Nora S. Vyas

A Diffusion Tensor Imaging Study of White Matter in Early-Onset Schizophrenia

BACKGROUND Voxel-based analysis of diffusion tensor magnetic resonance imaging (DTI) data was used to examine white matter integrity in adolescents with early-onset schizophrenia (EOS), defined as schizophrenia beginning before the 18th birthday. METHODS Nineteen patients with EOS, aged 13 to 19, were compared with 20 healthy volunteers matched for age, gender, and parental socioeconomic status. Diffusion tensor magnetic resonance imaging data were acquired on a GE Signa NVi 1.5 Tesla system (General Electric, Milwaukee, Wisconsin). Maps of fractional anisotropy (FA) were registered into standard space, and group differences were examined using a nonparametric statistical approach. RESULTS In comparison with healthy participants, EOS patients had significantly lower FA in the white matter of the parietal association cortex bilaterally and in the left middle cerebellar penduncle. No areas with significantly higher FA in patients were identified. CONCLUSIONS Parietal and cerebellar white matter abnormalities may contribute to the emergence of psychotic symptoms in adolescence.

Age of Onset of Schizophrenia: Perspectives From Structural Neuroimaging Studies

Many of the major neuropsychiatric illnesses, including schizophrenia, have a typical age of onset in late adolescence. Late adolescence may reflect a critical period in brain development making it particularly vulnerable for the onset of psychopathology. Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. In this review, we examine the evidence from 2 unique longitudinal cohorts that span the ages from early childhood through young adulthood; a study of childhood-onset schizophrenia where patients and siblings are followed from ages 6 through to their early twenties, and an ultra-high risk study where subjects (mean age of 19 years) are studied before and after the onset of psychosis. From the available evidence, we make an argument that subtle, regionally specific, and genetically influenced alterations during developmental age windows influence the course of psychosis and the resultant brain phenotype. The importance of examining trajectories of development and the need for future combined approaches, using multimodal imaging together with molecular studies is discussed.

Effect of age at onset of schizophrenia on white matter abnormalities

BACKGROUND The pattern of brain morphological changes at the early stages of schizophrenia may depend on the age at onset of illness; in children and adolescents with schizophrenia, grey matter deficits are seen in the parietal lobe whereas in individuals with adult onset these are more widespread. AIMS To examine whether white matter is similarly affected. METHOD Diffusion tensor imaging was used to compare fractional anisotropy measures in individuals with adolescent-onset (n = 17) and adult-onset schizophrenia (n = 17) with those in age- and gender-matched controls. RESULTS Compared with their respective controls, individuals with adolescent-onset schizophrenia showed fractional anisotropy decrease in parietal regions; individuals with adult onset showed additional fractional anisotropy reductions in frontal, temporal and cerebellar regions. A differential effect of age at onset (adolescent v. adult) was noted bilaterally in medial prefrontal white matter. CONCLUSIONS White matter abnormalities in frontal regions in schizophrenia may depend on developmental stage at the time of illness onset.

Positron Emission Tomography in Schizophrenia: A New Perspective

PET is an important functional imaging technique that can be used to investigate neurotransmitter receptors and transporters directly by mapping human brain function. PET is increasingly being used greatly to advance our understanding of the neurobiology and pathophysiology of schizophrenia. Methods: This review focuses on the use of PET tracers and kinetic modeling in identifying regional brain abnormalities and regions associated with cognitive functioning in schizophrenia. A variety of PET tracers have been used to identify brain abnormalities, including 11C, 15O-water, 18F-fallypride, and l-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-FDOPA). Results: Some studies have used compartmental modeling to determine tracer binding kinetics. The most consistent findings show a difference in the dopamine content in the prefrontal cortex, anterior cingulate gyrus, and hippocampus between healthy controls and patients with schizophrenia. Studies also show a higher density of D2 receptors in the striatum and neural brain dysconnectivity. Conclusion: Future investigations integrating clinical, imaging, genetic, and cognitive aspects are warranted to gain a better understanding of the pathophysiology of this disorder.

Neurobiology and phenotypic expression in early onset schizophrenia

Aim: Early‐onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult‐onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early‐onset schizophrenia.

Deficits in visual sustained attention differentiate genetic liability and disease expression for Schizophrenia from Bipolar Disorder

BACKGROUND There is mounting evidence for shared genetic liability to psychoses, particularly with respect to Schizophrenia (SZ) and Bipolar Disorder (BD), which may also involve aspects of cognitive dysfunction. Impaired sustained attention is considered a cardinal feature of psychoses but its association with genetic liability and disease expression in BD remains to be clarified. METHODS Visual sustained attention was assessed using the Degraded Symbol Continuous Performance Test (DS-CPT) in a sample of 397 individuals consisting of 50 remitted SZ patients, 119 of their first degree relatives, 47 euthymic BD patients, 88 of their first degree relatives and 93 healthy controls. Relatives with a personal history of schizophrenia or bipolar spectrum disorders were excluded. Performance on the DS-CPT was evaluated based on the response criterion (the amount of perceptual evidence required to designate a stimulus as a target) and sensitivity (a signal-detection theory measure of signal/noise discrimination). RESULTS We found no effect of genetic risk or diagnosis for either disorder on response criterion. In contrast, impaired sensitivity was seen in SZ patients and to a lesser degree in their relatives but not in BD patients and their relatives. These findings were not attributable to IQ, medication, age of onset or duration of illness. CONCLUSIONS Our results argue for the specificity of visual sustained attention impairment in differentiating SZ from BD. They also suggest that compromised visual information processing is a significant contributor to these deficits in SZ.

Treatment of early onset schizophrenia: recent trends, challenges and future considerations.

Early onset schizophrenia (onset before adulthood) is a rare, severe, and chronic form of schizophrenia. The clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities, poor response to neuroleptic treatment, greater admission rates, and poor prognosis. This is a brief, condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment-refractory cases. Based on the current literature, second-generation antipsychotics remain the mainstay of treatment, although current medications provide suboptimal response at best. Based on the adult literature, combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy. Indeed, early detection, identification of relevant biomarkers, coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies.

The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia

Positron emission tomography (PET) offers a strategic imaging platform to provide a map of functional neural correlates associated with the underlying cognitive deficits in schizophrenia. It enables regional cerebral glucose metabolism and dopaminergic and serotonergic receptor function to be studied. PET neuroimaging can therefore be used in drug development and to study putative treatments. Recent PET studies of the first-generation antipsychotics flupentixol and haloperidol, and of the second-generation antipsychotics risperidone, aripiprazole, quetiapine, sertindole, ziprasidone, paliperidone and olanzapine, have been carried out; modulation of limbic circuitry has been found to be a predictor of treatment response. PET can also be used to predict and monitor likely extrapyramidal side effects from antipsychotic treatment. PET and neuropsychological testing can together also allow the study of putative molecular genetic changes associated with schizophrenia. Advances in the imaging, cognition and molecular genetics are likely to lead to the development of future diagnostics, treatments and novel pharmacological agents.

Can PET/CT imaging advance our understanding of the neurobiology of schizophrenia?

Schizophrenia is a severe psychiatric disorder affecting approximately 1% of the population worldwide. The disorder is ranked among the top 10 causes of disability worldwide. New drugs and therapeutic interventions are therefore warranted to reduce symptomatology, delay onset, or potentially cure this devastating disorder. This would greatly help individuals in the early stages of schizophrenia. Although schizophrenia has a strong genetic basis (80%), owing to the nature of the neurobiological and genetic heterogeneity of the disorder, its a etiology has remained elusive. Schizophrenia is characterized by psychotic symptoms, emotional disturbances, and cognitive dysfunction. These symptoms may be the result of dopamine dysregulation in individuals with schizophrenia [1]. Advances in anatomical and functional imaging have provided useful insights into the neurobiological mechanisms of schizophrenia, enabling brain function to be studied at a molecular level. Recent imaging investigations using computed tomography (CT) and magnetic resonance imaging (MRI) have reported grey matter reduction and ventricular enlargement in schizophrenia [2], and functional MRI studies have reported abnormalities in the frontotemporal and frontoparietal function regions. Diffusion tensor imaging is used to provide an insight into white matter tract integrity and regional cerebral connectivity. Recent studies show abnormalities in frontoparietal and left cerebellar white matter tract integrity in schizophrenia [3]. Positron emission tomography (PET) is an effective functional imaging technique that uses radioactive tracers to help identify regions associated with brain function. It has been used to detect levels of dopaminergic activity in individuals with major psychiatric disorders. The most consistent findings from adult-onset schizophrenia studies are differences in dopaminergic content in the prefrontal cortex (PFC), anterior cingulate gyrus, and hippocampus between normal controls and patients with schizophrenia. Several PET tracers have been used to identify brain

Can genetics inform the management of cognitive deficits in schizophrenia

There is no doubt that schizophrenia has a significant genetic component and a number of candidate genes have been identified for this debilitating disorder. Of note, several of these are implicated in cognition. Cognitive deficits constitute core symptoms of schizophrenia, and while current antipsychotic treatment strategies aim to help psychosis-related symptomatology, the cognitive symptom domain is largely inadequately treated. A number of other pharmacological approaches (e.g. using drugs that target specific neurotransmitter systems) have also been attempted for the amelioration of cognitive deficits in this population; however, these too have had limited success so far. Psychological interventions appear promising, though there has been speculation regarding whether or not these produce long-term functional improvements. Pharmacogenetic studies of the cognitive effects of currently available antipsychotics, although in relatively early stages, suggest that the treatment of cognitive deficits in schizophrenia may be advanced by focusing on genetic variants associated with specific cognitive dysfunctions in the general population and using this to match the most relevant pharmacological and/or psychological interventions with the genetic and cognitive profiles of the target population. Such a strategy would encourage bottom-up advances in drug development and provide a platform for individualised treatment of cognitive deficits in schizophrenia.