Neural dynamics underlying self-control in the primate subthalamic nucleus.

The subthalamic nucleus (STN) is hypothesized to play a central role in neural processes that regulate self-control. Still uncertain, however, is how that brain structure participates in the dynamically evolving estimation of value that underlies the ability to delay gratification and wait patiently for a gain. To address that gap in knowledge, we studied the spiking activity of neurons in the STN of monkeys during a task in which animals were required to remain motionless for varying periods of time in order to obtain food reward. At the single-neuron and population levels, we found a cost-benefit integration between the desirability of the expected reward and the imposed delay to reward delivery, with STN signals that dynamically combined both attributes of the reward to form a single integrated estimate of value. This neural encoding of subjective value evolved dynamically across the waiting period that intervened after instruction cue. Moreover, this encoding was distributed inhomogeneously along the antero-posterior axis of the STN such that the most dorso-posterior-placed neurons represented the temporal discounted value most strongly. These findings highlight the selective involvement of the dorso-posterior STN in the representation of temporally discounted rewards. The combination of rewards and time delays into an integrated representation is essential for self-control, the promotion of goal pursuit, and the willingness to bear the costs of time delays.

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task.

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals' impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.

The anterior caudate nucleus supports impulsive choices triggered by pramipexole.

BACKGROUND: Pramipexole is a dopamine agonist used as a treatment in PD and restless legs syndrome to reduce motor symptoms, but it often induces impulse control disorders. In particular, patients with impulse control disorders tend to make more impulsive choices in the delay discounting task, that is, they choose small immediate rewards over larger delayed ones more often than patients without impulse control disorders and healthy subjects do. Yet the site of action of pramipexole that produces these impulsive choices remains unknown. Based on the heterogeneity of corticostriatal projections and the massive dopamine innervation of the striatum, we hypothesized that impulsive choices triggered by dopamine treatments may be supported by a specific striatal territory. OBJECTIVES: This study aims to determine by which anteriorstriatum territory the Pramipexole trigger impulsive choices; the caudate nucleus, the ventral striatum or the putamen. METHODS: We compared pramipexole intramuscular injections to intracerebral microinjections within the three striatal territories in healthy monkeys trained to execute the delay discounting task, a behavioral paradigm typically used to evaluate impulsive choices. RESULTS: We found that pramipexole intramuscular injections induced impulsive choices in all monkeys. Local microinjections were performed inside the anterior caudate nucleus, ventral striatum, and anterior putamen and reproduced those impulsive choices when pramipexole was directly injected into the caudate nucleus, whereas injections into the ventral striatum or putamen had no effect on monkeys' choices. CONCLUSIONS: These results, consistent with clinical studies, suggest that impulsive choices triggered by pramipexole are supported by the caudate nucleus, allowing us to emphasize the importance of dopamine modulation inside this striatal territory in decision processes underlying impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Local Field Potentials Reflect Dopaminergic and Non-Dopaminergic Activities within the Primate Midbrain.

Midbrain dopamine neurons are thought to play a crucial role in motivating behaviors toward desired goals. While the activity of dopamine single-units is known to adhere closely to the reward prediction error (RPE) signal hypothesized by learning theory, much less is known about the dynamic coordination of population-level neuronal activities in the midbrain. Local field potentials (LFPs) are thought to reflect the changes in membrane potential synchronized across a population of neurons nearby a recording electrode. These changes involve complex combinations of local spiking activity with synaptic processing that are difficult to interpret. Here we sampled LFPs from the substantia nigra pars compacta (SNc) of behaving monkeys to determine if local population-level synchrony encodes specific aspects of a reward/effort instrumental task and whether dopamine single-units participate in that signal. We found that reward-correlated information is encoded in a low-frequency signal (<32-Hz; delta and beta bands) that is synchronized across a neural population that includes dopamine neurons. Conversely, high-frequency power (>33-Hz; gamma band) was anticorrelated with predicted reward value and dopamine single-units were never phase-locked to those frequencies. This high-frequency signal may reflect inhibitory processes that were not otherwise observable. LFP encoding of movement-related parameters was negligible. Together, LFPs provide novel insights into the multidimensional processing of reward information subserved by dopaminergic and other components of the midbrain.

A selective role for ventromedial subthalamic nucleus in inhibitory control.

The subthalamic nucleus (STN) is hypothesized to play a central role in the rapid stopping of movement in reaction to a stop signal. Single-unit recording evidence for such a role is sparse, however, and it remains uncertain how that role relates to the disparate functions described for anatomic subdivisions of the STN. Here we address that gap in knowledge using non-human primates and a task that distinguishes reactive and proactive action inhibition, switching and skeletomotor functions. We found that specific subsets of STN neurons have activity consistent with causal roles in reactive action stopping or switching. Importantly, these neurons were strictly segregated to a ventromedial region of STN. Neurons in other subdivisions encoded task dimensions such as movement per se and proactive control. We propose that the involvement of STN in reactive control is restricted to its ventromedial portion, further implicating this STN subdivision in impulse control disorders.

Primary motor cortex of the parkinsonian monkey: altered encoding of active movement.

Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs.

Dopamine neurons encode errors in predicting movement trigger occurrence.

The capacity to anticipate the timing of events in a dynamic environment allows us to optimize the processes necessary for perceiving, attending to, and responding to them. Such anticipation requires neuronal mechanisms that track the passage of time and use this representation, combined with prior experience, to estimate the likelihood that an event will occur (i.e., the event's "hazard rate"). Although hazard-like ramps in activity have been observed in several cortical areas in preparation for movement, it remains unclear how such time-dependent probabilities are estimated to optimize response performance. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys during an arm-reaching task for which the foreperiod preceding the "go" signal varied randomly along a uniform distribution. After extended training, the monkeys' reaction times correlated inversely with foreperiod duration, reflecting a progressive anticipation of the go signal according to its hazard rate. Many dopamine neurons modulated their firing rates as predicted by a succession of hazard-related prediction errors. First, as time passed during the foreperiod, slowly decreasing anticipatory activity tracked the elapsed time as if encoding negative prediction errors. Then, when the go signal appeared, a phasic response encoded the temporal unpredictability of the event, consistent with a positive prediction error. Neither the anticipatory nor the phasic signals were affected by the anticipated magnitudes of future reward or effort, or by parameters of the subsequent movement. These results are consistent with the notion that dopamine neurons encode hazard-related prediction errors independently of other information.

Primary motor cortex of the parkinsonian monkey: altered neuronal responses to muscle stretch.

Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord.

Limited encoding of effort by dopamine neurons in a cost-benefit trade-off task.

Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits ("rewards"), costs, and the animal's internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys (Macaca mulatta) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an often-hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson's disease, lead to a breakdown of that balance.

Basal Ganglia preferentially encode context dependent choice in a two-armed bandit task.

Decision is a self-generated phenomenon, which is hard to track with standard time averaging methods, such as peri-event time histograms (PETHs), used in behaving animals. Reasons include variability in duration of events within a task and uneven reaction time of animals. We have developed a temporal normalization method where PETHs were juxtaposed all along task events and compared between neurons. We applied this method to neurons recorded in striatum and GPi of behaving monkeys involved in a choice task. We observed a significantly higher homogeneity of neuron activity profile distributions in GPi than in striatum. Focusing on the period of the task during which the decision was taken, we showed that approximately one quarter of all recorded neurons exhibited tuning functions. These so-called coding neurons had average firing rates that varied as a function of the value of both presented cues, a combination here referred to as context, and/or value of the chosen cue. The tuning functions were used to build a simple maximum likelihood estimation model, which revealed that (i) GPi neurons are more efficient at encoding both choice and context than striatal neurons and (ii) context prediction rates were higher than those for choice. Furthermore, the mutual information between choice or context values and decision period average firing rate was higher in GPi than in striatum. Considered together, these results suggest a convergence process of the global information flow between striatum and GPi, preferentially involving context encoding, which could be used by the network to perform decision-making.

Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons.

Dysfunction of primary motor cortex (M1) is thought to contribute to the pathophysiology of parkinsonism. What specific aspects of M1 function are abnormal remains uncertain, however. Moreover, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those questions were addressed by studying the resting activity of intratelencephalic-type corticostriatal neurons (CSNs) and distant-projecting lamina 5b pyramidal-tract type neurons (PTNs) in the macaque M1 before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Contrary to previous reports, the general population of M1 neurons (i.e., PTNs, CSNs, and unidentified neurons) showed reduced baseline firing rates following MPTP, attributable largely to a marked decrease in PTN firing rates. CSN firing rates were unmodified. Although burstiness and firing patterns remained constant in M1 neurons as a whole and CSNs in particular, PTNs became more bursty post-MPTP and less likely to fire in a regular-spiking pattern. Rhythmic spiking (found in PTNs predominantly) occurred at beta frequencies (14-32 Hz) more frequently following MPTP. These results indicate that MPTP intoxication induced distinct modifications in the activity of different M1 neuronal subtypes. The particular susceptibility of PTNs suggests that PTN dysfunction may be an important contributor to the pathophysiology of parkinsonian motor signs.

Shaping of motor responses by incentive values through the basal ganglia.

The striatum is a key neural interface for cognitive and motor information processing in which associations between reward value and visual stimulus can be used to modify motor commands. It can guide action-selection processes that occur farther downstream in the basal ganglia (BG) circuit, by encoding the reward value of an action. Here, we report on the study of simultaneously recorded neurons in the dorsal striatum (input stage of the BG) and the internal pallidum (output stage of the BG) in two monkeys performing a center-out motor task in which the visual targets were associated with different reward probabilities. We show that the tuning curves of motor-related neurons in both structures are modulated by the value of the action before movement initiation and during its execution. The representations of values associated with different actions change dynamically during the task in the internal globus pallidus, with a significant increase in the number of encoding neurons for the chosen target at the onset of movement. This report sheds additional light on the functional differences between the input and output structures of the BG and supports the assertion that the dorsal basal ganglia are involved in movement-related decision-making processes based on incentive values.