Daniel et al. (1991): Cerebral Blood Flow in Schizophrenia

Why investigate dopamine and the prefrontal cortex?

Daniel, Weinberger, Jones and colleagues’ 1991 study investigated whether amphetamine could change brain activation during a cognitive task in people with schizophrenia. It connects a biological explanation of schizophrenia with the study of thinking: could changing neurotransmitter activity affect both brain function and task performance?

Neurotransmitters are chemical messengers that carry signals between nerve cells. Monoamines are a group of neurotransmitters that includes dopamine, noradrenaline and serotonin. This study focused particularly on dopamine-related activity.

The prefrontal cortex (PFC) is the front part of the cerebral cortex and is involved in planning, decision-making and controlling behaviour. Previous research had suggested that this region was underactive in people with schizophrenia. Daniel and colleagues were particularly interested in the dorsolateral prefrontal cortex (DLPFC), a region towards the upper, outer sides of the PFC involved in demanding cognitive tasks.

Dopamine was thought to improve the brain’s ‘signal-to-noise’ balance: suppressing spontaneous activity unrelated to a task while strengthening activity responding to the task. Think of this as making a relevant conversation clearer by reducing background chatter. The prediction was therefore not simply that dopamine would make the whole brain more active, but that it would help focus activity where it was needed.

The aim and prediction

The researchers aimed to investigate the effect of dextroamphetamine, a drug that enhances dopamine-related activity, on DLPFC activation and regional cerebral blood flow (rCBF) during the Wisconsin Card Sort Test (WCST).

Regional cerebral blood flow means the flow of blood through a particular brain region. It provides an indicator of regional brain activity rather than a direct measurement of dopamine itself.

The hypothesis was that patients receiving dextroamphetamine would have a higher ratio of prefrontal to non-frontal blood flow during the WCST than when receiving a placebo. This relative comparison mattered: task-related activity could become more concentrated in the prefrontal cortex without blood flow increasing throughout the brain.

Who took part and how the experiment was designed

This was a double-blind, placebo-controlled laboratory experiment with a repeated-measures design. Each participant experienced both the active-drug and placebo conditions. The independent variable was whether they received dextroamphetamine or placebo; the dependent variables included regional cerebral blood flow and WCST performance.

A placebo is an inactive treatment. Comparing it with the active drug helps separate the drug’s effects from the effects of expecting to receive treatment. Double-blind testing means that neither the participants nor the researchers directly testing them knew which treatment was being administered, reducing the influence of expectations.

The sample consisted of ten patients with chronic schizophrenia from the National Institute of Mental Health research wards at the Neuroscience Centre at St Elizabeth’s in the USA. All met the American Psychiatric Association’s 1987 diagnostic criteria. They volunteered and gave informed consent.

All patients had been stabilised on the antipsychotic drug haloperidol, at 0.4 mg/kg per day, six weeks before the study. This provided a stable treatment background, but also meant the experiment concerned patients already receiving medication.

The tasks, scans and procedure

The researchers used three main materials:

• The Psychiatric Symptom Assessment Scale (PSAS) to monitor symptoms.
• Two automated tasks: the demanding WCST, associated with prefrontal cognitive activation, and a simpler BAR control task, in which participants matched the geometric orientation of bars.
• SPECT scanning to measure regional cerebral blood flow.

The BAR task provided a comparison with a simpler sensorimotor activity. Comparing it with the WCST helped researchers distinguish activation associated with a demanding cognitive task from activation accompanying simpler responding.

For the two weeks before testing, trained nursing staff assessed participants daily using the PSAS. They monitored negative symptoms, behavioural positive symptoms and verbal positive symptoms.

On each test day, participants took an oral dose of either placebo or 0.25 mg/kg dextroamphetamine approximately 120 minutes before blood-flow measurements. This timing was chosen because the drug’s blood-plasma levels were expected to peak two to three hours after oral administration.

Each participant underwent two sets of blood-flow measurements, 48–96 hours apart, completing the BAR task and WCST during scanning. The order of active medication and placebo was counterbalanced across participants. Varying the order reduced the risk that practice or fatigue would consistently favour one condition.

During scanning, participants sat semi-reclined in a comfortable chair with their head positioned in the scanner. Blood pressure was measured immediately afterwards, and respiratory measures were monitored. These checks accompanied the administration of a drug and the measurement of brain blood flow.

What changed after amphetamine?

The findings require a distinction between overall blood flow, regional activation and cognitive performance.

Amphetamine produced a modest overall reduction in blood flow during both the BAR task and WCST. However, this reduction was not statistically significant: it was not strong enough to confidently distinguish it from chance variation using the study’s statistical tests.

Despite this overall pattern, amphetamine significantly increased task-specific DLPFC activation during the prefrontal-linked cognitive task. The researchers interpreted this as better focusing of cortical activity in response to the WCST, rather than a general increase throughout the brain.

Amphetamine also produced small but statistically significant improvements in two WCST performance measures: the number of correct responses and the percentage of conceptual-level responses, a measure reflecting successful use of the task’s sorting concepts.

Not every relationship was significant. Amphetamine levels did not significantly correlate with regional cerebral blood flow during either task, or with changes in WCST performance. In the placebo condition, DLPFC blood flow did not significantly correlate with any performance measure. The results therefore did not establish a simple relationship in which higher drug levels always meant greater blood flow or better performance.

What the researchers concluded

Daniel and colleagues concluded that amphetamine appeared to enhance the cortex’s ability to focus activity on the WCST. Its effect was region-specific and task-specific, supporting the idea that dopamine-related activity contributes to prefrontal cognitive functioning.

The conclusion was tentative because the sample was small. The experiment showed that changing drug treatment could alter activation and aspects of performance in these patients; it did not establish that dopamine alone causes schizophrenia or that amphetamine is a cure.

How strong is the evidence?

The controlled design strengthens the comparison. Using the same patients in both conditions reduced the influence of individual differences. Placebo control and double-blind testing reduced expectation effects, while counterbalancing reduced order effects. Together, these features made a drug-related explanation more convincing than it would be in an uncontrolled observation.

The measurements were systematic, but limited in what they revealed. SPECT provided a physiological measure rather than relying only on patients’ reports. However, blood flow is an indicator of brain activity, not a direct measure of dopamine. The findings support an interpretation about dopamine-related functioning without directly measuring every step of that mechanism.

Generalisability is limited. Ten patients from one research setting cannot represent everyone with schizophrenia. In particular, findings from patients with chronic schizophrenia taking haloperidol may not apply to newly diagnosed or unmedicated patients. A small sample also makes conclusions more vulnerable to unusual individual results.

Existing medication complicates interpretation. Stabilising haloperidol treatment made the comparison more consistent, but the findings concerned amphetamine against that medication background. They cannot automatically be treated as the effects amphetamine would have in an unmedicated brain. This does not remove the value of the comparison, because the same patients experienced both conditions.

Ethical safeguards must be weighed against potential burdens. Participants volunteered, gave informed consent and had symptoms and physiological measures monitored. Nevertheless, drug administration and scanning required a justification in terms of expected research value and participant welfare.

Finally, the study takes a biologically reductionist approach: it examines a complex disorder through neurotransmitter-related activity, blood flow and task performance. This is useful for identifying a specific mechanism, but it cannot provide a complete explanation of schizophrenia’s psychological and social dimensions. Overall, it offers controlled evidence for a limited biological claim, rather than a complete account of the disorder.

Background and prediction

• Previous research suggested prefrontal underactivity in schizophrenia.
• Dopamine may improve ‘signal-to-noise’: less irrelevant activity, stronger task-related activity.
• Aim: investigate dextroamphetamine’s effects on DLPFC activation and rCBF during the WCST.
• Hypothesis: a higher PFC-to-non-frontal blood-flow ratio after dextroamphetamine than placebo during the WCST.

Method essentials

• Double-blind, placebo-controlled laboratory experiment; repeated measures.
• IV: dextroamphetamine versus placebo.
• DVs: regional cerebral blood flow and WCST performance.
• Sample: ten volunteers with chronic schizophrenia from US National Institute of Mental Health research wards.
• Stabilised on haloperidol: 0.4 mg/kg/day, six weeks before testing.
• PSAS: daily symptom monitoring for two weeks beforehand.
• SPECT: blood-flow measurements during WCST and BAR orientation-matching tasks.
• Dose: 0.25 mg/kg orally, approximately 120 minutes before measurement.
• Two measurement sessions 48–96 hours apart; drug/placebo order counterbalanced.

Findings and conclusion

• Modest overall blood-flow reduction: not statistically significant.
• Significant task-specific DLPFC activation during the prefrontal-linked task.
• Small significant improvements in correct responses and percentage of conceptual-level responses.
• Drug levels did not significantly correlate with rCBF or WCST performance changes.
• Under placebo, DLPFC blood flow did not significantly correlate with performance.
• Conclusion: amphetamine appeared to focus cortical activity on the task; conclusions remained tentative.

Evaluation links

• Control, blinding, counterbalancing: strengthen the drug/placebo comparison.
• Same participants: reduces individual-difference effects.
• Ten medicated patients: limited generalisability.
• Haloperidol background: limits application to unmedicated patients.
• Blood-flow measure: physiological evidence, but not direct dopamine measurement.
• Reductionism: investigates a biological mechanism, not the whole disorder.