Biomedical subjects

Kate Lawrence

Publications and source records attributed to Kate Lawrence.

7 recordsLinked to original sources

PubMed2006

Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome.

One-third of women with Turner syndrome (45,X) have autism-like social and communication difficulties, despite normal verbal IQ. Deletion mapping of the X-chromosome implicated 5 Mb of Xp11.3-4 as critical for recognition of facial fear, a quantitative measure of social cognition. Variability in fear recognition accuracy in Turner syndrome suggested the existence of a quantitative trait locus (QTL) revealed by X-monosomy. We aimed to identify the gene(s) influencing fear recognition by dense mapping of the 5 Mb region. Initial regression-based association mapping of fear recognition in 93 women with Turner syndrome across the critical region was performed, using genotype data at 242 single nucleotide polymorphisms (SNPs). We identified three regions of interest, in which 52 additional SNPs were genotyped. The third region then contained four SNPs associated with fear recognition (0.0030 > P > 0.00046). We obtained an independent sample of 77 Turner syndrome females that we genotyped for 77 SNPs in the initial regions of interest. Region three showed association in the same direction, maximal at SNPs rs7055196 and rs7887763 (P = 0.022 each). Four SNPs in strong linkage disequilibrium (LD), including this pair, span 40 kb within a novel transcript, EF-hand domain containing 2 (EFHC2). In the combined Turner syndrome samples, the most strongly associated SNP (P = 0.00007) has frequency of 8.8% and an estimated effect size accounting for over 13% of the variance in fear recognition. EFHC2 shows genealogy and extended LD consistent with directional selection. This novel QTL may influence social cognition in the general population and in autism.

Chromosome Mapping↗

PubMed2006

Measuring social-cognitive functions in children with somatotropic axis dysfunction.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) are expressed in specific regions of the central nervous system during early human development. They may consequently influence aspects of cognition, or emotional and behavioural adjustment from childhood to adulthood, in conditions associated with abnormalities of the somatotropic axis. GH receptors are relatively common within hippocampal and perihippocampal regions that are primarily involved in declarative memory for facts and events. They are also located in structures (e.g. the putamen) that are involved in the processing of social perceptions. IGF-I receptors have been discovered in the amygdala and prefrontal cortex, which contribute to the neural circuits known as the 'social brain'. The evaluation of emotional, social and behavioural adjustment among children who have deficiencies in GH or IGF-I functional integrity requires the objective assessment of their social-cognitive competence. We describe a computerized test battery, the Schedules for the Assessment of Social Intelligence (SASI), which has been shown to possess excellent psychometric properties in terms of reliability and validity. The SASI, which can be used by both children and adults, may provide new evidence for deficits and treatment effects of GH/IGF-I on emotional, behavioural and cognitive functions.

Adolescent↗

PubMed2006

Meanings in motion and faces: developmental associations between the processing of intention from geometrical animations and gaze detection accuracy.

Aspects of face processing, on the one hand, and theory of mind (ToM) tasks, on the other hand, show specific impairment in autism. We aimed to discover whether a correlation between tasks tapping these abilities was evident in typically developing children at two developmental stages. One hundred fifty-four normal children (6-8 years and 16-18 years) and 13 high-IQ autistic children (11-17 years) were tested on a range of face-processing and IQ tasks, and a ToM test based on the attribution of intentional movement to abstract shapes in a cartoon. By midchildhood, the ability accurately and spontaneously to infer the locus of attention of a face with direct or averted gaze was specifically associated with the ability to describe geometrical animations using mental state terms. Other face-processing and animation descriptions failed to show the association. Autistic adolescents were impaired at both gaze processing and ToM descriptions, using these tests. Mentalizing and gaze perception accuracy are associated in typically developing children and adolescents. The findings are congruent with the possibility that common neural circuitry underlies, at least in part, processing implicated in these tasks. They are also congruent with the possibility that autism may lie at one end of a developmental continuum with respect to these skills, and to the factor(s) underpinning them.

Autistic Disorder↗

PubMed2003

Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans.

The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.

Adolescent↗

PubMed2003

Interpreting gaze in Turner syndrome: impaired sensitivity to intention and emotion, but preservation of social cueing.

Women with Turner's syndrome (TS), who lack a complete X-chromosome, show an impairment in remembering faces and in classifying "fear" in face images. Could their difficulties extend to the processing of gaze? Three tasks, all of which rely on the ability to make use of the eye-region of a pictured face, are reported. Women with TS were impaired at judging mental state from images of the upper face ("reading the mind in the eyes"). They were also specifically impaired at interpreting "fear" from displays of the eye-region of the face. However, they showed normal susceptibility to direction of gaze as an attentional cue (social cueing), since they were as sensitive as controls to the validity of the cue, under conditions where it should be ignored. In this task, unlike those of reading the upper face for intention or expression, PIQ accounted for a significant amount of individual variance in task performance. The processing of displays of the eye region affording social and affective information is specifically affected in TS. We speculate that amygdala dysfunction is likely to be implicated in this anomalous behaviour. The presence in the female karyotype of two complete X-chromosomes is protective for some socio-cognitive abilities related to the modulation of behaviour by the interpretation of gaze.

Adolescent↗

PubMed2003

The amygdala and development of the social brain.

The amygdala comprises part of an extended network of neural circuits that are critically involved in the processing of socially salient stimuli. Such stimuli may be explicitly social, such as facial expressions, or they may be only tangentially social, such as abstract shapes moving with apparent intention relative to one another. The coordinated interplay between neural activity in the amygdala and other brain regions, especially the medial prefrontal cortex, the occipitofrontal cortex, the fusiform gyrus, and the superior temporal sulcus, allows us to develop social responses and to engage in social behaviors appropriate to our species. The harmonious functioning of this integrated social cognitive network may be disrupted by congenital or acquired lesions, by genetic anomalies, and by exceptional early experiences. Each form of disruption is associated with a slightly different outcome, dependent on the timing of the experience, the location of the lesion, or the nature of the genetic anomaly. Studies in both humans and primates concur; the dysregulation of basic emotions, especially the processing of fear and anger, is an almost invariable consequence of such disruption. These, in turn, have direct or indirect consequences for social behavior.

Amygdala↗

PubMed2003

Face and emotion recognition deficits in Turner syndrome: a possible role for X-linked genes in amygdala development.

Face recognition is thought to rely on configural visual processing. Where face recognition impairments have been identified, qualitatively delayed or anomalous configural processing has also been found. A group of women with Turner syndrome (TS) with monosomy for a single maternal X chromosome (45, Xm) showed an impairment in face recognition skills compared with normally developing women. However, normal configural face-processing abilities were apparent. The ability to recognize facial expressions of emotion, particularly fear, was also impaired in this TS subgroup. Face recognition and fear recognition accuracy were significantly correlated in the female control group but not in women with TS. The authors therefore suggest that anomalies in amygdala function may be a neurological feature of TS of this karyotype.

Adolescent↗