Hypofrontality -- a risk-marker related to schizophrenia?

In order to better understand whether cortical hypoactivation and hypofrontality is a possible risk marker for schizophrenia, we investigated resting EEG activity in 39 unmedicated schizophrenics and 21 persons with schizotypal personality. Compared to a normal control group, we found an increased, frontally pronounced delta activity in schizophrenic patients, a result that is in accordance with other studies. Subjects with schizotypal personality, who are believed to have an increased risk for schizophrenia, did not show an increase of delta activity. From this result, we concluded that cortical hypoactivation and hypofrontality -- defined as an increase of frontally pronounced delta activity during resting EEG -- cannot be interpreted as a risk factor for schizophrenia. However, since it is controversial whether subjects with schizotypal personality are at increased risk for schizophrenia, further studies in unaffected family members of schizophrenic patients are needed.     

The impact of gender and age at onset on the familial aggregation of schizophrenia

Summary Some recent family studies have shown that the familial risk for schizophrenia is higher in female than in male schizophrenics. It is debated whether the risks for the other disorders, such as schizotypal personality disorder or affective disorders in families of schizophrenics are similarly influenced by the proband's gender. Also, the reason for the effect of proband's gender on the recurrence risk for schizophrenia has not been clarified. This family study (159 probands, 589 first degree relatives) confirms that schizophrenia, but also schizophrenia spectrum disorders were more frequent in families of female compared with male schizophrenics. Neither age at onset in probands nor the interaction between gender and age at onset in probands had a relevant impact on the risk figures in relatives. Affective disorders occurred in families independently of the probands' gender. Aetiological heterogeneity or ascertainment bias may account for the modifying effect of proband's gender in schizophrenia.     

Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder

OBJECTIVE: The schizophrenia spectrum includes individuals with schizophrenia, their relatives, and individuals with schizotypal personality disorder. Subjects in the schizophrenia spectrum have disorders of attention, cognition, and information processing. Attention and information processing can be assessed by testing suppression of the P50 event-related potential; the amplitude of the P50 wave is measured in response to each of two auditory clicks. In normal subjects, the P50 wave following the second click is suppressed, or "gated." Schizophrenic patients and their relatives show less suppression of the second P50 wave. Deficits in P50 suppression have high heritability and show linkage to the alpha-7 subunit of the nicotinic cholinergic receptor gene in families with schizophrenia, suggesting that deficits in P50 suppression are trait markers for gating abnormalities in schizophrenia spectrum subjects. Although schizotypal subjects have been shown to have deficits in sensorimotor gating as measured by prepulse inhibition, to the authors' knowledge P50 sensory gating in schizotypal personality disorder has yet to be reported. METHOD: P50 suppression in 26 subjects with schizotypal personality disorder and 23 normal subjects was assessed through auditory conditioning and testing. RESULTS: The subjects with schizotypal personality had significantly less P50 suppression than did the normal subjects. CONCLUSIONS: Subjects with schizotypal personality disorder may have trait-linked sensory gating deficits similar to those in patients with schizophrenia and their relatives. Because these subjects may manifest sensory gating deficits without overt psychotic symptoms, it is likely that these deficits represent a core cognitive dysfunction of the schizophrenia spectrum.     

EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder

OBJECTIVE: The authors tested whether neural synchronization deficits were present in subjects with schizophrenia and schizotypal personality disorder. METHOD: Amplitude-modulated tones were used to evaluate auditory steady-state evoked potential entrainment in a combined group of 21 subjects with schizophrenia or schizoaffective disorder, 11 subjects with schizotypal personality disorder, and 22 nonpsychiatric comparison subjects. RESULTS: The schizophrenia or schizoaffective disorder group exhibited decreased power compared to the schizotypal personality disorder and nonpsychiatric comparison groups. There were no differences between groups in N100 amplitude. CONCLUSIONS: Subjects with schizophrenia but not subjects with schizotypal personality disorder have deficits in steady-state responses to periodic stimuli, despite an intact response to sensory-evoked potentials (N100). These deficits reflect aberrant neural synchronization or resolution and may contribute to disturbed perceptual and cognitive integration in schizophrenia.     

Elevated levels of schizotypal features in parents of patients with a family history of schizophrenia spectrum disorders

There is some evidence that schizotypal traits are related to a genetic or familial liability to develop schizophrenia. However, it is unclear whether the number of schizotypal traits is elevated in parents of schizophrenia patients compared with controls. This study used the Schizotypal Personality Questionnaire to investigate the difference in number of schizotypal traits between both parents of 36 patients with schizophrenia (n = 72 persons) and 26 healthy married control couples (n = 52 persons). Parents of patients had a lower score on the positive dimension of schizotypy than healthy controls. There was no difference on the negative or disorganization dimension between groups. The difference on the positive dimension might have been caused by a difference in response style between parents of patients and controls due to the fact that parents are more familiar with schizophrenia than controls. Of interest, parents with a family history of schizophrenia spectrum disorders had more positive and negative schizotypal traits than parents without a family history of schizophrenia spectrum disorders. Because these two groups of parents differ in only genetic risk, not familiarity with schizophrenia, results suggest that the negative and positive dimension of schizotypy are related to a familial or genetic vulnerability to schizophrenia.     

Age-of-onset in schizophrenia and schizotypal disorders. Clinical and genetic implications

Age-of-onset data were gathered on 93 chronic schizophrenic probands and 57 affected (mainly schizotypal) siblings. 55% of affected individuals were ill before age 20 and 14% had their onset before age 14. The risk period for schizophrenia and schizotypal personality disorders terminated at age 40. Age-of-onset did not distinguish paranoid from nonparanoid schizophrenics, or definite from probable schizotypal personalities. Schizophrenic and schizotypal subjects were similar in their age-of-onset patterns. Sex effect on age-of-onset was not present. A square-root normal distribution gave the best fit to the data. The implications of these findings for schizophrenia research were discussed.     

Schizotypal symptoms in the relatives of schizophrenia patients: an empirical analysis of the factor structure

This study examined the nature of schizotypal symptoms in the relatives of schizophrenia patients and investigated phenomenological differences in symptomatology manifested by a familial sample and a clinical sample of personality disorder patients. Confirmatory factor analyses were used to test models of DSM-III-R schizotypal symptoms in the first degree relatives (n = 172) of schizophrenia patients. A multisample analysis was conducted to determine whether the same model adequately described the schizotypal symptoms rated in the relatives of schizophrenia patients and in clinically selected personality disorder patients. The results indicated that a three-factor model consisting of cognitive/perceptual, interpersonal, and disorganization factors yielded the best fit to the data from the relatives of schizophrenia patients, but that this model did not adequately describe both the relatives of schizophrenia patients and personality disorder patients. These findings indicate that the structure of schizotypal symptoms in the relatives of schizophrenia patients is similar to the three-factor model of schizophrenia symptoms often reported, but not the same as the structure of schizotypal symptoms in clinically selected personality disorder patients.     

Auditory steady state response in the schizophrenia, first-degree relatives, and schizotypal personality disorder

The power and phase synchronization of the auditory steady state response (ASSR) at 40 Hz stimulation is usually reduced in schizophrenia (SZ). The sensitivity of the 40 Hz ASSR to schizophrenia spectrum phenotypes, such as schizotypal personality disorder (SPD), or to familial risk has been less well characterized. We compared the ASSR of patients with SZ, persons with schizotypal personality disorder, first degree relatives of patients with SZ, and healthy control participants. ASSRs were obtained to 20, 30, 40 and 50 Hz click trains, and assessed using measures of power (mean trial power or MTP) and phase consistency (phase locking factor or PLF). The MTP to 40 Hz stimulation was reduced in relatives, and there was a trend for MTP reduction in SZ. The 40 Hz ASSR was not reduced in SPD participants. PLF did not differ among groups. These data suggest the 40 Hz ASSR is sensitive to familial risk factors associated with schizophrenia.     

Schizotypal personality traits in nonpsychotic relatives are associated with positive symptoms in psychotic probands

There remains disagreement over whether increased risk of schizotypal personality disorder (SPD) is confined to the relatives of patients with a diagnosis of schizophrenia or whether it is a more general characteristic of the relatives of all psychotic patients. To examine the relationship between schizotypal dimensions in relatives and psychopathological syndromes in patients with functional psychoses, factor analysis was carried out on (1) ratings from Present State Examination (PSE) interviews with 172 consecutively admitted patients with psychosis (52% of them with schizophrenia), and (2) ratings on items from three schizotypal scales concerning 263 of their nonpsychotic first degree relatives. The factors derived from the patients' PSE interviews were correlated with the schizotypal factors and the nine DSM-IV criteria for SPD concerning the relatives and subjected to a canonical correlation analysis. In this study, no differences were observed concerning the distribution of schizotypal factors or DSM-IV schizotypal features in the relatives of patients with different psychotic diagnoses. However, a syndrome characterized by delusions, hallucinations, and thought interference (positive symptoms) in patients was correlated with high scores on the three schizotypy scales and with positive and negative schizotypal features in relatives.     

Relationship of schizotypal personality disorder to schizophrenia: genetics

The adoptive, family, and twin studies show that schizotypal personality features are found among the relatives of schizophrenics. However, it has not been shown that there is a higher risk of schizophrenia among the relatives of schizotypals. An explanation may be that the current DSM-III criteria of schizotypal personality disorder do not adequately define schizotypals genetically related to schizophrenia. While some of the cases that meet DSM-III criteria are within the schizophrenia spectrum, others are unrelated to schizophrenia. There is reason to believe that schizotypals characterized by distant relationship to others, suspiciousness, eccentricity, peculiar communication, and dysfunctional school and work performance are within the schizophrenic sphere, while individuals with psychotic-like symptoms phenomenologically similar to schizophrenia and diagnosed as schizotypal personality disorders in DSM-III represent decompensation of other personality disorders.     

Morbidity risk of psychiatric disorders among the first degree relatives of schizophrenia patients in Taiwan

This study aimed to assess the boundaries of the schizophrenia spectrum and whether inclusion of such phenotypes increases power for linkage analysis of schizophrenia. Participants were 234 first degree relatives (FDRs) of 94 schizophrenia probands in Northern Taiwan who completed a direct interview using the Diagnostic Interview for Genetic Studies (DIGS). Based on best estimate diagnosis, the morbidity risk in the relatives for schizophrenia was 2.5 percent (Weinberg's shorter method) or 3.9 percent (Kaplan-Meier estimate). Depending on the stringency of diagnosis, lifetime prevalence was 2.6 percent to 4.7 percent for schizotypal personality disorder, 3.4 percent to 8.6 percent for paranoid personality disorder, and 1.3 percent to 3.4 percent for schizoid personality disorder. These figures are significantly higher than the corresponding figures in the general population. However, none of the recurrence risk ratio for any spectrum that included both schizophrenia and a personality disorder (3.0 to 5.9) was greater than that of schizophrenia alone (9.3 to 14.4). Thus, including schizophrenia-related personality disorders in the spectrum did not increase power for linkage analysis of schizophrenia.     

Morphologic alterations of the parcellated superior temporal gyrus in schizophrenia spectrum

Morphologic abnormalities of the superior temporal gyrus (STG) as well as its sub-regions such as Heschl's gyrus (HG) or planum temporale (PT) have been reported in schizophrenia patients, but have not been extensively studied in schizotypal subjects. In the present study, magnetic resonance images were acquired from 65 schizophrenia patients, 39 schizotypal disorder patients, and 72 healthy controls. Volumetric analyses were performed using consecutive 1-mm coronal slices on the temporal pole (TP) and superior temporal sub-regions [planum polare (PP), HG, PT, rostral STG, and caudal STG]. The HG was significantly smaller in schizophrenia patients compared with controls but not in schizotypal patients, while volume reductions of the left PT and bilateral caudal STG were common to both disorders. The TP gray matter was larger in female schizotypal patients compared with female schizophrenia patients. There were no significant group differences in the PP and rostral STG volume. In the subgroup of early phase schizophrenia patients (illness duration <1.0 year), smaller volumes for the left PP and rostral STG were correlated with hallucinations and delusions. Our findings suggest that morphologic changes in the posterior regions of the STG are common to the schizophrenia spectrum, whereas less involvement of the HG, and possibly the PP and rostral STG might be related to the sparing of schizotypal patients from developing overt psychosis.     

Orbitofrontal sulcogyral pattern and olfactory sulcus depth in the schizophrenia spectrum

Morphological changes in the orbitofrontal cortex (OFC), such as an altered sulcogyral pattern of the ‘H-shaped’ orbital sulcus and a shallow olfactory sulcus, have been demonstrated in schizophrenia, possibly reflecting deviations in early neurodevelopment. However, it remains unclear whether patients with schizotypal features exhibit similar OFC changes. This magnetic resonance imaging study examined the OFC sulcogyral pattern (Types I, II, III, and IV) and olfactory sulcus morphology in 102 patients with schizophrenia, 47 patients with schizotypal disorder, and 84 healthy controls. The OFC sulcogyral pattern distribution between the groups was significantly different on the right hemisphere, with the schizophrenia patients showing a decrease in Type I (vs controls and schizotypal patients) and an increase in Type III (vs controls) expression. However, the schizotypal patients and controls did not differ in the OFC pattern. There were significant group differences in the olfactory sulcus depth bilaterally (schizophrenia patients < schizotypal patients < controls). Our findings suggest that schizotypal disorder, a milder form of schizophrenia spectrum disorders, partly shares the OFC changes (i.e., altered depth of the olfactory sulcus) with schizophrenia, possibly reflecting a common disease vulnerability. However, altered distribution of the OFC pattern specific to schizophrenia may at least partly reflect neurodevelopmental pathology related to a greater susceptibility to overt psychosis.     

Heredity-environment interaction and schizophrenia

The longitudinal prospective study of populations at risk is considered a powerful strategy towards disentangling hereditary and environmental factors. Data from Mednick and Schulsinger's 1962 study in Copenhagen, on children at high-risk for schizophrenia are used as an illustration. Pregnancy and birth complications, as well as institutional rearing in early childhood contributes towards schizophrenia in the risk children, but not in the low-risk controls. Risk children with an outcome of schizotypal personality disorder were hardly exposed to perinatal complications. To some extent, schizophrenia may be considered as a complicated form of schizotypal personality disorder, which again may be a genetically transmitted condition.     

Smaller left Heschl's gyrus volume in patients with schizotypal personality disorder

OBJECTIVE: Individuals with schizophrenia spectrum disorders evince similar genetic, neurotransmitter, neuropsychological, electrophysiological, and structural abnormalities. Magnetic resonance imaging (MRI) studies have shown smaller gray matter volume in patients with schizotypal personality disorder than in matched comparison subjects in the left superior temporal gyrus, an area important for language processing. In a further exploration, the authors studied two components of the superior temporal gyrus: Heschl's gyrus and the planum temporale. METHOD: MRI scans were acquired from 21 male, neuroleptic-naive subjects recruited from the community who met DSM-IV criteria for schizotypal personality disorder and 22 male comparison subjects similar in age. Eighteen of the 21 subjects with schizotypal personality disorder had additional comorbid, nonpsychotic diagnoses. The superior temporal gyrus was manually delineated on coronal images with subsequent identification of Heschl's gyrus and the planum temporale. Exploratory correlations between region of interest volumes and neuropsychological measures were also performed. RESULTS: Left Heschl's gyrus gray matter volume was 21% smaller in the schizotypal personality disorder subjects than in the comparison subjects, a difference that was not associated with the presence of comorbid axis I disorders. There were no between-group volume differences in right Heschl's gyrus or in the right or left planum temporale. Exploratory analyses also showed a correlation between poor logical memory and smaller left Heschl's gyrus volume. CONCLUSIONS: Smaller left Heschl's gyrus gray matter volume in subjects with schizotypal personality disorder may help to explain the previously reported abnormality in the left superior temporal gyrus and may be a vulnerability marker for schizophrenia spectrum disorders.     

Do schizotypal symptoms mediate the relationship between genetic risk for schizophrenia and impaired neuropsychological performance in co-twins of schizophrenic patients?

BACKGROUND: Neurocognitive deficits and symptoms of schizotypal personality disorder are both elevated in the first-degree relatives of schizophrenic patients, but their relationship to each other and their potential common genetic source remain unclear. METHODS: Fifty unaffected co-twins of schizophrenic patients and 123 control twins were assessed with a neuropsychological battery and structured clinical interviews. RESULTS: Working memory was influenced by genetic risk for schizophrenia but not schizotypal symptoms. Nearly all other domains were influenced by schizotypy symptoms but only in the co-twins of schizophrenic patients. Schizotypy symptoms in the absence of a family history did not seem to be related to impaired neurocognitive functioning. CONCLUSIONS: Schizotypy symptoms in those with genetic risk for schizophrenia are associated with increased risk for cognitive deficits. Some neurocognitive deficits might covary with subpsychotic symptoms due to a shared genetic factor. Community-ascertained schizotypal individuals might not be appropriate for modeling underlying genetic risk for schizophrenia.     

Prevalence of large cavum septi pellucidi and its relation to the medial temporal lobe structures in schizophrenia spectrum

Magnetic resonance imaging was used to evaluate the prevalence of the cavum septi pellucidi (CSP) in 154 schizophrenia patients, 47 schizotypal disorder patients, and 163 healthy controls. We also explored the relation of a large CSP (> or =6 mm) with medial temporal lobe structures. No significant difference was found in the prevalence of the CSP (76.0% of the schizophrenia patients, 81.6% of the controls, and 85.1% of the schizotypal patients) or the large CSP (6.5% of the schizophrenia patients, 7.4% of the controls, and 10.6% of the schizotypal patients) among the groups, but patients with a large CSP (10 schizophrenia and 5 schizotypal patients) had smaller volumes of bilateral amygdala and left posterior parahippocampal gyrus than patients without it. In the control subjects, the large CSP did not affect the volumes of the medial temporal lobe structures. These findings might reflect neurodevelopmental abnormalities in midline and associated limbic structures of the brain in schizophrenia spectrum.     

Schizotypal dimensions: continuity between schizophrenia and bipolar disorders

BACKGROUND: Family studies have suggested that schizophrenia and bipolar disorders share some susceptibility factors. Schizotypal personality disorder (SPD) may be an intermediate phenotype common both to schizophrenia and bipolar disorders. We explored the familiality of schizotypal dimensions by comparing the magnitude of schizotypal dimensions between schizophrenic and bipolar relatives. We also looked for intra-familial resemblance for these dimensions, and for an increased familial risk of schizophrenia and/or bipolar disorders associated with a particular schizotypal dimension. METHODS: We used the Schizotypal Personality Questionnaire (SPQ) to study the three schizotypal dimensions (disorganization, negative and positive) in a sample of unaffected first-degree relatives of schizophrenic (N=85), psychotic bipolar (N=63) and bipolar (N=32) probands. Differences between groups were tested using a two-tailed t-test or ANOVA for continuous variables and a chi-squared test for discrete variables. We used the intraclass correlation method to study the intra-familial correlation. Linear mixed models were used to measure the familial risk. RESULTS: The disorganization dimension appears to be common to relatives of both schizophrenia and psychotic bipolar disorders, but not in the relatives of non-psychotic bipolar probands. This dimension also increases the familial risk of these two disorders. The negative dimension shows intra-familial resemblance (R=0.29), we failed to observe the expected familiality for the disorganized dimension. CONCLUSIONS: The shared nature of the disorganization dimension shown by a similar familial risk for schizophrenia and psychotic bipolar disorders suggests that same genetic background may underlie psychotic disorders. Although, negative dimension is familial, it is not associated for an increased familial risk for both disorders.     

Volumetric MRI study of the short and long insular cortices in schizophrenia spectrum disorders

We have previously reported volume reductions of the insular cortex in schizophrenia, but it is still not clear whether insular cortex volume loss preferentially involves the anterior (short insular cortex) or posterior (long insular cortex) portion. On the other hand, no volumetric studies of the brain have examined changes in insular cortex volume in subjects with schizotypal features. In this study, we separately investigated the volumes of the short and long insular cortex portions using magnetic resonance imaging in 37 schizotypal disorder patients (24 males, 13 females), 62 schizophrenia patients (32 males, 30 females), and 69 healthy controls (35 males, 34 females). While the volumes of the short and long insular cortex were significantly reduced in schizophrenia patients compared with schizotypal disorder patients and control subjects, there was no difference between schizotypal disorder patients and control subjects. These results suggest that the volume reduction of the insular cortex may be specific to overt schizophrenia without topographically specific localization.     

Lack of normal gender differences of the perigenual cingulate gyrus in schizophrenia spectrum disorders

Abstract. We have previously reported a lack of normal gender differences of the perigenual cingulate gyrus in patients with schizophrenia. The purpose of this study was to examine the perigenual cingulate gyrus morphology in patients with schizotypal disorder. We investigated volume of the gray and white matter of the perigenual cingulate gyrus in 26 patients with schizotypal disorder (14 males, 12 females) in comparison with 61 age- and gender-matched healthy controls (30 males, 31 females) and 58 schizophrenia patients (31 males, 27 females) using magnetic resonance imaging. The volumetric measures of the perigenual cingulate gyrus were compared among the three groups that were entered into the same multiple analysis of variance model. The gray and white matter volume of the perigenual cingulate gyrus in the schizotypal patients did not differ significantly from the values in the healthy controls or the schizophrenia patients. Similar to schizophrenia, however, the schizotypal patients showed a lack of normal gender differences of the perigenual cingulate gray matter seen in the healthy controls (females > males). These results suggest that both schizotypal and schizophrenia patients may share the same disruption of the normal pattern of gender differences of the perigenual cingulate gyrus.