Sarah A. Eisenstein

A comparison of D2 receptor specific binding in obese and normal‐weight individuals using PET with (N‐[11C]methyl)benperidol

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R‐selective radioligand (N‐[11C] methyl)benperidol ([11C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal‐weight (mean BMI = 22.6 kg/m2) and 15 obese (mean BMI = 40.3 kg/m2) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal‐weight and obese groups. BMI values did not correlate with D2R BPND. Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity. Synapse 67:748–756, 2013..

Early Brain Vulnerability in Wolfram Syndrome

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

Functional anatomy of subthalamic nucleus stimulation in Parkinson disease

We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3‐dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.

Characterization of extrastriatal D2 in vivo specific binding of [18F](N‐methyl)benperidol using PET

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near‐equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [18F]N‐methylbenperidol ([18F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [18F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR‐PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [18F]NMB injection. Regional peak radioactivity was identified using a peak‐finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individuals MR image and tissue activity curves were extracted from coregistered PET images. [18F]NMB binding potentials (BPNDs) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BPND estimates were compared between Logan graphical methods and a three‐compartment kinetic tracer model. Radioactivity and BPND levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BPNDs. BPND estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [18F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states. Synapse 66:770–780, 2012.

Insulin, central dopamine D2 receptors, and monetary reward discounting in obesity

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans.

Emotional eating phenotype is associated with central dopamine D2 receptor binding independent of body mass index

PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[11C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10–14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R‐selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis

BACKGROUND Deep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood. OBJECTIVE The study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS. METHODS Thirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal. RESULTS STN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS. CONCLUSIONS PD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group.

Sweet dopamine: Sucrose preferences relate differentially to striatal D2 receptor binding and age in obesity

Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships between these variables and the impact of obesity on these relationships may reveal insight into the neurobiological basis of sweet preferences. We evaluated sucrose preferences, perception of sweetness intensity, and striatal D2R binding potential (D2R BPND) using positron emission tomography with a D2R-selective radioligand insensitive to endogenous dopamine, (N-[11C] methyl)benperidol, in 20 subjects without obesity (BMI 22.5 ± 2.4 kg/m2; age 28.3 ± 5.4 years) and 24 subjects with obesity (BMI 40.3 ± 5.0 kg/m2; age 31.2 ± 6.3 years). The groups had similar sucrose preferences, sweetness intensity perception, striatal D2R BPND, and age-related D2R BPND declines. However, both striatal D2R BPND and age correlated with sucrose preferences in subjects without obesity, explaining 52% of their variance in sucrose preference. In contrast, these associations were absent in the obese group. In conclusion, the age-related decline in D2R was not linked to the age-related decline in sweetness preferences, suggesting that other, as-yet-unknown mechanisms play a role and that these mechanisms are disrupted in obesity.

Mapping movement, mood, motivation and mentation in the subthalamic nucleus

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinsons disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patients clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially.