G. Leonard Watkins

Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients

BACKGROUND There have been reports that patients with schizophrenia have decreased metabolic activity in prefrontal cortex. However, findings have been confounded by medication effects, chronic illness, and difficulties of measurement. We aimed to address these problems by examination of cerebral blood flow with positron emission tomography (PET). METHODS We studied 17 neuroleptic-naïve patients at the early stages of illness by means of image analysis and statistical methods that can detect abnormalities at the gyral level. FINDINGS An initial omnibus test with a randomisation analysis indicated that patients differed from normal controls at the 0.06 level. In the follow-up analysis, three separate prefrontal regions had decreased perfusion (lateral, orbital, medial), as well as regions in inferior temporal and parietal cortex that are known to be anatomically connected. Regions with increased perfusion were also identified (eg, thalamus, cerebellum, retrosplenial cingulate), which suggests an imbalance in distributed cortical and subcortical circuits. INTERPRETATION These distributed dysfunctional circuits may form the neural basis of schizophrenia through cognitive impairment of the brain, which prevents it from processing input efficiently and producing output effectively, thereby leading to symptoms such as hallucinations, delusions, and loss of volition.

Effects of Smoking Marijuana on Brain Perfusion and Cognition

The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study. PET with [15Oxygen]-labeled water ([15O]H2O) was used to measure rCBF before and after smoking of marijuana and placebo cigarettes, as subjects repeatedly performed an auditory attention task. Smoking marijuana resulted in intoxication, as assessed by a behavioral rating scale, but did not significantly alter mean behavioral performance on the attention task. Heart rate and blood pressure increased dramatically following smoking of marijuana but not placebo cigarettes. However, mean global CBF did not change significantly. Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in “paralimbic” regions and may be related to marijuanas mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors.

Effects of frequent marijuana use on memory-related regional cerebral blood flow.

It is uncertain whether frequent marijuana use adversely affects human brain function. Using positron emission tomography (PET), memory-related regional cerebral blood flow was compared in frequent marijuana users and nonusing control subjects after 26+ h of monitored abstention. Memory-related blood flow in marijuana users, relative to control subjects, showed decreases in prefrontal cortex, increases in memory-relevant regions of cerebellum, and altered lateralization in hippocampus. Marijuana users differed most in brain activity related to episodic memory encoding. In learning a word list to criterion over multiple trials, marijuana users, relative to control subjects, required means of 2.7 more presentations during initial learning and 3.1 more presentations during subsequent relearning. In single-trial recall, marijuana users appeared to rely more on short-term memory, recalling 23% more than control subjects from the end of a list, but 19% less from the middle. These findings indicate altered memory-related brain function in marijuana users.

A Positron Emission Tomography Study of Binaurally and Dichotically Presented Stimuli: Effects of Level of Language and Directed Attention

Regional cerebral blood flow (rCBF) was measured using positron emission tomography with oxygen- 15 labeled water as 10 normal subjects listened to three types of auditory stimuli (environmental sounds, meaningless speech, and words) presented binaurally or dichotically. Binaurally presented environmental sounds and words caused similar bilateral rCBF increases in left and right superior temporal gyri. Dichotically presented stimuli (subjects attended to left or right ears) caused asymmetric activation in the temporal lobes, resulting from increased rCBF in temporal lobe regions contralateral to the attended ear and decreased rCBF in the opposite hemisphere. The results indicate that auditorily presented language and non-language stimuli activate similar temporal regions, that dichotic stimulation dramatically changes rCBF in temporal lobes, and that the change is due both to attentional mechanisms and to hemispheric specialization.

The cerebellum plays a role in conscious episodic memory retrieval.

The cerebellum has traditionally been considered to be primarily dedicated to motor functions. Its phylogenetic development and connectivity suggest, however, that it also may play a role in cognitive processes in the human brain. In order to examine a potential cognitive role for the cerebellum in human beings, a positron emission tomography (PET) study was conducted during a “pure thought experiment”: subjects intentionally recalled a specific past personal experience (consciously retrieved episodic memory). Since there was no motor or sensory input or output, the design eliminated the possibility that cerebellar changes in blood flow were due to motor activity. During silent recall of a consciously retrieved episodic memory, activations were observed in the right lateral cerebellum, left medial dorsal thalamus, medial and left orbital frontal cortex, anterior cingulate, and a left parietal region. These activations confirm a cognitive role for the cerebellum, which may participate in an interactive cortical‐cerebellar network that initiates and monitors the conscious retrieval of episodic memory. Hum. Brain Mapping 8:226–234, 1999.

II. PET Studies of Memory: Novel versus Practiced Free Recall of Word Lists

Positron emission tomography (PET) with the tracer H215O was used to measure regional cerebral blood flow in 13 healthy volunteers while they engaged in free recall of 15-item word lists from the Rey Auditory Verbal Learning task. The study was designed so that recall of well-practiced versus novel material could be compared. One week before the PET study, subjects were trained to perfect recall of List A, while they were exposed to list B only 60 s prior to PET data acquisition. As in the companion study of free recall of complex narratives, we observed that practice tended to decrease the size of activations in regions involved in the memory component of the task; we also observed that the novel recall task produced greater activation in left frontal regions, probably due to active encoding. A commonality of other regions observed in this pair of studies, as well as other studies of memory in the literature, suggests that the human brain may contain a distributed multinodal general memory system. Nodes on this network include the frontal, parietal, and temporal cortices, the thalamus, the anterior and posterior cingulate, the precuneus, and the cerebellum. There appears to be a commonality of components across tasks (e.g., retrieval, encoding) that is independent of content, as well as differentiation of some components that may be content-specific or tasks-specific. In addition, these results support a significant role for the cerebellum in cognitive functions such as memory.

Effects of timing and duration of cognitive activation in [15O]water PET studies.

The multiple injection [15O]water method offers unique opportunities for studying cognitive processing by the human brain. The influence of the duration and temporal placement of an activation task, in relation to the arrival of the radiotracer in the brain, is a fundamental methodologic question for cognitive activation studies. A quantitative positron emission tomography (PET) study of five normal volunteers was performed in which the stimulation consisted of a visual activation task (alternating checkerboard pattern) superimposed on an auditory baseline task (syllable monitoring). Ten injection conditions, with varying duration and timing of the visual activation, were used. Regional CBF (rCBF) in visual cortex was measured quantitatively using the autoradiographic method. A 20-s stimulation, centered on the bolus arrival in the brain, produced significant changes in rCBF. Because varying the duration and timing of the activation task technically violates the temporal homogeneity assumption of the autoradiographic model, a mathematical simulation was formulated to evaluate the potential influence of these variations. Results of the simulation are consistent with the PET data and suggest that activation can be limited to a narrow temporal window centered on the radiotracer uptake. The ability to observe significant changes in rCBF with short stimulation intervals is of particular interest in the use of [15O]water PET for studies of cognitive processes with a short time course.

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia

BACKGROUND Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.

Neural basis of novel and well-learned recognition memory in schizophrenia: a positron emission tomography study.

The level of familiarity of a given stimulus plays an important role in memory processing. Indeed, the novelty/familiarity of learned material has been proven to affect the pattern of activations during recognition memory tasks. We used visually presented words to investigate the neural basis of recognition memory for relatively novel and familiar stimuli in schizophrenia. Subjects were 34 healthy volunteers and 19 schizophrenia spectrum patients. Two experimental cognitive conditions were used: 1 week and again 1 day prior to the PET imaging subjects had to thoroughly learn a list of 18 words (well‐learned memory). Subjects were also asked to learn another set of 18 words presented 1 min before the PET experiment (novel memory). During the PET session, subjects had to recognize the list of 18 words among 22 new (distractor) words. Subjects also performed a control task (reading words). A nonparametric randomization test and a statistical t‐mapping method were used to determine between‐ and within‐group differences. In patients the recognition of novel material produced relatively less flow in several frontal areas, superior temporal gyrus, insular cortex, and parahippocampal areas, and relatively higher activity in parietal areas, visual cortex, and cerebellum, compared to controls. No significant differences in flow were seen when comparing well‐learned memory activations between groups. These results suggest that different neural pathways are engaged during novel recognition memory in patients with schizophrenia compared to healthy individuals. During recognition of novel material, patients failed to activate frontal/limbic regions, recruiting a set of posterior perceptual brain regions instead. Hum. Brain Mapping 12:219–231, 2001.

Kinetic Analysis of 3′-Deoxy-3′-18F-Fluorothymidine (18F-FLT) in Head and Neck Cancer Patients Before and Early After Initiation of Chemoradiation Therapy

The purpose of this study was to investigate the kinetic behavior of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) before and early after initiation of chemoradiation therapy in patients with squamous cell head and neck cancer. Methods: A total of 8 patients with head and neck cancer underwent 18F-FLT PET scans (7 patients at baseline and after 5 d [10 Gy] of radiation therapy given with concomitant chemotherapy and 1 patient only at baseline). Dynamic PET images were obtained with concurrent arterial or venous blood sampling. Kinetic parameters including the flux constant of 18F-FLT based on compartmental analysis (K-FLT), the Patlak influx constant (K-Patlak), and standardized uptake value (SUV) were calculated for the primary tumor and 18F-FLT–avid cervical lymph nodes for all scans. Results: Mean pretreatment values of uptake for the primary tumor and cervical nodes were 0.075 ± 0.006 min−1, 0.042 ± 0.004 min−1, and 3.4 ± 0.5 (mean ± SD) for K-FLT, K-Patlak, and SUV, respectively. After 10 Gy of radiation therapy, these values were 0.040 ± 0.01 min−1, 0.018 ± 0.016 min−1, and 1.8 ± 1.1 for K-FLT, K-Patlak, and SUV, respectively. For all lesions seen on pretherapy and midtherapy scans, the correlation was 0.90 between K-FLT and K-Patlak, 0.91 between K-FLT and SUV, and 0.99 between K-Patlak and SUV. Conclusion: The initial 18F-FLT uptake and change early after treatment in squamous head and neck tumors can be adequately characterized with SUV obtained at 45–60 min, which demonstrates excellent correlation with influx parameters obtained from compartmental and Patlak analyses.