Supplement: Seeing Schizophrenia

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Melinda Wenner
Dec 1, 2007
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There are also consistent reductions in the size of the medial temporal lobe and the left neocortical superior temporal gyrus in patients with schizophrenia; those areas are responsible for declarative memory and auditory processing, respectively. Some studies have also found that the total volume of grey matter is decreased in schizophrenic individuals compared to normal subjects, though this is most pronounced in the frontal and temporal lobes.2

What fMRI can tell us

Structural brain changes don't always correlate to alterations in brain function, however, so scientists often combine the two by looking at functional MRI (fMRI). Structural MRI scans detect only differences in tissue type, but fMRI also reveals changes in blood oxygenation levels, a correlate of localized neural activity. "The reason that functional imaging has become very important is that it provides us with an ability to get insights into the psychology of schizophrenia, including the nature...

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There are also consistent reductions in the size of the medial temporal lobe and the left neocortical superior temporal gyrus in patients with schizophrenia; those areas are responsible for declarative memory and auditory processing, respectively. Some studies have also found that the total volume of grey matter is decreased in schizophrenic individuals compared to normal subjects, though this is most pronounced in the frontal and temporal lobes.2

What fMRI can tell us

Structural brain changes don't always correlate to alterations in brain function, however, so scientists often combine the two by looking at functional MRI (fMRI). Structural MRI scans detect only differences in tissue type, but fMRI also reveals changes in blood oxygenation levels, a correlate of localized neural activity. "The reason that functional imaging has become very important is that it provides us with an ability to get insights into the psychology of schizophrenia, including the nature of the cognitive impairments that are present," says Cameron Carter, a psychiatrist at the University of California, Davis. "There's been a growing awareness over the last 15 years that this particular aspect of schizophrenia is very fundamental to the illness."

fMRI is helping correlate structural changes to function. what causes the functional deficits, however, is still unknown.

With fMRI, scientists compare brain activity in normal and schizophrenic brains as individuals perform cognitive tasks. In a meta-analysis of approximately 50 studies, Carter and his colleagues have found that schizophrenia's impact on the frontal lobes - particularly the dorsolateral prefrontal cortex and the anterior cingulate cortex, where activity seems to be reduced in schizophrenia - is crucial for explaining attention and memory deficits in schizophrenia.3,4 Other studies have observed deficits in the posterior parietal cortex and basal ganglia in patients performing similar tasks.5,6 Conversely, Carter has also found that lower in the frontal lobes, activity sometimes increases in schizophrenic patients.7 This could be because patients are recruiting these additional brain areas to assist with a task, Carter speculates.

What causes these functional deficits is still largely unknown. Some studies suggest, however, that disruptions in neural synchrony play a role.8 When the brain processes information in a coordinated way, thousands of neurons oscillate and fire on and off in synchrony with one another. Oscillations in the gamma band (about 40 Hz) appear to be important for a number of perceptual and cognitive processes, Carter says. A subset of quickly oscillating GABA neurons appear to be impaired in schizophrenia, and increases in gamma band oscillations in response to certain cognitive tasks are smaller in schizophrenics than in healthy subjects. Impaired neural synchrony may, then, be causing some of the cognitive and behavioral problems observed in the disorder, he says.

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Viewing schizophrenia in real time

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9 It's difficult, however, to predict how white matter disruptions might play out in terms of psychologic or cognitive deficits, or why these deficits occur in the first place. The tracts "seem to be either less well developed or not as pruned [in schizophrenics as compared to healthy subjects, but] it's not clear," says Aysenil Belger, director of neuroimaging at the University of North Carolina at Chapel Hill.

PET projects

More detailed functional information about the schizophrenic brain is available through the use of positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Providing more quantitative measures of cerebral blood flow and metabolism than fMRI, PET and SPECT create images based on the detection of radiation in the brain after patients are injected with radioactive compounds that target areas or molecules of interest. PET has been used, for instance, to discern the numbers of neurotransmitter receptors present in different parts of the brain as well as the rates of neurotransmitter synthesis and reuptake.10

Anissa Abi-Dargham, a psychiatrist and radiologist at Columbia University, uses PET to understand dopamine dysfunction in the striatum and cortex in individuals with schizophrenia; in this way, PET imaging provides key insights into both the molecular features of schizophrenia and how they correlate to different brain regions. Levels of subcortical dopamine might one day be used as biomarkers for schizophrenia vulnerability, says Abi-Dargham.

While all these imaging technologies are individually useful, their use in tandem represents "one of the most important future directions," says Carter of UC, Davis. It's now possible, for instance, to collect structural, functional, and white-matter tract MRI information as well as EEG data in a single patient session. This allows scientists to look at the same subjects in different situations, which is preferable to studying different patients, because "within the patient population, much like within healthy individuals, there's a lot of variation," says Belger.

The caveats

In order to tease out disease causes, it will also be necessary for scientists to combine imaging studies with other types of studies, such as longitudinal, postmortem, and animal studies. Imaging on its own provides scientists with snapshots of how schizophrenic brains differ from healthy brains, but it can only suggest correlations, not causality. Other types of studies are necessary to discern whether observed abnormalities cause disease symptoms, reflect efforts by the brain to respond to a different problem, or are consequences of the illness, like scars, says Rajiv Tandon, a psychiatrist at the Florida Department of Children and Families in Tallahassee.

In addition, imaging studies can be confounded by medication effects. When scientists assess patients with chronic disease who have been on antipsychotic medications for years, it may be unclear whether brain changes are the result of the disease or the medications. "You're imaging a drug effect and you're imaging a disease effect and you're imaging the interaction between the two," says Texas psychiatrist Tamminga. To work around this problem, scientists are beginning to study healthy relatives of schizophrenic patients, prodromal subjects who do not yet exhibit psychotic symptoms, and babies and children at high genetic risk for developing the disorder.

The flip side of medication effects is that imaging could also help evaluate potential treatments. fMRI and EEG can assess how well a treatment improves symptoms, while PET and SPECT can determine how accurately a treatment targets desired brain regions and molecules.

The hope, of course, is to someday use imaging to identify early markers of schizophrenia in high-risk patients and to administer treatments and interventions that prevent the disease from progressing. "If you can figure out where the abnormalities are, what the circuit is that's most stressed and why, you can intercede, [and] perhaps you can not just prevent but maybe reverse some of them," says Martha Shenton, a psychiatrist and radiologist at Brigham's and Women's Hospital in Boston (see References

1. S.B. Schwarzkopf et al., "Third and lateral ventricular volumes in schizophrenia: support for progressive enlargement of both structures," Psychopharmacol Bull, 26:385-91, 1990.
2. M.E. Shenton et al., "A review of MRI findings in schizophrenia," Schizophr Res, 49:1-52, 2001.
3. W.M. Perlstein et al., "Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia," Am J Psych, 158:1105-13 2001.
4. C.S. Carter et al., "Anterior cingulate cortex activity and impaired self-monitoring of performance in patients with schizophrenia: an event-related fMRI study," Am J Psych, 158:1423-8, 2001.
5. J. Danckert et al., "Attention, motor control and motor imagery in schizophrenia: implications for the role of the parietal cortex," Schizophr Res, 70:241-61, 2004.
6. D.S. Manoach et al., "Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance," Biol Psychiatry, 48:99-109, 2000.
7. A.W. MacDonald 3rd et al., "Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis," Am J Psych, 162:475-84, 2005.
8. R.Y. Cho et al., "Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia," Proc Natl Acad Sci, 103:19878-83, 2006.
9. M. Kubicki et al., "A review of diffusion tensor imaging studies in schizophrenia." J Psychiatr Res, 41:15-30, 2007.
10. R.B. Zipursky et al., "PET and SPECT imaging in psychiatric disorders," Can J Psychiatry, 52:146-57, 2007.