Hallucinations, perceptions in the absence of external stimuli, are prominent among the core symptoms of schizophrenia. The neural correlates of these brief, involuntary experiences are not well understood, and have not been imaged selectively. We have used new positron emission tomography (PET) methods to study the brain state associated with the occurrence of hallucinations in six schizophrenic patients. Here we present a group study of five patients with classic auditory verbal hallucinations despite medication, demonstrating activations in subcortical nuclei (thalamic, striatal), limbic structures (especially hippocampus), and paralimbic regions (parahippocampal and cingulate gyri, as well as orbitofrontal cortex). We also present a case study of a unique, drug-naive patient with visual as well as auditory verbal hallucinations, demonstrating activations in visual and auditory/linguistic association cortices as part of a distributed cortical-subcortical network. Activity in deep brain structures, identified with group analysis, may generate or modulate hallucinations, and the particular neocortical regions entrained in individual patients may affect their specific perceptual content. The interaction of these distributed neural systems provides a biological basis for the bizarre reports of schizophrenic patients.

SUMMARY1. Positron emission tomographic (PET) imaging of regional cerebral blood flow (rCBF), using a new 3-dimensional technique of data collection, was used to identify areas of neuronal activation associated with volitional inspiration and separately with volitional expiration in five normal male subjects. A comparison of the activated areas was also undertaken to isolate regions specific for one or other active task.2. Scans were performed during intravenous infusion of H2150 under conditions of (a) volitional inspiration with passive expiration, (b) passive inspiration with volitional expiration and (c) passive inspiration with passive expiration. Four measurements in these three conditions were performed in each subject. Breathing pattern was well matched between conditions. 3. Regional increases in brain blood flow, due to increased neural activity associated with either active inspiration or active expiration, were derived using a pixel by pixel comparison of images obtained during the volitional and passive ventilation phases. Data were pooled from all runs in all subjects and were then processed to detect statistically significant (P < 005) increases in rCBF comparing active inspiration with passive inspiration and active expiration with passive expiration.4. During active inspiration significant increases in rCBF were found bilaterally in the primary motor cortex dorsally just lateral to the vertex, in the supplementary motor area, in the right lateral pre-motor cortex and in the left ventrolateral thalamus.5. In active expiration significant increases in rCBF were found in the right and left primary motor cortices dorsally just lateral to the vertex, the right and left primary motor cortices more ventrolaterally, the supplementary motor area, the right lateral pre-motor cortex, the ventrolateral thalamus bilaterally, and the cerebellum.6. Using this modified and more sensitive PET technique, these findings essentially replicate those for volitional inspiration obtained in a previous study. 7. The technique used has been successful in demonstrating the regions of the brain involved in the generation of volitional breathing, and probably in the volitional modulation of automatic breathing patterns such as would be required for the production of speech.

Performance characteristics of a new design of positron tomograph with automatically retractable septa for brain imaging have been studied. The device, consisting of block BGO detectors (8 x 8 elements per block), has a ring diameter of 76 cm and an axial FOV of 106.5 mm. The in-plane resolution is on average 5.8 mm and 5.0 mm (FWHM) for stationary and wobble sampling, respectively, over the central 18 cm of the transaxial FOV. Its unique feature is the capability of data acquisition both in the 'conventional' 2D mode (with septa) or 3D mode (septa retracted) where coincidences between any of the 16 detector rings are acquired. When scattered events are subtracted, the efficiency for a 20 cm diameter uniform cylinder increases overall by a factor of 4.8 between 2D (septa extended) and 3D modes. For a 20 cm phantom the trues/singles ratio is higher for 3D than for 2D but for a given unscattered trues rate, the randoms rate in 3D is higher. At 380 keV the scatter fraction within a 20 cm cylinder is 10% (septa extended) and 36% (retracted). In spite of the increase in scatter when septa are retracted, the increased efficiency in the 3D mode of acquisition yields distinct advantages, particularly in the many studies where tracer concentration is low and consequently where dead time and random rates are less important.

Summary: Positron emission tomography regional CBF (rCBF) studies of cognitive processes have traditionally required 30--60 mCi of H21S0 per scan and intersubject averaging to achieve statistical significance. However, in tersubject anatomical, functional, and disease variability can make such an approach problematic. A new method that produces significant results in single subjects is pre sented. It is based upon high-sensitivity three dimensional imaging and a "slow" bolus administration of < 15 mCi of H21S0 per scan. The method is validated in four normal volunteers using control and auditory language activation tasks with four scans per condition and statistical parametric mapping analysis. It is demon strated that the rCBF distribution associated with the Functional brain imaging of regional CBF (rCBF) with positron emission tomography (PET) provides an in vivo index of localized synaptic activity asso ciated with cognitive and behavioral states in hu mans (Raichle, 1987). 150-labeled water, despite some limitation in diffusion (Eichling et aI., 1974), is currently the preferred CBF tracer because of its short half-life (2.05 min), ease of production and use, and low toxicity (Lammert sma and Mazoyer, Received November 4, 1992; final revision received January 21, 1993; accepted January 25, 1993 . Address correspondence and reprint requests to Dr. D. A. Silbersweig at MRC Cyclotron Unit, Hammersmith Hospital, DuCane Road, London WI2 OHS, England.Abbreviations used: BA, Brodmann's area; 3-D, three dimensional; NEC, noise equivalent count rate; PET, positron emission tomography; rCBF, regional CBF; SMA, supplemen tary motor area; SPM, statistical parametric map . 617cognitive state is detected during the arrival of radio tracer in the brain. This occurs over 30 s and constitutes a crit ical temporal window during which stimulation should be performed. A 90-s acquisition time is found to produce results of greater significance than a 60-s acquisition time. The implications of the results and the functional neuro anatomical findings are discussed. This method is suitable for the study of individual functional neuroanatomy in many neuropsychological, pharmacologic, and symptom states in normal subjects and in patients with psychiatric and neurologic disorders. Key Words: Functional brain imaging-ISO-labeled water-Positron emission tomog raphy-Regional cerebral blood flow-Single-subject analysis-Slow bolus technique. 1990). Qualitative subtraction studies utilizing 30-60 mCi of H2150 per scan and a two-dimensional scanning technique (with interplane septa) have provided valuable information concerning func tional neuroanatomy (Posner et aI., 1988; Zeki et aI. , 1991). However, limitations on acceptable doses of administered radioactivity and limitations of scanner sensitivity have necessitated the use of multiple subjects to obtain results of statistical sig nificance. While intersubject averaging may in crease the generalizability of results, it introduces additional problems associated with intersubject an at...