Roles of primate spinal interneurons in preparation and execution of voluntary hand movement.

To study the contribution of primate cervical interneurons (INs) to preparation and execution of normal voluntary hand movement we investigated their activity and correlational linkages to muscles in monkeys performing tracking tasks. During ramp-and-hold flexion-extension torques about the wrist most task-related spinal INs exhibited some activity during both flexion and extension, in unexpected contrast to the strictly unidirectional activity of corticomotoneuronal (CM) cells and motoneurons. Most INs increased their activity more in one of these two directions; response patterns in their preferred direction were typically tonic or phasic-tonic. Spike-triggered averages of EMG detected significant features in muscle activity for many task-related INs. Premotor INs (PreM-INs) were identified by post-spike facilitation or suppression with appropriate onset latencies after the trigger spike. Muscle fields of PreM-INs were smaller than those of supraspinal PreM cells in cortex and red nucleus, and rarely involved reciprocal effects on antagonist muscles. To investigate the relation of spinal INs to a repertoire of different muscle synergies, activity of INs was recorded from a macaque performing a multidirectional wrist task. The monkey generated isometric torques in flexion/extension, radial/ulnar deviation, pronation/supination, and executed a power grip that co-contracted wrist flexor and extensor muscles. Many INs showing task-modulated activity had preferred directions in this multidirectional space, typically with broadly tuned activation. The role of spinal INs in preparation for voluntary movement was revealed in monkeys performing instructed delay tasks. During the delay between a transient visual cue and a go signal a third of the tested INs showed significant delay modulation (SDM) of firing rate relative to the pre-cue rate. The SDM responses often differed from the INs' responses during the subsequent active torque period. In a monkey instructed by either visual or proprioceptive cues the delay period activity for many INs was similar in visual and perturbation trials, although other INs exhibited different SDM for visually and proprioceptively cued trials. These results suggest that spinal INs are involved, with cortex, in the earliest stages of movement preparation. The sensory input to INs could be identified in transient responses to the torque pulse, which showed two predominant patterns, consistent with inputs from cutaneous or proprioceptive receptors. We also investigated the task-dependent modulation of neural responses to peripheral input in a monkey performing wrist flexion/extension movements in a visually cued instructed delay task. Monosynaptic responses evoked by electrical stimulation of the superficial radial nerve through a cuff electrode were suppressed or abolished during the dynamic movement phase. Since task-related activity of the INs increased at the same time, the suppression was mediated by presynaptic rather than postsynaptic inhibition. These observations indicate that under normal behavioral conditions many spinal INs have response properties comparable to those previously documented for cortical neurons in behaving animals.

Distributed processing in the motor system: spinal cord perspective.

Recordings of spinal INs during a flexion/extension wrist task with an instructed delay period have shown directly that many spinal neurons modulate their rate during the preparatory period soon after a visual cue. The onset time and the relation between the delay period activity of spinal INs and the ensuing movement response suggest that this type of activity is not simply related to the forthcoming motor action, but rather reflects a correct match between the visual cue and the motor response. The existence of such activity further supports the notion that the motor system operates in a parallel mode of processing, so that even during early stages of motor processing multiple centers are activated regardless of their anatomical distance from muscles. The firing properties of spinal INs during the performance of the task seem to differ from the comparable properties of motor cortical cells. Spinal INs fire in a highly regular manner--their CV is substantially lower than the observed CV of cortical cells. Also, although neighboring cells tend to have similar response properties, the frequency of significant correlation is lower than for cortical cells and the anatomical extent of the correlation seems to be narrower. The similarity and differences between cortical and spinal cells in terms of response and firing properties suggests that while both type of cells are active in parallel throughout the behavioral phases of the motor task, each may operate in a different mode of information processing.

Functions of mammalian spinal interneurons during movement.

The major recent advances in understanding the role of spinal neurons in generating movement include new information about the modulation of classic reflex pathways during fictive locomotion and in response to pharmacological probes. The possibility of understanding movements in terms of spinal representations of a basic set of movement primitives has been extended by the analysis of normal reflexes. Recordings of the activity of cervical interneurons in behaving monkeys has elucidated their contribution to generating voluntary movement and revealed their involvement in movement preparation.

Primate spinal interneurons show pre-movement instructed delay activity.

Preparatory changes in neural activity before the execution of a movement have been documented in tasks that involve an instructed delay period (an interval between a transient instruction cue and a subsequently triggered movement). Such preparatory activity occurs in many motor centres in the brain, including the primary motor cortex, premotor cortex, supplementary motor area and basal ganglia. Activity during the instructed delay period reflects movement planning, as it correlates with parameters of the cue and the subsequent movement (such as direction and extent), although it occurs well before muscle activity. How such delay-period activity shapes the ensuing motor action remains unknown. Here we show that spinal interneurons also exhibit early pre-movement delay activity that often differs from their responses during the subsequent muscle activity. This delay activity resembles the set-related activity found in various supraspinal areas, indicating that movement preparation may occur simultaneously over widely distributed regions, including spinal levels. Our results also suggest that two processes occur in the spinal circuitry during this delay period: the motor network is primed with rate changes in the same direction as subsequent movement-related activity; and a superimposed global inhibition suppresses the expression of this activity in muscles.

Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys.

There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson's disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (GO and NO-GO). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey C developed motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number of GO mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the GO to the NO-GO mode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate ( approximately 70-80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.

Spatiotemporal structure of cortical activity: properties and behavioral relevance.

The study was designed to reveal occurrences of precise firing sequences (PFSs) in cortical activity and to test their behavioral relevance. Two monkeys were trained to perform a delayed-response paradigm and to open puzzle boxes. Extracellular activity was recorded from neurons in premotor and prefrontal areas with an array of six microelectrodes. An algorithm was developed to detect PFSs, defined as a set of three spikes and two intervals with a precision of +/-1 ms repeating significantly more than expected by chance. The expected level of repetition was computed based on the firing rate and the pairwise correlation of the participating units, assuming a Poisson distribution of event counts. Accordingly, the search for PFSs was corrected for rate modulations. PFSs were found in 24/25 recording sessions. Most PFSs (76%) were composed of spikes of more than one unit but usually not more than two units (67%). The PFSs spanned hundreds of milliseconds, and the average interval between two events within the PFSs was 200 ms. No traces of periodic oscillations were found in the PFS intervals. The bins of the matrix that were defined as PFSs were isolated temporally: the spikes that generated PFSs were not associated with high-frequency bursts or rapid coherent rate fluctuations. A given PFS tended to be correlated with the animal's behavior. Furthermore, for 19% of the PFS pairs that shared the same unit composition, each member of the pair was associated with a different type of behavior. The PFSs often appeared in clusters that were associated with particular phases of the behavior. The firing rate of single units did not provide a full explanation for the timing and structure of these clusters. A reduced spike train (RST) was defined for each unit by taking all spikes of that unit that were part of any PFS. In 88% of the cases the degree of modulation of the RST was higher than that of the complete spike train. The results suggest that relevant information is carried by the fine temporal structure of cortical activity. A coding scheme that involves such temporal structures is rich and sufficiently flexible to facilitate a rapid organization of cortical neurons into functional groups. The results can be accounted for by the synfire chain model, which suggests that cortical activity is mediated by synchronous activation of neural groups in a reverberatory mode.

Spatio-temporal firing patterns in the frontal cortex of behaving monkeys.

Recording the activity of several neurons in parallel in the frontal cortex of behaving monkeys reveals that firing times of neurons can maintain +/- 1 ms accuracy even after delays of over 400 ms. The accurate firing structures were associated with behavior. Neural networks that can sustain such accuracy can learn 'learn' to bind with each other and thus may serve as building blocks for cognitive processes.

Dynamics of neuronal interactions in monkey cortex in relation to behavioural events.

It is possible that brain cortical function is mediated by dynamic modulation of coherent firing in groups of neurons. Indeed, a correlation of firing between cortical neurons, seen following sensory stimuli or during motor behaviour, has been described. However, the time course of modifications of correlation in relation to behaviour was not evaluated systematically. Here we show that correlated firing between single neurons, recorded simultaneously in the frontal cortex of monkeys performing a behavioural task, evolves within a fraction of a second, and in systematic relation to behavioural events. Moreover, the dynamic patterns of correlation depend on the distance between neurons, and can emerge even without modulation of the firing rates. These findings support the notion that neurons can associate rapidly into a functional group in order to perform a computational task, at the same time becoming dissociated from concurrently activated competing groups. Thus, they call for a revision of prevailing models of neural coding that rely solely on single neuron firing rates.

Population responses to multifrequency sounds in the cat auditory cortex: one- and two-parameter families of sounds.

Population responses to multi-frequency sounds were recorded in primary auditory cortex of anesthetized cats. The sounds consisted of single-tone stimuli; two-tone stimuli; and nine-tone stimuli, with the tones evenly spaced on a linear frequency scale. The stimuli were presented through a sealed, calibrated sound delivery system. Single units, cluster activity (CA) and the short-time mean absolute value of the envelope of the neural signal (MABS) were recorded extracellularly from six microelectrodes simultaneously. The CA and MABS were interpreted as measures of the activity of large populations of neurons, in contrast with the single unit activity which is presumably recorded from single neurons. The responses of the MABS signal to simple stimuli were generally similar to those of the CA, but were more stable statistically. Thus, the MABS is better suited for studying the activity of populations of neurons. The responses to tones near the best frequency were strongly influenced by a second tone, even when the second tone was outside the single-tone response area. These influences could be both facilitatory and suppressory. They could not be predicted from the responses to single tones. The responses to the nine-tone stimuli could be explained qualitatively by the responses to the two-tone stimuli. It is concluded that the population responses in primary auditory cortex are shaped by the contributions of the individual frequencies appearing in the stimulus and by the interactions between pairs of frequencies. Interactions between stimulus components are therefore a necessary component of any attempt to explain the processing of complex sounds in the auditory cortex. They may play a role in a global representation of the stimulus spectrum in the primary auditory cortex. The presence of higher-order interactions cannot be excluded by the results presented here.

Population responses to multifrequency sounds in the cat auditory cortex: four-tone complexes.

Population responses to two-tone and four-tone sounds were recorded in primary auditory cortex of anesthetized cats. The stimuli were delivered through a sealed, calibrated sound delivery system. The envelope of the neural signal (short time mean absolute value, MABS) was recorded extracellularly from six microelectrodes simultaneously. A new method was developed to describe the responses to the four-tone complexes. The responses were represented as sums of contributions of different orders. The first order contributions described the effect of the single frequencies appearing in the stimulus. The second order contributions described the modulatory effect of the pairs of frequencies. Higher order contributions could in principle be computed. This paper concentrates on the mean onset responses. The extent to which the first and second order contributions described the onset responses was assessed in two ways. First, the actual responses to two-tone stimuli were compared with those predicted using the contributions computed from the four-tone stimuli. Second, the residual variance in the responses, after the subtraction of the first and second order contributions, was computed and compared with the variability in the responses to repetitions of the same stimulus. The first type of analysis showed good quantitative agreement between the predicted and the measured two-tone responses. The second type of analysis showed that the first and second order contributions were often sufficient to predict the responses to four-tone stimuli up to the level of the variability in the responses to repetitions of a single stimulus. In conjunction with the results of the companion paper (Nelken et al., 1994a) it is concluded that the onset responses to multifrequency sounds are shaped mainly by the single frequency content of the sound and by two-tone interactions, and that higher order interactions contribute much less to the responses. It follows that single-tone effects and two-tone interactions are necessary and sufficient to explain the mean population onset responses to the four-tone stimuli. More information can be coded in the temporal evolution of the responses.

In search of the best stimulus: an optimization procedure for finding efficient stimuli in the cat auditory cortex.

Units in the auditory cortex of cats respond to a large variety of stimuli: pure tones, AM- and FM-modulated signals, clicks, wideband noise, natural sounds, and more. However, no single family of sounds was found to be optimal (in the sense that oriented lines are optimal in the visual cortex). The search for optimal complex sounds is hard because of the high dimensionality of the space of interesting sounds. In an effort to overcome this problem, an automatic search procedure for finding efficient stimuli in high-dimensional sound spaces was developed. This procedure chooses the stimuli to be presented according to the responses to past stimuli, trying to increase the strength of the response. The results of applying this method to recordings of population activity in the primary auditory cortex of cats are described. The search was applied to single tones, two-tone stimuli, four-tone stimuli and to a two-dimensional subset of nine-tone stimuli, parametrized by the center frequency and the fixed difference between adjacent frequencies. The method was able to find efficient stimuli, and its performance improved with the dimension of the sound spaces. Efficient stimuli, found in different optimization runs using population activity recorded from the same electrode, often shared similar frequencies and pairs of frequencies, and tended to evoke similar levels of activity. This result indicates that a global analysis of the location of spectral peaks is performed at the level of the auditory cortex.