Suppression of human cortico-motoneuronal excitability during the Stop-signal task

ObjectiveTo investigate whether motor suppression is an active process, and to clarify its somatotopic organization, we investigated cortico-motoneuronal excitability using transcranial magnetic stimulation (TMS) during the Stop-signal task.MethodsSubjects were asked to press a button following a Go cue; a Stop-signal followed the Go cue by a certain time delay in 25% of trials, indicating to subjects that they were not to press the button. TMS was given to the primary motor area of the left or right-hand or leg at variable time delays. Motor evoked potentials (MEPs) were recorded from the hand and leg muscles bilaterally.ResultsWhen TMS was delivered 400 ms after the Go cue, there was significant suppression of the MEPs of the bilateral hand and leg muscles during successful Stop trials, but not during failed Stop trials.ConclusionsThe voluntary stopping of movement in the Stop-signal task is an active process, which likely suppresses not only the cortico-motoneuronal excitability of the task-performing hand, but also causes the widespread suppression of the motor system.SignificanceStudies in the normal physiology of response inhibition would be of help in understanding the pathophysiology of neuro-psychiatric disorders associated with deficits in motor suppression.     

Neural correlates of reward and attention in macaque area LIP

Saccade reaction times decrease and the frequency of target choices increases with the size of rewards delivered for orienting to a particular visual target. Similarly, increasing rewards for orienting to a visual target enhances neuronal responses in the macaque lateral intraparietal area (LIP), as well as other brain areas. These observations raise several questions. First, are reward-related modulations in neuronal activity in LIP, as well as other areas, spatially specific or more global in nature? Second, to what extent does reward modulation of neuronal activity in area LIP reflect changes in visual rather than motor processing? And third, to what degree are reward-related modulations in LIP activity independent of performance-related modulations thought to reflect changes in attention? Here we show that increasing the size of fluid rewards in blocks reduced saccade reaction times and improved performance in monkeys performing a peripherally-cued saccade task. LIP neurons responded to visual cues spatially segregated from the saccade target, and for many neurons visual responses were systematically modulated by expected reward size. Neuronal responses also were positively correlated with reaction times independent of reward size, consistent with re-orienting of attention to the saccade target. These observations suggest that motivation and attention independently contribute to the strength of sustained visual responses in LIP. Our data thus implicate LIP in the integration of the sensory, motor, and motivational variables that guide orienting.     

Precentral cortex unit activity during the M-wave and contingent negative variation in behaving squirrel monkeys

The firing of 96 units in the precentral cortex of four trained squirrel monkeys was examined in relation to the M-wave and contingent negative variation (CNV) evoked by two tone cues 1 s apart, to which the monkey had to respond by a bar-press within 1 or 2 s in order to receive a food reward. Many (92%) units showed increased or decreased firing during at least one of the two event-related potentials [(ERPs), the M-wave and CNV]. The finding of both increases and decreases in firing during the CNV is consistent with the hypothesis that the CNV represents a combination of EPSPs on superficial neuronal elements and IPSPs on deeperlying elements. Like the M-wave and CNV, many of the ERP-related changes in unit firing were apparently influenced by the animal's level of motivation; i.e., they differed in magnitude in successful vs. unsuccessful trials; in early vs. late successful trials; and/or in successful trials with more vs. less preferred food rewards. The timing of some of the firing increases during the CNV suggests that they correlate with two postulated components of the CNV, one related to the first cue, the other to preparation for the motor response. The increases in firing after cue 2, observed in 91% of the units and often influenced by motivation, occurred before and during the bar-press and suggest that the ERP-related neurons are also involved in the well-established role of the precentral cortex in motor output. We suggest that these neurons are the anatomic substrate by which the influence of motivation is transmitted to other neurons of the motor system, including those more directly related to the effectors.     

A proactive task set influences how response inhibition is implemented in the basal ganglia

Increasing a participant's ability to prepare for response inhibition is known to result in longer Go response times and is thought to engage a “top‐down fronto‐striatal inhibitory task set.” This premise is supported by the observation of anterior striatum activation in functional magnetic resonance imaging (fMRI) analyses that focus on uncertain versus certain Go trials. It is assumed that setting up a proactive inhibitory task set also influences how participants subsequently implement stopping. To assess this assumption, we aimed to manipulate the degree of proactive inhibition in a modified stop‐signal task to see how this manipulation influences activation when reacting to the Stop cue. Specifically, we tested whether there is differential activity of basal ganglia nuclei, namely the subthalamic nucleus (STN) and anterior striatum, on Stop trials when stop‐signal probability was relatively low (20%) or high (40%). Successful stopping was associated with increased STN activity when Stop trials were infrequent and increased caudate head activation when Stop trials were more likely, suggesting a different implementation of reactive response inhibition by the basal ganglia for differing degrees of proactive response control. Hum Brain Mapp 37:4706–4717, 2016. © 2016 Wiley Periodicals, Inc.     

EEG dipole analysis of motor-priming foreperiod activity reveals separate sources for motor and spatial attention components

OBJECTIVE: This study employed EEG source localisation procedures to study the contribution of motor preparatory and attentional processing to foreperiod activity in an S1-S2 motor priming task. METHODS: Behavioural and high-density event-related potential (ERP) data were recorded in an S1-S2 priming task where participants responded to S2 with a left or right-hand button press. S1 either provided information about response hand (informative) or ambiguous information (uninformative). RESULTS: Responses were significantly faster in informative trials compared with uninformative trials. Dipole source analysis of foreperiod lateralized ERPs revealed sources of motor preparatory activity in the dorsolateral premotor cortex (PMd) in line with previous work. In addition, two spatial attention components (ADAN, LDAP) were identified with generators in the PMd and occipitotemporal visual areas in the middle temporal (MT) region, respectively. Separation of motor-related and attentional PMd source locations was reliable along the rostral-caudal axis. CONCLUSIONS: The presence of attentional components in a motor priming paradigm supports the premotor theory of attention which suggests a close link between attention and motor preparatory processes. Separation of components in the premotor cortex is in accord with a functional division of PMd into rostral (higher-order processing) and caudal (motor-related processing) areas as suggested by imaging work. SIGNIFICANCE: A prime for response preparation is a trigger for separate, but closely linked, attention-related activity in premotor areas.     

Multisynaptic projections from the ventrolateral prefrontal cortex to the dorsal premotor cortex in macaques – anatomical substrate for conditional visuomotor behavior

Lines of evidence indicate that both the ventrolateral prefrontal cortex (vlPFC) (areas 45/12) and dorsal premotor cortex (PMd) (rostral F2 in area 6) are crucially involved in conditional visuomotor behavior, in which it is required to determine an action based on an associated visual object. However, virtually no direct projections appear to exist between the vlPFC and PMd. In the present study, to elucidate possible multisynaptic networks linking the vlPFC to the PMd, we performed a series of neuroanatomical tract‐tracing experiments in macaque monkeys. First, we identified cortical areas that send projection fibers directly to the PMd by injecting Fast Blue into the PMd. Considerable retrograde labeling occurred in the dorsal prefrontal cortex (dPFC) (areas 46d/9/8B/8Ad), dorsomedial motor cortex (dmMC) (F7 and presupplementary motor area), rostral cingulate motor area, and ventral premotor cortex (F5 and area 44), whereas the vlPFC was virtually devoid of neuronal labeling. Second, we injected the rabies virus, a retrograde transneuronal tracer, into the PMd. At 3 days after the rabies injections, second‐order neurons were labeled in the vlPFC (mainly area 45), indicating that the vlPFC disynaptically projects to the PMd. Finally, to determine areas that connect the vlPFC to the PMd indirectly, we carried out an anterograde/retrograde dual‐labeling experiment in single monkeys. By examining the distribution of axon terminals labeled from the vlPFC and cell bodies labeled from the PMd, we found overlapping labels in the dPFC and dmMC. These results indicate that the vlPFC outflow is directed toward the PMd in a multisynaptic fashion through the dPFC and/or dmMC.     

Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus

The subthalamic nucleus (STN) has been argued to be an important component of reward‐sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task‐related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision‐making processes.     

Encoding of target direction and speed during visual instruction and arm tracking in dorsal premotor and primary motor cortical neurons

The encoding of direction and speed in the discharge of dorsal premotor (PMd) and primary motor (MI) neurons was studied during two-dimensional visually-instructed pursuit arm movements in which eight directions and four constant speeds were independently manipulated. Each trial consisted of equal durations of visual observation of target movement without hand movement (cue) and visual pursuit-tracking of the target with the hand (track). A total of 240 neurons was recorded from PMd and MI in two Macaca mulatta monkeys. Two classes of regression analyses were used to relate neuronal firing during the cue and track periods to direction and speed. First, the average firing from each period was fitted to target direction or speed. Period-averaged firing significantly correlated with direction more frequently in the track than in the cue period. Conversely, correlations with speed (with or without direction) were more common in the cue than in the track period. Secondly, a binwise regression evaluated the temporal evolution of firing correlations with direction and speed. Supporting the period-based results, significant binwise correlations of the discharge with speed occurred preferentially during the cue period when there was no hand movement. Prior to movement, correlations of the firing with direction became significant and continued through the movement. Both analyses demonstrated a distinct tendency for neurons to be modulated by speed information early and by direction information later. This temporal parcellation reflects both the sequential demands of the task and constraints placed on the neural computations. The early representation of target speed is hypothesized to reflect the need to calculate a 'go signal' for the initiation of movement.     

Context-dependent responses of primate nucleus basalis neurons in a go/no-go task

In previous studies involving monkeys performing behavioral tasks, neurons in the nucleus basalis frequently had significant changes in discharge rate when the animal made a movement in response to a sensory stimulus in order to obtain a reward. To determine whether such responses of basalis neurons are primarily sensory or motor in nature, the activity of single basalis neurons was recorded in monkeys performing a go/no-go (GNG) task which provided a dissociation between sensory and motor neuronal responses. In a sample of 425 basalis neurons, 326 (77%) had significant changes in firing in at least one phase of the GNG task. Most of the task-related neurons (70%) responded in the choice phase in which the animal either made an arm movement (go condition) or kept its arm motionless (no-go condition) in order to obtain a water reward. Of 253 neurons that responded in the choice phase, 88% had changes in firing in the no-go condition that were equal to or, in some cases, greater than the changes in firing in the go condition. Therefore, most responses of basalis neurons in the choice phase could not be specific for the arm movement because they occurred when there was no arm movement at all. The visual stimulus presented in the choice phase was also presented earlier on each trial in the cue phase. Although 70% of the task-related basalis neurons responded in the choice phase, only 5% had detectable changes in firing in the cue phase. Of 251 neurons responding in the cue or choice phase, 59% had significantly larger changes in firing in the choice phase than in the cue phase, whereas only one neuron had a larger response in the cue phase. Therefore, most responses of basalis neurons in the choice phase could not be specific for the visual stimulus because similar responses did not occur when the same stimulus was presented in the cue phase. These results indicate that the frequent responses of basalis neurons in the choice phase are neither purely sensory nor motor in nature, but are highly dependent on the context of the stimulus or movement. The neuronal responses in the choice phase may reflect either transient increases in arousal or decision-making processes.     

The involvement of monkey premotor cortex neurones in preparation of visually cued arm movements

Some neurones in macaque postarcuate premotor area modulate their firing frequency in relation to motor tasks which require visual information. We previously reported that a large proportion of these neurones modulate during execution of a detour reaching task in which the movement phase was separated in time from the phase in which the monkey received a visual cue for the movement required to retrieve a food reward. A large proportion of task-related neurones (75%) modulated during this 'visual' phase, in which no task-related movements were made. This modulation was related to the position of the food reward, which served as the visual cue. Most of these neurones were located in cortical area 6, close to the arcuate curvature and its spur, but also more caudally in area 4 and rostrally in area 8. In the present chronic recording experiments in monkeys, several variations of the original task were used in order to test whether the 'visual'-related neuronal modulation could be involved in preparation of the upcoming movement. This modulation is unlikely to be related to any eye or arm movements occurring during the visual phase or to changes in environmental illumination. Neither can it be related to the presence of the visual cue in a particular part of the visual field, since the pattern of neuronal modulation was similar when a cue with a fixed position was used. This modulation was, however, contingent upon the occurrence of food retrieval during the subsequent 'movement phase', since it was abolished or diminished during presentation of a 'food-reward' which the monkey did not retrieve. For several neurones, modulation pattern during the visual phase depended on whether the food reward was to be retrieved with a gross hand movement or with relatively independent finger movements. It is likely, therefore, that neurones in the postarcuate premotor cortex are involved in preparation for arm movements with the help of visual cues. The results are discussed in view of corticocortical pathways which might be involved in transmission of visual information from visual areas through parietal association areas and premotor cortex to the primary motor cortex.     

A failure to stop and attention fluctuations: an evoked oscillations study of the stop-signal paradigm.

OBJECTIVE: It is not always clear whether inhibition or attention deficit underlies a failure to stop a prepared motor response. One possible way to approach this question is to resort to measures of evoked oscillations since functional correlates of different frequency oscillations are relatively well understood. METHODS: The present study examined event-related oscillations during a stop-signal task in non-clinical adults. In 25% of trials of an auditory discrimination tasks subjects had to refrain from a prepared motor response. RESULTS: In successful stop trials, the Go N2 peaked later and the Stop N2 peaked earlier than in failed stop trials. Relative to successful, failed stop trials were associated with a larger N1-N2 and Go P3, and a smaller Stop P3 in the central and posterior cortical regions. The latter effect was exclusively determined by evoked delta oscillations, whereas all other frequency bands contributed to enhanced responses in failed comparative to successful stop trials. CONCLUSIONS: The sum of presented evidence seems to show that success or failure to stop mostly depends on how the subject prepares for the Go and Stop stimuli in advance. If attention is more directed towards the Stop signal, the stopping succeeds, otherwise it fails. SIGNIFICANCE: These data may contribute to understanding the cognitive basis of successful and unsuccessful stopping performance.     

Premotor cortex and the conditions for movement in monkeys (Macaca fascicularis)

Cortical association areas direct their influence on motor cortex via premotor and supplementary motor cortex. In the present experiment premotor cortex was removed bilaterally in monkeys. The monkeys were unable to relearn a visual conditional motor task on which the correct action is specified by visual cues. It was shown that the same monkeys were able to learn a non-motor visual conditional task on which the visual cues specified which object should be chosen. It is concluded that the monkeys are only impaired when they must recall a movement from memory on the basis of a visual cue.     

Discriminative Cues Indicating Reward Magnitude Continue to Determine Reaction Time of Rats Following Lesions of the Nucleus Accumbens

The role of the nucleus accumbens in incentive motivation is accepted but poorly understood. In this study, we examined in the rat one aspect of motivated behaviour which might be mediated by the nucleus accumbens, namely the translation of a motivational signal (the expected value of a reward) into motor output (responding for the reward). Rats were trained in a reaction time task in which on each trial they received one, two or three pellets. The number of pellets for each trial was randomly determined in advance and signalled to the rats by cue lights. Rats responded with faster reaction times as the size of the expected reward increased. Following ibotenic acid lesions of the nucleus accumbens, there was no difference in the pattern or the speed of reaction times. Although lesions of the nucleus accumbens did not disconnect the motivational system from the motor system, it is possible that the nucleus accumbens is involved in the learning of the incentive salience of external stimuli. Therefore, after postoperative testing the cue contingencies were reversed. Initially, the cues continued to be interpreted according to their prior significance, but eventually both the lesioned rats and the control group acquired the new relationship and did so in equivalent times. We conclude that the nucleus accumbens is not involved in the acquisition or expression of the processes whereby the expectation of rewards of different value is translated into a motor initiation signal.     

Distinct information representation and processing for goal-directed behavior in the dorsolateral and ventrolateral prefrontal cortex and the dorsal premotor cortex

Although the lateral prefrontal cortex (lPFC) and dorsal premotor cortex (PMd) are thought to be involved in goal-directed behavior, the specific roles of each area still remain elusive. To characterize and compare neuronal activity in two sectors of the lPFC [dorsal (dlPFC) and ventral (vlPFC)] and the PMd, we designed a behavioral task for monkeys to explore the differences in their participation in four aspects of information processing: encoding of visual signals, behavioral goal retrieval, action specification, and maintenance of relevant information. We initially presented a visual object (an instruction cue) to instruct a behavioral goal (reaching to the right or left of potential targets). After a subsequent delay, a choice cue appeared at various locations on a screen, and the animals could specify an action to achieve the behavioral goal. We found that vlPFC neurons amply encoded object features of the instruction cues for behavioral goal retrieval and, subsequently, spatial locations of the choice cues for specifying the actions. By contrast, dlPFC and PMd neurons rarely encoded the object features, although they reflected the behavioral goals throughout the delay period. After the appearance of the choice cues, the PMd held information for action throughout the specification and preparation of reaching movements. Remarkably, lPFC neurons represented information for the behavioral goal continuously, even after the action specification as well as during its execution. These results indicate that area-specific representation and information processing at progressive stages of the perception-action transformation in these areas underlie goal-directed behavior.     

Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys

It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.     

Neuronal Activity during a Cued Strategy Task: Comparison of Dorsolateral, Orbital, and Polar Prefrontal Cortex

We compared neuronal activity in the dorsolateral (PFdl), orbital (PFo), and polar (PFp) prefrontal cortex as monkeys performed three tasks. In two tasks, a cue instructed one of two strategies: stay with the previous response or shift to the alternative. Visual stimuli served as cues in one of these tasks; in the other, fluid rewards did so. In the third task, visuospatial cues instructed each response. A delay period followed each cue. As reported previously, PFdl encoded strategies (stay or shift) and responses (left or right) during the cue and delay periods, while PFo encoded strategies and PFp encoded neither strategies nor responses; during the feedback period, all three areas encoded responses, but not strategies. Four novel findings emerged from the present analysis. (1) The strategy encoded by PFdl and PFo cells during the cue and delay periods was modality specific. (2) The response encoded by PFdl cells was task and modality specific during the cue period, but during the delay and feedback periods it became task and modality general. (3) Although some PFdl and PFo cells responded to or anticipated rewards, we could rule out reward effects for most strategy- and response-related activity. (4) Immediately before feedback, only PFp signaled responses that were correct according to the cued strategy; after feedback, only PFo signaled the response that had been made, whether correct or incorrect. These signals support a role in generating responses by PFdl, assigning outcomes to choices by PFo, and assigning outcomes to cognitive processes by PFp.     

Modulation of neural activity by motivational and spatial biases

Motivational biases and spatial attention both modulate neural activity and influence behavioural performance. The time course of motivational bias effects, as well as the relationship between motivation and attention across the time course of information processing, however, are relatively unknown. In the present study, event-related potentials (ERPs) were recorded whilst individuals performed a modified Posner task, in which cue stimuli indicated the reward stakes of a given trial and the probable spatial location of a subsequent target stimulus. Reaction times (RTs) were sensitive to motivation and to attention, with faster responses produced on valid and on rewarded trials. In addition, motivation modulated neural activity from the visual analysis of stimuli, with an earlier N1 peak for rewarded compared with non-rewarded stimuli. Effects of motivation were relatively independent from those of attention until late cognitive processing and response production, where motivation and attention interacted to enhance P300-like potentials and the lateralised readiness potential (LRP). The results suggest that multiple sources of modulatory influences may exist, with motivation and attention exerting independent influences over early stimulus and cognitive processing, followed by a late interaction allowing the construction of a comprehensive stimulus representation that contains information pertaining to both motivational and spatial expectations.     

Motor aspects of cue-related neuronal activity in premotor cortex of the rhesus monkey

Neurons in the premotor cortex of rhesus monkeys were studied under two conditions: (1) visuospatial cues were given to guide the amplitude, direction, and onset time of forearm movements or (2) physically identical visual cues were given when reward was contingent on withholding movement. Neurons with sustained activity following the cues were preferentially active when the cues triggered a movement. Thus, activity of certain neurons in this cortical field is linked to motor set, i.e. intention to make a movement in response to the cue, rather than the visual cue per se.     

Encoding problem-solving strategies in prefrontal cortex: activity during strategic errors

The primate prefrontal cortex (PF) plays a central role in choosing goals and strategies. To better understand its mechanisms, we recorded from PF neurons as monkeys used abstract response strategies to select a spatial goal. A visual cue, selected randomly from a set of three cues, appeared on each trial. All three cues were novel when neuronal recording commenced. From trial to trial, the cue could have either been repeated or changed from the previous trial; these were called repeat trials and change trials, respectively. On repeat trials, the monkeys used a Repeat–stay strategy to gain a reward by choosing the same spatial goal as on the previous trial; on change trials, they used a Change–shift strategy to reject the previous goal in favour of an alternative. We reported previously that when monkeys performed the task correctly, many PF neurons had activity encoding one of these two strategies. The monkeys sometimes chose the incorrect strategy, however. Strategy coding was weak or absent during the cue period of error trials which was, for correct trials, the time when the monkeys used a strategy to choose a future goal. By contrast, later in the trial, after the chosen goal had been attained and the monkeys awaited feedback, strategy coding was present and it reflected the strategy used, whether correct or incorrect. The weak cue-period strategy signal could, whatever its cause, have contributed to the errors made, whereas the activity prior to feedback suggests a role in monitoring task performance.     

The rewarding value of good motor performance in the context of monetary incentives

Whether an agent receives positive task feedback or a monetary reward, neural activity in their striatum increases. In the latter case striatal activity reflects extrinsic reward processing, while in the former, striatal activity reflects the intrinsically rewarding effects of performing well. There can be a "hidden cost of reward", which is a detrimental effect of extrinsic on intrinsic reward value. This raises the question how these two types of reward interact. To address this, we applied a monetary incentive delay task: in all trials participants received feedback depending on their performance. In half of the trials they could additionally receive monetary reward if they performed well. This resulted in high performance trials, which were monetarily rewarded and high performance trials that were not. This made it possible to dissociate the neural correlates of performance feedback from the neural correlates of monetary reward that comes with high performance. Performance feedback alone elicits activation increases in the ventral striatum. This activation increases due to additional monetary reward. Neural response in the dorsal striatum on the other hand is only significantly increased by feedback when a monetary incentive is present. The quality of performance does not significantly influence dorsal striatum activity. In conclusion, our results indicate that the dorsal striatum is primarily sensitive to optional or actually received external rewards, whereas the ventral striatum may be coding intrinsic reward due to positive performance feedback. Thus the ventral striatum is suggested to be involved in the processing of intrinsically motivated behavior.