Robert A. Koeppe

Age Differences in the Frontal Lateralization of Verbal and Spatial Working Memory Revealed by PET

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.

Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors

Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on μ-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of μ-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of μ-opioid receptor signaling in the human brain.

Verbal working memory load affects regional brain activation as measured by pet

We report an experiment that assesses the effect of variations in memory load on brain activations that mediate verbal working memory. The paradigm that forms the basis of this experiment is the n-back task in which subjects must decide for each letter in a series whether it matches the one presented n items back in the series. This task is of interest because it recruits processes involved in both the storage and manipulation of information in working memory. Variations in task difficulty were accomplished by varying the value of n. As n increased, subjects showed poorer behavioral performance as well as monotonically increasing magnitudes of brain activation in a large number of sites that together have been identified with verbal working-memory processes. By contrast, there was no reliable increase in activation in sites that are unrelated to working memory. These results validate the use of parametric manipulation of task variables in neuroimaging research, and they converge with the subtraction paradigm used most often in neuroimaging. In addition, the data support a model of working memory that includes both storage and executive processes that recruit a network of brain areas, all of which are involved in task performance.

The Role of Parietal Cortex in Verbal Working Memory

Neuroimaging studies of normal subjects and studies of patients with focal lesions implicate regions of parietal cortex in verbal working memory (VWM), yet the precise role of parietal cortex in VWM remains unclear. Some evidence (Paulesu et al., 1993; Awh et al., 1996) suggests that the parietal cortex mediates the storage of verbal information, but these studies and most previous ones included encoding and retrieval processes as well as storage and rehearsal of verbal information. A recent positron emission tomography (PET) study by Fiez et al. (1996) isolated storage and rehearsal from other VWM processes and did not find reliable activation in parietal cortex. This result suggests that parietal cortex may not be involved in VWM storage, contrary to previous proposals. However, we report two behavioral studies indicating that some of the verbal material used by Fiez et al. (1996) may not have required phonological representations in VWM. In addition, we report a PET study that isolated VWM encoding, retrieval, and storage and rehearsal processes in different PET scans and used material likely to require phonological codes in VWM. After subtraction of appropriate controls, the encoding condition revealed no reliable activations; the retrieval condition revealed reliable activations in dorsolateral prefrontal, anterior cingulate, posterior parietal, and extrastriate cortices, and the storage condition revealed reliable activations in dorsolateral prefrontal, inferior frontal, premotor, and posterior parietal cortices, as well as cerebellum. These results suggest that parietal regions are part of a network of brain areas that mediate the short-term storage and retrieval of phonologically coded verbal material.

Spatial versus object working memory: Pet investigations

We used positron emission tomography (PET) to answer the following question: Is working memory a unitary storage system, or does it instead include different storage buffers for different kinds of information? In Experiment 1, PET measures were taken while subjects engaged in either a spatial-memory task (retain the position of three dots for 3 sec) or an object-memory task (retain the identity of two objects for 3 sec). The results manifested a striking double dissociation, as the spatial task activated only right-hemisphere regions, whereas the object task activated primarily left-hemisphere regions. The spatial (right-hemisphere) regions included occipital, parietal, and prefrontal areas, while the object (left-hemisphere) regions included inferotemporal and parietal areas. Experiment 2 was similar to Experiment 1 except that the stimuli and trial events were identical for the spatial and object tasks; whether spatial or object memory was required was manipulated by instructions. The PET results once more showed a double dissociation, as the spatial task activated primarily right-hemisphere regions (again including occipital, parietal and prefrontal areas), whereas the object task activated only left-hemisphere regions (again including inferotemporal and parietal areas). Experiment 3 was a strictly behavioral study, which produced another double dissociation. It used the same tasks as Experiment 2, and showed that a variation in spatial similarity affected performance in the spatial but not the object task, whereas a variation in shape similarity affected performance in the object but not the spatial task. Taken together, the results of the three experiments clearly imply that different working-memory buffers are used for storing spatial and object information.

Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses

CONTEXT Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology. OBJECTIVE To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects. DESIGN AND SETTING Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting. PARTICIPANTS Twenty healthy men and women aged 20 to 30 years recruited by advertisement. MAIN OUTCOME MEASURES Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia. RESULTS Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects. CONCLUSIONS Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Relationships between biomarkers in aging and dementia.

Background: PET imaging using [18F]fluorodeoxyglucose (FDG) and [11C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. Methods: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as “positive” or “negative” for AD based on cutoffs established in patients with AD and controls from other cohorts. Results: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ1-42 measures (91% agreement, κ = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, κ = 0.50), and minimal agreement for other comparisons (κ <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ1-42, t-tau, and p-tau181p, whereas FDG-PET was correlated only with Aβ1-42. Conclusions: PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [18F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, impacting perceptions and biological processes. Using healthy human subjects, we examined the role of the nucleus accumbens (NAC), a region centrally involved in the encoding of reward expectation, in the formation of placebo responses. Employing functional molecular imaging, activation of NAC dopamine (DA) release was observed during placebo administration and related to its anticipated effects, perception-anticipation mismatches, and placebo effect development. In additional functional MRI studies, the expectation of monetary gain increased NAC synaptic activity in a manner proportional to placebo-induced DA release, anticipated effects, perception-anticipation differentials, and actual placebo effects. Individual variations in NAC response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia.

Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI

The Functional Activities Questionnaire (FAQ) and Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimers disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimers Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.

Compartmental Analysis of [11C]Flumazenil Kinetics for the Estimation of Ligand Transport Rate and Receptor Distribution Using Positron Emission Tomography

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20–30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV“), and thus provides independent estimates of ligand delivery and BZR binding.