Nature of the genetic contribution to psychotic illness--a continuum viewpoint

The recurrent psychoses, rather than, as Kraepelin supposed, constituting 2 major entities, manic depressive illness and schizophrenia, as separate diseases, may be distributed along a continuum that extends from unipolar depressive illness through bipolar and schizoaffective psychosis to schizophrenia with increasing severities of defect state. It is proposed that this continuum rests on a genetic base, variations in the form of the gene accounting for variations in form of psychosis. The simplest interpretation of the continuum is that such variation relates to changes at a single genetic locus. Evidence from a postmortem study of brain structure in schizophrenia suggests that this is the gene that determines the development of asymmetries in the human brain, i.e., the cerebral dominance gene or right shift factor of Annett; a possible genomic location is in the pseudoautosomal region of the sex chromosomes.     

Speech disorder in schizophrenia: review of the literature and exploration of its relation to the uniquely human capacity for language

The language capacity of modern humans is thought by some to be clearly distinct from that of nonhuman primates (Bickerton 1990). Crow (1997, 1998a) has proposed that a disturbance in the uniquely human aspects of language is central to the genetic etiology of schizophrenia. A review of the literature on language disorder in schizophrenia provides evidence for widespread deficits in comprehension, production, attention, and cerebral lateralization of language. We focused here on those anomalies that are uniquely human aspects of language. Bickerton's five distinctly human language devices were examined in patients with schizophrenia and their families by using a structured scoring format on oral soliloquies. The chronic patients showed reduced use of clausal embedding and used fewer words than first episode patients or well family members. The amount of sentence complexity was found to be familial and to cosegregate with schizophrenia within families. These data are consistent with previous literature and additionally show a familial component to these measures, thus suggesting that deficits in specifically human aspects of language may be related to the genetics of schizophrenia.     

Structural and functional brain asymmetries in human situs inversus totalis.

OBJECTIVE: To determine whether individuals with situs inversus totalis (SI), a condition in which there is a mirror-image reversal of asymmetric visceral organs, have alterations in brain asymmetries. BACKGROUND: The human brain is asymmetric in structure and function. Although correlations between anatomic asymmetries and functional lateralization in human brain have been demonstrated, it has been difficult to further analyze them. Characterization of asymmetries of brain structure and function in SI might advance the understanding of these relationships. METHODS: Using anatomic and functional MRI techniques, we analyzed asymmetries in the brains of three individuals with SI. RESULTS: Two major anatomic asymmetries of the cerebral hemispheres, the frontal and occipital petalia, were reversed in individuals with SI. In contrast, SI subjects had left cerebral hemisphere language dominance on functional MRI analysis as well as strong right-handedness. CONCLUSION: These observations suggest that the developmental factors determining anatomic asymmetry of the cerebral petalia and viscera are distinct from those producing the functional lateralization of language.     

The theory of an agnosic right shift gene in schizophrenia and autism.

The right shift (RS) theory (Annett, M., 1972. The distribution of manual asymmetry. Br. J. Psychol. 63, 343-358; Annett, M., 1985. Left, Right, Hand and Brain: The Right Shift Theory. Lawrence Erlbaum, London) suggests that the typical pattern of human cerebral and manual asymmetries depends on a single gene (RS+) which impairs speech-related cortex of the right hemisphere. The theory offers solutions to several puzzles, including the distribution of handedness in families (Annett, M., 1978. A Single Gene Explanation of Right and Left Handedness and Brainedness. Lanchester Polytechnic, Coventry; Annett, M., 1996. In defense of the right shift theory. Percept. Motor Skills 82, 115-137), relations between handedness and cerebral speech laterality (Annett, M., 1975. Hand preference and the laterality of cerebral speech. Cortex 11, 305-328; Annett, M., Alexander, M.P., 1996. Atypical cerebral dominance: predictions and tests of the right shift theory. Neuropsychologia 34, 1215-1227) and handedness and dyslexia (Annett, M. et al., 1996. Types of dyslexia and the shift to dextrality. J. Child Psychol. Psychiatry 37, 167-180). If Crow's (Crow, T.J. et al., 1989. Schizophrenia as an anomaly of development of cerebral asymmetry. A postmortem study and a proposal concerning the genetic basis of the disease. Arch. Gen. Psychiatry 46, 1145-1150; Crow, T.J., 1997. Is schizophrenia the price that Homo sapiens pays for language? Schizophr. Res. 28, 127-141) theory that schizophrenia is due to an anomaly of cerebral dominance is correct, and if the RS theory is correct, schizophrenia could be due to an anomaly of the RS+ gene. If the RS+ gene were at risk for a mutation which caused a loss of directional coding, the mutant could be described as 'agnosic' for left and right. Such a gene would impair either hemisphere at random. When paired with another RS+ gene, both hemispheres would be impaired in 50% of cases. The other 50% and people in whom the agnosic gene is paired with an RS-allele (neutral for asymmetry and not giving hemisphere impairment) would have one unaffected hemisphere and, thus, normal development. Quantitative predictions based on the RS genetic theory as previously developed, plus an agnosic mutant with frequency required to give schizophrenia in 1% of the population, are consistent with estimates of concordance for schizophrenia in relatives. Homozygotes of the agnosic mutant would occur at about the rate estimated for autism.     

Possible evolutionary origins of cognitive brain lateralization

Despite the substantial literature on the functional architecture of the asymmetries of the human brain, which has been accumulating for more than 130 years since Dax and Broca's early reports, the biological foundations of cerebral asymmetries are still poorly understood. Recent advances in comparative cognitive neurosciences have made available new animal models that have started to provide unexpected insights into the evolutionary origins and neuronal mechanisms of cerebral asymmetries. Animal model-systems, particularly those provided by the avian brain, highlight the interrelations of genetic, hormonal and environmental events to produce neural and behavioural asymmetries. Novel evidences showing that functional and structural lateralization of the brain is widespread among vertebrates (including fish, reptiles and amphibians) have accumulated rapidly. Perceptual asymmetries, in particular, seem to be ubiquitous in everyday behaviour of most species of animals with laterally placed eyes; in organisms with wider binocular overlap (e.g., amphibians), they appear to be retained for initial detection of stimuli in the extreme lateral fields. We speculate that adjustment of head position and eye movements may play a similar role in mammals with frontal vision as does the choice for right or left lateral visual fields in animals with laterally placed eyes. A first attempt to trace back the origins of brain asymmetry to early vertebrates is presented, based on the hypothesis that functional incompatibility between the logical demands associated with very basic cognitive functions is central to the phenomenon of cerebral lateralization.     

Biological determinants of cerebral dominance

This review summarizes the present evidence for a biological basis of functional brain asymmetry. Morphological asymmetries, despite long-standing knowledge, have only recently aroused general interest. The most striking asymmetries involve regions of the cerebral cortex located around the posterior end of the Sylvian fissures: mainly studied was the planum temporale, but others include the parietal operculum, inferior parietal lobule, and inferior frontal gyrus. In most instances, cortical areas proved to bear asymmetries favouring the left hemisphere. Architectonic studies also revealed asymmetrical features; especially area "Tpt", roughly similar to Wernicke's posterior language area, has been found up to 7 times larger on the left than on the right hemisphere. Similar asymmetries were discovered in fetal brains, as early as the 30th gestational week, as well as in the cerebral cortex of some apes. These data suggest that morphological asymmetries need not be the consequence of functional effects but rather a predetermined feature, probably widely spread throughout animal kingdom. An open question remains as to the functional significance of these asymmetries. In this regard, studies have dealt with possible correlations between morphological asymmetries (as assessed in vivo by cerebral neuro-imaging methods) and features of functional asymmetry, especially handedness and hemispheric dominance for language. Despite incomplete results, available data suggest a significant correlation, at least in dextrals. The exact nature of these relationships remains speculative. Knowledge about the contribution of genetic factors in determining cerebral dominance followed observations of familial clustering of functional asymmetries, especially sinistrality, as well as studies in mono- and dizygotic twins. However, a purely genetic model seems to be unable to account consistently for the data. Hypotheses emphasizing birth stress may be only exceptionally verified. Actually, current evidence points to a specific period in the fetal life, probably around the 6th gestational month, during which neurons in post-migrational stage set up their synaptic contacts. The final gyral pattern of the brain probably builds up during this period, as a consequence of a mechanism of competition for synapses among different cortical areas which regulates the amount of neuronal growth and death. Such a mechanism probably also accounts for the development of cortical asymmetries.(ABSTRACT TRUNCATED AT 400 WORDS)     

Perceptual asymmetries in schizophrenia: subtype differences in left hemisphere dominance for dichotic fused words

OBJECTIVE: Dichotic listening techniques have been used to study hemispheric dominance for language in schizophrenia. The authors' goal was to compare subjects with paranoid and undifferentiated subtypes of schizophrenia. METHOD: The Fused Rhymed Words Test was used to compare perceptual asymmetries in 16 patients with paranoid schizophrenia, 28 patients with undifferentiated schizophrenia, and 29 healthy comparison subjects. RESULTS: Patients with paranoid schizophrenia had the largest left hemisphere advantage and patients with undifferentiated schizophrenia had the smallest. The asymmetry of healthy subjects was intermediate. Hemisphere advantage varied as a function of gender only in the patients with undifferentiated schizophrenia. CONCLUSIONS: The findings support the hypotheses that undifferentiated schizophrenia is associated with underactivation of left hemisphere resources for verbal processing and that paranoid schizophrenia is characterized by preserved left hemisphere processing.     

Abnormal cerebral asymmetry and schizophrenia in a subject with Klinefelter's syndrome (XXY).

BACKGROUND: A high incidence of schizophrenia has been reported in individuals with sex chromosome aneuploides (SCAs), and extra-X aneuploidy appears to adversely affect neurodevelopment. We previously examined neurodevelopment in SCA subjects with structural magnetic resonance imaging (MRI) of the brain. We present an XXY subject who subsequently developed schizophrenia. Further examination of the MRI data was undertaken. METHODS: Graphs of MRI-determined regional brain to whole brain volume proportions and cerebral asymmetry indexes were generated for Klinefelter (n = 10) and male control subjects (n = 25) to allow inter-individual comparisons. RESULTS: The index case had reversed prefrontal and temporal lobe asymmetries, and these findings were more marked than in any other subject. CONCLUSIONS: It has been suggested that a genetic locus for schizophrenia may be found on the X chromosome and that the gene(s) concerned are implicated in the development of normal cerebral asymmetries. This case supports these arguments.     

Structural asymmetry of the insula is linked to the lateralization of gesture and language

The control of gesture is one of the most left‐lateralized functions, and the insular cortex is one of the most left‐biased structures in the human brain. Therefore, we investigated whether structural asymmetries of the insula are linked to the organization of functional activity during gesture planning. We reconstructed and parcellated the insular cortex of 27 participants. First, we tested 15 strongly left‐handed individuals because of a higher incidence of atypical organization of functions such as gesture and language in such a population. The inter‐hemispheric structural asymmetries were compared with the lateralization of activity for gesture in the supramarginal gyrus (the hotspot of signal increase regardless of the gesturing hand) and Broca's area (the hotspot of signal increase for language production). The more pronounced leftward structural asymmetries were accompanied by greater left‐hemisphere dominance for both of the studied functions. Conversely, an atypical, bilateral or rightward functional shift of gesture and language was accompanied by an attenuated leftward asymmetry of the insula. These significant relationships were driven primarily by differences in surface area. Subsequently, by adding 12 right‐handed individuals to these analyses we demonstrated that the observed significant associations are generalizable to the population. These results provide the first demonstration of the relationships between structural inter‐hemispheric differences of the insula and the cerebral specialization for gesture. They also corroborate the link between insular asymmetries and language lateralization. As such, these outcomes are relevant to the common cerebral specialization for gesture and language.     

Language processing and human voice perception in schizophrenia: a functional magnetic resonance imaging study.

BACKGROUND: Neuroimaging studies have demonstrated either reduced left-lateralized activation or reversed language dominance in schizophrenia. These findings of left hemispheric dysfunction could be attributed to language processing tasks, which activate mainly left hemispheric function. Recent functional magnetic resonance imaging studies reported right-lateralized temporal activation by human voice perception, but few studies have investigated activation by human voice in schizophrenia. We aimed to clarify the cerebral function of language processing in schizophrenia patients by considering cerebral activation of human voice perception. METHODS: Fourteen right-handed schizophrenia patients and 14 right-handed controls with matched handedness, sex, and education level were scanned by functional magnetic resonance imaging while listening to sentences (SEN), reverse sentences (rSEN), and identifiable non-vocal sounds (SND). RESULTS: Under the SEN-SND and SEN-rSEN contrasts including language processing, patients showed less activation of the left hemisphere than controls in the language-related fronto-tempo-parietal region, hippocampus, thalamus and cingulate gyrus. Under the rSEN-SND contrast including human voice perception, patients showed less activation than controls in the right-lateralized temporal cortices and bilateral posterior cingulate. CONCLUSIONS: Our results indicate that schizophrenia patients have impairment of broader bilateral cortical-subcortical regions related to both the semantic network in the left hemisphere and the voice-specific network in the right hemisphere.     

Regional differences in cerebral asymmetries of human cortical white matter

The form of the structural asymmetries across the cerebral hemispheres, that support well-established functional asymmetries, are not well understood. Although, many previous studies have investigated structural differences in areas associated with strong functional asymmetries, such as language processes, regions of the brain with less well established functional laterality have received less attention. The current study aims to address this by exploring global white matter asymmetries of the healthy human brain using diffusion tensor imaging (DTI) and tractography. DTI was conducted on twenty-nine healthy right-handed males, and pathways from the four major lobes were reconstructed using probabilistic tractography. Mean FA, parallel and perpendicular diffusion values were calculated and compared across hemispheres for each pathway generated. Significant asymmetries in the parietal (rightward asymmetry) and occipital (leftward asymmetry) pathways were found in FA measures. However, asymmetric patterns in parallel and/or perpendicular diffusion were observed in all four lobes, even in pathways with symmetrical FA. For instance, significant rightward asymmetry in parallel diffusion was found in the parietal and frontal lobes, whereas significant leftward asymmetry was found in the temporal and occipital lobes. We suggest that these different patterns of diffusion asymmetry reflect differences in microanatomy that support the known patterns of differential functional asymmetry. The different directions of anatomical asymmetry support the notion that there may be a number of different lateralising influences operating in the brain.     

Neuromagnetic correlates of impaired automatic categorical perception of speech sounds in schizophrenia

Schizophrenia is associated with dysfunction in language processing. At the earliest stage of language processing, dysfunction of categorical perception of speech sounds in schizophrenia has been demonstrated in a behavioral task. The aim of this study was to assess automatic categorical perception of speech sounds as reflected by event-related changes in magnetic field power in schizophrenia. Using a whole-head magnetoencephalographic recording, the magnetic counterpart of mismatch negativity (MMNm) elicited by a phonetic change was evaluated in 16 right-handed patients with chronic schizophrenia and in 19 age-, sex-, and parental socioeconomic status-matched normal control subjects. Three types of MMNm (MMNm in response to a duration decrement of pure-tone stimuli; a vowel within-category change [duration decrement of Japanese vowel /a/]; vowel across-category change [Japanese vowel /a/ versus /o/]) were recorded. While the schizophrenia group showed an overall reduction in magnetic field power of MMNm, a trend was found toward more distinct abnormalities under the condition of vowel across-category change than under that of duration decrement of a vowel or tone. The patient group did not show abnormal asymmetries of MMNm power under any of the conditions. This study provides physiological evidence for impaired categorical perception of speech sounds in the bilateral auditory cortex in schizophrenia. The language-related dysfunction in schizophrenic patients may be present at the early stage of auditory processing of relatively simple stimuli such as phonemes, and not just at stages involving higher order semantic processes.     

Schizophrenia and evolutionary psychopathology

Evolution can shape any characteristic appearing as a phenotype that is genetically rooted and possesses a long history. The stress-diathesis model suggests that psychiatric disorders have some genetic roots, and therefore the theory of evolution may be relevant for psychiatry. Schizophrenia is present in every human culture with approximately the same incidence. The great evolutionary paradox is: how can such illness persist despite fundamental reproductive disadvantages? Since the 1960s, several evolutionary explanations have been raised to explain the origins of schizophrenia. This article reviews all the major evolutionary theories about the possible origins of this disease. On the one hand, some researchers have proposed that schizophrenia is an evolutionary disadvantageous byproduct of human brain evolution (e.g. the evolution of hemispheric specialization, social brain or language skills). On the other hand, others have suggested that a compensatory advantage must exist either in the biological system of patients with schizophrenia (e.g. resistance against infectious diseases), or within the social domain (e.g. greater creativity of the relatives). According to some theories, shamanism and religion demonstrate some similarities to psychosis and provide clues regarding the origins of schizophrenia. At the end of this article we discuss this last theory in detail listing arguments for and against.     

Schizophrenia and the structure of language: the linguist's view

Patients with schizophrenia often display unusual language impairments. This is a wide ranging critical review of the literature on language in schizophrenia since the 19th century. We survey schizophrenic language level by level, from phonetics through phonology, morphology, syntax, semantics, and pragmatics. There are at least two kinds of impairment (perhaps not fully distinct): thought disorder, or failure to maintain a discourse plan, and schizophasia, comprising various dysphasia-like impairments such as clanging, neologism, and unintelligible utterances. Thought disorder appears to be primarily a disruption of executive function and pragmatics, perhaps with impairment of the syntax-semantics interface; schizophasia involves disruption at other levels. Phonetics is also often abnormal (manifesting as flat intonation or unusual voice quality), but phonological structure, morphology, and syntax are normal or nearly so (some syntactic impairments have been demonstrated). Access to the lexicon is clearly impaired, manifesting as stilted speech, word approximation, and neologism. Clanging (glossomania) is straightforwardly explainable as distraction by self-monitoring. Recent research has begun to relate schizophrenia, which is partly genetic, to the genetic endowment that makes human language possible.     

Superior temporal gyrus and planum temporale in schizophrenia: A selective review

1. 1. The normal structure of the superior temporal gyrus (STG) has been elucidated from human and non-human primate research. This brain region is structurally complex, contains several distinct cellular regions and the area known as the planum temporale.

2. 2. The STG connects with heteromodal neocortical regions and temporolimbic areas.

3. 3. Functional studies of the normal STG in animals and in humans, using electrophysiology and PET/ fMRI, emphasize the STG's role as part of a cortical network important in the interpretation, production and self-monitoring of language.

4. 4. There is evidence for structural abnormalities of the STG in schizophrenia including both volume reductions and disturbances of normal asymmetries.

5. 5. Functional studies of this region in schizophrenic patients, including measurements of evoked potentials and of bloodflow, are abnormal, especially when patients perform language tasks or experience hallucinations.

6. 6. This structural and functional pathology in the STG probably represents one example of a more general disruption in schizophrenia of the neocortical network of which this region is an essential part. This disturbance may be closely associated with the symptoms of formal thought disorder and of auditory hallucinations commonly seen in the disorder.

     

Handedness and schizotypal features in healthy subjects.

BACKGROUND: An excess of mixed-handedness has been repeatedly reported in schizophrenia and schizotypy. Handedness is a measure of atypical cerebral lateralization, which is considered as a risk factor for schizophrenia. Several studies have attempted to identify correlations between handedness and dimensions of psychosis but the results obtained so far remain inconclusive. OBJECTIVE: To explore a possible link between mixed-handedness and the three classical dimensions of psychosis. As speech and language disorders may be associated with cerebral lateralization, we predicted a correlation between mixed-handedness and disorganized dimension. METHODS: We used the Schizotypal Personality Questionnaire (SPQ) and the Edinburgh Handedness Inventory (EHI) to study the correlation between mixed-handedness scores and positive, negative or disorganized dimensions in a sample of 62 healthy subjects. RESULTS: We found a negative correlation between mixed-handedness and the disorganized dimension of schizotypy, as individuals with prominent mixed-handedness showed more severe disorganization. CONCLUSION: We have identified a link between mixed-handedness and the disorganized dimension that may help to identify genetic vulnerability factors involved in psychosis.     

Of mice and men - and lopsided birds

The article by Zucca and Sovrano (2008, this issue) represents part of a new wave of studies of lateralization in nonhuman species. This work is often in conflict with earlier studies of human cerebral asymmetry and handedness, and the associated claim that these asymmetries are uniquely human, and perhaps even a result of the "speciation event" that led to modern humans. It is now apparent that there are close parallels between human and nonhuman asymmetries, suggesting that they have ancient roots. I argue that asymmetries must be seen in the context of a bilaterally symmetrical body plan, and that there is a balance to be struck between the adaptive advantages of symmetry and asymmetry. In human evolution, systematic asymmetries were incorporated into activities that probably are unique to our species, but the precursors of these asymmetries are increasingly evident in other species, including frogs, fish, birds, and mammals - especially primates.     

Magical ideation, creativity, handedness, and cerebral asymmetries: a combined behavioural and fMRI study

Magical ideation has been shown to be related to measures of hand preference, in which those with mixed handedness exhibit higher levels of magical ideation than those with either consistent left- or right-handedness. It is unclear whether the relation between magical ideation and hand preference is the result of a bias in questionnaire-taking behaviour or of some neuropsychological concomitant of cerebral specialization. We sought to replicate this finding and further investigate how magical ideation is related to other measures of laterality, including handedness based on finger-tapping performance, and cerebral asymmetries for language, spatial judgment, and face processing as revealed by fMRI. Creative achievement was also assessed by questionnaire and correlated with magical ideation and the other measures. Magical ideation and creativity were positively correlated, and both were negatively correlated with absolute hand preference but not with hand performance or with any of the cerebral asymmetries being assessed. The results do not support the notion that the observed association between magical ideation, creativity and hand preference has a neuropsychological explanation based on reduced cerebral lateralization.     

Heritability and association of cortical petalias in rhesus macaques (Macaca mulatta)

Frontal and occipital petalias, the anterior or posterior protrusions of a cerebral lobe on one side or the other, are among the most striking anatomical asymmetries in human brains. Our previous studies of rhesus macaques revealed a relatively high frequency of right frontal petalias, whereas occipital petalias were seen less often and were equally common on right and left sides. In the present study, we test the hypothesis that variation in frontal and occipital lobular morphology is, in part, genetically based, and that frontal and occipital petalias are associated with one another. With a sample of 403 rhesus macaque endocasts, we found that right frontal petalias were more commonly associated with left occipital petalias than would be expected by chance. The concurrence of right frontal and left occipital petalias is the most common variant in human brains. We also found significant but moderate heritability for frontal petalias, while the heritability estimate for occipital petalias was relatively low and not statistically significant. This result suggests a genetic basis for variation in the degree of anatomical cerebral lateralization.     

Chromosomal Distribution of Schizophrenia Susceptibility Loci

In order to find the chromosomal distribution of polymorphic loci associated with the schizophrenia risk, the present study was carried out. Meta-analysis studies with information of genetic polymorphisms and schizophrenia risk were identified and used for the present study. There were 39 loci associated with schizophrenia risk. Statistical analysis revealed that the schizophrenia susceptible loci distributed non-randomly on human chromosomes. Human chromosome segments 6p21.1-p22.3 (P?<?0.001) bear significantly higher number of susceptible loci.