Naohiro Saito

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.

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.

Neural Basis of Impaired Cognitive Flexibility in Patients with Anorexia Nervosa

Background Impaired cognitive flexibility in anorexia nervosa (AN) causes clinical problems and makes the disease hard to treat, but its neural basis has yet to be fully elucidated. The purpose of this study was to evaluate the brain activity of individuals with AN while performing a task requiring cognitive flexibility on the Wisconsin Card Sorting Test (WCST), which is one of the most frequently used neurocognitive measures of cognitive flexibility and problem-solving ability. Methods Participants were 15 female AN patients and 15 age- and intelligence quotient-matched healthy control women. Participants completed the WCST while their brain activity was measured by functional magnetic resonance imaging during the task. Brain activation in response to set shifting error feedback and the correlation between such brain activity and set shifting performance were analyzed. Results The correct rate on the WCST was significantly poorer for AN patients than for controls. Patients showed poorer activity in the right ventrolateral prefrontal cortex and bilateral parahippocampal cortex on set shifting than controls. Controls showed a positive correlation between correct rate and ventrolateral prefrontal activity in response to set shifting whereas patients did not. Conclusion These findings suggest dysfunction of the ventrolateral prefrontal cortex and parahippocampal cortex as a cause of impaired cognitive flexibility in AN patients.

Discharge Synchrony during the Transition of Behavioral Goal Representations Encoded by Discharge Rates of Prefrontal Neurons

To investigate the temporal relationship between synchrony in the discharge of neuron pairs and modulation of the discharge rate, we recorded the neuronal activity of the lateral prefrontal cortex of monkeys performing a behavioral task that required them to plan an immediate goal of action to attain a final goal. Information about the final goal was retrieved via visual instruction signals, whereas information about the immediate goal was generated internally. The synchrony of neuron pair discharges was analyzed separately from changes in the firing rate of individual neurons during a preparatory period. We focused on neuron pairs that exhibited a representation of the final goal followed by a representation of the immediate goal at a later stage. We found that changes in synchrony and discharge rates appeared to be complementary at different phases of the behavioral task. Synchrony was maximized during a specific phase in the preparatory period corresponding to a transitional stage when the neuronal activity representing the final goal was replaced with that representing the immediate goal. We hypothesize that the transient increase in discharge synchrony is an indication of a process that facilitates dynamic changes in the prefrontal neural circuits in order to undergo profound state changes.

Visually based path-planning by Japanese monkeys

To construct an animal model of strategy formation, we designed a maze path-finding task. First, we asked monkeys to capture a goal in the maze by moving a cursor on the screen. Cursor movement was linked to movements of each wrist. When the animals learned the association between cursor movement and wrist movement, we established a start and a goal in the maze, and asked them to find a path between them. We found that the animals took the shortest pathway, rather than approaching the goal randomly. We further found that the animals adopted a strategy of selecting a fixed intermediate point in the visually presented maze to select one of the shortest pathways, suggesting a visually based path planning. To examine their capacity to use that strategy flexibly, we transformed the task by blocking pathways in the maze, providing a problem to solve. The animals then developed a strategy of solving the problem by planning a novel shortest path from the start to the goal and rerouting the path to bypass the obstacle.

Design of a head fixation device for experiments in behaving monkeys.

We have designed a new device for head fixation of behaving monkeys. The fixation device consists of a duralumin head ring mounted with four screw holders. It is firmly fixed to the animals skull with four stainless steel screw pins. The head ring is then attached to a primate chair in any desirable position and angle using a set of adjustable plates. The device has been used for behavioral training that requires accurate gaze monitoring and for recording single-unit activity over a several-month period. The advantage of our device is that it is simple to use; it can be attached readily without major surgical procedures and it can be quickly removed when experiments are not running. This head fixation system is suitable for behavioral experiments and single-unit recording studies. It may also be applicable for studies on functional imaging of the macaque brain, by constructing it of non-magnetic materials.

Functional imaging studies of hyposmia in Parkinson's disease

Hyposmia in Parkinsons disease (PD) was evaluated by using neuroimaging techniques. It is well known that olfactory impairments are one of the cardinal non-motor symptoms in PD. However, all smell tests used in previous studies depend on subjective answers by examinees and on sniffing of odorants, the latter of which may be impaired in PD as a consequence of motor impairments. We developed an fMRI system, which can visualize brain activation by olfactory stimuli during natural breathing. Although 7 age-matched controls demonstrated significant activations in various brain areas including precentral gyrus (BA6/6) and middle temporal gyrus (BA19/39) by the odorant stimuli, 9 patients with PD showed little activations by the same stimuli. These data suggest that the olfactory dysfunction in PD is not a simple reflection of impaired sniffing. Recent epidemiological studies demonstrate that the olfactory impairments may precede the onset of motor symptoms. Moreover, several pathological studies suggest that amygdala is one of the most frequently affected regions and is closely related to hyposmia in PD. Further brain imaging studies of hyposmia will shed light on the early pathological changes in PD.

Chapter 1 Involvement of the Prefrontal Cortex in Problem Solving

To achieve a behavioral goal in a complex environment, such as problem-solving situations, we must plan multiple steps of action. 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 while monkeys performed a maze path-finding task. In this task, we set monkeys the job of capturing a goal in the maze by moving a cursor on the screen. Cursor movement was linked to movements of each wrist. To dissociate the outcomes of the intended action from the motor commands, we trained the monkeys to use three different hand-cursor assignments. We found that monkeys were able to perform this task in a flexible manner. This report first introduces a problem-solving framework for studying the function of the PFC, from the view point of cognitive science. Then, this chapter will cover the neuronal representation of a series of actions, goal subgoal transformation, and synchrony of PFC neurons. We reported PFC neurons reflected final goals and immediate goals during the preparatory period. We also found some PFC neurons reflected each of all forthcoming steps of actions during the preparatory period and increased their activity step by step during the execution period. Recently, we found that the transient increase in synchronous activity of PFC neurons was involved in goal subgoal transformations. Our data suggest that the PFC is involved primarily in the dynamic representation of multiple future events that occur as a consequence of behavioral actions in problem-solving situations.

Orderly activations of human cortical areas during path-planning task.

The functional anatomy of planning was investigated using a path-planning task, which required subjects to find a path to a goal that avoided obstacles and then move a cursor along the path to the goal by manipulating four switches. We analyzed event-related activation in response to four consecutive events during the path-planning task using fMRI. We classified activated cortical regions into four groups based on when each cortical region showed the most significant activation in response to behavioral events during the path-planning task. Our data suggested that each prefrontal and motor cortical area was involved in a different phase of path planning.

A case of cerebrotendinous xanthomatosis presenting with epilepsy as an initial symptom with a novel V413D mutation in the CYP27A1 gene

Cerebrotendinous xanthomatosis (CTX) is a rare autosomalecessive lipid storage disease caused by mutations in the CYP27A1 ene, which lead to deficiency of the mitochondrial enzyme, sterol 7-hydroxylase, resulting in the accumulation of cholestanol in he serum and many affected lesions [1]. Genetic analysis revealed hat mutations in the CYP27A1 gene were responsible for CTX. To ate, about 50 different mutations, including missense mutations, rameshifts, and splice site mutations, have been reported worldide in patients with CTX. Clinical presentation in patients with TX is characterized by refractory diarrhea, juvenile cataracts, endon xanthomas, and progressive neurological dysfunctions; owever, combinations of symptoms vary from patient to patient. eurological abnormalities include mental retardation or demenia, neuropsychiatric symptoms, cerebellar signs, pyramidal igns, peripheral neuropathy, extrapyramidal manifestations, nd seizures. Systemic manifestations, such as osteoporosis and oronary heart disease, may also occur. Replacement treatment ith chenodeoxycholic acid (CDCA) has been reported to improve linical symptoms of CTX. Here we report a patient with CTX