Terry Lohrenz

At the foundation of neurotransmission, and by extension at the foundation of brain function, are coordinated programs of gene expression involving many thousands of genes. These programs are poorly defined in humans because most modern studies that characterize human brain gene expression use tissue obtained in the postmortem state when neurotransmission and brain function have ceased. Here, to advance knowledge of the gene expression programs at the foundation of neurotransmission in the human brain, gene expression was characterized in 130 prefrontal cortex (PFC) samples obtained from participants of the Living Brain Project (LBP) during neurosurgical procedures in conjunction with intracranial recordings of neurotransmission traits in deep brain structures. In a group of 15 procedures, participants performed a cognitive task during intracranial recordings of the substantia nigra; in the remaining group of 115 procedures, participants were at rest during intracranial recordings of either the subthalamic nucleus or the globus pallidus. Analyses of the data obtained from the group of 15 procedures, though underpowered to identify individual gene-trait associations, uncovered evidence of transcriptome-wide signatures of PFC gene expression that associated with neurotransmission traits. These signatures were reproduced in analyses of data from the group of 115 procedures and in analyses of data from a third independent human cohort. A set of genes with evidence of association to neurotransmission in multiple cohorts was termed the “transcriptional program associated with neurotransmission” (TPAWN) and analyses of data from studies of model systems and genetic variation in human populations validated the role of TPAWN genes in neurotransmission and brain function. In PFC excitatory neurons of LBP participants, higher expression of TPAWN genes tracked with higher expression of genes that in mouse frontal cortex are markers of excitatory neurons that connect the frontal cortex to deep brain structures. Taken together, the findings of this report help advance knowledge of the transcriptomic foundations of neurotransmission in the living human brain.

Biogenic amines are fundamental for physiological homeostasis and behavioral control in both vertebrates and invertebrates. Monoamine neurotransmitters released in target brain regions conjointly regulate adaptive learning and plasticity. However, our understanding of these multianalyte mechanisms remains nascent, in part due to limitations in measurement technology. Here, during associative conditioning in honey bees, we concurrently tracked subsecond fluctuations in octopamine, tyramine, dopamine, and serotonin in the antennal lobe, where plasticity influences odorant representations. By repeatedly pairing an odorant with subsequent sucrose delivery, we observed individual differences in the conditioned response to odor, which occurred after a variable number of pairings (learners) or not at all (non-learners). The distinction between learners and non-learners was reflected in neurotransmitter responses across experimental conditions. The speed of learning, the number of pairings prior to a proboscis extension reflex, could be predicted from monoamine opponent signaling (octopamine-tyramine), from both the first presentation of the odorant alone, prior to any pairing with sucrose, and the first conditioned response to the odorant, coming after a number of sucrose pairings. These results suggest that monoamine signaling phenotypes may relate directly to the now widely reported socially relevant genetic differences in honey bee learning.

Recent advances in deep brain stimulation (DBS) of the subcallosal cingulate (SCC) show promise in mitigating the symptoms of treatment-resistant depression (TRD) in humans ^1–3 . Monoamines, such as dopamine and serotonin, mediate the effects of pharmacological treatments of depression. However, their roles in recovery following DBS remain elusive, largely due to technical limitations of measuring these neurotransmitters in the living human brain. Here, by leveraging machine learning-enhanced electrochemistry ^4–7 , we show that dopamine and serotonin signaling following DBS to the SCC predicted later depressive symptom relief in humans with TRD. We found that both dopamine and serotonin levels increased following subtherapeutic intraoperative SCC stimulation, with each neurotransmitter showing selective responses to distinct decision-making tasks. Furthermore, acute dopamine increases predicted later mood improvements during a social decision-making task, while serotonin enhancement predicted faster responses during a non-social learning task longitudinally. Critically, changes in dopamine and serotonin levels during the social decision-making task jointly predicted depressive symptom remission at 6-month follow-up. These findings illustrate the contribution of both dopamine and serotonin signaling in predicting behavioral improvement and depressive symptom remission in humans with TRD. Such neurochemical plasticity may serve as potential mechanistic biomarkers for SCC DBS mechanism and TRD treatment response. Significance statement: Dopamine and serotonin levels increased following acute DBS to the SCC in humans. Acute dopamine and serotonin changes predicted later mood and response speed changes. Sustained TRD recovery was predicted by acute increases in both dopamine and serotonin estimates.

Dynamic changes in dopamine, noradrenaline, and serotonin release are believed to causally contribute to the neural computations that support reward-based decision making. Accordingly, changes in signaling by these systems are hypothesized to underwrite multiple cognitive and behavioral symptoms observed in many neurological disorders. Here, we characterize the release of these neurotransmitters measured concurrently in the caudate of patients with Parkinson's disease or essential tremor undergoing deep brain stimulation surgery as they played a social exchange game. We show that violations in the expected value of monetary offers are encoded by opponent patterns of dopamine and serotonin release in essential tremor, but not Parkinson's disease, patients. We also demonstrate that these changes in serotonin signaling comprise a neurochemical boundary that subsegments these two neuromotor diseases. Our combined results point to a neural signature of altered reward processing that can be used to understand the signaling deficiencies that underwrite these diseases.

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson’s disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value—akin to reward prediction errors—whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia’s main output structures reflect distinct social context and value signals.

Humans tend to discount information that undermines past choices and judgments. This confirmation bias has significant impact on domains ranging from politics to science and education. Little is known about the mechanisms underlying this fundamental characteristic of belief formation. Here we report a mechanism underlying the confirmation bias. Specifically, we provide evidence for a failure to use the strength of others’ disconfirming opinions to alter confidence in judgments, but adequate use when opinions are confirmatory. This bias is related to reduced neural sensitivity to the strength of others’ opinions in the posterior medial prefrontal cortex when opinions are disconfirming. Our results demonstrate that existing judgments alter the neural representation of information strength, leaving the individual less likely to alter opinions in the face of disagreement.

Early childhood educational investment produces positive effects on cognitive and non-cognitive skills, health, and socio-economic success. However, the effects of such interventions on social decision-making later in life are unknown. We recalled participants from one of the oldest randomized controlled studies of early childhood investment—the Abecedarian Project (ABC)—to participate in well-validated interactive economic games that probe social norm enforcement and planning. We show that in a repeated-play ultimatum game, ABC participants who received high-quality early interventions strongly reject unequal division of money across players (disadvantageous or advantageous) even at significant cost to themselves. Using a multi-round trust game and computational modeling of social exchange, we show that the same intervention participants also plan further into the future. These findings suggest that high quality early childhood investment can result in long-term changes in social decision-making and promote social norm enforcement in order to reap future benefits.

Cooperation and competition between human players in repeated microeconomic games offer a window onto social phenomena such as the establishment, breakdown and repair of trust. However, although a suitable starting point for the quantitative analysis of such games exists, namely the Interactive Partially Observable Markov Decision Process (I-POMDP), computational considerations and structural limitations have limited its application, and left unmodelled critical features of behavior in a canonical trust task. Here, we provide the first analysis of two central phenomena: a form of social risk-aversion exhibited by the player who is in control of the interaction in the game; and irritation or anger, potentially exhibited by both players. Irritation arises when partners apparently defect, and it potentially causes a precipitate breakdown in cooperation. Failing to model one’s partner’s propensity for it leads to substantial economic inefficiency. We illustrate these behaviours using evidence drawn from the play of large cohorts of healthy volunteers and patients. We show that for both cohorts, a particular subtype of player is largely responsible for the breakdown of trust, a finding which sheds new light on borderline personality disorder. In multi-round games in which players can benefit by trusting each other, swift and catastrophic breakdowns can arise amidst otherwise efficient cooperation. We present a model that quantifies this as a form of anger, and we exploit novel algorithmic improvements in inference based on the model to examine exchanges involving healthy volunteers and people suffering from personality disorders. This provides a new view on the problems that can underlie social interactions.