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Levels of autism traits in men with XXY and men from the general population as measured with the AQ. Scores in all individual dimensions were significantly higher in men with XXY.
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Klinefelter syndrome (KS) is a chromosomal condition (47, XXY) that may help us to unravel gene-brain behavior pathways to psychopathology. The phenotype includes social cognitive impairments and increased risk for autism traits. We used functional MRI to study neural mechanisms underlying social information processing. Eighteen nonclinical control...
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Klinefelter Syndrome (KS) is a genetic syndrome characterized by the presence of an extra X chromosome that appears to increase the risk of psychopathology, such as autism symptoms. The current study used functional MRI to determine underlying mechanisms related to this risk, with the aim of gaining insight into neural mechanisms behind social-cogn...
Citations
... Contrary to the impression that individuals with autistic tendency are "mind-blind" and inattentive to social cues, the narrative of affected individuals support the view that they shut down the flow of social information, because they are afraid of getting panicked by emotional disturbance caused by involvement with others and their gazes (330). Individuals with KS (128) and at least subsets of ASC (331,332) show increased physiological arousal in response to social cues, such as the human eye and mouth, but less activation of the amygdala and insula (333). It is difficult for them to assess and label affective responses, that underlies alexithymia (128). ...
... Insular volume in ASC is not different from that in TD, whereas hypoactivation in emotional empathy task corresponds to higher levels of alexithymia (36). For KS (333) and ASC (36), the identification of stimuli with negative emotional valence is difficult or hypoactivates brain areas for processing emotions, which might also correspond to a reduction in amygdala volume. To complicate the interpretation, the insula in ASC shows hyperactivation in different types of tasks. ...
Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one’s own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.
... Some studies suggest that this impairment is related to a compromised function of the amygdala, fusiform gyrus, insula, and superior temporal sulcus. 8 The patient's IQ was not surprising, since a low IQ is associated with a greater risk for schizophrenia. 9-11 Additionally, many genes responsible for cognitive development are in the X chromosome, 12,13 with approximately half of all intellectual disabilities presenting a defect in the X chromosome. ...
https://www.psychiatrist.com/pcc/schizophrenia/schizophrenia-klinefelter-syndrome/
... Thus, Bardsley et al. (2011) [93] confirmed that certain disorders, which usually accompany this syndrome, may appear in youngsters. Additionally, Van Rijn et al. (2012) [94] examined the cognitive disorders which commonly appear in Klinefelter syndrome stating that the analysis of cognitive functionality of patients' brains may deliver valuable information about neural mechanisms involved in social processing. In an experiment conducting a task based on judging facial expressions, men with this syndrome and healthy men were asked to assess faces as trustworthy or untrustworthy and asked to guess the age of the faces. ...
... During the second part of the task the perceptual face processing was also reduced in men with this syndrome. The studies elucidated direct relationships between abnormal social behaviors accompanying Klinefelter syndrome and a reduced functionality of the neural network [94][95][96]. ...
... Finally, with respect to disorders associated with the X chromosome, Klinefelter syndrome, as one of the most frequent genetic causes of male infertility (1 in 600 men), is well characterized. The authors described genetic pathogenesis, the presence of an extra chromosome X in the male karyotype, as well as phenotypic manifestations, including small testis, azoospermia, degeneration of spermatic ducts, as sometimes coupled with psychiatric impairments and learning delays [26][27][28][29][30]93,94]. A well-characterized genetic disorder is Kallmann syndrome, where the condition results from mutations in various genes, including KAL1, FGFR1, or FGF8. ...
We explain environmental and genetic factors determining male genetic conditions and infertility and evaluate the significance of environmental stressors in shaping defensive responses, which is used in the diagnosis and treatment of male infertility. This is done through the impact of external and internal stressors and their instability on sperm parameters and their contribution to immunogenetic disorders and hazardous DNA mutations. As chemical compounds and physical factors play an important role in the induction of immunogenetic disorders and affect the activity of enzymatic and non-enzymatic responses, causing oxidative stress, and leading to apoptosis, they downgrade semen quality. These factors are closely connected with male reproductive potential since genetic polymorphisms and mutations in chromosomes 7, X, and Y critically impact on spermatogenesis. Microdeletions in the Azoospermic Factor AZF region directly cause defective sperm production. Among mutations in chromosome 7, impairments in the cystic fibrosis transmembrane conductance regulator CFTR gene are destructive for fertility in cystic fibrosis, when spermatic ducts undergo complete obstruction. This problem was not previously analyzed in such a form. Alongside karyotype abnormalities AZF microdeletions are the reason of spermatogenic failure. Amongst AZF genes, the deleted in azoospermia DAZ gene family is reported as most frequently deleted AZF. Screening of AZF microdeletions is useful in explaining idiopathic cases of male infertility as well as in genetic consulting prior to assisted reproduction. Based on the current state of research we answer the following questions: (1) How do environmental stressors lessen the quality of sperm and reduce male fertility; (2) which chemical elements induce oxidative stress and immunogenetic changes in the male reproductive system; (3) how do polymorphisms correlate with changes in reproductive potential and pro-antioxidative mechanisms as markers of pathophysiological disturbances of the male reproductive condition; (4) how do environmental stressors of immunogenetic disorders accompany male infertility and responses; and (5) what is the distribution and prevalence of environmental and genetic risk factors.
... The few functional neuroimaging studies of KS males in the literature include investigations of executive functioning and stimulus adaptation (Wallentin et al., 2016), language processing and lateralization (Van Rijn et al., 2008;Wallentin et al., 2016) and social cognition (Brandenburg-Goddard et al., 2014;Van Rijn et al., 2012). ...
... Following up on the known social deficits associated with KS, two studies have investigated sensitivity to facial expressions (Brandenburg- Goddard et al., 2014;Van Rijn et al., 2012). One of these studies found that KS men exhibited less activation than controls in the amygdala and fusiform face area (Van Rijn et al., 2012), while another study found a tendency for increased activation in the amygdala (Brandenburg- Goddard et al., 2014). ...
... Following up on the known social deficits associated with KS, two studies have investigated sensitivity to facial expressions (Brandenburg- Goddard et al., 2014;Van Rijn et al., 2012). One of these studies found that KS men exhibited less activation than controls in the amygdala and fusiform face area (Van Rijn et al., 2012), while another study found a tendency for increased activation in the amygdala (Brandenburg- Goddard et al., 2014). The latter study also found that KS men relied more on prefrontal brain areas for processing of facial expressions (Bishop et al., 2011). ...
Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non‐verbal and visuo‐spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.
... Furthermore, regions we identify as being most anatomically vulnerable to SCD appear to partially overlap with regions of known functional alterations in SCAs. For example, individuals with XXY karyotypes demonstrate increased activation in the middle frontal gyrus, including Broca's area (Brandenburg-Goddard et al. 2014), and reduced activation in the fusiform gyrus and the superior temporal sulcus (van Rijn et al. 2012) during social information processing tasks, regions we found to be altered by SCD. Multimodal neuroimaging studies will be required to systematically assess the degree of overlap between structural and functional brain changes in SCA. ...
Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.
... Le DSM-5 et la CIM-10 [1,15] opposent antisocial personality disorder ou personnalité dyssociale (caracté risé e par l'incapacité à se conformer à la loi et à é prouver du remord, un caractè re irresponsable et instable) et borderline personality disorder ou personnalité é motionnellement labile (caracté risé e par les efforts was recently reported (Stochholm et al., 2012). Quite a few clinically relevant cases reports scattered in the literature, suggests the presence of a pattern of a specific subtype of KS inpatients among forensic population (Bé né zech, 1975 [29] (e.g. limbic system and temporal lobe abnormal volume, hemispheric specialization shortcoming) features may be helpful to understand comorbid symptoms psychopathology. ...
... Le DSM-5 et la CIM-10 [1,15] opposent antisocial personality disorder ou personnalité dyssociale (caracté risé e par l'incapacité à se conformer à la loi et à é prouver du remord, un caractè re irresponsable et instable) et borderline personality disorder ou personnalité é motionnellement labile (caracté risé e par les efforts was recently reported (Stochholm et al., 2012). Quite a few clinically relevant cases reports scattered in the literature, suggests the presence of a pattern of a specific subtype of KS inpatients among forensic population (Bé né zech, 1975 [29] (e.g. limbic system and temporal lobe abnormal volume, hemispheric specialization shortcoming) features may be helpful to understand comorbid symptoms psychopathology. ...
Résumé
Le syndrome de Klinefelter (47,XXY) constitue l’aneuploïdie des chromosomes sexuels la plus fréquente chez l’Homme (1 sur 650, 0,1 à 0,2 % de la population masculine). En raison d’une grande variabilité phénotypique, le syndrome est largement sous-diagnostiqué (moins de 25 % des sujets atteints diagnostiqués). Le profil neurocognitif est plus stable et spécifique. Dans la littérature, un quotient intellectuel total normal ou bas, associé à un quotient intellectuel verbal plutôt faible, des difficultés d’adaptation sociale et un taux élevé de comorbidités psychiatriques, incluant une agressivité précoce, sont classiquement décrits. Au Danemark, un risque plus élevé de commettre un crime sexuel et un incendie volontaire (comparativement à un sujet contrôle) a été récemment démontré. Un certain nombre de cas cliniques isolés, relatifs à des patients institutionnalisés, suggèrent la présence d’un sous-type « médico-légal » de patients Klinefelter. À l’heure actuelle, il existe peu de données robustes et exploitables en ce sens. Le syndrome de Klinefelter présente des spécificités neuropsychologiques, neurobiologiques et neuro-anatomiques bien documentées, qui peuvent être utiles à la compréhension de la psychopathologie des symptômes comorbides. Certains auteurs utilisent également les caractéristiques génétiques et épigénétiques des aneuploïdies des chromosomes sexuels afin de clarifier les liens génotype-phénotype. Avec nos collègues belges du CRDS (Centre de Recherche en Défense Sociale, Tournai, Belgique), nous recrutons actuellement des patients Klinefelter hospitalisés parmi la population médico-légale, afin d’évaluer leurs traits psychopathiques avec l’échelle de Hare (PCL-R). Nos premiers résultats (n = 3) confirment que l’échelle est utile à la caractérisation objective phénotypique clinique de la population. Nous avons mis en évidence deux diagnostics doubles « Klinefelter-psychopathe » (score de PCL total > = à 30/40). De façon plus intéressante, l’analyse dimensionnelle supporte notre hypothèse d’une prévalence importante du « profil explosif » relativement aux autres profils de psychopathie. Le présent article résume les arguments contextuels, historiques et actuels ayant motivé notre projet de recherche. Il discute certains des avantages offerts par l’étude de patients Klinefelter préalablement évalués à l’échelle de Hare, comme la lutte contre la stigmatisation et la discrimination, la meilleure compréhension de la psychopathologie et du rôle développemental complexe des facteurs biologiques, psychologiques et sociaux, pour chacune de ces deux entités cliniques.
... Evidence that trustworthiness activates the amygdala has been inconsistent. Studies that categorically compared trustworthy versus untrustworthy stimuli typically find greater amygdala responses to untrustworthy faces (Blasi et al., 2009;Pinkham et al., 2008a;Pinkham et al., 2008b;van Rijn et al., 2012). Similarly, some parametric studies have demonstrated that amygdala activity increases monotonically with untrustworthiness (Engell et al., 2007;Winston et al., 2002). ...
Background: Borderline Personality Disorder (BPD) is associated with sensitivity to signals of interpersonal threats and misplaced trust in others. The amygdala, an integral part of the threat evaluation and response network, responds to both fear- and trust-related stimuli in non-clinical samples, and is more sensitive to emotional stimuli in BPD compared to controls. However, it is unknown whether the amygdalar response can account for deficits of trust and elevated sensitivity to interpersonal threat in BPD.
Methods: Facial stimuli were presented to 16 medication-free women with BPD and 17 demographically-matched healthy controls (total n=33). Participants appraised fearfulness or trustworthiness of the stimuli while BOLD fMRI was obtained.
Results: Though BPD participants judged stimuli as less trustworthy compared to controls, trustworthiness did not correlate with amygdalar activity in either group. Trustworthiness correlated with prefrontal regional activity in the insula and lateral prefrontal cortex. Prefrontal BOLD activity while appraising trustworthiness was smaller in BPD compared to controls, and the size of the reduction was proportional to each participant’s response bias.
Conclusions: Neural substrates of trustworthiness appraisal are associated with the lateral prefrontal cortex and insula, not amygdala, suggesting that untrustworthy stimuli do not elicit a subcortical threat response. Current models of BPD and its treatment may need to include a focus on improving impairments in frontally mediated trustworthiness appraisal in addition to amygdala- driven emotional hyper-reactivity.
... Babinet et al. (2017) 8 sugeriram que as desordens na cognição social fazem parte do traço fenotípico da SK. Apresentam imaturidade, insegurança, timidez, baixa auto-estima, dificuldades de aprendizagem, capacidade de julgamento prejudicada e comportamento não-assertivo, caracterizado por um antagonismo radical de passividade e agressividade 9 , assim como, altos índices de distresse, neuroticismo e introversão 10 , além de serem mais suscetíveis a comorbidades psiquiátricas, como ansiedade, depressão e transtorno de conduta 11 , transtorno afetivo bipolar, esquizofrenia, autismo e TDAH 12,13 . As alterações cognitivas que comumente estão presentes são o QI abaixo da média, déficits atencionais, em funções frontoexecutivas, como capacidade de planejamento, flexibilidade mental e controle inibitório 9,10 , e dificuldades no desenvolvimento motor, tanto na motricidade fina, quanto grossa, que se assemelham aos sintomas de dispraxia. ...
The Klinefelter syndrome is a chromosomal aneuploidy caused by additional X chromosomes in men. The diagnosis is made by clinical observation and karyotype examination. Besides other characteristics, the phenotype involves infertility, hypogonadism, gynecomastia, and cognitive alterations, mainly in the language domain. This paper describes the case of a teenager with Klinefelter syndrome and history of difficulties in the learning process, behavioral and communication problems. The ethical guidelines were followed in the present report. The cognitive-communicative, pragmatic and syntactic profile was drawn from the speech and neuropsychological evaluations. The speech-language assessment showed deficits in expression and comprehension. Difficulties were also found in phonological awareness, mathematical operations, reading and writing, access to the lexicon, alterations in pragmatics and occasionally, in syntactics. The neuropsychological evaluation indicated impairments in tasks that require the identification of similarities, establishment of cause-effect relationships and analogies, demonstrating a compromised reasoning for logical operations, with intellectual level incompatible with the chronological age. This interdisciplinary clinical study favors intervention approaches in rehabilitation, to maximize the potential of the individuals affected, contributing to improve their quality of life.
... Studies with functional magnetic resonance imaging (MRI) found that the activation of the amygdala and the insula, areas involved in socioemotional function and in subjective emotional experience, respectively, were reduced in KS. Moreover, the activation of the fusiform gyrus and the superior temporal sulcus, which play a role in the perceptual processing of faces, was also reduced [29]. Lastly, in KS patients, a less lateralized language activity was demonstrated, due to increased activity in the right and reduced activity in the left hemisphere, particularly in the superior temporal gyrus and the supramarginal gyrus regions. ...
Background and objective:
Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47,XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders.
Methods:
To extent to the best of published literature on the topic, it was identified the appropriate keywords and MeSH terms and searched them in Pubmed. Finally, references of original articles and reviews were examined.
Results:
Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression, anxiety, were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplentation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism.
Conclusion:
Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identify the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS.
