Correlation between extraversion and regional cerebral blood flow in response to olfactory stimuli.

OBJECTIVE: Extraversion, a trait associated with individual differences in approach motivation and the experience of positive emotional states, is negatively correlated with certain psychiatric disorders, including depression and social phobia. The authors examined the correlation between extraversion and regional cerebral blood flow (rCBF) while participants were exposed to olfactory stimuli in order to further characterize individual differences in hedonic processing associated with this trait. METHOD: Twelve healthy participants were exposed to pleasant and unpleasant odors while rCBF was measured using [(15)O] water PET. The NEO Five-Factor Inventory was used to assess extraversion. Associations between extraversion scores and rCBF in each olfactory stimulus condition were assessed by correlational analysis. RESULTS: During the pleasant smell condition, extraversion was correlated with rCBF in the amygdala and occipital cortex. During the unpleasant smell condition, extraversion was correlated with rCBF in the occipital cortex and inferior temporal gyrus. CONCLUSIONS: These results provide important evidence for the biological basis of extraversion and indicate that there are systematic individual differences in patterns of brain activation in response to affective stimuli.

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.

Enhanced response of human head and neck cancer xenograft tumors to cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging.

PURPOSE: To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-D-glucose (2DG); whether 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. METHODS AND MATERIALS: Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. RESULTS: Use of CIS + 2DG enhanced cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. CONCLUSIONS: These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.

Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography.

OBJECTIVE: Schizophrenia is currently conceptualized as a disease of functional neural connectivity, leading to symptoms that affect aspects of mental activity, including perception, attention, memory, and emotion. The neural substrates of its emotional components have not been extensively studied with functional neuroimaging. Previous neuroimaging studies have examined medicated patients with schizophrenia. The authors measured regional cerebral blood flow (rCBF) during performance of a task that required unmedicated patients to recognize the emotional valence of visual images and to determine whether they were pleasant or unpleasant. METHOD: The authors examined rCBF in 17 healthy volunteers and 18 schizophrenia patients who had not received antipsychotic medications for at least 3 weeks during responses to pleasant and unpleasant visual stimuli. Areas of relative increases or decreases in rCBF were measured by using the [(15)O]H(2)O method. RESULTS: When patients consciously evaluated the unpleasant images, they did not activate the phylogenetically older fear-danger recognition circuit (e.g., the amygdala) used by the healthy volunteers, although they correctly rated them as unpleasant. Likewise, the patients showed no activation in areas of the prefrontal cortex normally used to recognize the images as pleasant and were unable to recognize them as such. Areas of decreased CBF were widely distributed and comprised subcortical regions such as the thalamus and cerebellum. CONCLUSIONS: This failure of the neural systems used to support emotional attribution is consistent with pervasive problems in experiencing emotions by schizophrenia patients. The widely distributed nature of the abnormalities suggests the importance of subcortical nodes in overall dysfunctional connectivity.

Neural correlates of naming animals from their characteristic sounds.

The neural correlates of naming stimuli presented through the auditory modality have scarcely been studied. Using a PET experiment in 10 normal subjects, we began to address this issue by testing the hypothesis that naming animals from their characteristic sounds will engage bilateral primary auditory and auditory association cortices, bilateral early visual association cortices, left inferotemporal (IT) cortices, and left frontal operculum. Subjects listened to characteristic animal sounds (e.g. a rooster crowing), and named the animals making the sounds. When contrasted with a baseline task that involved saying up/down to the direction of pitch change in tone sequences, the naming task produced activation in mesial occipital cortices, the left ventral IT region, and the left frontal operculum. We interpret the activation in visual association cortices to reflect the process of retrieving conceptual knowledge (e.g. physical structure) pertinent to the animals being named, as in visual images. The left IT activation is interpreted to reflect activation of a mediation system for word retrieval, that operates to link conceptual knowledge retrieval to word production, and whose triggering is independent of the sensory modality in which a stimulus is presented.

Neural systems underlying lexical retrieval for sign language.

Positron emission tomography was used to investigate whether signed languages exhibit the same neural organization for lexical retrieval within classical and non-classical language areas as has been described for spoken English. Ten deaf native American sign language (ASL) signers were shown pictures of unique entities (famous persons) and non-unique entities (animals) and were asked to name each stimulus with an overt signed response. Proper name signed responses to famous people were fingerspelled, and common noun responses to animals were both fingerspelled and signed with native ASL signs. In general, retrieving ASL signs activated neural sites similar to those activated by hearing subjects retrieving English words. Naming famous persons activated the left temporal pole (TP), whereas naming animals (whether fingerspelled or signed) activated left inferotemporal (IT) cortex. The retrieval of fingerspelled and native signs generally engaged the same cortical regions, but fingerspelled signs in addition activated a premotor region, perhaps due to the increased motor planning and sequencing demanded by fingerspelling. Native signs activated portions of the left supramarginal gyrus (SMG), an area previously implicated in the retrieval of phonological features of ASL signs. Overall, the findings indicate that similar neuroanatomical areas are involved in lexical retrieval for both signs and words.

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 [(15)Oxygen]-labeled water ([(15)O]H(2)O) 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 marijuana's 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.

Multimodality noninvasive imaging of gene transfer using the human sodium iodide symporter.

UNLABELLED: In this study we investigated the feasibility of using radionuclide accumulation mediated by the human sodium iodide symporter (hNIS) gene in conjunction with various imaging modalities as a reporter system to noninvasively monitor the expression of transgenes delivered for gene therapy. METHODS: NIS-expressing adenovirus (Ad-hNIS) was delivered in vitro to MB-435 breast carcinoma cells. NIS-mediated accumulation of (125)I(-), (99m)TcO(4)(-), and (76)Br(-) by the cells was visualized using autoradiography, gamma-camera scintigraphy, and PET imaging, respectively. RESULTS: For all imaging modalities, signal intensity generated by the cells correlated linearly both with the amount of Ad-hNIS and with the activity of radionuclide added to the cells. CONCLUSION: hNIS-mediated cellular accumulation of radionuclide was clearly visualized by all 3 imaging modalities tested. This preliminary study demonstrates the feasibility of using hNIS for monitoring the location and magnitude of expression of genes delivered during gene therapy.

[15O]water pharmacokinetics: influence of age and gender in normal subjects.

PURPOSE: To compile a normal database for the characterization of global [15O]water pharmacokinetic behavior. PROCEDURES: The influences of age, gender, and body habitus on the pharmacokinetics of [15O]water were investigated in a series of normal subjects, N = 100 (50 males, 50 females, age = 19-79) who were participants in cognitive activation studies. Arterial blood was analyzed by autosampler and parametric images were constructed using a 40-second summed image and the autoradiographic model. RESULTS: Males and females were comparable with respect to age, number of injections administered, and dose (mCi) administered per injection but differed significantly with respect to height, weight, and normalized dose (mCi/kg). There were significant gender-based differences in the bolus arrival time, global cerebral blood flow (gCBF), area-under-the-curve (AUC), summed image concentration, and dose-normalized concentration but not dose-normalized AUC. Bolus arrival time, gCBF and dose-normalized AUC were significantly influenced by age. CONCLUSION: Age and gender are significant determinants of [15O]water pharmacokinetic behavior.

Contamination levels in blood samples drawn from the injection intravenous line.

PURPOSE: Securing two intravenous lines, one for injection and one for blood sampling, can be nearly impossible in compromised patients, therefore, a need exists to quantify the potential error when simplified techniques are employed. METHOD: Two venous catheters were placed. 2-deoxy-2-[18F]fluoro-glucose (FDG) was infused through one of the catheters. Venous blood samples were drawn from each line. Triplicate aliquots of plasma were analyzed in duplicate. RESULTS: Concentrations from the infusion line were 2.0% higher than the concentrations from the noninfusion line. The average error was 3.3%, 2.0%, and 0.7% higher for the first, second, and third samples, respectively. CONCLUSIONS: Blood sampling through the infusion catheter is a viable alternative to the placement of separate venous catheters. Sampling from the injection catheter, even with tubing flush and replacement, will potentially incur small (generally < 10%) over-estimations in concentration in initial samples. Subsequent sampling reduces the error to essentially zero by the third sample.

Marijuana alters the human cerebellar clock.

The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors.

Effect of acute marijuana on cardiovascular function and central nervous system pharmacokinetics of [(15)O]water: effect in occasional and chronic users.

The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of [(15)O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [(15)O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [(15)O]water were made. Postsmoking, MJ influenced all measured CV and [(15)O]water PK parameters. C users reported significantly lower "highness" and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Delta(9)-tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [(15)O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole-body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [(15)O]water PK.

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.

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.

Effects of smoking marijuana on focal attention and brain blood flow.

Using an attention task to control cognitive state, we previously found that smoking marijuana changes regional cerebral blood flow (rCBF). The present study measured rCBF during tasks requiring attention to left and right ears in different conditions. Twelve occasional marijuana users (mean age 23.5 years) were imaged with PET using [15O]water after smoking marijuana or placebo cigarettes as they performed a reaction time (RT) baseline task, and a dichotic listening task with attend-right- and attend-left-ear instructions. Smoking marijuana, but not placebo, resulted in increased normalized rCBF in orbital frontal cortex, anterior cingulate, temporal pole, insula, and cerebellum. RCBF was reduced in visual and auditory cortices. These changes occurred in all three tasks and replicated our earlier studies. They appear to reflect the direct effects of marijuana on the brain. Smoking marijuana lowered rCBF in auditory cortices compared to placebo but did not alter the normal pattern of attention-related rCBF asymmetry (i.e., greater rCBF in the temporal lobe contralateral to the direction of attention) that was also observed after placebo. These data indicate that marijuana has dramatic direct effects on rCBF, but causes relatively little change in the normal pattern of task-related rCBF on this auditory focused attention task.

The neural correlates of spatial language in English and American Sign Language: a PET study with hearing bilinguals.

Rather than specifying spatial relations with a closed-class set of prepositions, American Sign Language (ASL) encodes spatial relations using space itself via classifier constructions. In these constructions, handshape morphemes specify object type, and the position of the hands in signing space schematically represents the spatial relation between objects. A [15O]water PET study was conducted to investigate the neural regions engaged during the production of English prepositions and ASL locative classifier constructions in hearing subjects with deaf parents (ASL-English bilinguals). Ten subjects viewed line drawings depicting a spatial relation between two objects and were asked to produce either an ASL locative classifier construction or an English preposition that described the spatial relation. The comparison task was to name the figure object (colored red) in either ASL or in English. Describing spatial relations in either ASL or English engaged parietal cortex bilaterally. However, an interaction analysis revealed that right superior parietal cortex was engaged to a greater extent for ASL than for English. We propose that right parietal cortex is involved in the visual-motoric transformation required for ASL. The production of both English prepositions and ASL nouns engaged Broca's area to a greater extent than ASL classifier constructions. We suggest that Broca's area is not engaged because these constructions do not involve retrieval of the name of an object or the name of a spatial relation. Finally, under the same task conditions, only left parietal activation was observed for monolingual English speakers producing spatial prepositions (H. Damasio et al., 2001, NeuroImage, 13). We conclude that the right hemisphere activation observed for ASL-English bilinguals was due to their life-long experience with spatial language in ASL.

Noninvasive radiological imaging of pulmonary gene transfer and expression using the human sodium iodide symporter.

PURPOSE: In this study we investigated the application of the human sodium iodide symporter (hNIS) as a reporter gene to noninvasively image in vivo gene transfer and expression in lung tissue in real time. METHODS: Human NIS-expressing adenoviruses (Ad-hNIS) or empty adenoviruses (Ad-Bgl II) were instilled into the lungs of Cotton rats via the nostrils. After 3, 10, and 17 days post infection, gamma camera scintigraphy with 99mTcO4- was performed to observe the distribution and duration of gene transfer. At 20 days after infection, reverse transcription polymerase chain reaction was performed to detect hNIS gene expression. Dual expressing vector Ad-hNIS-eGFP was used to detect transgene expression by fluorescence photomicroscopy in infected lung tissue. Positron emission tomography (PET) imaging of gene transfer to the lungs was performed using 124I- as tracer. Finally, hNIS transfer to a polarized human airway epithelial cell layer was evaluated by phosphorimaging. RESULTS: Lungs in animals infected with Ad-hNIS were clearly visible on scintigraphy and PET scans, while those infected with Ad-Bgl II were undetectable. Lungs in Ad-hNIS infected animals could still be visualized at 17 days but were no longer detectable at 20 days. Fluorescence microscopy showed that lung tissue infected with Ad-hNIS-eGFP had significantly higher GFP signal intensity than that infected with Ad-Bgl II. CONCLUSION: It is feasible to use the hNIS gene as a reporter gene to monitor the location, magnitude, and timing of expression of genes delivered during pulmonary gene therapy. The ability to noninvasively visualize gene expression tomographically in real time has significant translational implications in human gene therapy.

Technical issues in the determination of cerebrovascular reserve in elderly subjects using 15O-water PET imaging.

The accurate determination of cerebrovascular reserve (CVR), especially in elderly subjects, entails several technical issues. From a review of the literature, the optimal technique employs quantitative 15O-water PET imaging determinations of cerebral blood flow (CBF) and acetazolamide (ACZ) (1 g iv with measurements at 10- to 20-min post-administration) as the vasodilating agent. CBF and CVR measurements were made using this methodology on 12 elderly subjects (3 males, 9 females, 66-84 years of age) meeting criteria for mild cognitive impairment (MCI) without other significant medical problems. Applying this quantitative technique, the cognitive and emotional status of the subject during the imaging procedure influenced the magnitude of the measurements. The semiquantitative measures resulted in even more pronounced subject state influences. The conditions under which CBF or CVR measurements are made should be controlled and reported. If semiquantitative techniques (e.g., single-photon emission-computed tomography [SPECT] imaging) must be employed for the determination of CVR, the validity of any measurement is dependent on the careful control of the general physiological status (e.g., heart rate, blood pressure, level of anxiety) of the patient.

Cerebral blood flow changes associated with Schneiderian first-rank symptoms in schizophrenia.

The authors examined the severity of Schneiderian first-rank symptoms in relation to regional cerebral blood flow (rCBF) with the use of PET. Eighty-seven schizophrenic patients were imaged during an eyes-closed condition during which they were instructed to relax and not perform any specific task (random episodic silent thought, or REST). Schneiderian symptoms were rated by using structured assessment instruments. The Schneiderian score of the patients was positively correlated with rCBF in right superior parietal cortex and negatively correlated with rCBF in left posterior cingulate gyrus and in left lingual gyrus. The results of this study demonstrate a cerebral pattern of activation related to Schneiderian symptoms and reinforce the hypothesis of an involvement of cortical areas that mediate space and body representation in such phenomena.

Neural systems underlying spatial language in American Sign Language.

A [(15)O]water PET experiment was conducted to investigate the neural regions engaged in processing constructions unique to signed languages: classifier predicates in which the position of the hands in signing space schematically represents spatial relations among objects. Ten deaf native signers viewed line drawings depicting a spatial relation between two objects (e.g., a cup on a table) and were asked either to produce a classifier construction or an American Sign Language (ASL) preposition that described the spatial relation or to name the figure object (colored red). Compared to naming objects, describing spatial relationships with classifier constructions engaged the supramarginal gyrus (SMG) within both hemispheres. Compared to naming objects, naming spatial relations with ASL prepositions engaged only the right SMG. Previous research indicates that retrieval of English prepositions engages both right and left SMG, but more inferiorly than for ASL classifier constructions. Compared to ASL prepositions, naming spatial relations with classifier constructions engaged left inferior temporal (IT) cortex, a region activated when naming concrete objects in either ASL or English. Left IT may be engaged because the handshapes in classifier constructions encode information about object type (e.g., flat surface). Overall, the results suggest more right hemisphere involvement when expressing spatial relations in ASL, perhaps because signing space is used to encode the spatial relationship between objects.