Emerging Perspectives: Peering into the Brain's "Black Box" in Schizophrenia

Emerging Perspectives: Peering into the Brain’s "Black Box" in Schizophrenia

Provocative testing and neuroimaging offer new insights into what goes wrong in schizophrenia.

By using contemporary neuroimaging techniques, often combined with provocative psychological challenges, researchers are uncovering the compromised brain processes in schizophrenic patients that may account for specific clinical phenomena. Six reports in the March issue of the American Journal of Psychiatry identify pieces of this complex puzzle. All of the studies involved comparisons between medicated patients with schizophrenia and healthy controls.

A common conjecture regarding the disease is that lack of inhibitory capacity is a key deficit. In a functional MRI (fMRI) study by Gur et al., subjects were asked to respond to target images presented along with distracting symbols. Patients’ problems in focusing on salient targets were related to problems in top-down processing: Cortical areas needed for attention to targets generally showed diminished activation in patients, presumably signifying that their brains would have to exert greater effort in those regions to accomplish the task. Abnormal activation patterns in other brain areas suggested that patients also have difficulty with "bottom-up" processing — i.e., inhibitory filtering needed to keep extraneous stimuli from bubbling up into awareness.

Inhibition problems might also underlie the difficulties that schizophrenic patients have in settling into the healthy "idle" brain mode seen in normal individuals. Using fMRI, Garrity et al. found that when at rest, a network involving the frontal, cingulate, and parahippocampal cortices in schizophrenia patients exhibited irregular timing — not the regular, slow resonance seen in healthy people. Positive symptoms correlated with abnormal medial frontal, temporal, and cingulate activity.

The thalamic reticular nucleus is a thin sheet of inhibitory neurons between the thalamus and cortex, which generates sleep spindles and which appears to be hypoactive in schizophrenia. Ferrarelli et al. used a 256-channel EEG during sleep. In sleep spindles at 12 to 15 cycles per second, they found a specific deficit in schizophrenic subjects, compared with both healthy controls and patients with depression histories.

Similarly, Ford et al., in a study of auditory-evoked potentials, demonstrated that schizophrenic patients had poor inhibition of certain cortical areas, which normally occurs when preparing for speech. The authors postulate that this lack of inhibition contributes to patients’ difficulties in distinguishing others’ speech from their own.

Diffusion tensor imaging assesses the integrity of white matter by examining how water molecules align in myelin. Using this technique, Shergill et al. found that patients had an overall reduction in myelin pathways between the Broca and Wernicke areas (i.e., the frontal-lobe region that controls motor speech and the temporal-lobe region that controls receptive speech, respectively). Curiously, the pathways were closest to normal in patients with active auditory hallucinations.

Also using diffusion tensor imaging, Leitman et al. found deficient integrity in the connections to the auditory cortex ("acoustic radiation"). These decrements correlated with patients’ difficulties in using tone of voice to identify emotions and sentence type (question vs. statement) and even in determining whether common tunes were played with the correct notes. These findings may account for patients’ difficulties in evaluating other people’s emotions.

Comment: Over the decades, numerous neuropsychological difficulties have been described in patients with schizophrenia. What we call schizophrenia is a diverse group of syndromes that affect different patients in sundry ways. If all of these researchers had studied the same patients, we might have learned the extent to which this astounding array of deficits occurs concurrently and how specific phenomenologic features correlate with specific biologic findings.

An editorialist who attempts to make sense of this dizzying diversity of findings points out that all of the authors make good cases that their findings are due to uncorrected pathology rather than to medication effects. He hypothesizes that a single underlying pathology might affect different brain regions, as occurs in stroke patients. If so, clinical differences among patients might indicate individual variation in brain areas vulnerable to these underlying processes. Researchers could test this interesting idea by searching for more-fundamental common processes, e.g., whether these various neuroimpairments are associated with specific brain protein abnormalities.

— Joel Yager, MD

Published in Journal Watch Psychiatry April 13, 2007

Citation(s):

Gur RE et al. Visual attention circuitry in schizophrenia investigated with oddball event-related functional magnetic resonance imaging. Am J Psychiatry 2007 Mar; 164:442-9.

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Garrity AG et al. Aberrant "default mode" functional connectivity in schizophrenia. Am J Psychiatry 2007 Mar; 164:450-7.

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Ford JM et al. Synch before you speak: Auditory hallucinations in schizophrenia. Am J Psychiatry 2007 Mar; 164:458-66.

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Shergill SS et al. A diffusion tensor imaging study of fasciculi in schizophrenia. Am J Psychiatry 2007 Mar; 164:467-73.

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Leitman DI et al. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am J Psychiatry 2007 Mar; 164:474-82.