Sub-second fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans

Sands, Paul; Jiang, Angela; Liebenow, Brittany; DiMarco, Emily; Laxton, Adrian W.; Tatter, Stephen B.; Montague, Read; Kishida, Kenneth T.

doi:10.1101/2023.02.24.529709

Cited by 3 publications

(3 citation statements)

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“…According to the canonical view, the mesocorticolimbic system is responsible for signaling both the reward value and associated expectations. However, recent evidence 19,58 and our human fMRI 59,60 and rodent studies 61,62 implicate this circuit in aversive states and chronic pain. Yet, aversion-related mesocorticolimbic adaptations with long-term opioid exposure remain unknown 29 .…”

Section: Discussionmentioning

confidence: 77%

Neuropsychology of chronic back pain managed with long-term opioid use

Baliki,

Vigotsky,

Rached

et al. 2024

Preprint

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Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits’ dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.

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Section: Discussionmentioning

confidence: 77%

Neuropsychology of chronic back pain managed with long-term opioid use

Baliki,

Vigotsky,

Rached

et al. 2024

Preprint

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“…FSCV is a method for measuring the fluctuations of dopamine, serotonin, and norepinephrine concentrations in human brain tissue [21][22][23][24][25][26][27] . For the current report, FSCV recordings were made during 15 DBS surgeries while study participants (N = 9) played 60 rounds of the ultimatum game 28,29 approximately 10 minutes after a PFC biopsy was obtained.…”

Section: Identification Of Fscv De Signaturesmentioning

confidence: 99%

Multiomic foundations of human prefrontal cortex tissue function

Kopell,

Kaji,

Liharska

et al. 2024

Preprint

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The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations -- termed the "transcriptional program associated with neurotransmission" (TPAWN) -- were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

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“…This knowledge gap of how DA neurons integrate information about reward expectation and reward into RPEs is particularly salient in the human literature, due to difficulties of recording activity from deep DA nuclei in living humans. Previous studies have leveraged neurosurgical interventions to examine human dopaminergic activity using microelectrode recordings to record single unit activity from the SN 6,7 , or voltammetry approaches to record dopamine transients in the striatum [19][20][21] . These studies have demonstrated that post-reward activity in the human dopaminergic system reflects reward signals, including unexpected rewards and RPEs.…”

Section: Introductionmentioning

confidence: 99%

Human Substantia Nigra Neurons Encode Reward Expectations

Imtiaz,

Kato,

Kopell

et al. 2024

Preprint

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Dopamine (DA) signals originating from substantia nigra (SN) neurons are centrally involved in the regulation of motor and reward processing. DA signals behaviorally relevant events where reward outcomes differ from expectations (reward prediction errors, RPEs). RPEs play a crucial role in learning optimal courses of action and in determining response vigor when an agent expects rewards. Nevertheless, how reward expectations, crucial for RPE calculations, are conveyed to and represented in the dopaminergic system is not fully understood, especially in the human brain where the activity of DA neurons is difficult to study. One possibility, suggested by evidence from animal models, is that DA neurons explicitly encode reward expectations. Alternatively, they may receive RPE information directly from upstream brain regions. To address whether SN neuron activity directly reflects reward expectation information, we directly examined the encoding of reward expectation signals in human putative DA neurons by performing single-unit recordings from the SN of patients undergoing neurosurgery. Patients played a two-armed bandit decision-making task in which they attempted to maximize reward. We show that neuronal firing rates (FR) of putative DA neurons during the reward expectation period explicitly encode reward expectations. First, activity in these neurons was modulated by previous trial outcomes, such that FR were greater after positive outcomes than after neutral or negative outcome trials. Second, this increase in FR was associated with shorter reaction times, consistent with an invigorating effect of DA neuron activity during expectation. These results suggest that human DA neurons explicitly encode reward expectations, providing a neurophysiological substrate for a signal critical for reward learning.

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Sub-second fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans

Cited by 3 publications

References 60 publications

Neuropsychology of chronic back pain managed with long-term opioid use

Neuropsychology of chronic back pain managed with long-term opioid use

Multiomic foundations of human prefrontal cortex tissue function

Human Substantia Nigra Neurons Encode Reward Expectations

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