Biomedical subjects

John Suckling

Publications and source records attributed to John Suckling.

At least 19 recordsLinked to original sources

PubMed2006

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia.

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

Adult↗

PubMed2006

Evidence that brain tissue volumes are associated with HVA reactivity to metabolic stress in schizophrenia.

BACKGROUND: Although liability to psychosis is thought to have its origins in cerebral alterations, expressed as cerebral grey and white matter loss, less is known about the degree to which such vulnerabilities impact on functional parameters, in particular altered stress reactivity. Breier et al. [Breier, A., Davis, O.R., Buchanan, R.W., Moricle, L.A., Munson, R.C., 1993b. Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume. Arch. Gen. Psychiatry 50(7), 541-550] reported that lower prefrontal cortex volume was associated with altered metabolic stress response, but this finding has never been replicated. METHODS: Thirty-one patients with psychosis underwent structural magnetic resonance imaging scanning and a metabolic stress paradigm (glucoprivic 2-deoxyglucose (2DG) condition versus placebo condition) that yielded information on plasma homovanillic acid (HVA) reactivity. Total cerebral tissue volumes were derived from automated segmentation procedures. Associations between metabolic stress and tissue volumes (as well as their interactions) on the one hand, and plasma HVA level on the other, were investigated using multilevel random regression techniques. RESULTS: Analysis revealed a significant increase in plasma HVA over time in the 2DG condition. The increase in HVA in the stress condition was stronger in patients with lower grey and white matter volumes. There was no significant interaction between metabolic stress and CSF volume. CONCLUSION: Lower grey and white matter volumes in schizophrenia are associated with a dysregulated dopaminergic/noradrenergic mediated stress response. These findings may support the hypothesis that alterations in cortico-subcortical connections affect psychosis susceptibility through an altered stress response.

Adolescent↗

PubMed2006

Prediction of clinicopathologic response of breast cancer to primary chemotherapy at contrast-enhanced MR imaging: initial clinical results.

PURPOSE: To prospectively document changes in contrast agent kinetics in patients with primary breast cancer treated with systemic chemotherapy after one or two cycles and to determine whether kinetic measures can be used to predict final clinicopathologic response. MATERIALS AND METHODS: Institutional committees on clinical research and ethics approval and patient consent were obtained. Dynamic magnetic resonance (MR) examinations were performed in 25 women with primary breast cancer before treatment and after the first (n = 21) and second (n = 15) cycle of neoadjuvant chemotherapy. Kinetic parameters (transfer constant, leakage space, and rate constant) were derived for whole tumor regions of interest. Changes in histogram distributions of pixel data (median value and range) and MR imaging-derived size were correlated with final clinical and histologic response by using nonparametric methods. Receiver operating characteristic (ROC) analysis of tumor size and transfer constant changes were used to identify patients in whom no benefit was gained from chemotherapy. RESULTS: After the first cycle of treatment, 12 of 14 clinical responders showed decreases in tumor size, and six of seven nonresponders showed increases or no change in tumor size (P < .001). Transfer constant changes did not differ between responders and nonresponders for either clinical or pathologic assessments. After two cycles of treatment, there were tumor size increases in five of six nonresponders compared with decreases in eight of nine responders (P < .001). Reductions in transfer constant range were also observed in responders for both clinical and pathologic assessments (P = .008 and .02, respectively). No other kinetic parameter change predicted response. Size and transfer constant range were equally accurate for predicting the absence of pathologic response after two cycles of treatment (sensitivity, specificity, and area under ROC curve were 100%, 90%, and 0.93, respectively, for size and 100%, 75%, and 0.94, respectively, for transfer constant range). CONCLUSION: Reductions in MR imaging-determined size of the primary tumor best predict clinicopathologic response of breast cancer after one cycle of neoadjuvant chemotherapy. Transfer constant and size changes are equally sensitive in the identification of patients who would gain no clinical or pathologic benefit after two cycles of treatment.

Adult↗

PubMed2006

Gray matter abnormalities associated with duration of untreated psychosis.

PURPOSE: A long duration of untreated psychosis (DUP) is associated with relatively poor clinical and social outcomes. In order to identify whether an anatomically mediated mechanism may give rise to poorer outcomes, it is important to identify whether a long DUP is associated with greater brain structural abnormalities. METHOD: 81 patients with first-episode psychosis (schizophrenia, affective, and other psychoses) were scanned using high resolution Magnetic Resonance Imaging. DUP was defined as the number of days between first onset of psychotic symptoms and first contact with mental health services. High-resolution MRI images and voxel-based methods of image analysis were used to investigate brain structure in these patients. RESULTS: Longer DUP was associated with gray matter reductions in left middle and inferior temporal, left occipital and left fusiform cortices, and with gray matter excess of the left basal ganglia. All findings remained significant when co-varying for exposure to antipsychotic treatment. CONCLUSIONS: Temporal gray matter reductions are more marked in patients with a long DUP. This could reflect a progressive pathological process that is active prior to treatment. Alternatively, these abnormalities could be associated with a more insidious onset of illness and a later presentation to services.

Adolescent↗

PubMed2006

A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs.

Small-world properties have been demonstrated for many complex networks. Here, we applied the discrete wavelet transform to functional magnetic resonance imaging (fMRI) time series, acquired from healthy volunteers in the resting state, to estimate frequency-dependent correlation matrices characterizing functional connectivity between 90 cortical and subcortical regions. After thresholding the wavelet correlation matrices to create undirected graphs of brain functional networks, we found a small-world topology of sparse connections most salient in the low-frequency interval 0.03-0.06 Hz. Global mean path length (2.49) was approximately equivalent to a comparable random network, whereas clustering (0.53) was two times greater; similar parameters have been reported for the network of anatomical connections in the macaque cortex. The human functional network was dominated by a neocortical core of highly connected hubs and had an exponentially truncated power law degree distribution. Hubs included recently evolved regions of the heteromodal association cortex, with long-distance connections to other regions, and more cliquishly connected regions of the unimodal association and primary cortices; paralimbic and limbic regions were topologically more peripheral. The network was more resilient to targeted attack on its hubs than a comparable scale-free network, but about equally resilient to random error. We conclude that correlated, low-frequency oscillations in human fMRI data have a small-world architecture that probably reflects underlying anatomical connectivity of the cortex. Because the major hubs of this network are critical for cognition, its slow dynamics could provide a physiological substrate for segregated and distributed information processing.

Adult↗

PubMed2006

Permutation testing of orthogonal factorial effects in a language-processing experiment using fMRI.

The block-paradigm of the Functional Image Analysis Contest (FIAC) dataset was analysed with the Brain Activation and Morphological Mapping software. Permutation methods in the wavelet domain were used for inference on cluster-based test statistics of orthogonal contrasts relevant to the factorial design of the study, namely: the average response across all active blocks, the main effect of speaker, the main effect of sentence, and the interaction between sentence and speaker. Extensive activation was seen with all these contrasts. In particular, different vs. same-speaker blocks produced elevated activation in bilateral regions of the superior temporal lobe and repetition suppression for linguistic materials (same vs. different-sentence blocks) in left inferior frontal regions. These are regions previously reported in the literature. Additional regions were detected in this study, perhaps due to the enhanced sensitivity of the methodology. Within-block sentence suppression was tested post-hoc by regression of an exponential decay model onto the extracted time series from the left inferior frontal gyrus, but no strong evidence of such an effect was found. The significance levels set for the activation maps are P-values at which we expect <1 false-positive cluster per image. Nominal type I error control was verified by empirical testing of a test statistic corresponding to a randomly ordered design matrix. The small size of the BOLD effect necessitates sensitive methods of detection of brain activation. Permutation methods permit the necessary flexibility to develop novel test statistics to meet this challenge.

Algorithms↗

PubMed2006

Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces.

Happy facial expressions are innate social rewards and evoke a response in the striatum, a region known for its role in reward processing in rats, primates and humans. The cannabinoid receptor 1 (CNR1) is the best-characterized molecule of the endocannabinoid system, involved in processing rewards. We hypothesized that genetic variation in human CNR1 gene would predict differences in the striatal response to happy faces. In a 3T functional magnetic resonance imaging (fMRI) scanning study on 19 Caucasian volunteers, we report that four single nucleotide polymorphisms (SNPs) in the CNR1 locus modulate differential striatal response to happy but not to disgust faces. This suggests a role for the variations of the CNR1 gene in underlying social reward responsivity. Future studies should aim to replicate this finding with a balanced design in a larger sample, but these preliminary results suggest neural responsivity to emotional and socially rewarding stimuli varies as a function of CNR1 genotype. This has implications for medical conditions involving hypo-responsivity to emotional and social stimuli, such as autism.

Brain Mapping↗

PubMed2005

The structural brain correlates of neurological soft signs in healthy individuals.

It has yet to be established whether neurological soft signs (NSS), which include poor motor coordination, sensory perceptual difficulties and difficulties in sequencing of complex motor tasks, result from specific or diffuse brain structural abnormalities. Studying the neuroanatomical basis of NSS in healthy individuals may help to identify which brain areas are specifically associated with these signs, while excluding the potential confounding effects of psychiatric and neurological disorders. We investigated the relationship between brain structure and NSS in 43 healthy individuals, using the Neurological Evaluation Scale for neurological assessment, and high resolution MRI and voxel-based methods of image analysis to investigate brain structure. Higher rates of NSS were associated with a reduction of inferior frontal gyrus, middle and superior temporal gyrus, and anterior cingulate gyrus. It is of note that in a previous study of patients with psychosis we found that an excess of NSS was associated with a reduction of similar cortical areas. Therefore, we suggest that these cortical brain structural changes represent a common neuroanatomical substrate of NSS, across healthy individuals and patients with psychosis.

Adolescent↗

PubMed2005

Effects of ketamine on prefrontal and striatal regions in an overt verbal fluency task: a functional magnetic resonance imaging study.

RATIONALE: Glutamatergic dysfunction at N-methyl-D: -aspartate (NMDA) receptors has been proposed as a neurochemical model for schizophrenia. A key feature of this disorder is impairments in cognitive function. OBJECTIVE: The present study sought to investigate the effects of ketamine, an NMDA antagonist, on the performance and neural correlates of verbal fluency, a task that engages executive function. METHODS: Ten healthy dextral male volunteers received intravenous placebo normal saline or ketamine (bolus of 0.23 mg/kg and infusion of 0.65 mg/kg), administered in a double-blind, randomized order, during two functional magnetic resonance imaging sessions. During scanning, subjects performed a verbal fluency task. Two levels of cognitive load were examined in the task, and overt responses were acquired in order to measure subject performance on-line. RESULTS: Ketamine induced symptoms in the healthy individuals comparable to an acute psychotic state. Although ketamine did not significantly impair task performance relative to placebo, an interaction of task demand with ketamine was observed in the anterior cingulate, prefrontal, and striatal regions. CONCLUSIONS: The behavioural and functional effects of ketamine during verbal fluency in healthy individuals were comparable to those evident in patients with schizophrenia. The findings support a role for glutamatergic dysfunction in the pathophysiology of schizophrenia.

Corpus Striatum↗

PubMed2005

Age and cholinergic effects on hemodynamics and functional coherence of human hippocampus.

Aging is normally associated with increased predictability of neurophysiological processes. To test the related prediction of age-related increase in the Hurst exponent, H, of functional MRI time series, and its possible cholinergic mechanisms, two groups of healthy participants (old [mean age = 65 years]; young [mean age = 22 years]; N = 11 per group) were scanned twice at rest, following placebo and a muscarinic receptor antagonist, scopolamine 0.3 mg. Older age was associated with significant increase in H of fMRI time series in bilateral hippocampus. Similarly, scopolamine was associated with increased H in left hippocampus; and there was an age-by-drug interaction in medial temporal lobe whereby older participants specifically had increased H following scopolamine. Scopolamine also enhanced fronto-hippocampal low-frequency coherence, and this could be correlated with its effect on hippocampal H. Thus, increased persistence of hippocampal dynamics in older subjects is demonstrable by resting fMRI; scopolamine mimics these effects, especially in older subjects, implying a cholinergic mechanism for age-related change; and cholinergic effects on hippocampal dynamics are associated with enhanced functional connectivity between frontal cortex and hippocampus.

Acetylcholine↗

PubMed2005

Explicit and implicit facial affect recognition in manic and depressed States of bipolar disorder: a functional magnetic resonance imaging study.

BACKGROUND: The pathophysiology of abnormal mood states-mania and depression-in patients with bipolar disorder remains unclear. Facial affect processing paradigms are an effective way of studying behavioral and functional magnetic resonance imaging (fMRI) correlates of affective disorders. METHODS: We used a factorial design to measure the neural correlates of tasks, tapping explicit and implicit recognition of sad, fearful, and happy facial expressions using event-related fMRI paradigms in three groups of participants: eight bipolar depressed patients, eight bipolar manic patients, and eight control subjects. RESULTS: Depressed and manic patients exhibited overactivated responses to fearful faces, as well as to mood-incongruent facial expressions, with the depressed group exhibiting overactivity in fronto-striato-thalamic systems in response to happy faces and the manic group exhibiting overactivity in the fusiform gyrus in response to sad faces. For manic patients, task type also affected the neural response to sad faces, with the corticolimbic regions showing overactivation for implicit processing and underactivation for explicit processing. CONCLUSIONS: Depressed and manic patients exhibited abnormal neural responses to sad, fearful, and happy facial expressions. Additionally, the attentional level of sad facial affect processing has important consequences for abnormalities of amygdala and cingulate activation in manic patients.

Adult↗

PubMed2005

Undirected graphs of frequency-dependent functional connectivity in whole brain networks.

We explored properties of whole brain networks based on multivariate spectral analysis of human functional magnetic resonance imaging (fMRI) time-series measured in 90 cortical and subcortical subregions in each of five healthy volunteers studied in the (no-task) resting state. We note that undirected graphs representing conditional independence between multivariate time-series can be more readily approached in the frequency domain than the time domain. Estimators of partial coherency and normalized partial mutual information phi, an integrated measure of partial coherence over an arbitrary frequency band, are applied. Using these tools, we replicate the prior observations that bilaterally homologous brain regions tend to be strongly connected and functional connectivity is generally greater at low frequencies [0.0004, 0.1518 Hz]. We also show that long-distance intrahemispheric connections between regions of prefrontal and parietal cortex were more salient at low frequencies than at frequencies greater than 0.3 Hz, whereas many local or short-distance connections, such as those comprising segregated dorsal and ventral paths in posterior cortex, were also represented in the graph of high-frequency connectivity. We conclude that the partial coherency spectrum between a pair of human brain regional fMRI time-series depends on the anatomical distance between regions: long-distance (greater than 7 cm) edges represent conditional dependence between bilaterally symmetric neocortical regions, and between regions of prefrontal and parietal association cortex in the same hemisphere, are predominantly subtended by low-frequency components.

Brain↗

PubMed2005

Functional disconnectivity of the medial temporal lobe in Asperger's syndrome.

BACKGROUND: Autistic spectrum disorders (ASD) are neurodevelopmental conditions that may be caused by abnormal connectivity between brain regions constituting neurocognitive networks for specific aspects of social cognition. METHODS: We used three-way multidimensional scaling of regionally parcellated functional magnetic resonance imaging (fMRI) data to explore the hypothesis of abnormal functional connectivity in people with ASD. Thirteen high-functioning individuals with Asperger's syndrome and 13 healthy volunteers were scanned during incidental processing of fearful facial expressions. RESULTS: Using permutation tests for inference, we found evidence for significant abnormality of functional integration of amygdala and parahippocampal gyrus (p < .05, false discovery rate [FDR] corrected) in people with Asperger's syndrome. There were less salient abnormalities in functional connectivity of anterior cingulate, inferior occipital, and inferior frontal cortex, but there was no significant difference between groups in whole brain functional connectivity. CONCLUSIONS: We conclude there is evidence that functional connectivity of medial temporal lobe structures specifically is abnormal in people with Asperger's syndrome during fearful face processing.

Adult↗

PubMed2005

Frontotemporal white matter changes in amyotrophic lateral sclerosis.

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

Adult↗

PubMed2005

Fractional Gaussian noise, functional MRI and Alzheimer's disease.

Fractional Gaussian noise (fGn) provides a parsimonious model for stationary increments of a self-similar process parameterised by the Hurst exponent, H, and variance, sigma2. Fractional Gaussian noise with H < 0.5 demonstrates negatively autocorrelated or antipersistent behaviour; fGn with H > 0.5 demonstrates 1/f, long memory or persistent behaviour; and the special case of fGn with H = 0.5 corresponds to classical Gaussian white noise. We comparatively evaluate four possible estimators of fGn parameters, one method implemented in the time domain and three in the wavelet domain. We show that a wavelet-based maximum likelihood (ML) estimator yields the most efficient estimates of H and sigma2 in simulated fGn with 0 < H < 1. Applying this estimator to fMRI data acquired in the "resting" state from healthy young and older volunteers, we show empirically that fGn provides an accommodating model for diverse species of fMRI noise, assuming adequate preprocessing to correct effects of head movement, and that voxels with H > 0.5 tend to be concentrated in cortex whereas voxels with H < 0.5 are more frequently located in ventricles and sulcal CSF. The wavelet-ML estimator can be generalised to estimate the parameter vector beta for general linear modelling (GLM) of a physiological response to experimental stimulation and we demonstrate nominal type I error control in multiple testing of beta, divided by its standard error, in simulated and biological data under the null hypothesis beta = 0. We illustrate these methods principally by showing that there are significant differences between patients with early Alzheimer's disease (AD) and age-matched comparison subjects in the persistence of fGn in the medial and lateral temporal lobes, insula, dorsal cingulate/medial premotor cortex, and left pre- and postcentral gyrus: patients with AD had greater persistence of resting fMRI noise (larger H) in these regions. Comparable abnormalities in the AD patients were also identified by a permutation test of local differences in the first-order autoregression AR(1) coefficient, which was significantly more positive in patients. However, we found that the Hurst exponent provided a more sensitive metric than the AR(1) coefficient to detect these differences, perhaps because neurophysiological changes in early AD are naturally better described in terms of abnormal salience of long memory dynamics than a change in the strength of association between immediately consecutive time points. We conclude that parsimonious mapping of fMRI noise properties in terms of fGn parameters efficiently estimated in the wavelet domain is feasible and can enhance insight into the pathophysiology of Alzheimer's disease.

Aged↗

PubMed2005

Neurophysiological architecture of functional magnetic resonance images of human brain.

We investigated large-scale systems organization of the whole human brain using functional magnetic resonance imaging (fMRI) data acquired from healthy volunteers in a no-task or 'resting' state. Images were parcellated using a prior anatomical template, yielding regional mean time series for each of 90 regions (major cortical gyri and subcortical nuclei) in each subject. Significant pairwise functional connections, defined by the group mean inter-regional partial correlation matrix, were mostly either local and intrahemispheric or symmetrically interhemispheric. Low-frequency components in the time series subtended stronger inter-regional correlations than high-frequency components. Intrahemispheric connectivity was generally related to anatomical distance by an inverse square law; many symmetrical interhemispheric connections were stronger than predicted by the anatomical distance between bilaterally homologous regions. Strong interhemispheric connectivity was notably absent in data acquired from a single patient, minimally conscious following a brainstem lesion. Multivariate analysis by hierarchical clustering and multidimensional scaling consistently defined six major systems in healthy volunteers-- corresponding approximately to four neocortical lobes, medial temporal lobe and subcortical nuclei- - that could be further decomposed into anatomically and functionally plausible subsystems, e.g. dorsal and ventral divisions of occipital cortex. An undirected graph derived by thresholding the healthy group mean partial correlation matrix demonstrated local clustering or cliquishness of connectivity and short mean path length compatible with prior data on small world characteristics of non-human cortical anatomy. Functional MRI demonstrates a neurophysiological architecture of the normal human brain that is anatomically sensible, strongly symmetrical, disrupted by acute brain injury, subtended predominantly by low frequencies and consistent with a small world network topology.

Adult↗

PubMed2005

Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study.

Typical antipsychotic drugs act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors. Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors, and a high degree of occupancy of the serotoninergic receptors 5-HT2A. Whether these different pharmacological actions produce different effects on brain structure remains unclear. We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based, nonrandomized sample of patients at the first psychotic episode. Subjects were recruited as part of a large epidemiological study (AESOP: aetiology and ethnicity in schizophrenia and other psychoses). We evaluated 22 drug-free patients, 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics. We used high-resolution MRI and voxel-based methods of image analysis. The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes. However, typicals seem to affect more extensively the basal ganglia (enlargement of the putamen) and cortical areas (reductions of lobulus paracentralis, anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula, and precuneus), while atypical antipsychotics seem particularly associated with enlargement of the thalami. These changes are likely to reflect the effect of antipsychotics on the brain, as there were no differences in duration of illness, total symptoms scores, and length of treatment among the groups. In conclusion, we would like to suggest that even after short-term treatment, typical and atypical antipsychotics may affect brain structure differently.

Adolescent↗

PubMed2005

Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency.

OBJECTIVE: Impaired prefrontal cortical function is regarded as a central feature of schizophrenia. Although many neuroimaging studies have found evidence of abnormal prefrontal activation when patients with schizophrenia perform cognitive tasks, the extent to which this abnormality depends on the presence of active psychotic symptoms and on the demands of the task is unclear. The authors tested the hypothesis that prefrontal functional abnormalities in schizophrenia would be more evident in patients with active psychosis than in patients who were in remission and would become more apparent in the face of increasing task demands. METHOD: The authors used functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity during a paced letter verbal fluency task in three groups of subjects: acutely psychotic patients with schizophrenia, schizophrenia patients in remission, and healthy volunteers. Online subject performance was measured by utilizing a clustered fMRI acquisition sequence that allowed overt verbal responses to be made in the relative absence of scanner noise. RESULTS: Patients with schizophrenia showed less activation than the healthy comparison subjects in the anterior cingulate and the inferior frontal and right middle frontal cortices, independent of psychotic state and task demand. Acutely psychotic patients showed less activation than the healthy comparison subjects, but these differences were less marked than the differences between the patients in remission and the healthy comparison subjects. Acutely psychotic patients had less activation than the comparison subjects in the anterior cingulate but no significant difference in lateral prefrontal activation. Increasing task demand led to greater anterior cingulate and middle frontal activation in patients with active psychosis than in patients in remission. CONCLUSIONS: Schizophrenia is associated with impaired prefrontal function, but its manifestation depends on the severity of psychotic symptoms and the level of task difficulty.

Adult↗