Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors.

CONTEXT: Loss of the capacity to experience pleasure (anhedonia) is a core clinical feature of schizophrenia. Although functional imaging techniques have been successful in identifying the neural basis of cognitive impairments in schizophrenia, no attempts to date have been made to investigate neural systems underlying emotional disturbances. OBJECTIVE: To study the neural basis of emotional processing in schizophrenia by exploring the pattern of brain responses to olfactory stimuli in patients and healthy volunteers. DESIGN: Positron emission tomographic study of patients with schizophrenia and healthy volunteers. Positron emission tomographic data were collected between July 21, 1995, and September 11, 1997, and data analyses were conducted in 1999-2001. SETTING: The Mental Health Clinical Research Center at the University of Iowa, Iowa City. PARTICIPANTS: Sixteen healthy volunteers with a mean age of 29.5 years and 18 patients with schizophrenia and a mean age of 30.0 years. MAIN OUTCOME MEASURE: Areas of relative increase or decrease in regional cerebral blood flow, measured using positron emission tomography and the [(15)O]water method while participants performed an emotion-induction olfactory task to determine response to pleasant (vanillin) and unpleasant (4-methylvaleric acid) odors, compared between patients and healthy volunteers. RESULTS: Patients with schizophrenia subjectively experienced unpleasant odors in a manner similar to healthy volunteers but showed impairment in the experience of pleasant odors. The analysis of the regional cerebral blood flow revealed that patients failed to activate limbic/paralimbic regions (eg, insular cortex, nucleus accumbens, and parahippocampal gyrus) during the experience of unpleasant odors, recruiting a compensatory set of frontal cortical regions instead. CONCLUSION: Abnormalities in the complex functional interactions between mesolimbic and frontal regions may underlie emotional disturbances in schizophrenia.

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.

Acute marijuana effects on rCBF and cognition: a PET study.

The effects of smoking marijuana on cognition and brain function were assessed with PET using H2(15)O. Regional cerebral blood flow (rCBF) was measured in five recreational users before and after smoking a marijuana cigarette, as they repeatedly performed an auditory attention task. Blood flow increased following smoking in a number of paralimbic brain regions (e.g. orbital frontal lobes, insula, temporal poles) and in anterior cingulate and cerebellum. Large reductions in rCBF were observed in temporal lobe regions that are sensitive to auditory attention effects. Brain regions showing increased rCBF may mediate the intoxicating and mood-related effects of smoking marijuana, whereas reduction of task-related rCBF in temporal lobe cortices may account for the impaired cognitive functions associated with acute intoxication.

Cerebellar hypoactivity in frequent marijuana users.

It is uncertain whether frequent marijuana use adversely affects human brain function. Using PET, regional cerebral blood flow was compared in frequent marijuana users and comparable, non-using controls after at least 26 h of monitored abstention by all subjects. Marijuana users showed substantially lower brain blood flow than controls in a large region of posterior cerebellum, indicating altered brain function in frequent marijuana users. A cerebellar locus of some chronic and acute effects of marijuana is plausible, e.g. the cerebellum has been linked to an internal timing system, and alterations of time sense are common following marijuana smoking.

Novel vs. well-learned memory for faces: a positron emission tomography study.

Previous work has suggested that familiarity/novelty of learned materials affects the circuitry involved in memory, primarily in the size of activations rather than the pattern of activation. Although this work has examined both recall and recognition, it has been limited to verbal material. In this study, we set out to determine if the same result applies to nonverbal memory. We used the same experimental design, but used faces as the memory task. Healthy volunteers thoroughly learned a set of 18 faces a week prior to the Positron Emission Tomography (PET) experiment (well-learned memory) and were asked to remember another set of 18 faces, to which they were exposed 1 min before the PET experiment (novel memory). During the PET session, their task was to recognize the faces learned a week before and the faces seen a minute before; the "remembered faces" were interspersed among entirely new (distractor) faces. We found that, unlike for verbal material, the retention interval and the familiarity level of the faces affected both the pattern and the size of activations. Comparing the novel and well-learned recognition tasks revealed that novel memory for faces is primarily a frontal-lobe task, while well-learned recognition memory for faces utilizes a more distributed neural circuit, including visual areas, which appear to serve as memory-storage sites.

Regional neural dysfunctions in chronic schizophrenia studied with positron emission tomography.

OBJECTIVE: Whether chronicity of illness produces progressive neural abnormality is an important question in current schizophrenia research. Positron emission tomography (PET) offers an opportunity to visualize and measure blood flow in vivo to address this issue. The authors previously compared healthy volunteers with neuroleptic-naive patients experiencing their first episode of schizophrenia and reported that abnormalities in blood flow, including lower flow in prefrontal regions and higher flow in the thalamus and cerebellum, are present at the early stage of schizophrenic illness. The goal of the present study was to measure blood flow with PET in patients with chronic schizophrenia. METHOD: PET was used to examine regional cerebral blood flow (rCBF) in 30 patients with chronic schizophrenia and 30 normal comparison subjects. To determine if the patterns of flow abnormality in the patients with chronic schizophrenia were similar to those of patients experiencing their first episode of schizophrenia, the same cognitive condition was examined as in the earlier study. The patients with chronic schizophrenia in the current study had been neuroleptic-free for at least 3 weeks. RESULTS: As in the authors' previous study, the chronically ill patients showed lower flow in prefrontal areas and higher flow in thalamic and cerebellar regions than normal comparison subjects, suggesting that a similar neural dysfunction occurs in both first-episode and chronic schizophrenia. CONCLUSIONS: rCBF abnormalities in patients with chronic schizophrenia are not due to chronicity of illness or the effects of medication. These results provide evidence that the primary neural abnormalities in schizophrenia may occur in cortical, cerebellar, and thalamic regions and that the dysfunction in these regions may explain the "loosening of associations" that Bleuler considered to be the fundamental cognitive phenotype of schizophrenia. These abnormalities can be reconceptualized as "cognitive dysmetria."

Age-related changes in regional cerebral blood flow among young to mid-life adults.

Using PET with [(15)O]H2O, we examined age in relation to regional cerebral blood flow (rCBF) among young to mid-life adults. Previous work has largely contrasted rCBF between young and elderly age groups dichotomously. This study maps the continuum of normal age-related changes in rCBF from early to mid-adulthood. We obtained images from 37 healthy volunteers between 19 and 50 years of age during an eyes-closed resting baseline condition. There was a negative correlation between age and rCBF in mesial frontal cortex, involving the anterior cingulate region (r = 0.63, p<0.001). These findings reflect differences in the distribution of rCBF evident in early to mid-adulthood that may be associated with subsequent changes in memory and executive functioning in later life.

Cerebral blood flow changes associated with attribution of emotional valence to pleasant, unpleasant, and neutral visual stimuli in a PET study of normal subjects.

OBJECTIVE: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence. METHOD: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other. RESULTS: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus accumbens, precuneus, and visual cortex relative to the neutral condition. CONCLUSIONS: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.

Direct comparison of the neural substrates of recognition memory for words and faces.

For the purpose of identifying the relatively specific brain regions related to word and face recognition memory on the one hand and the regions common to both on the other, regional cerebral blood flow associated with different cognitive tasks for recognition memory was examined using [H215O]PET in healthy volunteers. The tasks consisted of recognizing two types of stimuli (faces and words) in two conditions (novel and familiar), and two baseline tasks (reading words and gender classification). The statistical analyses used to identify the specific regions consisted of three subtractions: novel words minus novel faces, familiar words minus familiar faces, and reading words minus gender classification. These analyses revealed relative differences in the brain circuitry used for recognizing words and for recognizing faces within a defined level of familiarity. In order to find the regions common to both face and word recognition, overlapping areas in four subtractions (novel words minus reading words, novel faces minus gender classification, familiar words minus reading words, and familiar faces minus gender classification) were identified. The results showed that the activation sites in word recognition tended to be lateralized to the left hemisphere and distributed as numerous small loci, and particularly included the posterior portion of the left middle and inferior temporal gyri. These regions may be related to lexical retrieval during written word recognition. In contrast, the activated regions for face recognition tended to be lateralized to the right hemisphere and located in a large aggregated area, including the right lingual and fusiform gyri. These findings suggest that strikingly different neural pathways are engaged during recognition memory for words and for faces, in which a critical role in discrimination is played by semantic cueing and perceptual loading, respectively. In addition, the investigation of the regions common to word and face recognition indicates that the anterior and posterior cingulate have dissociable functions in recognition memory that vary with familiarity, and that the cerebellum may serve as the co-ordinator of all four types of recognition memory processes.

Recalling word lists reveals "cognitive dysmetria" in schizophrenia: a positron emission tomography study.

OBJECTIVE: This study explored the neural circuitry used during recall of unstructured verbal material in schizophrenic patients and healthy volunteer subjects. METHOD: The subjects were 13 healthy volunteers and 14 schizophrenic patients. All patients were free of medication, and all subjects were right-handed. Two experimental cognitive conditions were used: recall of novel and practiced word lists (two 15-item lists from the Rey Auditory Verbal Learning Test). Both active recall tasks were compared with an eyes-closed resting baseline condition. A nonparametric randomization test was used to determine within- and between-group differences in regional cerebral blood flow. RESULTS: Performance on both the practiced and novel memory tasks was nonsignificantly different in the patients and control subjects. During the novel memory task, the patients showed decreased flow in the right anterior cingulate, right thalamus, and bilateral cerebellum (left greater than right) relative to the control subjects. When recalling the practiced word lists, the patients showed decreased flow in the left dorsolateral prefrontal cortex, bilateral medial frontal cortex, left supplementary motor area, left thalamus, left cerebellar regions, anterior vermis, and right cuneus. CONCLUSIONS: Patients with schizophrenia fail to activate cortical-cerebellar-thalamic-cortical circuitry during recall of both well-learned and novel word lists.

Cerebral blood flow and personality: a positron emission tomography study.

OBJECTIVE: This study sought to describe brain regions associated with the personality dimension of introversion/extraversion. METHOD: Measures of cerebral blood flow (CBF) were obtained from 18 healthy subjects by means of [150]H20 positron emission tomography. Correlations of regional CBF with introversion/extraversion were calculated, and a three-dimensional map of those correlations was generated. RESULTS: Overall, introversion was associated with increased blood flow in the frontal lobes and in the anterior thalamus. Regions in the anterior cingulate gyrus, the temporal lobes, and the posterior thalamus were found to be correlated with extraversion. CONCLUSIONS: The findings of the study lend support to the notion that introversion is associated with increased activity in frontal lobe regions. Moreover, the study suggests that individual differences in introversion and extraversion are related to differences in a fronto-striato-thalamic circuit.

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.

Dysfunctional cortico-cerebellar circuits cause 'cognitive dysmetria' in schizophrenia.

We examined regional cerebral blood flow (rCBF) during a long-term recognition memory task for words in schizophrenic patients and in healthy subjects using positron emission tomography (PET). The task was designed so that performance scores were similar in the patient and control subjects. This memory retrieval task did not increase rCBF in the patients' prefrontal cortex, precuneus and cerebellum as much as it did in the control group. These results point to a dysfunctional corticocerebellar circuit leading to poorly coordinated mental activity ('cognitive dysmetria'), which could explain the broad range of schizophrenic symptoms. In addition, other brain areas were more activated by the task in the patient group than in the control group and may form a compensatory network performing the memory retrieval task by assisting or replacing the dysfunctional cortico-cerebellar circuit.

Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography.

Positron Emission Tomography (PET) imaging of regional cerebral blood flow (rCBF) provides an in vivo method for studying brain function. We used [15O]H20 PET to assess the effect of antipsychotic medications on rCBF in 17 subjects with schizophrenia. Each subject was scanned while receiving antipsychotic medication, and after having been withdrawn from antipsychotic medication for a 3-week period. The two scans were subtracted from one another, using a within subjects design, and the areas of difference were identified using the Montreal method. Subjects treated with antipsychotic medication had significantly higher rCBF in the left basal ganglia and left fusiform gyrus compared with the "off-medication" condition. Significantly higher relative rCBF in the anterior cingulate, left dorsolateral and inferior frontal cortex, and left and right cerebellum was observed when off antipsychotic medication. Upregulation of dopamine D2 receptors may lead to a regional increase of blood flow and metabolism in the basal ganglia, which may explain recently reported anatomical enlargement in these regions.

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.

Emotional activation of limbic circuitry in elderly normal subjects in a PET study.

OBJECTIVE: This study was undertaken to identify brain structures associated with emotion in normal elderly subjects. METHOD: Eight normal subjects aged 55-78 years were shown film clips intended to provoke the emotions of happiness, fear, or disgust as well as a neutral state. During emotional activation, regional cerebral blood flow was measured with the use of [15O]H2O positron emission tomography imaging, and subjective emotional responses were recorded. Data were analyzed by subtracting the values during the neutral condition from the values in the various emotional activations. RESULTS: The stimuli produced a general activation in visual pathways that included the primary and secondary visual cortex, involving regions associated with object and spatial recognition. In addition, the specific emotions produced different regional limbic activations, which suggests that different pathways may be used for different types of emotional stimuli. CONCLUSIONS: Emotional activation in normal elderly subjects was associated with increases in blood flow in limbic and paralimbic brain structures. Brain activation may be specific to the emotion being elicited but probably involves complex sensory, association, and memory circuitry. Further studies are needed to identify activations that are specific for emotion.

Construction of a whole body blood flow model for use in positron emission tomography imaging with [15O]water.

A whole body blood flow model (WBBFM) was developed and tested using STELLA II, an icon-driven mathematical simulation software package. The WBBFM uses parallel chambers to represent gray and white areas of the brain, body organs such as lungs, heart (right and left halves), injection site, and blood sampling sites. Input values to the WBBFM include organ blood flows, organ volumes, tissue:blood partition coefficients, injected activity, and data acquisition times for a positron emission tomography (PET) camera. Input variables included an injection function (e.g., bolus), and a blood flow function (e.g., transient variations in flow). The kinetic behavior of [15O]water, a freely diffusible radiotracer employed in PET to characterize blood flow was examined by the WBBFM. The physiologic behavior of water in the human body was emulated using the WBBFM and the model's predictive value was verified by comparing calculated results with the following properties of water: diffusibility, tissue:blood partition coefficient of [15O]water, and the mixing of [15O]water with total body water. The WBBFM simulated Kety's autoradiographic method used in the estimation of regional cerebral blood flow by PET using [15O]water. The application of the model to a cognitive activation study paradigm based on Kety's method is presented and its results compared to published literature data. With appropriate modification in the half-life, tissue:blood partition coefficient, and the amount of administered radioactivity, the WBBFM should prove useful as a tool to examine kinetics of other freely diffusible radiotracers used in PET.

Auditory and visual attention assessed with PET.

Brain mechanisms involved in the maintenance of attention to auditory and visual stimuli at different spatial locations were assessed using positron emission tomography with [15O]water to measure regional cerebral blood flow (rCBF) changes in 13 normal volunteers. Simultaneous auditory [dichotically presented consonant-vowel-consonants (CVCs)] and visual stimuli (vertically oriented, CVCs presented to the left and right of fixation) were presented on every trial. In different conditions subjects attended for targets in a specified stimulus channel (left or right ears or left or right visual fields) while maintaining fixation on a central x. Attending left or right for auditory stimuli increased rCBF in primary auditory cortex in Heschl's gyrus and in temporal lobe auditory association cortices in both hemispheres. Attending left or right for visual stimuli did not change rCBF in primary visual cortex, and only attention to the right significantly increased rCBF in contralateral occipital cortex. Visual attention caused significant rCBF changes in a widespread network that included frontal, parietal, and temporal cortical regions as well as the cerebellum, whereas rCBF changes due to auditory attention were largely localized in the temporal lobes. The results suggest that spatially directed attention is mediated by different mechanisms in the auditory and visual modalities.

Sample size and statistical power in [15O]H2O studies of human cognition.

Determining the appropriate sample size is a crucial component of positron emission tomography (PET) studies. Power calculations, the traditional method for determining sample size, were developed for hypothesis-testing approaches to data analysis. This method for determining sample size is challenged by the complexities of PET data analysis: use of exploratory analysis strategies, search for multiple correlated nodes on interlinked networks, and analysis of large numbers of pixels that may have correlated values due to both anatomical and functional dependence. We examine the effects of variable sample size in a study of human memory, comparing large (n = 33), medium (n = 16,17), small (n = 11, 11, 11), and very small (n = 6,6,7,7,7) samples. Results from the large sample are assumed to be the "gold standard." The primary criterion for assessing sample size is replicability. This is evaluated using a hierarchically ordered group of parameters: pattern of peaks, location of peaks, number of peaks, size (volume) of peaks, and intensity of the associated t (or z) statistic. As sample size decreases, false negatives begin to appear, with some loss of pattern and peak detection; there is no corresponding increase in false positives. The results suggest that good replicability occurs with a sample size of 10-20 subjects in studies of human cognition that use paired subtraction comparisons of single experimental/baseline conditions with blood flow differences ranging from 4 to 13%.