event-related potentials.

Previous event-related potential (ERP) studies reported evidence of impaired auditory information processing in patients with schizophrenia. The recovery cycle of the auditory N1 ERP component was measured in 17 patients with schizophrenia and 17 age- and sex-matched healthy volunteers. Subjects performed a visual distraction task while listening to 80-dB SPL, 1000-Hz tone pairs, presented with intra-pair intervals of 1, 3, 5 or 7 s, with inter-pair intervals of 9-13 s. Patients with schizophrenia had significantly reduced N1 amplitudes for S1 stimuli compared with healthy volunteers. For N1 amplitudes elicited by S2 stimuli, there was a significant group effect whilst the main effect of intra-pair interval was not significant. These results provide additional evidence of inhibitory auditory processing deficits in schizophrenia.

Adult↗

PubMed2005

Functional MRI BOLD response to Tower of London performance of first-episode schizophrenia patients using cortical pattern matching.

Due to its three-dimensional folding pattern, the human neocortex poses a challenge for accurate co-registration of grouped functional brain imaging data. The present study addressed this problem by employing three-dimensional continuum-mechanical image-warping techniques to derive average anatomical representations for co-registration of functional magnetic resonance brain imaging data obtained from 10 male first-episode schizophrenia patients and 10 age-matched male healthy volunteers while they performed a version of the Tower of London task. This novel technique produced an equivalent representation of blood oxygenation level dependent (BOLD) response across hemispheres, cortical regions, and groups, respectively, when compared to intensity average co-registration, using a deformable Brodmann area atlas as anatomical reference. Somewhat closer association of Brodmann area boundaries with primary visual and auditory areas was evident using the gyral pattern average model. Statistically-thresholded BOLD cluster data confirmed predominantly bilateral prefrontal and parietal, right frontal and dorsolateral prefrontal, and left occipital activation in healthy subjects, while patients' hemispheric dominance pattern was diminished or reversed, particularly decreasing cortical BOLD response with increasing task difficulty in the right superior temporal gyrus. Reduced regional gray matter thickness correlated with reduced left-hemispheric prefrontal/frontal and bilateral parietal BOLD activation in patients. This is the first study demonstrating that reduction of regional gray matter in first-episode schizophrenia patients is associated with impaired brain function when performing the Tower of London task, and supports previous findings of impaired executive attention and working memory in schizophrenia.

Adolescent↗

PubMed2005

Vascular risk and low serum B12 predict white matter lesions in patients with major depression.

BACKGROUND: While patients with depression have been shown to have a greater incidence of vascular risk factors and structural brain changes, any association with dietary co-factors is unclear. METHODS: Forty-seven patients with major depression (mean age = 52.8 years, SD = 12.6) and 21 healthy volunteers (mean age = 54.7 years, SD = 9.1) underwent high-resolution magnetic resonance imaging scanning. T2-weighted films were scored for deep white matter (DWM), periventricular (PV), and subcortical (SC) hyperintensities. RESULTS: There was no difference in lesion severity between patients and control subjects. After controlling for age, vitamin B12 levels were predictive of DWM lesions in patients. DWM and SC lesions were associated with histories of hypertension and diabetes. LIMITATIONS: A relatively small sample of patients were recruited from specialist services and the findings may not represent those observed in larger or community-based cohorts. CONCLUSIONS: In patients with major depression, vitamin B12 levels and histories of hypertension and/or diabetes are predictive of white matter lesions.

Adult↗

PubMed2005

Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression.

BACKGROUND: Hippocampal volume reduction has been reported inconsistently in people with major depression. AIMS: To evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors. METHOD: Totals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected. RESULTS: Reduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance. CONCLUSIONS: Although reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.

Adult↗

PubMed2004

Cognitive generation of affect in bipolar depression: an fMRI study.

Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age-matched and sex-matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state-related or trait-related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance.

Adult↗

PubMed2003

Functional brain maps of Tower of London performance: a positron emission tomography and functional magnetic resonance imaging study.

Regional cerebral blood flow (rCBF) and blood oxygenation level-dependent (BOLD) contrasts represent different physiological measures of brain activation. The present study aimed to compare two functional brain imaging techniques (functional magnetic resonance imaging versus [(15)O] positron emission tomography) when using Tower of London (TOL) problems as the activation task. A categorical analysis (task versus baseline) revealed a significant BOLD increase bilaterally for the dorsolateral prefrontal and inferior parietal cortex and for the cerebellum. A parametric haemodynamic response model (or regression analysis) confirmed a task-difficulty-dependent increase of BOLD and rCBF for the cerebellum and the left dorsolateral prefrontal cortex. In line with previous studies, a task-difficulty-dependent increase of left-hemispheric rCBF was also detected for the premotor cortex, cingulate, precuneus, and globus pallidus. These results imply consistency across the two neuroimaging modalities, particularly for the assessment of prefrontal brain function when using a parametric TOL adaptation.

Adult↗

PubMed2003

Functional neuroanatomy of auditory mismatch processing: an event-related fMRI study of duration-deviant oddballs.

This study was designed to identify the neural networks underlying automatic auditory deviance detection in 10 healthy subjects using functional magnetic resonance imaging. We measured blood oxygenation level-dependent contrasts derived from the comparison of blocks of stimuli presented as a series of standard tones (50 ms duration) alone versus blocks that contained rare duration-deviant tones (100 ms) that were interspersed among a series of frequent standard tones while subjects were watching a silent movie. Possible effects of scanner noise were assessed by a "no tone" condition. In line with previous positron emission tomography and EEG source modeling studies, we found temporal lobe and prefrontal cortical activation that was associated with auditory duration mismatch processing. Data were also analyzed employing an event-related hemodynamic response model, which confirmed activation in response to duration-deviant tones bilaterally in the superior temporal gyrus and prefrontally in the right inferior and middle frontal gyri. In line with previous electrophysiological reports, mismatch activation of these brain regions was significantly correlated with age. These findings suggest a close relationship of the event-related hemodynamic response pattern with the corresponding electrophysiological activity underlying the event-related "mismatch negativity" potential, a putative measure of auditory sensory memory.

Adult↗

PubMed2003

Neuropsychological performance in patients with depression is associated with clinical, etiological and genetic risk factors.

The present study explores neuropsychological functioning in patients with depression with reference to key clinical, etiological and genetic features. In comparison to healthy volunteers, patients with severe depression demonstrated poorer performance on all neuropsychological tests except for WAIS-R Vocabulary and a 64-item computerized version of the Wisconsin Card Sorting Test. On average, patients exhibited significant impairments (greater than -2 standard deviation units) on tests of simple reaction time, Part B of the Trail Making Test and Raven's Colored Progressive Matrices. When performance decrements were analyzed with reference to key clinical features, patients with melancholia performed more poorly on WAIS-R Vocabulary, semantic fluency and choice reaction time than those with nonmelancholic depression. After controlling for age, those patients with late-onset depression (i.e., age of onset > or =50 years) exhibited poorer performance on a computerized version of the Tower of London test in comparison to those with an early onset. While there was no relationship between neuropsychological test scores and summed vascular risk factors or apolipoprotein E genotypes, presence of the methylenetetrahydrofolate reductase gene mutation was associated with slowed reaction time. The differential relationships between clinical, etiological and genetic risks and neuropsychological performance supports the presence of unique pathophysiological mechanisms in distinct subgroups of patients. These findings underscore the need to consider subtypes when investigating neuropsychological deficits in patients with depression.

Adult↗

PubMed2002

Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia.

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [3H]MK801, [3H]L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and [3H]kainate, which respectively label the N-methyl-D-aspartate (NMDA), AMPA, and kainate receptors of the ionotropic glutamate receptor family, in the left anterior cingulate cortex of 10 schizophrenia patients and 10 controls, matched for age, gender, and postmortem interval.AMPA receptor densities were higher in cortical layer II, whereas NMDA receptor densities were higher in cortical layers II-III in the anterior cingulate cortex of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [3H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared with the control group. Similarly, a significant 17% increase of [3H]MK801 binding was observed in layers II-III in the schizophrenia group. No statistically significant difference was observed for [3H] kainate binding between the schizophrenia and control groups. These results suggest that ionotropic glutamate receptors are differentially altered in the anterior cingulate region in schizophrenia. The increase in [3H]AMPA and [3H]MK801 binding in the superficial layers suggests a postsynaptic compensation for impaired glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia. The findings add to a growing body of literature that supports a dysfunction of excitatory activity in the anterior cingulate cortex in schizophrenia.

Adolescent↗

PubMed2002

Caudate nucleus volumes and genetic determinants of homocysteine metabolism in the prediction of psychomotor speed in older persons with depression.

OBJECTIVE: The authors sought to determine whether caudate nucleus volumes or specific genotypes predict psychomotor slowing in older persons with depression. METHOD: Forty-seven persons with depression (mean age=51.8 years, SD=12.4) and 20 healthy volunteers (mean age=56.1 years, SD=9.8) underwent clinical assessments, a neuropsychological test of psychomotor speed (part A of the Trail Making Test), high-resolution magnetic resonance imaging scans, and genotyping for the apolipoprotein E epsilon4 allele and a mutation of the methylenetetrahydrofolate reductase enzyme. RESULTS: Multivariate analyses revealed that psychomotor speed was uniquely predicted by age, a diagnosis of depression, right caudate nucleus volume, and mutation of the methylenetetrahydrofolate reductase enzyme. CONCLUSIONS: Psychomotor slowing, a key clinical and cognitive phenomenon in older persons with depression, is predicted by reduced caudate nucleus volumes and genetic determinants of homocysteine metabolism.

Adult↗