Sophie van Rijn

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome

Although Klinefelter syndrome (47,XXY) has been associated with psychosocial difficulties, knowledge of the social behavioral phenotype is limited. We examined specific social abilities and autism traits in Klinefelter syndrome. Scores of 31 XXY men on the Scale for Interpersonal Behavior and the Autism Spectrum Questionnaire were compared to 24 and 20 control men respectively. XXY men reported increased distress during social interactions and less engagement in specific social behaviors. In the XXY group, levels of autism traits were significantly higher across all dimensions of the autism phenotype. These findings call for a clinical investigation of vulnerability to autism in Klinefelter syndrome. Klinefelter syndrome might serve as a model for studying a role of the X chromosome in social behavioral dysfunction and autism-like behavior.

X Chromosomal effects on social cognitive processing and emotion regulation: a study with Klinefelter men (47,XXY)

Studying Klinefelter syndrome (47,XXY), a genetically defined disorder characterized by the presence of an additional X chromosome, can reveal insights into genotype-phenotype associations. Increased vulnerability to psychiatric disorders characterized by difficulties in social interactions, such as schizophrenia and autism, has been reported for this population. The reported social difficulties in 47,XXY men may arise as a consequence of impairments in the processing of social and emotional information. The present study is the first investigation of social-emotional information processing in this X chromosomal disorder. 32 Klinefelter men and 26 men from the general population, with the groups matched for age, educational level and I.Q., participated in the study. Several tasks were included, reflecting aspects of social-emotional information processing on levels of perception, experience and expression: labeling of facial expressions of emotion, emotion-cognition interactions in decision making and emotion regulation, that refers to subjective experience and identification of emotional arousal as well as verbal expression of emotions. A discrepancy between cognitive appraisal of emotions and emotional arousal was observed in Klinefelter syndrome. Taken together, Klinefelter men seem less accurate in perception of socio-emotional cues such as angry facial expressions, they are less able to identify and verbalize their emotions, but experience increased levels of emotional arousal, in comparison to the general population. Besides describing the social-emotional phenotype of this X chromosomal disorder, the present data may prove to be an important contribution to the development of more general models describing pathways to neuropsychiatric disorders characterized by social cognitive disturbances.

Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample

The presence of an additional X-chromosome in Klinefelter patients provides an opportunity to study the influence of this chromosome on psychiatric disorders. Previous studies have reported an excess of Klinefelter patients in psychiatric patient groups. We report an increased prevalence of psychiatric disorders including psychotic disorders in a sample of Klinefelter patients but could not find evidence of an effect of the parental origin of the extra X-chromosome on the psychiatric phenotype. Nevertheless, these findings provide further support for the role of the X-chromosome in the susceptibility to psychiatric disorders in general and psychotic disorders in particular.

Overlap of autistic and schizotypal traits in adolescents with Autism Spectrum Disorders

This study addresses the unraveling of the relationship between autism spectrum and schizophrenia spectrum traits in a population of adolescents with Autism Spectrum Disorders (ASD). Recent studies comparing isolated symptoms of both spectrum disorders as well as diagnostic criteria for each (DSM-IV-TR) suggest resemblances in the clinical phenotype. A group of 27 adolescents with ASD (11 to 18 years) and 30 typically developing adolescents, matched for age and gender, participated in this study. Within the ASD group 11 adolescents satisfied DSM-IV-TR criteria for schizotypal personality disorders. Autistic and schizotypal traits were identified by means of well validated questionnaires (Autism Questionnaire, AQ and Schizotypal Personality Questionnaire-Revised, SPQ). Significantly more schizotypal traits in adolescents with ASD were found than in typically developing controls. Besides high levels of negative symptoms, adolescents with ASD also displayed high levels of positive and disorganized symptoms. There appeared to be a relationship between the mean level of autistic symptoms and schizotypal traits, as well as specific associations between autistic symptoms and negative, disorganized and positive schizotypal symptoms within individuals. Schizotypal symptomatology in all sub dimensions that are reflected by the SPQ scores, was most prominently associated with attention switching problems of the autism symptoms from the AQ. These findings indicate that patients diagnosed with an ASD show schizophrenia spectrum traits in adolescence. Although other studies have provided empirical support for this overlap in diagnostic criteria between both spectrum disorders, the present findings add to the literature that behavioral overlap is not limited to negative schizotypal symptoms, but extends to disorganized and positive symptoms as well.

What is said or how it is said makes a difference : role of the right fronto-parietal operculum in emotional prosody as revealed by repetitive TMS

Emotional signals in spoken language can be conveyed by semantic as well as prosodic cues. We investigated the role of the fronto‐parietal operculum, a somatosensory area where the lips, tongue and jaw are represented, in the right hemisphere to detection of emotion in prosody vs. semantics. A total of 14 healthy volunteers participated in the present experiment, which involved transcranial magnetic stimulation (TMS) in combination with frameless stereotaxy. As predicted, compared with sham stimulation, TMS over the right fronto‐parietal operculum differentially affected the reaction times for detection of emotional prosody vs. emotional semantics, showing that there is a dissociation at a neuroanatomical level. Detection of withdrawal emotions (fear and sadness) in prosody was delayed significantly by TMS. No effects of TMS were observed for approach emotions (happiness and anger). We propose that the right fronto‐parietal operculum is not globally involved in emotion evaluation, but sensitive to specific forms of emotional discrimination and emotion types.

Neurobiology of emotion and high risk for schizophrenia: role of the amygdala and the X-chromosome.

Abnormalities in emotion processing and in structure of the amygdala have consistently been documented in schizophrenia. A major question is whether amygdala abnormalities reflect a genetic vulnerability for the disease. In the present paper, we reviewed Magnetic Resonance Imaging (MRI) studies that reported amygdala measures in several high-risk populations: subjects from the general population with subclinical schizophrenia symptoms and relatives of schizophrenia patients. In addition, we reviewed the evidence regarding Klinefelter syndrome (characterised by an additional X-chromosome), which has also been related to an increased risk for schizophrenia. Overall, the evidence points to structural abnormalities of the amygdala in individuals at increased risk for schizophrenia. Although the genetic basis of amygdala deficits remains unclear, abnormalities (of genes) on the X-chromosome might play a role as suggested by the evidence from individuals with sex chromosome aneuploidies. We propose that amygdala abnormalities are an endophenotype in schizophrenia and may account for subtle emotional processing deficits that have been described in these high-risk groups.

Effects of an extra X chromosome on language lateralization: An fMRI study with Klinefelter men (47,XXY)

De novo occurring genetic variations provide an opportunity to study the effects of genes on structure and function of the brain. The presence of an extra X chromosome in men (XXY karyotype) has been associated with language deficits. Recently, schizophrenia spectrum traits have been observed in XXY men, which is of interest as language deficits are prominent in schizophrenia. One possible neural mechanism underlying these deficits is reduced hemispheric specialization for language. However, there has been no study of brain activity patterns during language processing in XXY men. Also, it remains unclear whether reduced language lateralization may be related to mental functioning in these men. We used functional Magnetic Resonance Imaging (fMRI) to study language lateralization in 15 XXY men as compared to 14 control men. We used a psychiatric interview and a schizotypy questionnaire to explore the relation between language lateralization and mental functioning in these men, with special interest in disorganization of thought and language. Compared to controls, the XXY group showed reduced hemispheric specialization for language, which was due to decreased functional asymmetry in the superior temporal gyrus (STG) and the supramarginal gyrus (part of Wernickes area). Reduced lateralization in the STG correlated significantly with disorganization traits. These findings suggest the X chromosome may be involved in hemispheric specialization for language. Moreover, reduced hemispheric specialization for language processing in the superior temporal gyrus may have important consequences for mental functioning, as it was associated with disorganization of thought and language as seen in the schizophrenia spectrum.

Brain imaging, genetics and emotion

This paper reviews the published evidence on genetically driven variation in neurotransmitter function and brain circuits involved in emotion. Several studies point to a role of the serotonin transporter promoter polymorphism in amygdala activation during emotion perception. We also discuss other polymorphisms (e.g. the COMT val158met polymorphism, tryptophan hydroxylase-2 -703 G/T) and putative effects on affective processing in cortical and limbic regions. A different line of research concerns studies with genetic disorders. Although at a less fine-grained level, studies with individuals with aneuploidies of the X chromosome (Turner syndrome and Klinefelter syndrome), who display impairments in emotion processing, have resulted in new insights and hypotheses with regard to X chromosomal influences on brain systems supporting cognition and emotion. These have also implicated a key role for the amygdala. Integration of the emerging evidence, suggests that the study of polymorphisms using brain imaging can potentially elucidate biological pathways and mechanisms contributing to individual differences in brain circuits that may bias behavior and affect risk for psychiatric illness.

What it is said versus how it is said : Comprehension of affective prosody in men with Klinefelter (47,XXY) syndrome

Difficulties in social communication in individuals with Klinefelter syndrome (XXY chromosomal pattern) have largely been attributed to deficits in left hemisphere-mediated, language functions. This study examined the ability of XXY men to decode emotions from tone of voice, a pragmatic aspect of social communication that may be associated with right hemisphere functioning. A total of 26 XXY men and 20 men from the general population completed tasks involving emotion discrimination in speech, based on verbal content or tone of voice. The XXY group displayed relative difficulties in discriminating emotions in tone of voice, and, to a lesser extend, in verbal content. This finding suggests that the XXY chromosomal pattern may not only be associated with difficulties in semantic aspects of language, but with prosodic aspects, as well. Our findings may contribute to the development of more comprehensive models addressing the role of the X chromosome in normal and abnormal development of social communication.

Cognitive mechanisms underlying disorganization of thought in a genetic syndrome (47,XXY)

Because of the risk for development of psychopathology such as psychotic symptoms, it has been suggested that studying men with the XXY karyotype may help in the search for underlying cognitive, neural and genetic mechanisms. The aim of this study was to identify cognitive mechanisms that may contribute to disorganization of thought in XXY men. A group of 24 XXY men and two non-clinical control groups (N=20, N=18) participated in the study. The level of disorganization of thought was measured using the Schizotypal Personality Questionnaire. We assessed IQ, lateralization of verbal information processing and executive functions including inhibition and mental flexibility. XXY men with high levels of disorganization showed more severe impairments in mental flexibility and inhibition as compared to non-clinical controls and other XXY men. This subgroup also showed a stronger reduction in lateralization of verbal information processing. IQ measures did not differentiate XXY men with high versus low levels of disorganization. These findings indicate that executive impairments in the domains of inhibition and mental flexibility might play a role in the increased vulnerability for disorganized thought in the XXY group. Reduced lateralization of verbal information processing points to non-optimal cerebral specialization in the XXY group, especially in XXY men with high levels of disorganization. This fits with deficits in brain functions most vulnerable to such maturational disruptions, i.e. executive dysfunctions. Our findings are in line with those reported for schizophrenia patients with thought disorder. We speculate that the underlying mechanisms of thought disorder probably are deficit specific rather than disorder specific.