A motor area rostral to the supplementary motor area (presupplementary motor area) in the monkey: neuronal activity during a learned motor task.

1. The rostromesial agranular frontal cortex of macaque monkey (Macaca fuscata), traditionally defined as the supplementary motor area (SMA), was studied using various physiological techniques to delineate two different areas rostrocaudally. 2. Field and unitary responses to electrical stimulation of the primary motor cortex were distinct in the caudal part, but minimal or absent in the rostral part. Intracortical microstimulation readily evoked limb or orofacial movements in the caudal part, but only infrequently in the rostral part. Neuronal responses to visual stimuli prevailed in the rostral part, but somatosensory responses were rare. The opposite was true in the caudal part. 3. The rostral part, roughly corresponding to area 6a beta, was operationally defined as the presupplementary motor area (pre-SMA). The caudal part was redefined as the SMA proper. 4. Single-cell activity in the pre-SMA was quantitatively compared with that in the SMA proper in relation to a trained motor task. 5. Phasic responses to visual cue signals indicating the direction of forthcoming arm-reaching movement were more abundant in the pre-SMA. 6. Activity changes during the preparatory period, which lasted until the occurrence of the trigger signal for the reaching movement, were more frequent in the pre-SMA. 7. Phasic, movement-related activity was more frequent in the SMA, and its onset was often time locked to the movement onset. In the pre-SMA, the occurrences of response time locked to the movement-trigger signal were more frequent than in the SMA. 8. Among neurons in both areas, directional selectivity was found in all the cue, preparatory, and movement-related responses.     

Supplementary motor area encodes reward expectancy in eye-movement tasks

Neural activity signifying the expectation of reward has been found recently in many parts of the brain, including midbrain and cortical structures. These signals can facilitate goal-directed behavior or the learning of new skills based on reinforcements. Here we show that neurons in the supplementary motor area (SMA), an area concerned with movements of the body and limbs, also carry a reward expectancy signal in the postsaccadic period of oculomotor tasks. While the monkeys performed blocks of memory-guided and object-based saccades, the neurons discharged a burst after a approximately 200-ms delay following the target-acquiring saccade in the memory task but often fired concurrently with the target-acquiring saccade in the object task. The hypothesis that this postsaccadic bursting activity reflects the expectation of a reward was tested with a series of manipulations to the memory-guided saccade task. It was found that although the timing of the bursting activity corresponds to a visual feedback stimulus, the visual feedback is not required for the neurons to discharge a burst. Second, blocks of no-reward trials reveal an extinction of the bursting activity as the monkeys come to understand that they would not be rewarded for properly generated saccades. Finally, the delivery of unexpected rewards confirmed that in many of the neurons, the activity is not related to a motor plan to acquire the reward (e.g., licking). Thus we conclude that reward expectancy is represented by the activity of SMA neurons, even in the context of an oculomotor task. These results suggest that the reward expectancy signal is broadcast over a large extent of motor cortex, and may facilitate the learning of new, coordinated behavior between different body parts.     

Supplementary motor area activations in unconscious inhibition of voluntary action

It is widely accepted that regions within the dorsal medial frontal cortex are involved in the control of voluntary action. However, recent evidence suggests that a subset of these regions may also be important for unconscious and involuntary motor processes. Indeed, Sumner et al. (Neuron 54:697–711, 2007) showed that two patients with micro-lesions of the supplementary motor area (SMA) and supplementary eye field (SEF) demonstrated an absence of unconscious inhibition as evoked by masked-prime stimuli, while pre-SMA damage had no such effect. Here, we employ fMRI and a similar masked-prime task to test whether SMA and pre-SMA are similarly dissociated in healthy volunteers. Reaction times (RT) revealed that responses to compatible trials were slower than those to incompatible trials (negative compatibility effect, NCE), indicating automatic inhibition in every participant. BOLD signals in the SMA were modulated by prime compatibility, showing greater signal for compatible trials, but there was no change in pre-SMA. There was also no modulation in the hand motor cortex (HMC). These findings imply that the SMA is involved in automatic suppression of manual motor plans.     

Supplementary motor area activation while tapping bimanually different rhythms in musicians

Summary In 15 musicians, cortical DC-potentials were recorded from the scalp before and during the execution of bimanual motor sequences. Subjects (Ss) either tapped with their two index fingers in synchrony (quavers against quavers; 2 against 2) or they tapped quavers against triplets (2 against 3). Either the right or the left finger started tapping the quavers (onset time t₁), after about 4 s the other finger joined in (t₂) either with quavers as well (easy rhythm) or with triplets (difficult rhythm). Ss were free to start the sequences, i.e. to determine the onset times t₁ and t₂. Shifts of cortical DC potentials were averaged twice; (1) time-locked to t₁ and (2) time-locked to t₂. When moving in synchrony (easy rhythm) DC-potential shifts and maps of radial current densities across the scalp indicated activations of the two primary motor cortices (MI). When bimanually tapping different rhythms, there was not only an activation of MI cortices, but in addition a very large activation of the mesial, central cortex was observed. It is suggested that this cortical area which mainly contains the supplementary motor area (SMA) has the function of controlling the initiations of movements in the difficult sequence which have to fit into a very precise timing plan. Interestingly, activation of the mesial, central cortex preceded the actual performance of the difficult rhythm by about 4 s. This finding indicates that the preparatory set differs between the two tasks.     

Supplementary motor area in the monkey: activity of neurons during performance of a learned motor task.

1. Recordings were made of the natural discharges of neurons in the supplementary motor area (SMA) of conscious monkeys trained to perform stereotyped motor task, pulling a horizontal lever, with either hand. 2. Of the total population of cells, 80% showed modulation of their activity during particular movements of either limb. Many cells had a similar pattern of modulation regardless of whether the contralateral or ipsilateral hand was used. Of the remaining 20%, some cells were related to leg or body movements or to visual experience. 3. Cells whose activity was related to movements of distal joints were found in approximately equal numbers to those whose discharges occurred with proximal movements. 4. Only 5% of cells tested sent their axons into the pyramidal tract, and only 14% of units investigated showed responses to passive manipulation of the limbs. The effective afferent input usually was of a rather complex kind. 5. The findings suggest that the discharges of a large number of neurons in SMA are changing during particular movements of either arm, and that only a small number of cells receive peripheral afferent sensory input. These results contrast with those obtained in the primary motor area and suggest a different role for SMA in the control of movement.     

Contrasting neuronal activity in supplementary and precentral motor cortex of monkeys. I. Responses to instructions determining motor responses to forthcoming signals of different modalities

The present report contrasts neuronal activity in two motor cortical fields after instructions that determine which of two sensory signals will trigger a movement and which will not. The goal of the study was to determine possible differential roles of the two cortical fields in the process of preparing to move in response to one external cue and to ignore another. Single-cell recordings were made from the supplementary motor area (SMA) and the precentral motor area (PCM) of monkeys trained to perform key-press movements in two different modes. In the auditory mode, an instruction signal warned the animal to prepare to start the movement promptly in response to a forthcoming 1,000-Hz tone burst (trigger signal), but to remain motionless if the signal was vibrotactile (nontrigger signal). In the tactile mode, the trigger and nontrigger signals were reversed: a different instruction signal warned the animal to prepare to perform the key-press movement in response to the vibrotactile cue, but to withhold it in response to the 1,000-Hz tone. The instruction signals were auditory tones of 300 Hz for the auditory mode and 100 Hz for the tactile mode. Out of 259 task-related SMA neurons, 128 (49%) responded to instructions. Three types of instruction responses were observed: 1) 95 neurons showed continuous instruction-induced activity changes lasting until the occurrence of the movement-triggering signal, regardless of whether an intervening nontrigger signal occurred. 2) 24 neurons showed increased activity until the occurrence of the nontriggering signal, after which the activity subsided. When there was no nontrigger signal, the activity increased during a period when the nontrigger signal might have been given. 3) Nine neurons responded with a transient, short-latency discharge after the instruction. The responses of SMA neurons to two instructions were often different. Forty-four SMA neurons exhibited a selective response to only one of the two instructions. In 43 neurons the response was differential, with the magnitude of activity increase or decrease being at least three times greater after one instruction than the other. In the remaining 41 neurons the response was nondifferential. Out of 112 task-related PCM neurons, 25 (22%) responded to the instructions. In the majority of them (21 neurons), the instruction response was nondifferential.(ABSTRACT TRUNCATED AT 400 WORDS)     

Timing of bimanual movements in human and non-human primates in relation to neuronal activity in primary motor cortex and supplementary motor area

It has been established that repeated presentation of a transient target motion stimulus such as a constant-velocity ramp leads to the build up of steady state (SS), anticipatory smooth pursuit eye movements after two or three presentations. Each SS response is then composed of the anticipatory component of nonvisual origin, a visual component associated with the stimulus presentation and another nonvisual component that represents the decay of the response after extinction of the stimulus. Here we investigated the interactions that occur when each motion stimulus was itself a sequence containing more than one ramp component. Ramp components had a velocity of 15 degrees /s or 30 degrees /s to left or right and were separated by gaps of 200 ms duration. In an initial experiment, responses to 2-ramp stimuli were examined and compared with responses to the single-ramp stimuli from which they were constituted. We present evidence that the anticipatory, nonvisual components of the double-ramp response result from the linear summation of the nonvisual components of the responses to the constituent single-ramp components. In a 2nd experiment, we examined responses to a wide variety of 4-ramp sequences and again found evidence that, in the SS, the responses were formed from the linear summation of the constituent single-ramp components. Regression analysis performed on the velocity at onset of each ramp component indicated that this nonvisual part of the response was predictive of the upcoming ramp component. To confirm this, unexpected changes were introduced into single ramp components of the 4-ramp sequence after at least five prior presentations of the sequence had allowed a SS response to be established. Subjects continued to initiate a response to the modified component that was appropriate in velocity and direction for the corresponding part of the previous sequence and inappropriate for the newly modified stimulus. This preprogrammed response persisted unmodified for more than 170 ms after onset of the modified ramp component. In contrast, in the second presentation of the new sequence, the anticipatory component of the response was highly correlated with the SS response of the new sequence, but not with that of the prior sequence, showing that the preprogrammed response had been modified very rapidly. Similar behaviour was observed whichever of the 4-ramp components was modified, indicating that the velocity and direction of the anticipatory response to each component had been preprogrammed. The results suggest that velocity information related to at least four elements of a sequence can be temporarily stored and subsequently released with appropriate temporal order to form an anticipatory response throughout the whole sequence.     

Extended neuronal protection induced after sublethal ischemia adjacent to the area with delayed neuronal death

In the present study, we investigated whether neurons adjacent to an ischemic lesion acquire tolerance against subsequent ischemia or not. We initially used unilateral hemispheric ischemia for 3 min in gerbils to produce an ischemic lesion confined to the unilateral CA1 sector, and the presence of tolerance was examined in the adjacent CA3 sector through transient global ischemia by occlusion of both common carotid arteries. Attenuation of neuronal damage was clearly observed in neurons in the CA3 sector adjacent to the ischemic lesion in the CA1 sector. The phenomenon lasted for up to two weeks after the initial hemispheric ischemia, but was no longer present two months later. Reactive astrocytes as identified by the presence of glial fibrillary acidic protein were visible in the CA3 hippocampus four days and two weeks after hemispheric ischemia, but they were scarce two months later. Expression of heat shock protein 72 in the CA3 neurons was observed four days after hemispheric ischemia, but the reaction returned to the control level two weeks later.In conclusion, the present study showed that tolerance in the neurons adjacent to an ischemic lesion could be sustained at least for two weeks, and raised the possibility that reactive astrocytes might contribute to the extended tolerance in neurons.     

Differential roles of neuronal activity in the supplementary and presupplementary motor areas: from information retrieval to motor planning and execution

We explored functional differences between the supplementary and presupplementary motor areas (SMA and pre-SMA, respectively) systematically with respect to multiple behavioral factors, ranging from the retrieval and processing of associative visual signals to the planning and execution of target-reaching movement. We analyzed neuronal activity while monkeys performed a behavioral task in which two visual instruction cues were given successively with a delay: one cue instructed the location of the reach target, and the other instructed arm use (right or left). After a second delay, the monkey received a motor-set cue to be prepared to make the reaching movement as instructed. Finally, after a GO signal, it reached for the instructed target with the instructed arm. We found the following apparent differences in activity: 1) neuronal activity preceding the appearance of visual cues was more frequent in the pre-SMA; 2) a majority of pre-SMA neurons, but many fewer SMA neurons, responded to the first or second cue, reflecting what was shown or instructed; 3) in addition, pre-SMA neurons often reflected information combining the instructions in the first and second cues; 4) during the motor-set period, pre-SMA neurons preferentially reflected the location of the target, while SMA neurons mainly reflected which arm to use; and 5) when executing the movement, a majority of SMA neurons increased their activity and were largely selective for the use of either the ipsilateral or contralateral arm. In contrast, the activity of pre-SMA neurons tended to be suppressed. These findings point to the functional specialization of the two areas, with respect to receiving associative cues, information processing, motor behavior planning, and movement execution.     

Influences of motor instructions on the reaction times of saccadic eye movements

When a gap period is inserted between the fixation point extinction and the target presentation, the distribution of saccadic reaction times has two distinct peaks: one at 150-250 ms (ordinary saccades) and another at approximately 100 ms (express saccades). The distribution of saccadic reaction times can be explained by the linear approach to threshold with ergodic rate (LATER) model, in which the value of a decision signal increases linearly from a start level to initiate a saccade when the signal value reaches a threshold. We hypothesized that a gap period and/or an instruction signal can modulate the parameters of the model to determine when a saccade is initiated. Two reciprobit plots of reaction times, one for ordinary and the other for express saccades, for a task with both a gap period and visuospatial instruction, were constrained by a common infinite-time intercept, although no such constraint was observed during task performance without a visuospatial instruction. We interpreted the results that either the threshold, the start level, or the rate of increase of the decision signal of the model was switched in a bistable manner by both the visuospatial instruction and a gap period, but not by the gap period alone.     

From rule to response: neuronal processes in the premotor and prefrontal cortex

The ability to use abstract rules or principles allows behavior to generalize from specific circumstances (e.g., rules learned in a specific restaurant can subsequently be applied to any dining experience). Neurons in the prefrontal cortex (PFC) encode such rules. However, to guide behavior, rules must be linked to motor responses. We investigated the neuronal mechanisms underlying this process by recording from the PFC and the premotor cortex (PMC) of monkeys trained to use two abstract rules: "same" or "different." The monkeys had to either hold or release a lever, depending on whether two successively presented pictures were the same or different, and depending on which rule was in effect. The abstract rules were represented in both regions, although they were more prevalent and were encoded earlier and more strongly in the PMC. There was a perceptual bias in the PFC, relative to the PMC, with more PFC neurons encoding the presented pictures. In contrast, neurons encoding the behavioral response were more prevalent in the PMC, and the selectivity was stronger and appeared earlier in the PMC than in the PFC.     

Primate antisaccade. II. Supplementary eye field neuronal activity predicts correct performance

Neuronal activities were recorded in the supplementary eye field (SEF) of 3 macaque monkeys trained to perform antisaccades pseudorandomly interleaved with prosaccades, as instructed by the shape of a central fixation point. The prosaccade goal was indicated by a peripheral stimulus flashed anywhere on the screen, whereas the antisaccade goal was an unmarked site diametrically opposite the flashed stimulus. The visual cue was given immediately after the instruction cue disappeared in the immediate-saccade task, or during the instruction period in the delayed-saccade task. The instruction cue offset was the saccade gosignal. Here we focus on 92 task-related neurons: visual, eye-movement, and instruction/fixation neurons. We found that 73% of SEF eye-movement-related neurons fired significantly more before anti-saccades than prosaccades. This finding was analyzed at 3 levels: population, single neuron, and individual trial. On individual antisaccade trials, 40 ms before saccade, the firing rate of eye-movement-related neurons was highly predictive of successful performance. A similar analysis of visual responses (40 ms astride the peak) gave less-coherent results. Fixation neurons, activated during the initial instruction period (i.e., after the instruction cue but before the stimulus) always fired more on antisaccade than on prosaccade trials. This trend, however, was statistically significant for only half of these neurons. We conclude that the SEF is critically involved in the production of antisaccades.     

Change in neuronal firing patterns in the process of motor command generation for the ocular following response

To explore the process of motor command generation for the ocular following response, we recorded the activity of single neurons in the medial superior temporal (MST) area of the cortex, the dorsolateral pontine nucleus (DLPN), and the ventral paraflocculus (VPFL) of the cerebellum of alert monkeys during ocular following elicited by sudden movements of a large-field pattern. Using second-order linear-regression models, we analyzed the quantitative relationships between neuronal firing frequency patterns and eye movements or retinal errors specified by three parameters (position, velocity, and acceleration). We first attempted to reconstruct the temporal waveform of each neuronal response to each visual stimulus and computed the coefficients for each parameter using the least-square error method for each stimulus condition. The temporal firing patterns were generally well reconstructed [coefficient of determination index (CD) > 0.7] from either the retinal error or the associated ocular following response. In the MST and DLPN datasets, however, the fit with the retinal error model was generally better than with the eye-movement model, and the estimated coefficients of acceleration and velocity ranged widely, indicating that temporal patterns in these regions showed considerable diversity. The acceleration component is greater in MST and DLPN than in VPFL, suggesting that an integration occurs in this pathway. When we determined how well the temporal patterns of the neuronal responses of a given cell could be reconstructed for all visual stimuli using a single set of coefficients, good fits were found only for Purkinje cells (P- cells) in the VPFL using the eye-movement model. In these cases, the coefficients of acceleration and velocity for each cell were similar, and the mean ratio of the acceleration and velocity coefficients was close to that of motor neurons. These results indicate that individual MST and DLPN neurons are each encoding some selective aspects of the sensory stimulus (visual motion), whereas the P-cells in VPFL are encoding the complete dynamic command signals for the associated motor response (ocular following). We conclude that the sensory-to-motor transformation for the ocular following response occurs at the P-cells in VPFL.     

Premotor and supplementary motor cortex in rhesus monkeys: neuronal activity during externally- and internally-instructed motor tasks

Summary We compared neuronal activity in the premotor (PM) and supplementary motor cortex (SM) of two rhesus monkeys as they performed two tasks. In an externally-instructed task, a visuospatial instruction stimulus indicated which of two touch pads should be the target of a forelimb movement. In an internally-instructed task, the visuospatial stimulus was either irrelevant or not presented, but in either case the target alternated between the two touch pads in blocks of 20 trials each. In both tasks, the monkey withheld movement for a self-timed delay period. Neuronal activity modulation during the delay period (set-related activity) and immediately before movement (movement-related activity) was comparable in PM and SM, both in terms of the proportion of cells with both of those activity patterns and their depth of modulation. Thus, our findings do not provide strong support for a clear-cut functional division between PM and SM regarding the control of externally- and internally-instructed limb movements. Within PM, 57 out of 96 cells with set-related activity showed similar modulation during the two tasks, supporting the proposition that such activity contributes to the preparation for a limb movement. In 32 of the 39 PM set-related neurons that showed a significant activity difference between the two tasks, activity was greater in the externally-instructed task. This finding supports the hypothesis that set-related activity in PM contributes more to sensorially-instructed than to other movements.     

The contribution of the DNA damage response to neuronal viability

Neurons are extremely active cells and metabolize up to 20% of the oxygen that was consumed by the organism. Despite their highly oxygenic metabolism, neuronal cells have a lower capacity to neutralize the reactive oxygen species (ROS) that they generate or to which they are exposed. High levels of ROS can lead to accumulation of damage to various cellular macromolecules. One of the cellular macromolecules highly affected by intracellular as well as extracellular insults is DNA. Neurons are also highly differentiated, postmitotic cells that cannot be replenished after disease or trauma. Since neurons are irreplaceable and should survive as long as the organism does, they need elaborate defense mechanisms to ensure their longevity. This review article mainly focuses on certain mechanisms that contribute to neuronal longevity, and concentrates on the DNA damage response in neuronal cells. The various mechanisms of DNA repair are briefly described, and focus is on those mechanisms that are activated in neuronal cells following DNA damage. Evidence is presented to show that proper DNA damage response is critically important, not just for normal neuronal development but throughout the entire life of any organism. Defective DNA damage response in older human age can generate neurodegenerative disorders such as Alzheimer's or Parkinson diseases.     

Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1

Most functional brain imaging studies use task-induced hemodynamic responses to infer underlying changes in neuronal activity. In addition to increases in cerebral blood flow and blood oxygenation level-dependent (BOLD) signals, sustained negative responses are pervasive in functional imaging. The origin of negative responses and their relationship to neural activity remain poorly understood. Through simultaneous functional magnetic resonance imaging and electrophysiological recording, we demonstrate a negative BOLD response (NBR) beyond the stimulated regions of visual cortex, associated with local decreases in neuronal activity below spontaneous activity, detected 7.15 +/- 3.14 mm away from the closest positively responding region in V1. Trial-by-trial amplitude fluctuations revealed tight coupling between the NBR and neuronal activity decreases. The NBR was associated with comparable decreases in local field potentials and multiunit activity. Our findings indicate that a significant component of the NBR originates in neuronal activity decreases.