Hierarchical Organization Within the Ventral Premotor Cortex of the Macaque Monkey.

Recent studies have revealed that the ventral premotor cortex (PMv) of nonhuman primates plays a pivotal role in various behaviors that require the transformation of sensory cues to appropriate actions. Examples include decision-making based on various sensory cues, preparation for upcoming motor behavior, adaptive sensorimotor transformation, and the generation of motor commands using rapid sensory feedback. Although the PMv has frequently been regarded as a single entity, it can be divided into at least five functionally distinct regions: F4, a dorsal convexity region immediately rostral to the primary motor cortex (M1); F5p, a cortical region immediately rostral to F4, lying within the arcuate sulcus; F5c, a ventral convexity region rostral to F4; and F5a, located in the caudal bank of the arcuate sulcus inferior limb lateral to F5p. Among these, F4 can be further divided into dorsal and ventral subregions (F4d and F4v), which are involved in forelimb and orofacial movements, respectively. F5p contains "mirror neurons" to understand others' actions based on visual and other types of information, and F4d and F5p work together as a functional complex involved in controlling forelimb and eye movements, most efficiently in the execution and completion of coordinated eye-hand movements for reaching and grasping under visual guidance. In contrast, F5c and F5a are hierarchically higher than the F4d, F5p, and F5v complexes, and play a role in decision-making based on various sensory discriminations. Hence, the PMv subregions form a hierarchically organized integral system from decision-making to eye-hand coordination under various behavioral circumstances.

Movement-related activity in the periarcuate cortex of monkeys during coordinated eye and hand movements.

To determine the role of the periarcuate cortex during coordinated eye and hand movements in monkeys, the present study examined neuronal activity in this region during movement with the hand, eyes, or both as effectors toward a visuospatial target. Similar to the primary motor cortex (M1), the dorsal premotor cortex contained a higher proportion of neurons that were closely related to hand movements, whereas saccade-related neurons were frequently recorded from the frontal eye field (FEF). Interestingly, neurons that exhibited activity related to both eye and hand movements were recorded most frequently in the ventral premotor cortex (PMv), located between the FEF and M1. Neuronal activity in the periarcuate cortex was highly modulated during coordinated movements compared with either eye or hand movement only. Additionally, a small number of neurons were active specifically during one of the three task modes, which could be dissociated from the effector activity. In this case, neuron onset was either ahead of or behind the onset of eye and/or hand movement, and some neuronal activity lasted until reward delivery signaled successful completion of reaching. The present findings indicate that the periarcuate cortex, particularly the PMv, plays important roles in orchestrating coordinated movements from the initiation to the termination of reaching. NEW & NOTEWORTHY Movement-related neuronal activity was recorded throughout the periarcuate cortex of monkeys that performed a task requiring them to move their hand only, eyes only, or both hand and eyes toward visuospatial targets. Most typically, neurons were found that were commonly active regardless of different effectors, from movement initiation to completion of a successful outcome. The findings suggest that the periarcuate cortex as a whole plays a crucial role in initiating and completing coordinated eye-hand movements.

Similarity in Neuronal Firing Regimes across Mammalian Species.

UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.

The effects of voluntary control of respiration on the excitability of the primary motor hand area, evaluated by end-tidal CO2 monitoring.

OBJECTIVE: To investigate the effects of voluntary deep breathing on the excitability of the hand area in the primary motor cortex (M1). METHODS: We applied near-threshold transcranial magnetic stimulation (TMS) over M1 during the early phase of inspiration or expiration in both normal automatic and voluntary deep, but not "forced", breathing in eight healthy participants at rest. We monitored exhaled CO2 levels continuously, and recorded motor-evoked potentials (MEPs) simultaneously from the abductor pollicis brevis, first dorsal interosseous, abductor digiti minimi, flexor digitorum superficialis, and extensor incidis muscles. RESULTS: We observed that, during voluntary deep breathing, MEP amplitude increased by up to 50% for all recorded muscles and the latency of MEPs decreased by approximately 1ms, compared with normal automatic breathing. We found no difference in the amplitude or latency of MEPs between inspiratory and expiratory phases in either normal automatic or voluntary deep breathing. CONCLUSIONS: Voluntary deep breathing at rest facilitates MEPs following TMS over the hand area of M1, and MEP enhancement occurs throughout the full respiratory cycle. SIGNIFICANCE: The M1 hand region is continuously driven by top-down neural signals over the entire respiratory cycle of voluntary deep breathing.

Conditional selection of contra- and ipsilateral forelimb movements by the dorsal premotor cortex in monkeys.

It has been suggested that the dorsal premotor cortex (PMd) may contribute to conditional motor behavior. Thus when a selection is instructed by arbitrary conditional cues, it is possible that the unilateral PMd affects behavior, regardless of which arm, contra- or ipsilateral, is to be used. We examined this possibility by recording neuronal activity and injecting muscimol into the caudal PMd (PMdc) of monkeys while they were performing a reaching task toward visuospatial targets with either the right or left arm, as instructed by low-frequency or high-frequency tone signals. Following the injection of a small amount of muscimol (1 microL; 5 microg/microL) into the unilateral PMdc, monkeys exhibited two major deficits in behavioral performance: 1) erroneous selection of the arm not indicated by the instruction (selection errors) and 2) no movement initiation in response to a visuospatial target cue serving as a trigger signal for reaching within the reaction time limit (movement initiation errors). Errors were observed following unilateral muscimol injection into both right and left PMdc, although selection errors occurred with significantly greater frequency in the arm contralateral to the injection site. By contrast, movement initiation errors were more commonly observed in left-arm trials, regardless of whether the right or left PMdc was inactivated. Notably, errors rarely occurred following a ventral PM muscimol injection. These results suggest that the left and right PMdc cooperate to transform conditional sensory cues into appropriate motor output and can affect both contra- and ipsilateral body movement.

Relating neuronal firing patterns to functional differentiation of cerebral cortex.

It has been empirically established that the cerebral cortical areas defined by Brodmann one hundred years ago solely on the basis of cellular organization are closely correlated to their function, such as sensation, association, and motion. Cytoarchitectonically distinct cortical areas have different densities and types of neurons. Thus, signaling patterns may also vary among cytoarchitectonically unique cortical areas. To examine how neuronal signaling patterns are related to innate cortical functions, we detected intrinsic features of cortical firing by devising a metric that efficiently isolates non-Poisson irregular characteristics, independent of spike rate fluctuations that are caused extrinsically by ever-changing behavioral conditions. Using the new metric, we analyzed spike trains from over 1,000 neurons in 15 cortical areas sampled by eight independent neurophysiological laboratories. Analysis of firing-pattern dissimilarities across cortical areas revealed a gradient of firing regularity that corresponded closely to the functional category of the cortical area; neuronal spiking patterns are regular in motor areas, random in the visual areas, and bursty in the prefrontal area. Thus, signaling patterns may play an important role in function-specific cerebral cortical computation.

Laterality of movement-related activity reflects transformation of coordinates in ventral premotor cortex and primary motor cortex of monkeys.

The ventral premotor cortex (PMv) and the primary motor cortex (MI) of monkeys participate in various sensorimotor integrations, such as the transformation of coordinates from visual to motor space, because the areas contain movement-related neuronal activity reflecting either visual or motor space. In addition to relationship to visual and motor space, laterality of the activity could indicate stages in the visuomotor transformation. Thus we examined laterality and relationship to visual and motor space of movement-related neuronal activity in the PMv and MI of monkeys performing a fast-reaching task with the left or right arm, toward targets with visual and motor coordinates that had been dissociated by shift prisms. We determined laterality of each activity quantitatively and classified it into four types: activity that consistently depended on target locations in either head-centered visual coordinates (V-type) or motor coordinates (M-type) and those that had either differential or nondifferential activity for both coordinates (B- and N-types). A majority of M-type neurons in the areas had preferences for reaching movements with the arm contralateral to the hemisphere where neuronal activity was recorded. In contrast, most of the V-type neurons were recorded in the PMv and exhibited less laterality than the M-type. The B- and N-types were recorded in the PMv and MI and exhibited intermediate properties between the V- and M-types when laterality and correlations to visual and motor space of them were jointly examined. These results suggest that the cortical motor areas contribute to the transformation of coordinates to generate final motor commands.

The relationship between salivary biomarkers and state-trait anxiety inventory score under mental arithmetic stress: a pilot study.

Measurement of stress hormones is a common objective method for assessment of mental stress. However, the stress of blood sampling alone may also increase stress hormone levels. In the present study, we sampled salivary biomarkers from healthy volunteers under noninvasive conditions and determined their efficacy to assess mental stress. Specifically, we examined the relationship between State Anxiety Inventory score (STAI-s) in subjects exposed to arithmetic stress and salivary chromogranin-A, alpha-amylase, or cortisol. The STAI-s was significantly correlated to salivary alpha-amylase (r = 0.589; P < 0.01) but not to salivary chromogranin-A or cortisol. Therefore, salivary alpha-amylase is a useful indicator of psychosocial stress.

Activity properties and location of neurons in the motor thalamus that project to the cortical motor areas in monkeys.

The activity of neurons in the motor nuclei of the thalamus that project to the cortical motor areas (the primary motor cortex, the ventral and dorsal premotor cortex, and the supplementary motor area) was investigated in monkeys that were performing a task in which wrist extension and flexion movements were instructed by visuospatial cues before the onset of movement. Movement was triggered by a visual, auditory, or somatosensory stimulus. Thalamocortical neurons were identified by a spike collision, and exhibited 2 distinct types of task-related activity: 1) a sustained change in activity during the instructed preparation period in response to the instruction cues (set-related activity); and 2) phasic changes in activity during the reaction and movement time periods (movement-related activity). A number of set- and moment-related neurons exhibited direction selectivity. Most movement-related neurons were similarly active, irrespective of the different sensory modalities of the cue for movement. These properties of neuronal activity were similar, regardless of their target cortical motor areas. There were no significant differences in the antidromic latencies of neurons that projected to the primary and nonprimary motor areas. These results suggest that the thalamocortical neurons play an important role in the preparation for, and initiation and execution of, the movements, but are less important than neurons of the nonprimary cortical motor areas in modality-selective sensorimotor transformation. It is likely that such transformations take place within the nonprimary cortical motor areas, but not through thalamocortical information channels.

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.

Movement-related neuronal activity reflecting the transformation of coordinates in the ventral premotor cortex of monkeys.

We examined how the transformation of coordinates from visual to motor space is reflected by neuronal activity in the ventral premotor cortex (PMv) of monkeys. Three monkeys were trained to reach with their right hand for a target that appeared on a screen. While performing the task, the monkeys wore prisms that shifted the image of the target 10 degrees, left or right, or wore no prisms, for a block of 200 trials. The nine targets were located in the same positions in visual space regardless of whether the prisms were present. Wearing the prisms required the monkeys to initiate a movement in a direction that was different from the apparent target location. Thus using the prisms, we could dissociate visual space from motor space. While the monkey performed the behavioral task, we recorded neuronal activity in the left PMv and primary motor cortex (MI), and various kinds of task-related neuronal activity were found in the motor areas. These included neurons that changed their activity during a reaction time (RT) period (the period between target presentation and movement onset), which were called "movement-related neurons" and selected for analysis. In these neurons, activity during a movement time (MT) period was also compared. Using general linear models for our statistical analysis, the neurons were then classified into four types: those whose activity was consistently dependent on location of targets in the visual coordinates regardless of whether the prisms were present or absent (V type); those that were consistently dependent on target location in the motor coordinates only; those that had different activity for both of the motor and visual coordinates; and those that had nondifferential activity for the two types of coordinates. The proportion of the four types of the neurons differed significantly between the PMv and MI. Most remarkably, neurons with V-type activity were almost exclusively recorded in the PMv and were almost exclusively found during the RT period. Such activity was never observed in an electromyogram of the working forelimb. Based on these observations, we postulate that the V and other types may represent the various intermediate stages of the transformation of coordinates and that the PMv plays a crucial role in transforming coordinates from visual to motor space.

Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells.

OBJECTIVE: To clarify the influence of moderate hypothermia on the production of proinflammatory cytokines. DESIGN: Controlled in vitro study. SETTING: Research laboratory. SUBJECTS: Peripheral blood mononuclear cells from healthy adult human subjects. INTERVENTIONS: Stimulation with 1 microg/mL lipopolysaccharide at 33 degrees C and 37 degrees C. MEASUREMENTS: Concentrations of released tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were measured chronologically by enzyme immunoassay. The number of mRNA copies of these cytokines was determined by competitive reverse transcriptase-polymerase chain reaction analysis, and nuclear factor-kappaB activations were assessed by electrophoretic mobility shift assay. MAIN RESULTS: Significant reduction of the released-tumor necrosis factor-alpha concentration was observed 1 and 2 hrs after the stimulation with lipopolysaccharide at 33 degrees C compared with 37 degrees C. The peak release of interleukin-1beta at 33 degrees C was delayed 12 hrs later than that at 37 degrees C. A delayed peak in the release of interleukin-6 also was observed at 33 degrees C. The peaks of cytokines were confirmed at the mRNA expression level by competitive reverse transcriptase-polymerase chain reaction analysis at both temperatures. The peak of the tumor necrosis factor-alpha mRNA expression level was observed at 1 hr after the stimulation at 37 degrees C and 2 hrs after the stimulation at 33 degrees C. In the interleukin-1beta mRNA expression, at 37 degrees C the first peak appeared 1 hr and the second 6 hrs after the stimulation. In contrast, at 33 degrees C, the first peak appeared 2 hrs and the second 12 hrs after the stimulation. Whereas interleukin-6 mRNA expression at 37 degrees C peaked 6 hrs after the stimulation, no definite peak was observed at 33 degrees C and the expression level was approximately half of that at 37 degrees C. The maximum intensity of nuclear factor-kappaB activation at 33 degrees C was delayed by 1.5 hrs compared with that at 37 degrees C. CONCLUSIONS: Moderate hypothermia delays the induction of proinflammatory cytokines in human peripheral blood mononuclear cells.

Concerted Movement of Prestalk Cells in Migrating Slugs of Dictyostelium Revealed by the Localization of Myosin.

Localization of myosin in slugs of the cellular slime mold Dictyostelium discoideum was investigated by an immunofluorescence technique. Myosin is thought to provide the molecular machinery for cellular movement. We found that myosin could be visualized as c-shaped fluorescence at the cortex of prestalk cells in a migrating slug, and that the open regions of all c-shaped fluorescence point in the direction of the slug's migration. We reported previously that the c-shaped fluorescence of myosin can be seen at the cortex of the tail region of actively locomoting cells at the unicellular stage (39, 41). These results suggest that prestalk cells move actively in the slug, and that their direction of movement, which can be identified from the polarity of c-shaped fluorescence, correspond with the direction of the slug's migration. The distribution of c-shaped fluorescence in slugs during migration, phototaxis and avoidance of ammonia strongly suggests that the slug's behavior is controlled by the concerted movement of prestalk cells.