Neurophysiology of the pedunculopontine tegmental nucleus.

The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising target for deep brain stimulation in movement disorders. The PPTg is highly interconnected with the main basal ganglia nuclei and relays basal ganglia activity to thalamic and brainstem nuclei and to spinal effectors. In this review, we address the functional role of the main PPTg outputs directed to the basal ganglia, thalamus, cerebellum and spinal cord. Together, the data that we discuss show that the PPTg may influence thalamocortical activity and spinal motoneuron excitability through its ascending and descending output fibers, respectively. Cerebellar nuclei may also relay signals from the PPTg to thalamic and brainstem nuclei. In addition to participating in motor functions, the PPTg participates in arousal, attention, action selection and reward mechanisms. Finally, we discuss the possibility that the PPTg may be involved in excitotoxic degeneration of the dopaminergic neurons of the substantia nigra through the glutamatergic monosynaptic input that it provides to these neurons.

Cholinergic excitation from the pedunculopontine tegmental nucleus to the dentate nucleus in the rat.

In spite of the existence of pedunculopontine tegmental nucleus (PPTg) projections to cerebellar nuclei, their nature and functional role is unknown. These fibers may play a crucial role in postural control and may be involved in the beneficial effects induced by deep-brain stimulation (DBS) of brainstem structures in motor disorders. We investigated the effects of PPTg microstimulation on single-unit activity of dentate, fastigial and interpositus nuclei. The effects of PPTg stimulation were also studied in rats whose PPTg neurons were destroyed by ibotenic acid and subsequently subjected to iontophoretically applied cholinergic antagonists. The main response recorded in cerebellar nuclei was a short-latency (1.5-2 ms) and brief (13-15 ms) orthodromic activation. The dentate nucleus was the most responsive to PPTg stimulation. The destruction of PPTg cells reduced the occurrence of PPTg-evoked activation of dentate neurons, suggesting that the effect was due to stimulation of cell bodies and not due to fibers passing through or close to the PPTg. Application of cholinergic antagonists reduced or eliminated the PPTg-evoked response recorded in the dentate nucleus. The results show that excitation is exerted by the PPTg on the cerebellar nuclei, in particular on the dentate nucleus. Taken together with the reduction of nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in lesioned animals, the iontophoretic experiments suggest that the activation of dentate neurons is due to cholinergic fibers. These data help to explain the effects of DBS of the PPTg on axial motor disabilities in neurodegenerative disorders.

Unilateral deep brain stimulation of the pedunculopontine tegmental nucleus in idiopathic Parkinson's disease: effects on gait initiation and performance.

The pedunculopontine tegmental nucleus (PPTg) is a component of the locomotor mesencephalic area. In recent years it has been considered a new surgical site for deep brain stimulation (DBS) in movement disorders. Here, using objective kinematic and spatio-temporal gait analysis, we report the impact of low frequency (40 Hz) unilateral PPTg DBS in ten patients suffering from idiopathic Parkinson's disease with drug-resistant gait and axial disabilities. Patients were studied for gait initiation (GI) and steady-state level walking (LW) under residual drug therapy. In the LW study, a straight walking task was employed. Patients were compared with healthy age-matched controls. The analysis revealed that GI, cadence, stride length and left pelvic tilt range of motion (ROM) improved under stimulation. The duration of the S1 and S2 sub-phases of the anticipatory postural adjustment phase of GI was not affected by stimulation, however a significant improvement was observed in the S1 sub-phase in both the backward shift of centre of pressure and peak velocity. Speed during the swing phase, step width, stance duration, right pelvic tilt ROM phase, right and left hip flexion-extension ROM, and right and left knee ROM were not modified. Overall, the results show that unilateral PPTg DBS may affect GI and specific spatio-temporal and kinematic parameters during unconstrained walking on a straight trajectory, thus providing further support to the importance of the PPTg in the modulation of gait in neurodegenerative disorders.

Effects of unilateral pedunculopontine stimulation on electromyographic activation patterns during gait in individual patients with Parkinson's disease.

In Parkinson's disease (PD), the effects of deep brain stimulation of the pedunculopontine nucleus (PPTg-DBS) on gait has been object of international debate. Some evidence demonstrated that, in the late swing-early stance phase of gait cycle, a reduced surface electromyographic activation (sEMG) of tibialis anterior (TA) is linked to the striatal dopamine deficiency in PD patients. In the present study we report preliminary results on the effect of PPTg-DBS on electromyographic patterns during gait in individual PD patients. To evaluate the sEMG amplitude of TA, the root mean square (RMS) of the TA burst in late swing-early stance phase (RMS-A) was normalized as a percent of the RMS of the TA burst in late stance-early swing (RMS-B). We studied three male patients in the following conditions: on PPTg-DBS/on L: -dopa, on PPTg-DBS/off L: -dopa, off PPTg-DBS/on L: -dopa, off PPTg-DBS/off L: -dopa. For each assessment the UPDRS III was filled in. We observed no difference between on PPTg-DBS/off L: -dopa and off PPTg-DBS/off L: -dopa in UPDRS III scores. In off PPTg-DBS/off L: -dopa, patient A (right implant) showed absence of the right and left RMSA, respectively, in 80% and 83% of gait cycles. Patient B (right implant) showed absence of the right RMS-A in 86% of cycles. RMS-A of the patient C (left implant) was bilaterally normal. In on PPTg- DBS/off L: -dopa, no patient showed reduced RMS-A. Although the very low number of subjects we evaluated, our observations suggest that PPTg plays a role in modulating TA activation pattern during the steady state of gait.

Commentary: the pedunculopontine nucleus: clinical experience, basic questions and future directions.

This issue is dedicated to a potential new target for the treatment of movement disorders, the pedunculopontine tegmental nucleus (PPTg), or, more simply, the pedunculopontine nucleus, that some authors abbreviate as PPN. We provide an overview of the field as an introduction to the general reader, beginning with the clinical experience to date of Mazzone and co-workers in Rome, some basic questions that need to be addressed, and potential future directions required in order to ensure that the potential benefits of this work are realized.

Stereotactic surgery of nucleus tegmenti pedunculopontine [corrected].

The nucleus tegmenti pedunculopontine (PPTg) is a new target for deep brain stimulation (DBS) in Parkinson's disease (PD), in particular for ameliorating postural abnormalities and gait disturbances. The objective of the study is to describe the pre-operative planning, the surgical procedures and results of the DBS of PPTg in humans. Thirteen patients were considered. The surgical approach evolved from the traditional 'indirect' method based on stereotactic ventriculography (5 patients) to a more recent 'direct' method, based on both a digital elaboration of axial stereotactic CT scan and on the 'direct' visual 3D representation of the PPTg (8 patients). No major complication occurred. The direct approach allowed to eliminate the major sources of variability caused by the use of the traditional stereotactic approach. The DBS of PPTg induced a significant amelioration of the following clinical symptoms: gait disturbances, freezing on, speech and arising from the chair. These symptoms are usually not improved by levodopa treatment. The implantation of PPTg proved safe and effective in the treatment of levodopa resistant PD patients. The classic determination of stereotactic coordinates, through a proportional system based on ventriculography, utilising as landmark the CA-CP line and the top of the thalamus, and stereotactic atlases, can hardly be applied to brainstem surgery. The 'direct' method, based on both a digital elaboration of axial stereotactic CT scan and, on the 'direct' visualisation of brainstem borders as well as on the 3D representation of the PPTg, permits a better adaptation to individual anatomic features.

The pedunculopontine nucleus projection to the parafascicular nucleus of the thalamus: an electrophysiological investigation in the rat.

Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the thalamus were done in normal rats and in rats bearing lesions of either the cerebellar nuclei or the entopeduncular nucleus to investigate the functional control of the pedunculopontine nucleus on the parafascicular nucleus. A total of 97 neurons were recorded in the parafascicular nucleus in intact rats, 83 in rats bearing a chronic electrolytic lesion of the ipsilateral deep cerebellar nuclei, and 69 in rats bearing an ibotenate lesion of the ipsilateral entopeduncular nucleus. Lesions of the cerebellar nuclei or the entopeduncular nucleus were made to evaluate the participation of cerebellothalamic fibers or of polysynaptic basal ganglia circuits in the responses recorded in parafascicular neurons following electrical microstimulation of the ipsilateral pedunculopontine nucleus. Two types of excitation and one type of inhibition were the main responses observed in neurons of the parafascicular nucleus following stimulation of the pedunculopontine nucleus. The first type of excitation, observed in 49.5% of neurons recorded in normal rats, had an onset of 1.8 +/- 0.6 ms, lasted 9.2 +/- 0.8 ms and was able to follow high frequency stimulation over 300 Hz. The second type of excitation, observed in a smaller percentage of neurons recorded (3.1%), was a long-latency (8.3 +/- 0.7 ms) activation lasting 19.0 +/- 4.5 ms. It did not follow stimulation frequencies higher than 50-100 Hz. The inhibitory response was observed in 17.5% of the neurons recorded. The latency of this inhibition was 4.5 +/- 1.8 ms and the duration 41.9 +/- 6.8 ms. In rats bearing a lesion of the deep cerebellar nuclei or of the entopeduncular nucleus, the short-latency activation was still present in 24.1% and 31.9% of neurons recorded, respectively. However, the occurrence of the long-latency excitation rats bearing lesions of either the cerebellum or the entopeduncular nucleus increased to 12.1% and to 17.4%, respectively, while the occurrence of the inhibition rose to 22.9% and to 28.9%. These results show that an excitatory influence on the parafascicular nucleus is exerted by the pedunculopontine nucleus irrespectively of the presence of cerebellofugal fibers. This influence appears to be also independent from the integrity of basal ganglia circuits having a relay at the level of the entopeduncular nucleus. However, the variety of responses recorded suggests that the influences of the pedunculopontine nucleus on the parafascicular nucleus are by far more complex than those exerted on its basal ganglia targets such as the substantia nigra. The results are discussed according to a model of functioning of pedunculopontine fibers directed to thalamic and basal ganglia nuclei.

Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat.

Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in behavioral tasks requiring a preparatory period before the execution of externally cued conditioned movements. In the present study, we describe the effects of lesions of the pedunculopontine nucleus (PPN), a structure located on the outflow of the STN to lower brainstem and spinal motor nuclei, on the anticipatory responding caused by a unilateral lesion of the STN in a delayed sensorimotor task. Rats were instructed to keep a lever pressed down by the presentation of a composite visual and acoustic signal, and were required to hold the lever pressed until a trigger stimulus occurred after an unpredictable delay. The trigger stimulus required the animals to release the lever and to press a second lever for food reinforcement. The task was evaluated according to analysis of movement parameters and errors made by the animals during the preparative and executive phases of the conditioned movement. An ibotenate lesion was placed into the STN in either side of the brain. This lesion was followed 3 weeks later by an ibotenate lesion of the PPN ipsilaterally to the STN previously lesioned. The results indicate that the anticipatory responding induced by the STN lesion was not alleviated by the subsequent PPN lesion. However, the animals bearing the combined lesion were severely impaired in conditioned responding to salient stimuli involved in the paradigm and showed side-specific lengthening of reaction and movement times without global motor impairments. The results suggest that the anticipatory responses caused by STN lesions do not require the intervention of the PPN and that the disruption of the dopaminergic nigrostriatal pathway following the combined lesion may be responsible for impairments observed.

Role of tonically-active neurons in the control of striatal function: cellular mechanisms and behavioral correlates.

1. The striatum is primarily involved in motor planning and motor learning. Human diseases involving its complex circuitry lead to movement disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Moreover the striatum has been involved in processes linked to reward, cognition and drug addiction. 2. The high content of acetylcholine (ACh) found in the striatum is due to the presence of cholinergic interneurons. The intrinsic electrical and synaptic properties of these interneurons have been recently characterized. However, their functional significance is far from being fully elucidated. 3. In vivo electrophysiological experiments from behaving monkeys have identified these cholinergic interneurons as "Tonically Active Neurons" (TANs). They are activated by presentation of sensory stimuli of behavioral significance or linked to reward. 4. Experimental evidence showed that integrity of the nigrostriatal dopaminergic system is essential for TANs to express learned activity. 5. PD is known to be due to the loss of the nigrostriatal dopaminergic pathway and the ensuing imbalance between the content of dopamine and acetylcholine in the striatum. This evidence supports the hypothesis that cholinergic interneurons, or TANs, play a key role in the modulation of striatal function.

Dopamine denervation of specific striatal subregions differentially affects preparation and execution of a delayed response task in the rat.

In the present study, the effects of unilateral or bilateral dopamine denervation of either the dorsal or ventral striatum on the preparation and execution of a delayed response task in the rat were investigated. Animals were instructed to hold a lever pressed down by the presentation of a visual and/or acoustic signal, and were required to hold the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signal represented the preparation phase preceding movement. The motor performance was evaluated by using reaction and movement times in addition to correct responses in each session. Dopaminergic denervation of either the dorsal or ventral striatum ipsilaterally to the side in which the second lever to be pressed was located did not significantly change reaction and movement times, although it reduced the percentage of correct trials. A significant increase of both reaction and movement times was recorded only after bilateral denervation of the ventral striatum. The analysis of incorrect responses indicated that dopaminergic innervation of the two striatal subregions had different functions in the correct execution of the behavioral paradigm. In the group of animals with dorsal lesions the most frequent incorrect response was represented by a lack of the conditioned response to the presentation of the instruction stimulus starting the trial. If the animals reacted properly to this signal, the performance thereafter was correct in the majority of trials. Conversely, animals with ventral lesions exhibited a large repertoire of incorrect responses throughout the paradigm, including premature release or delayed press of levers, and omission of the second lever press. Histological verification of brain coronal sections by tyrosine-hydroxylase immunoreactivity showed that the lesions were confined in either the dorsal or ventral striatum, sparing the lateral region. The data support the hypothesis that dopaminergic innervation enables the two striatal regions to differently participate in the preparation and execution of complex delayed sensorimotor tasks. Indeed, the dorsal striatum seems to be involved in the correct utilization of external sensory information for the initiation of conditioned behavior, whereas, the ventral striatum appears to be mainly concerned with the temporal expectation of impending stimuli that trigger reward-reinforced movements.

The function of the pedunculopontine nucleus in the preparation and execution of an externally-cued bar pressing task in the rat.

In the present study the role of the pedunculopontine nucleus (PPN) in the preparation and execution of an externally-cued rewarded motor act was investigated. Animals were instructed to press down a lever at the presentation of a combined visual and acoustic signal and were required to hold down the lever until a trigger stimulus occurred after an unpredictable delay ranging from 2 to 4 s. The trigger stimulus required animals to release the lever and to press a second lever for food reinforcement. The time between instruction and trigger signals represented the preparation phase preceding movement. Unilateral ibotenic acid-induced focal degeneration of pedunculopontine neurons did not influence either reaction and movement times, or capacity of the animals to correctly respond to presentation of stimuli of behavioral significance. On the contrary, bilateral lesions increased both reaction and movement times, and dramatically reduced the percentage of correct responses. The analysis of incorrect responses suggested that the most striking deficit exhibited by the animals following the bilateral lesion was a lack of conditioned response to the signal initiating each trial. However, the animals retained the capability to respond correctly in some trials, and were able to collect the reward when delivered outside the behavioral context. Histological analysis of lesions showed that in addition to loss of neurons within the pedunculopontine region, reduction of tyrosine-hydroxylase positive neurons had occurred in the pars compacta of the substantia nigra. The data suggest that the PPN is involved in the preparation and execution of externally-cued movements, and demonstrate that its destruction mimics the main effects produced by the dopaminergic denervation of the dorsal striatum.

Transplantation of mesencephalic cell suspension in dopamine-denervated striatum of the rat. II. Effects on corticostriatal transmission.

The present study has been designed to investigate whether intrastriatal implantation of mesencephalic dopamine (DA)-synthetizing neurons into the striatum (ST) of rats whose substantia nigra (SN) was previously destroyed by 6-hydroxydopamine (6-OHDA) restores the pattern of corticostriatal transmission from the medial prelimbic and sensorimotor cortices. In 6-month-old normal animals electrical stimulation of these two functionally unrelated cortices evoked a short latency and brief excitation in 81.6% of neurons recorded in the dorsolateral ST. This percentage decreased significantly (70.6%) in age-matched animals whose dopaminergic nigrostriatal pathway was unilaterally destroyed by 6-OHDA 3 months before recording. However a significant increase in neurons (36.9%) which could be simultaneously activated from the two cortices in comparison to intact rats was noted. In addition the lesion caused a significant decrease in the threshold current required to evoke activation of striatal neurons from the sensorimotor cortex. The increase in the number of striatal neurons responding simultaneously to cortical stimulations demonstrates that destruction of the dopaminergic nigrostriatal pathway causes a loss of the focusing action of DA on corticostriatal transmission. Transplantation of embryonic mesencephalic neurons appears to reestablish this action since the number of convergent responses was significantly decreased in grafted animals (23.5%) in comparison to denervated (36.9%) and sham-grafted (35.1%) animals. Furthermore, the grafts showed a trend to increase current intensities required to evoke activation of striatal cells from both cortices. The action of grafted mesencephalic neurons over prelimbic and sensorimotor cortical inputs to the dorsal ST could be involved in recovery of grafted animals in the correct execution of complex sensorimotor tasks requiring integration of different cortical signals within the ST.

Transplantation of mesencephalic cell suspension in dopamine-denervated striatum of the rat.I. Effects on spontaneous activity of striatal neurons.

These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational behavior induced by amphetamine and apomorphine. Animals which responded positively to these tests received two suspensions of mesencephalic embryonic neurons into the dorsal striatum (ST) ipsilateral to the denervated side. Sham-grafted rats received the suspension medium only. The vitality of the graft was assessed by the disappearance or reversion of rotational movements induced by amphetamine. Extracellular recordings of neurons located throughout the ST were carried out 3 months after grafting, when the animals reached the age of 6 months. The 6-OHDA-induced nigral lesion caused a net increase both in the number of striatal neurons spontaneously active and in their discharging rates. The signs of increased neuronal activity were also present in sham-grafted animals. The grafting of embryonal cells strongly reduced the number of active neurons and decreased significantly their discharging rate. The effects of the intrastriatal graft appeared to be present within a radius of 1.5-2 mm from the core of the grafted area. The presence of tyrosine-hydroxylase-immunopositive neurons innervating the host ST confirmed the viability of the grafts at the time of electrophysiological recording. The results show that besides compensating motor asymmetries caused by DA denervation, intrastriatally grafted dopaminergic neurons are able to only partially restore the electrophysiological action of DA in discrete striatal domains.

Transplantation of Mesencephalic Cell Suspension in Dopamine-Denervated Striatum of the Rat

These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational behavior induced by amphetamine and apomorphine. Animals which responded positively to these tests received two suspensions of mesencephalic embryonic neurons into the dorsal striatum (ST) ipsilateral to the denervated side. Sham-grafted rats received the suspension medium only. The vitality of the graft was assessed by the disappearance or reversion of rotational movements induced by amphetamine. Extracellular recordings of neurons located throughout the ST were carried out 3 months after grafting, when the animals reached the age of 6 months. The 6-OHDA-induced nigral lesion caused a net increase both in the number of striatal neurons spontaneously active and in their discharging rates. The signs of increased neuronal activity were also present in sham-grafted animals. The grafting of embryonal cells strongly reduced the number of active neurons and decreased significantly their discharging rate. The effects of the intrastriatal graft appeared to be present within a radius of 1.5-2 mm from the core of the grafted area. The presence of tyrosine-hydroxylase-immunopositive neurons innervating the host ST confirmed the viability of the grafts at the time of electrophysiological recording. The results show that besides compensating motor asymmetries caused by DA denervation, intrastriatally grafted dopaminergic neurons are able to only partially restore the electrophysiological action of DA in discrete striatal domains.

Short-latency excitation of hindlimb motoneurons induced by electrical stimulation of the pontomesencephalic tegmentum in the rat.

The monosynaptic reflex response evoked by stimulating the dorsal root L6 was greatly facilitated when a low intensity conditioning stimulus was applied to the pontomesencephalic tegmentum (PT) 1-2 ms in advance. When increasing the stimulus strength or the number of stimuli, motor discharges were recorded in the ventral roots and in nerves innervating hindlimb muscles. The lowest threshold site for reflex facilitation was found in a region just ventral to the superior colliculus. A descending volley was recorded from the medulla midline, in the region of the medial longitudinal fascicle (MLF) and from the spinal cord surface at thoracic and lumbar level. The latency of the descending volley and of the motor responses indicates that excitation of hindlimb motoneurons was due to activation of a disynaptic pathway having a relay in the lower brainstem. All spinal and peripheral responses evoked by PT stimulation disappeared when a small electrolytic lesion was placed in the MLF 1-2 mm rostral to the obex. The results show that in the rat the PT region may exert a powerful facilitatory action on hindlimb motoneurons.

Influence of prelimbic and sensorimotor cortices on striatal neurons in the rat: electrophysiological evidence for converging inputs and the effects of 6-OHDA-induced degeneration of the substantia nigra.

These studies were designed to investigate whether there are convergent prelimbic and sensorimotor cortical inputs onto striatal neurons in the rat and whether dopaminergic (DA) nigrostriatal fibers regulate these inputs. The influence of the nigrostriatal DA system was assessed in rats with either small or large 6-hydroxydopamine-induced lesions of the substantia nigra. In normal rats 39 out of 74 neurons (52.7%) were excited by stimulation of both the prelimbic and the sensorimotor cortex. No marked change in corticostriatal transmission was evident in rats with small 6-OHDA-induced lesions (defined as 10-35% decrease in [3H]DA uptake in striatal synaptosomes). In rats with large lesions (75-85% decrease in striatal [3H]DA uptake), however, a complete rearrangement of the corticostriatal transmission occurred. This was evident in a decrease of thresholds to obtain cortical responses, by modifications of the discharge properties of striatal neurons receiving input from cortices and by an increase in the number of neurons responding to cortical stimulation. In addition, a significantly higher percentage of striatal neurons responded to stimulation of both prelimbic and sensorimotor cortices in rats with large lesions than in rats with small lesions or in control rats. This data suggests that: (1) no functional separation of prelimbic and sensorimotor cortical inputs occurs in the rat striatum, (2) the nigrostriatal DA system exerts a focusing effect on these inputs, (3) the striatum is actively involved in the integrative processing of descending cortical information.

Neuronal activity in monkey ventral striatum related to the expectation of reward.

Projections from cortical and subcortical limbic structures to the basal ganglia are predominantly directed to the ventral striatum. The present study investigated how the expectation of external events with behavioral significance is reflected in the activity of ventral striatal neurons. A total of 420 neurons were studied in macaque monkeys performing in a delayed go-no-go task. Lights of different colors instructed the animal to do an arm-reaching movement or refrain from moving, respectively, when a trigger light was illuminated a few seconds later. Task performance was reinforced by liquid reward in both situations. A total of 60 ventral striatal neurons showed sustained increases of activity before the occurrence of individual task events. In 43 of these neurons, activations specifically preceded the delivery of reward, independent of the movement or no-movement reaction. In a series of additional tests, these activations were time locked to the subsequent reward, disappeared within a few trials when reward was omitted, and were temporally unrelated to mouth movements. Changes in the appetitive value of the reward liquid modified the magnitude of activations, suggesting a possible relationship to the hedonic properties of the expected event. Activations also occurred when reward was delivered in a predictable manner outside of any behavioral task. These data suggest that neurons in the ventral striatum are activated during states of expectation of individual environmental events that are predictable to the subject through its past experience. The prevalence of activations related to the expectation of reward suggests that ventral striatal neurons have access to central representations of reward and thereby participate in the processing of information underlying the motivational control of goal-directed behavior.