Increased Cerebellar Functional Connectivity With the Default-Mode Network in Unaffected Siblings of Schizophrenia Patients at Rest

The default-mode network (DMN) is vital in the neurobiology of schizophrenia, and the cerebellum participates in the high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities remains unclear in unaffected siblings of schizophrenia patients. Forty-six unaffected siblings of schizophrenia patients and 46 healthy controls were recruited for a resting-state scan. The images were analyzed using the functional connectivity (FC) method. The siblings showed significantly increased FCs between the left Crus I and the left superior medial prefrontal cortex (MPFC), as well as between the lobule IX and the bilateral MPFC (orbital part) and right superior MPFC compared with the controls. No significantly decreased FC was observed in the siblings relative to the controls. The analyses were replicated in 49 first-episode, drug-naive patients with schizophrenia, and the results showed that the siblings and the patients shared increased FCs between the left Crus I and the left superior MPFC, as well as between the lobule IX and the left MPFC (orbital part) compared with the controls. These findings suggest that increased cerebellar-DMN connectivities emerge earlier than illness onset, which highlight the contribution of the cerebellum to the DMN alterations in unaffected siblings. The shared increased cerebellar-DMN connectivities between the patients and the siblings may be used as candidate endophenotypes for schizophrenia.Key words: unaffected siblings of schizophrenia patients, schizophrenia, cerebellum, functional connectivity, default-mode network     

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.Key words: ventral striatum, orbitofrontal cortex, ventromedial prefrontal cortex, monetary incentive delay task, genetic vulnerability, cue processing     

Galectin-1 and Galectin-3 Levels in Patients with Schizophrenia and their Unaffected Siblings

Many hypothesis suggest that inflammation plays an important role in schizophrenia. Galectins can regulate inflammatory response in central nervous system. The relation between galectins and neuropsyhchiatric diseases and schizophrenia is unclear. The present study compared levels of Gal-1 and Gal-3 of patients with schizophrenia to that of first-degree relatives without the disease and healthy controls in order to evaluate any possible association. Sixty-two patients with schizophrenia, fifty-five unaffected siblings and fifty-eight age- and sex-matched healthy controls enrolled. Serum Gal-1, Gal-3 and CRP levels were measured. PANNS and CGI-S were used to evaluate the severity of disease. There was a statistically significant difference in serum Gal-1 levels among the patient, sibling, and control groups. There were no statistically significant correlations between serum CRP ??and serum Gal-1 or Gal-3 levels. Gal-1 values were significantly higher in the unaffected siblings compared to both the patient group and the healthy control group. Gal-3 levels were elevated in the sibling group relative to the patient group. In the literature, the relationship between galectins and schizophrenia is very limited and appears to be a new field of study. Future studies are needed to evaluate the protective roles of galectins.

     

Anatomical Distance Affects Functional Connectivity in Patients With Schizophrenia and Their Siblings

Background: The efficiency of human brain depends on the integrity of both long- and short-range connections, but the long-range connections need to be “penalized” to reduce overall wiring costs. This principle, termed as the anatomical distance function (ADF), refers to the presence of an inverse relationship between anatomical distance and connectivity. A crucial developmental feature that occurs in normal adolescence is the weakening of ADF, which is characterized by a selective strengthening of long-distance connections. Schizophrenia is associated with widespread dysconnectivity that is linked to aberrant cortical development. Methods: We studied the ADF in adults with schizophrenia (n = 28), their age-matched siblings (n = 28), and healthy controls (n = 60). We investigated the proportional abnormalities in the long-range connections involving interhemispheric, subcortical, frontal, and salience network regions and localized the connections showing most significant changes in schizophrenia. The groups were discriminated on the basis of short- and long-range connectivity using a machine-learning algorithm. Results: Both patients and their siblings showed abnormally pronounced ADF. This was associated with a disproportionate reduction in the number of long-range connections, affecting the subcortical, interhemispheric, and the salience network connections. The abnormalities in long-range connections had superior ability to accurately identify group membership. Conclusions: A crucial organizing principle of the brain architecture that becomes apparent during normal adolescence is disturbed in schizophrenia. While siblings show some evidence of compensating for this deficit, patients lack putative compensatory changes. Age-related shift in ADF provides an explanatory framework for the developmental emergence of widespread dysconnectivity that is influenced by genetic risk in schizophrenia.Key words: anatomical distance, schizophrenia, genetic risk, functional connectivity, wiring cost, salience network     

Correction to: Galectin-1 and Galectin-3 Levels in Patients with Schizophrenia and their Unaffected Siblings

Psychiatric Quarterly - The original version of this article unfortunately contained a mistake. The name of the 5th author was incorrectly listed as Çi?dem Yüksel, when it is...     

Schizophrenic Patients and Their Unaffected Siblings Share Increased Resting-State Connectivity in the Task-Negative Network but Not Its Anticorrelated Task-Positive Network

Background:

Abnormal connectivity of the anticorrelated intrinsic networks, the task-negative network (TNN), and the task-positive network (TPN) is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings enable further understanding of illness susceptibility and pathophysiology. We examined the resting-state connectivity differences in the intrinsic networks between schizophrenic patients, their unaffected siblings, and healthy controls.

Methods:

Resting-state functional magnetic resonance images were obtained from 25 individuals in each subject group. The posterior cingulate cortex/precuneus and right dorsolateral prefrontal cortex were used as seed regions to identify the TNN and TPN through functional connectivity analysis. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to all subject groups.

Results:

Schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. By contrast, schizophrenic patients alone demonstrated increased connectivity between the posterior cingulate cortex/precuneus and left inferior temporal gyrus and between the ventral medial prefrontal cortex and right lateral parietal cortex in the TNN. Schizophrenic patients exhibited increased connectivity between the left dorsolateral prefrontal cortex and right inferior frontal gyrus in the TPN relative to their unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls.

Conclusion:

Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.     

Odor Hedonic Capacity and Anhedonia in Schizophrenia and Unaffected First-Degree Relatives of Schizophrenia Patients

Objective: There is increasing evidence that schizophrenia patients have difficulties in the hedonic appraisal of odors. In a prior study, we assessed olfactory hedonic perception birhinally and found that males with schizophrenia failed to attach the appropriate hedonic valence to a pleasant odor, despite correctly perceiving changes in odor intensity. Female patients, in contrast, exhibited normal responses. The current study extends this work by examining odor valence processing in unaffected first-degree relatives of schizophrenia patients, to determine the extent to which this abnormality may be genetically mediated. We also examine odor valence processing unirhinally, rather than birhinally, to probe possible lateralized differences in patients’ hedonic processing deficits. Method: Individuals with schizophrenia (n = 54), first-degree unaffected family members (n = 22), and demographically matched controls (n = 45) were administered the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test. Results: In contrast to family members and controls, both male and female schizophrenia probands underevaluated the hedonic characteristics of amyl acetate at lower concentrations and overevaluated its pleasantness at concentrations perceived as unpleasant by both controls and relatives. These patient-specific differences could not be explained by differences in smoking habit, medication use, or subjective ratings of odor intensity. However, they were associated with increased levels of anhedonia/asociality and negative symptomatology. Conclusions: Our findings suggest that both male and female schizophrenia patients have difficulties in the unirhinal appraisal of hedonic valence. Normal responses in unaffected first-degree relatives suggest that this is an environmentally, rather than genetically, mediated abnormality denoting negative symptomatology.     

Cognitive Factor Structure and Invariance in People With Schizophrenia,Their Unaffected Siblings,and Controls

Introduction: Separable, but positively correlated, factors emerge from analyses of cognitive test data in schizophrenia and control samples (eg, verbal memory and processing speed) and these factors guide data reduction. Additionally, data support a hierarchical model of cognitive performance, in which these correlations reflect the influence of a higher-order factor, referred to as “g.” We tested these findings in large, carefully screened samples of people with schizophrenia (n = 496), their unaffected siblings (n = 504), and controls (n = 823). Furthermore, we tested the hypothesis that cognitive performance in schizophrenia is more generalized across domains than among siblings and controls. Method: A combination of exploratory and confirmatory factor analyses (EFA and CFA) and multiple groups CFA (MCFA) was used. Results: EFA yielded factors for verbal memory, visual memory, processing speed, working memory span, nback performance, and card sorting. The solution was consistent across groups, in terms of the factor assignments of individual cognitive variables and the magnitude of loadings. Method variance may have contributed to the card sorting, visual memory, and nback factors. CFA indicated that the hierarchical model, incorporating a “g” factor, was a good fit for data from all groups. MCFA suggested that this hierarchical structure was fully invariant for controls and siblings. While the variable/factor loadings for the schizophrenia group also were invariant with comparison groups, factor/“g” loadings were higher in schizophrenia, as were correlations among factor-based composite scores. Conclusions: Cognitive variables sort into domains consistently in schizophrenia, unaffected siblings, and controls. However, performance in schizophrenia is more generalized and less domain specific.     

Autonomic Dysfunction in Unaffected First-Degree Relatives of Patients Suffering From Schizophrenia

Recent studies revealed cardiac autonomic dysfunction in patients with acute schizophrenia, which appears to be mainly related to reduced vagal and increased sympathetic modulation. To understand the significance of cardiac autonomic function in patients with schizophrenia, we extended these studies to relatives of patients. In this study, we assessed cardiac autonomic modulation in healthy first-degree relatives of patients with schizophrenia (n = 36) to investigate a putative genetic influence. Data were compared with control subjects matched for age, gender, and physical activity as well as to patients suffering from schizophrenia. First-degree relatives showed an attenuated, yet identical pattern in autonomic dysfunction as patients with decreased vagal modulation of heart rate, decreased baroreflex sensitivity, but no difference in blood pressure variability could be detected. The patients'' relatives also showed a similar pattern in regards to QT variability. In addition, the subgroup comparison of offspring vs. siblings showed a significant difference in heart rate variability suggesting a higher degree of heritability in offspring. In conclusion, the pattern of autonomic dysfunction seen in patients and relatives might indicate underlying disease-inherent genetic vulnerability, especially because autonomic parameters are heritable. In addition, these findings may be of value to identify the high-risk group of patients'' relatives in regards to serious cardiovascular events so that early preventive measures can be taken.     

Morbidity Risk of Schizophrenia to Parents and Siblings of Schizophrenic Patients

Abstract: In order to estimate the familial morbidity risk of schizophrenia, parents and siblings of 1,691 inpatients meeting the DSM-III criteria for schizophrenia were investigated on the basis of a review of medical records, family history data and/or personal interviews. The morbidity risks of schizophrenia to parents and siblings of the schizophrenic probands were 4.0% and 4.1%, respectively, which were greater than the morbidity risk in the general population. Siblings of 118 probands whose parents suffered from schizophrenia were at a significantly greater risk of schizophrenia than siblings of 1,493 probands whose parents did not have schizophrenic illness. These findings support thenotion of familial transmission of schizophrenia. A total of 16.4% of the schizophrenic probands had at least one first-degree relative with schizophrenia. This is significantly greater in the female probands than in the male probands.     

School Functions in Unaffected Siblings of Youths with Autism Spectrum Disorders

This study investigated school functioning among unaffected siblings of youths with autistic spectrum disorder (ASD) and identified the correlates for school maladjustment. We recruited 66 youths with a clinical diagnosis of ASD, aged 8–19, their unaffected siblings and 132 typically developing controls (TD). We found that ASD youths had poorer school functions than unaffected siblings and TD. Unaffected siblings had poorer attitude toward schoolwork and more severe behavioral problems at school than TD. Several associated factors for different scholastic functional domains (i.e., academic performance, attitude toward school work, social interactions, behavioral problems) in the siblings included IQ, autistic traits, inattention/oppositional symptoms, sibling relationships, etc. Our findings suggest the need of assessing school functions in unaffected siblings of ASD. Trial registration: Clinical trial registration identifier: NCT01582256