John M. Hoffman

Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development

2-[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non–small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

Ecstasy and Agony: Activation of the Human Amygdala in Positive and Negative Emotion

Considerable evidence indicates that the amygdala plays a critical role in negative, aversive human emotions. Although researchers have speculated that the amygdala plays a role in positive emotion, little relevant evidence exists. We examined the neural correlates of positive and negative emotion using positron emission tomography (PET), focusing on the amygdala. Participants viewed positive and negative photographs, as well as interesting and uninteresting neutral photographs, during PET scanning. The left amygdala and ventromedial prefrontal cortex were activated during positive emotion, and bilateral amygdala activation occurred during negative emotion. High-interest, unusual photographs also elicited left-amygdala activation, a finding consistent with suggestions that the amygdala is involved in vigilance reactions to associatively ambiguous stimuli. The current results constitute the first neuroimaging evidence for a role of the amygdala in positive emotional reactions elicited by visual stimuli. Although the amygdala appears to play a more extensive role in negative emotion, it is involved in positive emotion as well.

Brain Blood Flow Alterations Induced by Therapeutic Vagus Nerve Stimulation in Partial Epilepsy: I. Acute Effects at High and Low Levels of Stimulation

Summary: Purpose: Left cervical vagus nerve stimulation (VNS) decreases complex partial seizures (CPS) by unknown mechanisms of action. We hypothesized that therapeutic VNS alters synaptic activities at vagal afferent terminations and in sites that receive polysynaptic projections from these medullary nuclei.

Reduced Cerebral Glucose Metabolism in Asymptomatic Subjects at Risk for Huntington's Disease

Symptomatic patients with Huntingtons disease may have reduced glucose metabolism in the caudate nuclei. We used positron emission tomography and [18F]fluorodeoxyglucose to study cerebral glucose metabolism in 95 subjects: 58 clinically asymptomatic (chorea-free) subjects at risk for Huntingtons disease, 10 symptomatic patients with the disease, and 27 controls. All the symptomatic patients had marked reductions in caudate glucose metabolism. Despite a normal structural appearance on computed tomography, caudate glucose metabolism was bilaterally reduced in 31 percent of the subjects at risk (18 of 58). Using each at-risk subjects age and the sex of the affected parent, we averaged individual risk estimates for the development of Huntingtons disease for this group and predicted that the probability of having the clinically unexpressed Huntingtons disease gene should be 33.9 +/- 6.0 percent for the group. Thus, there was excellent agreement between the predicted percentage of carriers of the Huntingtons disease gene (33.9 +/- 6.0 percent) and the percentage with metabolic abnormalities of the caudate nuclei (31 percent). These results indicate that the measurement of glucose metabolism may allow the observation of the pathophysiologic effects of the Huntingtons disease gene during the natural development of the disease. It may also provide a direct means to monitor the response to experimental treatments during both the clinically asymptomatic and the symptomatic phases of the disorder.

Dissociable Neural Pathways Are Involved in the Recognition of Emotion in Static and Dynamic Facial Expressions

Facial expressions of emotion powerfully influence social behavior. The distributed network of brain regions thought to decode these social signals has been empirically defined using static, usually photographic, displays of such expressions. Facial emotional expressions are however highly dynamic signals that encode the emotion message in facial action patterns. This study sought to determine whether the encoding of facial expressions of emotion by static or dynamic displays is associated with different neural correlates for their decoding. We used positron emission tomography to compare patterns of brain activity in healthy men and women during the explicit judgment of emotion intensity in static and dynamic facial expressions of anger and happiness. Compared to judgments of spatial orientation for moving neutral facial expressions, the judgment of anger in dynamic expressions was associated with increased right-lateralized activity in the medial, superior, middle, and inferior frontal cortex and cerebellum, while judgments of happiness were associated with relative activation of the cuneus, temporal cortex, and the middle, medial, and superior frontal cortex. In contrast, the perception of anger or happiness in static facial expressions activated a motor, prefrontal, and parietal cortical network previously shown to be involved in motor imagery. The direct contrast of dynamic and static expressions indicated differential activation of visual area V5, superior temporal sulcus, periamygdaloid cortex, and cerebellum for dynamic angry expressions and differential activation of area V5, extrastriate cortex, brain stem, and middle temporal cortical activations for dynamic happy expressions. Thus, a distribution of neural activations is related to the analysis of emotion messages in the nearly constant biological motion of the face and differ for angry and happy expressions. Static displays of facial emotional expression may represent noncanonical stimuli that are processed for emotion content by mental strategies and neural events distinct from their more ecologically relevant dynamic counterparts.

Feeling with the mind's eye

MENTAL imagery is thought to play a key role in certain aspects of visual perception and to depend on neural activity in visual cortex. We asked whether tactile discrimination of grating orientation, which appears to involve visual mental imagery, recruits visual cortical areas. H215O positron emission tomography was performed in humans during presentation of gratings to the right index fingerpad. Selective attention to grating orientation significantly increased regional cerebral blood flow, relative to a control task involving selective attention to grating dimensions, in a region located in left parieto-occipital cortex. We propose that this activation reflects the use of imagery-related visuo-spatial processes to enable the tactile discrimination of orientation.

The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy

Objective: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. Background: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). Methods: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. Results: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). Conclusions: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

Kinetics and modeling of L-6-[18F]fluoro-DOPA in human positron emission tomographic studies

Kinetics of l-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) in striatum and cerebellum were measured in 10 normal human subjects with positron emission tomography (PET) from 0 to 120 min after an intravenous bolus injection of the tracer. The time course of the arterial plasma concentrations of the tracer and its metabolites was also assayed biochemically. FDOPA compartmental models that are based on biochemical information were investigated for their consistency with the measured striatal and cerebellar tissue kinetics. A modeling approach was also developed for separating plasma FDOPA and metabolite time-activity curves from the measured total 18F time-activity curve in plasma. Results showed that a model consisting of three separate compartments for tissue FDOPA, tissue 6-[18F]fluorodopamine (FDA) and its metabolites, and tissue l-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) could describe adequately the striatal kinetics in humans. Based on this model, the FDOPA transport constant across the blood–brain barrier (BBB) (K1), the FDOPA decarboxylation rate constant (k3), and the turnover rate constant of FDA and its metabolites (k4) could be estimated by model fitting to the tissue kinetics and were found for the normal subjects to be 0.031 ± 0.006 ml/min/g (mean ± SD), 0.041 ± 0.015/min, and 0.004 ± 0.002/min, respectively. About 50% of the FDOPA that crossed the BBB from plasma to striatum was decarboxylated. The decarboxylation constant with respect to plasma FDOPA (K3) was 0.015 ± 0.003 ml/min/g. The BBB transport corresponded to a permeability–surface area product of 0.032 ml/min/g for FDOPA. For 3-OMFD, the BBB transport was 1.7 times faster. The effects of tissue heterogeneity on the FDOPA kinetics and on the estimated model parameters were also investigated. The usefulness and implications of these findings for interpretation of PET FDOPA studies are discussed.

Neural Evidence Linking Visual Object Enumeration and Attention

Visual object enumeration is rapid and accurate for four or fewer items but slow and error-prone for over four items. This dichotomy has recently been linked to visual attentional phenomena by findings suggesting that subitizing of small sets of objects is preattentive whereas counting of over four items demands spatial shifts of attention. We evaluated this link at a neural level, using H215O positron emission tomography to measure changes in regional cerebral blood flow while subjects enumerated the number of target vertical bars that popped outof a 16-bar visual display consisting of both horizontal and vertical bars. Relative to a condition with a single target, subitizing (one to four targets) activated foci in the occipital extras-triate cortex, consistent with involvement of early, preattentive visual processes. Relative to subitizing, counting (five to eight targets) activated a widespread network of brain regions, including multiple foci implicated in shifting visual attention large regions of the superior parietal cortex bilaterally and a focus in the right inferior frontal cortex. These results offer the first direct neural support for mapping the subitizing-counting dichotomy onto separable processes mediating preattentive vision and shifts of visual attention.