Objective Measurement of Hyperactivity Using Mobile Sensing and Machine Learning (Preprint)

UNSTRUCTURED Although hyperactivity is a core symptom of ADHD, there are no objective measures that are widely used in clinical settings. We describe the development of a smartwatch application to measure hyperactivity in school-age children. The LemurDx prototype is a software system for smartwatches that uses wearable sensor technology and machine learning (ML) to measure hyperactivity, with the goal of differentiating children with ADHD combined presentation or predominantly hyperactive/impulsive presentation from children with typical levels of activity. In this pilot study, we recruited 30 children (ages 6-11) to wear the smartwatch with the LemurDx app for two days. Parents also provided activity labels for 30-minute intervals to help train the algorithm. Half the sample had ADHD combined presentation or predominantly hyperactive/impulsive presentation (n = 15) and half were healthy controls (n = 15). Results indicated high usability scores and an overall diagnostic accuracy of .89 (sensitivity = .93; specificity = .86) when the motion sensor output was paired with the activity labels, suggesting that state-of-the-art sensors and ML may provide a promising avenue for the objective measurement of hyperactivity.

Parkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report

Background Paraneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies. Case presentation We report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months. Conclusions Our findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.

Endophenotype-Wide Association Study Reveals Genetic Substrates of Core Symptom Domains and Neurocognitive Function in Autism.

Background Autism is a neurodevelopmental disorder largely attributable to rare and common genetic variants. Additionally, environmental factors such as maternal immune activation and air pollution exposure can also increase the risk of autism. Genetic heterogeneity of autism has been well-recognized from gene discovery efforts over the past decade; however, genetic substrates of endophenotypes that constitute phenotypic heterogeneity are not known yet. Methods Whole-genome sequencing (WGS) data and a set of phenotype scores that represent neurocognitive development and the severity of core symptoms of autism were collected from the iHART and MSSNG databases and the phenotype database of Autism Speaks. Endophenotype-wide association analysis was performed with genome-wide genotype and 29 phenotype scores. Results One or more genetic loci were associated with each of phenotype scores at a genome-wide significance threshold ( P =5×10 -8 ) except for a total score of the Social Responsiveness Scale-2. An intergenic locus on chromosome 15q26.1 was significant for three core symptom domain scores of ADOS Module 1 while each phenotype score was associated with a unique set of genetic loci. The Repetitive Behaviors Scale total score was associated with the largest number of loci (N=132) including the loci that overlapped with the genes involved in brain development and neurodegenerative disorders. Among the significant genotype-endophenotype associations, verbal intelligence and the OSTN gene was notable. The secretory peptide osteocrin—encoded by OSTN —is implicated in activity dependent dendritic growth in human and has potential for a biomarker of autism and an endophenotype marker for verbal intelligence. Limitations Validation of our findings in another cohort is required. Several associations involving the ADI-R and ADOS scores may indicate inherited allelic differences between affected and unaffected individuals since unaffected siblings were included in our analysis. Conclusions Our results suggest that autism candidate genes discovered by case-control GWAS may include trait-associated genes for core symptoms.

Loneliness in Bereavement: Measurement Matters

The role of loneliness in the bereavement experience has been reported as substantial, with the death of a close person leaving a considerable void in the life of the bereaved. Yet, there is lack of agreement about its precise role and, notably, whether loneliness should be included as a core symptom for diagnosis of grief complications. The ongoing threat of heightened social isolation due to the COVID-19 pandemic underlines the need to understand the impact of loneliness, and to accurately chart its prevalence, intensity, duration, and associated difficulties in the context of bereavement. Assessment issues are central to this endeavor. In this article, we review the scientific literature to examine how loneliness after bereavement has been operationalized and measured. Sixty-three articles analyzing 51 independent datasets were reviewed. Results show major disparities: approximately half of the projects assessed loneliness by means of one of two validated scales (spanning different versions); the remainder included only single- or few-item measures. Diverse instructions, content and answer categories were used. While one size does not fit all, awareness of assessment options and dis/advantages may aid selection of the most appropriate measure, to suit the goals of a particular study and the specific groups under investigation. Our conclusion is that, in selecting a loneliness measure, health care professionals should come to their own well-informed decision, aided by the information provided in our review.

Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

Neuroleptic Malignant Syndrome (NMS) on Clozapine with a Potential Atypical Interaction with Paliperidone

Neuroleptic Malignant Syndrome (NMS) associated with the use of first-generation antipsychotics is a widely known phenomenon. This idiosyncratic reaction is less significant with the use of second-generation antipsychotics, and only a few cases in the literature exist, describing this reaction with clozapine use. While being titrated on clozapine, the patient developed major and minor criteria features of NMS as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) criteria except for fever, a core symptom which created diagnostic uncertainty. Initially, clozapine was temporarily discontinued due to his deteriorating mental and physical state. A rechallenge was considered at a much lower dose, but due to a rapid increase in his creatinine kinase (CK) levels within a 12-hour timeframe, clozapine was permanently stopped. The evidence further suggests that the presentation of NMS for patients on this medication may be different to the classical presentation, and other criteria for diagnosis are suggested, which may lower the threshold for investigating NMS for patients on clozapine.

Core-Symptom-Defined Cortical Gyrification Differences in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a heterogeneous disease that is characterized by abnormalities in social communication and interaction as well as repetitive behaviors and restricted interests. Structural brain imaging has identified significant cortical folding alterations in ASD; however, relatively less known is whether the core symptoms are related to neuroanatomical differences. In this study, we aimed to explore core-symptom-anchored gyrification alterations and their developmental trajectories in ASD. We measured the cortical vertex-wise gyrification index (GI) in 321 patients with ASD (aged 7–39 years) and 350 typically developing (TD) subjects (aged 6–33 years) across 8 sites from the Autism Brain Imaging Data Exchange I (ABIDE I) repository and a longitudinal sample (14 ASD and 7 TD, aged 9–14 years in baseline and 12–18 years in follow-up) from ABIDE II. Compared with TD, the general ASD patients exhibited a mixed pattern of both hypo- and hyper- and different developmental trajectories of gyrification. By parsing the ASD patients into three subgroups based on the subscores of the Autism Diagnostic Interview—Revised (ADI-R) scale, we identified core-symptom-specific alterations in the reciprocal social interaction (RSI), communication abnormalities (CA), and restricted, repetitive, and stereotyped patterns of behavior (RRSB) subgroups. We also showed atypical gyrification patterns and developmental trajectories in the subgroups. Furthermore, we conducted a meta-analysis to locate the core-symptom-anchored brain regions (circuits). In summary, the current study shows that ASD is associated with abnormal cortical folding patterns. Core-symptom-based classification can find more subtle changes in gyrification. These results suggest that cortical folding pattern encodes changes in symptom dimensions, which promotes the understanding of neuroanatomical basis, and clinical utility in ASD.

Exploring anhedonia in adolescents with Chronic Fatigue Syndrome (CFS): A mixed-methods study

Background: Chronic Fatigue Syndrome (CFS/ME) may get in the way of enjoying activities. A substantial minority of adolescents with CFS/ME are depressed. Anhedonia is a core symptom of depression. Anhedonia in adolescents with CFS/ME has not been previously investigated. Method: One hundred and sixty-four adolescents, age 12 to 18, with CFS/ME completed a diagnostic interview (K-SADS) and questionnaires (HADS, RCADS). We used a mixed-methods approach to explore the experience of anhedonia and examine how common it is, comparing those with clinically significant anhedonia to those without. Results: Forty-two percent of adolescents with CFS/ME reported subclinical or clinical levels of anhedonia. Fifteen percent had clinically significant anhedonia. Thematic analysis generated two themes: (1) stopping activities that they previously enjoyed and (2) CFS/ME obstructs enjoyment. Most (72%) of those who reported clinically significant anhedonia met the depression diagnostic criteria. Those who were depressed used more negative language to describe their experience of activities than in those who were not depressed, although the themes were broadly similar. Conclusions: Experiencing pleasure from activities may be affected in CFS/ME, particularly in those who are depressed. Anhedonia may get in the way of behavioural strategies used within CFS/ME treatments.

Assessing the relationship between the human learned helplessness depression model and anhedonia

The learned helplessness (LH) model is one of the most commonly used acute stress models to explain depression and it has shown good face and predictive validity. However, despite being able to induce depressed-like behaviors and corresponding psychophysiological changes, there is little evidence showing that the LH paradigm can produce anhedonia, a core symptom seen in all forms of depression in humans. So far a couple of studies showed that rodents bred for helplessness develop anhedonic-like behaviors in response to stress; yet, to the best of our knowledge, no similar human research has tried to investigate the direct relationship between the LH model and anhedonia. In the present study, we use a modified version of the original LH task to experimentally and temporarily induce learned helplessness in college students and then examine if the human LH paradigm induces anhedonia. We aim to 1: address the ill-defined connection between the LH model and anhedonia, and 2: directly assess helplessness in humans as opposed to the majority of non-human animal subjects used in the helplessness literature. We believe that our study will fill an important gap in the learned helplessness model literature, and will advance our understanding of the relationship between depression and perceived control, as well as place limitations to what can and cannot be inferred from non-human animal data in this topic.

Clinical data mining on network of symptom and index and correlation of tongue-pulse data in fatigue population

Background Fatigue is a kind of non-specific symptom, which occurs widely in sub-health and various diseases. It is closely related to people's physical and mental health. Due to the lack of objective diagnostic criteria, it is often neglected in clinical diagnosis, especially in the early stage of disease. Many clinical practices and researches have shown that tongue and pulse conditions reflect the body's overall state. Establishing an objective evaluation method for diagnosing disease fatigue and non-disease fatigue by combining clinical symptom, index, and tongue and pulse data is of great significance for clinical treatment timely and effectively. Methods In this study, 2632 physical examination population were divided into healthy controls, sub-health fatigue group, and disease fatigue group. Complex network technology was used to screen out core symptoms and Western medicine indexes of sub-health fatigue and disease fatigue population. Pajek software was used to construct core symptom/index network and core symptom-index combined network. Simultaneously, canonical correlation analysis was used to analyze the objective tongue and pulse data between the two groups of fatigue population and analyze the distribution of tongue and pulse data. Results Some similarities were found in the core symptoms of sub-health fatigue and disease fatigue population, but with different node importance. The node-importance difference indicated that the diagnostic contribution rate of the same symptom to the two groups was different. The canonical correlation coefficient of tongue and pulse data in the disease fatigue group was 0.42 (P < 0.05), on the contrast, correlation analysis of tongue and pulse in the sub-health fatigue group showed no statistical significance. Conclusions The complex network technology was suitable for correlation analysis of symptoms and indexes in fatigue population, and tongue and pulse data had a certain diagnostic contribution to the classification of fatigue population.