Biomedical subjects

E T Bullmore

Publications and source records attributed to E T Bullmore.

At least 19 recordsLinked to original sources

PubMed2006

Brain mechanisms of successful compensation during learning in Alzheimer disease.

OBJECTIVE: To determine whether patients with Alzheimer disease (AD) compensate for neuropathologic changes when performing a mnemonic task by recruiting 1) the same brain regions as age-matched, healthy controls, but to a greater extent; 2) additional brain regions not activated by controls; or 3) both. METHODS: Twelve patients with mild probable AD and 12 healthy age- and education-matched controls participated in an fMRI study of successful encoding and retrieval of visuospatial paired associates. To ensure successful performance in both groups, participants were given multiple attempts to learn associations between two and three object locations. RESULTS: The pattern of brain activity in patients with AD performing an easy version of the task was indistinguishable from that of controls performing a harder version of the task. Increased activation in left medial and right lateral prefrontal cortices was found in patients with AD compared to controls during encoding of two object locations, but not when this level of encoding in patients was compared with encoding of three object locations in controls. CONCLUSIONS: There was no evidence of neural plasticity in the form of recruitment of novel brain regions in patients with Alzheimer disease. Data supported greater recruitment of the same brain regions as age-matched controls as a means of compensating for neuropathology and associated cognitive impairment in Alzheimer disease.

Aged↗

PubMed2006

Neuroanatomical correlates of memory deficits in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a multisystem syndrome classically associated with the occurrence of focal brain dysplasias. We used structural magnetic resonance imaging to test for neuroradiological abnormalities in TSC (tubers, white matter lesions, and subependymal nodules) and to explore the relationships between these lesions and computational morphometric abnormalities of gray and white matter distribution. We tested memory function in TSC and investigated the relationship between memory function and both morphometric variation and lesion load. Patients demonstrated deficits bilaterally in volume of subcortical gray matter regions including thalamus, basal ganglia, insula, and cerebellum, as well as white matter deficits bilaterally in intrahemispheric tracts. Morphometric deficits could not be explained as local effects of lesions. Patients demonstrated deficits in executive working memory and recall memory, sparing recognition. Structure-function mapping showed long-term and working memory function was positively correlated with gray matter density (in thalamus, caudate nucleus, and frontal cortex) but not with lesion load. The neuroanatomical endophenotype of TSC is more extensive than previously recognized and comprises abnormalities in the distribution of gray and white matter in addition to classical lesions. Normal intelligence quotient patients with TSC show a profile of long-term and working memory impairment that is related to gray matter deficits in thalamus and basal ganglia components of fronto-striatal circuits.

Adult↗

PubMed2006

Psychological effects of ketamine in healthy volunteers. Phenomenological study.

BACKGROUND: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically. AIM: To examine the effects of ketamine in healthy people using a structured psychiatric interview. METHOD: Ketamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms. RESULTS: Ketamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers. CONCLUSIONS: Ketamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.

Adult↗

PubMed2005

Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes.

RATIONALE: Methylphenidate (MPH) is a dopamine and noradrenaline enhancing drug used to treat attentional deficits. Understanding of its cognition-enhancing effects and the neurobiological mechanisms involved, especially in elderly people, is currently incomplete. OBJECTIVES: The aim of this study was to investigate the relationship between MPH plasma levels and brain activation during visuospatial attention and movement preparation. METHODS: Twelve healthy elderly volunteers were scanned twice using functional magnetic resonance imaging (fMRI) after oral administration of MPH 20 mg or placebo in a within-subject design. The cognitive paradigm was a four-choice reaction time task presented at two levels of difficulty (with and without spatial cue). Plasma MPH levels were measured at six time points between 30 and 205 min after dosing. FMRI data were analysed using a linear model to estimate physiological response to the task and nonparametric permutation tests for inference. RESULTS: Lateral premotor and medial posterior parietal cortical activation was increased by MPH, on average, over both levels of task difficulty. There was considerable intersubject variability in the pharmacokinetics of MPH. Greater area under the plasma concentration-time curve was positively correlated with strength of activation in motor and premotor cortex, temporoparietal cortex and caudate nucleus during the difficult version of the task. CONCLUSION: This is the first pharmacokinetic/pharmacodynamic study to find an association between plasma levels of MPH and its modulatory effects on brain activation measured using fMRI. The results suggest that catecholaminergic mechanisms may be important in brain adaptivity to task difficulty and in task-specific recruitment of spatial attention systems.

Aged↗

PubMed2005

Reduced volume of parietal and frontal association areas in patients with schizophrenia characterized by passivity delusions.

BACKGROUND: In patients with schizophrenia, passivity delusions are characterized by a difficulty in determining the agency of purposive actions. Neuropsychological and functional neuroimaging data suggest that passivity delusions are associated with dysfunction of the parietal lobe association cortex. METHOD: Cortical volume calculated from magnetic resonance imaging data in a group of 12 patients with schizophrenia characterized by motor passivity delusions was compared statistically with the cortical volume of 11 patients without passivity delusions. RESULTS: Reduced cortical volume was observed in parietal and frontal association cortices in the passivity group. CONCLUSIONS: These data provide direct evidence for the involvement of the parietal lobe in the pathophysiology of passivity delusions in schizophrenia.

Adult↗

PubMed2004

Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

Adolescent↗

PubMed2004

Dopaminergic effects on electrophysiological and functional MRI measures of human cortical stimulus-response power laws.

Power laws have been widely used to formulate relationships between objective intensity of stimulation and subjective intensity of sensation. We investigated the effects of dopaminergic drug treatment (sulpiride) on the relationship between somatosensory stimulus intensity and cortical response measured electrophysiologically by somatosensory-evoked potentials (SEP) and functional magnetic resonance imaging (fMRI). The intensity of stimulation was related by a simple power law to both electrophysiological and fMRI measures of cortical response, with overlapping confidence intervals for both power law exponents. Sulpiride did not modulate the power law exponent, but significantly attenuated the "gain" of both stimulus-response functions. Using path analysis we decomposed dopaminergic effects on fMRI data into an indirect component (16%), predictable by drug effects on SEP, and a direct component (84%), not explained electrophysiologically. Results indicate that sulpiride has comparable effects on power law parameters estimated from SEP and fMRI, but fMRI has superior sensitivity to detect drug effects on somatosensory cortical recruitment by graded stimulation.

Adult↗

PubMed2004

A comparative evaluation of wavelet-based methods for hypothesis testing of brain activation maps.

Wavelet-based methods for hypothesis testing are described and their potential for activation mapping of human functional magnetic resonance imaging (fMRI) data is investigated. In this approach, we emphasise convergence between methods of wavelet thresholding or shrinkage and the problem of hypothesis testing in both classical and Bayesian contexts. Specifically, our interest will be focused on the trade-off between type I probability error control and power dissipation, estimated by the area under the ROC curve. We describe a technique for controlling the false discovery rate at an arbitrary level of error in testing multiple wavelet coefficients generated by a 2D discrete wavelet transform (DWT) of spatial maps of fMRI time series statistics. We also describe and apply change-point detection with recursive hypothesis testing methods that can be used to define a threshold unique to each level and orientation of the 2D-DWT, and Bayesian methods, incorporating a formal model for the anticipated sparseness of wavelet coefficients representing the signal or true image. The sensitivity and type I error control of these algorithms are comparatively evaluated by analysis of "null" images (acquired with the subject at rest) and an experimental data set acquired from five normal volunteers during an event-related finger movement task. We show that all three wavelet-based algorithms have good type I error control (the FDR method being most conservative) and generate plausible brain activation maps (the Bayesian method being most powerful). We also generalise the formal connection between wavelet-based methods for simultaneous multiresolution denoising/hypothesis testing and methods based on monoresolution Gaussian smoothing followed by statistical testing of brain activation maps.

Algorithms↗

PubMed2004

Effects of very low birthweight on brain structure in adulthood.

Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period. We wished to determine how such early brain lesions affect brain structure in adulthood. Thirty-two VLBW adults (20 female, 12 male) and 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 3.4). Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space. Images were then warped to a template image in standard space. There was no significant between-group difference in whole brain, grey matter, white matter, or total cerebral spinal fluid (CSF) volumes. However, lateral ventricular volume was significantly increased by 41% in those with VLBW. The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW. Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals. Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter. We conclude that these diffuse abnormalities of grey and white matter are a consequence of the interaction of perinatal brain injury and ongoing neurodevelopmental processes.

Adolescent↗

PubMed2004

Functional magnetic resonance imaging of the cerebral response to visual stimulation in medically unexplained visual loss.

BACKGROUND: Medically unexplained visual loss occurs in 1 to 5% of patients attending ophthalmology clinics and for many it runs a chronic course. A psychogenic aetiology is presumed in such cases, but little is known about the underlying neural mechanisms. Recent studies have established the value of functional magnetic resonance imaging (fMRI) in understanding the mechanisms of unexplained motor and sensory symptoms. The purpose of this study was to use a similar strategy (fMRI) to evaluate the cerebral responses to visual stimulation in a group of patients with medically unexplained visual loss, in an attempt to determine the underlying neural mechanisms. METHOD: Brain activation induced by periodic (monocular) 8 Hz visual stimulation was detected by fMRI in five patients with unexplained visual loss who fulfilled DSM-IV criteria for conversion disorder, and seven normal volunteers. Between-group differences in mean power of activation were estimated by fitting a one-way analysis of variance (ANOVA) model at each intracerebral voxel in standard space. RESULTS: Compared with controls, patients showed reduced activation in visual cortices, but increased activation in left inferior frontal cortex, left insula-claustrum, bilateral striatum and thalami, left limbic structures, and left posterior cingulate cortex. CONCLUSIONS: This preliminary study has identified novel neural correlates in patients with unexplained visual loss. The abnormal pattern of activation may reflect inhibition of primary visual cortex or a shift towards non-conscious (implicit) processing.

Adolescent↗

PubMed2004

Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania.

BACKGROUND: The processing of facial emotion involves a distributed network of limbic and paralimbic brain structures. Many of these regions are also implicated in the pathophysiology of mood disorders. Behavioural data indicate that depressed subjects show a state-related positive recognition bias for faces displaying negative emotions. There are sparse data to suggest there may be an analogous, state-related negative recognition bias for negative emotions in mania. We used functional magnetic resonance imaging (fMRI) to investigate the behavioural and neurocognitive correlates of happy and sad facial affect recognition in patients with mania. METHOD: Functional MRI and an explicit facial affect recognition task were used in a case-control design to measure brain activation and associated behavioural response to variable intensity of sad and happy facial expressions in 10 patients with bipolar I mania and 12 healthy comparison subjects. RESULTS: The patients with mania had attenuated subjective rating of the intensity of sad facial expressions, and associated attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, with increased activation in the posterior cingulate and posterior insula. No behavioural or neurocognitive abnormalities were found in response to presentation of happy facial expressions. CONCLUSIONS: Patients with mania showed a specific, mood-congruent, negative bias in sad facial affect recognition, which was associated with an abnormal profile of brain activation in paralimbic regions implicated in affect recognition and mood disorders. Functional imaging of facial emotion recognition may be a useful probe of cortical and subcortical abnormalities in mood disorders.

Adult↗

PubMed2004

Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study.

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

Adult↗

PubMed2004

Lateralisation of language function in young adults born very preterm.

OBJECTIVE: To explore, using functional magnetic resonance imaging (MRI), the functional organisation of phonological processing in young adults born very preterm. SUBJECTS: Six right handed male subjects with radiological evidence of thinning of the corpus callosum were selected from a cohort of very preterm subjects. Six normal right handed male volunteers acted as controls. METHOD: Blood oxygenation level dependent contrast echoplanar images were acquired over five minutes at 1.5 T while subjects performed the tasks. During the ON condition, subjects were visually presented with pairs of non-words and asked to press a key when a pair of words rhymed (phonological processing). This task alternated with the OFF condition, which required subjects to make letter case judgments of visually presented pairs of consonant letter strings (orthographic processing). Generic brain activation maps were constructed from individual images by sinusoidal regression and non-parametric testing. Between group differences in the mean power of experimental response were identified on a voxel wise basis by analysis of variance. RESULTS: Compared with controls, the subjects with thinning of the corpus callosum showed significantly reduced power of response in the left hemisphere, including the peristriate cortex and the cerebellum, as well as in the right parietal association area. Significantly increased power of response was observed in the right precentral gyrus and the right supplementary motor area. CONCLUSIONS: The data show evidence of increased frontal and decreased occipital activation in male subjects with neurodevelopmental thinning of the corpus callosum, which may be due to the operation of developmental compensatory mechanisms.

Adolescent↗

PubMed2003

Dopaminergic drug effects on physiological connectivity in a human cortico-striato-thalamic system.

Cortico-striato-thalamic (CST) systems are anatomical substrates for many motor and executive functions and are implicated in diverse neuropsychiatric disorders. Electrophysiological studies in rats, monkeys and patients with Parkinson's disease have shown that power and coherence of low frequency oscillations in CST systems can be profoundly modulated by dopaminergic drugs. We combined functional MRI with correlational and path analyses to investigate functional and effective connectivity, respectively, of a prefronto-striato-thalamic system activated by object location learning in healthy elderly human subjects (n = 23; mean age = 72 years). Participants were scanned in a repeated measures, randomized, placebo-controlled design to measure modulation of physiological connectivity between CST regions following treatment with drugs which served both to decrease (sulpiride) and increase (methylphenidate) dopaminergic transmission, as well as non-dopaminergic treatments (diazepam and scopolamine) to examine non-specific effects. Functional connectivity of caudate nucleus was modulated specifically by dopaminergic drugs, with opposing effects of sulpiride and methylphenidate. The more salient effect of sulpiride was to increase functional connectivity between caudate and both thalamus and ventral midbrain. A path diagram based on prior knowledge of unidirectional anatomical projections between CST components was fitted satisfactorily to the observed inter-regional covariance matrix. The effect of sulpiride was defined more specifically in the context of this model as increased strength of effective connection from ventral midbrain to caudate nucleus. In short, we have demonstrated enhanced functional and effective connectivity of human caudate nucleus following sulpiride treatment, which is compatible both with the anatomy of ascending dopaminergic projections and with electrophysiological studies indicating abnormal coherent oscillations of CST neurons in parkinsonian states.

Aged↗

PubMed2003

GABAergic inhibitory mechanisms for repetition-adaptivity in large-scale brain systems.

Molecular mechanisms for systems level adaptivity of brain activation are largely unknown but a key role for active inhibition by gamma-aminobutyric acid (GABA) is plausible. We used functional magnetic resonance imaging to contrast the modulatory effects on brain adaptivity to task repetition and task difficulty of two GABAergic drugs, lorazepam and flumazenil. In a working memory paradigm, occipitotemporal regions clearly demonstrated attenuation of activation as a function of within-session task repetition or practice in data acquired following placebo, but this spatiotemporal pattern of repetition adaptivity was abolished by both lorazepam and flumazenil. However, in other brain systems flumazenil enhanced repetition adaptivity compared to placebo: in frontal cortex, flumzenil induced attenuation of signal related to task repetition and in hippocampus it exaggerated normal enhancement of signal with repetition. In contrast, there were no significant effects of either flumazenil or lorazepam on areas of frontal cortex which normally demonstrated significant neurocognitive load response or adaptivity to task difficulty. We argue that repetition adaptivity of large-scale brain systems is regulated by GABAergic inhibitory mechanisms and that expression of repetition adaptivity in a given brain system may show an "inverted-U" form of relationship with pharmacologically manipulable levels of GABAergic inhibitory tone.

Adult↗

PubMed2003

The functional neuroanatomy of schizophrenic subsyndromes.

BACKGROUND: There is considerable variability between patients in their expression of the diverse range of symptoms encompassed by the syndrome of schizophrenia, which may modulate functional activation to cognitive processing. METHOD: Here we investigate associations between schizophrenic subsyndrome scores, identified by factor analysis, and experimentally controlled brain activation. Five factors were defined by rotated principal components analysis of PANSS rating scale measurements in 100 patients with schizophrenia. A subsample of 30 patients and a group of 27 comparison subjects were studied using functional magnetic resonance imaging (fMRI) during the performance of two periodically designed cognitive activation experiments: verbal working memory and psychomotor sequencing. RESULTS: Factor analysis replicated the five dimensions consistently reported. Within the patient group. power of activation by working memory was negatively associated with global symptom severity in left lingual and temporo-parietal cortices; negatively associated with positive subsyndrome scores in left inferior frontal and superior temporal cortices and basal ganglia; and positively associated with negative subsyndrome scores in lateral and medial premotor cortex. No relationship was observed between subsyndrome scores and functional activation during the motor task. Between-group comparisons demonstrated reduced power of response to the working memory task by patients in bilateral dorsolateral prefrontal and left pre- and post-central cortices. CONCLUSIONS: In this study we observed task-specific modulation of functional response associated with symptom expression in schizophrenia. Our findings are compatible with previous empirical findings and theoretical conceptualization of human brain function, in terms of capacity constraints on activation in the face of competing demands from pathological and task-related cognitive activity.

Adult↗

PubMed2003

Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease.

Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

Adult↗

PubMed2002

Functional magnetic resonance imaging of the cortical response to photic stimulation in humans following optic neuritis recovery.

Recovery from optic neuritis has been shown to be associated with an abnormal functional MRI (fMRI) response following exposure of the eye to an epoch based (ON-OFF design) flickering photic stimulus. Visual cortex activation is reduced during photic stimulation, whilst extra-occipital areas are extensively activated with a peak blood oxygen level dependent response during the OFF phase of the stimulus paradigm. We performed a further fMRI experiment to determine whether the abnormal extra-occipital response is a phase-specific phenomenon or whether it results from a delayed haemodynamic response. A cohort of patients that recovered from optic neuritis was studied, this time using a longer photic stimulation epoch (40 s). The extra-occipital response again peaked during the baseline condition, indicating that the phenomenon is phase dependent. Our results also reinforce the important findings of extra-occipital activation following optic neuritis which may represent an adaptive reorganization of the cerebral response.

Adult↗