Biomedical subjects

Stephen M Lawrie

Publications and source records attributed to Stephen M Lawrie.

At least 19 recordsLinked to original sources

PubMed2026

Neurometabolites and Antipsychotic Response in Psychosis: A Mega-Analysis.

IMPORTANCE: Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. OBJECTIVE: To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. DATA SOURCES: Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. STUDY SELECTION: Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. DATA EXTRACTION AND SYNTHESIS: Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses. MAIN OUTCOMES AND MEASURES: Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia. RESULTS: The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P = .02), glutamate plus glutamine (Glass Δ = 0.29; P = .002), choline (Glass Δ = 0.22; P = .03), and myo-inositol (Glass Δ = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. CONCLUSIONS AND RELEVANCE: These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

Humans↗

PubMed2006

Prefrontal cortical functional abnormality in major depressive disorder: a stereotactic meta-analysis.

OBJECTIVE: First, the objective was to test the hypothesis that prefrontal cortical regions most often reported to be maximally abnormal in studies of major depressive disorder, correspond to those regions reported maximally active when healthy subjects engage in diverse emotional tasks. Second, the objective was to determine whether such regions are reported typically to be either over or under-active. METHOD: Medline and Embase were used to search for neuroimaging studies of major depressive disorder from 1990 to 2005. Forty-two original studies using voxel based techniques were included, and compared with data from our previous meta-analysis on healthy subjects which included one hundred and eighty-one original studies [Steele, J.D., Lawrie, S.M., 2004b. Segregation of cognitive and emotional function in the prefrontal cortex: a stereotactic meta-analysis. Neuroimage 21, 868-875]. RESULTS: The medial prefrontal cortex is the region reported maximally abnormal most often when healthy subjects experience emotion. The region is centred on Broadmans Area (BA) 32 but extends into BA 25. Two further clusters of reported loci were identified in the lateral prefrontal cortex: one in the lateral orbitofrontal region reported active when healthy subjects experience emotion (BA 47); the other centred on a dorsolateral region (BA 46 and 9) associated with cognitive tasks. No reporting bias for overactivity or underactivity was identified. LIMITATIONS: This study pooled data from diverse studies deliberately. There were insufficient numbers of original studies to support sub-group analyses. CONCLUSIONS: Despite the variability of reports in the literature, activity reported to be abnormal in depressive disorder is particularly localised to those brain regions that represent the substrate for normal emotional experience in healthy subjects.

Brain Mapping↗

PubMed2006

Grey matter changes can improve the prediction of schizophrenia in subjects at high risk.

BACKGROUND: We hypothesised that subjects at familial high risk of developing schizophrenia would have a reduction over time in grey matter, particularly in the temporal lobes, and that this reduction may predict schizophrenia better than clinical measurements. METHODS: We analysed magnetic resonance images of 65 high-risk subjects from the Edinburgh High Risk Study sample who had two scans a mean of 1.52 years apart. Eight of these 65 subjects went on to develop schizophrenia an average of 2.3 years after their first scan. RESULTS: Changes over time in the inferior temporal gyrus gave a 60% positive predictive value (likelihood ratio >10) of developing schizophrenia compared to the overall 13% risk in the cohort as a whole. CONCLUSION: Changes in grey matter could be used as part of a predictive test for schizophrenia in people at enhanced risk for familial reasons, particularly for positive predictive power, in combination with other clinical and cognitive predictive measures, several of which are strong negative predictors. However, because of the limited number of subjects, this test requires independent replication to confirm its validity.

Brain↗

PubMed2006

Emotional memory in schizophrenia.

Emotionally arousing scenes are better remembered than neutral ones. The biological basis of this emotional memory effect has been studied in lesion and neuro-imaging studies and depends upon an interaction between the amygdala and medial temporal lobe memory systems including the hippocampus. This study sought to investigate whether patients with schizophrenia had performance deficits on emotional memory tasks consistent with abnormal amygdala function. Patients with schizophrenia and matched control subjects were shown scenes with negative, positive and neutral emotional content. Subjects rated the slides according to how emotionally arousing they found them and then performed surprise memory tests at 10 min (recall) and 3 weeks (recall and recognition). Subjects with schizophrenia did not differ from control subjects in their ratings of the slides. However, patients showed a significant loss of the emotional enhancement of recognition memory for both negative and positive scenes. In addition, patients showed an overall deficit in recall memory, with a selective impairment in recall of the most arousing negative slides. These findings are consistent with the view that medial temporal lobe and in particular amygdala function is abnormal in schizophrenia.

Adult↗

PubMed2006

A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms.

NRG1, encoding neuregulin 1, is a susceptibility gene for schizophrenia, but no functional mutation causally related to the disorder has yet been identified. Here we investigate the effects of a variant in the human NRG1 promoter region in subjects at high risk of schizophrenia. We show that this variant is associated with (i) decreased activation of frontal and temporal lobe regions, (ii) increased development of psychotic symptoms and (iii) decreased premorbid IQ.

Adult↗

PubMed2006

Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis.

BACKGROUND: There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. METHODS: In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. RESULTS: The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. CONCLUSIONS: The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.

Adolescent↗

PubMed2006

Structural correlates of intellectual impairment and autistic features in adolescents.

Intellectual disability, a common but under-researched condition, is strongly associated with autism spectrum disorders (ASD). Although studies have investigated the neural correlates of intelligence quotient (IQ) and ASD in intellectually unimpaired subjects, these issues have not been addressed in intellectually impaired subjects. We studied 63 intellectually disabled adolescents receiving additional learning support and 72 controls using whole brain tissue volumes extracted from native space and voxel-based morphometry (VBM) in normalised space. We applied a qualitative and quantitative review of VBM preprocessing and modified the optimised method to establish optimum co-registration of the brains in normalised space. We report tissue density differences at cluster level with adjustment for underlying smoothness. Individuals with intellectual disability had smaller total white matter and total brain tissue volumes than controls, as well as reduced grey matter density in the right cerebellar hemisphere and left temporo-parietal cortex, and reduced white matter density in the posterior corpus callosum. Intellectually disabled subjects were additionally subgrouped according to their degree of reported autistic features. Reduced grey matter density was detected in the thalamus of subjects with autistic features scoring within the pervasive developmental disorder range as compared to subjects below the threshold for ASD, and increased white matter density was detected in the left superior temporal gyrus of subjects scoring above the threshold for autism as compared to subjects below the threshold for ASD.

Adolescent↗

PubMed2006

Brain-behaviour relationships in people at high genetic risk of schizophrenia.

The brain is known to be structurally abnormal in schizophrenia, with replicated findings between anatomical deficits and some dysfunctions. These structure-function associations have, however, only very rarely been studied in relatives at risk of schizophrenia. We studied the relationships between structure and schizotypal features (assessed using RISC and SIS) and verbal learning and memory (measured using RAVLT) in relatives at high risk of developing schizophrenia and normal controls. Since these behavioural test scores are strong predictors of schizophrenia in the Edinburgh High Risk Study, we hypothesised that these relationships would differ between those high-risk subjects who will develop schizophrenia from those who will not. We performed multiple regressions of the grey matter segments of the subjects and controls, produced using grey matter optimised, voxel-based morphometry, with their RAVLT, SIS and RISC scores in SPM. Where significant relationships were found, we used SPSS to test for subject group by behavioural score interactions. In those high-risk subjects who became ill, grey matter density (GMD) was significantly correlated with RISC in the left superior temporal gyrus. In subjects who remained well, SIS was significantly correlated with GMD in the right pulvinar. Across the whole HR group, GMD in the right medial dorsal thalamic nucleus was significantly correlated with RAVLT. In those subjects who developed symptoms, RAVLT significantly correlated with GMD in right parahippocampal gyrus whereas in those who became ill, significant correlations existed bilaterally in the pulvinar. These results suggest complex and changing patterns of structural-functional relationships in those subjects at high-risk of schizophrenia.

Adolescent↗

PubMed2006

Parcellating the temporal lobes from magnetic resonance images using generic software in subjects at high risk of developing schizophrenia.

A number of reliable techniques have been described that can parcellate temporal neo-cortex from MRI images to preserve topographical characteristics of individual brains, but these tend to use in-house software. We describe here an adaptation of the methods previously described by Kim et al. [Kim, J.J., Crespo-Facorro, B., Andreasen, N.C., O'Leary, D.S., Zhang, B., Harris, G., Magnotta, V.A., 2000. An MRI-based parcellation method for the temporal lobe. Neuroimage 11, 271-288], but utilising commercially and, therefore, generally available software. Using Analyze, we traced individual sulci and identified coronal bounding planes, and used a combination of three orthogonal plane views, manual limit tracing and semi-automated edge detection to parcellate 13 sub-regions of temporal neo-cortex from sets of serial coronal slices. We applied this technique to the baseline scans of the first seven subjects in the Edinburgh High Risk Study (EHRS) who developed schizophrenia, and a matched group of healthy controls, to see if temporal lobe sub-regional volumes could predict the onset of schizophrenia. Two relatively inexperienced raters developed these techniques in a short time period, and intra-rater intra-class correlation coefficients (ICC) ranged from 0.56 to 0.99, while the mean inter-rater ICC was 0.90 (range 0.55-0.99). There were, however, no significant differences in temporal lobe sub-regional volumes between the two groups we examined. We have, therefore, developed a reliable parcellation technique that requires relatively little training. It is, however, a laborious process, and it remains uncertain whether it is more sensitive to early disease processes in pre-schizophrenia than are other image-analysis techniques.

Adolescent↗

PubMed2006

Automated computation of the Gyrification Index in prefrontal lobes: methods and comparison with manual implementation.

In this paper, we introduce an automated method of calculating Gyrification Index (GI), a measure of cortical folding. Automated GI (A-GI) is an in vivo GI implementation applied to MRI T1 weighted scans and is designed as an extension to the SPM analysis package. The A-GI tool is unbiased in its application, and is unlimited in the size of test cohort to which it can be applied. In comparison to manual methods, A-GI substantially reduces the time costs and improves repeatability. The current A-GI implementation is limited to analysis of prefrontal lobes, but an extension to provide whole brain A-GI is under consideration. In determination of the GI inner contour, A-GI traces high spatial frequencies typically missed in manual tracing, and thus, A-GI reports a high GI value. We examine the operation of this tool in two scan cohorts. We establish that the tool has good repeatability through its application to a cohort where 5 well individuals were scanned 5 times over a period of 6 months. This indicates that A-GI has low susceptibility to scanner noise and is not affected by the variability in brain representation given by repeat scans. We demonstrate replication of hand tracing results by comparisons with a manual GI study that has shown differences between high risk subjects who go on to develop schizophrenia and those who are at high risk but remain well. Direct scan by scan comparisons are carried out between manual and A-GI methods. In respect of scan orientation and coronal sampling, the methods differ, and these considerations contribute to a between methods right prefrontal ICC of 0.67 and left prefrontal ICC of 0.63. The replication results demonstrate that A-GI has discriminatory power equivalent to manual methods. A-GI is therefore a reliable measure of cortical folding that could be usefully applied to a number of MRI data sets of the brain in health and disease.

Frontal Lobe↗

PubMed2006

Functional imaging as a predictor of schizophrenia.

BACKGROUND: Prospective studies of young individuals at high risk of schizophrenia allow the investigation of whether neural abnormalities predate development of illness and, if present, have the potential to identify those who may become ill. METHODS: We studied young individuals with at least two relatives with the disorder. At baseline functional magnetic resonance imaging (fMRI) scan, none met criteria for any psychiatric disorder, but four subjects subsequently developed schizophrenia. We report the baseline functional imaging findings in these subjects performing a sentence completion task compared with normal control subjects (n = 21) and those at high risk with (n = 21) and without (n = 41) psychotic symptoms who have not developed the disorder. RESULTS: High-risk subjects who became ill demonstrated increased activation of the parietal lobe, decreased activation of the anterior cingulate, and smaller increases in activation with increasing task difficulty in the right lingual gyrus and bilateral temporal regions. The hypothesized predictive power of parietal activation was supported only in combination with lingual gyrus activity, which gave a positive predictive value in this sample of .80. CONCLUSIONS: Although these findings should be considered cautiously, as only four subjects who had an fMRI scan subsequently became ill, they suggest functional abnormalities are present in high-risk subjects who later became ill, which distinguish them not only from normal control subjects but also those at high risk who had not developed the disorder. These differences are detectable with fMRI and may have clinical utility.

Adolescent↗

PubMed2006

Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure.

Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect.

Algorithms↗

PubMed2006

Neuropsychological performance over time in people at high risk of developing schizophrenia and controls.

BACKGROUND: Neuropsychological assessments of relatives of schizophrenics have shown subtle impairments in verbal memory, executive and intellectual function, which are stable in those beyond the age of maximum risk for the disorder. We sought to: (1) determine baseline neurocognitive predictors of psychosis, and (2) compare performance over time between relatives within the age of maximum risk, and controls. METHODS: (1) and (2) were examined in 118 individuals at familial high risk of schizophrenia (HR) and 30 controls (C), using one-way analyses of variance (ANOVAs) and repeated measures analyses of covariance (ANCOVAs), controlling for intelligence quotient, time between and number of assessments, and correcting for multiple comparisons. RESULTS: HR who became ill (n = 13) performed nonsignificantly less well at baseline than HR who did not (n = 105) on a test of verbal learning (t(109) = 2.1, p = .03). Across assessments, C performed significantly better than the entire HR group on immediate (F(3,133) = 5.11, p = .002) and delayed (F(3,133) = 5.02, p = .002) story recall. There were no significant interactions of time by group. CONCLUSIONS: Results suggest greater verbal memory impairment in HR who go on to develop schizophrenia. Stable differences between groups over time suggest a trait deficit, which is relatively unaffected by the presence of psychotic symptoms and psychosis onset. Alternatively, small numbers may have precluded detection of group by time interactions.

Adult↗

PubMed2006

Event-related fMRI of word classification and successful word recognition in subjects at genetically enhanced risk of schizophrenia.

BACKGROUND: Verbal declarative memory is a core deficit in schizophrenia patients, seen to a lesser extent in unaffected biological relatives. Neuroimaging studies suggest volumetric differences and aberrant function in prefrontal and temporal regions in schizophrenia patients compared to controls. These deficits are also reflected in the small number of similar investigations in unaffected biological relatives. However, it is unclear the extent to which dysfunction is genetically mediated or a feature of the established illness. METHOD: Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation in 68 biological relatives of schizophrenia patients (of whom 27 experienced transient or isolated psychotic symptoms) and 21 controls during verbal classification and recognition. RESULTS: During word classification, the high-risk group showed a greater response relative to controls in the right inferior frontal gyrus. During correct recognition (relative to correct rejection), the high-risk group showed significantly greater response relative to controls in the right cerebellum. When the high-risk group was split into those with (HR+) and without (HR-) psychotic symptoms, the increased response in the right inferior frontal gyrus was only seen when the HR+ were compared to controls. The greater cerebellar response was seen when both HR groups were compared to controls. CONCLUSIONS: Activation increases in the right inferior frontal gyrus and cerebellum in high-risk subjects compared to controls during a relatively low-load memory task are likely to represent compensation for genetically mediated abnormalities. This is consistent with a leftward shift of the inverted 'U' load-response model of cognitive function in schizophrenia.

Adolescent↗

PubMed2006

Functional specialization within rostral prefrontal cortex (area 10): a meta-analysis.

One of the least well understood regions of the human brain is rostral prefrontal cortex, approximating Brodmann's area 10. Here, we investigate the possibility that there are functional subdivisions within this region by conducting a meta-analysis of 104 functional neuroimaging studies (using positron emission tomography/functional magnetic resonance imaging). Studies involving working memory and episodic memory retrieval were disproportionately associated with lateral activations, whereas studies involving mentalizing (i.e., attending to one's own emotions and mental states or those of other agents) were disproportionately associated with medial activations. Functional variation was also observed along a rostral-caudal axis, with studies involving mentalizing yielding relatively caudal activations and studies involving multiple-task coordination yielding relatively rostral activations. A classification algorithm was trained to predict the task, given the coordinates of each activation peak. Performance was well above chance levels (74% for the three most common tasks; 45% across all eight tasks investigated) and generalized to data not included in the training set. These results point to considerable functional segregation within rostral prefrontal cortex.

Algorithms↗

PubMed2005

Declarative memory in unaffected adult relatives of patients with schizophrenia: a systematic review and meta-analysis.

Despite evidence for diverse neuropsychological impairment in schizophrenia, verbal declarative memory has emerged as a core deficit in the disorder. Similar but less marked impairments have been demonstrated in unaffected biological relatives of patients with schizophrenia, but the nature and extent of the memory impairment in relatives compared to controls is unclear. We have conducted a systematic review and meta-analysis of the literature investigating declarative memory in unaffected biological relatives of schizophrenics and controls, with the aim of quantifying memory deficits in relatives. The standardised mean difference between groups was calculated for nine measures of declarative memory and two measures of intellectual ability, based on 21 studies of several hundred relatives of schizophrenics and controls. Unaffected relatives showed poorer performance relative to controls on all tests of memory examined. Small to moderate effect sizes, with overlapping 95% confidence intervals, were greatest on immediate (trial 1) list recall (0.65), followed by immediate (0.53) and delayed story recall (0.52). Verbal and general IQ showed smaller standardised mean differences as the latter tests, while the smallest standardised mean difference was shown on delayed visual recall (0.32). Results suggest greater deficits on tests of increasing memory load or which place demands on effective encoding processes but more studies with these tasks are needed. Investigation of sub-groups within these cohorts (e.g. age groups within or beyond the maximum age of risk) is recommended in order to identify deficits specific to the disease process.

Adult↗

PubMed2005

Empirical comparison of maximal voxel and non-isotropic adjusted cluster extent results in a voxel-based morphometry study of comorbid learning disability with schizophrenia.

We present an empirical comparison of cluster extent and maximal voxel results in a voxel-based morphometry (VBM) study of brain structure. The cluster extents are adjusted for underlying deviation from uniform smoothness. We implement this comparison on a four-group cohort that has previously shown evidence of a neuro-developmental component in schizophrenia (Moorhead, T.W.J., Job, D.E., Whalley, H.C., Sanderson, T.L., Johnstone, E.C. and Lawrie, S.M. 2004. Voxel-based morphometry of comorbid schizophrenia and learning disability: analyses in normalized and native spaces using parametric and nonparametric statistical methods. NeuroImage 22: 188-202.). We find that adjusted cluster extent results provide information on the nature of deficits that occur in the schizophrenia affected groups, and these important structural differences are not all shown in maximal voxel results. The maximal voxel and cluster extent results are corrected for multiple comparisons using Random Fields (RF) methods. In order to apply the cluster extent measures, we propose a post-hoc method for determining the primary threshold in the analysis. Unadjusted cluster extent results are reported, for these, no allowance is made for non-isotropic smoothness, and comparison with the adjusted extent results shows that the unadjusted results can be either conservative or anti-conservative depending upon the underlying tissue distributions.

Cluster Analysis↗

PubMed2005

White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives.

BACKGROUND: This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. METHODS: Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. RESULTS: Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. CONCLUSIONS: Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders.

Adult↗