Intracranial subsecond dopamine measurements during a "sure bet or gamble" decision-making task in patients with alcohol use disorder suggest diminished dopaminergic signals about relief.

OBJECTIVE: To the authors' knowledge, no data have been reported on dopamine fluctuations on subsecond timescales in humans with alcohol use disorder (AUD). In this study, dopamine release was monitored in 2 patients with and 2 without a history of AUD during a "sure bet or gamble" (SBORG) decision-making task to begin to characterize how subsecond dopamine responses to counterfactual information, related to psychological notions of regret and relief, in AUD may be altered. METHODS: Measurements of extracellular dopamine levels were made once every 100 msec using human voltammetric methods. Measurements were made in the caudate during deep brain stimulation electrode implantation surgeries (for treatment of movement disorders) in patients who did (AUD, n = 2) or did not (non-AUD, n = 2) have a history of AUD. Participants performed an SBORG decision-making task in which they made choices between sure bets and 50%-chance monetary gamble outcomes. RESULTS: Fast changes were found in dopamine levels that appear to be modulated by "what could have been" and by patients' AUD status. Positive counterfactual prediction errors (related to relief) differentiated patients with versus without a history of AUD. CONCLUSIONS: Dopaminergic encoding of counterfactual information appears to differ between patients with and without AUD. The current study has a major limitation of a limited sample size, but these data provide a rare insight into dopaminergic physiology during real-time decision-making in humans with an addiction disorder. The authors hope future work will expand the sample size and determine the generalizability of the current results.

Gamma Knife Stereotactic Radiosurgery favorably changes the clinical course of hemangioblastoma growth in von Hippel-Lindau and sporadic patients.

PURPOSE: This is the first single-institution study of its size to characterize the treatment impact and to address the question of whether hemangioblastoma treatment with Gamma Knife Stereotactic Radiosurgery (GKRS) in both sporadic and VHL patients changes the characteristic saltatory hemangioblastoma growth pattern. METHODS: The authors reviewed a single-institution tumor registry to identify patients who had received GKRS for hemangioblastomas between January 1st, 1999, and December 31st, 2017. RESULTS: 15 patients with 101 lesions met search criteria with a median age of first GKRS of 39.2 years (interquartile range [IQR] of 25.7-57.4 years), including 96 VHL and 5 sporadic lesions. The median time from GKRS to last follow-up was 5.4 years (IQR 2.3-11.5 years). 4 lesions (4%) and 3 patients (20%) experienced a local failure. The 1-year, 3-year, and 5-year freedom from new hemangioblastoma formation rates were 97%, 80%, and 46% respectively. Multivariate analysis revealed a reduction in tumor volume after GKRS. Several variables associated with a greater percent reduction in volume from GKRS to last follow-up: non-cystic status (p = .01), no prior craniotomy (p = .04), and follow-up time from GKRS (p < .0001). CONCLUSIONS: GKRS is a successful long-term treatment option for hemangioblastomas changing the clinical course from saltatory growth to reduction in tumor volume. Non-cystic tumors and those without prior craniotomy were associated with a greater percent reduction in volume from GKRS at last follow-up.

Subjective feelings associated with expectations and rewards during risky decision-making in impulse control disorder.

Impulse Control Disorder (ICD) in Parkinson's disease is a behavioral addiction induced by dopaminergic therapies, but otherwise unclear etiology. The current study investigates the interaction of reward processing variables, dopaminergic therapy, and risky decision-making and subjective feelings in patients with versus without ICD. Patients with (n = 18) and without (n = 12) ICD performed a risky decision-making task both 'on' and 'off' standard-of-care dopaminergic therapies (the task was performed on 2 different days with the order of on and off visits randomized for each patient). During each trial of the task, participants choose between two options, a gamble or a certain reward, and reported how they felt about decision outcomes. Subjective feelings of 'pleasure' are differentially driven by expectations of possible outcomes in patients with, versus without ICD. While off medication, the influence of expectations about risky-decisions on subjective feelings is reduced in patients with ICD versus without ICD. While on medication, the influence of expected outcomes in patients with ICD versus without ICD becomes similar. Computational modeling of behavior supports the idea that latent decision-making factors drive subjective feelings in patients with Parkinson's disease and that ICD status is associated with a change in the relationship between factors associated with risky behavior and subjective feelings about the experienced outcomes. Our results also suggest that dopaminergic medications modulate the impact expectations have on the participants' subjective reports. Altogether our results suggest that expectations about risky decisions may be decoupled from subjective feelings in patients with ICD, and that dopaminergic medications may reengage these circuits and increase emotional reactivity in patients with ICD.

Subsecond fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans.

In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine's role in punishment-learning) has limited direct evidence in humans. We report intracranial, subsecond measurements of dopamine release in human striatum measured, while volunteers (i.e., patients undergoing deep brain stimulation surgery) performed a probabilistic reward and punishment learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors within distinct time intervals via independent valence-specific pathways in the human brain.

Time perception reflects individual differences in motor and non-motor symptoms of Parkinson's disease.

Dopaminergic signaling in the striatum has been shown to play a critical role in the perception of time. Decreasing striatal dopamine efficacy is at the core of Parkinson's disease (PD) motor symptoms and changes in dopaminergic action have been associated with many comorbid non-motor symptoms in PD. We hypothesize that patients with PD perceive time differently and in accordance with their specific comorbid non-motor symptoms and clinical state. We recruited patients with PD and compared individual differences in patients' clinical features with their ability to judge millisecond to second intervals of time (500ms-1100ms) while on or off their prescribed dopaminergic medications. We show that individual differences in comorbid non-motor symptoms, PD duration, and prescribed dopaminergic pharmacotherapeutics account for individual differences in time perception performance. We report that comorbid impulse control disorder is associated with temporal overestimation; depression is associated with decreased temporal accuracy; and PD disease duration and prescribed levodopa monotherapy are associated with reduced temporal precision and accuracy. Observed differences in time perception are consistent with hypothesized dopaminergic mechanisms thought to underlie the respective motor and non-motor symptoms in PD, but also raise questions about specific dopaminergic mechanisms. In future work, time perception tasks like the one used here, may provide translational or reverse translational utility in investigations aimed at disentangling neural and cognitive systems underlying PD symptom etiology. One Sentence Summary: Quantitative characterization of time perception behavior reflects individual differences in Parkinson's disease motor and non-motor symptom clinical presentation that are consistent with hypothesized neural and cognitive mechanisms.

Time perception reflects individual differences in motor and non-motor symptoms of Parkinson's disease.

Decreasing dopaminergic function is at the core of Parkinson's disease (PD) motor symptoms and changes in dopaminergic action are associated with many comorbid non-motor symptoms in PD. Notably, dopaminergic signaling in the striatum has been shown to play a critical role in the perception of time. We hypothesize that patients with PD perceive time differently and in accordance with their specific comorbid non-motor symptoms and clinical state. This means that individual differences in clinical symptoms may be reflected in individual differences in timing behavior. To test this hypothesis, we recruited patients with PD and compared individual differences in patients' clinical state with their ability to judge intervals of time ranging from 500 ms to 1100 ms while on and off their prescribed dopaminergic medications. We show that medication state (on vs. off medications) did not affect timing behavior, but individual differences in timing behavior are able to predict individual differences in comorbid non-motor symptoms, duration of PD diagnosis, and prescribed dopaminergic medications. We show that comorbid impulse control disorder is associated with temporal overestimation; depression is associated with decreased temporal accuracy; and increased PD duration and prescribed levodopa monotherapy are associated with reduced temporal precision and accuracy. Observed differences in time perception are consistent with hypothesized dopaminergic mechanisms thought to underlie the respective motor and non-motor symptoms in PD. In future work, time perception tasks may augment clinical diagnosis strategies, or help disentangle the neural and cognitive mechanisms underlying PD motor and non-motor symptom etiology.

Sub-second Dopamine Signals during Risky Decision-Making in Patients with Impulse Control Disorder.

Background: Impulse Control Disorder (ICD) in Parkinson's disease is a behavioral addiction arising secondary to dopaminergic therapies, most often dopamine receptor agonists. Prior research implicates changes in striatal function and heightened dopaminergic activity in the dorsal striatum of patients with ICD. However, this prior work does not possess the temporal resolution required to investigate dopaminergic signaling during real-time progression through various stages of decision-making involving anticipation and feedback. Methods: We recorded high-frequency (10Hz) measurements of extracellular dopamine in the striatum of patients with (N=3) and without (N=3) a history of ICD secondary to dopamine receptor agonist therapy for Parkinson's disease symptoms. These measurements were made using carbon fiber microelectrodes during awake DBS neurosurgery and while participants performed a sequential decision-making task involving risky investment decisions and real monetary gains and losses. Per clinical standard-of-care, participants withheld all dopaminergic medications prior to the procedure. Results: Patients with ICD invested significantly more money than patients without ICD. On each trial, patients with ICD made smaller adjustments to their investment levels compared to patients without ICD. In patients with ICD, dopamine levels rose or fell on sub-second timescales in anticipation of investment outcomes consistent with increased or decreased confidence in a positive outcome, respectively; dopamine levels in patients without ICD were significantly more stable during this phase. After outcome revelation, dopamine levels in patients with ICD rose significantly more than in inpatients without ICD for better-than-expected gains. For worse-than-expected losses, dopamine levels in patients with ICD remained level whereas dopamine levels in patients without ICD fell. Conclusion: We report significantly increased risky behavior and exacerbated phasic dopamine signaling, on sub-second timescales, anticipating and following the revelation of the outcomes of risky decisions in patients with ICD. Notably, these results were obtained when patients who had demonstrated ICD in the past but were, at the time of surgery, in an off-medication state. Thus, it is unclear whether observed signals reflect an inherent predisposition for ICD that was revealed when dopamine receptor agonists were introduced or whether these observations were caused by the introduction of dopamine receptor agonists and the patients having experienced ICD symptoms in the past. Regardless, future work investigating dopamine's role in human cognition, behavior, and disease should consider the signals this system generates on sub-second timescales.

Intracranial approach for sub-second monitoring of neurotransmitters during DBS electrode implantation does not increase infection rate.

INTRODUCTION: Currently, sub-second monitoring of neurotransmitter release in humans can only be performed during standard of care invasive procedures like DBS electrode implantation. The procedure requires acute insertion of a research probe and additional time in surgery, which may increase infection risk. We sought to determine the impact of our research procedure, particularly the extended time in surgery, on infection risk. METHODS: We screened 602 patients who had one or more procedure codes documented for DBS electrode implantation, generator placement, programming, or revision for any reason performed at Wake Forest Baptist Medical Center between January 2011 through October 2020 using International Classification of Diseases (ICD) codes for infection. During this period, 116 patients included an IRB approved 30-minute research protocol, during the Phase 1 DBS electrode implantation surgery, to monitor sub-second neurotransmitter release. We used Fisher's Exact test (FET) to determine if there was a significant change in the infection rate following DBS electrode implantation procedures that included, versus those that did not include, the neurotransmitter monitoring research protocol. RESULTS: Within 30-days following DBS electrode implantation, infection was observed in 1 (0.21%) out of 486 patients that did not participate in the research procedure and 2 (1.72%) of the 116 patients that did participate in the research procedure. Notably, all types of infection observed were typical of those expected for DBS electrode implantation. CONCLUSION: Infection rates are not statistically different across research and non-research groups within 30-days following the research procedure (1.72% vs. 0.21%; p = 0.0966, FET). Our results demonstrate that the research procedures used for sub-second monitoring of neurotransmitter release in humans can be performed without increasing the rate of infection.

Computational reinforcement learning, reward (and punishment), and dopamine in psychiatric disorders.

In the DSM-5, psychiatric diagnoses are made based on self-reported symptoms and clinician-identified signs. Though helpful in choosing potential interventions based on the available regimens, this conceptualization of psychiatric diseases can limit basic science investigation into their underlying causes. The reward prediction error (RPE) hypothesis of dopamine neuron function posits that phasic dopamine signals encode the difference between the rewards a person expects and experiences. The computational framework from which this hypothesis was derived, temporal difference reinforcement learning (TDRL), is largely focused on reward processing rather than punishment learning. Many psychiatric disorders are characterized by aberrant behaviors, expectations, reward processing, and hypothesized dopaminergic signaling, but also characterized by suffering and the inability to change one's behavior despite negative consequences. In this review, we provide an overview of the RPE theory of phasic dopamine neuron activity and review the gains that have been made through the use of computational reinforcement learning theory as a framework for understanding changes in reward processing. The relative dearth of explicit accounts of punishment learning in computational reinforcement learning theory and its application in neuroscience is highlighted as a significant gap in current computational psychiatric research. Four disorders comprise the main focus of this review: two disorders of traditionally hypothesized hyperdopaminergic function, addiction and schizophrenia, followed by two disorders of traditionally hypothesized hypodopaminergic function, depression and post-traumatic stress disorder (PTSD). Insights gained from a reward processing based reinforcement learning framework about underlying dopaminergic mechanisms and the role of punishment learning (when available) are explored in each disorder. Concluding remarks focus on the future directions required to characterize neuropsychiatric disorders with a hypothesized cause of underlying dopaminergic transmission.

Diminished single-stimulus response in vmPFC to favorite people in children diagnosed with Autism Spectrum Disorder.

From an early age, individuals with autism spectrum disorder (ASD) spend less time engaged in social interaction compared to typically developing peers (TD). One reason behind this behavior may be that the brains of children diagnosed with ASD do not attribute enough value to potential social exchanges as compared to the brains of typically developing children; thus, potential social exchanges are avoided because other environmental stimuli are more highly valued by default. Neurobiological investigations into the mechanisms underlying value-based decision-making has shown that the ventral medial prefrontal cortex (vmPFC) is critical for encoding the expected outcome value of different actions corresponding to distinct environmental cues. Here, we tested the hypothesis that the responsiveness of the vmPFC in children diagnosed with ASD (compared to TD controls) is diminished for visual cues that represent highly valued social interaction. Using a passive picture viewing task and functional magnetic resonance imaging (fMRI) we measured the response of an a priori defined region of interest in the vmPFC in children diagnosed with ASD and an age-matched TD cohort. We show that the average response of the vmPFC is significantly diminished in the ASD group. Further, we demonstrate that a single-stimulus and less than 30 s of fMRI data are sufficient to differentiate the ASD and TD cohorts. These findings are consistent with the hypothesis that the brains of children with ASD do not encode the value of social exchange in the same manner as TD children. The latter finding suggests the possibility of utilizing single-stimulus fMRI as a potential biologically based diagnostic tool to augment traditional clinical approaches.