Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction.

Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1-4 Hz in the medial frontal cortex. We explored cerebellar-frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia-related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing.

Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.

CONTEXT: Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness. OBJECTIVES: To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia. DATA SOURCES: Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved. STUDY SELECTION: 30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria. DATA EXTRACTION: Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. DATA SYNTHESIS: The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity. CONCLUSIONS: Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.

MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse.

BACKGROUND: Adolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14-CNR1 gene-gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis. METHOD: We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA. RESULTS: Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse. CONCLUSIONS: Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14-CNR1 gene-gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes.

Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia.

Cognitive deficits in recent-onset and chronic schizophrenia.

Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.

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.

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow.

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [(15)O]H(2)O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

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.

Effects of olanzapine on cerebellar functional connectivity in schizophrenia measured by fMRI during a simple motor task.

BACKGROUND: According to current theories, schizophrenia results from altered connectivity in brain circuits for fundamental cognitive operations. Consequently, the poorly understood mechanisms of neuroleptic treatment may be explainable by altered functional interactions within such networks. The 'cognitive dysmetria' model hypothesizes that one key structure in these circuits is the cerebellum. To investigate the effects of olanzapine on cerebellar functional connectivity (CFC), a seed-voxel correlation analysis (SVCA) was used in a functional magnetic resonance imaging (fMRI) study of a simple finger-tapping task. METHODS: fMRI scans were obtained from six schizophrenic patients under both drug-free and olanzapine-treated conditions and from a matched control group of six healthy subjects at corresponding time points. SVCAs were performed for anatomically and functionally standardized seed voxels in the anterior cerebellum. SVCA results were then processed by three different randomization analyses. RESULTS: The analyses revealed that olanzapine caused widespread changes of CFC, including prominent changes in prefrontal cortex and mediodorsal thalamus. Significant changes in motor structures were found after subtractions within both groups and may thus indicate repetition effects rather than drug effects. Olanzapine 'normalized' the patients' CFC patterns for the right, but not for the left cerebellum. CONCLUSION: Even for a simple motor task, olanzapine affects functional interactions between the cerebellum and many non-motor brain regions, including elements of the 'cognitive dysmetria' circuit. Altogether, our findings suggest that olanzapine has a stronger differential effect on neural activity in prefrontal cortex and thalamus than in motor structures.

The relationship of akathisia with suicidality and depersonalization among patients with schizophrenia.

An association of suicidality and depersonalization with akathisia has been reported, but it is not clear whether these phenomena are specific to akathisia or are nonspecific manifestations of distress. The authors used the Barnes Akathisia Rating Scale, Brief Psychiatric Rating Scale, and Hamilton Rating Scale for Depression (Ham-D) to examine the relationships between suicidality, depersonalization, dysphoria, and akathisia in 68 patients with schizophrenia or schizophreniform disorder. Akathisia was associated with higher scores on the Ham-D ratings of suicidality, depersonalization, and agitation. In a logistic regression model, depressive mood and subjective awareness of akathisia appeared to be the only predictors of suicidality and depersonalization, respectively. These findings support the association between akathisia and both suicidality and depersonalization. However, these symptoms appear to be nonspecific responses to accompanying depressive mood and the subjective awareness of the akathisia syndrome, respectively.

Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors.

CONTEXT: Loss of the capacity to experience pleasure (anhedonia) is a core clinical feature of schizophrenia. Although functional imaging techniques have been successful in identifying the neural basis of cognitive impairments in schizophrenia, no attempts to date have been made to investigate neural systems underlying emotional disturbances. OBJECTIVE: To study the neural basis of emotional processing in schizophrenia by exploring the pattern of brain responses to olfactory stimuli in patients and healthy volunteers. DESIGN: Positron emission tomographic study of patients with schizophrenia and healthy volunteers. Positron emission tomographic data were collected between July 21, 1995, and September 11, 1997, and data analyses were conducted in 1999-2001. SETTING: The Mental Health Clinical Research Center at the University of Iowa, Iowa City. PARTICIPANTS: Sixteen healthy volunteers with a mean age of 29.5 years and 18 patients with schizophrenia and a mean age of 30.0 years. MAIN OUTCOME MEASURE: Areas of relative increase or decrease in regional cerebral blood flow, measured using positron emission tomography and the [(15)O]water method while participants performed an emotion-induction olfactory task to determine response to pleasant (vanillin) and unpleasant (4-methylvaleric acid) odors, compared between patients and healthy volunteers. RESULTS: Patients with schizophrenia subjectively experienced unpleasant odors in a manner similar to healthy volunteers but showed impairment in the experience of pleasant odors. The analysis of the regional cerebral blood flow revealed that patients failed to activate limbic/paralimbic regions (eg, insular cortex, nucleus accumbens, and parahippocampal gyrus) during the experience of unpleasant odors, recruiting a compensatory set of frontal cortical regions instead. CONCLUSION: Abnormalities in the complex functional interactions between mesolimbic and frontal regions may underlie emotional disturbances in schizophrenia.

Effects of retroactive and proactive interference on word list recall in schizophrenia.

Schizophrenia spectrum patients (N = 143) and healthy controls (N = 160) were administered the Rey Auditory Verbal Learning Test (RAVLT) and tests of executive functioning to directly investigate the effects of proactive interference (PI) and retroactive interference (RI) on word list recall. It was hypothesized that by virtue of the predicted preferential association between executive functioning and RI (relative to PI), patients would demonstrate increased susceptibility to RI in their ability to recall word lists. Results indicated that patients show increased susceptibility to RI relative to PI. Furthermore, this difference appeared to be related to the frontally-mediated central executive functions that were preferentially associated with RI but not PI susceptibility.

Population-based association analyses of the HOPA12bp polymorphism for schizophrenia and hypothyroidism.

HOPA is an Xq13 chromosome gene that codes for a RXR nuclear receptor co-activator. In a prior study of the genetic basis of schizophrenia, we showed that exonic polymorphisms in HOPA were associated with increased risk of schizophrenia and hypothyroidism in a large cohort of probands from New York. In an attempt to replicate these findings, we examined this relationship in a cohort of 173 schizophrenic probands (128 males and 45 females providing 218 alleles) from Iowa. Consistent with the prior findings, we found an increased rate of the HOPA12bP exonic polymorphism in schizophrenic probands compared with random newborn controls (9 of 218 alleles vs. 33 of 2,049 alleles, P < 0.02). Furthermore, retrospective review of the medical records showed that two of the nine probands possessing the HOPA12bp allele in whom thyroid function was assessed were hypothyroid compared with 6 of 164 probands possessing the normal HOPAwild allele(s) (P < 0.06). We conclude that the HOPA12bp polymorphism shows a nominally significant association with schizophrenia and a nominal trend for association with hypothyroidism in our study and that further studies are required to define the features of this syndrome and the molecular mechanisms of disease pathogenesis.

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.

BACKGROUND: Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS: Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS: Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS: The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.