Cerebellar Asymmetry and Cortical Connectivity in Monozygotic Twins with Discordant Handedness.

Handedness differentiates patterns of neural asymmetry and interhemispheric connectivity in cortical systems that underpin manual and language functions. Contemporary models of cerebellar function incorporate complex motor behaviour and higher-order cognition, expanding upon earlier, traditional associations between the cerebellum and motor control. Structural MRI defined cerebellar volume asymmetries and correlations with corpus callosum (CC) size were compared in 19 pairs of adult female monozygotic twins strongly discordant for handedness (MZHd). Volume and asymmetry of cerebellar lobules were obtained using automated parcellation.CC area and regional widths were obtained from midsagittal planimetric measurements. Within the cerebellum and CC, neurofunctional distinctions were drawn between motor and higher-order cognitive systems. Relationships amongst regional cerebellar asymmetry and cortical connectivity (as indicated by CC widths) were investigated. Interactions between hemisphere and handedness in the anterior cerebellum were due to a larger right-greater-than-left hemispheric asymmetry in right-handed (RH) compared to left-handed (LH) twins. In LH twins only, anterior cerebellar lobule volumes (IV, V) for motor control were associated with CC size, particularly in callosal regions associated with motor cortex connectivity. Superior posterior cerebellar lobule volumes (VI, Crus I, Crus II, VIIb) showed no correlation with CC size in either handedness group. These novel results reflected distinct patterns of cerebellar-cortical relationships delineated by specific CC regions and an anterior-posterior cerebellar topographical mapping. Hence, anterior cerebellar asymmetry may contribute to the greater degree of bilateral cortical organisation of frontal motor function in LH individuals.

Disconnection agraphia in a case of multiple sclerosis: the isolation of letter movement plans from language.

We report the case of a left-handed man (MCR), who presented with a peripheral agraphia as an early sign of multiple sclerosis. His left-handed writing was neologistic, whilst oral spelling, typing and spelling with the right hand were intact. Structural MRI scanning revealed a lesion of the body of the corpus callosum. Dichotic listening tests indicated that MCR displayed left hemisphere dominance for language. It is proposed that MCR represents a case of a disconnection syndrome in which right hemisphere systems that provide the basis for movement templates during left-handed writing are isolated from left hemisphere language systems. Analysis of left-handed writing indicated that peripheral movement control was highly structured with both individual letter frequency and sequential dependencies between letters represented within these motor control units. This case represents an opportunity to explore the mechanisms of movement control for writing and to examine the characteristics of isolated letter templates.

Frontal and temporal lobe brain volumes in schizophrenia. Relationship to symptoms and clinical subtype.

BACKGROUND: Quantitative magnetic resonance imaging (MRI) studies demonstrate reduced brain volumes in schizophrenics, but specific structural abnormalities have not been clearly delineated. The structural abnormalities of this disorder are likely to be heterogeneous, consistent with its diverse clinical presentation. To investigate the relationship between structural abnormality and clinical symptoms, we examined regional brain and cerebral spinal fluid (CSF) volumes in a large sample of schizophrenic patients and controls, with patients aggregated into clinical subtypes. METHODS: Right and left hemisphere frontal and temporal lobe brain and CSF volumes were quantified from 5-mm axial spin-echo MRIs for 71 schizophrenic patients and 77 age- and sex-matched controls. The following four standardized rating scales were used to assess symptom severity: Negative Symptoms, Disorganization, Schneiderian Delusions and Hallucinations, and Suspicion-Hostility. Patients were also subtyped as either deficit or nondeficit on the basis of enduring negative symptoms. RESULTS: Schizophrenic patients overall exhibited abnormal brain asymmetry, with selective decrease in brain volume in the left temporal and right frontal regions. Left temporal lobe parenchymal volume reduction and CSF volume increase were correlated with the severity of negative symptoms. Consistent with this, the subtype analysis revealed abnormal temporal lobe asymmetry for the deficit subgroup only. Right frontal lobe volume reduction correlated with the duration of illness, independent of symptom severity or schizophrenic subtype. CONCLUSIONS: Abnormal lateral asymmetry suggests selective structural deficits in schizophrenia, rather than diffusely undifferentiated CNS abnormalities. The pattern of regional abnormalities is related to clinical symptoms, with negative symptoms being associated with left temporal lobe rather than frontal lobe abnormality. This is consistent with suggestions of a temporolimbic prefrontal network abnormality in schizophrenia. Further longitudinal studies are warranted, using higher-resolution MRI technology and gray matter-white matter segmentation to confirm and extend these findings.

Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia.

BACKGROUND: Converging neuroanatomic, neurophysiological, and neurobehavioral evidence implicate prefrontal subregions in schizophrenia. Neuroanatomic studies with magnetic resonance (MR) imaging enable regional volume parcellation. Inconsistent reports may relate to variable methods and small samples. We attempted to resolve volume differences within sectors of the prefrontal lobe in a large sample, relating volumes to clinical and neurocognitive features. METHODS: Magnetic resonance imaging was performed in 70 patients with schizophrenia (40 men and 30 women; 29 neuroleptic naive and 41 previously treated) and 81 healthy controls (34 men and 47 women). Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Reduced prefrontal gray matter volume was observed in patients. The reduction was evident for the dorsolateral area in men (9%) and women (11%), for the dorsomedial area only in men (9%), and for orbital regions only in women (23% and 10% for lateral and medial, respectively). The reduction of orbital volume in women was associated with poorer premorbid functioning, more severe negative symptoms, and depression. Volume of dorsal cortex was positively associated with better performance on abstraction and attention tasks across all groups. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector. The effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function. This is not a by-product of treatment, since the differences are evident in neuroleptic-naive patients.

Temporolimbic volume reductions in schizophrenia.

BACKGROUND: Neuroanatomic studies of schizophrenia have reported temporolimbic abnormalities. Most magnetic resonance imaging studies have evaluated small samples of primarily men with chronic schizophrenia. Our goal was to evaluate sex differences in segmented temporal lobe subregions with reliable parcellation methods, relating volume with clinical and neurocognitive parameters. METHODS: Magnetic resonance imaging was performed in 100 patients with schizophrenia (58 men, 42 women; 39 neuroleptic naive, 61 previously treated) and 110 healthy controls (51 men, 59 women). Gray and white matter volumes of temporolimbic (hippocampus and amygdala) and neocortical regions (superior temporal gyrus and temporal pole) were examined. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Hippocampal gray matter volume was reduced in men (7%) and women (8.5%) with schizophrenia. In the amygdala, however, decreased volume was evident for men (8%) whereas women (10.5%) had increased volume. Magnetic resonance imaging of the temporal pole showed decreased gray matter in men (10%) and women (8.5%). For the superior temporal gyrus, the decrease exceeded that of whole-brain only in men (11.5%). Volumes were largely uncorrelated with clinical measures, but higher hippocampal volumes were associated with better memory performance for all groups. Cortical volumes were associated with better memory performance in healthy women. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in temporolimbic structures. In men, reduction was manifested in all regions, whereas women showed decreased hippocampal volumes but increased amygdala volumes. The abnormalities are evident in patients with first-episode schizophrenia and correlate more strongly with cognitive performance than with symptom severity.

Sex differences in neuroanatomical and clinical correlations in schizophrenia.

OBJECTIVE: The purpose of this study was to investigate sex differences in relationships between brain and behavior in schizophrenia. METHOD: Frontal lobe, temporal lobe, and whole brain volumes were obtained from magnetic resonance images of 91 patients with schizophrenia (54 men and 37 women) and 114 healthy comparison subjects (62 men and 52 women). Four independent symptom scales, based on the following symptom clusters, were derived from clinical data: negative, disorganization, Schneiderian hallucinations-delusions, and suspicion-hostility. Regression analyses incorporating the four clinical scales and neuroanatomical volumes were performed to investigate possible interactions between brain region and sex. RESULTS: Significant interactive effects of sex and frontal lobe volume were found in regression analyses of the disorganization and suspicion-hostility symptom scales. In men, higher frontal lobe volume was associated with milder severity of disorganization but was not correlated with severity of suspicion-hostility. In women, higher frontal lobe volume was associated with more severe disorganization as well as more severe suspicion-hostility. No associations were found between brain volume and severity of negative or Schneiderian symptoms. CONCLUSIONS: Differences between male and female patients were observed in the relationships between frontal lobe volume and two of the four clinical dimensions examined. These findings suggest that aspects of the neuropathological basis for some symptoms of schizophrenia may be sexually dimorphic.

Multiple dimensions of handedness and the human corpus callosum.

Consistency of right-hand preference correlates with callosal isthmus size. Anterior corpus callosum (CC) regions vary as a function of sex and right- versus left-hand preference. We analyzed regional CC anatomy in a sample of right- and left-handed men and women on the basis of both degree ("Consistency") and direction ("Hand") of hand preference scores. Significant Hand x Consistency effects indicated that both are important factors in CC organization. These data also suggested that a single continuum of hand preference and regional CC size may not be applicable across all subjects.

Corpus callosum: interactive effects of infantile handling and testosterone in the rat.

Previous research found that the corpus callosum of male rats is larger than that of females; handling rats in infancy enhances this sex difference; and female rat pups, when handled in infancy and given 1 injection of testosterone propionate (TP) on Day 4 of life, will have callosa as large as those of males. In 2 experiments, male pups were castrated on Day 1 or received sham surgery; female pups were injected with TP on Day 4 or received an oil injection. Litters were handled or nonhandled. The previous finding that females, when handled and given TP in infancy, have a larger callosum was confirmed; however, a TP effect when administered to nonhandled females was not found. Because handling is known to cause a corticosterone release, these findings were interpreted as evidence of a developmental interaction between adrenal and gonadal hormones at the cortical level.

Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism.

In this study we report a convergence of behavioural and neuroanatomical evidence in support of an amygdala hypothesis of autism. We find that people with high-functioning autism (HFA) show neuropsychological profiles characteristic of the effects of amygdala damage, in particular selective impairment in the recognition of facial expressions of fear, perception of eye-gaze direction, and recognition memory for faces. Using quantitative magnetic resonance (MR) image analysis techniques, we find that the same individuals also show abnormalities of medial temporal lobe (MTL) brain structure, notably bilaterally enlarged amygdala volumes. These results combine to suggest that developmental malformation of the amygdala may underlie the social-cognitive impairments characteristic of HFA. This malformation may reflect incomplete neuronal pruning in early development.

A factor analysis of the human's corpus callosum.

We have recently developed a computer program for measuring midsagittal sections of the human corpus callosum, similar to one used for the rat. Callosal area, perimeter, axis length, and 99 widths for 104 subjects were entered into a factor analysis in order to define regional clusters. Seven width factors were obtained. Regional widths were found to be sensitive to Sex X Handedness interactions in the anterior body, with right-handed females and left-handed males being larger. In the posterior body males had wider callosa than females. A further analysis within the 'isthmus' region compared consistent and non-consistent right-handed males and females. Consistent right-handed males and both female groups had smaller callosa than non-consistent right-handed males. These findings confirmed the use of consistency of handedness as an important independent variable with respect to human callosal morphology.

Corpus callosum: ovarian hormones and feminization.

The rat's corpus callosum is sexually dimorphic with the male's being larger. This difference appears to depend in part on the neonatal presence of testosterone in the male and ovarian hormones in the female. To further investigate the possibility that ovarian hormones participate in the differentiation of the rat's callosum, females received one of the following treatments on postnatal day 8, 12 or 16: (1) ovariectomy (Ovx); (2) 1 mg of testosterone propionate (TP); or (3) sham surgery. All animals were handled daily from birth until weaning. They were sacrificed at 110 days and a mid-sagittal section of the callosum was obtained. From this section measures of callosal area, perimeter, length, and 99 widths were derived. Widths were averaged into 7 factors as defined by prior factor analysis. Ovariectomy, whether on day 8, 12 or 16, enlarged callosal area and 3 of the callosal width factors. TP had no effect on any callosal variable when administered on day 8, 12 or 16. A comparison of control males and females replicated our prior findings of sexual dimorphism. We conclude that ovarian hormones act to feminize the female callosum, and that their removal results in defeminization. Furthermore, the fact that ovariectomy was effective as late as day 16, while TP treatment on day 8 or later had no effect, suggests that masculinization and feminization of this structure constitute separate processes with distinct sensitive periods.

Corpus callosum: effects of neonatal hormones on sexual dimorphism in the rat.

The rat's corpus callosum is sexually dimorphic, with the male's being larger. In addition, giving rats extra stimulation in infancy via handling increases callosal area in males, but not in females. To determine if this dimorphism is testosterone-dependent, male pups were castrated on Day 1 of life while females received an injection of testosterone propionate (TP) on Day 4. Control males had sham surgery and control females received an injection of sesame oil. All animals were handled daily from birth until weaning. Animals were sacrificed at 110 days and a mid-sagittal section of the callosum was obtained. From this section measures of callosal area, perimeter, length, and 99 widths were derived. We verified our previous finding that the male callosum is larger than that of the female. Neonatal TP treatment masculinized the callosa of the females, but castration did not affect the males. TP treatment affected the width dimension of the callosum but not callosal length or brain weight. In a related study the synthetic estrogen DES did not increase callosal size for castrated males or for intact females, while the estrogen blocker, tamoxifen, had a defeminizing effect on females' callosa. These findings suggest that there is an estrogen-dependent active process of feminization of cortical tissue in the female brain.

Corpus callosum: demasculinization via perinatal anti-androgen.

The male rat's corpus callosum is significantly larger than the female's. This dimorphism depends in part on the early presence of testosterone, since postnatal administration of testosterone to female pups enlarges their callosa in adulthood to the size of males. However, castrating males on day 1 is ineffective in reducing (demasculinizing) the size of their callosa as adults. We then addressed the question as to whether testosterone acts prior to day 1 to enlarge the callosa of males. To investigate this hypothesis pregnant rats were administered a non-steroidal androgen blocker, flutamide, during the last 5 days of pregnancy, while controls received vehicle only. Male pups from flutamide litters were castrated on day 3 to prevent postnatal recovery following clearance of flutamide, while others received sham surgery. Callosal sex differences were found between males and females of control litters, but not between males and females from flutamide litters. The absence of sex effects among flutamide litters was a consequence of small callosal size in flutamide-castrated males as compared to control males. We concluded that the prenatal production of testosterone in the male rat pup contributes to sexual dimorphism in the callosa of adult rats.

Laterality in animals: relevance to schizophrenia.

Anomalies in the laterality of numerous neurocognitive dimensions associated with schizophrenia have been documented, but their role in the etiology and early development of the disorder remain unclear. In the study of normative neurobehavioral organization, animal models have shed much light on the mechanisms underlying and the factors affecting adult patterns of both functional and structural asymmetry. Nonhuman species have more recently been used to investigate the environmental, genetic, and neuroendocrine factors associated with developmental language disorders in humans. We propose that the animal models used to study the basis of lateralization in normative development and language disorders such as dyslexia could be modified to investigate lateralized phenomena in schizophrenia.

Ovarian estrogen acts to feminize the female rat's corpus callosum.

The rat corpus callosum (CC) is sexually dimorphic, with the male CC being larger. Ovariectomy (Ovx) on day 12 has been shown to eliminate this sex difference, with callosal values of Ovx females approaching those of male controls. This suggested that postnatal ovarian estrogen affects the size of the female CC. In the present experiment, one group of female rats received Ovx on day 12, and a second group received Ovx followed by chronic implantation of a silastic tube containing beta-estradiol on day 25. Unmanipulated males and sham females served as controls. Examination of the CC at 110 days confirmed our prior findings that males have larger callosa than females and that the Ovx group had increased CC's compared to sham controls. Our new finding was that estrogen treatment was capable of reversing the effects of Ovx. Ovx+estrogen-treated females had decreased CC size as compared to Ovx alone. Indeed, they also had smaller CC values than control females. These findings indicate that ovarian estrogen plays a role in determining CC morphology and that estrogen in the female acts to inhibit overall callosal growth as measured by changes in gross callosal size.

A developmental study of sex and age interactions in the human corpus callosum.

Regional analysis of the corpus callosum (CC) has demonstrated that the development of this fiber tract is sexually dimorphic. Midsagittal CC tracings from magnetic resonance images (MRIs) of 73 pairs of age-matched (age 2-79 years) males and females were digitized using computer assisted software. Area, axis length, perimeter, and 99 widths were obtained. Widths were grouped into the following regions based upon prior factor analysis: widths 3-18 (W3-18), W22-39, W49-62, W65-74, W77-85, W89-94, and W95-99. Trend analyses were performed with Sex and Age (blocked into 10-year bins) as independent variables. Higher order Sex by Age interactions were significant in regions W3-18 and W22-39 and were marginal in W95-99. In all 3 regions, females did not attain maximum width until Age 41-50 whereas males had peaked at 20 years and declined thereafter. There were no significant interactions between Sex and Age in the remaining CC regions, nor were there any dramatic decreases once maximum width was reached in adulthood. These results suggest that sex differences may also exist in CC ultrastructure over the human lifespan.

Corpus callosum: multiple parameter measurements in rodents and humans.

A magnified drawing of a human or a rodent corpus callosum is traced on a digitizing tablet. From this tracing the computer calculates callosal area, perimeter, length, and 99 widths, one for each percentile location along the longitudinal axis of the callosum. In addition, the human program encloses the callosum within a rectangle to obtain several other measures. The use of percentile widths allows one to generate a callosum profile to compare different clinical groups or different species. The human callosum program is compared to one recently reported by another research group.

Comment on delayed left-ear accuracy in dichotic listening.

Moulden and Persinger recently reported on the emergence of left-ear accuracy during childhood and adolescence. This commentary briefly discusses their findings with reference to previous studies that have reported on dichotic listening paradigms and, in particular, those in which a left-ear focus was used as a behavioral probe sensitive to developmental sex differences.

fMRI and corpus callosum relationships in monozygotic twins discordant for handedness.

To further investigate brain structure and function in 26 handedness discordant monozygotic twin pairs (MzHd), MRI and behavioural assessments were carried out. These showed significant correlation between language-specific functional laterality in inferior and middle frontal gyri, and anterior corpus callosum. Previous studies of handedness discordant monozygotic twins failed to resolve the issue concerning handedness and hemispheric laterality for language due to methodological disparities. The results would be relevant to genetic theories as well as to brain structure:function explanations. MzHd twins underwent MRI and fMRI scanning as well as behavioural assessment of motor performance and cognition. There were significant differences on MRI and fMRI laterality measures, as well as a significant correlation between anterior callosal widths and functional laterality. LH twins showed higher frequencies of atypical functional laterality. There was no significant within-twin pair correlation on fMRI verbal laterality, nor did results show within-twin pair differences on verbal fluency or IQ. Implications for the field of laterality research pertain to frontal hemispheric equipotentiality for verbal processes in healthy individuals. In particular, there can be an apparent lack of cognitive 'cost' to atypical laterality. An fMRI verbal laterality index correlated significantly with corpus callosum widths near Broca's area.

Corpus callosum morphology and microstructure assessed using structural MR imaging and diffusion tensor imaging: initial findings in adults with neurofibromatosis type 1.

BACKGROUND AND PURPOSE: Imaging studies have shown that children with NF-1 have increased brain volumes compared with age-matched controls and the CCs are disproportionately large. The purpose of this study was to determine if the CC in adults with NF-1 differed from that in matched controls by using DTI and volumetric imaging. MATERIALS AND METHODS: MR imaging with DTI was performed in 10 adults with NF-1 and in 10 age-, sex-, and handedness-matched controls by using a 3T system. Total brain volumes and the areas and central lengths of the CC were calculated, along with the radial width of callosal subdivisions, in the 2 groups. RESULTS: Our results showed that the total brain volume was not significantly different between adults with NF-1 and matched controls. The length and total cross-sectional area of the CC were statistically larger in adults with NF-1 compared with controls (approximately 10% longer and 20% greater area). On DTI we found a preservation of the primary eigenvalue with increases in the minor eigenvalues at the genu. CONCLUSIONS: We have shown that the increased size of the CC found in children with NF-1 is also present in adults with the syndrome, whereas no difference in total brain volume was found.