Matti O. Huttunen

Genetic influences on brain structure

Here we report on detailed three-dimensional maps revealing how brain structure is influenced by individual genetic differences. A genetic continuum was detected in which brain structure was increasingly similar in subjects with increasing genetic affinity. Genetic factors significantly influenced cortical structure in Brocas and Wernickes language areas, as well as frontal brain regions (r2MZ > 0.8, p < 0.05). Preliminary correlations were performed suggesting that frontal gray matter differences may be linked to Spearmans g, which measures successful test performance across multiple cognitive domains (p < 0.05). These genetic brain maps reveal how genes determine individual differences, and may shed light on the heritability of cognitive and linguistic skills, as well as genetic liability for diseases that affect the human cortex.

Spatial working memory as an endophenotype for schizophrenia

BACKGROUND Spatial working memory impairments are among the neurocognitive deficits that may mark genetic predisposition toward schizophrenia. We previously reported that impairment on the spatial span subtask of the Wechsler Adult Intelligence Scale-Revised increased in a dose-dependent manner with increasing genetic predisposition toward schizophrenia in a sample of discordant twins; however, it remains to be determined whether these deficits reflect difficulties with encoding, maintenance, manipulation, time-tagging of visual spatial information, storage capacity, or complex motor response. METHODS We developed a spatial delayed response task in which memory set size was parametrically varied, holding constant manipulation and decision processes. We then reassessed 80 of the previously studied twins (17 probands with 8 monozygotic co-twins and 13 dizygotic co-twins, and 42 healthy twins). RESULTS The spatial delayed response task was sensitive to genetic loading for schizophrenia but did not provide evidence for capacity limitations in probands or their co-twins. CONCLUSIONS The findings suggest that deficits in the encoding or storage aspects of short-term spatial mnemonic processing may be an effective endophenotypic marker for schizophrenia.

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice

Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.

Prenatal teratogens and the development of adult mental illness.

Our findings in the Helsinki Influenza Study and the Danish Forty Year Study lead us to conclude that a 2nd-trimester maternal influenza infection may increase risk for adult schizophrenia or adult major affective disorder. More recently we have also reported an increase of unipolar depression among offspring who were exposed prenatally to a severe earthquake (7.8 on the Richter scale) in Tangshan, China. Among the earthquake-exposed males (but not the females), we observed a significantly greater depression response for those individuals exposed during the 2nd trimester of gestation. These findings suggest that maternal influenza infection and severe maternal stress may operate (in different ways) as teratogens, disrupting the development of the fetal brain and increasing risk for developing schizophrenia or depression in adulthood.

Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia.

OBJECTIVE The authors sought to determine whether prenatal exposure to infection and a positive family history of psychotic disorders interact synergistically to increase the risk of later developing schizophrenia. METHOD The authors linked two national registers, the Medical Birth Register and the Finnish Population Register, to identify all women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection (N=9,596) between 1947 and 1990. The Finnish Hospital Discharge Register was used to ascertain psychiatric outcomes in adulthood of offspring exposed to infection prenatally. Family history of psychotic disorders was determined by linking the Hospital Discharge Register and the Population Register. The authors used an additive statistical interaction model to calculate the amount of biological synergism between positive family history and prenatal exposure to infection. RESULTS Prenatal exposure to infection did not significantly increase the risk of schizophrenia. However, the effect of prenatal exposure to pyelonephritis was five times greater in those who had a family history of psychosis compared to those who did not. The synergy analysis suggested that an estimated 38%-46% of the offspring who developed schizophrenia and had both prenatal exposure to infection and a positive family history of psychotic disorders did so as a result of the synergistic action of both risk factors. CONCLUSIONS These findings support a mechanism of gene-environment interaction in the causation of schizophrenia.

The Genetic Epidemiology of Schizophrenia in a Finnish Twin Cohort

Methods: All monozygotic (1180 male and 1315 female pairs) and same-sex dizygotic (2765 male and 2613 female pairs) twins born from 1940 to 1957 in Finland were screened for nonorganic psychotic disorder diagnoses as recorded on an inpatient or outpatient basis or from an eligibility review for a disability pension. Results: The lifetime prevalence of schizophrenia was 2.0%, with a marginally higher prevalence in men (2.2%) than women (1.8%). Model fitting indicated that 83% of the variance in liability was due to additive genetic factors, and the remaining 17% was due to unique environmental factors. Sex-limitation modeling revealed no evidence of sex-specific genetic effects and no sex difference in the magnitude of heritability. A multiple threshold model incorporating affective and other psychoses as a phenotype intermediate between schizophrenia and no diagnosis was rejected. Conclusions: In a population-based twin study of schizophrenia, heritability was estimated at 83%, with the remaining variance in liability attributed to environmental factors not shared in common among co-twins. Despite the notable limitation of using diagnoses ascertained through treatment contacts, the heritability estimate in this study is almost identical to those reported in recent studies of index pairs using standardized applications of DSM-III or later criteria. Arch Gen Psychiatry. 1998;55:67-74

The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects

While behavioral research shows working memory impairments in schizophrenics and their relatives, functional neuroimaging studies of patients and healthy controls show conflicting findings of hypo- and hyperactivation, possibly indicating different relationships between physiological activity and performance. In a between-subjects regression analysis of fMRI activation and performance, low performance was associated with relatively lower activation in patients than controls, while higher performance was associated with higher activation in patients than controls in DLPFC and parietal cortex, but not occipital cortex, with unaffected twins of schizophrenics being intermediate between the groups. Accordingly, this supports the idea that both hyper and hypoactivation may be possible along a continuum of behavioral performance in a way consistent with a neural inefficiency model. Further, this study offers preliminary evidence that the relationship between behavior and physiology in schizophrenia may be heritable.

Maintenance and Manipulation in Spatial Working Memory: Dissociations in the Prefrontal Cortex

Two experiments were conducted to compare thec ries of the functional organization of spatial working memory within the human prefrontal cortex. In Experiment I, memory set size for locations was parametrically varied, allowing for the assessment of BOLD signal across maintenance requirements. In the sec ond experiment, manipulation of spatial information held in working memory was contrasted with simple maintenance of that information. Both experiment evoked significant activity in a distributed spatia working memory network. Although dorsolateral prefrontal activation increased monotonically with memory set size, this region was differentially engaged in task conditions involving explicit manipulation of in ternal representations. Activation in the superior frontal sulcal region was associated with maintenance of spatial information, increasing with memory se size. In contrast, ventrolateral prefrontal activation was present only at the highest memory set size, possibly due to the differential use of organizational strategies with more complex stimuli. These results sup port claims that the dorsolateral prefrontal cortex is involved in the manipulation of internal representa tions and that the superior frontal sulcal region is involved in the maintenance of spatial information but they suggest a complex role for the ventrolatera prefrontal region.

A twin study of genetic contributions to hippocampal morphology in schizophrenia.

Our goal was to establish whether altered hippocampal morphology represents a trait marker for genetic vulnerability in schizophrenia. We outlined the hippocampi on high-resolution MR images obtained from matched samples of control and discordant monozygotic and dizygotic co-twins (N = 40 pairs). Hippocampal measures were used in statistical tests specifically designed to identify disease-associated genetic and nongenetic influences on morphology. 3D surface average maps of the hippocampus were additionally compared in biological risk groups. Smaller hippocampal volumes were confirmed in schizophrenia. Dizygotic affected co-twins showed smaller left hippocampi compared to their healthy siblings. Disease-associated effects were not present between monozygotic discordant co-twins. Monozygotic, but not dizygotic, unaffected co-twins exhibited smaller left hippocampi compared to control twins, supporting genetic influences. Surface areas and posterior volumes similarly revealed schizophrenia and genetic liability effects. Results suggest that hippocampal volume reduction may be a trait marker for identifying individuals possessing a genetic predisposition for schizophrenia.

Proton MRS in twin pairs discordant for schizophrenia

Proton magnetic resonance spectroscopy (1H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that 1H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.