Biology subjects

Kishida, K. T.

Publications and source records attributed to Kishida, K. T..

8 recordsLinked to original sources

bioRxiv2025

Dopamine and serotonin transients predict depressive symptom relief following deep brain stimulation of human subcallosal cingulate cortex

Recent advances in deep brain stimulation (DBS) of the subcallosal cingulate (SCC) show promise in mitigating the symptoms of treatment-resistant depression (TRD) in humans1-3. 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 electrochemistry4-7, 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 statementO_LIDopamine and serotonin levels increased following acute DBS to the SCC in humans. C_LIO_LIAcute dopamine and serotonin changes predicted later mood and response speed changes. C_LIO_LISustained TRD recovery was predicted by acute increases in both dopamine and serotonin estimates. C_LI

neuroscience↗

bioRxiv2025

Striatal dopamine modulates reward-reinforced temporal learning in humans.

The neurobiological mechanisms underlying human time perception remain elusive. Evidence has consistently linked striatal dopamine to timing behaviors, but it is still uncertain how rapid changes in dopamine may modulate human time perception. Many tasks designed to measure time perception utilize instrumental conditioning paradigms that reinforce correctly timed intervals. In these tasks, subjects are shown to improve their performance following repeated presentations of temporal cues - a phenomenon known as temporal learning. We sought to determine the association between rapid changes in human dopamine levels and temporal learning on an interval timing task that tested the reproduction of 1000ms, 3000ms, and 5000ms intervals in the presence and absence of monetary reinforcement. We utilized human voltammetry to measure real-time dopamine concentrations from the striatum of patients with Parkinsons disease while they performed the interval timing task. We first compared task behavior between patients with Parkinsons disease and neurologically healthy controls and found significant differences in the reproduction of 1000ms intervals, but not 3000ms or 5000ms intervals of time. Further, we observed that during 1000ms intervals, increases in striatal dopamine concentrations were associated with increases in temporal errors, but only during the expectation of monetary reinforcement. We also demonstrated that as temporal errors decrease overtime during temporal learning, so do striatal dopamine concentrations. These results suggest that dopamine may be driving temporal learning through the generation of temporal errors in response to positive reinforcement. These findings may have significant implications in our understanding of the role that dopamine plays in time perception. Significance StatementHuman time perception is a fundamental cognitive ability but the interaction between how the human brain perceives time and dopamines role is unclear. This study is the first of its kind to apply human voltammetry to measure rapid changes in dopamine levels associated with temporal learning in the presence and absence of positive reinforcement. We demonstrate that temporal learning may be affected by moment-to-moment changes in dopamine levels, which are also counterintuitively related to the generation of temporal errors in the presence of expectations of rewarding feedback.

neuroscience↗

bioRxiv2024

Expected reward value and reward prediction errors reinforce but also interfere with human time perception.

Time perception is often investigated in animal models and in humans using instrumental paradigms where reinforcement learning (RL) and associated dopaminergic processes have modulatory effects. For example, interval timing, which includes the judgment of relatively short intervals of time (ranging from milliseconds to minutes), has been shown to be modulated by manipulations of striatal dopamine. The expected value of reward (EV) and reward prediction errors (RPEs) are key variables described in RL-theory that explain dopaminergic signals during reward processing during instrumental learning. Notably, the underlying connection between RL-processes and time perception in humans is relatively underexplored. Herein, we investigated the impact of EV and RPEs on interval timing in humans. We tested the hypotheses that EV and RPEs modulate the experience of short time intervals. We demonstrate that expectations of monetary gains or losses increases the initial performance error for 1000ms intervals. Temporal learning over repeated trials is observed with accelerated learning of non-reinforced 1000ms intervals; however, RPEs - specifically about rewards and not punishments - appear to reinforce performance errors, which effectively interferes with the rate at which (reinforced) 1000ms intervals were learned. These effects were not significant for 3000ms and 5000ms intervals. Our results demonstrate that EV and RPEs influence human behavior about 1000ms time intervals. We discuss our results considering model-free temporal difference RL-theory, which suggests the hypothesis that interval timing may be mediated by dopaminergic signals that reinforce the learning and prediction of dynamic state-transitions which could be encoded without an explicit reference to time intervals.

neuroscience↗

bioRxiv2023

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

BackgroundImpulse Control Disorder (ICD) in Parkinsons 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. MethodsWe 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 Parkinsons 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. ResultsPatients 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. ConclusionWe 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 dopamines role in human cognition, behavior, and disease should consider the signals this system generates on sub-second timescales.

neuroscience↗

bioRxiv2023

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 Parkinsons 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 SummaryQuantitative characterization of time perception behavior reflects individual differences in Parkinsons disease motor and non-motor symptom clinical presentation that are consistent with hypothesized neural and cognitive mechanisms.

neuroscience↗

bioRxiv2022

Acute hyper- and hypoglycemia uncouples the metabolic cooperation between glucose and lactate to disrupt sleep

The sleep-wake cycle is a master regulator of metabolic and neuronal activity and when altered, can have profound effects on metabolic health and disease. Although consideration is given to how fluctuations in blood glucose affect peripheral physiology and metabolism, less is known about how glucose dysregulation impacts the intrinsic cooperation between brain metabolism and neuronal activity to regulate sleep. To understand the effect of peripheral hyper- and hypoglycemia on these relationships, we paired biosensors measuring hippocampal interstitial fluid (ISF) levels of glucose and lactate with cortical EEG/EMG recordings to produce simultaneous subsecond recordings of ISF glucose, lactate, and sleep-wake states. First, we describe a conserved temporal relationships between ISF glucose and lactate based on their intrinsic oscillations, diurnal rhythms, and sleep/wake cycles. ISF glucose and lactate oscillations are largely anti-correlated but the frequency of their oscillations dictate their power, coherence, and phase. While ISF glucose and lactate both have diurnal fluctuations, only ISF lactate is consistently elevated during wake. During wake, fluctuations in ISF lactate are associated with changes in the EEG power spectrum, suggesting wake-related activity is more closely associated with ISF lactate. Modulation of glucose availability via both hyper- or hypoglycemia disrupts the relationship between peripheral metabolism, brain metabolism, and sleep. Hyper- and hypo-glycemia increase ISF lactate, decrease NREM, and alter EEG spectral activity, again demonstrating ISF lactate drives wake-associated behaviors and disrupts sleep. Taken together, these studies demonstrate that peripheral glucose homeostasis is necessary for maintaining the relationships between brain metabolism, neuronal activity, and sleep-wake patterns and deviations in blood glucose levels are sufficient to disrupt the metabolic signature of sleep-wake states, putting the brain at risk in diseases like type-2-diabetes and Alzheimers disease. Graphical Abstract. Peripheral glucose homeostasis directly modifies sleep/wake patterns O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/507967v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@9102eborg.highwire.dtl.DTLVardef@5699c5org.highwire.dtl.DTLVardef@1897ebeorg.highwire.dtl.DTLVardef@1e00661_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2021

A Dynamic Affective Core to Bind the Contents, Context, and Value of Conscious Experience

The private and dynamic nature of conscious subjective experience poses an empirical challenge that has led neuroscience-based theories about consciousness to note the importance of the hard problem of explaining how subjective phenomenal experience can arise from neural activity but set it aside and focus on the easier problems associated with information representation and behavior. This approach leaves a major gap in our understanding of the neural mechanisms underlying conscious subjective experience and its dynamic nature. However, computational methods integrated with a variety of tools for measuring human brain activity are beginning to link dynamic changes in subjective affect with reproducible neurobehavioral signals in humans. In particular, research applying computational reinforcement learning theory has shown tremendous utility in investigating human choice behavior and the role the dopaminergic system plays in dynamic behavioral control. This research is beginning to reveal an explicit connection between the dynamics of dopaminergic signals and dynamic changes in subjective affect. However, it should be obvious that the dopaminergic system alone is not sufficient to explain all of the complexities of affective dynamics. We review foundational work, highlight current problems and open questions, and propose a Dynamic Affective Core Hypothesis that integrates advances in our understanding of the representation of the content and context of conscious experiences with our nascent understanding about how these representations acquire and retain affective subjective value.

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bioRxiv2019

Random burst sensing of neurotransmitters

We introduce a random sensing approach to neurotransmitter detection that provides concurrent, co-localized detection of dopamine, serotonin, norepinephrine and pH. The approach generates high quality out-of-sample predictions at 10 milliseconds per estimate. Similar high-quality estimates result when the data are down-sampled suggesting that even more dramatic speedups are possible. The method also works using electrophysiological probes in routine use in clinical preparations thus transforming these and similar electrodes into ultra-fast sources of multi-transmitter information.

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