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Handedness, heritability, neurocognition and brain asymmetry in schizophrenia

Amy Deep-Soboslay, Thomas M. Hyde, Joseph P. Callicott, Marc S. Lener, Beth A. Verchinski, José A. Apud, Daniel R. Weinberger, Brita Elvevåg
DOI: http://dx.doi.org/10.1093/brain/awq160 3113-3122 First published online: 17 July 2010

Summary

Higher rates of non-right-handedness (i.e. left- and mixed-handedness) have been reported in schizophrenia and have been a centrepiece for theories of anomalous lateralization in this disorder. We investigated whether non-right-handedness is (i) more prevalent in patients as compared with unaffected siblings and healthy unrelated control participants; (ii) familial; (iii) associated with disproportionately poorer neurocognition; and (iv) associated with grey matter volume asymmetries. We examined 1445 participants (375 patients with schizophrenia, 502 unaffected siblings and 568 unrelated controls) using the Edinburgh Handedness Inventory, a battery of neuropsychological tasks and structural magnetic resonance imaging data. Patients displayed a leftward shift in Edinburgh Handedness Inventory laterality quotient scores as compared with both their unaffected siblings and unrelated controls, but this finding disappeared when sex was added to the model. Moreover, there was no evidence of increased familial risk for non-right-handedness. Non-right-handedness was not associated with disproportionate neurocognitive disadvantage or with grey matter volume asymmetries in the frontal pole, lateral occipital pole or temporal pole. Non-right-handedness was associated with a significant reduction in left asymmetry in the superior temporal gyrus in both patients and controls. Our data neither provide strong support for ‘atypical’ handedness as a schizophrenia risk-associated heritable phenotype nor that it is associated with poorer neurocognition or anomalous cerebral asymmetries.

  • schizophrenia
  • handedness
  • neurocognition
  • brain asymmetry

Introduction

Schizophrenia is believed to be a neurodevelopmental disorder in which changes in the brain occur many years before the illness expresses itself in a florid fashion (Weinberger, 1986, 1987; Murray and Lewis, 1987). Brain asymmetry is a core metric of neurodevelopment and has been examined in numerous developmental disorders—including schizophrenia—and has invoked various hypotheses such as the left hemisphere lag, the left hemisphere being especially vulnerable to insults, and frank differences in hemispheric specialization (Gruzelier, 1981; Geschwind and Galaburda, 1985). In fact, anomalous lateralization has been promoted as a centrepiece for a theory of schizophrenia involving language and human speciation (Crow, 1997). The central idea encapsulated in these theories is that deviations in lateral preference are epigenetic processes that, in toto with genetic factors, are likely to contribute to the pathogenesis of this illness.

The anatomic lateralization of brain function has been known for over a century, beginning with the seminal observation by Broca (1861) that left hemispheric lesions were associated with language disorders. However, evidence for structural asymmetries and the resulting functional asymmetries have reached wide acceptance only recently (Galaburda et al., 1978; Binder et al., 1997). The advent of brain imaging technologies was accompanied by a plethora of reports of diminished anatomical asymmetry in schizophrenia [e.g. volume reduction in left planum temporale (Luchins et al., 1979; Kwon et al., 1999; Shenton et al., 2001)], as well as subsequent reports of functional differences in cerebral lateralization in schizophrenia, especially in the left-sided language functions, which were taken to suggest a familial heritable component that is also present in those ‘at-risk’ for schizophrenia (Li et al., 2007a,b). However, a number of negative reports have challenged each of these observations (Bartley et al., 1993; Kulynych et al., 1995, 1996). These inconsistent findings may be attributable to sampling biases, gender effects, the precision of regions being measured or other methodological variations, such as MRI slice thickness. It is important to appreciate, however, that asymmetric pathology is not necessarily pathology of asymmetry and that similar reductions or reversals of asymmetry have been described in a variety of putatively developmental neuropsychiatric disorders, such as autism (Hier, 1978; Hier et al., 1979), delayed speech onset (Rosenberger and Hier, 1980), developmental dyslexia (Hier et al., 1978), attention deficit-hyperactivity disorder (Castellanos et al., 1994), bipolar disorder (Savitz et al., 2007) and Tourette’s syndrome (Hyde et al., 1995) (for a review, see Hendren et al., 2000), and as such are not specific to any of these diagnoses.

Hand preference—or dominance—has been extensively used as an easy-to-measure proxy of brain asymmetry, since it has been regarded as a manifestation of cerebral dominance and thus is closely correlated with anatomical asymmetry (Sommer et al., 2001). In general (non-clinical) population studies, left-handedness has been reported in ∼10% of people (Hardyck and Petrinovich, 1977; McManus, 1991; Hugdahl and Davidson, 2003), with slightly higher rates for males (∼12% in males versus 10% in females). However, the largest of these studies have been limited to self-report measures and/or handwriting preference, and have included mixed-handed individuals (Gilbert and Wysocki, 1992; Perelle and Ehrman, 2005; Peters et al., 2006). Moreover, it is hard to extrapolate exact rates of mixed-handedness from small samples (e.g. a rate of 0–2% mixed-handedness in 74 non-clinical participants) (Satz et al., 1989), and because it has been measured and defined in a variety of ways i.e. limited to a single measure of preferred writing hand, or by exhibition of just one left-handed trait (Perelle and Ehrman, 1994). Cultural influences on hand preference, including the negative stigma associated with left-handedness and encouragement of left-handed individuals towards right-handedness, may also influence reported rates of non-right-handedness in some cultures and eras (Laland et al., 1995).

There have been many reports of patients with schizophrenia being more non-right-handed than the healthy population. A review by Satz and Green (1999) concluded that there was an ‘atypical leftward shift in the handedness distribution’ of patients with schizophrenia, and that specific patterns of this shift are associated (in a complex way) with certain clinical and neuropsychological presentations of the illness. Two recent meta-analyses of handedness both reported a higher prevalence of non-right-handedness in patients with schizophrenia as compared with controls (Sommer et al., 2001; Dragovic and Hammond, 2005) and that this was not simply attributable to an increase in mixed-handedness alone. These findings have been taken to suggest that such ‘atypical’ hand dominance is a result of a ‘failure to establish cerebral asymmetry’ and that this is a central feature of the pathophysiology of the illness (Dragovic and Hammond, 2005).

However, despite a large body of literature examining the relationship of handedness and schizophrenia, there are many methodological issues of concern. First, the manner in which samples are collected and diagnosed has been historically inconsistent, with inclusion of patients not meeting Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) or other standardized criteria for schizophrenia, particularly those with Axis II schizotypy or ‘pre-schizophrenic participants’, inclusion of cases with neurological disorders, diagnosis of cases by chart diagnoses alone or even by parental self-report, as well as liberal inclusion (i.e. limited clinical screening) of siblings and control participants. Second, methods for assessing handedness have varied greatly, including self-reports of hand preference, or behavioural measures of asymmetry including indices of hand preference, sighting dominance, (right) ear advantage and even measures of finger dermatoglyphic asymmetry. Indeed, in the aforementioned meta-analytic study by Dragovic and Hammond (2005), 19 different assessment methods were used for handedness, ranging from one item (i.e. handwriting) up to 32 items. Thus, the subsequent classification of handedness has been quite problematic, with the majority of studies reporting only dichotomous handedness categories (i.e. left-right, non-right-right and mixed-lateralized categories). Third, there have been a wide range of sample sizes employed. A recent meta-analysis of over 40 studies of handedness in schizophrenia pooled samples ranging from as few as 42 participants up to several thousand participants (Dragovic and Hammond, 2005). In short, only a handful of studies on handedness in schizophrenia have simultaneously taken into account all of the above-mentioned essential components, namely a standardized diagnostic method for all participants, a standardized handedness assessment and adequate sample sizes of both patients and controls. Fourth, although only a few studies have examined cognitive functioning in the context of this putative ‘anomalous’ handedness and schizophrenia and the findings have at times been weak, a case has been made that non-right-handed patients display poorer neurocognitive performance. Specifically, as compared with right-handed patients, left-handed patients with schizophrenia have been shown to score lower on measures of intelligence and display poorer executive functioning (Katsanis and Iacono, 1989), as well as poorer verbal fluency and attention (Dragovic et al., 2005). Also, there have been reports that these patients display deficits on rhythmic recall and on other measures of short-term verbal memory compared with right-handed patients (Faustman et al., 1991). These few studies were limited by their use of just a handful of neurocognitive measures and small patient samples, once again casting doubt on the notion of poorer neurocognition in non-right-handed patients with schizophrenia.

Handedness has been extensively studied in terms of heritability, primarily via twin studies (Medland et al., 2006). Despite at least 37 published twin studies on the genetics of handedness, these studies have also been largely underpowered and fraught with similar methodological problems regarding how to define handedness, and thus their findings remain contentious (Medland et al., 2006). A recent large-scale twin study of the heritability of handedness estimated that 24% of sample variance was due to ‘additive genetic effects’, while the remaining 76% was due to non-shared environmental influences (Medland et al., 2009). Of interest here is the putative link of ‘anomalous’ handedness and increased risk for schizophrenia, namely whether the phenotype of ‘anomalous’ handedness tends to run in families of patients with schizophrenia.

Studies of handedness in unaffected relatives of patients with schizophrenia compared with their ill relatives have generated mixed results, with some finding no evidence of a heritable component (Bartley et al., 1993; Clementz et al., 1994; DeLisi et al., 2002; Dragovic et al., 2005), while others did (Orr et al., 1999). However, these studies have been largely underpowered, as the unaffected relative samples have been small (all less than 100).

To address the aforementioned limitations of previous studies, we have included only those participants meeting DSM-IV Axis I criteria for schizophrenia or schizoaffective disorder, depressed type [using both the Structured Clinical Interview for DSM-IV Disorders (First, 1997) and medical record review to determine diagnosis], thereby excluding all patients meeting criteria for schizophrenia spectrum disorders as well as those with current comorbid substance abuse. Furthermore, we excluded all siblings affected with schizophrenia. Second, we utilized the Edinburgh Handedness Inventory (EHI), a professionally administered, valid and reliable measure of handedness based on 12 different tasks, 10 of which measure hand preference. We used the resulting quantitative data as a continuous measure as well as a categorical measure, which to our knowledge only one other study of handedness in schizophrenia has done (Buijsrogge et al., 2002). Third, we sought to evaluate any putative neurocognitive disadvantage in non-right-handed patients by employing a large neurocognitive battery assessing intelligence, spatial and verbal processing speed, verbal and visual episodic memory, verbal and spatial working memory and executive function. Lastly, we incorporated 3D structural MRI data to explore possible cerebral asymmetry that may relate to handedness. To our knowledge, the current study is the largest investigation concerning handedness in schizophrenia that involves standardized diagnostic procedures, an objective and validated laterality screening measure used quantitatively, conservatively screened unaffected siblings of patients and controls, a large standardized neuropsychological battery and structural MRI data.

Materials and methods

Participants

A total of 1445 participants were included, derived from the Clinical Brain Disorders Branch National Institute of Mental Health ‘Sibling Study’ protocol, which is an ongoing investigation of neurobiological abnormalities related to genetic risk for schizophrenia. Details of participant recruitment, screening and examination are described elsewhere (Egan et al., 2001). Participants were volunteers recruited nationally and through the local community, as well as from the National Institute of Mental Health Inpatient Schizophrenia Research Program. After a complete description of the study was given, all participants gave written informed consent according to National Institute of Mental Health/National Institutes of Health Institutional Review Board guidelines and the regulations and ethical guidelines of the National Institutes of Health Office of Human Subjects Research. Participants were aged between 17 and 64 years and included 375 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type (77.6% male; 82.7% Caucasian), 502 unaffected siblings (40.6% male, 87.5% Caucasian) and 568 unrelated healthy controls (46.0% male; 81.3% Caucasian).

All participants were evaluated by a research psychiatrist for lifetime psychiatric illness and substance use with the Structured Clinical Interview for DSM-IV Disorders (First, 1997). All psychiatric diagnoses for patients were verified using third-party informants (i.e. either psychiatric records or a treating clinician). Detailed demographic and clinical narratives were compiled on each patient, and in every case final diagnoses were independently confirmed by two board-certified psychiatrists.

All participants were screened and excluded for substance abuse in three ways: (i) if they had a positive blood toxicology for alcohol or illicit drugs (amphetamines, benzodiazepines, cannabinoids, cocaine, opiates or any of their metabolites) as sampled on the actual day of study in our outpatient laboratory; (ii) if they met DSM-IV criteria for substance abuse/dependence within the past year as determined by clinical interview; or (iii) if they had a lifetime history of abuse/dependence that exceeded 5 years. Participants were also excluded if they had a history of significant medical or neurological disorders, such as epilepsy or traumatic brain injury. None of the healthy controls had a lifetime history of any DSM-IV Axis I or Axis II disorder. Additional cognitive exclusions for all participants included: (i) a current intelligence quotient (IQ) of 70 or less, as assessed by a short form of the Wechsler Adult Intelligence Scale–Revised IQ (WAIS-R estimated IQ < 70) (Wechsler, 1981; Kaufman, 1990; Missar et al., 1994); (ii) a score of 90 or less on the Wide Range Achievement Test–Revised (WRAT-R) (Jastak, 1984) [a standard test of reading proficiency used as a putative measure of premorbid intellectual functioning in patients with schizophrenia (Wiens, 1993; Goldberg et al., 1995; Kremen et al., 1995)] coupled with >20 point difference between WAIS-R and WRAT-R scores [WRAT < 90 and (WAIS − WRAT) > 20]; (iii) a WRAT-R score >90 coupled with a 25-point difference between the WAIS-R and WRAT-R [WRAT > 90 and (WAIS − WRAT) > 25]; or (iv) a diagnosis of schizophrenia spectrum disorders. The rationale for these latter exclusions was to control for childhood reading and language disorders such as dyslexia. For patients, 99.7% were outpatients and 92.8% were on antipsychotic medication at the time of study. For demographic data on participants, see Table 1.

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Table 1

Demographics for patients, siblings and controls

Patients (n = 375)Siblings (n = 502)Controls (n = 568)
MeanSEMMeanSEMMeanSEM
Age, yearsa35.20.5136.90.4432.20.41
Education, yearsa13.90.1015.60.0916.10.08
WAIS-R IQa92.30.55106.10.47107.30.45
WRAT-R IQa101.50.53106.50.45107.70.43
n%n%n%
Maleb29177.620440.626146.0
Right-handed29578.741382.346982.6
Non-right-handed8021.38917.79917.4
  • WAIS-R IQ = Wechsler Adult Intelligence Scale–Revised IQ; WRAT-R IQ = Wide-Range Achievement Test-Revised Reading IQ; EHI Laterality Quotients, Right-Handed from +71 to +100, Non-Right-Handed from +70 to −100.

  • a All demographic continuous variables significantly different by 1-way ANOVA at P < 0.01.

  • b Chi-squares significantly different for sex between patients and siblings, and patients and controls at P < 0.01.

Design

Handedness

Handedness was ascertained by a board-certified neurologist or psychiatrist, who administered the EHI to every participant (Oldfield, 1971). The EHI is a valid and reliable quantitative measurement tool that assesses a participant’s hand, eye and foot preference for 12 tasks (Ransil and Schachter, 1994). Participants were asked by the examiner to sit with their hands on their thighs and asked to demonstrate their performance of writing, drawing a picture, throwing a ball, using scissors, brushing their teeth, cutting with a knife, eating with a spoon, striking a match, sweeping with a broom, opening a box, kicking a ball and using a camera or telescope; using the words ‘show me how you’, but without the use of visual cues or prompts. In the current analysis, only the first 10 items assessing hand preference were used, resulting in a laterality quotient along a continuum of –100 (completely left-handed) to +100 (completely right-handed). Participants were also categorically coded for some statistical analysis as follows: left-handed from −100 to −71; mixed-handed (i.e. neither strong right- nor strong left-handed preference) from −70 to +70; and right-handed from +71 to +100 according to previously defined cut-offs (Dragovic, 2004; Dragovic et al., 2005). These cut-offs were based upon work by Dragovic and colleagues (2004), who set out to determine statistically EHI cut-off scores that would reliably select individuals with single-hand preference lateralization from other handedness classes. The study used latent class analysis to identify three distinct hand-preference clusters (i.e. left, mixed, right) and found that the highest agreement between latent class analysis and other types of arbitrary handedness classification criteria ranged between 0 ± 50 and 0 ± 70 of the laterality quotient (Dragovic, 2004). For other statistical analyses in this study, we defined categorical non-right-handedness as lack of strong right-hand preferences (i.e. left-handed or mixed-handed with an EHI laterality quotient of +70 to −100).

Neuropsychological tests

All participants completed an extensive battery of neuropsychological tests to assess multiple cognitive domains. As mentioned above, two tests were used to index intellectual function, the WAIS-R IQ (one of three available short forms, consisting of four subtests: Similarities, Arithmetic, Digit Symbol and Picture Completion, which has been found to most reliably estimate full-scale IQ) (Missar et al., 1994) and WRAT-R IQ. Processing speed was assessed in the spatial domain by the Trail Making Test and in the verbal domain by the Controlled Oral Word Association Test or Letter Fluency and the Category Fluency task. Attention was assessed using both the vigilance (one number flashing) and distractibility (one number flashing with two simultaneously flashing ‘distracter’ digits on either side) components of the Gordon Continuous Performance Test. Verbal episodic memory was assessed using the logical memory (story recall) immediate and 30 min delayed recall from the Wechsler Memory Scale–Revised (Wechsler, 1987), as well as the California Verbal Learning Test, which is a standardized word list learning task. Visual episodic memory was assessed using the visual reproduction (immediate and 30 min delay) tests from the Wechsler Memory Scale–Revised (Wechsler, 1987). Verbal working memory was assessed by forwards and backwards digit span tasks. Spatial working memory was measured by a spatial N-back task (Goldberg et al., 2003). Executive function was evaluated using the Wisconsin Card Sorting Test. For more information on the neuropsychological testing battery see Egan et al. (2001). Some data were normalized and reported in t-scores (Trail A, Trail B, California Verbal Learning Test and Wisconsin Card Sorting Test), with all four tests normalized for age; Trails A and B and Wisconsin Card Sorting Testing normalized for education, and Trails A and B and the California Verbal Learning Test normalized for sex. Additional published normative data for other neurocognitive tests can be found elsewhere (Kern et al., 2008).

Structural MRI—laterality indices

Three-dimensional structural MRI data were available for the total sample, passing quality control criteria (i.e. free of visible artefact, distortion, incomplete acquisition or evidence of neurological abnormality) for 113 patients with schizophrenia (79.6% right-handed, 13.3% mixed-handed, 7.1% left-handed) and 264 controls (86.7% right-handed, 6.8% mixed-handed, 6.4% left-handed). MRI scans were acquired on a 1.5 T GE scanner (GE Medical Systems, Milwaukee, WI) using a T1-weighted spoiled gradient recalled sequence (repetition time 24 ms, echo time 5 ms, number of excitations 1, flip angle 45°, matrix size 256 × 256, field of view 24 × 24 cm), with 124 sagittal slices (0.94 × 0.94 × 1.5 mm resolution). Using automated surface reconstruction and parcellation as described previously (Goldman et al., 2009), we obtained grey matter volume from regions known to show laterality effects, including the frontal poles, the occipital poles, the superior temporal gyrus and temporal poles. Laterality indices of grey matter volume from these four regions were calculated based on the standard formula [(left – right)/(left + right)]. Laterality indices were analysed using analysis of co-variance to assess for effects of diagnosis and handedness (with handedness first as a categorical predictor and then as a continuous predictor), with age, sex and total grey matter volume as covariates.

Statistics

Statistical analyses of group differences were computed with chi-square analyses and analysis of variance (ANOVA). Heritability analysis was computed using both relative risk calculation and intra-class correlations. Linear relationships between handedness and cognition were computed using multiple regression analysis in Statistica 8.0 (Statsoft, Inc., 2008; http://www.statsoft.com). Structural MRI data were analysed using Statistical Package for the Social Sciences version 16.0 (SPSS, Inc., 2008).

Results

Demographics

Participant demographics were analysed for diagnostic group differences (patients, siblings and controls) by one-way ANOVA. Not surprisingly, patients, siblings and controls differed significantly from one another in age, years of education, WAIS-R IQ and WRAT-R (all F > 31.9, all P < 0.01, Table 1). The patient group included significantly more male participants than either sibling or control groups [both χ2(1) > 93.2, both P < 0.01].

Handedness and diagnosis

Handedness was analysed using the EHI data in two ways: both quantitatively (–100 to +100) and categorically (i.e. left, mixed, right or right/non-right) (Oldfield, 1971). First, we compared EHI laterality quotients for each diagnostic group using one-way ANOVA. We found that patients displayed a leftward shift from siblings (68.8 versus 76.3, respectively) and from controls (68.8 versus 77.0, respectively) [F(2,1442) = 3.06, P = 0.05, Table 2]. Since it is well documented that non-right-handedness is more prevalent in males than females, and given the larger proportion of males than females in our patient group, we also performed secondary analyses of sex in this and all subsequent cognitive and neuroimaging data analyses in an attempt to factor sex into our analyses where possible. Thus, when sex was accounted for in a factorial ANOVA, patients did not differ significantly from controls or siblings [F (2,1439) = 1.51, P = 0.22, Table 2]. Next, to address whether categorical left-handedness (EHI −100 to −71) or mixed-handedness (EHI −70 to +70) was more prevalent in patients with schizophrenia as compared with their unaffected siblings or unrelated healthy controls, we compared these proportions using chi-square analysis. No significant differences were found among any of the diagnostic groups for left-handedness or mixed-handedness (all P > 0.15). Lastly, to address whether non-right-handedness (i.e. collapsing mixed- and left-handed participants, EHI −100 to +70) was more prevalent in patients, we compared the rates of non-right-handedness among each diagnostic group. We found no significant difference in the proportion of non-right-handed patients as compared with controls (all P > 0.12). Based on these findings, we subsequently chose to combine left- and mixed-handed participants for all further statistical analyses requiring categorical data to balance our sample size and increase power.

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Table 2

Differences in Edinburgh Handedness Inventory laterality quotients among patients, siblings and controls

Patients (n = 375)Siblings (n = 502)Controls (n = 568)Group differences
MeanSEMMeanSEMMeanSEMFdfP
All subjects (one-way)a68.82.776.32.477.02.23.062, 14420.05
All subjects (two-way)b70.73.376.52.476.62.21.272, 14390.28
  • EHI laterality quotients = −100 (fully left-handed) to +100 (fully right-handed).

  • a One-way ANOVA among diagnostic groups; post hoc significant differences between patients versus siblings P = 0.04; patients versus controls P = 0.02.

  • b Two-way ANOVA with diagnosis and sex as factors; no main effect of diagnosis or sex (both P > 0.11).

Familiality of non-right-handedness in families with schizophrenia

To determine if non-right-handedness per se was familial, we analysed whether non-right-handed patients had a greater proportion of non-right-handed siblings as compared with right-handed patients. Using every family for whom both one patient and at least one or more related sibling participated (n = 384), we found no significant difference in the proportion of non-right-handed siblings [non-right-handed siblings of non-right-handed patients = 13.8% versus non-right-handed siblings of right-handed patients = 17.6%, respectively; χ2(1) = 0.72, P = 0.40].

To assess further whether siblings from pairs with a non-right-handed proband were at increased ‘risk’ for inheriting ‘atypical handedness’ (i.e. non-right-handedness), we calculated relative risk using the proportion of non-right-handed siblings of non-right-handed patients (0.138) divided by the proportion of non-right-handedness in our control group (0.174) and found that relative risk for inheriting non-right-handedness was not increased (λS = 0.79) (Risch, 1990; Egan et al., 2001). Next, using the EHI quantitative data, we performed an intra-class correlation between patient–sibling pairs to determine the degree to which patients and siblings resembled one another on EHI laterality quotient scores and found no agreement between patient–sibling pairs [Intra-class correlation = −0.04; F (383, 763) = 0.93, P = 0.75]. This lack of increased atypical lateralization in unaffected siblings is not surprising, given its consistency with several previous studies (Clementz et al., 1994; Byrne et al., 2004). Since siblings did not manifest non-right-handedness at a rate that suggests that this trait is related to increased genetic risk for schizophrenia, nor did they differ significantly from controls on EHI laterality quotient scores, we chose to limit subsequent analyses of neurocognition and brain asymmetry in handedness to patients and healthy controls.

Handedness and neurocognition

As expected and previously reported by our group, patients and controls significantly differed on all neuropsychological measures (all P < 0.001; see Supplementary Table 1 for mean differences between right-handed and non-right-handed patients and controls). To determine if handedness in schizophrenia uniquely predicted neurocognitive performance, we performed within-group multiple regression analyses between the quantitative EHI and each cognitive test (with age, sex and years of education as regressors). Within patients, and in separate analyses within controls, we found no significant relationships between the EHI and any cognitive measures that survived Bonferroni correction (Table 3). Thus, we did not find any evidence to support the idea that non-right-handedness is associated with a general neurocognitive disadvantage in schizophrenia or in healthy controls.

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Table 3

Summary of within-group multiple regression analysis to determine if quantitative Edinburgh Handedness Inventory laterality quotients uniquely predict cognitive performance in patients and controls

Patients (n = 375)Controls (n = 568)
MeasureβSE βPaβ SE βPa
Processing speed
    Trails A −0.010.050.80−0.090.040.05
    Trails B0.020.050.74−0.010.040.91
Language production/retrieval 
    Letter fluency0.060.050.27−0.060.040.18
    Category fluency0.090.050.06−0.030.040.41
Attention
    CPT vigilance correct−0.030.050.55−0.050.040.29
    CPT vigilance errors−0.060.050.220.040.040.32
    CPT distractibility correct−0.040.050.45−0.070.040.10
    CPT distractibility errors−0.04 0.050.450.04 0.040.40
Verbal episodic memory
    WMS-R logical memory (immediate)−0.010.050.870.050.040.22
    WMS-R logical memory (delayed)0.010.050.860.050.040.26
    CVLT−0.01 0.060.750.002 0.040.97
Visual episodic memory
    Visual reproduction (immediate)0.080.050.11−0.050.050.36
    Visual reproduction (delayed)0.04 0.050.390.04 0.050.40
Working memory
    WMS-R forward0.030.050.550.020.050.71
    WMS-R backwards0.010.050.860.010.050.91
    N-back one0.060.060.31−0.020.040.61
    N-back two0.0020.060.98−0.030.040.50
    N-back three0.03 0.060.600.03 0.040.51
Executive functioning
    WCST % perseverative errors0.070.050.18−0.010.040.90
    WCST categoriesb0.06 0.050.21−0.01 0.040.74
  • CPT = Gordon Continuous Performance Test—Vigilance and Distractibility Components; WMS-R = Wechsler Memory Scale–Revised—Logical Memory and Visual Memory Immediate and Delayed Recall; CVLT = California Verbal Learning Test; N-back; WCST = Wisconsin Card Sorting Test.

  • a No significant relationship between EHI laterality quotient and cognition with Bonferroni corrected P = 0.002, with age, sex and education as regressors.

  • b WCST number of categories, estimation of number of categories in standard 128 card version calculated as follows: (number of categories completed/number of trials)*128.

Handedness and laterality indices

For EHI quantitative handedness, we found no significant effects of diagnosis or handedness on the laterality index measures for frontal, lateral occipital or temporal poles, or superior temporal gyrus (all P > 0.05). For categorical handedness, we did not find any significant effects of diagnosis or handedness, or a diagnosis by handedness interaction, in the frontal, lateral occipital or temporal poles (all P > 0.22). However, we found a significant effect of EHI categorical handedness on laterality indices in the superior temporal gyrus grey matter volume [laterality index right = 0.048, laterality index non-right = 0.033; F(1,367) = 4.72, P = 0.03], but no diagnosis effect [F(1,367) = 1.45, P = 0.23] nor an interaction between diagnosis and handedness [F(1,367) = 1.96, P = 0.16] (Table 4). Thus, non-right-handed participants had significantly reduced left asymmetry in the superior temporal gyrus compared with right-handed participants. In summary, EHI categorical, but not quantitative handedness or diagnosis, predicted gross anatomical lobar brain structure in the superior temporal gyrus only.

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Table 4

Laterality indicesa of brain volume in patients and controls

PatientsControl Diagnosis × handedness
Right (n = 90)Non-right (n = 23)Right (n = 229)Non-right (n = 35)
Region of interestMeanSEMMeanSEMMeanSEMMeanSEMFdfP
Frontal pole−0.1240.018−0.0780.031−0.1030.009−0.0980.0230.9410.33
Temporal pole0.0390.0160.0470.0280.0460.0080.0390.0210.1610.69
Lateral occipital pole0.0680.0070.0600.0130.0690.0040.0800.0091.6010.21
Superior temporal gyrusb0.0590.0060.0330.0100.0380.0030.0320.0081.9010.16
  • a Laterality index of brain volume = (left − right)/(left + right), where + laterality index = left asymmetry and – lateral index = right asymmetry.

  • b Main effect of handedness, P = 0.03, with age, sex and total grey matter volume as covariates.

Discussion

Left–right asymmetrical brain function has long been thought to underlie much of human behaviour and cognition. Originating in 19th-century phrenology, the inequality in size and maturity between the left and right frontal lobes was theorized to reflect our intellectual capacity for self-improvement. Since the left half of the brain controls the right half of the body, learning to write with the right hand was considered a logical indicator of the dominance of this putative superior left side of the brain. Furthermore, as the effects of education were believed inheritable, brains likely became more asymmetric—and hence increasingly intelligent—as our societies evolved. By cultivating this view of the left side of the brain as the intelligent and educated side, there was a simultaneous growth in suspicion and fear towards the unintelligent right hemisphere. The domination of this undesirable right hemisphere was increasingly blamed for the supposed inferiority of certain human groups, especially the insane, women and non-whites (Hugdahl and Davidson, 2003). Indeed, against this colourful—and shameful—historical backdrop, wide-ranging notions of the putative inferiority of left-handers continue to attract media attention even in the 21st century and seemingly resonate easily with popular mythology, such that suggestions that left-handers have shorter lifespans are readily accepted as plausible (Halpern and Coren, 1988). Indeed, ‘There is almost no pattern of cerebral lateralization or handedness that has not at some time been mooted as the cause or correlate of one kind of developmental disorder’ (Bishop, 1990).

Our results suggest that despite the longevity of such ideas—especially of the increased prevalence of left-handedness in schizophrenia and its putative negative role in neurocognition—a large-scale empirical investigation of this does not lend support to this theory. This may be because previous studies that have reported differences in schizophrenia as a function of handedness (Dragovic et al., 2005) have employed comparatively few neurocognitive measures. In contrast, we employed a large battery of neurocognitive tests but did not find supporting evidence that non-right-handedness is associated with neurocognitive deficits in schizophrenia.

We recognize that cerebral lateralization is probably not a categorical function, which is why we also examined quantitative handedness data to reduce any systematic bias in arbitrarily assigning handedness categories. While we found a difference, an 8-point leftward shift in EHI laterality quotients in patients versus controls and a 7.5-point leftward shift in patients versus siblings, importantly these effects disappeared when sex was included in the model. Thus, these findings lend little support to the idea of increased left- or non-right-handedness in schizophrenia compared with healthy controls. Nonetheless, we cannot completely discount the fact that there was a slight drift in lateralization in the patients, perhaps because of some early developmental deviations in a few participants; but in the context of our overall findings this seems extremely improbable. Interestingly, to our knowledge the only other study that examined the EHI quantitatively as opposed to categorically (in 73 outpatients with schizophrenia and 81 controls) reached a similar conclusion (Buijsrogge et al., 2002). In toto these findings provide further confirmation of the lack of a genetic lateralization bias related to schizophrenia risk.

By assessing rates of non-right-handedness in siblings from families of non-right patients (14%) and right-handed patients (18%), and subsequently calculating both relative risk in unaffected siblings and an intraclass correlation between patient–sibling pairs, we did not find evidence that non-right-handedness was familial in this sample or that it was linked to increased genetic risk for schizophrenia. Since non-right-handedness was not significantly over-represented in patients with schizophrenia as compared with siblings or controls, given that non-right-handedness does not appear to be enriched in family members of patients with schizophrenia, and since it is estimated that only 25% of the variance in twin studies of handedness heritability may be due to genetic influences (Medland et al., 2006), handedness is unlikely to be a good phenotype for assessing genetic vulnerability to schizophrenia.

It is noteworthy of course that handedness is simply an indirect and developmentally labile proxy of anatomical asymmetry. Indeed, a recent neuroimaging study in schizophrenia challenges the very usefulness of handedness as a metric in that it finds that cerebral anatomical asymmetries represented as torque occur through mechanisms dissociable from those affecting handedness (Narr et al., 2007). Nonetheless, in so far as our handedness data in schizophrenia are relevant, the putative leftward shift in patients disappeared when sex was taken into account, and furthermore there was no support for non-right-handedness being a heritable phenotype in schizophrenia.

Our findings are clearly at odds with many studies that report increased non-right-handedness in patients with schizophrenia. Despite any methodological limitations of these studies (e.g. diagnostic issues, varied methods for assessing handedness, small sample sizes), it is of course very likely that some of these studies did indeed include participants with increased non-right-handedness. However, we suggest that it is possible that some of these samples may have been enriched with patients having attention deficit-hyperactivity disorder, dyslexia and perhaps other childhood developmental problems that may have spuriously led to the assumption that the link of increased non-right-handedness was with schizophrenia specifically. In contrast, we specifically attempted to exclude participants with childhood reading or language disorders in our study, by way of discrepancies between WAIS-R IQ and WRAT-R reading IQ scores, which again may account for the absence of any putative cognitive deficits as a function of hand laterality, as opposed to some previous studies (Katsanis and Iacono, 1989; Faustman et al., 1991; Dragovic et al., 2005). To the extent that schizophrenia can be differentiated pathophysiologically from other disorders that have been associated with increased non-right-handedness, our data indicate that non-right-handedness is not associated with schizophrenia per se. We found no evidence of handedness or diagnosis differences as a function of grey matter volume asymmetries in the frontal, lateral occipital or temporal poles as measured by a global laterality index, which is consistent with previously reported global measures of brain volume. However, we found that categorical non-right-handedness (but not quantitative handedness or diagnosis) was associated with a reduction of leftward asymmetry in the superior temporal gyrus in our sample, which is consistent with a review of a number of previous studies of handedness and asymmetry (Shapleske et al., 1999). In particular, Habib and colleagues (1995) also found that in 40 healthy controls, the categorical but not quantitative EHI handedness measure was associated with a significantly larger leftward asymmetry in the planum temporale in 24 ‘consistent right-handers’ compared with the 16 non-right-handers. It is suggested by Shapleske et al. (1999) that in studies of the planum temporale in schizophrenia, only 5 of 16 studies measured handedness using standardized subjective measures, concluding that the manner in which handedness is assayed (e.g. dichotomous versus continuous, self-report versus a standardized assessment) greatly influences studies of anatomical asymmetry in schizophrenia and handedness. Our findings, along with previously published work on the planum temporale, suggest that handedness, regardless of diagnosis, is associated with brain asymmetry in the superior temporal gyrus.

Our study was limited by several factors that merit consideration in future studies. First, we did not collect data on parental handedness. This would be useful so as to explore the heritability of handedness in greater detail. Second, we relied upon a single EHI administration to determine laterality quotients. Although repeat EHI administration would have been ideal, it was impractical given time constraints. Furthermore, given that the EHI has been shown to have good test-retest reliability, and has at times been used only as a self-report measure, we believe that the professional administration of this test is a strength that compensates for our lack of repeat administrations. Third, our control sample included significantly more females than males. Although sex was included as a predictor in secondary analyses, our patient sample included a disproportionately larger number of males, which in turn may have contributed to the leftward shift observed in the EHI quantitative data. Future large-scale studies of handedness and schizophrenia that are better balanced for sex and have the statistical power to explore putative sex differences of the issues we have addressed are clearly needed. In conclusion, in so far as handedness is a proxy for cerebral lateralization, our study does not lend strong support to notions of an abnormality in this aspect of brain development in schizophrenia, nor that ‘atypical’ handedness is a heritable phenotype linked to genetic risk for schizophrenia, nor that it is associated with poorer neurocognition. Handedness, but not schizophrenia, is associated with global brain laterality measures of the superior temporal gyrus. In conclusion, theories of schizophrenia based on anomalous lateralization related to handedness are unsupported by our data.

Funding

Intramural Research Program of the National Institute of Mental Health, National Institutes of Health.

Supplementary material

Supplementary material is available at Brain online.

Acknowledgements

The authors gratefully acknowledge Drs Dwight Dickinson and Richard Coppola for their statistical assistance. The authors also thank John Meyers BS, Krista Wisner BA and Sally Cheung BS. for their assistance with data management.

Footnotes

  • Abbreviations
    EHI
    Edinburgh Handedness Inventory
    WAIS-R IQ
    Wechsler Adult Intelligence Scale–Revised Intelligence Quotient
    WRAT-R IQ
    Wide Range Achievement Testing–Revised Intelligence Quotient
    DSM-IV
    Diagnostic and Statistical Manual of Mental Disorders (fourth edition)
  • References

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