Genetic structure of reciprocal social behavior

OBJECTIVE: The study examined the genetic structure of deficits in reciprocal social behavior in an epidemiologic sample of male twins. METHOD: Parents of 232 pairs of 7-15-year-old male twins completed the Social Reciprocity Scale to provide data on their children's reciprocal social behavior. Scale scores were analyzed by using structural equation modeling. RESULTS: Intraclass (twin-twin) correlations for scores on the Social Reciprocity Scale were 0.73 for monozygotic twins (N=98 pairs) and 0.37 for dizygotic twins (N=134 pairs). The best fitting model of causal influences on reciprocal social behavior incorporated additive genetic influences and unique environmental influences. CONCLUSIONS: For school-age boys in the general population, reciprocal social behavior is highly heritable, with a genetic structure similar to that reported for autism in clinical samples. Continuous measures of reciprocal social behavior may be useful for characterizing the broader autism phenotype and may enhance the statistical power of genetic studies of autism.     

Agoraphobic behavior and panic attack: a study of male twins

We used data from 3372 pairs of male twins from the Vietnam Era Twin Registry to examine comorbidity and familial influences on the frequently observed association between agoraphobic behavior and panic. Due to low prevalence of DSM-III-R-defined panic disorder, we also examined subjects who had experienced at least one panic attack during their lives. Agoraphobic behavior among individuals with a history of panic attacks showed familial aggregation (odds ratio = 5.7; P = .018 ). Probands with panic attacks and agoraphobic behavior and their co-twins had higher risk of major depression than probands without agoraphobic avoidance and their co-twins (P = .01). Groups did not differ for alcohol dependence or antisocial personality. Agoraphobic behavior associated with panic attack is familial and associated with comorbid major depression. Agoraphobia following panic attack does not seem to reflect severity as agoraphobic behavior in the proband was unrelated to risk of panic attacks in the co-twin.     

Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice

Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism.     

Neurasthenia: a paradigm of social psychopathology in a transitional society.

A particular social aspect of an illness is reflected in an emphasis on those symptoms that the society considers socially detrimental and/or destabilizing. Thus, in the work- and production-oriented society, chronic fatigue, which affects one's productivity and ability to work, becomes a hallmark of neurasthenia or neurasthenia-like syndrome. In a society based on rigid social structures and severely limited possibilities for social change, excessive irritability and outbursts of anger are perceived as a greater threat to the stability of the existing social order, and therefore they come to dominate the concept of neurasthenia. In Yugoslavia, neurasthenia has been primarily conceived of as a manifestation of an accumulated social frustration and anger; neurasthenia has then been constructed as a mental disorder because anger was expressed in a way that the society considered inappropriate, maladaptive, and pathological. A far-reaching, underlying purpose of this conceptualization of neurasthenia has been a preservation of the social status quo. While neurasthenia as a distinct mental disorder remains controversial, its dependence on the social context cannot be denied. Although the designation of neurasthenia so often seems provisional, because it symbolizes limitations and failures of our diagnostic and nosological systems, it serves a definite social purpose, which varies from time to time, and from one culture to another.     

Tonic pain and social behavior in male rabbits

The 4 subjects each of 6 all-male colonies of rabbits studied in a seminatural setting rapidly established a dominance hierarchy. A combination of behavioral parameters obtained in two experimental situations was used to assign each individual a quantitative score of dominance. The situations were: 'intermale' activity between the residents and 'intruder test', i.e. the reactivity to the introduction of a male conspecific. Fifteen days later, tonic pain (formalin injection) was inflicted on the dominant, and the short-term effects on the treated animal and the social behavior of the group were studied. Licking of the injected foot was used to measure the intensity of pain; this reached a peak 4-8 h after injection and persisted with decreasing intensity into the second day. The painful condition resulted in a general dramatic decrease in motor and social activity including aggressive elements during the intruder test. A positive correlation was found between reduction in motor activity and pain intensity. However, the treated animals did not develop submissive behavior, while the untreated subordinates persisted in their prevalence of submissive over aggressive elements. This contributed to maintain in most cases the behavioral asymmetry of the agonistic activity of the different ranking animals. The possible mechanisms of the observed behavioral modifications are discussed.     

Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function

Reduced NMDA receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor. The present study tested the hypothesis that these NR1 hypomorphic mice would exhibit deficits in sensorimotor and conspecific interactions, analogous to deficits observed in schizophrenic patients. F1 hybrid mice homozygous for the NR1 hypomorphic mutation (NR1 -/-) were generated by crossing heterozygous mice (NR1 +/-) from C57BL/6 and 129 Sv/Ev backgrounds. To assess sensorimotor gating, mice were tested in the paradigm of prepulse inhibition of acoustic startle. The NR1 hypomorphic mice exhibited increased acoustic startle responses and also showed deficits in prepulse inhibition. Startle responses were differentially altered by predator odor exposure in the male NR1 -/- mice, in comparison to control mice. In a test of social affiliation, the wild type mice spent significantly more time investigating a novel mouse in comparison to the NR1 -/- mice. In a resident-intruder test, marked deficits were found in sex-specific aggressive behavior between the wild type and mutant mice. These data support the contention that the NR1 hypomorphic mice exhibit alterations in sensorimotor gating and typical conspecific interactions, reminiscent of behavioral disturbances associated with schizophrenia. The NR1 hypomorphic mice could represent a model system to explore novel treatment and preventative strategies for certain symptoms of schizophrenia.     

Subclinical psychopathology and socio-economic status in unaffected twins discordant for affective disorder

BACKGROUND: The most potent risk factor for affective disorders is a family history of affective disorder but the specific factors that are transmitted in families are unknown. It is possible to investigate the relation between risk factors and affective disorder by using a high-risk design e.g.: a study of the healthy relatives of patients with affective disorders. AIM: To compare psychopathology and socio-economic status between twins with a co-twin history of affective disorder and twins without. METHODS: In a cross-sectional high-risk case-control study, healthy monozygotic and dizygotic twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nation-wide registers. Participants were assessed using semi-structured psychiatric interviews and self-rating of psychopathology. RESULTS: High-Risk twins had a lower education level, a lower work position and tendency towards being more often unemployed and early retired than the Low-Risk twins. Furthermore, they presented higher rates of subclinical affective symptoms and were more likely to experience a minor psychiatric diagnosis. CONCLUSION: Healthy twins with a high genetic liability to affective disorder seem to present lower socio-economic status, higher rates of subclinical affective symptoms and more often experience a minor psychiatric diagnosis than twins with no familial history of affective disorder. It is not possible from the present cross-sectional data to determine the causality of these findings, thus genetic liability to affective disorder, socio-economic status and minor psychopathology seem to have a complex interrelation.     

Premorbid functioning in a national population of male twins discordant for psychoses

OBJECTIVE: The goal of the current study was to compare premorbid behavioral and cognitive functioning between co-twins discordant for psychotic disorder and between these pairs of twins and pairs of twins with no psychotic disorders. METHOD: The authors linked data from the Israeli Draft Board Registry, which contains cognitive and behavioral assessments of all 16-17-year-old male Israeli twins, with data from the National Psychiatric Hospitalization Case Registry. Pairs of male twins who were healthy at the time of testing but discordant for psychoses later on were compared with one another and with pairs of healthy male twins. RESULTS: The affected twins performed significantly worse than healthy twins on measures of individual autonomy, social functioning, and physical activity and nonsignificantly worse on measures of abstract reasoning. There were no significant differences in cognitive or behavioral scores between the co-twins who did or did not develop psychotic disorders. CONCLUSIONS: The authors conclude that these findings underscore the familial nature of behavioral and cognitive deficits antecedent to psychoses.     

Phenotypic variation of a new P0 mutation in genetically identical twins

We have identified a new point mutation in the myelin protein zero (P0) gene in two genetically identical twins with a demyelinating neuropathy. The G to A transition at nucleotide position 382 caused an aspartic acid to asparagine substitution in exon 3. Moreover, we found clear clinical differences which were most evident at an early age. These observations suggest that the expression of this P0 mutation may be susceptible to external, non-genetic influences that may act early in the course of the disease to alter the phenotype. Received: 4 August 1998 Received in revised form: 29 October 1998 Accepted: 19 January 1999     

Default mode network connectivity and reciprocal social behavior in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is a genetic mutation associated with disorders of cortical connectivity and social dysfunction. However, little is known about the functional connectivity (FC) of the resting brain in 22q11DS and its relationship with social behavior. A seed-based analysis of resting-state functional magnetic resonance imaging data was used to investigate FC associated with the posterior cingulate cortex (PCC), in (26) youth with 22qDS and (51) demographically matched controls. Subsequently, the relationship between PCC connectivity and Social Responsiveness Scale (SRS) scores was examined in 22q11DS participants. Relative to 22q11DS participants, controls showed significantly stronger FC between the PCC and other default mode network (DMN) nodes, including the precuneus, precentral gyrus and left frontal pole. 22q11DS patients did not show age-associated FC changes observed in typically developing controls. Increased connectivity between PCC, medial prefrontal regions and the anterior cingulate cortex, was associated with lower SRS scores (i.e. improved social competence) in 22q11DS. DMN integrity may play a key role in social information processing. We observed disrupted DMN connectivity in 22q11DS, paralleling reports from idiopathic autism and schizophrenia. Increased strength of long-range DMN connectivity was associated with improved social functioning in 22q11DS. These findings support a ‘developmental-disconnection’ hypothesis of symptom development in this disorder.     

Deficits in beat perception and dyslexia: evidence from French

Recent research has suggested a novel link between deficits in the perception of cues relevant to speech rhythm (i.e., deficits in amplitude envelope rise time processing, or beat perception) and the phonological deficits seen in most dyslexic children. In this research, we investigated whether these beat perception deficits were specific to a stress-timed language, such as English, or whether they would generalize to languages with different rhythmic properties, such as French. Eighteen dyslexics, 18 reading level controls, and 20 chronological age controls were tested on a battery of phonological tasks, reading tasks and psychoacoustic tests. The results suggest that deficits in the perception of cues important for speech rhythm may be universal in developmental dyslexia.     

Deficits in facial affect recognition in unaffected siblings of Xhosa schizophrenia patients: evidence for a neurocognitive endophenotype

The present study in an African Xhosa sample examined whether familial vulnerability to schizophrenia is associated with deficits in facial affect recognition. Healthy comparison subjects, unaffected siblings of schizophrenia patients, and schizophrenia patients were tested with a task requiring rapid recognition of matched positive (happy), negative (angry), and neutral facial expressions. Siblings and patients demonstrated impaired recognition of negative relative to positive facial expressions whereas comparison subjects recognized negative and positive expressions at an equal level of accuracy. These results suggest that deficits in the processing negative affect from social cues are transmitted in families and may represent a heritable endophenotype of schizophrenia.     

Seasonal differences in psychopathology of male suicide completers

Suicide is known to vary according to season, with peaks in the spring and troughs in the winter. The presence of psychopathology is a significant predictor of suicidality, and it is possible that the seasonal variation of suicide completion may be related to seasonality in the manifestation of psychiatric disorders common to suicide completers. In the current study, we evaluated 115 French-Canadian male suicide completers from the Greater Montreal Area for DSM-IV psychiatric disorders using proxy-based diagnostic interviews. Subjects were assessed for seasonal differences in the prevalence of DSM-IV psychiatric diagnoses just before their deaths. Diagnoses of major depressive disorder (MDD) without comorbid cluster B personality disorders, and schizophrenia were differently distributed between seasons. Most (63.4%) subjects with MDD committed suicide in the spring/summer (P =.038). However, closer examination revealed that depressed suicides with comorbid cluster B personality disorders did not show seasonality, while 83.3% of depressed suicides without comorbid cluster B personality disorders committed suicide in the spring/summer (P =.019). 87.5% of those suicides with schizophrenia committed suicide in the fall/winter (P =.026), and the only suicide with schizophrenia who died in the spring/summer was also the only one without positive symptomology. Our study is limited to male suicide completers, and results should not be generalized to women. We conclude that seasonal variation in suicide manifests itself differently in patients with different psychopathology. These findings indicate that assessment of suicide risk may need to include consideration of possible seasonal effects, depending on psychopathology.     

Neutrophil secretion during blood coagulation: evidence for a prekallikrein independent pathway

In association with blood coagulation, neutrophils undergo a secretory response (Plow, J Clin Invest 69: 564, 1982) and it has been suggested that plasma kallikrein is responsible for inducing this reaction (Wachtfogel et al., J Clin Invest 72: 1672, 1983). To assess the contribution of kallikrein to this response, the capacity of normal and prekallikrein-deficient blood and plasma to support secretion has been compared utilizing elastase as a marker of secretion. Serial dilutions of prekallikrein-deficient plasma were as effective as normal plasma in supporting neutrophil release of elastase. The extent of elastase release in spontaneously clotting normal and prekallikrein-deficient blood was similar. At 37 degrees C in whole blood or at 22 degrees C in plasma, prekallikrein activators had the same effect in neutrophil secretion in normal and prekallikrein-deficient blood and plasma samples. Taken together, these results provide evidence for the existence of a prekallikrein independent pathway that can function as a predominant mechanism for induction of neutrophil secretion during blood coagulation.     

Electrophysiological evidence for reciprocal insulo-insular connectivity of baroreceptor-related neurons

The recent indications of specialized lateralization of cardiovascular regulation within the right and left posterior insular cortex of the rat, suggest the possibility of transcallosal connectivity between these regions. This has not been previously demonstrated using physiological techniques. Extracellular neural recordings in 34 urethane anesthetized male Sprague-Dawley rats demonstrated reciprocal interinsular antidromic and orthodromic activation, elicited with similar median onset latencies (18 ms). The corresponding conduction velocity of these fibers (0.6 m/s) suggests that they may be unmyelinated. Many of the cells showing interhemispheric connectivity also responded to baroreceptor activation, further emphasizing the connectivity pattern in baroreceptor-related units. Both 1 and 25 Hz microstimulation of the contralateral insula indicated that the most frequent orthodromic response was inhibitory, either alone or as part of a biphasic pattern including activation. Chemical stimulation of the insula using L-glutamate was associated with both excitatory and inhibitory orthodromic activation of the contralateral posterior insula, confirming that the orthodromic electrical stimulation was not solely due to activation of fibers of passage. These data suggest that the two insulae may communicate with each other to integrate and balance cardiovascular function between hemispheres.     

The differential diagnosis of impaired reciprocal social interaction in children: a review of disorders

Impairment in reciprocal social interaction in children that is less severe than autism can be difficult to diagnose due to the variety of developmental pathways that may lead to this problem. Seven childhood disorders are reviewed that include impaired reciprocal interaction: multisystem developmental disorder, nonverbal learning disability syndrome, semantic-pragmatic disorder, attachment disorders (including a developmental theory of limbic system damage), multiplex developmental disorder, schizoid personality disorder, and pervasive developmental disorder not otherwise specified. Clarification is needed for most of the disorders in the areas of operationalized criteria, assessment tools, and documenting causal relationships.     

The developmental psychopathology of social anxiety in adolescents

To evaluate a developmental psychopathology approach for understanding adolescent social anxiety, parent-reported predictors of social anxiety were examined in a nonclinical sample of adolescents. Structured diagnostic interviews were obtained from biological parents of 770 participants. Potential risk factors assessed included child characteristics: negative affect, shyness, separation anxiety disorder, and childhood chronic illness, as well as parent characteristics: major depression, panic disorder, and agoraphobia. Adolescent social anxiety was measured multiple times during high school. Findings indicate stability in social anxiety symptoms across time. Parent-reported, childhood negative affect, shyness, and chronic illness as well as parental panic disorder or agoraphobia were associated with adolescent social anxiety. Interactions were observed between parent-reported childhood shyness and gender and between parent-reported childhood shyness and parent-reported childhood chronic illness in the prediction of social anxiety. Parent-reported childhood shyness was a stronger predictor of adolescent social anxiety in females compared to males. The combined effect of subjects being positive for both parent-reported childhood shyness and parent-reported childhood chronic illness was greater than would be expected based on additive effects. This study provides support for a multifactorial and developmentally informed understanding of adolescent social anxiety.