Discharge to home from a palliative care unit: impact on survival and factors associated with home death after the discharge: a cohort study.

BACKGROUND: Staying at home during the dying process is important for many patients; and palliative care units (PCUs) can help facilitate home death. This study compared patient survival between those who were discharged to home from a palliative care unit and those who were not, and aimed to identify the factors associated with home death after the discharge. METHODS: This retrospective cohort study used a database of patients admitted to a palliative care unit at Kouseiren Takaoka Hospital in Japan. All consecutive patients admitted to the hospital's PCU between October 2016 and March 2020 were enrolled. Patient survival and factors potentially associated with survival and place of death were obtained. A total of 443 patients with cancer were analyzed, and 167 patients were discharged to home and 276 were not. RESULTS: Propensity score matching analyses revealed that median survival time was significantly longer in patients who were discharged to home than those who were not (57 vs. 27 days, P < 0.001). Multiple logistic regression analysis identified that worse Palliative Prognostic Index (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.03-1.44, p = 0.025) and family members' desire for home death (OR = 6.30, 95% CI = 2.32-17.1, p < 0.001) were significantly associated with home death after their discharge. CONCLUSIONS: Discharge to home from palliative care units might have some positive impacts on patient survival.

Dual-MEG interbrain synchronization during turn-taking verbal interactions between mothers and children.

Verbal interaction and imitation are essential for language learning and development in young children. However, it is unclear how mother-child dyads synchronize oscillatory neural activity at the cortical level in turn-based speech interactions. Our study investigated interbrain synchrony in mother-child pairs during a turn-taking paradigm of verbal imitation. A dual-MEG (magnetoencephalography) setup was used to measure brain activity from interactive mother-child pairs simultaneously. Interpersonal neural synchronization was compared between socially interactive and noninteractive tasks (passive listening to pure tones). Interbrain networks showed increased synchronization during the socially interactive compared to noninteractive conditions in the theta and alpha bands. Enhanced interpersonal brain synchrony was observed in the right angular gyrus, right triangular, and left opercular parts of the inferior frontal gyrus. Moreover, these parietal and frontal regions appear to be the cortical hubs exhibiting a high number of interbrain connections. These cortical areas could serve as a neural marker for the interactive component in verbal social communication. The present study is the first to investigate mother-child interbrain neural synchronization during verbal social interactions using a dual-MEG setup. Our results advance our understanding of turn-taking during verbal interaction between mother-child dyads and suggest a role for social "gating" in language learning.

Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder.

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

Decomposed Temporal Complexity Analysis of Neural Oscillations and Machine Learning Applied to Alzheimer's Disease Diagnosis.

Despite growing evidence of aberrant neuronal complexity in Alzheimer's disease (AD), it remains unclear how this variation arises. Neural oscillations reportedly comprise different functions depending on their own properties. Therefore, in this study, we investigated details of the complexity of neural oscillations by decomposing the oscillations into frequency, amplitude, and phase for AD patients. We applied resting-state magnetoencephalography (MEG) to 17 AD patients and 21 healthy control subjects. We first decomposed the source time series of the MEG signal into five intrinsic mode functions using ensemble empirical mode decomposition. We then analyzed the temporal complexities of these time series using multiscale entropy. Results demonstrated that AD patients had lower complexity on short time scales and higher complexity on long time scales in the alpha band in temporal regions of the brain. We evaluated the alpha band complexity further by decomposing it into amplitude and phase using Hilbert spectral analysis. Consequently, we found lower amplitude complexity and higher phase complexity in AD patients. Correlation analyses between spectral complexity and decomposed complexities revealed scale-dependency. Specifically, amplitude complexity was positively correlated with spectral complexity on short time scales, whereas phase complexity was positively correlated with spectral complexity on long time scales. Regarding the relevance of cognitive function to the complexity measures, the phase complexity on the long time scale was found to be correlated significantly with the Mini-Mental State Examination score. Additionally, we examined the diagnostic utility of the complexity characteristics using machine learning (ML) methods. We prepared a feature pool using multiple sparse autoencoders (SAEs), chose some discriminating features, and applied them to a support vector machine (SVM). Compared to the simple SVM and the SVM after feature selection (FS + SVM), the SVM with multiple SAEs (SAE + FS + SVM) had improved diagnostic accuracy. Through this study, we 1) advanced the understanding of neuronal complexity in AD patients using decomposed temporal complexity analysis and 2) demonstrated the effectiveness of combining ML methods with information about signal complexity for the diagnosis of AD.

Markers for the central serotonin system correlate to verbal ability and paralinguistic social voice processing in autism spectrum disorder.

Impairment in verbal communication abilities has been reported in autism spectrum disorder (ASD). Dysfunction of the serotonergic system has also been reported in ASD. However, it is still unknown how the brain serotonergic system relates to impairment in verbal communication abilities in individuals with ASD. In the present study, we investigated the correlation between brain serotonergic condition and brain sensitivity to paralinguistic stimuli (i.e., amplitude in the human voice prosodic change-evoked mismatch field) measured by magnetoencephalography (MEG) or verbal ability in 10 adults with ASD. To estimate the brain serotonergic condition, we measured the serotonin transporter nondisplaceable binding potential cerebrum-wide using positron emission tomography with [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C] DASB). The results demonstrated a significant positive correlation between brain activity to paralinguistic stimuli and brain serotonin transporter binding potential in the left lingual gyrus, left fusiform gyrus and left calcarine cortex. In addition, there were significant positive correlations between verbal ability and serotonergic condition in the right anterior insula, right putamen and right central operculum. These results suggested that the occipital cortex is implicated in recognition of the prosodic change in ASD, whereas the right insula-involved serotonergic system is important in nurturing verbal function in ASD.Trial registration: UMIN000011077.

Auditory steady-state response at 20 Hz and 40 Hz in young typically developing children and children with autism spectrum disorder.

AIM: The early detection of autistic tendencies in children is essential for providing proper care and education. The auditory steady-state response (ASSR) provides a passive, non-invasive technique for assessing neural synchrony at specific response frequencies in many mental disorders, including autism spectrum disorder (ASD), but few studies have investigated its use in young children. This study investigated the ASSR at 20 Hz and 40 Hz in typically developing (TD) children and children with ASD aged 5-7 years. METHODS: The participants were 23 children with ASD and 32 TD children aged 5-7 years. Using a custom-made magnetoencephalography device, we measured ASSR at 20 Hz and 40 Hz, compared the results between groups, and evaluated the association with intellectual function as measured by Kaufmann Assessment Battery for Children. RESULTS: Responses to 20 Hz and 40 Hz were clearly detected in both groups with no significant difference identified. Consistent with previous findings, right dominance of the 40-Hz ASSR was observed in both groups. In the TD children, the right-side 40-Hz ASSR was correlated with age. The Kaufmann Assessment Battery for Children score was correlated with the left-side 40-Hz ASSR in both groups. CONCLUSION: Right-dominant ASSR was successfully detected in young TD children and children with ASD. No difference in ASSR was observed between the children with ASD and the TD children, although the right-side 40-Hz ASSR increased with age only in the TD children. Left-side 40-Hz ASSR was associated with intelligence score in both groups.

Brief Report: Odour Awareness in Young Children with Autism Spectrum Disorders.

The elucidation of odour awareness in children with autism spectrum disorders (ASD) is important. We compared the odour awareness of young children with ASD with those of typical development (TD) children using the Children's Olfactory Behavior in Everyday Life (COBEL) questionnaire, which is a self-report measure that mainly assesses odour awareness. Forty-five young boys (aged 5-6 years), including 20 children with ASD and 25 TD children, participated in this study. The total COBEL score of the young children with ASD was lower than that of the TD children (p < 0.01). Moreover, the total COBEL score was significantly correlated with the total VABS II score (p < 0.05). Our results improve understanding of the odour awareness in children with ASD.

How the Realism of Robot Is Needed for Individuals With Autism Spectrum Disorders in an Interview Setting.

The preliminary efficacy of interview training using an android robot whose appearance and movements resemble those of an actual human for treating social and communication difficulties in individuals with autism spectrum disorders (ASD) has been demonstrated. Patient preferences regarding the appearance of robots are crucial for incentivizing them to undergo robot-assisted therapy. However, very little is known about how the realistic nature of an android robot is related to incentivizing individuals with ASD in an interview setting. In this study, individuals with ASD underwent an interview with a human interviewer and an android robot. Twenty-three individuals with ASD (age, 17-25 years) participated in this study. After the interview, the participants were evaluated in terms of their motivation to practice an interview with an android robot and their impression of the nature of the android robot in terms of humanness. As expected, subjects exhibited higher motivation to undergo interview training with an android robot than with a human interviewer. Higher motivation to undergo an interview with the android robot was negatively correlated with the participants' impressions of the extent to which the android robot exhibited humanness. This study brings us one step closer to understanding how such an android robot should be designed and implemented to provide sufficiently realistic interview training that can be of therapeutic value.

Atypical body movements during night in young children with autism spectrum disorder: a pilot study.

Children with autism spectrum disorder (ASD) reportedly suffer from sleep problems at a higher rate than typically developing (TD) children. Several previous studies have reported differences in sleep indices (e.g., sleep latency) in children with ASD. However, no previous studies have focused specifically on the time course of body movements. In the present study, we investigated the time course of body movements in young TD children and young children with ASD as well as the relationship between body movements during night and social ability. Seventeen TD children and 17 children with ASD participated in this study (5 to 8 years old). We used an accelerometer attached to the waist to record movements during night and measured the average time course of body movements for 3 nights. Our results demonstrated that the rate of body movement 2 to 3 hours after the onset of body stillness was higher in children with ASD than in TD children. In addition, the higher rate of body movement at 0.5 to 1 hour after the onset of body stillness was associated with a lower social ability in the children with ASD. Our results suggested that the time course of body movements is an objective behavioural index for young children with ASD.

Endogenous dopamine release under transcranial direct-current stimulation governs enhanced attention: a study with positron emission tomography.

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants' accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.

Expression of Transcripts Selective for GABA Neuron Subpopulations across the Cortical Visuospatial Working Memory Network in the Healthy State and Schizophrenia.

Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of γ-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1.

Brief Report: Evaluating the Utility of Varied Technological Agents to Elicit Social Attention from Children with Autism Spectrum Disorders.

Technological agents could be effective tools to be used in interventions for enhancing social orienting for some young children with ASD. We examined response to social bids in preschool children with ASD and typical development (TD) at a very early age (i.e., around 3 years) using social prompts presented by technological agents of various forms and human comparisons. Children with ASD demonstrated less response overall to social bids compared to TD controls, across agents or human. They responded more often to a simple humanoid robot and the simple avatar compared to the human. These results support the potential utilization of specific robotic and technological agents for harnessing and potentially increasing motivation to socially-relevant behaviors in some young children with ASD.

Association Between Magnetoencephalographic Interictal Epileptiform Discharge and Cognitive Function in Young Children With Typical Development and With Autism Spectrum Disorders.

Electroencephalograms of individuals with autism spectrum disorders (ASD) show higher rates of interictal epileptiform discharges (IEDs), which are known to have an inverse association with cognitive function in typically developed (TD) children. Nevertheless, that phenomenon has not been investigated adequately in children with ASD. From university and affiliated hospitals, 163 TD children (84 male, 79 female, aged 32-89 months) and 107 children (85 male, 22 female, aged 36-98 months) with ASD without clinical seizure were recruited. We assessed their cognitive function using the Kaufman Assessment Battery for Children (K-ABC) and recorded 10 min of MEG. Original waveforms were visually inspected. Then a linear regression model was applied to evaluate the association between the IED frequency and level of their cognitive function. Significantly higher rates of IEDs were found in the ASD group than in the TD group. In the TD group, we found significant negative correlation between mental processing scale scores (MPS) and the IED frequency. However, for the ASD group, we found significant positive correlation between MPS scores and the IED frequency. In terms of the achievement scale, correlation was not significant in either group. Although we found a correlative rather than a causal effect, typically developed children with higher IED frequency might better be followed up carefully. Furthermore, for children with ASD without clinical seizure, clinicians might consider IEDs as less harmful than those observed in TD children.

Longitudinal changes in the mismatch field evoked by an empathic voice reflect changes in the empathy quotient in autism spectrum disorder.

Autism spectrum disorders (ASDs) are neurodevelopmental conditions with impairments in social communication and interaction. Empathy is the ability to understand and share another person's inner life, and it is an essential process in social cognition, which is deficient in ASD. The mismatch field (MMF) has been used as a neurophysiological marker for the automatic detection of changes in auditory stimuli. In the present study, we focused on long-term changes in MMF evoked by an empathic voice and changes in the empathy quotient (EQ) in ASD during an 8-week clinical trial using oxytocin (OT). Ten males with ASD without intellectual disability participated in this pilot study. The results demonstrated a significant positive correlation between the change in the MMF amplitude in the auditory cortex (i.e., right banks of the superior sulcus) and the change in the EQ score during the 8-week clinical trial, whereas no significant change was observed in the MMF amplitude or EQ score after the administration period of OT. Although we cannot conclude that the observed relationships were caused by OT's effect or by natural changes, our results suggest that MMF evoked by social voice can be a state-dependent marker of empathic abilities in male adults with ASD.

Oxytocin and excitation/inhibition balance in social recognition.

Social recognition is the sensitive domains of complex behavior critical for identification, interpretation and storage of socially meaningful information. Social recognition develops throughout childhood and adolescent, and is affected in a wide variety of psychiatric disorders. Recently, new data appeared on the molecular mechanisms of these processes, particularly, the excitatory-inhibitory (E/I) ratio which is modified during development, and then E/I balance is established in the adult brain. While E/I imbalance has been proposed as a mechanism for schizophrenia, it also seems to be the common mechanism in autism spectrum disorder (ASD). In addition, there is a strong suggestion that the oxytocinergic system is related to GABA-mediated E/I control in the context of brain socialization. In this review, we attempt to summarize the underpinning molecular mechanisms of E/I balance and its imbalance, and related biomarkers in the brain in healthiness and pathology. In addition, because there are increasing interest on oxytocin in the social neuroscience field, we will pay intensive attention to the role of oxytocin in maintaining E/I balance from the viewpoint of its effects on improving social impairment in psychiatric diseases, especially in ASD.

The impact of robotic intervention on joint attention in children with autism spectrum disorders.

Background: A growing body of anecdotal evidence indicates that the use of robots may provide unique opportunities for assisting children with autism spectrum disorders (ASD). However, previous studies investigating the effects of interventions using robots on joint attention (JA) in children with ASD have shown insufficient results. The robots used in these studies could not turn their eyes, which was a limitation preventing the robot from resembling a human agent. Methods: We compared the behavior of children with ASD with that of children with typical development (TD) during a JA elicitation task while the children interacted with either a human or a robotic agent. We used the robot "CommU," which has clear eyes and can turn its eyes, for the robotic intervention. The age range of the participants was limited to 5-6 years. Results: Sixty-eight participants participated in this study, including 30 (10 females and 20 males) children with ASD and 38 (13 females and 25 males) children with TD. The participants were randomly assigned to one of the following two groups: the robotic intervention group or the control group. JA in the children with ASD was better during the robotic intervention than during the human agent intervention. These children exhibited improved performance in the JA task with human after interacting with the robot CommU. JA was differentially facilitated by the human and robotic agents between the ASD and TD children. Conclusions: The findings of this study significantly contribute to the literature on the impact of robots on JA and provide information regarding the suitability of specific robot types for therapeutic use.

Altered Gamma Oscillations during Motor Control in Children with Autism Spectrum Disorder.

Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by inhibitory interneuron dysfunction, which is associated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely reported in autism. However, no study has focused on the gamma oscillations during motor control in autism. In the present study, we investigated the motor-related gamma oscillations in autism using magnetoencephalography. Magnetoencephalographic signals were recorded from 14 right-handed human children with autism (5 female), aged 5-7 years, and age- and IQ-matched 15 typically developing children during a motor task using their right index finger. Consistent with previous studies, the autism group showed a significantly longer button response time and reduced amplitude of motor-evoked magnetic fields. We observed that the autism group exhibited a low peak frequency of motor-related gamma oscillations from the contralateral primary motor cortex, and these were associated with the severity of autism symptoms. The autism group showed a reduced power of motor-related gamma oscillations in the bilateral primary motor cortex. A linear discriminant analysis using the button response time and gamma oscillations showed a high classification performance (86.2% accuracy). The alterations of the gamma oscillations in autism might reflect the cortical excitatory and inhibitory imbalance. Our findings provide an important clue into the behavioral and neurophysiological alterations in autism and a potential biomarker for autism.SIGNIFICANCE STATEMENT Currently, the diagnosis of autism has been based on behavioral assessments, and a crucial issue in the diagnosis of autism is to identify objective and quantifiable clinical biomarkers. A key hypothesis of the neurophysiology of autism is an excitatory and inhibitory imbalance in the brain, which is associated with the generation of gamma oscillations. On the other hand, motor deficits have also been widely reported in autism. This is the first study to demonstrate low motor performance and altered motor-related gamma oscillations in autism, reflecting a brain excitatory and inhibitory imbalance. Using these behavioral and neurophysiological parameters, we classified autism and control group with good accuracy. This work provides important information on behavioral and neurophysiological alterations in patients with autism.

Developmental Trajectory of Infant Brain Signal Variability: A Longitudinal Pilot Study.

The infant brain shows rapid neural network development that considerably influences cognitive and behavioral abilities in later life. Reportedly, this neural development process can be indexed by estimating neural signal complexity. However, the precise developmental trajectory of brain signal complexity during infancy remains elusive. This study was conducted to ascertain the trajectory of magnetoencephalography (MEG) signal complexity from 2 months to 3 years of age in five infants using multiscale entropy (MSE), which captures signal complexity at multiple temporal scales. Analyses revealed scale-dependent developmental trajectories. Specifically, signal complexity predominantly increased from 5 to 15 months of age at higher temporal scales, whereas the complexity at lower temporal scales was constant across age, except in one infant who showed decreased complexity. Despite a small sample size limiting this study's power, this is the first report of a longitudinal investigation of changes in brain signal complexity during early infancy and is unique in its application of MSE analysis of longitudinal MEG data during infancy. The results of this pilot study may serve to further our understanding of the longitudinal changes in the neural dynamics of the developing infant brain.

Changes in maternal feelings for children with autism spectrum disorder after childbirth: The impact of knowledge about the disorder.

The social interactions between caregivers and their children play a crucial role in childhood development; therefore, caregivers' feelings for children are critical for the development of social minds. Mothers of children with autism spectrum disorder (ASD) are known to experience higher levels of stress. However, knowledge regarding mothers' feelings for their children before receiving a clinical diagnosis is limited. This study retrospectively investigated the time course of mothers' feelings from the time of birth and the effect of protective factors. The participants were 5- to 8-year-old children with an ASD diagnosis and their mothers. The mothers of the children with ASD had less positive feelings toward their children than the mothers of the typically developed (TD) children before receiving a clinical diagnosis. Intriguingly, prior knowledge of ASD may relieve maternal mental distress during the child-rearing years and at the time of diagnosis.