Theory of Mind as a potential trait marker of schizophrenia: A family study

Introduction. Although there is some evidence that Theory of Mind (ToM) deficits may be trait markers of schizophrenia it is not clear yet if ToM deficits are primary deficits, that is, to be independent of deficits in general intellectual abilities and executive function. The aim was to examine if ToM deficits may be trait markers of the illness and the effect of cognitive inhibition, general intellectual abilities and depression on ToM abilities of patients with schizophrenia and their unaffected parents.

Methods. We assessed ToM abilities (first-order and second-order ToM stories, The Revised Eyes Test), cognitive inhibition (Stroop Task), general intellectual ability (Standard Progressive Matrices Test Plus) in patients with schizophrenia (N=21) and their unaffected fathers (N=21) and mothers (N=21) in comparison with healthy control families (healthy control males, N=21, healthy control fathers, N=21, healthy control mothers, N=21)

Results. Patients showed deficits in first-order ToM tasks but some of these deficits were mediated by general intellectual abilities. Impairments in cognitive inhibition mediated only patients’ performance in The Revised Eyes Test. Patients showed deficits in second-order ToM stories independently of deficits in general intellectual abilities and cognitive inhibition. Unaffected parents did not show deficits in first-order ToM tasks, whereas they showed deficits in second-order ToM stories. However, the deficits that unaffected parents showed in second-order ToM stories were mediated by their deficits in general intellectual abilities, and there was an effect of remitted depression on the unaffected mothers’ performance.

Conclusions. The results suggest that intact neurocognitive and general intellectual abilities are necessary in order patients and their unaffected parents to pass successfully ToM tasks. Patients and their unaffected parents show ToM deficits but these deficits are not similar. Patients show ToM deficits but these deficits seem to be a component of the pathophysiology of the illness (e.g., deficits in executive function, general intellectual abilities).     

Heritability of the limbic networks

Individual differences in cognitive ability and social behaviour are influenced by the variability in the structure and function of the limbic system. A strong heritability of the limbic cortex has been previously reported, but little is known about how genetic factors influence specific limbic networks. We used diffusion tensor imaging tractography to investigate heritability of different limbic tracts in 52 monozygotic and 34 dizygotic healthy adult twins. We explored the connections that contribute to the activity of three distinct functional limbic networks, namely the dorsal cingulum (‘medial default-mode network’), the ventral cingulum and the fornix (‘hippocampal-diencephalic-retrosplenial network’) and the uncinate fasciculus (‘temporo-amygdala-orbitofrontal network’). Genetic and environmental variances were mapped for multiple tract-specific measures that reflect different aspects of the underlying anatomy. We report the highest heritability for the uncinate fasciculus, a tract that underpins emotion processing, semantic cognition, and social behaviour. High to moderate genetic and shared environmental effects were found for pathways important for social behaviour and memory, for example, fornix, dorsal and ventral cingulum. These findings indicate that within the limbic system inheritance of specific traits may rely on the anatomy of distinct networks and is higher for fronto-temporal pathways dedicated to complex social behaviour and emotional processing.     

Dermatoglyphics and Schizophrenia: a meta-analysis and investigation of the impact of obstetric complications upon a-b ridge count

BACKGROUND: Patients with schizophrenia show deviances in their dermatoglyphics, in particular reductions in palmar a-b ridge counts (ABRCs), which are evidence of an early developmental deviance. However, the severity or the origin of these ABRC changes has not been established. METHOD: (i) We examined the published literature on the ABRC in patients with schizophrenia against controls with a random effects meta-analysis. (ii) We used linear regression to study the ABRC in our sample of families including 125 patients with schizophrenia, 107 of their unaffected relatives and 98 controls. (iii) The effect of obstetric complications on the patient's ABRC was examined using the Lewis Murray scale. RESULTS: The pooled standardised effect size of ABRC differences between patients and controls obtained by our meta-analysis was 0.39 (95% CI: 0.05-0.73; p=0.03). In our sample, there were no significant differences in ABRCs between those with schizophrenia, their relatives and controls. Only those patients with obstetric complications had significantly reduced ABRC compared to controls (p=0.01). CONCLUSIONS: We confirmed the presence of significant yet mild ABRC reductions in schizophrenia. These represent a subtle deviance from the norm and could be present in certain subsets of patients, possibly those who suffered early developmental insults.     

Verbal memory deficit in patients with schizophrenia: an important future target for treatment

Despite more than two-thirds of patients with schizophrenia showing reductions in delusions and hallucinations following optimum available treatment, many are left with crippling cognitive impairments. Neurocognitive deficit is a core feature of schizophrenia, but the question arises as to whether efforts should be geared towards ameliorating and normalizing these deficits. Verbal memory dysfunction is one of the most consistently reported cognitive deficits and among the best predictors of functional outcome in schizophrenia. Therefore, a better understanding of the nature of this deficit could lead to treatments that not only improve the specific systems mediating the impairment, but could also have wider implications for clinical and social outcome.     

Substantial shared genetic influences on schizophrenia and event-related potentials

OBJECTIVE: Several components of event-related potentials--P50 suppression, P300 amplitude and latency, and mismatch negativity--have been proposed as potential endophenotypes for schizophrenia on the basis of family studies. The present study used a twin design to estimate the extent of genetic overlap between these indices and the liability to schizophrenia. METHOD: The authors measured mismatch negativity, P300, and P50 suppression in 16 monozygotic twin pairs concordant for schizophrenia, nine monozygotic twin pairs discordant for schizophrenia, and 78 healthy comparison twin pairs. The study design was based on a power calculation. Structural equation modeling was used to quantify the genetic and environmental contributions to the phenotypic covariance between schizophrenia and each of the event-related potential indices. RESULTS: Significant phenotypic correlation with schizophrenia was found for each of the event-related potential components. Genetic factors were the main source of the phenotypic correlations. P50 suppression had the greatest genetic correlation with schizophrenia, followed by P300 amplitude, P300 latency, and mismatch negativity. CONCLUSIONS: All four event-related potential indices are potentially valid endophenotypes for schizophrenia, but P50 suppression and P300 amplitude show the closest genetic relationship to schizophrenia.     

Selective attention deficits reflect increased genetic vulnerability to schizophrenia

BACKGROUND: Impairment in attention is prominent in schizophrenia and may be a valuable genetic indicator for vulnerability to this disease. AIMS: We set out to characterize the attention deficits that may be associated with genetic liability to schizophrenia. METHODS: We compared attention performance in 55 people with schizophrenia, 95 of their first-degree relatives, and 61 unrelated controls. We also segregated presumed obligate carriers of genetic risk (POCs, N=12) and compared their performance with that of controls. RESULTS: Although the relatives of people with schizophrenia did not significantly differ from the normal controls on the tasks of attention, their scores were significantly ordered such that patients>relatives>normal controls during tasks of sustained and selective attention as measured by the Jonckheere-Terpstra Test (p<.05). Additionally, POCs were significantly worse than normal controls during selective attention tasks such as the Stroop (p=.03) and Letter Cancellation Task (p=.04). CONCLUSIONS: Heterogeneity in the first-degree relatives may have diluted the attention deficits present in those who are at genetic risk for schizophrenia. On the other hand, our findings in the more homogeneous group of POCs suggest that selective attention may be an indicator of genetic liability for schizophrenia.     

Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives

Structural brain abnormalities are consistently reported in schizophrenic subjects but the etiology of these abnormalities remains unclear. We tested the contribution of genetic predisposition and obstetric complications to the structural brain abnormalities found in schizophrenic probands and their relatives. MRI scans were carried out on 35 schizophrenic probands from families multiply affected with the disorder, and 63 of their unaffected relatives, including 10 parents who appeared to transmit genetic risk to their children; as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives; and finally 68 controls. Volumetric measurements of whole brain, lateral ventricles, third ventricle, cerebellum, and temporal lobes were completed for each subject. The impact of obstetric complications on brain structure was assessed across the gradient of presumed genetic predisposition. Both groups of schizophrenic probands displayed enlargement of the lateral and third ventricles, and there was a gradient of ventricular enlargement amongst the unaffected relatives in proportion to their likelihood of carrying schizophrenic genes. Ventricular enlargement was largely confined to males in both probands and unaffected relatives. Obstetric complications were associated with ventricular enlargement only in the familial probands. Non-familial probands displayed reduced volume of the temporal lobes bilaterally. In families with several schizophrenic members, ventricular enlargement is a marker for genetic liability, particularly in males. Individuals inheriting the susceptibility to schizophrenia appear particularly prone to develop ventricular enlargement in response to obstetric complications.     

Episodic memory performance predicted by the 2bp deletion in exon 6 of the "alpha 7-like" nicotinic receptor subunit gene

OBJECTIVE: There is evidence of linkage between chromosome 15q14 and the P50 auditory evoked response, a heritable neuropsychological marker associated with increased risk of schizophrenia. Chromosome 15q14 harbors the alpha-7 nicotinic receptor subunit gene (CHRNA7) and a hybrid gene of unknown function (CHRFAM7A). CHRNA7 is involved in memory formation, a core dysfunction in schizophrenia. The authors set out to determine if this locus is associated with memory dysfunction in schizophrenia. METHOD: A 2bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene and has previously been associated with P50 deficit, was genotyped in 251 individuals from the Maudsley Family Study of schizophrenia. Episodic memory function was assessed using the Wechsler Memory Scale. RESULTS: Significant associations were identified with delayed recall and percentage retained, with the presence of the deletion predicting worse performance. CONCLUSIONS: These observations indicate that episodic memory function is a schizophrenia endophenotype and implicate the CHRFAM7A/CHRNA7 locus in modulating its function.