Association of Psychiatric Emergency Visits and Warm Ambient Temperature during Pregnancy: A Time-Stratified Case-Crossover Study.

BACKGROUND: Acute exposure to high ambient temperature and heat waves during the warm season has been linked with psychiatric disorders. Emerging research has shown that pregnant people, due to physiological and psychological changes, may be more sensitive to extreme heat, and acute exposure has been linked to increased risk of pregnancy complications; however, few studies have examined psychiatric complications. OBJECTIVE: Our objective was to examine the association between acute exposure to warm ambient temperatures and emergency department (ED) visits for mental disorders during pregnancy. METHODS: A time-stratified case-crossover design with conditional logistic regression was performed on ∼206,000 psychiatric ED visits for pregnant patients in North Carolina, from May to September 2016 to 2019. Daily average ambient temperature was the main exposure and was linked to daily visits by maternal zip code of residence for prenatal mood and anxiety disorders (PMAD), severe mental illness (SMI), mental disorder of pregnancy (MDP), suicidal thoughts (SUIC), and any psychiatric disorder (Any). Effect modification by trimester, residential segregation, economic segregation, urbanicity, and availability of greenspace was also investigated. RESULTS: Each 5°C increase in same-day exposure to warm ambient temperature on case days was associated with an increase in incidence rate ratio (IRR) for any psychiatric disorder [IRR = 1.07; 95% confidence interval (CI): 1.01, 1.14] including anxiety (IRR = 1.14; 95% CI: 1.00, 1.30), bipolar disorder (IRR = 1.28; 95% CI: 0.98, 1.67), and suicidal thoughts (IRR = 1.28; 95% CI: 1.00, 1.65) compared to control days. In general, the associations were strongest for warm season temperatures on the same day of exposure or for temperatures averaged over the 3 or 6 d preceding the ED visit. The greatest risk of an incident ED admission for PMAD (RR = 1.20; 95% CI: 1.04, 1.39), particularly for anxiety (RR = 1.30; 95% CI: 1.07, 1.59), and any psychiatric disorder (RR = 1.17; 95% CI: 1.07, 1.28) occurred following cumulative exposure to hot temperatures the week before admission. Higher psychiatric burden from temperature was observed in urban areas and on extreme heat days. CONCLUSIONS: For this pregnant population in the southeastern United States, short-term exposure to high ambient temperatures during the warm season was associated with a greater risk of ED visits for an array of psychiatric disorders. Findings show that climate-related increases in ambient temperature may contribute to psychiatric morbidity in pregnant people. https://doi.org/10.1289/EHP13293.

DAT1 and BDNF polymorphisms interact to predict Aß and tau pathology.

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal ß-amyloid (Aß) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aß-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease. However, it is unclear to what extent LC structure reflects underlying catecholamine function, and how LC structure and neurochemical function are collectively associated with cognitive performance. Methods: A partial least squares correlation (PLSC) analysis was applied to 19 participants' LC structural MRI measures and catecholamine synthesis capacity measures assessed using [18F]Fluoro-m-tyrosine ([18F]FMT) positron emission tomography (PET). Results: We found no direct association between LC-MRI and LC-[18F]FMT measures for rostral, middle, or caudal portions of the LC. We found significant associations between LC neuroimaging measures and neuropsychological performance that were driven by rostral and middle portions of the LC, which is in line with LC cortical projection patterns. Specifically, associations with executive function and processing speed arose from contributions of both LC structure and interactions between LC structure and catecholamine synthesis capacity. Conclusion: These findings leave open the possibility that LC MRI and PET measures contribute unique information and suggest that their conjoint use may increase sensitivity to brain-behavior associations in small samples.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and ß-amyloid (Aß) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality. Objective: To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023. Study Selection: English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available. Main Outcomes and Measures: Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms. Results: A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339). Conclusions and Relevance: No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.

New perspectives on the basal forebrain cholinergic system in Alzheimer's disease.

The basal forebrain cholinergic system (BFCS) has long been implicated in age-related cognitive changes and the pathophysiology of Alzheimer's disease (AD). Limitations of cholinergic interventions helped to inspire a shift away from BFCS in AD research. A resurgence in interest in the BFCS following methodological and analytical advances has resulted in a call for the BFCS to be examined in novel frameworks. We outline the basic structure and function of the BFCS, its role in supporting cognitive and affective function, and its vulnerability to aging and AD. We consider the BFCS in the context of the amyloid hypothesis and evolving concepts in AD research: resilience and resistance to pathology, selective neuronal vulnerability, trans-synaptic pathology spread and sleep health. We highlight 1) the potential role of the BFCS in cognitive resilience, 2) recent work refining understanding about the selective vulnerability of BFCS to AD, 3) BFCS connectivity that suggests it is related to tau spreading and neurodegeneration and 4) the gap between BFCS involvement in AD and sleep-wake cycles.

An integrative effort: Bridging motivational intensity theory and recent neurocomputational and neuronal models of effort and control allocation.

An increasing number of cognitive, neurobiological, and computational models have been proposed in the last decade, seeking to explain how humans allocate physical or cognitive effort. Most models share conceptual similarities with motivational intensity theory (MIT), an influential classic psychological theory of motivation. Yet, little effort has been made to integrate such models, which remain confined within the explanatory level for which they were developed, that is, psychological, computational, neurobiological, and neuronal. In this critical review, we derive novel analyses of three recent computational and neuronal models of effort allocation-the expected value of control theory, the reinforcement meta-learner (RML) model, and the neuronal model of attentional effort-and establish a formal relationship between these models and MIT. Our analyses reveal striking similarities between predictions made by these models, with a shared key tenet: a nonmonotonic relationship between perceived task difficulty and effort, following a sawtooth or inverted U shape. In addition, the models converge on the proposition that the dorsal anterior cingulate cortex may be responsible for determining the allocation of effort and cognitive control. We conclude by discussing the distinct contributions and strengths of each theory toward understanding neurocomputational processes of effort allocation. Finally, we highlight the necessity for a unified understanding of effort allocation, by drawing novel connections between different theorizing of adaptive effort allocation as described by the presented models. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

A Mouse Model with Ablated Asparaginase and Isoaspartyl Peptidase 1 (Asrgl1) Develops Early Onset Retinal Degeneration (RD) Recapitulating the Human Phenotype.

We previously identified a homozygous G178R mutation in human ASRGL1 (hASRGL1) through whole-exome analysis responsible for early onset retinal degeneration (RD) in patients with cone-rod dystrophy. The mutant G178R ASRGL1 expressed in Cos-7 cells showed altered localization, while the mutant ASRGL1 in E. coli lacked the autocatalytic activity needed to generate the active protein. To evaluate the effect of impaired ASRGL1 function on the retina in vivo, we generated a mouse model with c.578_579insAGAAA (NM_001083926.2) mutation (Asrgl1mut/mut) through the CRISPR/Cas9 methodology. The expression of ASGRL1 and its asparaginase activity were undetectable in the retina of Asrgl1mut/mut mice. The ophthalmic evaluation of Asrgl1mut/mut mice showed a significant and progressive decrease in scotopic electroretinographic (ERG) response observed at an early age of 3 months followed by a decrease in photopic response around 5 months compared with age-matched wildtype mice. Immunostaining and RT-PCR analyses with rod and cone cell markers revealed a loss of cone outer segments and a significant decrease in the expression of Rhodopsin, Opn1sw, and Opn1mw at 3 months in Asrgl1mut/mut mice compared with age-matched wildtype mice. Importantly, the retinal phenotype of Asrgl1mut/mut mice is consistent with the phenotype observed in patients harboring the G178R mutation in ASRGL1 confirming a critical role of ASRGL1 in the retina and the contribution of ASRGL1 mutations in retinal degeneration.

Associations among locus coeruleus catecholamines, tau pathology, and memory in aging.

The locus coeruleus (LC) is the brain's major source of the neuromodulator norepinephrine, and is also profoundly vulnerable to the development of Alzheimer's disease (AD)-related tau pathology. Norepinephrine plays a role in neuroprotective functions that may reduce AD progression, and also underlies optimal memory performance. Successful maintenance of LC neurochemical function represents a candidate mechanism of protection against the propagation of AD-related pathology and may facilitate the preservation of memory performance despite pathology. Using [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure catecholamine synthesis capacity in LC regions of interest, we examined relationships among LC neurochemical function, AD-related pathology, and memory performance in cognitively normal older adults (n = 49). Participants underwent [11C]Pittsburgh compound B and [18F]Flortaucipir PET to quantify ß-amyloid (n = 49) and tau burden (n = 42) respectively. In individuals with substantial ß-amyloid, higher LC [18F]FMT net tracer influx (Kivis) was associated with lower temporal tau. Longitudinal tau-PET analyses in a subset of our sample (n = 30) support these findings to reveal reduced temporal tau accumulation in the context of higher LC [18F]FMT Kivis. Higher LC catecholamine synthesis capacity was positively correlated with self-reported cognitive engagement and physical activity across the lifespan, established predictors of successful aging measured with the Lifetime Experiences Questionnaire. LC catecholamine synthesis capacity moderated tau's negative effect on memory, such that higher LC catecholamine synthesis capacity was associated with better-than-expected memory performance given an individual's tau burden. These PET findings provide insight into the neurochemical mechanisms of AD vulnerability and cognitive resilience in the living human brain.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.

Making the jump: Expert guidance on transitioning to academic independence.

Obtaining a position as an independent investigator is a daunting prospect, and often requires skill sets that are not emphasized during graduate or postdoctoral training. Here, we present insight from a seminar series designed to guide young researchers looking to "make the jump", covering the fundamental steps of the job search (preparation of an application package, Skype/remote interview, campus visit, and negotiations). We summarize the many useful insights distilled throughout these roundtable sessions with the goal of providing information and guidance to a broader community of researchers on the best way to prepare for and tackle the faculty job market.

Poor Sleep Quality and Compromised Visual Working Memory Capacity.

OBJECTIVES: Reduction in the amount of information (storage capacity) retained in working memory (WM) has been associated with sleep loss. The present study examined whether reduced WM capacity is also related to poor everyday sleep quality and, more importantly, whether the effects of sleep quality could be dissociated from the effects of depressed mood and age on WM. METHODS: In two studies, WM was assessed using a short-term recall task, producing behavioral measures for both the amount of retained WM information (capacity) and how precise the retained WM representations were (precision). Self-report measures of sleep quality and depressed mood were obtained using questionnaires. RESULTS: In a sample of college students, Study 1 found that poor sleep quality and depressed mood could independently predict reduced WM capacity, but not WM precision. Study 2 generalized these sleep- and mood-related WM capacity effects to a community sample (aged 21-77 years) and further showed that age was associated with reduced WM precision. CONCLUSIONS: Together, these findings demonstrate dissociable effects of three health-related factors (sleep, mood, and age) on WM representations and highlighte the importance of assessing different aspects of WM representations (e.g., capacity and precision) in future neuropsychological research.

Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety.

Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [11C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [11C]raclopride PET scans per participant. We contrasted baseline [11C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [11C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.SIGNIFICANCE STATEMENT It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.

Age-related variability in decision-making: Insights from neurochemistry.

Despite dopamine's significant role in models of value-based decision-making and findings demonstrating loss of dopamine function in aging, evidence of systematic changes in decision-making over the life span remains elusive. Previous studies attempting to resolve the neural basis of age-related alteration in decision-making have typically focused on physical age, which can be a poor proxy for age-related effects on neural systems. There is growing appreciation that aging has heterogeneous effects on distinct components of the dopamine system within subject in addition to substantial variability between subjects. We propose that some of the conflicting findings in age-related effects on decision-making may be reconciled if we can observe the underlying dopamine components within individuals. This can be achieved by incorporating in vivo imaging techniques including positron emission tomography (PET) and neuromelanin-sensitive MR. Further, we discuss how affective factors may contribute to individual differences in decision-making performance among older adults. Specifically, we propose that age-related shifts in affective attention ("positivity effect") can, in some cases, counteract the impact of altered dopamine function on specific decision-making processes, contributing to variability in findings. In an effort to provide clarity to the field and advance productive hypothesis testing, we propose ways in which in vivo dopamine imaging can be leveraged to disambiguate dopaminergic influences on decision-making, and suggest strategies for assessing individual differences in the contribution of affective attentional focus.

The Influence of Dopamine on Cognitive Flexibility Is Mediated by Functional Connectivity in Young but Not Older Adults.

Dopaminergic signaling in striatum is strongly implicated in executive functions including cognitive flexibility. However, there is a paucity of multimodal research in humans defining the nature of relationships between endogenous dopamine, striatal network activity, and cognition. Here, we measured dopamine synthesis capacity in young and older adults using the PET tracer 6-[18F]fluoro-l- m-tyrosine and examined its relationship with cognitive performance and functional connectivity during an fMRI study of task switching. Aging is associated with alteration in dopamine function, including profound losses in dopamine receptors but an apparent elevation in dopamine synthesis. A compensatory benefit of upregulated dopamine synthesis in aging has not been established. Across young and older adults, we found that cognitive flexibility (low behavioral switch cost) was associated with stronger task-related functional connectivity within canonical fronto-striato-thalamic circuits connecting left inferior frontal gyrus, dorsal caudate nucleus (DCA) and ventral lateral/ventral anterior thalamic nuclei. In young adults, functional connectivity mediated the influence of DCA dopamine synthesis capacity on switch cost. For older adults, these relationships were modified such that DCA synthesis capacity and connectivity interacted to influence switch cost. Older adults with most elevated synthesis capacity maintained the pattern of connectivity-cognition relationships observed in youth, whereas these relationships were not evident for older adults with low synthesis capacity. Together, these findings suggest a role of dopamine in tuning striatal circuits to benefit executive function in young adults and clarify the functional impact of elevated dopamine synthesis capacity in aging.

Spontaneous eye blink rate and dopamine synthesis capacity: preliminary evidence for an absence of positive correlation.

Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioural proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies. Yet, this hypothesis has not been validated using in vivo measures of dopamine function in humans. To fill this gap, we measured sEBR and striatal dopamine synthesis capacity using [18 F]DOPA PET in 20 participants (nine healthy individuals and 11 pathological gamblers). Our results, based on frequentist and Bayesian statistics, as well as region-of-interest and voxel-wise analyses, argue against a positive relationship between sEBR and striatal dopamine synthesis capacity. They show that, if anything, the evidence is in favour of a negative relationship. These results, which complement findings from a recent study that failed to observe a relationship between sEBR and dopamine D2 receptor availability, suggest that caution and nuance are warranted when interpreting sEBR in terms of a proxy measure of striatal dopamine.

Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release.

Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (Ki) using 6-[18F]fluoro-l-m-tyrosine ([18F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [11C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [11C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [18F]FMT Ki and the baseline (placebo) [11C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [18F]FMT and methylphenidate-induced [11C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.

Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction.

BACKGROUND: The hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects. METHODS: This was achieved using [18F]fluoro-levo-dihydroxyphenylalanine dynamic positron emission tomography scans and striatal regions of interest that were hand-drawn based on visual inspection of individual structural magnetic resonance imaging scans. RESULTS: Our results show that dopamine synthesis capacity was increased in pathological gamblers compared with healthy control subjects. Dopamine synthesis was 16% higher in the caudate body, 17% higher in the dorsal putamen, and 17% higher in the ventral striatum in pathological gamblers compared with control subjects. Moreover, dopamine synthesis capacity in the dorsal putamen and caudate head was positively correlated with gambling distortions in pathological gamblers. CONCLUSIONS: Taken together, these results provide empirical evidence for increased striatal dopamine synthesis in pathological gambling.