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Unilateral spatial neglect (USN) was originally regarded as a parietal syndrome, but it has become evident that USN is a disturbance in the widespread attention network. Here, we focused on an interaction between spatial neglect and non-spatial aspect of attention deficit, and aimed to establish a novel evaluation approach based on the characteristics of the spatial distribution of reaction times. We tested 174 patients with right hemisphere damage and divided them based on their prescreening scores on the Behavioral Inattention Test (BIT): (1) USN++ (n = 79: BIT131), (2) USN+ (n = 47: BIT≥131 with history of USN), and (3) RHD (n = 48: without neglect symptom). The patients were asked to conduct a touch panel-based pointing task toward 2D-arranged (seven columns × five rows) circular targets on a PC monitor, and the reaction time to each object was recorded. To evaluate aspects of attention deficit and neglect symptoms, we calculated the total average of the reaction time for all objects (RT

Highlights • Patients with chronic pain due to postherpetic neuralgia (PHN) were used. • Hemodynamic activity in the dorsolateral prefrontal cortex (dlPFC) was analyzed. • PHN showed less placebo effects and smaller hemodynamic responses in the right dlPFC. • PHN symptoms were associated with smaller placebo effects and right dlPFC responses. • Deficits in placebo effects due to dlPFC disturbance are involved in chronic pain., The dorsolateral prefrontal cortex (dlPFC) is functionally linked to the descending pain modulation system and has been implicated in top down pain inhibition, including placebo analgesia. Therefore, functions of the dlPFC may be impaired in patients with chronic pain. Postherpetic neuralgia (PHN) is one of several syndromes with chronic neuropathic pain. In the present study, we investigated possible dysfunction of the dlPFC in chronic pain using patients with PHN. In a conditioning phase, heathy controls (n = 15) and patients with PHN (n = 7) were exposed to low (LF) and high (HF) frequency tones associated with noxious stimuli: weak (WS) and strong (SS) electrical stimulation, respectively. After the conditioning, cerebral hemodynamic activity was recorded from the bilateral dlPFC while the subjects were subjected to the cue tone-noxious electrical stimulation paradigm, in which incorrectly cued noxious stimuli were sometimes delivered to induce placebo and nocebo effects. The results indicated that hemodynamic responses to the LF tone in the right dlPFC was significantly lower in patients with PHN compared to the healthy controls. Furthermore, the same hemodynamic responses in the right dlPFC were correlated with placebo effects. In addition, clinical symptoms of PHN were negatively correlated to cerebral hemodynamic responses in the right dlPFC and magnitudes of the placebo effects. The results suggest that the right dlPFC, which is closely associated with the descending pain modulation system, is disturbed in PHN.

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aβ1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aβ1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aβ1-42 were significantly greater than those of LMW-Aβ1-42. Therapeutic reduction of HMW-Aβ1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage.

The subcortical visual pathway including the superior colliculus (SC), pulvinar, and amygdala has been implicated in unconscious visual processing of faces, eyes, and gaze direction in blindsight. Our previous studies reported that monkey SC and pulvinar neurons responded preferentially to images of faces while performing a delayed non-matching to sample (DNMS) task to discriminate different visual stimuli (Nguyen et al., 2013, 2014). However, the contribution of SC and pulvinar neurons to the discrimination of the facial images and subsequent behavioral performance remains unknown. Since gamma oscillations have been implicated in sensory and cognitive processes as well as behavioral execution, we hypothesized that gamma oscillations during neuronal responses might contribute to achieving the appropriate behavioral performance (i.e., a correct response). In the present study, we re-analyzed those neuronal responses in the monkey SC and pulvinar to investigate possible relationships between gamma oscillations in these neurons and behavioral performance (correct response ratios) during the DNMS task. Gamma oscillations of SC and pulvinar neuronal activity were analyzed in three phases around the stimulus onset [inter-trial interval (ITI): 1000ms before trial onset; Early: 0-200ms after stimulus onset; and Late: 300-500ms after stimulus onset]. We found that human facial images elicited stronger gamma oscillations in the early phase than the ITI and late phase in both the SC and pulvinar neurons. Furthermore, there was a significant correlation between strengths of gamma oscillations in the early phase and behavioral performance in both the SC and pulvinar. The results suggest that gamma oscillatory activity in the SC and pulvinar contributes to successful behavioral performance during unconscious perceptual and behavioral processes.

Sensorimotor incongruence (SMI) is associated with pathological pain, such as phantom limb pain. Additionally, patients with pathological pain and brain dysfunction typically present with movement disorders, including diminished voluntary control and increased variability in bimanual movement performance. In healthy subjects, SMI leads to dysesthesia and bimanual movement motor dysfunction. However, the brain localization of this activity remains unclear, particularly in SMI-induced dysesthesia and decrease in movement accuracy. In this study, 17 healthy participants were asked to perform repetitive flexion/extension exercises with their wrists in a congruent/incongruent position while viewing the activity in a mirror. Indeed, SMI induced dysesthesia and decreased bimanual movement accuracy. Moreover, beta band activities of the bilateral presupplementary (P 0.01) and bilateral cingulate (P 0.05) motor areas were decreased. Collectively, our findings indicate that SMI induces dysesthesia and movement disorders and reduces beta band activities in motor-related areas.

Eye tracking is an effective tool for identifying behavioural aspects of unilateral spatial neglect (USN), which is a common neurological syndrome that develops after a right hemisphere lesion. Here, we attempted to elucidate how the neglect symptom affects the symmetry of the gaze pattern, by performing an analysis of gaze distribution during the free viewing of a pair of horizontally flipped images. Based on their Behavioural Inattention Test (BIT) scores, 41 patients with right-hemisphere damage were classified into those with USN (n = 27) and those without USN (right hemisphere damaged - RHD; n = 14). Eye movement was recorded while the patients viewed six pairs of horizontally flipped images on a computer display. A pair of flipped images has both similar and consistent elements, as well as a reversed spatial location of objects (right-left). We calculated the gaze distribution, extent of gaze shift, total gaze distance, and gaze velocity in each direction. Our results demonstrated a significantly larger rightward gaze shift in the USN group, which showed a significant correlation with the BIT score. More importantly, the extent of gaze shift and total gaze distance were similarly modulated by the contents of the displayed images in both the USN and RHD groups. Our findings suggest that analyses of gaze distribution during the free viewing of a pair of horizontally flipped images have the potential to precisely reveal neglect behaviour, and our results provide important implications for rehabilitation.

Walking speed is strongly influenced by the severity of motor paralysis in post-stroke patients. Nevertheless, some patients with mild motor paralysis still walk slowly. Factors associated with this difference in walking speed have not been elucidated. To confirm walking characteristics of patients with mild motor paralysis and slow walking speed, this study identified patient subgroups based on the association between the severity of motor paralysis and walking speed. Fugl-Meyer assessment synergy score (FMS) and the walking speed were measured (n = 42), and cluster analysis was performed based on the association between FMS and walking speed to identify the subgroups. FMS and walking speed were associated (ρ = 0.50); however, some patients walked slowly despite only mild motor paralysis. Cluster analysis using FMS and walking speed as the main variables classified patients into subgroups. Patients with mild motor paralysis (FMS: 18.4 ± 2.09 points) and slow walking speed (0.28 ± 0.14 m/s) exhibited poorer trunk stability, increased co-contraction of the shank muscle, and increased intramuscular coherence in walking compared to other clusters. This group was identified by their inability to fully utilize the residual potential of motor function. In walking training, intervention in instability and excessive cortical control may be effective.

To develop a real-time neurofeedback system from the anterior prefrontal cortex (aPFC) using functional near-infrared spectroscopy (fNIRS) for motor rehabilitation, we investigated the effects of motor imagery training with neurofeedback from the aPFC on hand dexterity and cerebral hemodynamic activity during a motor rehabilitation task. Thirty-one right-handed healthy subjects participated in this study. They received motor imagery training six times for 2 weeks under fNIRS neurofeedback from the aPFC, in which they were instructed to increase aPFC activity. The real group subjects (n = 16) were shown real fNIRS neurofeedback signals from the aPFC, whereas the sham group subjects (n = 15) were shown irrelevant randomized signals during neurofeedback training. Before and after the training, hand dexterity was assessed by a motor rehabilitation task, during which cerebral hemodynamic activity was also measured. The results indicated that aPFC activity was increased during the training, and performance improvement rates in the rehabilitation task after the training was increased in the real group when compared with the sham group. Improvement rates of mean aPFC activity across the training were positively correlated with performance improvement rates in the motor rehabilitation task. During the motor rehabilitation task after the training, the hemodynamic activity in the left somatosensory motor-related areas [premotor area (PM), primary motor area (M1), and primary somatosensory area (S1)] was increased in the real group, whereas the hemodynamic activity was increased in the supplementary motor area in the sham group. This hemodynamic activity increases in the somatosensory motor-related areas after the training correlated with aPFC activity during the last 2 days of motor imagery training. Furthermore, improvement rates of M1 hemodynamic activity after the training was positively correlated with performance improvement rates in the motor rehabilitation task. The results suggest that the aPFC might shape activity in the somatosensory motor-related areas to improve hand dexterity. These findings further suggest that the motor imagery training using neurofeedback signals from the aPFC might be useful to patients with motor disability.

Growing evidence suggests that oxidative stress due to amyloid β (Aβ) accumulation is involved in Alzheimer’s disease (AD) through the formation of amyloid plaque, which leads to hyperphosphorylation of tau, microglial activation, and cognitive deficits. The dysfunction or phenotypic loss of parvalbumin (PV)-positive neurons has been implicated in cognitive deficits. Astaxanthin is one of carotenoids and known as a highly potent antioxidant. We hypothesized that astaxanthin’s antioxidant effects may prevent the onset of cognitive deficits in AD by preventing AD pathological processes associated with oxidative stress. In the present study, we investigated the effects of astaxanthin intake on the cognitive and pathological progression of AD in a mouse model of AD. The AppNL-G-F/NL-G-F mice were fed with or without astaxanthin from 5-to-6 weeks old, and cognitive functions were evaluated using a Barnes maze test at 6 months old. PV-positive neurons were investigated in the hippocampus. Aβ42 deposits, accumulation of microglia, and phosphorylated tau (pTau) were immunohistochemically analyzed in the hippocampus. The hippocampal anti-oxidant status was also investigated. The Barnes maze test indicated that astaxanthin significantly ameliorated memory deficits. Astaxanthin reduced Aβ42 deposition and pTau-positive areal fraction, while it increased PV-positive neuron density and microglial accumulation per unit fraction of Aβ42 deposition in the hippocampus. Furthermore, astaxanthin increased total glutathione (GSH) levels, although 4-hydroxy-2,3-trans-nonenal (4-HNE) protein adduct levels (oxidative stress marker) remained high in the astaxanthin supplemented mice. The results indicated that astaxanthin ameliorated memory deficits and significantly reversed AD pathological processes (Aβ42 deposition, pTau formation, GSH decrease, and PV-positive neuronal deficits). The elevated GSH levels and resultant recovery of PV-positive neuron density, as well as microglial activation, may prevent these pathological processes.

The retrosplenial cortex (RSC) has been implicated in wayfinding using different sensory cues. However, the neural mechanisms of how the RSC constructs spatial representations to code an appropriate route under different sensory cues are unknown. In this study, rat RSC neurons were recorded while rats ran on a treadmill affixed to a motion stage that was displaced along a figure-8-shaped track. The activity of some RSC neurons increased during specific directional displacements, while the activity of other neurons correlated with the running speed on the treadmill regardless of the displacement directions. Elimination of visual cues by turning off the room lights and/or locomotor cues by turning off the treadmill decreased the activity of both groups of neurons. The ensemble activity of the former group of neurons discriminated displacements along the common central path of different routes in the track, even when visual or locomotor cues were eliminated where different spatial representations must be created based on different sensory cues. The present results provide neurophysiological evidence of an RSC involvement in wayfinding under different spatial representations with different sensory cues.

BackgroundCompression of myofascial trigger points (MTrPs) in muscles is reported to reduce chronic musculoskeletal pain. Although the prefrontal cortex (PFC) is implicated in development of chronic pain, the mechanisms of how MTrP compression at low back regions affects PFC activity remain under debate. In this study, we investigated effects of MTrP compression on brain hemodynamics and EEG oscillation in subjects with chronic low back pain.MethodsThe study was a prospective, randomized, parallel-group trial and an observer and subject-blinded clinical trial. Thirty-two subjects with chronic low back pain were divided into two groups: subjects with compression at MTrPs (n = 16) or those with non-MTrPs (n = 16). Compression at MTrP or non-MTrP for 30 s was applied five times, and hemodynamic activity (near-infrared spectroscopy; NIRS) and EEGs were simultaneously recorded during the experiment.ResultsThe results indicated that compression at MTrPs significantly (1) reduced subjective pain (P < 0.05) and increased the pressure pain threshold (P < 0.05), (2) decreased the NIRS hemodynamic activity in the frontal polar area (pPFC) (P < 0.05), and (3) increased the current source density (CSD) of EEG theta oscillation in the anterior part of the PFC (P < 0.05). CSD of EEG theta oscillation was negatively correlated with NIRS hemodynamic activity in the pPFC (P < 0.05). Furthermore, functional connectivity in theta bands between the medial pPFC and insula cortex was significantly decreased in the MTrP group (P < 0.05). The functional connectivity between those regions was positively correlated with subjective low back pain (P < 0.05).DiscussionThe results suggest that MTrP compression at the lumbar muscle modulates pPFC activity and functional connectivity between the pPFC and insula, which may relieve chronic musculoskeletal pain.Trial registrationThis trial was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000033913) on 27 August 2018, at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000038660.

Human babies respond preferentially to faces or face-like images. It has been proposed that an innate and rapid face detection system is present at birth before the cortical visual pathway is developed in many species, including primates. However, in primates, the visual area responsible for this process is yet to be unraveled. We hypothesized that the superior colliculus (SC) that receives direct and indirect retinal visual inputs may serve as an innate rapid face-detection system in primates. To test this hypothesis, we examined the responsiveness of monkey SC neurons to first-order information of faces required for face detection (basic spatial layout of facial features including eyes, nose, and mouth), by analyzing neuronal responses to line drawing images of: (1) face-like patterns with contours and properly placed facial features; (2) non-face patterns including face contours only; and (3) nonface random patterns with contours and randomly placed face features. Here, we show that SC neurons respond stronger and faster to upright and inverted face-like patterns compared to the responses to nonface patterns, regardless of contrast polarity and contour shapes. Furthermore, SC neurons with central receptive fields (RFs) were more selective to face-like patterns. In addition, the population activity of SC neurons with central RFs can discriminate face-like patterns from nonface patterns as early as 50 ms after the stimulus onset. Our results provide strong neurophysiological evidence for the involvement of the primate SC in face detection and suggest the existence of a broadly tuned template for face detection in the subcortical visual pathway.

Environmental exposure to dioxins, consumption of a high fat diet, and platelet-derived growth factor receptor β signaling in the brain affect feeding behavior, which is an important determinant of body growth. In the present study, we investigated the effects of prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and high fact diet after weaning on body growth and expression of platelet-derived growth factor receptor β in the brain in rat pups. Subjects from the control and dioxin exposure groups were assigned to 1 of 3 different diet groups: standard diet, high fat diet in the juvenile period, or high fat diet in adulthood. Body weight gain rate in the juvenile high fat diet group and the length gain rate in the adult high fat diet group were greater than the corresponding values in the standard diet group only in male offspring, although the effects of dioxin exposure on growth were not significant. Consumption of a high fat diet decreased platelet-derived growth factor receptor β levels in the amygdala and hippocampus in both sexes compared to control groups, while 2,3,7,8-tetrachlorodibenzo-p-dioxin decreased platelet-derived growth factor receptor platelet-derived growth factor receptor β levels in the amygdala and striatum only in females receiving an high fat diet. Furthermore, platelet-derived growth factor receptor β levels in the hippocampus and platelet-derived growth factor receptor β striatum were inversely correlated with increases in body length, while changes in platelet-derived growth factor receptor β in the amygdala and nucleus accumbens were significantly correlated to body weight gain or body mass index. In conclusion, these findings suggest that these 2,3,7,8-tetrachlorodibenzo-p-dioxin and high fat diet-induced changes in body growth and feeding behaviors might be partially mediated by changes in brain platelet-derived growth factor receptor β levels.

Summary Visuospatial neglect (VSN) is a neurological syndrome of higher brain functions in which an individual fails to detect stimuli on a space that is contralateral to a hemispheric lesion. We performed a comprehensive multivariate analysis based on the principal component analysis (PCA) and cluster analysis in patients with right hemisphere stroke and then performed a determination of different elements of VSN. PCA-based cluster analysis detected distinct aspects of VSN as follows: cluster 1: low arousal and attention state, cluster 2: exogenous neglect, cluster 3: spatial working memory (SWM) deficit. Lesion analysis revealed neural correlates for each cluster and highlighted “disturbance of the ventral attention network” for the stagnation of exogenous attention and “parietal damage” for SWM deficit. Our results reveal a pathological structure of VSN as multiple components of an attention network deficit, and they contribute to the understanding of the mechanisms underlying VSN., Graphical abstract, Highlights • This study attempted to establish the pathological structure of visuospatial neglect • PCA revealed four distinct fundamental components underlying visuospatial neglect • GMM-based clustering detected six subtypes of visuospatial attention network deficit, Medical Imaging; Behavioral Neuroscience; Systems Neuroscience; Computer Modeling

Snakes and conspecific faces are quickly and efficiently detected in primates. Because the medial prefrontal cortex (mPFC) has been implicated in attentional allocation to biologically relevant stimuli, we hypothesized that it might also be highly responsive to snakes and conspecific faces. In this study, neuronal responses in the monkey mPFC were recorded, while monkeys discriminated 8 categories of visual stimuli. Here, we show that the monkey mPFC neuronal responses to snakes and conspecific faces were unique. First, the ratios of the neurons that responded strongly to snakes and monkey faces were greater than those of the neurons that responded strongly to the other stimuli. Second, mPFC neurons responded stronger and faster to snakes and monkey faces than the other categories of stimuli. Third, neuronal responses to snakes were unaffected by low-pass filtering of the images. Finally, activity patterns of responsive mPFC neurons discriminated snakes from the other stimuli in the second 50 ms period and monkey faces in the third period after stimulus onset. These response features indicate that the mPFC processes fast and coarse visual information of snakes and monkey faces, and support the hypothesis that snakes and social environments have shaped the primate visual system over evolutionary time.

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aβ

Although motor training programs have been applied to childhood apraxia of speech (AOS), the neural mechanisms of articulation learning are not well understood. To this aim, we recorded cerebral hemodynamic activity in the left hemisphere of healthy subjects (n = 15) during articulation learning. We used near-infrared spectroscopy (NIRS) while articulated voices were recorded and analyzed using spectrograms. The study consisted of two experimental sessions (modified and control sessions) in which participants were asked to repeat the articulation of the syllables "i-chi-ni" with and without an occlusal splint. This splint was used to increase the vertical dimension of occlusion to mimic conditions of articulation disorder. There were more articulation errors in the modified session, but number of errors were decreased in the final half of the modified session; this suggests that articulation learning took place. The hemodynamic NIRS data revealed significant activation during articulation in the frontal, parietal, and temporal cortices. These areas are involved in phonological processing and articulation planning and execution, and included the following areas: (i) the ventral sensory-motor cortex (vSMC), including the Rolandic operculum, precentral gyrus, and postcentral gyrus, (ii) the dorsal sensory-motor cortex, including the precentral and postcentral gyri, (iii) the opercular part of the inferior frontal gyrus (IFGoperc), (iv) the temporal cortex, including the superior temporal gyrus, and (v) the inferior parietal lobe (IPL), including the supramarginal and angular gyri. The posterior Sylvian fissure at the parietal-temporal boundary (area Spt) was selectively activated in the modified session. Furthermore, hemodynamic activity in the IFGoperc and vSMC was increased in the final half of the modified session compared with its initial half, and negatively correlated with articulation errors during articulation learning in the modified session. The present results suggest an essential role of the frontal regions, including the IFGoperc and vSMC, in articulation learning, with sensory feedback through area Spt and the IPL. The present study provides clues to the underlying pathology and treatment of childhood apraxia of speech.

Objectives We quantitatively examined the motor‐imagery ability in stroke patients using a bimanual circle‐line coordination task (BCT) and clarified the relationship between motor‐imagery ability and motor function of hemiplegic upper limbs and the level of use of paralyzed limbs. Methods We enrolled 31 stroke patients. Tasks included unimanual‐line (U‐L)—drawing straight lines on the nonparalyzed side; bimanual circle‐line (B‐CL)—drawing straight lines with the nonparalyzed limb while drawing circles with the paralyzed limb; and imagery circle‐line (I‐CL)—drawing straight lines on the nonparalyzed side during imagery drawing on the paralyzed side, using a tablet personal computer. We calculated the ovalization index (OI) and motor‐imagery ability (image OI). We used the Fugl–Meyer motor assessment (FMA), amount of use (AOU), and quality of motion (QOM) of the motor activity log (MAL) as the three variables for cluster analysis and performed mediation analysis. Results Clusters 1 (FMA

Unilateral spatial neglect is a common neurological syndrome following predominantly right hemispheric stroke. While most patients lack insight into their neglect behaviour and do not initiate compensatory behaviours in the early recovery phase, some patients recognize it and start to pay attention towards the neglected space. We aimed to characterize visual attention capacity in patients with unilateral spatial neglect with specific focus on cortical processes underlying compensatory gaze shift towards the neglected space during the recovery process. Based on the Behavioural Inattention Test score and presence or absence of experience of neglect in their daily life from stroke onset to the enrolment date, participants were divided into USN+‰‰+ (do not compensate, n = 15), USN+ (compensate, n = 10), and right hemisphere damage groups (no neglect, n = 24). The patients participated in eye pursuit-based choice reaction tasks and were asked to pursue one of five horizontally located circular objects flashed on a computer display. The task consisted of 25 trials with 4-s intervals, and the order of highlighted objects was randomly determined. From the recorded eye tracking data, eye movement onset and gaze shift were calculated. To elucidate the cortical mechanism underlying behavioural results, electroencephalagram activities were recorded in three USN+‰‰+, 13 USN+ and eight patients with right hemisphere damage. We found that while lower Behavioural Inattention Test scoring patients (USN+‰‰+) showed gaze shift to non-neglected space, some higher scoring patients (USN+) showed clear leftward gaze shift at visual stimuli onset. Moreover, we found a significant correlation between Behavioural Inattention Test score and gaze shift extent in the unilateral spatial neglect group (r = -0.62, P < 0.01). Electroencephalography data clearly demonstrated that the extent of increase in theta power in the frontal cortex strongly correlated with the leftward gaze shift extent in the USN+‰‰+ and USN+ groups. Our results revealed a compensatory strategy (continuous attention to the neglected space) and its neural correlates in patients with unilateral spatial neglect. In conclusion, patients with unilateral spatial neglect who recognized their own neglect behaviour intentionally focused on the neglected space as a compensatory strategy to avoid careless oversight.

Emerging evidence suggests that traditional diets and nutrition have a significant impact on brain development, and could contribute to the promotion of mental health and prevention of psychiatric disorders in children and adolescents. Moreover, deficits in parvalbumin (PV)-immunoreactive and/or GABAergic neurons are closely associated with various psychiatric disorders in children and adolescents. To investigate the possible neural mechanisms of diet involvement in mental health, we analyzed the effects of dried-bonito dashi (Japanese fish broth) (DBD) on PV-immunoreactive neurons and emotional behaviors in young mice.Male mice after weaning were fed DBD for 60 days, and tested with a resident-intruder test for aggressiveness and a forced swimming test for depression-like symptoms. After the behavioral testing, PV-immunoreactive neurons in the brain were immunohistochemically analyzed.The results indicated that DBD intake decreased aggressiveness and depression-like symptoms, and increased the densities of PV-immunoreactive neurons in the medial prefrontal cortex (mPFC), amygdala, hippocampus, and superior colliculus. These behavioral changes were correlated with the densities of PV-immunoreactive neurons in the mPFC, amygdala, and hippocampus. However, subdiaphragmatic vagotomy did not affect the effects of DBD on emotional behaviors, although it nonspecifically decreased the densities of PV-immunoreactive neurons.The results suggest that DBD might modulate emotional behaviors by promoting PV-immunoreactive and/or GABAergic neuronal activity through parallel routes. The present results highlight a new mechanism for diet involvement in brain functions, and suggest that DBD might have therapeutic potential for the promotion of mental health.

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

The novel object recognition (NOR) test has been widely used to test memory function. We developed a 3D computerized video analysis system that estimates nose contact with an object in Long Evans rats to analyze object exploration during NOR tests. The results indicate that the 3D system reproducibly and accurately scores the NOR test. Furthermore, the 3D system captures a 3D trajectory of the nose during object exploration, enabling detailed analyses of spatiotemporal patterns of object exploration. The 3D trajectory analysis revealed a specific pattern of object exploration in the sample phase of the NOR test: normal rats first explored the lower parts of objects and then gradually explored the upper parts. A systematic injection of MK-801 suppressed changes in these exploration patterns. The results, along with those of previous studies, suggest that the changes in the exploration patterns reflect neophobia to a novel object and/or changes from spatial learning to object learning. These results demonstrate that the 3D tracking system is useful not only for detailed scoring of animal behaviors but also for investigation of characteristic spatiotemporal patterns of object exploration. The system has the potential to facilitate future investigation of neural mechanisms underlying object exploration that result from dynamic and complex brain activity.

Certain eating behaviors are characterized by a trend of elevated food consumption. However, neural mechanisms mediating the motivation for food consumption are not fully understood. Food impacts the brain-rewarding-system via both oral-sensory and post-ingestive information. Recent studies have reported an important role of visceral gut information in mediating dopamine (DA) release in the brain rewarding system. This is independent of oral sensation, suggesting a role of the gut-brain-DA-axis in feeding behavior. In this study, we investigated the effects of intra-gastric (IG) self-administration of glucose on neuronal firings in the nucleus accumbens (NA) of water-deprived rats. Rats were trained in an operant-licking paradigm. During training, when the light was on for 2 min (light-period), rats were required to lick a spout to acquire the water oral-intake learning, and either an IG self-infusion of 0.4 M glucose (GLU group) or water (H2O group). Rats rested in the dark-period (3 min) following the light-period. Four cycles of the operant-licking paradigm consisting of the light–dark periods were performed per day, for 4 consecutive days. In the test session, the same rats licked the same spout to acquire the IG self-administration of the corresponding solutions, without oral water ingestion (dry licking). Behavioral results indicated IG self-administration of glucose elicits more dry-licking behavior than that of water. Neurophysiological results indicated in the dark period, coefficient of variance (CV) measuring the inter-spike interval variability of putative medial spiny neurons (pMSNs) in the NA was reduced in the H2O group compared to the GLU group, while there was no significant difference in physical behaviors in the dark period between the two groups. Since previous studies reported that DA release increases CV of MSNs, the present results suggest that greater CV of pMSNs in the GLU group reflects greater DA release in the NA and elevated motivation in the GLU group, which might increase lickings in the test session in the GLU group compared to the H2O group.

Cerebral deposition of amyloid β protein (Aβ) is an invariant feature of Alzheimer disease (AD), and epidemiological evidence suggests that moderate consumption of foods enriched with phenolic compounds reduce the incidence of AD. We reported previously that the phenolic compounds myricetin (Myr) and rosmarinic acid (RA) inhibited Aβ aggregation in vitro and in vivo. To elucidate a mechanistic basis for these results, we analyzed the effects of five phenolic compounds in the Aβ aggregation process and in oligomer-induced synaptic toxicities.Wenow report that the phenolic compounds blocked Aβ oligomerization, and Myr promoted significantNMRchemical shift changes of monomeric Aβ. Both Myr and RA reduced cellular toxicity and synaptic dysfunction of the Aβ oligomers. These results suggest that Myr and RA may play key roles in blocking the toxicity and early assembly processes associated with Aβ through different binding. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Impairment of insulin and IGF-I signaling in the brain is one of the causes of dementia associated with diabetes mellitus and Alzheimer’s disease. However, the precise pathological processes are largely unknown. In the present study, we found that SH2-containing inositol 5′-phosphatase 2 (SHIP2), a negative regulator of phosphatidylinositol 3,4,5-trisphosphate-mediated signals, is widely expressed in adult mouse brain. When a dominant-negative mutant of SHIP2 was expressed in cultured neurons, insulin signaling was augmented, indicating physiological significance of endogenous SHIP2 in neurons. Interestingly, SHIP2 mRNA and protein expression levels were significantly increased in the brain of type 2 diabetic db/db mice. To investigate the impact of increased expression of SHIP2 in the brain, we further employed transgenic mice overexpressing SHIP2 and found that increased amounts of SHIP2 induced the disruption of insulin/IGF-I signaling through Akt. Neuroprotective effects of insulin and IGF-I were significantly attenuated in cultured cerebellar granule neurons from SHIP2 transgenic mice. Consistently, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay demonstrated that the number of apoptosis-positive cells was increased in cerebral cortex of the transgenic mice at an elderly age. Furthermore, SHIP2 transgenic mice exhibited impaired memory performance in the Morris water maze, step-through passive avoidance, and novel-object-recognition tests. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that SHIP2 is a potent negative regulator of insulin/IGF-I actions in the brain, and excess amounts of SHIP2 may be related, at least in part, to brain dysfunction in insulin resistance with type 2 diabetes.