Abnormal brain structure in adults with Van der Woude syndrome.

Van der Woude syndrome (VWS) is an autosomal dominant disorder manifested in cleft lip and/or palate and lip pits. Isolated clefts of the lip and/or palate (ICLP) have both genotype and phenotype overlap with VWS. Subjects with ICLP have abnormalities in brain structure and function. Given the similarities between VWS and ICLP, the current study was designed to evaluate the pattern of brain structure of adults with VWS. Fourteen adults with VWS were compared to age- and gender-matched healthy controls. Brain structure was evaluated using magnetic resonance imaging. All subjects with VWS had enlarged volumes of the anterior regions of the cerebrum. Men with VWS had reduced volumes of the posterior cerebrum. Anterior cerebrum volume was negatively correlated with intelligent quotient in the subjects with VWS indicating that the enlargement of this brain region was 'pathologic.' The pattern of brain structure in VWS is nearly identical to those seen in ICLP. In addition, men are affected more severely. Pathologic enlargement of the tissue and a gender effect with men affected more severely are common features of neurodevelopmental disorders supporting the notion that the brain structure of VWS and ICLP may be because of abnormal brain development.

Structure and function of the superior temporal plane in adult males with cleft lip and palate: pathologic enlargement with no relationship to childhood hearing deficits.

BACKGROUND: In a previous study from our lab, adult males with non-syndromic cleft lip and/or palate (NSCLP) were shown to have significantly lower temporal lobe gray matter volume than matched controls. The current study was designed to begin a regional analysis of specific subregions of the temporal lobe. The superior temporal plane (STP) is a brain region involved in the governance of auditory processing and aspects of language. The cognitive deficit of subjects with NSCLP is characterized by specific deficits in language; therefore this region of the temporal lobe is particularly important to investigate in this population. The STP has been found to be structurally abnormal in subjects with dyslexia, another developmental disorder involving language deficit. The hypothesis for the current study was that the STP in subjects with NSCLP would be structurally abnormal and that the abnormality would be related to cognitive deficit, but not to developmental hearing deficit. METHODS: Manual tracing of the STP in NSCLP males and matched controls was performed on magnetic resonance imaging (MRI) scans. Ratios of STP to total temporal lobe gray matter volume were calculated and compared across groups. In addition, the morphology of the STP was correlated to cognitive function as well as measures of hearing deficit during infancy and childhood. RESULTS: Despite overall deficit in temporal lobe gray matter, the STP is disproportionately large in subjects with NSCLP compared to controls. Further, gray matter volume of the STP was inversely correlated with IQ and language test scores in CLP subjects. Hearing loss throughout childhood and adulthood was not significantly correlated with brain morphology. CONCLUSIONS: The structure of the superior temporal plane in adult males with NSCLP was disproportionately large. This abnormally increased volume was directly related to IQ, with greater STP volume being associated with lower cognitive functioning, thus characterizing the finding as 'pathologic enlargement'. Moreover, there was no relationship between the structure of the STP and measures of childhood hearing impairment, supporting the notion that the language deficits of this population are more likely due to abnormal brain development than to the effects of hearing deficit during childhood.

Color enhancement of multispectral MR images: improving the visualization of subcortical structures.

PURPOSE: The current investigation was undertaken to evaluate a new method for creating MR multispectral color images, which we call "Superimages." They were developed to improve the delineation of small brain structures composed of mixed tissue types, such as the basal ganglia. METHOD: To qualitatively validate the method, visual comparisons were made of six unimodal and multispectral images, including the Superimage. Quantitative validation was undertaken by comparing the reliability values for parcellation of the globus pallidus (GP) using either a gray scale (T1-weighted) image or the Superimage. RESULTS: Qualitative assessment of the Superimage revealed enhanced visualization of the GP, caudate, and putamen. Quantitative assessment resulted in good reliability for Superimage traces. CONCLUSION: The Superimage significantly improves both the visualization and the parcellation of structures visualized by MRI.

Increased incidence of a midline brain anomaly in patients with nonsyndromic clefts of the lip and/or palate.

BACKGROUND AND PURPOSE: Nonsyndromic clefts of the lip and palate (CLP) are developmental craniofacial abnormalities that are often associated with cognitive dysfunction. This study was designed to evaluate, in patients with CLP, the presence of a specific midline brain anomaly (enlarged cavum septi pellucidi [CSP]) that has been shown in other developmental syndromes to be related to poor cognitive function. METHODS: Brain images were obtained using magnetic resonance imaging on 49 adult men with CLP and 75 healthy controls. Size of CSP was measured using consecutive coronal images. RESULTS: The incidence of large CSP in the CLP group was 8% (4 of 49), significantly higher than that found in the control group. In 2 of these 4 subjects, the anomaly was complete nonfusion of the septal leaflets, known as a combined CSP and cavum vergae. Furthermore, there was a significant inverse relationship of IQ and CSP in CLP patients that was not present in controls. That is, in individuals with CLP, the larger the CSP, the lower the IQ. CONCLUSIONS: Adult men with CLP have an increased prevalence of enlarged CSP. Moreover, this anomaly is directly related to cognitive deficits. This study provides further evidence that the development of the face and the development of the brain are intimately related and that defects in craniofacial development are most likely associated with defects in brain development.

Sex differences in the absence of massa intermedia in patients with schizophrenia versus healthy controls.

OBJECTIVE: To evaluate sexual dimorphism and incidence of absent massa intermedia (MI), a midline thalamic structure, in patients with schizophrenia and healthy controls. METHODS: Thin slice magnetic resonance images of the brain were obtained. The presence of MI was determined by viewing sagittal, coronal, and axial planes. RESULTS: In healthy controls, females had a significantly lower incidence of absent MI (13.56%) compared with males (32.08%). In patients with schizophrenia, there was a sex by diagnosis interaction. Female patients had significantly higher incidence of absent MI (32.76%) compared with their healthy controls (13.56%), whereas the male patients showed no difference in incidence of absent MI compared with their controls. CONCLUSION: The MI, a sexually dimorphic midline structure, is more commonly absent in female patients with schizophrenia. These results support the growing literature reporting structural aberration of the thalamus, as well as other midline structures in the brains of patients with schizophrenia.

An MRI study of midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, and cerebellar neural circuitry.

BACKGROUND: The midbrain contains the perikarya of all the dopamine neurons in the human brain. Although other neurochemicals may well be involved, dopamine dysregulation is central in the pathophysiology of psychosis. Despite this, few imaging studies have evaluated the morphology of the midbrain. METHODS: Using high-resolution magnetic resonance imaging, morphology of three posterior fossa and brain stem structures were measured: midbrain, pons, and medulla. The patient sample consisted of 50 men with schizophrenia, matched by gender and age to 50 healthy control subjects. RESULTS: Patients had significantly smaller midbrain measures compared with control subjects. There were no differences between groups in measures of pons or medulla. Furthermore, midbrain size was significantly and inversely correlated with positive symptoms and cumulative neuroleptic exposure, but not with negative or disorganized symptoms. After controlling for the effect of cumulative neuroleptic exposure, the relationship between midbrain morphology and positive symptoms remained significant. CONCLUSIONS: Midbrain morphology of patients with schizophrenia is abnormal, being smaller in patients compared with control subjects. Although this appears to be specifically related to psychotic symptoms, there is also a robust medication effect, with greater exposure to neuroleptics being associated with greater morphologic abnormality. We discuss the role of dopaminergic dysregulation and possible neural circuit involvement.

Abnormal brain morphology in patients with isolated cleft lip, cleft palate, or both: a preliminary analysis.

OBJECTIVE: The aim of this study was to determine whether adult men with cleft lip and palate (CLP) have aberrant cerebral morphology. DESIGN: Brain morphology of 14 adult men with isolated CLP were analyzed and compared with 14 healthy controls matched for sex, age, and parental socioeconomic status. SETTING: The research took place at a large, tertiary care hospital, with participation on an outpatient basis. PARTICIPANTS: The 14 males with CLP were recruited from a large cleft lip and palate registry, while their 14 matched controls were selected from a registry of healthy volunteers collected via the Mental Health Clinical Research Center. RESULTS: The males with CLP have significantly smaller cerebellar size (p = .04), significantly larger frontal lobes (p = .02), and significantly smaller temporal and occipital lobes (p = .02; p = .009, respectively). No significant difference in gray/white matter ratios or laterality were found. CONCLUSIONS: Adult males with CLP have a significantly different pattern of brain morphology, compared with healthy controls, which is most likely due to aberrant cerebral development. This study highlights the complex interaction and interdependence of craniofacial and cerebral development.

Enlarged cavum septi pellucidi in patients with schizophrenia: clinical and cognitive correlates.

Enlarged cavum septi pellucidi (CSP) is a neurodevelopmental anomaly that has been associated with schizophrenia. This study was designed to evaluate, in patients with schizophrenia, the relationship between the severity of this anomaly and measures of symptom and cognitive skills. Three groups were used: patients with large CSP (n=14), patients without large CSP (n=14), and healthy control subjects (n=14). In patients with large CSP, a significant, inverse relationship was found between size of CSP and measures of cognitive deficit. Thus, the greater the size of the anomaly, the greater the cognitive deficit. No relationship was found between severity of CSP and symptom measures.

Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia.

OBJECTIVE: Previous studies have suggested that there may be an association between longer duration of untreated psychosis and poor outcome in schizophrenia. These studies have been interpreted as providing evidence that untreated psychosis may constitute an "active morbid process" that is "toxic" to the brain. If untreated psychosis is neurotoxic, this would form a strong basis for early intervention in schizophrenia. METHOD: Seventy-four neuroleptic-naive patients with DSM-IV schizophrenia were evaluated 6 months after their first inpatient hospitalization. The authors examined the relationship between untreated initial psychosis duration (measured from onset of first symptom as well as from onset of full positive syndrome) and quality of life, symptom severity, and time to remission of positive symptoms. RESULTS: Earlier age at illness onset was associated with longer duration of untreated prodromal psychotic symptoms. There were no significant gender differences in duration of untreated initial psychosis, nor were there any significant associations between untreated initial psychosis duration and premorbid functioning. After controlling for the effects of age at onset, the duration of untreated initial psychosis did not significantly impair subsequent quality of life, symptom severity, or remission of positive symptoms. CONCLUSIONS: Duration of untreated initial psychosis was not prognostic of poor outcome early in the course of schizophrenia. Biological measures of neurotoxicity are needed to examine the "toxic psychosis" hypothesis more directly.

Developmental brain anomalies in children with attention-deficit hyperactivity disorder.

The pathoetiology of attention-deficit hyperactivity disorder (ADHD) has been considered to be neurodevelopmental, yet the timing and processes involved are not clearly identified. Neurodevelopmental brain anomalies have been associated with a variety of psychiatric conditions. However, they have never been evaluated in a population of patients with ADHD. This study was designed to determine the frequency of specific developmental brain anomalies in a group of children with ADHD (n = 85; mean age, 10.9 years) and healthy control children (n = 95; mean age, 11.7 years) by visually inspecting brain magnetic resonance imaging scans. Compared to controls, the ADHD group showed an increase in frequency of two developmental anomalies: (1) gray-matter heterotopia, a neuronal migration anomaly, in 2 of 85 patients versus 0 of 95 controls; and (2) posterior fossa abnormality (excess cerebrospinal fluid in the posterior fossa) in 8 of 85 patients versus 2 of 95 controls. There were no differences in frequency of enlarged cavum septi pellucidi between the two groups. These findings support and extend the idea that ADHD is of developmental origin, and further suggest that the timing of aberrant brain development could be in early gestation.

Sexual dimorphism in the human brain: evaluation of tissue volume, tissue composition and surface anatomy using magnetic resonance imaging.

Magnetic resonance imaging (MRI) was used to evaluate sex differences in brain morphology by comparing measures of brain tissue volume, brain tissue composition (proportions of gray and white matter), and measures of cortical surface anatomy. A large and well-matched sample of healthy women (n=42) and healthy men (n=42) were evaluated. There was a significant gender effect on intracranial volume, males being larger. However, this increase in size was limited to the cerebrum as there was no sex difference in the volume of the cerebellum. The gender difference in size of the cerebral volume was evenly distributed, with all four lobes equally larger in males compared to females. Gray and white matter tissue proportions were similar between the sexes globally. Regional tissue composition analysis showed sex differences within the parietal lobes with females having proportionately more gray matter on the right side. There were no differences between the sexes in cortical surface anatomy measures. Overall, against the background of similarity in morphology, there are differences between the sexes with regard to general and regional brain measures. The functional significance of these sex differences is unclear, but may represent the differential effects of gonadal hormones during brain growth and development.

A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia.

BACKGROUND: Risperidone and olanzapine have each been demonstrated to be efficacious and safe in the treatment of patients with chronic schizophrenia. To evaluate their relative effectiveness, and to better understand the advantages and limitations of each neuroleptic during actual clinical use, we compared one directly against the other. METHOD: Forty-two subjects with DSM-IV schizophrenia had received open-label treatment with either risperidone or olanzapine. Symptoms, global functioning, and extrapyramidal side effects before and after acute treatment were compared within and across groups. At 6-month follow-up, the relative effectiveness of these 2 atypical neuroleptics on symptoms and quality of life were further evaluated. RESULTS: Following an average of 4 weeks of acute treatment, both risperidone and olanzapine were effective in reducing negative, psychotic, and disorganized symptoms. Although both neuroleptics were associated with low occurrence of treatment-emergent parkinsonism, risperidone was more likely to induce akathisia. The measures for parkinsonism were no different across treatment groups, even after taking into account the higher rate of anticholinergic use in the risperidone group. Following 6 months of treatment with these 2 atypical neuroleptics, there was a significantly greater reduction in psychotic symptoms among risperidone-treated subjects. Otherwise, risperidone and olanzapine appear to be equally effective in reducing disorganized and negative symptoms and in improving the quality of life. CONCLUSION: Risperidone and olanzapine were equally effective as acute treatments. Risperidone was more effective for treatment of psychotic symptoms at 6 months, but otherwise the 2 medications were equally effective in the routine clinical care of patients with schizophrenia. If low (<6 mg/day) doses of risperidone are used, the 2 medications have comparable rates of parkinsonian side effects.

Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms.

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia.

OBJECTIVE: Whether cognitive function in schizophrenia deteriorates, improves, or remains stable is a crucial question. Few studies have examined the longitudinal stability of cognitive function and the relationship between cognitive performance and clinical symptoms over time in a cohort of well-treated patients with schizophrenia. METHOD: In the present study, 54 patients with first-episode and recent-onset schizophrenia completed a comprehensive cognitive test battery and were rated on symptom measures at index hospitalization and again after 5 years. RESULTS: Performance IQ and full-scale IQ significantly improved, whereas verbal IQ did not change. Group performance improved on some of the neuropsychological tests, including the Circle A letter-cancellation task, free recall of logical memory test score, and the Wisconsin Card Sorting Test. Mean finger-tapping performance worsened over time, whereas performance on other neuropsychological tests did not change. Negative, psychotic, and disorganized symptoms significantly improved over the time period. Changes in negative symptoms were correlated with performance changes in verbal IQ and full-scale IQ but not performance IQ. Improvement in verbal cognition was observed when negative symptoms improved. Psychotic and disorganized symptom dimensions were not correlated with any IQ measure. CONCLUSIONS: These results indicate that in a cohort of young patients receiving neuroleptic treatment early in their illness, cognitive performance does not deteriorate--and may improve. Only one of the three symptom dimensions--negative--was associated with change in cognitive performance. This study supports the view that negative symptoms are associated with a poor long-term cognitive outcome and may be closely related to the primary cognitive deficit in schizophrenia.

An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept.

BACKGROUND: Cumulative evidence suggests the cerebellum is involved in cognition and may be important in the pathoetiology of schizophrenia. Functional imaging studies have identified a possible neural circuit that includes the cerebellum and may be abnormal in patients with schizophrenia, manifesting as a fundamental cognitive deficit conceptualized as cognitive dysmetria. To explore the role of the cerebellum in cognitive dysfunction and schizophrenia, this study was designed to evaluate the morphology of the cerebellar vermis, its relationship to other cortical areas, and to cognitive function in patients with schizophrenia. METHODS: Male patients with schizophrenia (n = 65) were matched by age and gender to 65 healthy male controls. Volume measures of the 4 cerebral lobes and total cerebellum were obtained using automated methods. The area of the cerebellar vermis (divided into three lobes) was traced on a midsaggital MRI slice. RESULTS: Patients had smaller frontal and temporal lobes. There were no group differences in total cerebellar volume. Patients had a smaller vermis area, accounted for by a smaller anterior lobe. The anterior vermis area was positively correlated with total cerebellar volume, temporal lobe volume, and FSIQ in patients, but not controls. CONCLUSIONS: These findings support the theory that regions of the cerebellum may be involved in a neural circuit that is structurally and functionally abnormal in patients with schizophrenia, leading to cognitive dysmetria.

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network.

BACKGROUND: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.

Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics.

OBJECTIVE: For many years, it has been assumed that medications affect brain chemistry and physiology but not structure. Recent reports suggest that neuroleptic medication changes basal ganglia volume. To explore this possibility, the authors assessed for basal ganglia volume change in individuals who had their basal ganglia structures delineated and measured on magnetic resonance scans at the beginning and end of a 2-year period and who received neuroleptic medication during this time. METHOD: The basal ganglia volumes of 23 male patients with schizophrenia spectrum disorders were measured from manual traces delineating the caudate and lenticular nucleus on magnetic resonance images at admission and 2 years later. Patients' neuroleptic exposure was calculated over the 2 years by using a dose-year formula. RESULTS: During the 2-year period, mean basal ganglia volume of patients receiving predominantly typical neuroleptics increased, while the opposite was observed for patients receiving mostly atypical neuroleptics. Correlation analysis for the entire group showed a positive relationship between the 2-year exposure to typical neuroleptic medication and change in basal ganglia volume and the reverse for exposure to atypical neuroleptics. CONCLUSIONS: In this group, basal ganglia volume increased following exposure to typical neuroleptics and decreased following exposure to atypical neuroleptics.

Quantitative in vivo measurement of gyrification in the human brain: changes associated with aging.

Clinical observation suggests that the aging process affects gyrification, with the brain appearing more 'atrophic' with increasing age. Empirical studies of tissue type indicate that gray matter volume decreases with age while cerebrospinal fluid increases. Quantitative changes in cortical surface characteristics such as sulcal and gyral shape have not been measured, however, due to difficulties in developing a method that separates abutting gyral crowns and opens up the sulci -- the 'problem of buried cortex'. We describe a quantitative method for measuring brain surface characteristics that is reliable and valid. This method is used to define the gyral and sulcal characteristics of atrophic and non-atrophic brains and to examine changes that occur with aging in a sample of 148 normal individuals from a broad age range. The shape of gyri and sulci change significantly over time, with the gyri becoming more sharply and steeply curved, while the sulci become more flattened and less curved. Cortical thickness also decreases over time. Cortical thinning progresses more rapidly in males than in females. The progression of these changes appears to be relatively stable during midlife and to begin to progress some time during the fourth decade. Measurements of sulcal and gyral shape may be useful in studying the mechanisms of both neurodevelopmental and neurodegenerative changes that occur during brain maturation and aging.

Prevalence of depressive symptoms early in the course of schizophrenia.

OBJECTIVE: The rate of depressive symptoms early in the course of schizophrenia was determined. METHOD: Seventy subjects with recent-onset schizophrenia were followed for 5 years by using semistructured interview instruments. The initial assessment included ratings of each criterion A symptom of a DSM-III-R major depressive episode. The rates of symptoms experienced with at least moderate severity were calculated, and an algorithm based on DSM identified subjects meeting the criteria for a major depressive episode. RESULTS: Four symptoms were present to at least a moderate degree in a majority of subjects, while no symptom was present in fewer than 12% of subjects. More than one-third of the subjects met the algorithmic criteria for a major depressive episode at the time of intake. CONCLUSIONS: Depressive symptoms are common early in the course of schizophrenia. This finding is consistent with other recent data and has potential implications for current diagnostic and treatment practices.