Dr. Crespo-Facorro and Colleagues Reply

To the Editor: We thank Drs. K and Janka for their thoughtful comments about our recent PET study. Among other findings, we reported that compared to healthy volunteers, patients with schizophrenia showed a relative decrease in regional cerebral blood flow (rCBF) in the left rostral supplementary motor area when they recalled a practiced word list. Drawing from the findings of McGuire et al., Drs. K and Janka suggest that the presence of hallucinating patients in our study group could explain the underactivation of the supplementary motor area. However, only five of 14 patients in our study had a clear history of auditory hallucinations (hearing voices commenting or conversing). Therefore, the majority of patients in our group were not hallucinators. This study was not designed to compare hallucinating and nonhallucinating patients.

Moreover, the cognitive paradigm in our study was not a task involving the generation and monitoring of inner speech. However, even if we assumed that the patients were performing some monitoring of their inner speech, similar rCBF decreases in the supplementary motor area would have been shown during the novel as well as the practiced conditions.

It is difficult to be certain whether patients do or do not experience auditory hallucinations during the performance of brief cognitive tasks in a PET session. We debrief patients and question them about the occurrence of auditory hallucinations after each injection. In our experience, patients rarely hallucinate when performing a cognitive task (e.g., remembering a list of words), especially when behavioral data confirm the task execution. Therefore, we think it unlikely that the relative decrease in rCBF in the supplementary motor area is associated with either the presence of hallucinators in our group or with hallucinations concurrent with scanning.

We and other groups have reported—albeit using different terminology and somewhat different concepts—converging results on the neuroanatomic substrates underlying the pathophysiological mechanisms of schizophrenia (1). The pre-supplementary motor area is involved in the internal representation of time and is activated during complex response-selection tasks (2). Reduced supplementary motor area activity has been associated with the impairment of self-generated willed actions (negative symptoms) and impairment of the self-monitoring of inner speech (positive symptoms versus auditory hallucinations) in schizophrenia (see Drs. K and Janka’s letter). The pre-supplementary motor area is connected to brain regions extensively related to the pathophysiological mechanisms of schizophrenia, such as the prefrontal cortex, nucleus medialis, dorsalis of the thalamus, caudate nucleus, and cerebellum.

The “cognitive dysmetria” model of schizophrenia posits that a disruption in the normal coordination and sequence of mental processes may lead to a dysfunction in a fundamental cognitive process that defines the phenotype of the illness. Abnormalities in the circuit linking the brain regions involved in timing and sequencing mental functions (i.e., the cerebellum and pre-supplementary motor area) to regions involved in higher-level cognitive processes (i.e., frontal and parietal regions) might lead to this core cognitive impairment (3).