[Functional Parcellation of Frontal Higher Order Motor Cortex].

Motor areas in the frontal cortex are classified into medial and lateral functional groups. The dorsal premotor areas in the lateral groups are involved in motor guidance based on behavioral rules. The ventral premotor cortex contributes to motor guidance relying on spatial aspects of sensory information. The supplementary motor complex in the medial groups is related to the bimanual and temporal organization of multiple motor acts. The cingulate motor area is involved in motor control based on reward-prediction errors. The supplementary eye field is involved in monitoring performance and the adjustment of sequential visual search. The motor areas are coordinated in a context-dependent manner, influenced by top-down signals from the prefrontal cortex and by bottom-up signals from the parietal cortex, which are also organized into the lateral and medial functional groups. Evidence suggests that the medial and lateral functional groups are balanced by the insula cortex and anterior cingulate cortex which serve as salience detectors for changes in bodily states.

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.

Neurons in the cingulate motor area signal context-based and outcome-based volitional selection of action.

Volitional selection of action is subject to continuous adjustment under the influence of information obtained by monitoring behavioral consequences and by exploiting behavioral context based on prior knowledge about the environment. The rostral cingulate motor area (CMAr) is thought to be responsible for adjusting behavior by monitoring its consequences. To investigate whether the CMAr also plays a role in exploitation of behavioral context in action selection, we recorded neuronal activities from the CMAr while monkeys performed a reward-based motor selection task that required them to switch from one action to the other based on the amount of reward. We examined both the behavior of monkeys and the activity of CMA neurons quantitatively by constructing a hybrid reinforcement learning model incorporating context-based and outcome-based action values into a new action value. We found that CMAr neurons encoded the context-based action value by increasing or decreasing their firing rates gradually with the number of repetitions of the same movement (i.e., behavioral context). We also found that CMAr neurons encoded the context-based and outcome-based action values in two distinct time windows at single neuron and population levels. Our findings indicate that the CMAr is involved in behavioral adjustment of action selection by exploiting the behavioral context and not merely by monitoring reward outcome.

Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling.

BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) have increased activity in the insula and reduced activation of the dorsolateral prefrontal cortex (DLPFC) in response to visceral stimulation. We investigated whether they have latent impairments in cognitive flexibility because of dysfunction in the DLPFC and insula and altered connectivity between brain regions. METHODS: We analyzed data from 30 individuals with IBS (15 men; age, 21.7 ± 3.0 y) diagnosed based on Rome III criteria, along with 30 individuals matched for age, sex, and education level (controls). Event-related functional magnetic resonance imaging of the brain was performed to evaluate cognitive flexibility and was assessed by the Wisconsin Card Sorting Test, in which subjects are allowed to change choice criteria, defined as set-shifting in response to error feedback. Brain images were analyzed with statistical parametric mapping 5 and 8 software and dynamic causal modeling. RESULTS: Subjects with IBS had significantly more Nelson perseverative errors (P < .05) and set-maintenance difficulties (P < .05) than controls. They also showed significantly decreased activity of the right DLPFC (Brodmann's area 9; P < .001) and right hippocampus (P < .001), and significantly increased activity of the left posterior insula (P < .001) at error feedback during set-shifting. Dynamic causal modeling analysis during set-shifting revealed significantly less connectivity from the DLPFC to pre-supplementary motor area in subjects with IBS, compared with controls (P = .012). CONCLUSIONS: Individuals with IBS have latent impairments in cognitive flexibility as a result of altered activity of the DLPFC, insula, and hippocampus, and impaired connectivity between the DLPFC and pre-supplementary motor area.

Deciphering elapsed time and predicting action timing from neuronal population signals.

The proper timing of actions is necessary for the survival of animals, whether in hunting prey or escaping predators. Researchers in the field of neuroscience have begun to explore neuronal signals correlated to behavioral interval timing. Here, we attempt to decode the lapse of time from neuronal population signals recorded from the frontal cortex of monkeys performing a multiple-interval timing task. We designed a Bayesian algorithm that deciphers temporal information hidden in noisy signals dispersed within the activity of individual neurons recorded from monkeys trained to determine the passage of time before initiating an action. With this decoder, we succeeded in estimating the elapsed time with a precision of approximately 1 s throughout the relevant behavioral period from firing rates of 25 neurons in the pre-supplementary motor area. Further, an extended algorithm makes it possible to determine the total length of the time-interval required to wait in each trial. This enables observers to predict the moment at which the subject will take action from the neuronal activity in the brain. A separate population analysis reveals that the neuronal ensemble represents the lapse of time in a manner scaled relative to the scheduled interval, rather than representing it as the real physical time.

Deficits in action selection based on numerical information after inactivation of the posterior parietal cortex in monkeys.

A previous study identified neuronal activity in area 5 of the monkey posterior parietal cortex that reflects the numerosity of a series of self-performed actions. It is not known, however, whether area 5 is crucially involved in the selection of an action based on numerical information or, instead, merely reflects numerosity-related signals that originate in other brain regions. We transiently and focally inactivated area 5 to test its functional contributions to numerosity-based action selection. Two monkeys were trained to either push or turn a handle in response to a visual trigger signal. The selection of the action was solely based on numerical information from a series of actions performed by the monkey: select A five times, select B five times, and then return to A in a cyclical fashion. When muscimol was applied to a portion of area 5 in which the activity in the numerosity-selective cells was recorded, the error rate in the selection task increased significantly. This transient neural inactivation also caused omission errors that were not observed before the muscimol injection. A control task showed that the errors were not caused by motor deficits or impaired ability to select between two possible actions. Our results indicate that area 5 is crucial for selecting actions on the basis of numerical information about a series of actions performed by the tested individual.

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.

Interval time coding by neurons in the presupplementary and supplementary motor areas.

Interval timing is an essential guiding force of behavior. Previous reports have implicated the prefrontal and parietal cortex as being involved in time perception and in temporal decision making. We found that neurons in the medial motor areas, in particular the presupplementary motor area, participate in interval timing in the range of seconds. Monkeys were trained to perform an interval-generation task that required them to determine waiting periods of three different durations. Neuronal activity contributed to the process of retrieving time instructions from visual cues, signaled the initiation of action in a time-selective manner, and developed activity to represent the passage of time. These results specify how medial motor areas take part in initiating actions on the basis of self-generated time estimates.

Spatial distribution of cingulate cortical cells projecting to the primary motor cortex in the rat.

We examined the location and spatial distribution of cingulate cortical cells projecting to the primary motor cortex (M1) in rats, using a double retrograde-labeling technique. The orofacial, forelimb, and hindlimb areas of M1 were physiologically identified based on the findings of intracortical microstimulation and single cell recording. Two different tracers, diamidino yellow and fast blue, were injected into two sites of M1 in each rat. Retrograde-labeled cells in the cingulate cortex were plotted with an automated plotting system. Cells projecting to the orofacial and forelimb areas of M1 were distributed in the anterior cingulate cortex (area 24) but not in the posterior cingulate cortex (retrosplenial cortex; area 29), according to topographical mapping. On the other hand, few or no cells of the cingulate cortex were observed projecting to the hindlimb area of M1. These findings suggest that the cingulate cortex projecting to the M1 in the rat are involved in the regulation of motor activity that involves the orofacial and forelimb, but not hindlimb, parts of the body.

Concept-based behavioral planning and the lateral prefrontal cortex.

Many lines of evidence implicate the lateral prefrontal cortex (LPFC) in the executive control of behavior. In early studies, neuronal activity in this area was thought to retain information about forthcoming movements for a short period until they were executed. However, later studies have stressed its role in the cognitive aspects of behavioral planning, such as behavioral significance, behavioral rules and behavioral goals. The consequence of the intended action (i.e. a change in the state of the target object), rather than the intended movement, is primarily represented in the LPFC during planning. Recent studies show that the LPFC is involved in more abstract aspects of conceptual processes, such as in representing categories of multiple actions at the stage of behavioral planning.

Categorization of behavioural sequences in the prefrontal cortex.

Although it has long been thought that the prefrontal cortex of primates is involved in the integrative regulation of behaviours, the neural architecture underlying specific aspects of cognitive behavioural planning has yet to be clarified. If subjects are required to remember a large number of complex motor sequences and plan to execute each of them individually, categorization of the sequences according to the specific temporal structure inherent in each subset of sequences serves to facilitate higher-order planning based on memory. Here we show, using these requirements, that cells in the lateral prefrontal cortex selectively exhibit activity for a specific category of behavioural sequences, and that categories of behaviours, embodied by different types of movement sequences, are represented in prefrontal cells during the process of planning. This cellular activity implies the generation of neural representations capable of storing structured event complexes at an abstract level, exemplifying the development of macro-structured action knowledge in the lateral prefrontal cortex.

Binary-coded monitoring of a behavioral sequence by cells in the pre-supplementary motor area.

To regulate the temporal structure of a series of behavioral sequences involving multiple actions, it is essential to monitor the progress of the entire behavioral process. To identify the involvement of three cortical motor areas in monitoring behavioral sequences, we examined neuronal activity while monkeys sequentially performed a series of motor tasks in accordance with a predetermined behavioral schedule that included a numerical structure. We found that neurons in the pre-supplementary motor area exhibited activity that appeared to monitor the performance of the behavioral trials in a binary-coded manner. One-half of the activity represented odd-numbered trials within a behavioral sequence, whereas the other one-half represented even-numbered trials. Such neuronal activity, resembling the operation of binary counting elements widely used for constructing artificial computing devices, was rare in the supplementary motor area or in the primary motor cortex.

Prefrontal cortical cells projecting to the supplementary eye field and presupplementary motor area in the monkey.

We examined the location and spatial distribution of prefrontal cortical (PF) cells projecting to the supplementary eye field (SEF) and presupplementary motor area (pre-SMA) using a double retrograde-labeling technique in monkeys (Macaca fuscata). The SEF and pre-SMA were physiologically identified based on the findings of intracortical microstimulation and single cell recordings. Two fluorescent tracers, diamidino yellow and fast blue, were injected into the SEF and pre-SMA of each monkey. Retrogradely labeled cells in the PF were plotted with an automated plotting system. The cells projecting to the SEF and pre-SMA were mainly distributed in the upper and lower banks of the principal sulcus (area 46), with little overlap. Cells projecting to the SEF, but not to the pre-SMA, were observed in areas 8a, 8b, 9, 12, and 45. These findings suggest that the SEF and pre-SMA receive different sets of information from the PF cells.

Cingulate cortical cells projecting to monkey frontal eye field and primary motor cortex.

We compared the distribution of cingulate cortical cells projecting to the frontal eye field (FEF) and primary motor cortex (MI) using a multiple retrograde labeling technique. Two fluorescent tracers were injected into physiologically identified FEF and MI in each monkey. The location of cells projecting to the forelimb area of MI served to identify the rostral (CMAr) and caudal (CMAc) cingulate motor areas. We found two foci of cells projecting to the FEF: rostral (CEFr) and caudal (CEFc) cingulate eye field. The CEFr was located rostral to the CMAr, while the CEFc was located rostro-ventral to the CMAc. Cells projecting to the FEF and MI scarcely overlapped, indicating that each area receives different sets of information from the cingulate cortex.

Differences in spiking patterns among cortical neurons.

Spike sequences recorded from four cortical areas of an awake behaving monkey were examined to explore characteristics that vary among neurons. We found that a measure of the local variation of interspike intervals, L(V), is nearly the same for every spike sequence for any given neuron, while it varies significantly among neurons. The distributions of L(V) values for neuron ensembles in three of the four areas were found to be distinctly bimodal. Two groups of neurons classified according to the spiking irregularity exhibit different responses to the same stimulus. This suggests that neurons in each area can be classified into different groups possessing unique spiking statistics and corresponding functional properties.

New classification scheme of cortical sites with the neuronal spiking characteristics.

Multiple cortical areas are mutually compared on the bases of neuronal spiking characteristics measured through three dimensionless interspike interval statistical coefficients. The spike sequences were recorded from the prefrontal cortical area (PF), the pre-supplementary motor area (Pre-SMA), the supplementary motor area (SMA) and the rostral cingulate motor area (CMAr) of a behaving monkey performing a waiting period task. The distribution of three statistical coefficients is found to be largely dependent on the recording site. By measuring the Hellinger distances among those distributions, Pre-SMA, SMA and CMAr are found to be mutually similar in comparison with PF.

Spatial distribution and density of prefrontal cortical cells projecting to three sectors of the premotor cortex.

The spatial distribution of prefrontal cortical cells projecting to three different sectors in the premotor cortex was examined. The cells projecting to the three sectors were distributed in separate regions in the dorsolateral prefrontal cortex with a small overlap. Cells projecting to the ventral sector were distributed in the lower bank of the principal sulcus (PS). Those projecting to the restro-dorsal sector were located near the superior limb of the arcuate sulcus, and in the dorsal convexity and upper bank of the PS. Cells projecting to the caudo-dorsal sector were observed in the upper bank of the PS and in the area 8a. These findings suggest that each of the three sectors of the premotor cortex receive different sets of information from the prefrontal cortex.

Numerical representation for action in the parietal cortex of the monkey.

The anterior part of the parietal association area in the cerebral cortex of primates has been implicated in the integration of somatosensory signals, which generate neural images of body parts and apposed objects and provide signals for sensorial guidance of movements. Here we show that this area is active in primates performing numerically based behavioural tasks. We required monkeys to select and perform movement A five times, switch to movement B for five repetitions, and return to movement A, in a cyclical fashion. Cellular activity in the superior parietal lobule reflected the number of self-movement executions. For the most part, the number-selective activity was also specific for the type of movement. This type of numerical representation of self-action was seen less often in the inferior parietal lobule, and rarely in the primary somatosensory cortex. Such activity in the superior parietal lobule is useful for processing numerical information, which is necessary to provide a foundation for the forthcoming motor selection.

Effects of morphine on two types of nucleus raphe dorsalis neurons in awake cats.

Forty-nine neurons recorded within the nucleus raphe dorsalis (NRD) in awake cats were classified into 2 groups: 29 regularly firing (clock-like) and 20 irregularly firing (non-clock-like) neurons. Hardly any of the clock-like neurons were influenced either by noxious stimulation (0.1 ml of 5% formalin, s.c.) or by a single dose (1 mg/kg, i.p.) or cumulative doses (0.25, 0.5, 1 mg/kg) of morphine. In contrast, about half the non-clock-like neurons were activated both by noxious stimulation and by administration of morphine. Morphine-induced activation of non-clock-like neurons was dose-related and reversed by naloxone (0.2 mg/kg, i.p.). These findings suggest that clock-like neurons in the NRD are not involved in morphine analgesia. Non-clock-like neurons, however, may play a role in the mediation of such analgesia.

Arthritis induced in cat by sodium urate: a possible animal model for tonic pain.

An attempt has been made to determine whether cats rendered arthritic by the injection of monosodium urate (MSU) crystals (rod-shaped 40-130 micrometers length) into one knee joint capsule can be used as animal model of tonic (chronic) pain. A limp and a decrease in body weight supported by the injected hind leg's paw occurred approximately 1 h after the MSU (20 mg) injection, reached a maximum at 2-3 h, and lasted for more than 6 h before a gradual return to pre-injection levels. They were diminished by systemic administration and local (the dorsal part of the nucleus raphe dorsalis) application of morphine, this effect being blocked by naloxone. This suggests that the limping and the paw pressure decrease are the reflexion of pain. It is suggested that the animal model of the MSU-induced arthritis is useful for the study of tonic pain.