Gait analysis as a robust pain behavioural endpoint in the chronic phase of the monoiodoacetate-induced knee joint pain in the rat.

The monoiodoacetate-induced rat model of osteoarthritis knee pain is widely used. However, there are between-study differences in the pain behavioural endpoints assessed and in the dose of intraarticular monoiodoacetate administered. This study evaluated the robustness of gait analysis as a pain behavioural endpoint in the chronic phase of this model, in comparison with mechanical hyperalgesia in the injected (ipsilateral) joint and development of mechanical allodynia in the ipsilateral hind paws. Groups of Sprague-Dawley rats received a single intraarticular injection of monoiodoacetate at 0.5, 1, 2 or 3 mg or vehicle (saline) into the left (ipsilateral) knee joint. An additional group of rats were not injected (naïve group). The pain behavioural methods used were gait analysis, measurement of pressure algometry thresholds in the ipsilateral knee joints, and assessment of mechanical allodynia in the ipsilateral hind paws using von Frey filaments. These pain behavioural endpoints were assessed premonoiodoacetate injection and for up to 42-days postmonoiodoacetate injection in a blinded manner. Body weights were also assessed as a measure of general health. Good general health was maintained as all rats gained weight at a similar rate for the 42-day study period. In the chronic phase of the model (days 9-42), intraarticular monoiodoacetate at 3 mg evoked robust alterations in multiple gait parameters as well as persistent mechanical allodynia in the ipsilateral hind paws. For the chronic phase of the monoiodoacetate-induced rat model of osteoarthritis knee pain, gait analysis, such as mechanical allodynia in the ipsilateral hind paws, is a robust pain behavioural measure.

Externalizing behavior in healthy young adults is associated with lower cortisol responses to acute stress and altered neural activation in the dorsal striatum.

The externalizing spectrum is characterized by disinhibition, impulsivity, antisocial-aggressive behavior as well as substance (mis)use. Studies in forensic samples and mentally impaired children suggested that higher rates of externalization are linked to lower cortisol stress responses and altered affect-related neural activation. In this fMRI-study, we investigated whether externalizing behavior in healthy participants is likewise associated with altered cortisol responses and neural activity to stress. Following a quasi-experimental approach, we tested healthy participants (N = 61, 31 males) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure. All participants were exposed to ScanSTRESS, a standardized psychosocial stress paradigm for scanner environments. In both groups, ScanSTRESS induced a significant rise in cortisol levels with the high externalization group showing significantly lower cortisol responses to stress than the low externalization group. This was mainly driven by males. Further, individual increases in cortisol predicted neural response differences between externalization groups, indicating more activation in the dorsal striatum in low externalization. This was primarily driven by females. In contrast, post-hoc analysis showed that hypothalamic-pituitary-adrenal axis hyporeactivity in males was associated with prefrontal and hippocampal activation. Our data substantiate that individuals from the general population high on externalization, show reduced cortisol stress responses. Furthermore, dorsal striatum activity as part of the mesolimbic system, known to be sensitive to environmental adversity, seems to play a role in externalization-specific cortisol stress responses. Beyond that, a modulating influence of gender was disclosed.

Apolipoprotein E e4 is associated with worse self-reported neurobehavioral symptoms following uncomplicated mild traumatic brain injury in U.S. military service members.

Past research has found a relationship between the apolipoprotein E (APOE) e4 allele and worse neurobehavioral functioning following mild traumatic brain injury (MTBI) in civilian populations. The purpose of this study was to examine this relationship in service members and veterans (SMVs) following MTBI. Participants were 151 SMVs (103 uncomplicated MTBI; 48 Injured Controls [IC]) prospectively enrolled in the DVBIC-TBICoE 15-Year Longitudinal TBI Study. Participants completed a battery of self-reported neurobehavioral symptom measures on average 76.2 months post-injury (SD = 31.8). APOE genotyping was undertaken using non-fasting blood samples. Participants were classified into four subgroups based on injury (MTBI vs. IC) and APOE e4 allele status (e4 present/absent). In the IC group, there were no significant differences across APOE e4 status subgroups for all measures. In the MTBI group, participants with the APOE e4 allele had significantly worse scores on measures of depression, pain, anxiety, grief, positive well-being, social participation, and resilience compared to those without the e4 allele (d = .44 to d = .69). When comparing the number of 'clinically elevated' neurobehavioral measures simultaneously, the MTBI/e4 present subgroup consistently had a higher number of elevated measures compared to the MTBI/e4 absent, IC/e4 present, and IC/e4 absent subgroups. The APOE e4 allele was associated with poorer neurobehavioral outcome in SMVs in the chronic phase of recovery following MTBI. APOE e4 could be incorporated into screening tools to predict SMVs at risk for poor long-term neurobehavioral outcome in an effort to provide early intervention to improve long-term clinical outcome.

Maturity of gray matter structures and white matter connectomes, and their relationship with psychiatric symptoms in youth.

Brain predicted age difference, or BrainPAD, compares chronological age to an age estimate derived by applying machine learning (ML) to MRI brain data. BrainPAD studies in youth have been relatively limited, often using only a single MRI modality or a single ML algorithm. Here, we use multimodal MRI with a stacked ensemble ML approach that iteratively applies several ML algorithms (AutoML). Eligible participants in the Healthy Brain Network (N = 489) were split into training and test sets. Morphometry estimates, white matter connectomes, or both were entered into AutoML to develop BrainPAD models. The best model was then applied to a held-out evaluation dataset, and associations with psychometrics were estimated. Models using morphometry and connectomes together had a mean absolute error of 1.18 years, outperforming models using a single MRI modality. Lower BrainPAD values were associated with more symptoms on the CBCL (pcorr  = .012) and lower functioning on the Children's Global Assessment Scale (pcorr  = .012). Higher BrainPAD values were associated with better performance on the Flanker task (pcorr  = .008). Brain age prediction was more accurate using ComBat-harmonized brain data (MAE = 0.26). Associations with psychometric measures remained consistent after ComBat harmonization, though only the association with CGAS reached statistical significance in the reduced sample. Our findings suggest that BrainPAD scores derived from unharmonized multimodal MRI data using an ensemble ML approach may offer a clinically relevant indicator of psychiatric and cognitive functioning in youth.

Social impairments in mice lacking the voltage-gated potassium channel Kv3.1.

Parvalbumin (PV)-expressing neurons have been implicated in the pathology of autism spectrum disorders (ASD). Loss of PV expression and/or reduced number of PV-expressing neurons have been reported not only in genetic and environmental rodent models of ASD, but also in post-mortem analyses of brain tissues from ASD vs. healthy control human subjects. PV-expressing neurons play a pivotal role in the maintenance of the balance between excitation and inhibition within neural circuits in part because of their fast-spiking properties. Their high firing rate is mostly regulated by the voltage-gated potassium channel Kv3.1. It is yet unknown whether disturbances in the electrophysiological properties of PV-expressing neurons per se can lead to behavioral disturbances. We assessed locomotor activity, social interaction, recognition and memory, and stereotypic behaviors in Kv3.1 wild-type (WT) and knockout (KO) mice. We then used Western Blot analyses to measure the impact of Kv3.1 deficiency on markers of GABA transmission (PV and GAD67) and neural circuit activity (Egr1). Deficiency in Kv3.1 channel is sufficient to induce social deficits, hyperactivity and stereotypic behaviors. These behavioral changes were independent of changes in GAD67 levels and associated with increased levels of PV protein in the prefrontal cortex and striatum. These findings reveal that a loss of PV expression is not a necessary factor to induce an ASD-like phenotype in mice and support the need for further investigation to fully understand the contribution of PV-expressing neurons to ASD pathology.

Dynamic brain connectome and high risk of mental problem in clinical nurses.

With the growing population and rapid change in the social environment, nurses in China are suffering from high rates of stress; however, the neural mechanism underlying this occupation related stress is largely unknown. In this study, mental status was determined for 81 nurses and 61 controls using the Symptom Checklist 90 (SCL-90) scale. A subgroup (n = 57) was further scanned by resting-state functional MRI with two sessions. Based on the SCL-90 scale, "somatic complaints" and "diet/sleeping" exhibited the most prominent difference between nurses and controls. This mental health change in nurses was further supported by the spatial independent component analysis on functional MRI data. First, dynamic functional connectome analysis identified two discrete connectivity configurations (States I and II). Controls had more time in the State I than II, while the nurses had more time in the State II than I. Second, nurses showed a similar static network topology as controls, but altered dynamic properties. Third, the symptom-imaging correlation analysis suggested the functional alterations in nurses as potential imaging biomarkers indicating a high risk for "diet/sleeping" problems. In summary, this study emphasized the high risk of mental deficits in nurses and explored the underlying neural mechanism using dynamic brain connectome, which provided valuable information for future psychological intervention.

Associations between autonomic nervous system activity and risk-taking and internalizing behavior in young adolescents.

Dysregulated autonomic nervous system (ANS) activity has been associated with adolescent risk-taking and internalizing behavior, but previous results in community samples have been mixed. We investigated whether ANS activity was associated with higher risk-taking and internalizing behavior in young adolescents (age 11/12; n = 875), and whether adolescents' gender, parents' parenting style or a combination of both moderated these associations. Adolescents and their parents were recruited as part of the population-based, longitudinal Amsterdam Born Children and their Development (ABCD) study. Risk-taking behavior was assessed with the Balloon Analogue Risk Task and the personality characteristics sensation seeking and impulsivity, measured with the Substance Use Risk Profile Scale (SURPS). Internalizing behavior was assessed via the SURPS subscales anxiety sensitivity and hopelessness. Authoritative (AUTH-SW) and authoritarian (AUTH-S) parenting styles were measured with the Parenting Styles and Dimensions Questionnaire. Resting ANS activity was assessed via heart rate and respiratory sinus arrhythmia (RSA). Hierarchical, multivariable regression analyses showed higher RSA, but not heart rate, being associated with higher risk-taking behavior and sensation seeking. The associations between ANS activity and risk-taking variables were not significantly moderated by gender, parenting, or interactions between gender and parenting. Our findings suggest that RSA activity may be a relevant factor in mild to moderate risk-taking behavior in adolescents from the general population, regardless of their gender or the type of parenting they experience.

Emotional and behavioral problems in pediatric patients with migraine and tension-type headache.

OBJECTIVE: This study aimed to investigate the associations between psychopathological characteristics of children and adolescents with primary headache, as measured by the Strengths and Difficulties Questionnaire (SDQ), and treatment outcomes. METHODS: A cohort study was conducted on 124 pediatric patients with primary headache. At the first consultation, the SDQ was completed by the parents. The analysis of treatment efficacy was conducted on 90 patients with a follow-up period of at least one year. Treatment responders were defined as those who showed 50% reduction in the headache frequency. First, an analysis of the SDQ total scores and five subscales, among the migraine and tension-type headache groups, was conducted for 124 participants. Second, the association between the SDQ scores and treatment outcomes in the groups with periods of improvement of less than three months and three months or more were analyzed in 90 patients. RESULTS: Migraine patients displayed more difficulties than strengths in terms of the total score (p = .004) and in the emotional symptoms subscale (p = .012) compared with tension-type headache patients. Migraine patients who required more than three months to show improvement displayed more peer problems (p = .020), while tension-type headache patients who required more than three months to show improvement displayed fewer conduct problems (p = .007). CONCLUSION: Evaluation of patient characteristics using the SDQ at first consultation can predict the treatment outcome. Moreover, it can help provide appropriate initial treatment and improve outcome of primary headache in children.

Functional Role of the Cerebellum in Parkinson Disease: A PET Study.

OBJECTIVES: To test for cerebellar involvement in motor and nonmotor impairments in Parkinson disease (PD) and to determine patterns of metabolic correlations with supratentorial brain structures, we correlated clinical motor, cognitive, and psychiatric scales with cerebellar metabolism. METHODS: We included 90 patients with PD. Motor, cognitive, and psychiatric domains were assessed, and resting-state 18FDG-PET metabolic imaging was performed. The motor, cognitive, and psychiatric scores were entered separately into a principal component analysis. We looked for correlations between these 3 principal components and cerebellar metabolism. Furthermore, we extracted the mean glucose metabolism value for each significant cerebellar cluster and looked for patterns of cerebrum-cerebellum metabolic correlations. RESULTS: Severity of impairment was correlated with increased metabolism in the anterior lobes and vermis (motor domain); the right crus I, crus II, and declive (cognitive domain); and the right crus I and crus II (psychiatric domain). No results survived multiple testing corrections regarding the psychiatric domain. Moreover, we found distributed and overlapping, but not identical, patterns of metabolic correlations for motor and cognitive domains. Specific supratentorial structures (cortical structures, basal ganglia, and thalamus) were strongly correlated with each of the cerebellar clusters. CONCLUSIONS: These results confirm the role of the cerebellum in nonmotor domains of PD, with differential but overlapping patterns of metabolic correlations suggesting the involvement of cerebello-thalamo-striatal-cortical loops.

Behavioural change in Prader-Willi syndrome during COVID-19 pandemic.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disorder that in many cases is associated with mental health disorders, in addition to characteristic symptoms such as hyperphagia. The current Sars-CoV-2 coronavirus pandemic has led to massive restrictions in health care and social life worldwide. People with PWS represent a particularly vulnerable population group to these restrictions, with unknown impact on their mental health. METHODS: We conducted an online questionnaire to assess the impact of the restrictions associated with the COVID-19 pandemic on the mental health of people with PWS. RESULTS: One hundred and eight caregivers completed the survey about individuals with PWS. Individuals with PWS > 6 years (n = 89) were included for evaluation with regard to psychopathological change. Respondents frequently reported an increase in psychopathological symptoms associated with PWS during the lockdown, with 51.7% reporting increased temper outbursts, 43.8% showing signs of sadness, 38.2% being anxious, 55.0% more irritable, and 39.3% showing more food seeking behaviour. Adjusted for the type of accommodation food seeking behaviour and irritability is increased to a significantly lesser extent in people with PWS accommodated in specialised care facilities compared with those living in their family home. No significant difference could be found between the sexes. CONCLUSION: The COVID-19 pandemic has had a significant effect on the mental health of individuals with PWS, evidenced by an increase in behaviours associated with PWS, including temper outbursts, food-seeking, and irritability, which again underlines their need for specialised care. Individuals living with their families were particularly vulnerable, indicating that they and their families are in special need of support.

Cognitive and behavioural flexibility: neural mechanisms and clinical considerations.

Cognitive and behavioural flexibility permit the appropriate adjustment of thoughts and behaviours in response to changing environmental demands. Brain mechanisms enabling flexibility have been examined using non-invasive neuroimaging and behavioural approaches in humans alongside pharmacological and lesion studies in animals. This work has identified large-scale functional brain networks encompassing lateral and orbital frontoparietal, midcingulo-insular and frontostriatal regions that support flexibility across the lifespan. Flexibility can be compromised in early-life neurodevelopmental disorders, clinical conditions that emerge during adolescence and late-life dementias. We critically evaluate evidence for the enhancement of flexibility through cognitive training, physical activity and bilingual experience.

The effect of age and chronotype on seasonality, sleep problems, and mood.

Seasonal affective disorder has been associated with sleep problems, young age, and an evening chronotype. A chronotype refers to an individual's preference in the timing of their sleep-wake cycle, as well as the time during the sleep-wake cycle when a person is most alert and energetic. Seasonality refers to season-dependent fluctuations in sleep length, social activity, mood, weight, appetite, and energy level. Evening chronotype is more common in young adults and morning chronotype more common in the elderly. This study aimed to estimate the differential contribution of chronotype and age on seasonality. A sample of n=410 participants were included in the study. The age groups showed significantly different results according to sleep parameters, depression, anxiety, stress, seasonality, and chronotype. The oldest group (>59 years) showed the lowest scores on all of these scales. According to a path analysis, chronotype and age predict propensity for seasonality. However, sleep problems were linked to chronotype but not to age. Older adults seem to be more resistant to seasonal changes that are perceived as a problem than young and middle aged adults. Future studies would benefit from considering cultural aspects and examine seasonality, chronotype, depression, and insomnia in longitudinal designs.

Furthering the Understanding of Wechsler Adult Intelligence Scale-Fourth Edition Factor Structure in a Clinical Sample.

The Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) is a commonly administered battery for assessing intellectual and cognitive abilities. Despite its popularity, construct validation studies primarily utilize the WAIS-IV normative sample rather than ecologically-valid clinical samples. The current study expands the literature on the validity of WAIS-IV by testing a bifactor model in such a sample. We examined archival data from 300 concurrent psychological evaluations performed at a university-based community clinic. Participants received the full WAIS-IV standard battery. Consistent with recent literature, confirmatory factor analyses (CFAs) favored a direct hierarchical model, where the g factor has a direct influence on WAIS-IV subtest performance and index scores explain only modest degrees of residual variance. Results challenge traditional intelligence nosologies and suggest consideration of a two-step method of WAIS-IV interpretation in clinical samples, whereby the Full Scale IQ score (FSIQ) score is examined first and individual subtest scores are analyzed second.

Change in mental health symptoms during the COVID-19 pandemic: The role of appraisals and daily life experiences.

OBJECTIVE: When confronted with major threats, people often experience decline in well-being. The central purpose of this study was to identify mechanisms underlying change of well-being in times of threat, using the example of the COVID-19 pandemic, with a focus on appraisals of the pandemic and affective states, stress, as well as mindfulness in daily life. METHOD: We conducted a study across 3.5 weeks, including pretest, posttest, and a diary phase in-between. We worked with a sample of 460 adults, pre- and post-test information, as well as 7,189 observations from the diary phase. RESULTS: Results showed that deterioration in mental health symptoms across the duration of the study was associated with (a) change towards less fortunate appraisals of the pandemic and (b), more negative affect and less mindfulness in daily life. Furthermore, appraisals of the pandemic at pretest predicted experiences in daily life, with more negative appraisals of the pandemic predicting more negative affect and stressor occurrence as well as less mindfulness. CONCLUSIONS: These findings speak to the dynamic nature of well-being and appraisals in times of threat, and highlight the role of experiences in daily life in changes in well-being.

G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease.

Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target. Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies. Results: Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an "overload" hypothesis for the etiology of the psychiatric symptoms of Parkinson disease. Limitations: Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types. Conclusion: GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.

Behavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans.

BACKGROUND: Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known. RESEARCH QUESTION: What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin? STUDY DESIGN AND METHODS: Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli. RESULTS: Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R2 = 0.53). INTERPRETATION: Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing.

Age of onset and behavioral manifestations in Huntington's disease: An Enroll-HD cohort analysis.

Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll-HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid-adult onset (30-59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid-adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one-year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one-year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals.

Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice.

AIMS: Neurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of neuropsychiatric disorders, we assessed multiple domains of behavioral phenotypes in Nrgn KO mice using a comprehensive behavioral test battery including tests of homecage locomotor activity and nesting behavior. METHODS: Adult Nrgn KO mice (28-54 weeks old) were subjected to a battery of comprehensive behavioral tests, which examined general health, nesting behavior, neurological characteristics, motor function, pain sensitivity, locomotor activity, anxiety-like behavior, social behavior, sensorimotor gating, depression-like behavior, and working memory. RESULTS: The Nrgn KO mice displayed a pronounced decrease in nesting behavior, impaired motor function, and elevated pain sensitivity. While the Nrgn KO mice showed increased locomotor activity in the open field test, these mice did not show hyperactivity in a familiar environment as measured in the homecage locomotor activity test. The Nrgn KO mice exhibited a decreased number of transitions in the light-dark transition test and decreased stay time in the center of the open field test, which is consistent with previous reports of increased anxiety-like behavior. Interestingly, however, these mice stayed on open arms significantly longer than wild-type mice in the elevated plus maze. Consistent with previous studies, the mutant mice exhibited decreased prepulse inhibition, impaired working memory, and decreased sociability. CONCLUSIONS: In the current study, we identified behavioral phenotypes of Nrgn KO mice that mimic some of the typical symptoms of neuropsychiatric diseases, including impaired executive function, motor dysfunction, and altered anxiety. Most behavioral phenotypes that had been previously identified, such as hyperlocomotor activity, impaired sociability, tendency for working memory deficiency, and altered sensorimotor gating, were reproduced in the present study. Collectively, the behavioral phenotypes of Nrgn KO mice detected in the present study indicate that Nrgn KO mice are a valuable animal model that recapitulates a variety of symptoms of neuropsychiatric disorders, such as schizophrenia, ADHD, and Alzheimer's disease.

Identifying neural signatures mediating behavioral symptoms and psychosis onset: High-dimensional whole brain functional mediation analysis.

Along the pathway from behavioral symptoms to the development of psychotic disorders sits the multivariate mediating brain. The functional organization and structural topography of large-scale multivariate neural mediators among patients with brain disorders, however, are not well understood. Here, we design a high-dimensional brain-wide functional mediation framework to investigate brain regions that intermediate between baseline behavioral symptoms and future conversion to full psychosis among individuals at clinical high risk (CHR). Using resting-state functional magnetic resonance imaging (fMRI) data from 263 CHR subjects, we extract an α brain atlas and a ß brain atlas: the former underlines brain areas associated with prodromal symptoms and the latter highlights brain areas associated with disease onset. In parallel, we identify and separate mediators that potentially positively and negatively mediate symptoms and psychosis, respectively, and quantify the effect of each neural mediator on disease development. Taken together, these results paint a brain-wide picture of neural markers that are potentially mediating behavioral symptoms and the development of psychotic disorders; additionally, they underscore a statistical framework that is useful to uncover large-scale intermediating variables in a regulatory biological system.

[Behavioural Changes Caused by Parasites: The Parasite Manipulation Hypothesis]. / Wie beeinflussen Parasiten das Verhalten ihres Wirts? Die parasitäre Manipulationshypothese.

Bacteria, archaeae, fungi and viruses of the intestinal microbiome play an important role as symbionts in the complex human ecosystem. Parasites, which account for about 40 % of the earth's biodiversity, depend on hosts to complete their life cycle. This article explains how they use them and which signalling pathways play a role in this, using toxoplasmosis and malaria as examples. The parasitic manipulation hypothesis is based on impressive observations in the wild and under laboratory conditions, especially in invertebrates. For the assumption of an adaptive manipulation, every step from the genotype, the translated messenger, and its source via the used signalling pathways to the altered host behaviour must be proven. The assumption of an adaptive manipulation of humans by T. gondii in the sense of a cause-effect relationship is not proven. Alternative explanations include the inflammatory and immunological processes on the host side, which change the neuronal signal transduction as concomitant symptoms of an infection. Even without confirmation of parasitic manipulation in humans, it could be worthwhile to further investigate the observed associations in order to develop new possibilities for diagnosis and therapy, e. g. for schizophrenia.