Schizophrenia as Failure of Left Hemispheric Dominance for the Phonological Component of Language

Background

T. J. Crow suggested that the genetic variance associated with the evolution in Homo sapiens of hemispheric dominance for language carries with it the hazard of the symptoms of schizophrenia. Individuals lacking the typical left hemisphere advantage for language, in particular for phonological components, would be at increased risk of the typical symptoms such as auditory hallucinations and delusions.

Methodology/Principal Findings

Twelve schizophrenic patients treated with low levels of neuroleptics and twelve matched healthy controls participated in an event-related potential experiment. Subjects matched word-pairs in three tasks: rhyming/phonological, semantic judgment and word recognition. Slow evoked potentials were recorded from 26 scalp electrodes, and a laterality index was computed for anterior and posterior regions during the inter stimulus interval. During phonological processing individuals with schizophrenia failed to achieve the left hemispheric dominance consistently observed in healthy controls. The effect involved anterior (fronto-temporal) brain regions and was specific for the Phonological task; group differences were small or absent when subjects processed the same stimulus material in a Semantic task or during Word Recognition, i.e. during tasks that typically activate more widespread areas in both hemispheres.

Conclusions/Significance

We show for the first time how the deficit of lateralization in the schizophrenic brain is specific for the phonological component of language. This loss of hemispheric dominance would explain typical symptoms, e.g. when an individual''s own thoughts are perceived as an external intruding voice. The change can be interpreted as a consequence of “hemispheric indecision”, a failure to segregate phonological engrams in one hemisphere.     

Front Cover

This review highlights the scientific advances concerning the origins of human right‐handedness and language (speech and gestures). The comparative approach we adopted provides evidence that research on human and non‐human animals’ behavioural asymmetries helps understand the processes that lead to the strong human left‐hemisphere specialisation. We review four major non‐mutually exclusive environmental factors that are likely to have shaped the evolution of human and non‐human primates’ manual asymmetry: socioecological lifestyle, postural characteristics, task‐level complexity and tool use. We hypothesise the following scenario for the evolutionary origins of human right‐handedness: the right‐direction of modern humans’ manual laterality would have emerged from our ecological (terrestrial) and social (multilevel system) lifestyle; then, it would have been strengthened by the gradual adoption of the bipedal stance associated with bipedal locomotion, and the increasing level of complexity of our daily tasks including bimanual coordinated actions and tool use. Although hemispheric functional lateralisation has been shaped through evolution, reports indicate that many factors and their mutual intertwinement can modulate human and non‐human primates’ manual laterality throughout their life cycle: genetic and environmental factors, mainly individual sociodemographic characteristics (e.g., age, sex and rank), behavioural characteristics (e.g., gesture per se and gestural sensory modality) and context‐related characteristics (e.g., emotional context and position of target). These environmental (evolutionary and life cycle) factors could also have influenced primates’ manual asymmetry indirectly through epigenetic modifications. All these findings led us to propose the hypothesis of a multicausal origin of human right‐handedness.     

Association Process and Functional Brain Asymmetry

Analysis is presented of word associations produced by subjects with left hemispheric (group 1), right hemispheric (group 2), and bilateral (group 3) speech representation. The strategy for producing extralinguistic responses was found to prevail over the strategy for producing linguistic associations in all subjects, irrespective of their type of speech representation. This strategy was more pronounced in subjects with right hemispheric speech laterality, suggesting a correlation between the generation of extralinguistic associations and functional brain asymmetry. Producing linguistic associations also depended on the type of cerebral organization of speech. The most important linguistic associations are syntagmatic. Syntagmatic associations were more closely related to the lateralization of speech to the left hemisphere. The data are compared to the results of studies of the ontogeny of associative processes.     

Hemispheric dominance of cortical activity evoked by focal electrogustatory stimuli.

Functional magnetic resonance imaging was used to observe cortical hemodynamic responses to electric taste stimuli applied separately to the right and left sides of the tongue tip. In 11 right-handed normal adults activation occurred primarily in the insular cortex, superior temporal lobe, inferior frontal lobe, including premotor regions, and in inferior parts of the postcentral gyrus. Unexpectedly, the location and laterality of activation were largely identical regardless of the side of the tongue stimulated. Activation in the superior insula, the presumed location of primary gustatory cortex, was predominantly, but not exclusively, in the right hemisphere, whereas central (more inferior) insular activations were more evenly bilateral. Right hemispheric dominance of activation also occurred in premotor regions (Brodmann areas 6 and 44), whereas left hemispheric dominance occurred only in the superior temporal cortex (Brodmann areas 22/42). The electric taste-evoked hemodynamic response pattern was more consistent with activation of the gustatory system than activation of somatosensory systems. The results suggest that the sites for cortical processing of electric taste information are dependent on hemispheric specialization.     

A Screen for Nonconditional Dauer-Constitutive Mutations in Caenorhabditis Elegans

In Caenorhabditis elegans, formation of the developmentally arrested dauer larva is induced by high levels of a constitutively secreted pheromone. Synergy between two groups of incompletely penetrant dauer-constitutive (Daf-c) mutations has recently led to a proposal that these two groups of genes are partially redundant and function in two parallel pathways that regulate dauer formation. A possible weakness in this reasoning is that the mutations used to identify the synergy were specifically obtained as incompletely penetrant mutations. Here we use screens to identify new Daf-c alleles without any requirement for partial penetrance. Nevertheless, 22 of the 25 new mutations are incompletely penetrant mutations in 6 previously identified genes. Among these are mutations in daf-8 and daf-19, genes for which only one mutation had been previously identified. Also included in this group are three daf-1 alleles that do not exhibit the maternal rescue characteristic of other daf-1 alleles. Two of the 25 new mutations are fully penetrant and are alleles of daf-2, the one gene in which a fully penetrant mutation had been found earlier. Finally, one of the 25 new mutations is semidominant, temperature-sensitive, and identifies a new gene, daf-28. The results demonstrate that an incompletely penetrant Daf-c phenotype is characteristic of mutations in most Daf-c genes other than daf-2. This finding strengthens the hypothesis that a branched genetic pathway controls dauer formation.     

Klinefelter's syndrome as a model of anomalous cerebral laterality: Testing gene dosage in the X chromosome pseudoautosomal region using a DNA microarray

Consistent handedness and language laterality are two of the most striking behavioral and cognitive asymmetries observed in humans. Alterations in the typical pattern of cerebral laterality, termed “anomalous dominance,” is observed in left-handers and some patients with verbal learning disabilities. We undertook the study of a genetically distinct group of subjects, XXY males (Klinefelter's syndrome; KS), who demonstrate anomalous dominance in a variety of testing paradigms in order to begin to elucidate the molecular basis of anomalous dominance in this population. KS subjects manifest specific verbal learning disability, evidence of altered functional laterality for phonologic processing, and an increase in left-handedness when measured by skill. It is proposed that an alteration in gene dosage in the pseudoautosomal region (PAR) of the sex chromosomes is the most likely explanation for anomalous dominance in these patients. This is especially intriguing in light of previously described genetic models of cerebral laterality that suggest a contributing locus in the PAR, or adjacent high homology regions of the X chromosome. We have developed an ordered DNA microarray covering the X chromosome PAR at high resolution for hybridization with two-color fluorescently labeled probes. We demonstrate the ability to detect changes in hybridization signal that will facilitate efficient large-scale screening of this region for alterations in gene dosage associated with features of anomalous dominance and other cognitive or behavioral phenotypes. Dev. Genet. 23:215–229, 1998. © 1998 Wiley-Liss, Inc.     

Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia

There is evidence that brain lateralization underlying hemispheric specialization can be observed also at biochemical level. However, hemispheric differences in nitric oxide mediator system have not yet been evaluated. The hippocampus and planum temporale are highly asymmetrical regions but the degree of their laterality is altered in demented or psychotic people. In the study, l-glutamate/l-arginine/l-citrulline concentrations, nitric oxide synthase activities/expressions and nitrites/nitrates levels were estimated in autoptic hippocampi. Right/left laterality in endothelial synthase activity and in nitrites/nitrates was observed in controls. Lateral changes were estimated in patients with Alzheimer disease (a marked increase in activities of constitutive synthases and in expression of inducible enzyme in the left side) and schizophrenia (an increase in activities of all enzymes especially in the right side). Significant shifts from positive to negative correlations were found between laterality of some components of nitric oxide pathway and of planum temporale volumetry under pathological conditions. The hippocampal nitric oxide system appears to be globally right/left lateralized, especially via actions of highly asymmetrical endothelial synthase. The results suggest a specific involvement of all synthases in the development of selected diseases and show that lateral analyses are of sufficient sensitivity to reveal subtle links. The volumetric asymmetry of the planum temporale as a marker of handedness is not probably simply linked to brain laterality at biochemical level but reflects alterations due to pathological processes.     

Language-related hemispheric asymmetry in healthy subjects and patients with temporal lobe epilepsy as studied by event-related brain potentials and intracarotid amobarbital test

There are current attempts to replace the WADA test for pre-surgical evaluation of hemispheric language capabilities by one of the methods of functional brain imaging. Recent PET and fMRI studies using verbal cognitive tasks like verb generation, semantic monitoring or semantic (`deep') encoding of words showed asymmetries of activation in the fronto-lateral cortex. In a previous ERP study subjects were required to indicate whether pronounceable non-words and abstract geometric figures were presented for the first time (`new item') or whether they had been shown before (`old item'). Group analyses of this study showed significant material-specific hemispheric asymmetries with ERPs being more negative-going in recordings of the posterior part of the left hemisphere with verbal material (CP5/6) but more negative-going in recordings of the right hemisphere with the spatial material (P7/8). The aim of the present study was to test statistically ERP lateralization effects in individual healthy subjects as well as WADA-tested patients suffering from seizures of the mesio-temporal lobe (MTL). In all subjects ERP lateralization with verbal material was tested in the electrode pair CP5/6, and ERP lateralization with figures in the electrode pair P7/8. Statistical analyses of single trials showed that in 20 out of 24 subjects ERPs with verbal material started to be more negative-going in CP5 as compared to CP6 in the period between 100 and 200 ms after stimulus onset or the subsequent time epoch (200–300 ms). In one subject not CP5/6 but the closely adjacent electrode pair P7/P8 showed this verbal material-related hemispheric effect. In patients language dominance as indicated by ERPs was not always consistent with the data of the WADA test. In one patient with left MTL seizures ERPs with verbal material and figures were found to be significantly lateralized to the right hemisphere although the WADA test assigned this patient to have a language-dominant left hemisphere.     

THE LOCI OF EVOLUTION: HOW PREDICTABLE IS GENETIC EVOLUTION?

Is genetic evolution predictable? Evolutionary developmental biologists have argued that, at least for morphological traits, the answer is a resounding yes. Most mutations causing morphological variation are expected to reside in the cis‐regulatory, rather than the coding, regions of developmental genes. This “cis‐regulatory hypothesis” has recently come under attack. In this review, we first describe and critique the arguments that have been proposed in support of the cis‐regulatory hypothesis. We then test the empirical support for the cis‐regulatory hypothesis with a comprehensive survey of mutations responsible for phenotypic evolution in multicellular organisms. Cis‐regulatory mutations currently represent approximately 22% of 331 identified genetic changes although the number of cis‐regulatory changes published annually is rapidly increasing. Above the species level, cis‐regulatory mutations altering morphology are more common than coding changes. Also, above the species level cis‐regulatory mutations predominate for genes not involved in terminal differentiation. These patterns imply that the simple question “Do coding or cis‐regulatory mutations cause more phenotypic evolution?” hides more interesting phenomena. Evolution in different kinds of populations and over different durations may result in selection of different kinds of mutations. Predicting the genetic basis of evolution requires a comprehensive synthesis of molecular developmental biology and population genetics.     

Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes

Background

There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.

Methodology and Principal Findings

We performed targeted capillary resequencing of HNF1A exons 8–10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤45 years) and/or family history of T2D (≥1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9−24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.

Conclusions and Significance

We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.     

Effects of Caller Characteristics on Auditory Laterality in an Early Primate (Microcebus murinus)

Background

Auditory laterality is suggested to be characterized by a left hemisphere dominance for the processing of conspecific communication. Nevertheless, there are indications that auditory laterality can also be affected by communicative significance, emotional valence and social recognition.

Methodology/Principal Findings

In order to gain insight into the effects of caller characteristics on auditory laterality in the early primate brain, 17 gray mouse lemurs were tested in a head turn paradigm. The head turn paradigm was established to examine potential functional hemispheric asymmetries on the behavioral level. Subjects were presented with playbacks of two conspecific call types (tsak calls and trill calls) from senders differing in familiarity (unfamiliar vs. familiar) and sex (same sex vs. other sex). Based on the head turn direction towards these calls, evidence was found for a right ear/left hemisphere dominance for the processing of calls of the other sex (Binomial test: p = 0.021, N = 10). Familiarity had no effect on the orientation biases.

Conclusions/Significance

The findings in this study support the growing consensus that auditory laterality is not only determined by the acoustic processing of conspecific communication, but also by other factors like the sex of the sender.     

Medical sequencing at the extremes of human body mass

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96-Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese population compared with the lean population. In addition, computational analysis predicted a greater fraction of deleterious variants within the obese cohort. Together, these data suggest that multiple rare alleles contribute to obesity in the population and provide a medical sequencing-based approach to detect them.     

Fitness advantages of the biased use of paired laterally symmetrical penises in an insect

The evolution of laterality, that is the biased use of laterally paired, morphologically symmetrical organs, has attracted the interest of researchers from a variety of disciplines. It is, however, difficult to quantify the fitness benefits of laterality because many organs, such as human hands, possess multimodal functions. Males of the earwig Labidura riparia (Insecta: Dermaptera: Labiduridae) have morphologically similar laterally paired penises, only one of which is used for inseminating the female during a single copulation bout, and thus provide a rare opportunity to address how selection pressure may shape the evolution of population‐level laterality. Our population studies revealed that in 10 populations, located at 2.23–43.3° north, the right penis is predominantly used for copulating (88.6%). A damaged penis was found in 23% of rare left‐handers, suggesting that the left penis can function as a spare when the right one is damaged. By pairing L. riparia females with surgically manipulated males, we found that males forced to use the right penis outperformed left‐handed males in copulation (the probability of establishing genital coupling during the 1‐hr observation period: odds ratio [OR] of 3.50) and insemination (probability of transferring a detectable amount of sperm: OR of 2.94). This right‐handed advantage may be due to the coiled morphology of the sperm storage organ with a right‐facing opening. Thus, female genital morphology may play a significant role in the evolution of handedness and may have acted as a driving force to reduce penis number in related taxa.     

Gene(s) and individual feeding behavior: Exploring eco‐evolutionary dynamics underlying left‐right asymmetry in the scale‐eating cichlid fish Perissodus microlepis

The scale‐eating cichlid fish Perissodus microlepis is a textbook example of bilateral asymmetry due to its left or right‐bending heads and of negative frequency‐dependent selection, which is proposed to maintain this stable polymorphism. The mechanisms that underlie this asymmetry remain elusive. Several studies had initially postulated a simple genetic basis for this trait, but this explanation has been questioned, particularly by reports observing a unimodal distribution of mouth shapes. We hypothesize that this unimodal distribution might be due to a combination of genetic and phenotypically plastic components. Here, we expanded on previous work by investigating a formerly identified candidate SNP associated to mouth laterality, documenting inter‐individual variation in feeding preference using stable isotope analyses, and testing their association with mouth asymmetry. Our results suggest that this polymorphism is influenced by both a polygenic basis and inter‐individual non‐genetic variation, possibly due to feeding experience, individual specialization, and intraspecific competition. We introduce a hypothesis potentially explaining the simultaneous maintenance of left, right, asymmetric and symmetric mouth phenotypes due to the interaction between diverse eco‐evolutionary dynamics including niche construction and balancing selection. Future studies will have to further tease apart the relative contribution of genetic and environmental factors and their interactions in an integrated fashion.     

Laterality and sex differences in tactile detection and two-point thresholds modified by body surface area and body fat ratio

Tactile detection and two-point discrimination tests are commonly used in neurological examinations. However, questions remain about the influence of both body and patient characteristics on test thresholds. The left side of the body has sometimes been reported more tactilely sensitive than the right, and females are said to be more sensitive than males. We measured tactile detection and two-point discrimination thresholds on the finger, palm, and forehead of a large sample of young adults (N=171), examining laterality and sex differences, and the effects of body surface area (BSA) and body fat ratio (BFR). In tactile detection, there were no effects of laterality, BSA, or BFR, although females had lower thresholds than males. In two-point discrimination, there was an effect of laterality, with lower thresholds on the left side. This probably reflects hemispheric spatial processing differences. A significant BFR effect implies that subcutaneous fat affects skin deformation, but there were no effects of sex or BSA. The two-point discrimination findings differ in several respects from recent findings using grating orientation discriminations. A small positive correlation between the tasks, falling far short of test-retest reliabilities, indicates that they use largely disjoint but partially overlapping processes.     

Genetic support for random mating between left and right‐mouth morphs in the dimorphic scale‐eating cichlid fish Perissodus microlepis from Lake Tanganyika

Population genetic analyses were conducted to investigate whether random mating occurs between left and right‐mouth morphs of the dimorphic scale‐eating cichlid fish Perissodus microlepis from two geographical sites in southern Lake Tanganyika. The mitochondrial and nuclear DNA markers (13 microsatellite loci) revealed no genetic differentiation between left and right morphs (i.e. widespread interbreeding). The observed lack of genetic divergence between the different morphs allowed for the exclusion of the possibility of assortative mating between same morph types. The microsatellite data showed no significant departures of heterozygosity from Hardy–Weinberg equilibrium, suggesting purely random mating between the morphs. Overall, this study indicated no genetic evidence for either assortative or disassortative mating, but it did provide support for the random mating hypothesis. Highly significant, albeit weak, spatial population structure was also found when samples of different morphs were pooled according to geographical sites. An additional analysis of two microsatellite loci that were recently suggested to be putatively linked to the genetic locus that determines the laterality of these mouth morphs did not show any such association.     

Laterality and sex differences in tactile detection and two-point thresholds modified by body surface area and body fat ratio

Tactile detection and two-point discrimination tests are commonly used in neurological examinations. However, questions remain about the influence of both body and patient characteristics on test thresholds. The left side of the body has sometimes been reported more tactilely sensitive than the right, and females are said to be more sensitive than males. We measured tactile detection and two-point discrimination thresholds on the finger, palm, and forehead of a large sample of young adults (N?=?171), examining laterality and sex differences, and the effects of body surface area (BSA) and body fat ratio (BFR). In tactile detection, there were no effects of laterality, BSA, or BFR, although females had lower thresholds than males. In two-point discrimination, there was an effect of laterality, with lower thresholds on the left side. This probably reflects hemispheric spatial processing differences. A significant BFR effect implies that subcutaneous fat affects skin deformation, but there were no effects of sex or BSA. The two-point discrimination findings differ in several respects from recent findings using grating orientation discriminations. A small positive correlation between the tasks, falling far short of test–retest reliabilities, indicates that they use largely disjoint but partially overlapping processes.     

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole‐exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.     

Hemispheric lateralization in the processing of odor pleasantness versus odor names

It is well established that for most people linguistic processing is primarily a left hemisphere activity, whereas recent evidence has shown that basic odor perception is more lateralized to the right hemisphere. Importantly, under certain conditions, emotional responding also shows right hemisphere laterality. Hedonic (pleasantness) assessments constitute basic level emotional responses. Given that olfaction is predominantly ipsilateral in function, it was hypothesized that odor pleasantness evaluations may be accentuated by right nostril perception and that odor naming would be superior with left nostril perception. To test this prediction we presented eight familiar neutral-mildly pleasant odors for subjects to sniff through the left and right nostrils. Subjects smelled each odor twice (once through each nostril) at two different sessions, separated by 1 week. At each session subjects provided pleasantness, arousal and naming responses to each odorant. Results revealed that odors were rated as more pleasant when sniffed through the right nostril and named more correctly when sniffed through the left. No effects for arousal were obtained. These findings are consistent with previously demonstrated neural laterality in the processing of olfaction, emotion and language, and suggest that a local and functional convergence may exist between olfaction and emotional processing.