Hajime Mushiake

Selective coding of motor sequence in the supplementary motor area of the monkey cerebral cortex.

SummaryWe describe a property of neurons in the supplementary motor area (SMA) of the cerebral cortex of monkey that is different from those in the primary motor area (MI) in relation to execution of a sequential motor task. A group of SMA neurons was active when the animal remembered and pressed three touch-pads in a predetermined sequence but inactive when the same movement was guided by sequentially presented visual signals. This finding indicates that the SMA is involved in the performance of sequential movements on the basis of the information stored inside the brain.

Activity in the Lateral Prefrontal Cortex Reflects Multiple Steps of Future Events in Action Plans

To achieve a behavioral goal in a complex environment, we must plan multiple steps of motor behavior. On planning a series of actions, we anticipate future events that will occur as a result of each action and mentally organize the temporal sequence of events. To investigate the involvement of the lateral prefrontal cortex (PFC) in such multistep planning, we examined neuronal activity in the PFC of monkeys performing a maze task that required the planning of stepwise cursor movements to reach a goal. During the preparatory period, PFC neurons reflected each of all forthcoming cursor movements, rather than arm movements. In contrast, in the primary motor cortex, most neuronal activity reflected arm movements but little of cursor movements during the preparatory period, as well as during movement execution. Our data suggest that the PFC is involved primarily in planning multiple future events that occur as a consequence of behavioral actions.

Reorganization of activity in the supplementary motor area associated with motor learning and functional recovery

SummaryThe supplementary motor area (SMA) of primates has been implicated in the initiation and execution of limb movements. However, when a motor task was extensively overlearned, few SMA neurons, if any, were active before the movement onset. Subsequent lesions of the primary motor cortex gave rise to the appearance of premovement activity changes, indicating usedependent reorganization of the neuronal activity in SMA.

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.

Visual Properties of Transgenic Rats Harboring the Channelrhodopsin-2 Gene Regulated by the Thy-1.2 Promoter

Channelrhodopsin-2 (ChR2), one of the archea-type rhodopsins from green algae, is a potentially useful optogenetic tool for restoring vision in patients with photoreceptor degeneration, such as retinitis pigmentosa. If the ChR2 gene is transferred to retinal ganglion cells (RGCs), which send visual information to the brain, the RGCs may be repurposed to act as photoreceptors. In this study, by using a transgenic rat expressing ChR2 specifically in the RGCs under the regulation of a Thy-1.2 promoter, we tested the possibility that direct photoactivation of RGCs could restore effective vision. Although the contrast sensitivities of the optomotor responses of transgenic rats were similar to those observed in the wild-type rats, they were enhanced for visual stimuli of low-spatial frequency after the degeneration of native photoreceptors. This result suggests that the visual signals derived from the ChR2-expressing RGCs were reinterpreted by the brain to form behavior-related vision.

An output zone of the monkey primary motor cortex specialized for bilateral hand movement

SummaryWe have identified a subregion in the monkey primary precentral motor cortex (MI) that is characterized by its relationship to bilateral or ipsilateral hand movements. The subregion is located between the digit and face representation areas. The majority of single cells in this portion of MI exhibit distinct activity before and during visually triggered key-press movements performed by means of ipsilateral or contralateral digit flexion. Intracortical microstimulation evoked responses of ipsilateral, in addition to contralateral, digit muscles.

Comparison of neuronal activity in the supplementary motor area and primary motor cortex

Neuronal activity in the supplementary motor area (SMA) and primary motor cortex (MI) have been compared in many experiments during performance of many different motor tasks. On one hand, the activity in both areas may appear similar, especially when the motor task is simple. On the other hand, if the motor tasks are more demanding, neuronal activity in the SMA exhibits a variety of complex relationship to many different aspects of motor behavior, while the activity in MI is mostly related to execution of motor task itself. Of particular interest is the neuronal activity in the SMA during preparation and execution of motor tasks when no external cues for the retrieval of appropriate motor act is available. Temporal sequencing of multiple movements is a typical example of the kind of motor task that requires profound activity in the SMA.

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.

Opto-Current-Clamp Actuation of Cortical Neurons Using a Strategically Designed Channelrhodopsin

Background Optogenetic manipulation of a neuronal network enables one to reveal how high-order functions emerge in the central nervous system. One of the Chlamydomonas rhodopsins, channelrhodopsin-1 (ChR1), has several advantages over channelrhodopsin-2 (ChR2) in terms of the photocurrent kinetics. Improved temporal resolution would be expected by the optogenetics using the ChR1 variants with enhanced photocurrents. Methodology/Principal Findings The photocurrent retardation of ChR1 was overcome by exchanging the sixth helix domain with its counterpart in ChR2 producing Channelrhodopsin-green receiver (ChRGR) with further reform of the molecule. When the ChRGR photocurrent was measured from the expressing HEK293 cells under whole-cell patch clamp, it was preferentially activated by green light and has fast kinetics with minimal desensitization. With its kinetic advantages the use of ChRGR would enable one to inject a current into a neuron by the time course as predicted by the intensity of the shedding light (opto-current clamp). The ChRGR was also expressed in the motor cortical neurons of a mouse using Sindbis pseudovirion vectors. When an oscillatory LED light signal was applied sweeping through frequencies, it robustly evoked action potentials synchronized to the oscillatory light at 5–10 Hz in layer 5 pyramidal cells in the cortical slice. The ChRGR-expressing neurons were also driven in vivo with monitoring local field potentials (LFPs) and the time-frequency energy distribution of the light-evoked response was investigated using wavelet analysis. The oscillatory light enhanced both the in-phase and out-phase responses of LFP at the preferential frequencies of 5–10 Hz. The spread of activity was evidenced by the fact that there were many c-Fos-immunoreactive neurons that were negative for ChRGR in a region of the motor cortex. Conclusions/Significance The opto-current-clamp study suggests that the depolarization of a small number of neurons wakes up the motor cortical network over some critical point to the activated state.

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 (Brodmanns 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.