Biomedical subjects

P C Fletcher

Publications and source records attributed to P C Fletcher.

At least 19 recordsLinked to original sources

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

Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory.

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.

Adolescent↗

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 brain mapping of psychopathology.

In this paper, we consider the impact that the novel functional neuroimaging techniques may have upon psychiatric illness. Functional neuroimaging has rapidly developed as a powerful tool in cognitive neuroscience and, in recent years, has seen widespread application in psychiatry. Although such studies have produced evidence for abnormal patterns of brain response in association with some pathological conditions, the core pathophysiologies remain unresolved. Although imaging techniques provide an unprecedented opportunity for investigation of physiological function of the living human brain, there are fundamental questions and assumptions which remain to be addressed. In this review we examine these conceptual issues under three broad sections: (1) characterising the clinical population of interest, (2) defining appropriate levels of description of normal brain function, and (3) relating these models to pathophysiological conditions. Parallel advances in each of these questions will be required before imaging techniques can impact on clinical decisions in psychiatry.

Brain↗

PubMed2002

The influence of explicit instructions and stimulus material on lateral frontal responses to an encoding task.

In this functional magnetic resonance imaging study, we explored the effects of both stimulus material and encoding task demands on activation in lateral prefrontal cortex (PFC). Two factors were manipulated: material type and task instructions. Subjects encoded words or abstract figures (factor 1: stimulus type) and were required to make either a meaning-based or a form-based (letter or shape) decision about each stimulus (factor 2: task instructions). Abstract figures engendered significantly higher levels of right PFC activity than did words. This effect was seen for meaning-based and form-based processing tasks and was significantly greater for the former. We did not observe a differential response of left lateral PFC to verbal and pictorial material. A double dissociation, however, was found within left PFC. A ventrolateral region (within left inferior frontal gyrus) showed the highest levels of activity when words were processed according to their meaning whereas activity in a more dorsolateral region (within left middle frontal gyrus) was greatest when words were processed according to their form (constituent letters). We have therefore observed a main effect of material type in producing lateralized activation of frontal lobes, although the strength of this effect is sensitive to the nature of the task that subjects are asked to perform. Left-side lateral PFC activity is also sensitive to task instructions but this effect was specific to verbal material. The complex patterns of frontal effect counsel against any simple dichotomy of frontal function at the level of either material or task type.

Adult↗

PubMed2001

Preliminary examination of oral contraceptive use among university-aged females.

The etymology and use of oral contraceptives (OCs) has greatly influenced the sexual practices and social lives (e.g., decisions concerning childbearing, careers) of adolescent and adult women. In addition, OCs have the potential to benefit or harm its users depending upon the utilization practices and characteristics/lifestyle habits of the women consuming them. A 28-item questionnaire was distributed to female students at a university in Central Ontario and examined: (1) socio-demographic information; (2) background information concerning oral contraceptive use (e.g., length of time taking the pill, concerns about pill use, side effects while on the pill); and (3) procedure for taking the pill (e.g. maximizing effectiveness and safety). Preliminary analysis indicated that females may not be equipped with adequate knowledge or receiving the necessary support to practice the most efficacious behaviours surrounding pill use.

Adolescent↗

PubMed2001

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory.

Learning depends on surprise and is not engendered by predictable occurrences. In this functional magnetic resonance imaging (fMRI) study of causal associative learning, we show that dorsolateral prefrontal cortex (DLPFC) is associated specifically with the adjustment of inferential learning on the basis of unpredictability. At the outset, when all associations were unpredictable, DLPFC activation was maximal. This response attenuated with learning but, subsequently, activation here was evoked by surprise violations of the learned association. Furthermore, the magnitude of DLPFC response to a surprise event was sensitive to the relationship that had been learned and was predictive of subsequent behavioral change. In short, the physiological response properties of right DLPFC satisfied specific predictions made by associative learning theory.

Adult↗

PubMed2001

Decision-making in mania: a PET study.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Adult↗

PubMed2001

Frontal lobes and human memory: insights from functional neuroimaging.

The new functional neuroimaging techniques, PET and functional MRI (fMRI), offer sufficient experimental flexibility and spatial resolution to explore the functional neuroanatomical bases of different memory stages and processes. They have had a particular impact on our understanding of the role of the frontal cortex in memory processing. We review the insights that have been gained, and attempt a synthesis of the findings from functional imaging studies of working memory, encoding in episodic memory and retrieval from episodic memory. Though these different aspects of memory have usually been studied in isolation, we suggest that there is sufficient convergence with respect to frontal activations to make such a synthesis worthwhile. We concentrate in particular on three regions of the lateral frontal cortex--ventrolateral, dorsolateral and anterior--that are consistently activated in these studies, and attribute these activations to the updating/maintenance of information, the selection/manipulation/monitoring of that information, and the selection of processes/subgoals, respectively. We also acknowledge a number of empirical inconsistencies associated with this synthesis, and suggest possible reasons for these. More generally, we predict that the resolution of questions concerning the functional neuroanatomical subdivisions of the frontal cortex will ultimately depend on a fuller cognitive psychological fractionation of memory control processes, an enterprise that will be guided and tested by experimentation. We expect that the neuroimaging techniques will provide an important part of this enterprise.

Animals↗

PubMed2000

The role of the right anterior prefrontal cortex in episodic retrieval.

Regional brain activity was measured with H(2) (15)O PET while participants attempted to complete word-stem and word-fragment retrieval cues with previously studied words. The retrieval cue manipulation was employed to gain control over the monitoring operations associated with evaluating the episodic status of alternative cue completions. These operations were more constrained for fragments, which had fewer possible completions than each corresponding stem. In one condition (zero target), during the scanning interval none of the cues could be completed with studied items, whereas in another condition (high target), 80% of cues belonged to studied items. Relative to baseline tasks, right anterior prefrontal activity was greater for stems than for fragments in the zero target condition. The target density manipulation did not modulate right anterior prefrontal activity, but was associated with increased activity in right dorsolateral prefrontal cortex. These findings are consistent with the proposal that the right anterior prefrontal cortex supports monitoring operations during episodic retrieval tasks. In addition, the findings add to evidence suggesting that the dorsolateral and anterior right prefrontal cortex make functionally distinct contributions to episodic retrieval.

Adult↗

PubMed2000

"Sculpting the response space"--an account of left prefrontal activation at encoding.

Left lateral prefrontal cortex (PFC) is consistently activated in neuroimaging studies of memory encoding. Its role, however, remains unclear. We describe two functional magnetic resonance imaging (fMRI) studies addressing this question. In the first we used a blocked experimental design to explore the effect of repeated encoding of word paired associates. Initial presentation of word pairs was associated with left ventrolateral PFC activation that attenuated with subsequent presentations of the same lists. When well-learned lists were presented with word pairs rearranged, a left PFC activation, greater than that associated with the initial presentation, was observed. In a second experiment, the formation of these associative relationships was explored using an event-related design. Two types of word pairs were presented: closely related (e.g., King...Queen) and distantly related (e.g., Net...Ship). The same region of left PFC was differentially sensitive to these two event-types, showing a greater response for distantly related pairs. We suggest that left PFC activity, at memory encoding, reflects operations necessary to the formation of meaningful associations in the service of optimal learning. A crucial feature of such associative processing lies in selecting appropriate, and inhibiting inappropriate, semantic attributes of the study material.

Adult↗

PubMed2000

Reading the mind in cartoons and stories: an fMRI study of 'theory of mind' in verbal and nonverbal tasks.

Previous functional imaging studies have explored the brain regions activated by tasks requiring 'theory of mind'--the attribution of mental states. Tasks used have been primarily verbal, and it has been unclear to what extent different results have reflected different tasks, scanning techniques, or genuinely distinct regions of activation. Here we report results from a functional magnetic resonance imaging study (fMRI) involving two rather different tasks both designed to tap theory of mind. Brain activation during the theory of mind condition of a story task and a cartoon task showed considerable overlap, specifically in the medial prefrontal cortex (paracingulate cortex). These results are discussed in relation to the cognitive mechanisms underpinning our everyday ability to 'mind-read'.

Adult↗

PubMed1999

Segregating the functions of human hippocampus.

It is now accepted that hippocampal lesions impair episodic memory. However, the precise functional role of the hippocampus in episodic memory remains elusive. Recent functional imaging data implicate the hippocampus in processing novelty, a finding supported by human in vivo recordings and event-related potential studies. Here we measure hippocampal responses to novelty, using functional MRI (fMRI), during an item-learning paradigm generated from an artificial grammar system. During learning, two distinct types of novelty were periodically introduced: perceptual novelty, pertaining to the physical characteristics of stimuli (in this case visual characteristics), and exemplar novelty, reflecting semantic characteristics of stimuli (in this case grammatical status within a rule system). We demonstrate a left anterior hippocampal response to both types of novelty and adaptation of these responses with stimulus familiarity. By contrast to these novelty effects, we also show bilateral posterior hippocampal responses with increasing exemplar familiarity. These results suggest a functional dissociation within the hippocampus with respect to the relative familiarity of study items. Neural responses in anterior hippocampus index generic novelty, whereas posterior hippocampal responses index familiarity to stimuli that have behavioral relevance (i.e., only exemplar familiarity). These findings add to recent evidence for functional segregation within the human hippocampus during learning.

Adolescent↗

PubMed1999

The role of the prefrontal cortex in recognition memory and memory for source: an fMRI study.

We employed fMRI to index neural activity in prefrontal cortex during tests of recognition and source memory. At study, subjects were presented with words displayed either to the left or right of fixation, and, depending on the side, performed one of two orienting tasks. The test phase consisted of a sequence of three 10-word blocks, displayed in central vision. For one block, subjects performed recognition judgements on a mixture of two old and eight new words (low density recognition). For another block, recognition judgements were performed on a mixture of eight old and two new words (high density recognition). In the remaining block, also consisting of eight old and two new items, the requirement was to judge whether each word had been presented at study on the left or the right. Relative to the low density condition, high density recognition was associated with increased activity in right and, to a lesser extent, left, anterior prefrontal cortex (BA 10), replicating the findings of two previous PET studies. Right anterior prefrontal activity did not show any further increase during the source task. Instead, greater activity was found, relative to high density recognition, in left BA 10, left inferior frontal gyrus (BA 45/47), and bilateral opercular cortices (BA 45/47). The findings are inconsistent with the proposal that activation of right anterior prefrontal cortex during memory retrieval reflects "postretrieval" processing demands, such demands being considerably greater for judgments of source than recognition. The findings provide further evidence that the left prefrontal cortex plays a role in episodic memory retrieval when the task explicitly requires recovery of contextual as well as item information.

Adult↗

PubMed1999

Abnormal neural integration related to cognition in schizophrenia.

A striking feature of schizophrenia is the diversity of the phenomenology both within and between patients. This diversity can be contrasted with the well-circumscribed and stable deficits seen in classic neuropsychological syndromes. The argument will be advanced that the classic lesion model, based on the notion of a segregated deficit, is inappropriate in schizophrenia. Instead the idea will be developed that a more appropriate model is one derived from concepts of neural integration across large-scale brain networks. Empirical data derived from positron emission tomography (PET) within our laboratory that provide support for this suggestion will be presented. One critical observation from these data is a disruption of prefrontal-temporal interactions, under a variety of cognitive activation paradigms, in both chronic medicated and acute unmedicated schizophrenic patients. Furthermore, these data indicate that both regional and interregional neuronal function, including prefrontal-temporal interactions, can be significantly modulated by a neurochemical perturbation of ascending dopaminergic systems. The latter observations suggest that the deficit of abnormal cortico-cortical interactions are to some extent modifiable by neuromodulatory neurotransmitter systems.

Acute Disease↗

PubMed1998

Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging.

BACKGROUND: Functional neuroimaging experiments have implicated prefrontal cortex (PFC) in memory processes. Several studies of schizophrenic patients have shown failure of activation in the dorsolateral region of PFC (DLPFC). We used a graded memory challenge to characterize functional neuroanatomical differences between schizophrenic and control subjects. The graded manipulation of task demands enabled us to assess group differences in the context of normal and abnormal psychological task performance. METHODS: Memory-related activity was assessed using positron emission tomography in schizophrenic patients and age-matched controls during performance of a graded memory task. Subjects underwent scanning while learning and recalling word lists of variable length. RESULTS: We used a model that assessed linear and nonlinear effects of memory load. Nonlinear group differences in DLPFC activation were observed. Controls showed a steepening slope of DLPFC increase as task demands increased. By contrast, schizophrenic subjects showed initial DLPFC increases that fell away with increasing memory load. The DLPFC response in schizophrenic subjects was closely related to measured task performance. In addition, schizophrenic subjects failed to show task-related decreases in activity in the left superior temporal and inferior parietal gyrus. CONCLUSIONS: Patients with schizophrenia showed a failure in DLPFC activation only in the face of diminished performance measures, suggesting that a full characterization of task-related changes in DLPFC activation must consider performance levels. However, striking failures of deactivation in superior temporal and inferior parietal regions were independent of task performance, possibly reflecting a core abnormality of the condition.

Adult↗

PubMed1998

Neural correlates of memory retrieval during recognition memory and cued recall.

Regional brain activity, measured by H215O PET, was investigated during recognition memory and word-stem cued recall of words in order to compare the neural correlates of two components of memory retrieval-effort and success-as a function of task. For each task there was a baseline and two retrieval conditions. In one retrieval condition (zero density), none of the test items corresponded to words encoded in a preceding study phase. Differences in activity between this condition and the baseline were employed to characterize the neural correlates of retrieval effort in each task. In the other retrieval condition (high density), 80% of the test items had been studied previously. Differences in brain activity between this condition and the zero-density condition were taken to represent the neural correlates of successful retrieval. The principal findings concern the right anterior prefrontal cortex, a region demonstrated previously to be active during episodic retrieval. Relative to baseline, this region showed no evidence of activation in the zero-density condition of the recognition task, but did show enhanced activity in the equivalent condition of the cued-recall task. In contrast, relative to the zero-density condition, the high-density condition was associated with increased right prefrontal activity during recognition, but reduced activity during cued recall. It is proposed that the right prefrontal cortex supports cognitive processes that operate on information retrieved in response to a test item and that these processes contribute to the evaluation of whether the information represents an appropriate prior episode.

Adult↗

PubMed1998

Neural correlates of depth of processing effects on recollection: evidence from brain potentials and positron emission tomography.

The probability that words would be recollected during tests of recognition memory was varied by manipulating depth of processing at study. Experiment 1 employed scalp-recorded event-related potentials (ERPs), and identified as a correlate of recollection a late (onset c. 500 ms), strongly left-lateralized positive-going modulation of the ERP waveform. The findings from experiment 2, which employed positron emission tomography (PET), indicated that recollection was associated with activation of the left hippocampal formation together with an extensive region of left temporal and frontal cortex. The findings support current ideas about the role of the hippocampal formation in episodic memory retrieval, and provide complementary information about the time course and localization of the cortical correlates of the recollection of recently experienced words.

Behavior↗