Ken-ichi Okada

Different Pedunculopontine Tegmental Neurons Signal Predicted and Actual Task Rewards

The dopamine system has been implicated in guiding behavior based on rewards. The pedunculopontine tegmental nucleus (PPTN) of the brainstem receives afferent inputs from reward-related structures, including the cerebral cortices and the basal ganglia, and in turn provides strong excitatory projections to dopamine neurons. This anatomical evidence predicts that PPTN neurons may carry reward information. To elucidate the functional role of the PPTN in reward-seeking behavior, we recorded single PPTN neurons while monkeys performed a visually guided saccade task in which the predicted reward value was informed by the shape of the fixation target. Two distinct groups of neurons, fixation target (FT) and reward delivery (RD) neurons, carried reward information. The activity of FT neurons persisted between FT onset and reward delivery, with the level of activity associated with the magnitude of the expected reward. RD neurons discharged phasically after reward delivery, with the levels of activity associated with the actual reward. These results suggest that separate populations of PPTN neurons signal predicted and actual reward values, both of which are necessary for the computation of reward prediction error as represented by dopamine neurons.

Reward prediction-related increases and decreases in tonic neuronal activity of the pedunculopontine tegmental nucleus

The neuromodulators serotonin, acetylcholine, and dopamine have been proposed to play important roles in the execution of movement, control of several forms of attentional behavior, and reinforcement learning. While the response pattern of midbrain dopaminergic neurons and its specific role in reinforcement learning have been revealed, the roles of the other neuromodulators remain elusive. Reportedly, neurons in the dorsal raphe nucleus, one major source of serotonin, continually track the state of expectation of future rewards by showing a correlated response to the start of a behavioral task, reward cue presentation, and reward delivery. Here, we show that neurons in the pedunculopontine tegmental nucleus (PPTN), one major source of acetylcholine, showed similar encoding of the expectation of future rewards by a systematic increase or decrease in tonic activity. We recorded and analyzed PPTN neuronal activity in monkeys during a reward conditioned visually guided saccade task. The firing patterns of many PPTN neurons were tonically increased or decreased throughout the task period. The tonic activity pattern of neurons was correlated with their encoding of the predicted reward value; neurons exhibiting an increase or decrease in tonic activity showed higher or lower activity in the large reward-predicted trials, respectively. Tonic activity and reward-related modulation ended around the time of reward delivery. Additionally, some tonic changes in activity started prior to the appearance of the initial stimulus, and were related to the anticipatory fixational behavior. A partially overlapping population of neurons showed both the initial anticipatory response and subsequent predicted reward value-dependent activity modulation by their systematic increase or decrease of tonic activity. These bi-directional reward- and anticipatory behavior-related modulation patterns are suitable for the presumed role of the PPTN in reward processing and motivational control.

A Neural Correlate of Predicted and Actual Reward-Value Information in Monkey Pedunculopontine Tegmental and Dorsal Raphe Nucleus during Saccade Tasks

Dopamine, acetylcholine, and serotonin, the main modulators of the central nervous system, have been proposed to play important roles in the execution of movement, control of several forms of attentional behavior, and reinforcement learning. While the response pattern of midbrain dopaminergic neurons and its specific role in reinforcement learning have been revealed, the role of the other neuromodulators remains rather elusive. Here, we review our recent studies using extracellular recording from neurons in the pedunculopontine tegmental nucleus, where many cholinergic neurons exist, and the dorsal raphe nucleus, where many serotonergic neurons exist, while monkeys performed eye movement tasks to obtain different reward values. The firing patterns of these neurons are often tonic throughout the task period, while dopaminergic neurons exhibited a phasic activity pattern to the task event. The different modulation patterns, together with the activity of dopaminergic neurons, reveal dynamic information processing between these different neuromodulator systems.

Characterization of oculomotor and visual activities in the primate pedunculopontine tegmental nucleus during visually guided saccade tasks

The pedunculopontine tegmental nucleus (PPTN) has anatomical connections with numerous visuomotor areas including the basal ganglia, thalamus, superior colliculus and frontal eye field. Although many anatomical and physiological studies suggest a role for the PPTN in the control of conditioned behavior and associative learning, the detailed characteristics of saccade‐ and visual‐related activities of PPTN neurons remain unclear. We recorded the activity of PPTN neurons in monkeys (Macaca fuscata ) during visually guided saccade tasks, and examined the response properties of saccade‐ and visual‐related activities such as time course, direction selectivity and contextual modulation. Saccade‐related activity occurred either during saccade execution or after saccade end. The preferred directions of the neuronal activity were biased toward the contralateral and upward sides. Half of the saccade‐related neurons showed activity modulation only for task saccades and not for spontaneous saccades outside the task. Visually‐responsive neurons responded with short latencies. Some responded to the appearance of the visual stimulus in a directionally selective manner, and others responded to both the appearance and disappearance of the visual stimulus in a directionally non‐selective manner. Many of these neurons exhibited distinct visual responses to the appearance of two different stimuli presented under different stages of the task, whereas a population of the neurons responded equally to the disappearance of the two stimuli. Thus, many PPTN neurons exhibited context‐dependent activity related to the visuomotor events, consistent with a role in controlling conditioned behavior.

Fixational saccade-related activity of pedunculopontine tegmental nucleus neurons in behaving monkeys.

Fixational saccades are small, involuntary eye movements that occur during attempted visual fixation. Recent studies suggested that several cognitive processes affect the occurrence probability of fixational saccades. Thus, there might be an interaction between fixational saccade‐related motor signals and cognitive signals. The pedunculopontine tegmental nucleus (PPTN) in the brainstem has anatomical connections with numerous saccade‐related and limbic areas. Previously, we reported that a group of PPTN neurons showed transient phasic bursts or a pause in activity during large visually guided and spontaneous saccades, and also showed sustained tonic changes in activity with task context. We hypothesised that single PPTN neurons would relay both fixational saccade‐related and task context‐related signals, and might function as an interface between the motor and limbic systems. We recorded the activity of PPTN neurons in behaving monkeys during a reward‐biased task, and analysed neuronal activity for small fixational saccades during visual fixation, and compared it with the activity for large visually guided targeting saccades and large spontaneous saccades during intertrial intervals. A population of PPTN neurons exhibited a fixational saccade‐related phasic increase in activity, and the majority of them also showed activity modulation with large targeting saccades. In addition, a group of these neurons showed a task‐related tonic increase in activity during the fixation period, and half of them relayed the saccade signal only when the neuron exhibited higher tonic activity during the task execution period. Thus, fixational saccade‐related signals of PPTN neurons overlap with tonic task‐related signals, and might contribute to the cognitive modulation of fixational saccades.

The Pedunculopontine Tegmental Nucleus as a Motor and Cognitive Interface between the Cerebellum and Basal Ganglia

As an important component of ascending activating systems, brainstem cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg) are involved in the regulation of motor control (locomotion, posture and gaze) and cognitive processes (attention, learning and memory). The PPTg is highly interconnected with several regions of the basal ganglia, and one of its key functions is to regulate and relay activity from the basal ganglia. Together, they have been implicated in the motor control system (such as voluntary movement initiation or inhibition), and modulate aspects of executive function (such as motivation). In addition to its intimate connection with the basal ganglia, projections from the PPTg to the cerebellum have been recently reported to synaptically activate the deep cerebellar nuclei. Classically, the cerebellum and basal ganglia were regarded as forming separated anatomical loops that play a distinct functional role in motor and cognitive behavioral control. Here, we suggest that the PPTg may also act as an interface device between the basal ganglia and cerebellum. As such, part of the therapeutic effect of PPTg deep brain stimulation (DBS) to relieve gait freezing and postural instability in advanced Parkinson’s disease (PD) patients might also involve modulation of the cerebellum. We review the anatomical position and role of the PPTg in the pathway of basal ganglia and cerebellum in relation to motor control, cognitive function and PD.

Rhythmic Firing of Pedunculopontine Tegmental Nucleus Neurons in Monkeys during Eye Movement Task

The pedunculopontine tegmental nucleus (PPTN) has been thought to be involved in the control of behavioral state. Projections to the entire thalamus and reciprocal connections with the basal ganglia nuclei suggest a potential role for the PPTN in the control of various rhythmic behaviors, including waking/sleeping and locomotion. Recently, rhythmic activity in the local field potentials was recorded from the PPTN of patients with Parkinsons disease who were treated with levodopa, suggesting that rhythmic firing is a feature of the functioning PPTN and might change with the behaving conditions even within waking. However, it remains unclear whether and how single PPTN neurons exhibit rhythmic firing patterns during various behaving conditions, including executing conditioned eye movement behaviors, seeking reward, or during resting. We previously recorded from PPTN neurons in healthy monkeys during visually guided saccade tasks and reported task-related changes in firing rate, and in this paper, we reanalyzed these data and focused on their firing patterns. A population of PPTN neurons demonstrated a regular firing pattern in that the coefficient of variation of interspike intervals was lower than what would be expected of theoretical random and irregular spike trains. Furthermore, a group of PPTN neurons exhibited a clear periodic single spike firing that changed with the context of the behavioral task. Many of these neurons exhibited a periodic firing pattern during highly active conditions, either the fixation condition during the saccade task or the free-viewing condition during the intertrial interval. We speculate that these task context-related changes in rhythmic firing of PPTN neurons might regulate the monkeys attentional and vigilance state to perform the task.

Reward and Behavioral Factors Contributing to the Tonic Activity of Monkey Pedunculopontine Tegmental Nucleus Neurons during Saccade Tasks

The pedunculopontine tegmental nucleus (PPTg) in the brainstem plays a role in controlling reinforcement learning and executing conditioned behavior. We previously examined the activity of PPTg neurons in monkeys during a reward-conditioned, visually guided saccade task, and reported that a population of these neurons exhibited tonic responses throughout the task period. These tonic responses might depend on prediction of the upcoming reward, successful execution of the task, or both. Here, we sought to further distinguish these factors and to investigate how each contributes to the tonic neuronal activity of the PPTg. In our normal visually guided saccade task, the monkey initially fixated on the central fixation target (FT), then made saccades to the peripheral saccade target and received a juice reward after the saccade target disappeared. Most of the tonic activity terminated shortly after the reward delivery, when the monkey broke fixation. To distinguish between reward and behavioral epochs, we then changed the task sequence for a block of trials, such that the saccade target remained visible after the reward delivery. Under these visible conditions, the monkeys tended to continue fixating on the saccade target even after the reward delivery. Therefore, the prediction of the upcoming reward and the end of an individual trial were separated in time. Regardless of the task conditions, half of the tonically active PPTg neurons terminated their activity around the time of the reward delivery, consistent with the view that PPTg neurons might send reward prediction signals until the time of reward delivery, which is essential for computing reward prediction error in reinforcement learning. On the other hand, the other half of the tonically active PPTg neurons changed their activity dependent on the task condition. In the normal condition, the tonic responses terminated around the time of the reward delivery, while in the visible condition, the activity continued until the disappearance of the saccade target (ST) after reward delivery. Thus, for these neurons, the tonic activity might be related to maintaining attention to complete fixation behavior. These results suggest that, in addition to the reward value information, some PPTg neurons might contribute to the execution of conditioned task behavior.

BS15. An evaluation of repetitive transcranial magnetic stimulation effectiveness on cardinal and eye movement control of patients with Parkinson’s disease

Introduction Changes in motor symptoms and mood resulting from repetitive transcranial magnetic stimulation (rTMS) in patients with Parkinson’s disease (PD) have been addressed. However, the best area of the brain to target for stimulation has been still unknown. Since oculomotor behavior suggests a common mechanism underlying a general deficit in the motor control, recording of eye movement might offer a new quantitative evaluation of PD pathophysiology. Methods We assessed the effects of high-frequency rTMS (HF-rTMS) on motor and mood disturbances in patients with PD to identify the best target for treatment in the primary motor area (M1), the supplementary motor area (SMA), and the dorsolateral prefrontal cortex (DLPFC). This randomized, double-blind crossover-design study examined 19 patients and investigated the efficacy of 3 consecutive days of HF-rTMS over the M1, SMA, and DLPFC. The results of rTMS at each location were compared to sham stimulation. We used several motor and/or non-motor scales to evaluate the Parkinsonian symptoms. Next, we enrolled 7 patients in order to learn how the performance of volitional saccade tasks and fixational eye movements were affected by HF-rTMS. We investigated bilateral 5 Hz rTMS over the M1 and assessed eye movement, which was recorded binocularly using a fast video-based eye tracker (the temporal and spatial resolutions were 500 Hz and 0.01°). Results The changes in the scores of the Unified Parkinson’s Disease Rating Scale part III (UPDRS–III) following the application of HF-rTMS over the M1 and SMA were significantly greater than those following sham stimulation. However, after the application of HF-rTMS over the DLPFC, the UPDRS–III scores were similar to those following sham stimulation. No significant improvements in mood disturbances were demonstrated. In the eye-movement study, the change of response time in anti-saccade performance improved significantly in patients with PD after applying HF-rTMS over the M1. The change of performance of saccade and frequency of fixational saccades for anti-saccade task which required reflex suppression showed a strong correlation with the posture and walk symptoms in PD. Conclusion The application of HF-rTMS to M1 and SMA significantly improved motor symptoms in patients with PD but did not affect mood disturbances. The volitional saccade performance may possibly reflect the pathogenesis of PD.

The pedunculopontine tegmental nucleus neurons encode predicted reward signal by tonic regular firing and given reward signal phasically

Motion of the observer generally causes image motion on the retina, regardless of whether the objects in our surroundings are stationary or moving; nevertheless moving or stationary surroundings are usually perceived as they are. This indicates that our brain has a mechanism that effectively compensates the retinal image motion which originates in our own motion, allowing us to know the motion of the surroundings on the head-centric (or world) coordinates. Previous studies suggested that there are plenty of visual motion sensitive neurons in the posterior parts of the superior temporal sulcus (STS) of monkey cortex. The present study was carried out to reveal functional differences between motion sensitive neurons in the middle temporal (MT) and dorsal part of the medial superior temporal (MSTd) areas in the STS. We used the signal detection theory, which allowed us to determine the motion to which a neuron is more sensitive, i.e., “motion on the screen” or “motion on the retina”. Given that a neuron is motion sensitive, its firing rate is a numeric value that represents the degree to which an instance is a member of the motion in the preferred direction, and hence it classifies the stimulus motion into two classes, i.e., motion in the preferred and motion in the anti-preferred directions. Two receiver operating characteristic curves, one as a classifier for motion on the retina and the other motion on the screen, were calculated based on the neural responses to random-dot patterns moving at different speeds in the preferred or anti-preferred direction during smooth pursuit at different speeds. We found that almost all MT neurons worked better as classifiers for motion on the retina (i.e., sensitive to retinal motion), whereas the majority of MSTd neurons worked better as classifiers for motion on the screen (i.e., sensitive to actual motion), indicating a functional difference between these two areas. Research fund: KAKENHI (21240037).