[in Japanese]

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[in Japanese]

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[in Japanese]

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Alexithymia refers to difficulty in identifying and expressing emotion in self and is related to disturbedemotional regulation. Alexithymia was originally proposed as a personality trait which plays acentral role in psychosomatic diseases. Although neuroscientific studies on this alexithymia arerequisite, there has been no integrative reviews so far which overview the entire studies ofneuroimaging studies of alexithymia. Here we overviewed the literatures of neuroimaging studies onalexithymia, and found that people with alexithymia showed reduced neural responses to emotionalstimuli from external environment and reduced response to imagery in their limbic and paralimbicareas（amygdala, insula, anterior/posterior cingulate cortex）. In contrast, they showed enhancedneural response to stimuli or tasks which involve any ‘physical’ contexts like somatosensory andsensorimotor function in the insula and other somatosensory/sensorimotor areas. They havehampered neural activity when they are involved in social tasks in the medial prefrontal and insulacortex. Their blunted response to external emotional stimuli and oversensitive response tosensorimotor stimuli should result in exaggerated physical symptoms which some individuals withalexithymia express.

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The superior temporal sulcus（STS）and the amygdala are often implicated in the functional imagingliterature as the neural substrates for social cognition, such as gaze processing. In this study, weinvestigated the impact of lesions in these areas upon covert gaze processing. Adopting Posner'sspatial cueing paradigm, we tested gaze-triggered orienting along with arrow-triggered orienting inone subject with a circumscribed right superior temporal gyrus（STG）lesion, and a group of fivesubjects with unilateral amygdala lesions. Results showed that in contrast to healthy subjects whodemonstrate attentional orienting to both gaze and arrow cues, the STG case and the amygdala groupdemonstrated deficient gaze-triggered orienting, but intact arrow-triggered orienting. Thisdiscrepancy between biological（gaze）and non-biological（arrow）signals implicates that componentsof the social brain, such as the STS and the amygdala, are specialized in processing biologicalsignals, and work in concert to support social cognition.

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[in Japanese]

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Atypical use of prosody has been identified as one of the hallmarks of children with Autism Spectrum Disorder（ASD）. Focusing on prosodic processing, here we show a couple of auditory study usingnear infrared spectroscopy（NIRS）on Children with ASD. These studies tried to reveal the cerebralmechanism underlying this difficulty of prosody and phonemic processing in Children with ASD.Specifically, with NIRS, we measured auditory evoked-responses in the temporal areas by contrastingbaseline stimuli against deviant stimuli including phonemic and prosodic conditions. Using a similarexperimental paradigm, it has been revealed that right-handed adults show left-dominant temporalresponse to phonemic contrast whereas right-dominant response to prosodic contrast. Furthermore,we have performed a series of NIRS study using the same paradigm on typically developinginfants/children from newborns to 4 year-old. We discuss results of Children with ASD in light ofthe functional lateralization in typically developing children given from our previous study.

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[in Japanese]

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Unilateral spatial neglect（USN）is a disorder that results mainly from rightward bias of spatial attention and is accompanied with some general disorders such as motivational dysfunction. USN may fail to respond to stimuli in left hemispace and show a lot of problems in activities of daily living. Although many studies attempt to clarify the pathophysiology of USN, it is still unknown the relationship between anatomical brain dysfunction and pathophysiology of USN. A major challenge for pathophysiological study of USN in neurological patients is that brain lesions vary tremendously in extent and location between individuals. In our study, patients of left hemiplegia with USN, patients of left hemiplegia without USN, patients of right hemiplegia without USN and age-matched healthy volunteers were recruited for recording exploratory eye movements（EEMs）on the visual search task. The patients of USN were diagnosed by the behavioral inattention test（BIT）score above 24. At the results, left hemiplegia with USN patients only searched their right side during EEM recording. The mean gazing time of left hemiplegia with USN patients was significantly longer than that of other subjects. In addition, the total number of gazing points of left hemiplegia with USN patients was significantly smaller than that of healthy volunteers. Interestingly, the patients of right hemiplegia without USN tended to search their left side. The relationship between EEM data and BIT score was significantly correlated. These results suggested that visual input from the right part of an object was projected to the left visual cortex. The damaged right hemisphere utilized this input via corpus callosum and constructed a totalized image of the object. This tendency to construct a totalized image suppressed the visuospatial ability of the left hemisphere. Such interactions between right and left hemispheres might play an important role in USN. Furthermore, it is useful for analyzing the pathophysiology of USN to use this kind of neurophysiological approach.

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[in Japanese]

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[in Japanese]

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Empathy is a basic function of social cognition. Emotional response to display of emotion of the others can be classified into four categories. Unhappiness of others causes unhappiness（negative emotion）, happiness of others causes happiness（positive empathy）, happiness of others causes unhappiness（reversed empathy）and unhappiness of others causes happiness（Schadenfreude）. Experimental works with mice confirmed presence of the negative empathy, the positive empathy and the reversed empathy in this species. The Schadenfreude was, however, not confirmed in mice suggesting this complex emotional response emerged in highly complex and long lasting society such as human society.

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It is difficult to study “hedonic” or “pleasant” emotion with nonhuman animals. We have to deal with objectively observable behavior. In this regard, we investigated neural mechanisms of reward seeking. In a series of experiments, we have shown that（1）the endogenous nociceptin modulates preference for high fat diet,（2）the theta rhythm in the hippocampus possibly relates to prediction of reward,（3） dopamine receptors in the hippocampus increased along with the formation of reward memory, and （4）dopamine receptors in the amygdala play an important role in the behavioral expression of preference. These results indicate the significance of learning and memory in reward seeking. Although reward seeking is an essential biological function for survival, the very same system is also responsible for the pathological states such as addiction and dependence. We must further study and clarify both natural and aberrant aspects of reward seeking. The revealed nature of which will then sheds light on the structure and function of “hedonic” or “pleasant” emotion.

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Humans tend to be sensitive to threatening stimuli, such as angry faces and snakes. Humans quickly and accurately find a threatening face among a crowd of friendly faces than vice versa. A picture of snake among those of flowers is also quickly detected by humans. This quick detection has been attributed to neural circuitry that involves a direct pathway via the superior culliculs and the pulvinar nucleus of the thalamus that quickly activates the hub in the brain’s fear center, the amygdala. This starts activating defense responses via connections to the hypothalamus and the brainstem before fine information arrives from the sensory cortices. We found that even young children of three years old detected a picture of snake among flower pictures, which suggests that humans are innately sensitive to snakes. However, through learning and experiences, ontogenetic fear-relevant stimuli such as a picture of pointed gun can also trigger a quick detection. Therefore, it was not clear whether young children learned in early period of life that snakes and/or angry face are threatening via direct or vicarious learning. To elucidate whether snakes and/or angry face are phylogenetic fear-relevant stimuli, we carried out a visual search task with Japanese monkeys reared in a laboratory with no experience with snakes. The monkeys respond to pictures of snakes among those of flowers faster than vice versa irrespective of the color properties of those pictures. These results strongly suggest that primates including humans evolved to be wary of snakes. However, the results of our other study showed that monkeys showed great individual differences of fear responses in front of live snakes. These individual differences may relate to variations in the promoter region of the serotonine transporter gene（5-HTTLPR）that has been shown to influence both behavioral measures of social anxiety and the amygdala response to social threats. Our on-going analyses of length polymorphisms in the 5-HTTLPR of Japanese monkeys may shed light on variations in each individual to innately embedded threat stimuli.

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Starting with the introductory presentation of autobiography of Alois Alzheimer, this review summarized various endeavors to treat Alzheimer’s disease in the past, at present and in the near future. Surprisingly, it is not explicitly documented when specific treatment for Alzheimer’s disease （AD）began. Various nootropics were in common use in Japan in the 70’s and 80’s while vitamin E, selegiline, gingko biloba, estrogen and NSAIDs have been tried as therapeutic strategies for AD, but unfortunately without establishing convincing evidence. Since the advent of tacrine in 1983, the era of cholinesterase inhibitors（ChEIs）has begun. Donepezil hydrochloride was introduced to Japanese AD patients in 1999. Two other ChEIs, galantamine and rivastigmine, had to wait for over 10 years before being approved in Japan and these medications will be on market in 2011. The year of 2011 is also highlighted by approval of NMDA receptor antagonist memantine in this country. Combination therapy of memantine and a ChEI （donepezil）is suggested effective in severe AD patients when either one has lost initial efficacy. In order to surmount the limitations of ChEIs and memantine as symptomatic treatments, big expectations are directed toward causative therapies that reduce amount of beta-amyloid and phosphorylated tau. Preventive strategies to reduce monomers, oligomers and soluble fibrils may include a-secretase agonist, b and g-secretase inhibitors and substances that reduce amyloid aggregation or accelerate degradation and disposal of amyloid.Contrary to theoretical righteousness and good hope for successful application to humans, some g-secretase inhibitors and modulators have been branded as non-effective and withdrawn from clinical trials. Amyloid vaccination is another expectation for the future treatment of AD both in the clinical and preclinical stages. It is a well-known disappointment that AN-1792 with adjuvants QS 21/ polysorbate-80 caused lethal encephalitis among antibody-positive responders, leading to premature termination of the clinical trial. Since then other vaccination methods have been investigated : passive immunization with monoclonal antibodies and active oral immunization with non-pathological vector adenovirus loaded with amyloid DNA that, when taken by mouth, stimulates lymphocytes within the epithelial cells of colon and produces antibodies. Besides lethal encephalitis, amyloid vaccination also suffers from a generally low responding rate（20 to 25%）. With regard to the use of monoclonal antibodies, high cost, need for repeated intravenous administration and higher incidents of intracerebral microbleeds may limit their usefulness. Strategies to reduce phosphorylated tau may include the use of inhibitors of tau kinases that accelerate phosphorylation and inhibition of degrading enzymes for phosphatases that de-phosphorylate abnormal tau. Methylene blue（methylthioninium chloride : Rember）is one of the promising agents that suppress tau aggregation. Some other symptomatic treatments with latrepirdine（Dimebon）, and inhibitors for phosphodiesterases, RAGE and hydroxytryptamine receptors are also discussed.

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According to the capacity of the retention period, memory is classified into short-term and long-term memory. The duration of short-term memory is defined to be in the order of seconds, whereas long-term memory stores a seemingly unlimited amount of capacity. Short-term memory includes working memory which is used temporarily storing information such as telephone numbers. Long-term memory is classified into declarative memory which can be consciously recalled such as facts and events and non-declarative memory which refers to unconscious memories such as skills （e.g. learning to swimming and ride a bicycle）. Declarative memory is further classified into episodic memory which is refers to the memory of autobiographical events and semantic memory which is refers to the memory of meanings, understandings, and other concept-based knowledge. Episodic memory tends to decay along the adult lifespan whereas semantic memory is relatively preserved during aging. Retrograde amnesia refers to a loss of memory for information acquired before the onset of brain injury, whereas anterograde amnesia is refers to the impairment in learning new information after the onset of brain injury. There is a time-gradient in retrograde amnesia, such that recent memories are more likely to be lost.

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