Joanna Gray

NEURAL RESPONSES TO FACIAL AND VOCAL EXPRESSIONS OF FEAR AND DISGUST

Neuropsychological studies report more impaired responses to facial expressions of fear than disgust in people with amygdala lesions, and vice versa in people with Huntingtons disease. Experiments using functional magnetic resonance imaging (fMRI) have confirmed the role of the amygdala in the response to fearful faces and have implicated the anterior insula in the response to facial expressions of disgust. We used fMRI to extend these studies to the perception of fear and disgust from both facial and vocal expressions. Consistent with neuropsychological findings, both types of fearful stimuli activated the amygdala. Facial expressions of disgust activated the anterior insula and the caudate–putamen; vocal expressions of disgust did not significantly activate either of these regions. All four types of stimuli activated the superior temporal gyrus. Our findings therefore (i) support the differential localization of the neural substrates of fear and disgust; (ii) confirm the involvement of the amygdala in the emotion of fear, whether evoked by facial or vocal expressions; (iii) confirm the involvement of the anterior insula and the striatum in reactions to facial expressions of disgust; and (iv) suggest a possible general role for the perception of emotional expressions for the superior temporal gyrus.

Time courses of left and right amygdalar responses to fearful facial expressions.

Despite the many studies highlighting the role of the amygdala in fear perception, few have examined differences between right and left amygdalar responses. Using functional magnetic resonance imaging (fMRI), we examined neural responses in three groups of healthy volunteers (n = 18) to alternating blocks of fearful and neutral faces. Initial observation of extracted time series of both amygdalae to these stimuli indicated more rapid decreases of right than left amygdalar responses to fearful faces, and increasing magnitudes of right amygdalar responses to neutral faces with time. We compared right and left responses statistically by modeling each time series with (1) a stationary fit model (assuming a constant magnitude of amygdalar response to consecutive blocks of fearful faces) and (2) an adaptive model (no assumptions). Areas of significant sustained nonstationarity (time series points with significantly greater adaptive than stationary model fits) were demonstrated for both amygdalae. There was more significant nonstationarity of right than left amygdalar responses to neutral, and left than right amygdalar responses to fearful faces. These findings indicate significant variability over time of both right and left amygdalar responses to fearful and neutral facial expressions and are the first demonstration of specific differences in time courses of right and left amygdalar responses to these stimuli. Hum. Brain Mapping 12:193–202, 2001.

Functional Magnetic Resonance Image Analysis of a Large-Scale Neurocognitive Network

Many higher-order mental functions are subserved by large-scale neurocognitive networks comprising several spatially distributed and functionally specialized brain regions. We here report statistical and graphical methods of functional magnetic resonance imaging data analysis which can be used to elucidate the functional relationships (i.e., connectivity and distance) between elements of a neurocognitive network in a single subject. Data were acquired from a normal right-handed volunteer during periodic performance of a task which demanded visual and semantic processing of words and subvocalization of a decision about the meaning of each word. Major regional foci of activation were identified (by sinusoidal regression modeling and spatiotemporal randomization tests) in left extrastriate cortex, angular gyrus, supramarginal gyrus, superior and middle temporal gyri, lateral premotor cortex, and Brocas area. Principal component (PC) analysis was initially undertaken by singular value decomposition (SVD) of the raw time series observed at 170 activated voxels. This revealed a large functional distance (negative connectivity) between visual processing systems and all other brain regions in the space of the first PC. SVD of a matrix of fitted time series, and a matrix of six sinusoidal regression parameters estimated at each activated voxel, were developed as less noisy (more informative) alternatives to SVD of the raw data. Canonical variate analysis of denoised data was then used to clarify functional relationships between the major regional foci. Visual input analysis systems (extrastriate cortex and angular gyrus) were colocalized in the space of the first canonical variate (CV) and significantly separated from all other brain regions. Semantic analysis systems (supramarginal and temporal gyri) were colocalized and significantly separated in the space of the second CV from the subvocal output system (Brocas area). These results are provisionally interpreted in terms of underlying hemodynamic events and cognitive psychological theory.

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

The aim of this study was to investigate genetic predictors of an increase in suicidal ideation during treatment with a selective serotonin reuptake inhibitor or a tricyclic antidepressant. A total of 796 adult patients with major depressive disorder who were treated with a flexible dosage of escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP) were included in the sample and provided data on suicidal ideation. Nine candidate genes involved in neurotrophic, serotonergic, and noradrenergic pathways were selected based on previous association studies with suicidal ideation or behavior. Using a logistic regression model, 123 polymorphisms in these genes were compared between subjects with an increase in suicidal ideation and those without any increase in suicidal ideation. Polymorphisms in BDNF, the gene encoding the brain-derived neurotrophic factor, were significantly associated with an increase in suicidal ideation. The strongest association was observed for rs962369 in BDNF (p=0.0015). Moreover, a significant interaction was found between variants in BDNF and NTRK2, the gene encoding the BNDF receptor (p=0.0003). Among men taking nortriptyline, suicidality was also associated with rs11195419 SNP in the alpha2A-adrenergic receptor gene (ADRA2A) (p=0.007). The associations observed with polymorphisms in BDNF suggest the involvement of the neurotrophic system in vulnerability to suicidality. Epistasis between BDNF and NTRK2 suggests that genetic variations in the two genes are involved in the same causal mechanisms leading to suicidality during antidepressant treatment. Among men, genetic variation in noradrenergic signaling may interact with norepinephrine reuptake-inhibiting antidepressants, thereby contributing to suicidality.

Personality factors correlate with regional cerebral perfusion

There is an increasing body of evidence pointing to a neurobiological basis of personality. The purpose of this study was to investigate the biological bases of the major dimensions of Eysencks and Cloningers models of personality using a noninvasive magnetic resonance perfusion imaging technique in 30 young, healthy subjects. An unbiased voxel-based analysis was used to identify regions where the regional perfusion demonstrated significant correlation with any of the personality dimensions. Highly significant positive correlations emerged between extraversion and perfusion in the basal ganglia, thalamus, inferior frontal gyrus and cerebellum and between novelty seeking and perfusion in the cerebellum, cuneus and thalamus. Strong negative correlations emerged between psychoticism and perfusion in the basal ganglia and thalamus and between harm avoidance and perfusion in the cerebellar vermis, cuneus and inferior frontal gyrus. These observations suggest that personality traits are strongly associated with resting cerebral perfusion in a variety of cortical and subcortical regions and provide further evidence for the hypothesized neurobiological basis of personality. These results may also have important implications for functional neuroimaging studies, which typically rely on the modulation of cerebral hemodynamics for detection of task-induced activation since personality effects may influence the intersubject variability for both task-related activity and resting cerebral perfusion. This technique also offers a novel approach for the exploration of the neurobiological correlates of human personality.

Neuroimaging correlates of negative priming

Many theoretical accounts of selective attention and memory retrieval include reference to active inhibitory processes, such as those argued to underlie the negative priming effect. fMRI was used in order to investigate the areas of cortical activation associated with Stroop interference, Stroop facilitation and Stroop negative priming tasks. The most significant activation within the negative priming task was within the inferior parietal lobule, left temporal lobe and frontal lobes. Areas of cortical activation are discussed with reference to theoretical accounts of the negative priming effect.

Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein. We explored the TSNAX–DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX–DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX–DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX–DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder

It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A haplotype of SNPs located in CHRM2 (rs1824024-rs2061174-rs324650) has been significantly associated with MDD in a previous study. We report the first study investigating this gene in a large, adequately powered, clinical depression case-control sample (n = 1420 cases, 1624 controls). Our data fail to support association with the CHRM2 polymorphisms previously implicated in the genetic aetiology of depression. It is possible our failure to replicate may be a consequence of differences in definition of the MDD phenotype and/or ethnic differences.

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

BackgroundSuicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment.MethodsIn a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline.ResultsSuicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI.ConclusionIncreases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment.Trial registrationEudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).

Adverse life event reporting and worst illness episodes in unipolar and bipolar affective disorders measuring environmental risk for genetic research

BACKGROUNDnStudies exploring gene-environment interplay in affective disorders now include very large numbers of participants. Methods for evaluating the role of adversity in such studies need to be developed that do not rely on lengthy and labour-intensive interviews. In the present study, a brief questionnaire method for measuring 11 adverse events reported before interview and before their worst illness episodes by bipolar, unipolar and healthy control participants, participating in genetic association studies, was evaluated.nnnMETHODnFive hundred and twelve bipolar disorder (BD) participants, 1447 participants with recurrent unipolar depression (UPD) and 1346 psychiatrically healthy control participants underwent the researcher-administered version of the List of Threatening Experiences Questionnaire (LTE-Q) for the 6 months before their worst affective episodes for UPD and BD participants, and for the 6 months before interview for the UPD participants and controls.nnnRESULTSnUPD and BD cases were significantly more likely to report at least one event, as well as more events in the 6 months before interview and before their worst illness episodes, than healthy controls. Both manic and depressive episodes were significantly associated with adverse events in the BD cases. Depressed mood at the time of interview influenced event reporting in UPD and control participants but not the BD cases. Age was negatively correlated with the number of events reported by controls.nnnCONCLUSIONSnThe researcher-administered LTE-Q provides a measure of case-control differences for adversity that is applicable in large genetic association studies. Confounding factors for event reporting include present mood and age.