A comprehensive multivariate analysis of the center of pressure during quiet standing in patients with Parkinson's disease.

BACKGROUND: We hypothesized that postural instability observed in individuals with Parkinson's disease (PD) can be classified as distinct subtypes based on comprehensive analyses of various evaluated parameters obtained from time-series of center of pressure (CoP) data during quiet standing. The aim of this study was to characterize the postural control patterns in PD patients by performing an exploratory factor analysis and subsequent cluster analysis using CoP time-series data during quiet standing. METHODS: 127 PD patients, 47 aged 65 years or older healthy older adults, and 71 healthy young adults participated in this study. Subjects maintain quiet standing for 30 s on a force platform and 23 variables were calculated from the measured CoP time-series data. Exploratory factor analysis and cluster analysis with a Gaussian mixture model using factors were performed on each variable to classify subgroups based on differences in characteristics of postural instability in PD. RESULTS: The factor analysis identified five factors (magnitude of sway, medio-lateral frequency, anterio-posterior frequency, component of high frequency, and closed-loop control). Based on the five extracted factors, six distinct subtypes were identified, which can be considered as subtypes of distinct manifestations of postural disorders in PD patients. Factor loading scores for the clinical classifications (younger, older, and PD severity) overlapped, but the cluster classification scores were clearly separated. CONCLUSIONS: The cluster categorization clearly identifies symptom-dependent differences in the characteristics of the CoP, suggesting that the detected clusters can be regarded as subtypes of distinct manifestations of postural disorders in patients with PD.

Rat Retrosplenial Cortical Involvement in Wayfinding Using Visual and Locomotor Cues.

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.

High molecular weight amyloid ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid ß-protein (Aß) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aß 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-Aß1-42 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-Aß1-42 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-Aß1-42 were significantly greater than those of LMW-Aß1-42. Therapeutic reduction of HMW-Aß1-42 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 ß1-42 oligomers induce neurotoxicity via plasma membrane damage.

Superior Neuronal Detection of Snakes and Conspecific Faces in the Macaque Medial Prefrontal Cortex.

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.

Intentional gaze shift to neglected space: a compensatory strategy during recovery after unilateral spatial neglect.

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.

Ingestion of dried-bonito broth (dashi) facilitates PV-parvalbumin-immunoreactive neurons in the brain, and affects emotional behaviors in mice.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Effects of high fat diet and perinatal dioxin exposure on development of body size and expression of platelet-derived growth factor receptor ß in the rat brain.

Environmental exposure to dioxins, consumption of a high fat diet, and platelet-derived growth factor receptor ß 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 ß 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 ß 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 ß levels in the amygdala and striatum only in females receiving an high fat diet. Furthermore, platelet-derived growth factor receptor ß levels in the hippocampus and platelet-derived growth factor receptor ß striatum were inversely correlated with increases in body length, while changes in platelet-derived growth factor receptor ß 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 ß levels.

Phenolic compounds prevent the oligomerization of α-synuclein and reduce synaptic toxicity.

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.

Relative contribution of sensory and motor deficits on grip force control in patients with chronic stroke.

OBJECTIVE: This study aimed to characterize grasping behavior in static (weight-dependent modulation and stability of control) and dynamic (predictive control) aspects specifically focusing on the relative contribution of sensory and motor deficits to grip force control in patients with chronic stroke. METHODS: Twenty-four chronic stroke patients performed three manipulative tasks: five trials of 5-s grasp-lift-holding, 30-s static holding, and vertical dynamic/cyclic oscillation of holding the object. RESULTS: Exerted static grip force on the paretic side exhibited statistically greater than that on the non-paretic side. Spearman's rank correlation coefficient revealed that the contribution to static grip force control was larger in sensory deficits than in motor deficits. In addition, the sensory deficit is related to the reduced coupling between grip force and load force, suggesting difficulty in predictive control due to the absence of sensory feedback. CONCLUSIONS: Given that grip force control involves predictive feedforward and online feedback control, the evaluation of grip force might be an important and feasible evaluation manner for the assessment of sensorimotor control in patients post-stroke. SIGNIFICANCE: Detailed evaluation of grip force control would help to understand the mechanisms underlying hand dysfunction in stroke patients.

Phenolic compounds prevent amyloid ß-protein oligomerization and synaptic dysfunction by site-specific binding.

Cerebral deposition of amyloid ß protein (Aß) 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 Aß aggregation in vitro and in vivo. To elucidate a mechanistic basis for these results, we analyzed the effects of five phenolic compounds in the Aß aggregation process and in oligomer-induced synaptic toxicities. We now report that the phenolic compounds blocked Aß oligomerization, and Myr promoted significant NMR chemical shift changes of monomeric Aß. Both Myr and RA reduced cellular toxicity and synaptic dysfunction of the Aß oligomers. These results suggest that Myr and RA may play key roles in blocking the toxicity and early assembly processes associated with Aß through different binding.

Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine.

Bitterness is an important physiological function in the defense responses to avoid toxic foods. The taste receptor 2 family is well known to mediate bitter taste perception in Type II taste cells. Here, we report that the polycystic kidney disease 2-like 1 (PKD2L1) channel is a novel sensor for the bitter aftertaste in Type III taste cells. The PKD2L1 channel showed rebound activation after the washout of quinine, a bitter tastant, in electrophysiological whole-cell recordings of the PKD2L1-expressing HEK293T cells and Ca2+-imaging analysis of Type III taste cells isolated from wild-type PKD2L1 mice. In the short-term two-bottle preference and lick tests in vivo, the wild-type mice avoided normal water while the PKD2L1-knockout mice preferred normal water after they ingested the quinine-containing water. These results may explain the new mechanism of the quinine-triggered bitter aftertaste perception in Type III taste cells.

Pathological structure of visuospatial neglect: A comprehensive multivariate analysis of spatial and non-spatial aspects.

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.

Neuronal Representation of Locomotion During Motivated Behavior in the Mouse Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is located within the dorsomedial prefrontal cortex (PFC), and processes and facilitates goal-directed behaviors relating to emotion, reward, and motor control. However, it is unclear how ACC neurons dynamically encode motivated behavior during locomotion. In this study, we examined how information for locomotion and behavioral outcomes is temporally represented by individual and ensembles of ACC neurons in mice during a self-paced locomotor reward-based task. By recording and analyzing the activity of ACC neurons with a microdrive tetrode array while the mouse performed the locomotor task, we found that more than two-fifths of the neurons showed phasic activity relating to locomotion or the reward behavior. Some of these neurons showed significant differences in their firing rate depending on the behavioral outcome. Furthermore, by applying a demixed principal component analysis, the ACC population activity was decomposed into components representing locomotion and the previous/future outcome. These results indicated that ACC neurons dynamically integrate motor and behavioral inputs during goal-directed behaviors.

Interaction between spatial neglect and attention deficit in patients with right hemisphere damage.

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: BIT<131), (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 (RTmean) and the ratios of the right and left space (L/Rratio), respectively. The results revealed that RTmean and L/Rratio can be regarded as independent evaluation parameters for attention deficit and neglect symptoms, respectively. Voxel-based lesion-symptom mapping based on RTmean and L/Rratio values revealed relevant lesions with attention-related brain areas (middle temporal gyrus, angular gyrus, and inferior frontal gyrus), and neglect-related brain areas (superior temporal gyrus and superior longitudinal fascicules). A cluster analysis with Gaussian mixture model detected six different states of USN with an interaction between neglect symptoms and attention deficit. Interestingly, the recovery process after USN can be properly explained by the transition pattern from one cluster to another. Our results suggest that a novel evaluation approach to distinguish between neglect symptoms and attention deficit, namely the characterization of the interaction between RTmean and L/Rratio, provides useful information for understanding pathological features of USN.

Effects of Tool Novelty and Action Demands on Gaze Searching During Tool Observation.

Technical reasoning refers to making inferences about how to use tools. The degree of technical reasoning is indicated by the bias of the gaze (fixation) on the functional part of the tool when in use. Few studies have examined whether technical reasoning differs between familiar and unfamiliar novel tools. In addition, what effect the intention to use the tool has on technical reasoning has not been determined. This study examined gaze shifts in relation to familiar or unfamiliar tools, under three conditions (free viewing, lift, and use), among 14 healthy adults (mean age ± standard deviation, 29.4 ± 3.9 years). The cumulative fixation time on the functional part of the tool served as a quantitative indicator of the degree of technical reasoning. The two-way analysis of variance for tools (familiar and unfamiliar) and conditions (free viewing, lift, and use) revealed that the cumulative fixation time significantly increased under free viewing and use conditions, compared to lift conditions. Relative to the free viewing condition, cumulative fixation time for unfamiliar tools significantly decreased in the lift condition and significantly increased in the use condition. Importantly, the results showed that technical reasoning was performed in both the use and the free viewing conditions. However, technical reasoning in the free viewing condition was not as strong as in the use condition. The difference between technical reasoning in free viewing and use conditions may indicate the difference between automatic and intentional technical reasoning.

Walking characteristics including mild motor paralysis and slow walking speed in post-stroke patients.

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.

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice.

Growing evidence suggests that oxidative stress due to amyloid ß (Aß) 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. Aß42 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 Aß42 deposition and pTau-positive areal fraction, while it increased PV-positive neuron density and microglial accumulation per unit fraction of Aß42 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 (Aß42 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.

Motor Imagery Training With Neurofeedback From the Frontal Pole Facilitated Sensorimotor Cortical Activity and Improved Hand Dexterity.

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.

Impaired hemodynamic activity in the right dorsolateral prefrontal cortex is associated with impairment of placebo analgesia and clinical symptoms in postherpetic neuralgia.

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.