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Paul C Fletcher

Publications and source records attributed to Paul C Fletcher.

16 recordsLinked to original sources
PubMed2006

Does the brain have a baseline? Why we should be resisting a rest.

In the last few years, the notion that the brain has a default or intrinsic mode of functioning has received increasing attention. The idea derives from observations that a consistent network of brain regions shows high levels of activity when no explicit task is performed and participants are asked simply to rest. The importance of this putative "default mode" is asserted on the basis of the substantial energy demand associated with such a resting state and of the suggestion that rest entails a finely tuned balance between metabolic demand and regionally regulated blood supply. These observations, together with the fact that the default network is more active at rest than it is in a range of explicit tasks, have led some to suggest that it reflects an absolute baseline, one that must be understood and used if we are to develop a comprehensive picture of brain functioning. Here, we examine the assumptions that are generally made in accepting the importance of the "default mode". We question the value, and indeed the interpretability, of the study of the resting state and suggest that observations made under resting conditions have no privileged status as a fundamental metric of brain functioning. In doing so, we challenge the utility of studies of the resting state in a number of important domains of research.

Journal Article↗
PubMed2006

Differences in orbitofrontal activation during decision-making between methadone-maintained opiate users, heroin users and healthy volunteers.

OBJECTIVE: Previously, we reported that opiate users enrolled in methadone treatment made 'risky' choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials. METHODS: We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous [see text] positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin. RESULTS: We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to 'play risky'. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to 'play safe'. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. 'Playing safe' following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users. CONCLUSION: Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used.

Adult↗
PubMed2006

Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits.

Drug models of mental illness are considered useful if they provoke its characteristic symptoms. In this respect, ketamine and tetrahydrocannabinol (cannabis) are coming under increasing scrutiny as models for schizophrenia. However, although both undoubtedly produce psychotic symptoms characteristic of the disorder, we argue here that, because schizophrenia is also accompanied by cognitive deficits, a full understanding of the impact of these drugs on cognition will be crucial in taking these models further. Memory deficits are pronounced in schizophrenia and we focus upon patterns of working and episodic memory impairment produced by ketamine and cannabis, identifying overlaps between drug and illness. We suggest that close attention to these deficits can offer insights into core pathophysiology of schizophrenia.

Age Factors↗
PubMed2006

Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis.

CONTEXT: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. OBJECTIVE: To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. DESIGN: Within-subject, randomized, placebo-controlled study. SETTING: Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. PARTICIPANTS: Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. INTERVENTIONS: Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. MAIN OUTCOME MEASURES: Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). RESULTS: Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). CONCLUSIONS: These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

Adult↗
PubMed2006

The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: implications for pharmacological modelling of core symptoms of schizophrenia.

Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) x 2(depth of processing) x 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.

Adolescent↗
PubMed2005

The origin of pharmacopsychology: Emil Kraepelin's experiments in Leipzig, Dorpat and Heidelberg (1882-1892).

This historical review shows that the early history of cognitive psychopharmacology, originally labelled as "pharmacopsychology", is closely linked to developments in experimental psychology and academic psychiatry. At the beginning of his scientific career, the German psychiatrist Emil Kraepelin (1856-1926) joined Wilhelm Wundt's laboratory of experimental psychology at the University of Leipzig. Although Kraepelin was fired from his clinical position at the university's psychiatric hospital, he completed his habilitation, the German equivalent of Ph.D., and started a series of pharmacological investigations in healthy volunteers using common recreational drugs (alcohol, coffee, tea) or medicinal products (amyl nitrite, chloral hydrate, chloroform, ethyl ether, morphine, paraldehyde) together with innovative psychological tasks. This paper reviews Kraepelin's pharmacopsychological research and his methodological innovations, providing translations, for the first time, from original papers, his monograph On the Modulation of Simple Psychological Processes by Some Medicines and from other sources. Kraepelin's contributions to psychopharmacology and clinical neuropsychology were far ahead of his time and his conceptual achievements have been largely neglected by modern psychiatry and cognitive neuroscience.

History, 19th Century↗
PubMed2005

Impairment of specific episodic memory processes by sub-psychotic doses of ketamine: the effects of levels of processing at encoding and of the subsequent retrieval task.

RATIONALE: The precise nature of the impact of the N-methyl-D-aspartate antagonist, ketamine, upon human episodic memory, has yet to be elucidated fully. OBJECTIVES: This study sought to assess the effects of ketamine on the sub-processes facilitating memory encoding and retrieval. METHODS: We evaluated the effects of the drug on a series of memory performance measures depending upon whether it was administered at the encoding or retrieval stage and on the nature of the encoding task used. Twelve healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. Intravenous infusions of placebo, 50 ng/ml ketamine or 100 ng/ml ketamine were administered. We investigated the effects of ketamine on three key aspects of episodic memory: encoding vs retrieval processes, source memory, and depth of processing. Data were analysed using both multinomial modelling and standard measures of item discrimination and response bias. RESULTS: Deleterious effects of ketamine on episodic memory were primarily attributable to its effects on encoding, rather than retrieval processes. Recognition memory was impaired for items encoded at an intermediate level of processing, but preserved for shallowly and deeply encoded items. Increased source guessing bias was also observed when encoding took place under ketamine. CONCLUSIONS: The effects of ketamine upon episodic memory seem, therefore, to predominate at encoding. Furthermore, our results are also consistent with a specific impairment of encoding processes that result in subsequent recollective, as opposed to familiarity-based, retrieval. The observed effects are compatible with memory deficits seen in schizophrenia and thus provide some support for the ketamine model of the disease.

Adolescent↗
PubMed2005

Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function.

It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.

Adult↗
PubMed2005

Distinct roles for lateral and medial anterior prefrontal cortex in contextual recollection.

A key feature of human recollection is the ability to remember details of the context in which events were experienced, as well as details of the events themselves. Previous studies have implicated a number of regions of prefrontal cortex in contextual recollection, but the role of anterior prefrontal cortex has so far resisted detailed characterization. We used event-related functional MRI (fMRI) to contrast recollection of two forms of contextual information: 1) decisions one had previously made about stimuli (task memory) and 2) which of two temporally distinct lists those stimuli had been presented in (list memory). In addition, a retrieval cue manipulation permitted evaluation of the stage of the retrieval process in which the activated regions might be involved. The results indicated that anterior prefrontal cortex responded significantly more during recollection of task than list context details. Furthermore, activation profiles for lateral and medial aspects of anterior prefrontal cortex suggested differing roles in recollection. Lateral regions seem to be more involved in the early retrieval specification stages of recollection, with medial regions contributing to later stages (e.g., monitoring and verification).

Adolescent↗
PubMed2005

Anterior prefrontal cortex and the recollection of contextual information.

Recollective memory can involve the retrieval of many different kinds of contextual information, including where and when an event took place, as well as our thoughts and feelings at the time. The brain regions associated with this ability were examined in an event-related fMRI experiment, where participants made decisions about words or famous faces which were presented either on the left or right of a monitor screen. Subsequently, the studied words and faces were again presented and participants underwent fMRI brain scanning while recollecting either which of the decisions they had made on each item ("task memory"), or whether it had been presented on the left or right of the screen ("position memory"). A functional dissociation was observed within anterior prefrontal cortex (principally Brodmann's area 10), with activation in lateral regions associated with remembering either type of information (relative to baseline), and a medial anterior PFC region showing significantly greater activation during the "task memory" conditions. These results suggest different roles for lateral and medial anterior prefrontal cortex in recollection.

Adult↗
PubMed2004

Prediction error during retrospective revaluation of causal associations in humans: fMRI evidence in favor of an associative model of learning.

Associative learning theory assumes that prediction error is a driving force in learning. A competing view, probabilistic contrast (PC) theory, is that learning and prediction error are unrelated. We tested a learning phenomenon that has proved troublesome for associative theory--retrospective revaluation--to evaluate these two models. We previously showed that activation in right lateral prefrontal cortex (PFC) provides a reliable signature for the presence of prediction error. Thus, if the associative view is correct, retrospective revaluation should be accompanied by right lateral PFC activation. PC theory would be supported by the absence of this activation. Right PFC and ventral striatal activation occurred during retrospective revaluation, supporting the associative account. Activations appeared to reflect the degree of revaluation, predicting later brain responses to revalued cues. Our results support a modified associative account of retrospective revaluation and demonstrate the potential of functional neuroimaging as a tool for evaluating competing learning models.

Adult↗
PubMed2004

The role of the lateral frontal cortex in causal associative learning: exploring preventative and super-learning.

Prediction error--a mismatch between expected and actual outcome--is critical to associative accounts of inferential learning. However, it has proven difficult to explore the effects of prediction error using functional magnetic resonance imaging (fMRI) while excluding the confounding effects of stimulus novelty and incorrect responses. In this event-related fMRI study we used a three-stage experiment generating preventative- and super-learning conditions. In both cases, it was possible to generate prediction error within a causal associative learning experiment while subtracting the effects of novelty and error. We show that right lateral prefrontal cortex (PFC) activation is sensitive to the magnitude of prediction error. Furthermore, super-learning activation in this region of PFC correlates, across subjects, with the amount learned. We thus provide direct evidence for a brain correlate of the surprise-dependent mechanisms proposed by associative accounts of causal learning. We show that activity in right lateral PFC is sensitive to the magnitude, though not the direction, of the prediction error. Furthermore, its activity is not directly explicable in terms of novelty or response errors and appears directly related to the learning that arises out of prediction error.

Adult↗
PubMed2004

The hippocampal region is involved in successful recognition of both remote and recent famous faces.

There is currently a debate regarding the precise role of medial temporal regions in memory, in particular regarding the time scale of their involvement in conscious recollection of information stored in long-term memory. Using event-related fMRI, we have attempted to contribute to this debate by identifying brain regions associated with the successful recognition of famous faces from two different periods: "Old" faces of people who became famous in the 1960s-1970s and "Recent" faces of people who became famous in the 1990s. We demonstrate that the hippocampus is involved in the successful recognition of famous faces from both periods and does not appear to distinguish between these two periods. We also highlight a network of brain regions, including the left prefrontal cortex, the retrosplenial cortex, the temporo-parietal junction, the caudate and the right cerebellum, which is activated in association with successful recognition of famous faces. Finally, an analysis of the results obtained during a post hoc episodic recognition task shows the specific involvement of anterior hippocampus in the successful encoding of the unfamiliar faces, which were presented during the fame decision task, suggesting a functional distinction between anterior and posterior parts of the hippocampus, the former being specifically involved in successful episodic encoding and the latter being associated with successful retrieval of semantic information.

Brain↗
PubMedDate not supplied

Regional brain activations predicting subsequent memory success: an event-related fMRI study of the influence of encoding tasks.

We determined the brain regions that were differentially sensitive to two, randomly inter-mixed tasks: Deep Encoding, in which subjects processed items according to their meaning (is the word pleasant or unpleasant?) and Shallow Encoding, in which items were processed according to two underlined letters in the word (are the letters in alphabetical order?). The former task was associated with activations in a set of brain regions including left lateral prefrontal cortex (PFC) and left medial temporal cortex. The latter showed relatively greater activation in right PFC. Both findings are consistent with predictions made on the basis of previous functional neuroimaging work. Following scanning, each subject underwent a recognition memory task. The results of these provided the basis for a further sub-division of encoding events, according to whether they were predictive of subsequent recognition success or not. Unsurprisingly, recognition performance was greater for words that had been deeply encoded. For both encoding conditions, words that were subsequently recognised were associated with greater activation in a sub-set of regions identified by the deep versus shallow contrast. These included left PFC and medial temporal regions. In left PFC this performance-predicting activation was significantly greater for the deep encoding condition. Our results support previous studies suggesting a role for left PFC and medial temporal cortex in episodic memory encoding. They provide more evidence, too, for a less consistent finding: the interaction between the encoding task and the success of subsequent recognition.

Adult↗