Laura L. Boles Ponto

The Cerebellum and Emotional Experience

While the role of the cerebellum in motor coordination is widely accepted, the notion that it is involved in emotion has only recently gained popularity. To date, functional neuroimaging has not been used in combination with lesion studies to elucidate the role of the cerebellum in the processing of emotional material. We examined six participants with cerebellar stroke and nine age and education matched healthy volunteers. In addition to a complete neuropsychological, neurologic, and psychiatric examination, participants underwent [15O]water positron emission tomography (PET) while responding to emotion-evoking visual stimuli. Cerebellar lesions were associated with reduced pleasant experience in response to happiness-evoking stimuli. Stroke patients reported an unpleasant experience to frightening stimuli similar to healthy controls, yet showed significantly lower activity in the right ventral lateral and left dorsolateral prefrontal cortex, amygdala, thalamus, and retrosplenial cingulate gyrus. Frightening stimuli led to increased activity in the ventral medial prefrontal, anterior cingulate, pulvinar, and insular cortex. This suggests that alternate neural circuitry became responsible for maintaining the evolutionarily critical fear response after cerebellar damage.

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.

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.

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.

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.

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 Heschls 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. Hum. Brain Mapping 5:422–436, 1997.

A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy.

BACKGROUND AND PURPOSE The purpose of this study was to design a radiation therapy treatment planning approach that would spare hematopoietically active bone marrow using [(18)F]FLT PET imaging. MATERIALS AND METHODS We have developed an IMRT planning methodology to incorporate functional PET imaging using [(18)F]FLT scans. Plans were generated for two simulated cervical cancer patients, where pelvic active bone marrow regions were incorporated as avoidance regions based on the ranges: SUV4 ≥ 4; 4>SUV3 ≥ 3; and 3 > SUV2 ≥ 2. Dose objectives were set to reduce bone marrow volume that received 10 (V(10)) and 20 (V(20))Gy. RESULTS Active bone marrow regions identified by [(18)F]FLT with an SUV ≥ 2, SUV ≥ 3, and SUV ≥ 4 represented an average of 43.0%, 15.3%, and 5.8%, respectively of the total osseous pelvis for the two cases studied. Improved dose-volume histograms for all identified bone marrow SUV volumes and decreases in V(10), and V(20) were achieved without clinically significant changes to PTV or OAR doses. CONCLUSIONS Incorporation of [(18)F]FLT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in pelvic malignancies.

Global cerebral blood flow after CO2 inhalation in normal subjects and patients with panic disorder determined with [15O]water and PET

OBJECTIVE To determine the effect of CO2 inhalation on global cerebral blood flow (gCBF) and pCO2-adjusted gCBF in normal subjects and panic disorder patients. METHOD Global cerebral blood flow was determined using quantitative [15O] water imaging in normal subjects (n = 12) and panic disorder patients (n = 14) after inhalations of medical grade air and of 35%/65% CO2/O2 mixture, a known inducer of panic. The gCBF was calculated as an area-weighted mean value. The pCO2 -adjusted gCBF values were calculated based on the formula of Reiman et al. [Am. J. Psychiatr. 143 (1986) 469]. Data were analyzed using repeated-measures ANOVA and regression analyses. RESULTS The pCO2 values did not differ statistically between normals and panic patients. Panic patients exhibited a decrease in gCBF and stable pCO2-adjusted gCBF values in comparisons of AIR and CO2 inhalations, whereas normals exhibited stable gCBF and increasing pCO2-adjusted gCBF values. CONCLUSIONS Patients with panic disorder, especially when symptomatic, exhibited an abnormal pattern in gCBF response to provocation.

Assessment of Blood Flow in Solid Tumors Using PET.

OBJECTIVE: To develop a technique for the evaluation of tumor perfusion prior to and during chemo- and radiation therapy.METHODS: Using the [(15)O]water autoradiographic technique and positron emission tomography (PET), perfusion in solid cervical tumors was investigated in a series of women prior to and during radiation therapy for cervical cancer. A 60-second summed image was used with the arterial blood curve to create a parametric image. The parametric images were registered to sagittal magnetic resonance (MR) images. Regions drawn on the MR images encompassing the tumor were transferred to the corresponding co-registered PET images.RESULTS: All tumors were easily visualized by both imaging modalities and tissue heterogeneity could be evaluated. Mean pre- and during therapy flow values averaged 41.5 +/- 11.9 and 48.2 +/- 7.2 mL/min/100 g tumor, respectively.CONCLUSIONS: Perfusion status of solid tumors, an assumed predictor of response potential, can be assessed using PET and the [(15)O]water technique.

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 models 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 Ketys 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 Ketys 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 us a tool to examine kinetics of other freely diffusible radiotracers used in PET.