Pathological and neurochemical correlates of locus coeruleus functional network activity.

The locus coeruleus (LC) produces the neuromodulators norepinephrine and dopamine, and projects widely to subcortical and cortical brain regions. The LC has been a focus of neuroimaging biomarker development for the early detection of Alzheimer's disease (AD) since it was identified as one of the earliest brain regions to develop tau pathology. Our recent research established the use of positron emission tomography (PET) to measure LC catecholamine synthesis capacity in cognitively unimpaired older adults. We extend this work by investigating the possible influence of pathology and LC neurochemical function on LC network activity using functional magnetic resonance imaging (fMRI). In separate sessions, participants underwent PET imaging to measure LC catecholamine synthesis capacity ([18F]Fluoro-m-tyrosine), tau pathology ([18F]Flortaucipir), and amyloid-ß pathology ([11C]Pittsburgh compound B), and fMRI imaging to measure LC functional network activity at rest. Consistent with a growing body of research in aging and preclinical AD, we find that higher functional network activity is associated with higher tau burden in individuals at risk of developing AD (amyloid-ß positive). Critically, relationships between higher LC network activity and higher pathology (amyloid-ß and tau) were moderated by LC catecholamine synthesis capacity. High levels of LC catecholamine synthesis capacity reduced relationships between higher network activity and pathology. Broadly, these findings support the view that individual differences in functional network activity are shaped by interactions between pathology and neuromodulator function, and point to catecholamine systems as potential therapeutic targets.

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.

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.

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.

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.

Distinct Frontoparietal Networks Underlying Attentional Effort and Cognitive Control.

We investigated the brain activity patterns associated with stabilizing performance during challenges to attention. Our findings revealed distinct patterns of frontoparietal activity and functional connectivity associated with increased attentional effort versus preserved performance during challenged attention. Participants performed a visual signal detection task with and without presentation of a perceptual-attention challenge (changing background). The challenge condition increased activation in frontoparietal regions including right mid-dorsal/dorsolateral PFC (RPFC), approximating Brodmann's area 9, and superior parietal cortex. We found that greater behavioral impact of the challenge condition was correlated with greater RPFC activation, suggesting that increased engagement of cognitive control regions is not always sufficient to maintain high levels of performance. Functional connectivity between RPFC and ACC increased during the challenge condition and was also associated with performance declines, suggesting that the level of synchronized engagement of these regions reflects individual differences in attentional effort. Pretask, resting-state RPFC-ACC connectivity did not predict subsequent performance, suggesting that RPFC-ACC connectivity increased dynamically during task performance in response to performance decrement and error feedback. In contrast, functional connectivity between RPFC and superior parietal cortex not only during the task but also during pretask rest was associated with preserved performance in the challenge condition. Together, these data suggest that resting frontoparietal connectivity predicts performance on attention tasks that rely on those same cognitive control networks and that, under challenging conditions, other control regions dynamically couple with this network to initiate the engagement of cognitive control.

Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility.

Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging. SIGNIFICANCE STATEMENT: Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.

What do phasic cholinergic signals do?

In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection.