Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.

An fMRI study of visual attention and sensorimotor function before and after antipsychotic treatment in first-episode schizophrenia.

While much is known about receptor affinity profiles of antipsychotic medications, less is known about their impact on functional brain systems in patients with schizophrenia. We conducted functional magnetic resonance imaging (fMRI) studies with first-episode schizophrenia patients as they made saccades to unpredictable visual targets before and after 4-6 weeks of antipsychotic treatment. Matched healthy individuals were scanned at similar time intervals. Pretreatment, patients had less activation in frontal and parietal eye fields and cerebellum. After treatment these disturbances were not present, suggesting improved function in attentional and sensorimotor systems. Other pretreatment abnormalities were noted in sensory and ventromedial prefrontal cortex, but after treatment these abnormalities were absent or less prominent, in line with improved function in attentional systems. In addition, although not abnormal at baseline, there was reduced activity after treatment in dorsal prefrontal cortex, dorsal striatum, and dorsomedial thalamus, suggesting a potential adverse effect of treatment on frontostriatal systems, perhaps related to dopamine blockade in the caudate. These findings provide evidence for a complex impact of antipsychotic medication on functional brain systems in schizophrenia and illustrate the potential of neuroimaging biomarkers for both adverse and beneficial drug effects on functional brain systems.

No difference in the prevalence of cavum septum pellucidum (CSP) between first-episode schizophrenia patients, offspring of schizophrenia patients and healthy controls.

The reported prevalence of cavum septum pellucidum (CSP), is extremely variable (from 0.1% to 85%) depending upon the measurement method or imaging resolution. Higher prevalence of CSP has been found in schizophrenia. In this study, we examined the prevalence of CSP in a large number of first-episode schizophrenia patients, young relatives of schizophrenia patients and healthy controls. We manually measured CSP using 1.5 mm T1 MRI scans from ongoing studies at University of Pittsburgh in 89 first-episode patients with schizophrenia (age=23.8+/-7.4, M/F=61/28), 64 genetically at-risk individuals (offspring and siblings of schizophrenia patients, age 15.2+/-3.7, M/F=29/32) and 120 comparison subjects (n=120, age=22.1+/-7.9, M/F62/50). CSP was present in 64% of the first-episode patients (mean length 1.87+/-2.3 mm), 64.6% of the at-risk individuals (1.64+/-1.96 mm) and 64.2% of the normal controls (1.88+/-2.0 mm). There was no difference in the prevalence of CSP exceeding 4 mm. We also did not find any influence of the sex or age in the presence or size of CSP. Our data cast doubt on the significance of CSP as markers of neurodevelopmental pathology in schizophrenia.

Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments.

INTRODUCTION: A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia. METHODS: Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information. RESULTS: Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy. DISCUSSION: A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.

Premorbid indicators and risk for schizophrenia: a selective review and update.

Prospective studies of young relatives at risk for schizophrenia (high-risk studies, HR) can shed light on premorbid precursors of schizophrenia. Early HR studies pointed to a wide prevalence of schizophrenia spectrum psychopathology among young relatives at increased genetic risk. Recent studies suggest that young HR relatives have neurobehavioral deficits and structural, physiological, and neurochemical brain abnormalities that may date back to childhood or earlier. In this paper, we provide a selected overview of the lessons and limitations of early "first generation" studies and the beginning insights from recent "second generation" studies. We also provide an interim summary of data from the ongoing studies of young relatives at risk for schizophrenia in Pittsburgh. Collectively, such data may help us to predict the eventual emergence of schizophrenia, and schizophrenia spectrum or non-spectrum psychopathology.

Reduced superior temporal gyrus volume in young offspring of patients with schizophrenia.

OBJECTIVE: The superior temporal gyrus, a heteromodal auditory and language association cortex, has been found to be smaller in patients with schizophrenia than in normal subjects. However, genetic and/or neurodevelopmental underpinnings of superior temporal gyrus alterations are unknown. Nonpsychotic children with greater genetic risk for schizophrenia exhibit language deficits. The authors studied the superior temporal gyrus in nonpsychotic children at risk for schizophrenia. METHOD: Magnetic resonance imaging was used to measure the right and left superior temporal gyrus of 29 young nonpsychotic subjects who had a parent with schizophrenia and 27 age- and sex-matched comparison subjects who had no family psychiatric history. RESULTS: After controlling for age and intracranial volume, the authors found that the volumes of the right and left superior temporal gyrus of the subjects at risk for schizophrenia were significantly smaller than those of the comparison subjects. Comparison subjects, but not at-risk subjects, showed an inverse correlation between age and left superior temporal gyrus volume. CONCLUSIONS: These findings provide new evidence that superior temporal gyrus abnormalities may result from genetically mediated developmental deviance reflecting greater susceptibility to schizophrenia. Further studies and follow-up will lead to greater understanding of the role of the superior temporal gyrus in the premorbid vulnerability to schizophrenia.

Early intervention and the treatment of prodrome in schizophrenia: a review of recent developments.

OBJECTIVE: Strategies for preventing the development of schizophrenia are in their infancy but are associated with much hope and potential. The relatively long prodrome in schizophrenia allows for indicated prevention as an effective intervention. "High-risk" individuals have subtle symptoms and, without intervention, a third would develop psychosis within 1 year, and many will have poor functional outcomes, even in the absence of psychosis. Research in this area is preliminary but encouraging. METHODS: A literature search was performed using databases including PubMed, PsychInfo, and Cochrane, as well as a search of individual journals through cross-referencing. The search used the following key words: schizophrenia, psychosis, psychotic disorders, first episode, early, prodrome, prodromal, prevention, ultra high risk, at risk, and intervention. RESULTS: Strategies for preventing the development of schizophrenia are divided into universal, selective, and indicated levels of prevention. The common preventive methods include treatment with antipsychotic medications and psychotherapy. Early intervention helps at risk individuals with symptom reduction and appears to delay conversion to full blown psychosis. However, the criteria for identifying at risk individuals have low predictive value, which raises concerns about unnecessary and potentially harmful interventions. CONCLUSION: Although a range of interventions appear to be effective in reducing rates of transition to psychosis, they are inadequately differentiated and require further study. Current data suggest that clinicians take an individualized approach to intervention, considering the risk-benefit ratio on a case-by-case basis.

Alterations in the cerebral white matter of genetic high risk offspring of patients with schizophrenia spectrum disorder.

Alterations in white matter (WM) may be seen in young relatives at risk and may underlie vulnerability to schizophrenia. We were interested in exploring which of the WM regions were altered in adolescent offspring at familial risk for schizophrenia. We examined structural alterations in the offspring of subjects with schizophrenia or schizoaffective disorder (HR; n=65; 36 males) and healthy controls (HC; n=80: 37 males) matched for age and education. MRI images were collected using a GE 1.5 T scanner at the University of Pittsburgh Medical Center. Image processing was done using FreeSurfer (MGH) by an experienced rater blind to clinical data. We used multivariate analysis of covariance, with intracranial volume (p>0.05) and age as covariates. High Risk offspring had significant reductions in total WM, hemispheric WM and WM within left parietal and left cingulate cortices. Male offspring had more pronounced right hemisphere WM reductions than females.

Reduced activation of superior temporal gyrus during auditory comprehension in young offspring of patients with schizophrenia.

BACKGROUND: Smaller Superior Temporal Gyrus (STG) and reduced activation with language tasks have been found in schizophrenia emphasizing the involvement of parts of language network. Recently, we reported smaller STG in individuals at risk for psychosis. In this study, we examined the brain activation for auditory comprehension using fMRI in a group of young offspring of schizophrenia patients (HR) with a hypothesis that HR subjects will not activate STG as well as comparison subjects. METHODS: Fifteen HR (7M, 8F, mean age 15.9±3.1) and 17 comparison subjects (9M and 8F, mean age 14.5±3.5) participated. BOLD fMRI images were obtained using a 4 Tesla scanner with a multi echo-planar imaging sequence. The participants were asked to listen to 30 sec blocks of a story alternated with blocks of the same reading played backwards. The data were analyzed using Statistical Parametric Mapping (SPM5) and a BOLD activation exceeding a threshold of T>2.58 (p<0.01, uncorrected) was considered significant. RESULTS: The HR showed significantly lower BOLD activation at the STG bilaterally compared to normal controls (left STG; x=-64, y=-48, z=12, Z=2.95, right STG; x=62, y=-50, z=-16, Z=2.77). The effect was more pronounced in males and on left STG. CONCLUSIONS: These data suggest that adolescents at risk for schizophrenia show reduced activation of the STG compared to control subjects during a language related task (listening). This finding adds support to the idea that abnormal development of the language related cortex is a marker of increased susceptibility to schizophrenia and that such deviant development may be mediated by familial/genetic factors.

Progressive alterations of the auditory association areas in young non-psychotic offspring of schizophrenia patients.

BACKGROUND: Schizophrenia may involve progressive alterations of structure and hemispheric lateralization of auditory association areas (AAA) within the superior temporal gyrus. These alterations may be greater in male patients. It is unclear if these deficits are state-dependent or whether they predate illness onset and reflect familial diathesis. AIMS: We sought to compare AAA cortical thickness, surface area and lateralization across adolescent and young adult non-psychotic offspring of schizophrenia patients (OS) and healthy controls at baseline and one year follow-up. We also assessed the moderating effect of gender on these measures. METHODS: Fifty-six OS and thirty-six control subjects were assessed at baseline and at follow-up on AAA surface area and thickness using FreeSurfer to process T1-MRI-images. We used repeated measures ANCOVAs, controlling intra cranial volume and age with assessment-time and side as within-subject factors and gender and study group as between-subject factors. RESULTS: Surface area deficit in OS was greater on the left than on the right, as reflected in a lower surface area laterality-index (left-right/left + right × 100) in OS compared to controls. Left, but not right surface area and surface area laterality-index showed a longitudinal decline in OS compared to controls. Male OS declined more than controls on surface area and thickness. CONCLUSIONS: Left AAA surface area may progressively decline in young non-psychotic offspring at familial diathesis for schizophrenia causing a continuing reversal of the leftward AAA lateralization. Progressive surface area reduction and thinning of AAA may be more prominent in young non-psychotic male offspring at risk for schizophrenia.

Cortical surface characteristics among offspring of schizophrenia subjects.

BACKGROUND: A systematic study of cortical surface parameters in adolescent offspring of schizophrenia subjects before clinical manifestation could clarify neurodevelopmental antecedents of increased genetic risk. We examined these measures obtained on structural magnetic resonance imaging (MRI) scans at baseline and one year on a series of offspring of schizophrenia parents and healthy subjects. METHODS: We measured cortical surface area, curvature and thickness using BRAINS2 on structural MRI scans acquired using 1.5 T GE whole body scanner on all subjects. We examined the differences between study groups at baseline using mixed-effects models, and longitudinal trajectory of these measures using linear mixed-effects models. RESULTS: At baseline, offspring of schizophrenia parents showed reduced gyral surface area in the fronto-parietal lobes along with increased sulcal curvature and parietal gyral cortical thinning compared to healthy subjects. Prospective follow up of these subjects for one year showed shrinking of the total surface area, especially in the bilateral frontal and occipital regions along with preservation of cortical thickness among offspring of schizophrenia parents whereas healthy subjects showed preserved or increased surface area and cortical thinning. Correlation of these measures with lobar volumes was not observed at baseline cross-sectional comparisons but was observed in longitudinal examinations. DISCUSSION: Our observations suggest that adolescents with genetically elevated risk for schizophrenia show altered cortical surface measures affecting cortical surface area and thickness differentially suggesting a divergent trajectory of neurodevelopment. Cortical surface measures appear to be more sensitive to genetic liability to schizophrenia compared to volumetric measures.

Use of aripiprazole in tardive dyskinesia: an open label study of six cases.

Aripiprazole, a partial dopamine agonist has been reported to help reduce symptoms of tardive dyskinesia (TD). In a prospective, open label study of a series of cases, we examined the effectiveness of aripiprazole in reducing TD symptoms. Six clinically stable patients with schizophrenia or Schizoaffective disorder and a moderate to severe TD participated in this study. They were systematically cross-titrated from their current medication to aripiprazole and maintained for 16 weeks. The mean extra pyramidal symptom score measured by Abnormal Involuntary Movement Scale (AIMS) improved from a baseline score of 15.8 to final score of 5 (paired t-test; P=0.0009). The severity of psychiatric symptoms remained unchanged. This study supports our hypothesis that clinically stable patients with moderate tardive dyskinesia who are under treatment with other first- or second-generation antipsychotics may benefit from switching to aripiprazole with a reduction of TD symptoms but with out any significant benefit in psychiatric symptoms. The results need to be viewed with caution and not considered as indicative of a viable treatment option for TD as this is an open label study, and a small sample size.

Verbal fluency deficits and altered lateralization of language brain areas in individuals genetically predisposed to schizophrenia.

Alterations of verbal fluency may correlate with deficits of gray matter volume and hemispheric lateralization of language brain regions like the pars triangularis (PT) in schizophrenia. Examining non-psychotic individuals at high genetic risk (HR) for schizophrenia may clarify if these deficits represent heritable trait markers or state dependent phenomena. We assessed adolescent and young adult HR subjects (N=60) and healthy controls (HC; N=42) using verbal fluency tests and Freesurfer to process T1-MRI scans. We hypothesized volumetric and lateralization alterations of the PT and their correlation with verbal fluency deficits. HR subjects had letter verbal fluency deficits (controlling for IQ), left PT deficits (p=.00), (controlling ICV) and reversal of the L>R PT asymmetry noted in HC. Right Heschl's (p=.00), left supramarginal (p=.00) and right angular gyrii (p=.02) were also reduced in HR subjects. The L>R asymmetry of the Heschl's gyrus seen in HC was exaggerated and asymmetries of L>R of supramarginal and R>L of angular gyri, seen in HC were attenuated in HR subjects. L>R asymmetry of the PT predicted better verbal fluency across the pooled HR and HC groups. Young relatives of schizophrenia patients have verbal fluency deficits, gray matter volume deficits and reversed asymmetry of the pars triangularis. A reversed structural asymmetry of the PT in HR subjects may impair expressive language abilities leading to verbal fluency deficits. Volumetric deficits and altered asymmetry in inferior parietal and Heschl's gyrii may accompany genetic liability to schizophrenia.

Caudate volume in offspring of patients with schizophrenia.

Caudate nuclei are smaller in drug-naive people with schizophrenia but larger in antipsychotic-treated patients. In this magnetic resonance imaging study we found volume reduction of right and left caudate by 8.9 and 8.1% respectively in 50 offspring without psychosis of patients with schizophrenia compared with 53 age- and gender-matched controls, providing new evidence that caudate volume reduction may be a trait-related abnormality in schizophrenia.