LONI: Laboratory of Neuro Imaging

Schizophrenia

HISTORY

Schizophrenia is a disease of the brain. People with schizophrenia, more than 1% of the world's population across all cultures, suffer from a socially isolating and economically debilitating condition that usually begins during late adolescence through mid-adulthood. People often confuse schizophrenia with a split personality or a multiple personality, but this is an incorrect description. People affected with schizophrenia have difficulty differentiating what is generated by their imagination and what is real.

Schizophrenia can be traced back as far Egypt in the second millennium BC. Many of the clinical symptoms commonly used to describe schizophrenia today, such as depression, dementia, and thought disturbances, were described in detail in the Book of Hearts of the Eber papyrus.
In 1851 Falvet first described schizophrenia as a 'Folie Circulaire' or cyclical madness. Twenty years later Hecker coined the term 'Hebephrenia', or a silly, undisciplined mind. Kahlbaum documented both catatonic and paranoid disorders. In 1878 Emil Kraepelin, combined these disorders into a single disease, that he called dementia praecox, with four subtypes - simple, marked by slow social decline and withdrawal; paranoid, defined by persecutory delusions and fear; hebephrenic, marked by rambling and incoherent speech and incongruous affect; and catatonic, characterized by a severely limited movement and expression. In 1911, Eugen Bleuler first used the term 'schizophrenia' and described the four "A's" of schizophrenia; affect, associations, ambivalence and autism. Each of the these A’s identified a disturbance in the afflicted individual.

Schizophrenia remains an enigma that has fascinated the foremost minds of psychiatry and neuroscience for more than a hundred years. At stake is more than just the crucial welfare of the millions afflicted, for schizophrenia research may represent the key to an understanding of the mechanisms by which the brain filters, prioritizes and processes the information gathered both internally and externally.

DIAGNOSIS

A diagnosis of schizophrenia is determined from behavioral observations by clinicians and from self-reports by individuals about their abnormal mental experiences. According to the American Psychiatric Association, symptoms that must be present for diagnosis include a defined combination of delusions, hallucinations, and characteristic disturbances in affect, goal oriented behavior, form of thought and psychomotor behavior that cannot be established as the result of an organic disturbance. Individuals must also show continuous signs of the illness for at least six months where occupational and social functioning have deteriorated and an acute period of active symptoms must be present for at least one week.

Typically, the clinical symptoms of schizophrenia are divided into ‘positive’ and ‘negative’ types.

Positive symptoms include delusions (irrational beliefs), hallucinations (sensory perceptions with no outside stimulus), thought disorder (e.g., loosened associations) and bizarre behavior.
Negative symptoms include flat affect, social withdrawal, lack of motivation and initiative, impaired judgment and difficulty in planning.

Schizophrenia, however, is notably heterogeneous and the clinical symptoms may vary considerably between patients, often with no obvious overlap. Efforts have been made to characterize biologically meaningful ‘subtypes’ of schizophrenia defined by the cross-sectional clinical picture and by symptoms that co-occur. Subtypes include paranoid, disorganized, catatonic, undifferentiated, and residual types.

CURRENT RESEARCH

Schizophrenia as a Brain Disease

Early in the last century, Emil Kraepelin described what is now known as schizophrenia, as an organic brain disease. In recent decades, empirical evidence from postmortem, in vivo imaging, neurochemical and neuropsychological studies have confirmed that microscopic and macroscopic structural brain abnormalities, biochemical abnormalities and impairments in brain functioning are present in patients with schizophrenia. People with schizophrenia show a generalized impairment with IQ lower than normal and specific deficits in attention, memory, abstraction, spatial working memory and executive functioning. Structural brain abnormalities observed from postmortem and magnetic imaging data are diverse, but suggest abnormalities in specific cortical (e.g., frontal and temporal association areas) and subcortical (e.g., lateral and third ventricles and medial-temporal regions) brain regions with some consistency. Similarly, functional imaging studies using PET and fMRI, have uncovered altered brain activity in components of distributed neural circuitry in neocortical and medial-temporal systems, as well as in other regions, in association with specific cognitive tasks.

Genetics

As discussed above, evidence supports that schizophrenia is highly heritable. That is, individuals that are biologically related to a patient with schizophrenia appear to possess a greater risk for developing the disease compared to those that are unrelated. Shared environmental experiences, however, could also account for the increased incidence of schizophrenia within families compared to the general population. Twin and adoption studies support that both genetic and harmful environmental events are contributors to schizophrenia. Even though schizophrenia has a large heritable component, investigators have had difficulty identifying the genes involved. A single gene hypothesis does not appear to explain the familial patterns of schizophrenia. A multi-factorial genetic model is now more widely hypothesized to explain the genetic contributions of schizophrenia. According to this hypothesis, schizophrenia if the result of the additive effect of multiple genes and environmental factors until a critical threshold is met whereupon an individual develops schizophrenia.

Environment

The genetic model alone does not fully explain familial schizophrenia. Moreover, different genotype-environmental interactions have been hypothesized to contribute to the incidence and development of schizophrenia. Specifically, it has been hypothesized that environmental factors have differing effects on individuals with different genotypes, where some individuals may have an increased genetic susceptibility towards developing schizophrenia compared to others. Harmful environmental influences that may contribute to cause schizophrenia may include psychosocial factors, drug abuse, psychosis related to brain insults, and infections and/or complications during pregnancy and birth.

Neurodevelopment

It is clear that both genetic and environmental risk factors contribute to the incidence and development of schizophrenia although how these factors interact is less certain. Genetic factors and harmful environmental events such as obstetric complications occur well before disease onset. A neurodevelopmental model of schizophrenia helps to explain how these factors add or interact to contribute to schizophrenia and serves to explain the timing of genetic or environmental influences that ultimately result in disease.

The hypothesis that schizophrenia is of neurodevelopmental origin is now the most widely accepted explanation for schizophrenia pathophysiology. From the neurodevelopmental perspective, schizophrenia is assumed an ongoing process, rather than the result of a specific static event occurring sometime between conception and adulthood. A growing amount of data supports that the pathophysiology of schizophrenia involves abnormalities in normal brain development. Such evidence comes from studies that have identified associations between viral infections during pregnancy, obstetrical complications, and evidence of childhood behavioral and neurological abnormalities before disease onset in adulthood. Further, neuroimaging abnormalities that are observed in patients with first episode schizophrenia, in first-degree biological relatives and in schizotypal personality disorder, including deficits in cortical gray matter and reduced volumes in mesiotemporal regions, indicate that some anatomical abnormalities predate the onset of schizophrenia further supporting a neurodevelopmental origination and development of the disease.

Gender Differences

Distinct gender differences are similarly observed in the clinical features of schizophrenia. For example, negative symptoms appear more prominent in male patients and males have an earlier age of onset, a worse course of illness and more cognitive impairments. There is some evidence that structural abnormalities such as ventricular enlargements and alterations in callosal and temporal lobe shape are more apparent in male schizophrenia groups. Gender and age are therefore considered important variables when assessing structural brain alterations in patients with schizophrenia and their biological relatives compared to normal controls.

RESEARCH AT LONI

It is widely accepted that neuroanatomic abnormalities are present in schizophrenic. To investigate the regional specificity of abnormal neural systems in schizophrenia, we have used magnetic resonance imaging (MRI) and anatomical surface-based mesh modeling and brain atlasing approaches to look for regional anatomical differences. We have also employed standard statistical procedures to compare brain regions of interest in patients with schizophrenia compared to normal control groups. Experimental tests have concentrated on cortical and subcortical regions widely implicated in schizophrenia neuropathology and on the hypothesized alterations of normal cerebral asymmetries.

Enormous challenges exist in identifying neuroanatomic abnormalities in schizophrenia that are potentially disease specific. Large inter-individual variability in neuroanatomic structure in normal individuals, and the notable clinical heterogeneity in schizophrenia all decrease the likelihood of detecting disease-specific brain abnormalities. The diffuse nature and varying magnitude of cerebral anomalies found in schizophrenic populations further complicate localization strategies. In our analyses of brain structure, however, we have benefited from the improved spatial resolution of our imaging data and from the development of sensitive image analysis techniques that can preserve information on individual variability across many complex regions in three dimensions.

Development and Progression

To investigate the neurodevelopmental and/or the progression of structural neuropathology in schizophrenia we have studied some specific brain systems in acute-onset patients as well as in chronic schizophrenia patients.

Studies of drug-naïve first episode (FE) patients with schizophrenia may confirm the presence of structural neuropathology at the onset of the disease.
Comparisons of brain abnormalities observed at disease onset with those exhibited in chronic schizophrenia may reveal which neural systems are most vulnerable in schizophrenia and implicate which brain regions are susceptible to degenerative processes.
Longitudinal MR data from first episode patients may confirm which brain abnormalities are of a progressive nature and explain how these abnormalities relate to a number of factors such as different antipsychotic medication treatments.

Genetics & Environment

To investigate the genetic and/or environmental origins of structural neuropathology in schizophrenia we have examined potentially vulnerable brain regions in individuals who have an increased biological or environmental risk for developing schizophrenia. We have hypothesized that neuroanatomic abnormalities will manifest along a continuum of increased biological relatedness of an individual to a patient with schizophrenia. According to this model, structural brain abnormalities observed in biological relatives of patients, who show no overt symptoms of the disease, should by default, also be present at disease onset and in chronic schizophrenia. Conversely, brain abnormalities observed in acute onset patients or in patients that have experienced a chronic course of illness, will not necessarily manifest in healthy biological relatives.

In our investigations of structural neuropathology in schizophrenia, we have assessed a number of widely implicated brain regions along the continuum of genetic proximity, but only if these abnormalities were first identified in chronic or first episode schizophrenia. Specifically, we have included imaging data from monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia and normal control twin pairs to dissociate genetic versus environmental contributions to macroscopic structural brain abnormalities in schizophrenia.

By comparing brain abnormalities between MZ affected (schizophrenic) and non-affected (non-schizophrenic) twins, the significance and magnitude of disease specific (environmental) contributions towards alterations in brain structure have been determined.
By comparing regional brain abnormalities between non-schizophrenic (healthy) co-twins of schizophrenic patients to normal twin pairs, the genetic influences of schizophrenia on brain structure have been ascertained.
The contributions of shared environmental versus purely genetic influences to regional brain abnormalities have been estimated by comparing the patterns of structural brain abnormalities between MZ and DZ affected and unaffected co-twins.

Asymmetry

To investigate hypothesized alterations in functional and structural asymmetries in schizophrenia, we have examined asymmetric brain regions and lateralized functional systems in schizophrenia patients compared to normal controls. Structural asymmetries in posterior temporo-parietal regions, previously established as important for language processing, have been examined in patients in their first episode and in chronic schizophrenia patients to determine whether schizophrenia is related to pathophysiological processes that may interfere with the specialization of the two cerebral hemispheres. Behavioral paradigms have been employed simultaneously in chronic schizophrenia patients and normal control groups to determine whether functional lateralization and information transfer between the two cerebral hemispheres through the corpus callosum, are disturbed.