Biomedical subjects

P F Liddle

Publications and source records attributed to P F Liddle.

At least 19 recordsLinked to original sources

PubMed2005

Dysfunction of a distributed neural circuitry in schizophrenia patients during a working-memory performance.

BACKGROUND: In a recent longitudinal study of first-episode schizophrenia patients, we found that while dysfunction of the right dorsolateral prefrontal cortex (DLPFC), right thalamus, left cerebellum and cingulate gyrus normalized with antipsychotic treatment and significant reduction in symptomatology, the left DLPFC, left thalamus, and right cerebellum remained disturbed. In the present study we investigated whether these abnormalities are also present in clinically stable, relatively well-functioning schizophrenia patients in comparison to control subjects during performance of the N-back working-memory task. METHOD: Twelve schizophrenia and 12 control subjects completed the study. The functional images collected during scanning were analyzed using a random-effects model in a restricted set of six regions of interest (ROIs). In addition, the exploratory search in the entire brain volume was performed. RESULTS: The ROI analyses revealed relative underactivation in the region of the left DLPFC and the right cerebellum, as well as overactivation in the left cerebellum. The exploratory whole-brain search exposed additional overactivation in the medial frontal, anterior cingulate, and left parietal cortices. CONCLUSIONS: The present study provides evidence of significant underactivations in stable schizophrenia patients in regions that we have previously observed to be dysfunctional in acutely psychotic and partially remitted patients, together with extensive overactivations in several regions that potentially reflect some compensatory mechanism or increased effort on the working-memory task.

Adult↗

PubMed2004

Neurological soft signs discriminating mood disorders from first episode schizophrenia.

OBJECTIVE: To investigate the specificity of neurological soft signs (NSS) for first episode schizophrenia compared with mood disorders. METHOD: We assessed NSS in a sample of 60 healthy controls, 191 first episode psychosis patients and 81 mood disorder patients. We used a principle component analysis to identify dimensions of NSS. We subsequently investigated the specificity of these dimensions for schizophrenia and their relationships with medication and symptom scores. RESULTS: We identified five dimensions; coordination disorders, movement disorders, increased reflexes, dyskinesia and catatonia. These dimensions were related to neural circuits associated with schizophrenia and mood disorders and included the fronto-striatal-thalamic and the fronto-cerebellar pathway. The movement disorder dimension, which was suggestive for the involvement of the fronto-striatal-thalamic pathway, was specific for first episode schizophrenia independent from medication. CONCLUSION: NSS are the result of circuitry dysfunctions rather than overall dysfunction and a particular set of NSS shows specificity for schizophrenia.

Adolescent↗

PubMed2004

Changes in distributed neural circuitry function in patients with first-episode schizophrenia.

BACKGROUND: A number of functional brain abnormalities have been reported in schizophrenia, but it remains to be determined which of them represent trait and state markers of the illness. AIMS: To delineate regional brain dysfunctions that remain stable and those that fluctuate during the course of schizophrenia. METHOD: A cohort of patients with first-episode schizophrenia and a matched group of control participants underwent functional magnetic resonance imaging on two occasions 6-8 weeks apart during performance of a working memory task. The patients' disease was in partial remission at the second scan. RESULTS: Relative to control participants, the function of the left dorsolateral prefrontal cortex, left thalamus and right cerebellum remained disturbed in the people with schizophrenia, whereas the dysfunction of the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and cingulate gyrus normalised, with significant reduction in symptoms. CONCLUSIONS: These results suggest that dysfunction of the left fronto-thalamo-cerebellar circuitry is a relatively stable characteristic of schizophrenia, whereas disturbance of the right circuitry and cingulate gyrusis predominantly a state-related phenomenon.

Adult↗

PubMed2002

Reversed lateralization of temporal activation during speech production in thought disordered patients with schizophrenia.

BACKGROUND: Formal thought disorder is a core symptom of schizophrenia. It is associated with a reversed lateralization of the superior temporal cortex volume, an area that is implicated in lexical retrieval. We investigated the neural correlates of word retrieval during continuous speech in patients with formal thought disorder using functional magnetic resonance imaging (fMRI). METHODS: Blood oxygenation level dependent (BOLD) contrast was measured with fMRI while six patients with schizophrenia and six healthy control subjects spoke about seven Rorschach inkblots for 3 min each. Subjects produced varying amounts of speech during each run. In a within subject design, the number of words produced was correlated with the BOLD contrast in the two runs in each participant who showed the highest variance of speech output. RESULTS: In control subjects, the amount of speech produced was mainly correlated with activation in the left superior temporal gyrus. In the patient group, the main correlations were in the right superior temporal gyrus. CONCLUSIONS: During the production of continuous speech, patients with formal thought disorder showed a reversed laterality of activation in the superior temporal cortex. This is consistent with findings of perturbed hemispheric interaction in schizophrenia, particularly in patients with formal thought disorder.

Adult↗

PubMed2002

Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naïve schizophrenic patients: correlations with symptom change.

OBJECTIVE: Different symptom patterns have been shown to be associated with specific patterns of cerebral metabolic activity in schizophrenia. Treatment with various neuroleptic drugs results in decreased metabolism in frontal cortical regions. The temporal and regional relation between changes in metabolism and symptom improvement after treatment with risperidone was studied in eight previously unmedicated schizophrenic patients. METHOD: Cerebral metabolic activity was measured using PET before neuroleptic exposure, after the first dose of risperidone, and after 6 weeks of treatment. Pearson correlations were calculated for regions of significant change in metabolism and symptom change. RESULTS: After 6 weeks of treatment significant deactivations were seen in the left lateral cortical frontal region and medial frontal cortex. Significant changes were detectable in the medial frontal region 90 minutes after the first dose of risperidone. Patients with higher baseline activity in the identified medial frontal cluster had higher baseline positive symptom scores and reduction in medial frontal metabolism was correlated with reduction in positive symptom score. CONCLUSION: The evidence suggests that the reduction in medial-frontal activity after treatment with risperidone is a direct effect of risperidone and not a consequence of symptom improvement. Reduction of medial frontal metabolism may be one of the physiological mechanisms by which risperidone alleviates symptoms of psychosis in schizophrenia.

Adult↗

PubMed2001

Limbic abnormalities in affective processing by criminal psychopaths as revealed by functional magnetic resonance imaging.

BACKGROUND: Psychopathy is a complex personality disorder of unknown etiology. Central to the disorder are anomalies or difficulties in affective processing. METHODS: Functional magnetic resonance imaging was used to elucidate the neurobiological correlates of these anomalies in criminal psychopaths during performance of an affective memory task. RESULTS: Compared with criminal nonpsychopaths and noncriminal control participants, criminal psychopaths showed significantly less affect-related activity in the amygdala/hippocampal formation, parahippocampal gyrus, ventral striatum, and in the anterior and posterior cingulate gyri. Psychopathic criminals also showed evidence of overactivation in the bilateral fronto-temporal cortex for processing affective stimuli. CONCLUSIONS: These data suggest that the affective abnormalities so often observed in psychopathic offenders may be linked to deficient or weakened input from limbic structures.

Adult↗

PubMed2001

Detection of sounds in the auditory stream: event-related fMRI evidence for differential activation to speech and nonspeech.

The detection of speech in an auditory stream is a requisite first step in processing spoken language. In this study, we used event-related fMRI to investigate the neural substrates mediating detection of speech compared with that of nonspeech auditory stimuli. Unlike previous studies addressing this issue, we contrasted speech with nonspeech analogues that were matched along key temporal and spectral dimensions. In an oddball detection task, listeners heard nonsense speech sounds, matched sine wave analogues (complex nonspeech), or single tones (simple nonspeech). Speech stimuli elicited significantly greater activation than both complex and simple nonspeech stimuli in classic receptive language areas, namely the middle temporal gyri bilaterally and in a locus lateralized to the left posterior superior temporal gyrus. In addition, speech activated a small cluster of the right inferior frontal gyrus. The activation of these areas in a simple detection task, which requires neither identification nor linguistic analysis, suggests they play a fundamental role in speech processing.

Acoustic Stimulation↗

PubMed2001

An event-related functional magnetic resonance imaging study of an auditory oddball task in schizophrenia.

Schizophrenia is a diffuse brain disease that affects many facets of cognitive function. One of the most replicated findings in the neurobiology of schizophrenia is that the event-related potentials to auditory oddball stimuli are abnormal, effects believed to be related to abnormalities in attentional and memory processes. Although event-related potentials provide excellent resolution regarding the time course of information processing, such studies are poor at characterizing the spatial location of these abnormalities. To address this issue, we used event-related functional magnetic resonance imaging techniques to elucidate the neural areas underlying target detection in schizophrenia. Consistent with recent event-related functional magnetic resonance imaging results, target processing by control participants was associated with bilateral activation in the anterior superior temporal gyri, inferior and superior parietal lobules, and activation in anterior and posterior cingulate, thalamus, and right lateral frontal cortex. For the schizophrenic patients, selective deficits were observed in both the extent and strength of activation associated with target processing in the right lateral frontal cortex, thalamus, bilateral anterior superior temporal gyrus, anterior and posterior cingulate, and right inferior and superior parietal lobules. These findings are consistent with the evidence for abnormal processing of oddball stimuli suggested by event-related potential studies in schizophrenic patients, but provide much more detailed evidence regarding the anatomical sites implicated. These data are consistent with the hypothesis that schizophrenia is characterized by a widespread pathological process affecting many cerebral areas, including association cortex and thalamus.

Adult↗

PubMed2001

Neural correlates of formal thought disorder in schizophrenia: preliminary findings from a functional magnetic resonance imaging study.

BACKGROUND: Formal thought disorder (FTD) is a core symptom of schizophrenia, but its pathophysiology is little understood. We examined the neural correlates of FTD using functional magnetic resonance imaging. METHODS: Blood oxygenation level-dependent contrast was measured using functional magnetic resonance imaging while 6 patients with schizophrenia and 6 control subjects spoke about 7 Rorschach inkblots for 3 minutes each. In patients, varying degrees of thought-disordered speech were elicited during each "run." In a within-subject design, the severity of positive FTD was correlated with the level of blood oxygenation level-dependent contrast in the 2 runs that showed the highest variance of FTD in each patient. RESULTS: The severity of positive FTD in patients was negatively correlated (P<.001) with signal changes in the left superior and middle temporal gyri. Positive correlations were evident in the cerebellar vermis, the right caudate body, and the precentral gyrus. CONCLUSIONS: The severity of positive FTD was inversely correlated with the level of activity in the Wernicke area, a region implicated in the production of coherent speech. Reduced activity in this area might contribute to the articulation of incoherent speech. Because of the small sample size, these findings should be considered preliminary.

Adult↗

PubMed2001

Event-related fMRI study of response inhibition.

Event-related functional magnetic resonance imaging (erfMRI) was employed to measure the hemodynamic response during a Go/No-go task in 16 healthy subjects. The task was designed so that Go and No-go events were equally probable, allowing an unbiased comparison of cerebral activity during these two types of trials. In accordance with prediction, anterior cingulate was active during both the Go and No-go trials, dorsolateral and ventrolateral prefrontal cortex was more active during the No-go trials, while primary motor cortex, supplementary motor area, pre-motor cortex and cerebellum were more active during Go trials. These findings are consistent with the hypothesis that the anterior cingulate cortex is principally engaged in making and monitoring of decisions, while dorsolateral and ventral lateral prefrontal sites play a specific role in response inhibition.

Adult↗

PubMed2001

Removal of confounding effects of global signal in functional MRI analyses.

Local signals obtained from BOLD fMRI are generally confounded by global effects. In this paper, we make an essential distinction between global effects and the global signal. Global effects have a similar influence on local signals from a large proportion of cerebral voxels. They may reflect diffuse physiological processes or variations in scanner sensitivity and are difficult to measure directly. Global effects are often estimated from the global signal, which is the spatial average of local signals from all cerebral voxels. If the global signal is strongly correlated with experimental manipulations, meaningfully different results may be obtained whether or not global effects are modeled (G. K. Aguirre et al., 1998, NeuroImage, 8, 302-306). In particular, if local BOLD signals make a significant contribution to the global signal, analyses using ANCOVAor proportional scaling models may yield artifactual deactivations. In this paper, we present a modification to the proportional scaling model that accounts for the contribution of local BOLD signals to the global signal. An event-related oddball stimulus paradigm and a block design working memory task were used to illustrate the efficacy of our model.

Acoustic Stimulation↗

PubMed2001

The role of the anterior cingulate cortex in conflict processing: evidence from reverse stroop interference.

A recent theoretical account delineated the role of the anterior cingulate cortex (ACC) in cognitive control as the detection of conflict between competing information streams. Using functional magnetic resonance imaging, we examined the activity of this brain structure during different forms and degrees of conflict between the word and the color dimensions of Stroop stimuli. Overall, our results showed a dissociation between the degree of conflict and ACC activation. More specifically, although ACC activation was very extensive when print color interfered with word reading performance, the level of conflict, as measured by reaction time costs, was only moderate compared to other conditions. These results suggest that either the ACC is differentially sensitive to various types of conflict or its function should be extended to include other cognitive constructs, such as resolution of prior inhibition.

Adult↗

PubMed2001

Neural network analysis of the pattern of functional connectivity between cerebral areas in schizophrenia.

Recent evidence suggests that the core abnormality of cerebral function in schizophrenia is a disruption of functional connectivity between diverse cerebral sites. Functional connectivity is defined as the correlation between neuronal activity at remote sites. It can be measured using functional imaging techniques such as positron emission tomography (PET). This paper reports an analysis using a neural network to discriminate between the patterns of functional connectivity in schizophrenic patients and healthy subjects. The data was derived from a PET study of regional cerebral blood flow during word generation in 6 healthy subjects and 16 schizophrenic patients with established illness, in whom the clinical diagnosis could be made with confidence. After training on data from two healthy subjects and seven schizophrenic patients, the neural network successfully assigned all members of a test set of four healthy subjects and nine schizophrenic patients to the correct diagnostic category. While this result should be interpreted with caution on account of the small sample size, it indicates that neural network analysis is potentially of value in the diagnosis of schizophrenia.

Case-Control Studies↗

PubMed2001

Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study.

BACKGROUND: The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown. AIMS: To determine the effects of RTD on brain 5-HT(2) receptors using positron emission tomography (PET) and (18)F-labelled setoperone. METHOD: Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days. RESULTS: The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT(2) receptor binding in various cortical regions following the RTD session. CONCLUSIONS: When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT(2) receptors, these findings suggest that a decrease in 5-HT(2) binding following RTD might be an adaptive response that provides protection against depressive symptoms.

Adult↗

PubMed2001

Neural sources involved in auditory target detection and novelty processing: an event-related fMRI study.

We used event-related functional magnetic resonance imaging (erfMRI) techniques to examine the cerebral sites involved with target detection and novelty processing of auditory stimuli. Consistent with the results from a recent erfMRI study in the visual modality, target processing was associated with activation bilaterally in the anterior superior temporal gyrus, inferior and middle frontal gyrus, inferior and superior parietal lobules, anterior and posterior cingulate, thalamus, caudate, and the amygdala/hippocampal complex. Analyses of the novel stimuli revealed activation bilaterally in the inferior frontal gyrus, insula, inferior parietal lobule, and in the inferior, middle, and superior temporal gyri. These data suggest that the scalp recorded event-related potentials (e.g., N2 and P3) elicited during similar tasks reflect an ensemble of neural generators located in spatially remote cortical areas.

Acoustic Stimulation↗

PubMed2000

Reaction time, symptom profiles and course of illness in schizophrenia.

Schizophrenic subjects perform more poorly than normal controls on a wide range of neurocognitive tasks. Some studies suggest that patients with persistent illness may have different patterns of cognitive deficits and different associations between cognitive deficits and symptom profiles compared with patients with fluctuating illness. This study uses simple reaction time, choice reaction time and Stroop tasks to explore the relationship between reaction time and symptom profiles in patients with fluctuating illness (n=24), persistent illness (n=17) and normal controls (n=16). We tested the hypothesis that in patients with persistent illness, psychomotor poverty is associated with impaired initiation of activity, and that disorganization is associated with impaired selection in both persistent and fluctuating illness. There were no differences in the severity of symptoms in the patient groups. In the simple reaction time task, patients with persistent illness performed more poorly than patients with fluctuating illness and controls. Both patient groups performed more poorly than controls in the choice reaction time tasks. Psychomotor poverty was associated with simple reaction time in patients with persistent symptoms. Disorganization was associated with poorer performance on the choice reaction time task in both patient groups. These results suggest the possibility that persistent illness, negative symptoms, and impaired initiation may reflect dysfunction associated with enduring structural abnormalities. In the case of impaired selection processes and disorganization, our data indicate that these abnormalities occur in both persistent and fluctuating illness. This suggests that enduring brain damage might create a predisposition to impaired selection and disorganization, but these clinical features can also arise as a result of transient biochemical imbalance.

Adult↗

PubMed2000

An event-related potential investigation of response inhibition in schizophrenia and psychopathy.

BACKGROUND: Schizophrenia and psychopathy are both characterized by impulsive, poorly planned behavior. This behavior may originate from a weak or poorly coordinated response inhibition system. We tested the hypothesis that schizophrenia and psychopathy are associated with abnormal neural processing during the suppression of inappropriate responses. METHODS: The participants were schizophrenic patients, nonpsychotic psychopaths, and nonpsychotic, nonpsychopathic control subjects (defined by the Hare Psychopathy Checklist-Revised), all incarcerated in a maximum security psychiatric facility. We recorded behavioral responses and event-related potentials (ERPs) during a Go/No Go task. RESULTS: Schizophrenic patients made more errors of commission than did the nonpsychopathic offenders. As expected, the nonpsychopathic nonpsychotic participants showed greater frontal ERP negativity (N275) to the No Go stimuli than to the Go stimuli. This effect was small in the schizophrenic patients and absent in the psychopaths. For the nonpsychopaths, the P375 ERP component was larger on Go than on No Go trials, a difference that was absent in schizophrenic patients and in the opposite direction in psychopaths. CONCLUSIONS: These findings support the hypothesis that the neural processes involved in response inhibition are abnormal in both schizophrenia and psychopathy; however, the nature of these processes appears to be different in the two disorders.

Adolescent↗

PubMed2000

Brain serotonin2 receptors in major depression: a positron emission tomography study.

BACKGROUND: Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone). METHODS: Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis. RESULTS: There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels. CONCLUSION: This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.

Adult↗