The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6+ T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.

NLGN4X TCR transgenic T cells to treat gliomas.

BACKGROUND: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma. METHODS: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T). Functional profiling of NLGN4X-TCR-T was performed by flow cytometry and cytotoxicity assays. Therapeutic efficacy of intracerebroventricular NLGN4X-TCR-T was assessed in NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) (NSG MHC I/II KO) mice bearing NLGN4X-expressing experimental gliomas. RESULTS: An HLA-A*02-restricted vaccine-induced T cell receptor specifically binding NLGN4X131-139 was applied for preclinical therapeutic use. Reactivity, cytotoxicity, and polyfunctionality of this NLGN4X-specific TCR are demonstrated in various cellular models. Intracerebroventricular administration of NLGN4X-TCR-T prolongs survival and leads to an objective response rate of 44.4% in experimental glioma-bearing NSG MHC I/II KO mice compared to 0.0% in control groups. CONCLUSION: NLGN4X-TCR-T demonstrate efficacy in a preclinical glioblastoma model. On a global scale, we provide the first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.Keywords cell therapy | glioblastoma | T cell receptor | tumor antigen.

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.

T cell receptor dynamic and transcriptional determinants of T cell expansion in glioma-infiltrating T cells.

Background: Glioblastoma (GBM) is characterized by low numbers of glioma-infiltrating lymphocytes (GIL) with a dysfunctional phenotype. Whether this dysfunctional phenotype is fixed or can be reversed upon ex vivo culturing is poorly understood. The aim of this study was to assess T cell receptor (TCR)-dynamics and -specificities as well as determinants of in vitro GIL expansion by sequencing-based technologies and functional assays to explore the use of GIL for cell therapy. Methods: By means of flow cytometry, T cell functionality in GIL cultures was assessed from 9 GBM patients. TCR beta sequencing (TCRB-seq) was used for TCR repertoire profiling before and after in vitro expansion. Microarrays or RNA sequencing (RNA-seq) were performed from 6 micro-dissected GBM tissues and healthy brain RNA to assess the individual expression of GBM-associated antigens (GAA). GIL reactivity against in silico predicted tumor-associated antigens (TAA) and patient-individual GAA was assessed by ELISpot assay. Combined ex vivo single cell (sc)TCR-/RNA-seq and post-expansion TCRB-seq were used to evaluate transcriptional signatures that determine GIL expansion. Results: Human GIL regains cellular fitness upon in vitro expansion. Profound TCR dynamics were observed during in vitro expansion and only in one of six GIL cultures, reactivity against GAA was observed. Paired ex vivo scTCR/RNA-seq and TCRB-seq revealed predictive transcriptional signatures that determine GIL expansion. Conclusions: Profound TCR repertoire dynamics occur during GIL expansion. Ex vivo transcriptional T cell states determine expansion capacity in gliomas. Our observation has important implications for the use of GIL for cell therapy including genetic manipulation to maintain both antigen specificity and expansion capacity.

How the COVID-19 pandemic divides society: Towards a better understanding of differences between supporters and opponents of the COVID-19 pandemic lockdown in Germany.

Implemented COVID-19 containment measures have been fiercely discussed in Germany and corona-related protests have emerged. We assessed mental health in response to the lockdown in Germany and aimed at detecting factors differentiating opponents and supporters of the COVID-19 containment measures. Using a cross-sectional online survey (n = 1219) with a mixed-methods approach, we found increased levels of anxiety and depressive symptoms (PHQ-4 and GAD-7), overall lower well-being (WHO-5), worsened sleep, increased prevalence of interpersonal violence (5.2%) as well as more pronounced irritability including anger and aggression compared to pre-COVID-19 times for all participants. Moreover, opponents demonstrated a more pronounced mental burden with more depression and anxiety, more anger and coping difficulties compared to supporters. In line with previous research, we found opponents to be well-educated, financially stable and strongly estranged by their political institutions. Additionally, applying regression analysis, we found anxiety and negative self-concept to differentiate between opponents and supporters of the COVID-19 pandemic lockdown. Qualitative data confirms an increase in mental burden. Taken together, we identify a more vulnerable group opposing COVID-19 containment measures. Our results inform the public about opponents' motives, concerns and needs and open another perspective on the effects of the COVID-19 pandemic and its related containment measures.

Neuronal effects of glabellar botulinum toxin injections using a valenced inhibition task in borderline personality disorder.

Previous studies have indicated that glabellar botulinum toxin (BTX) injections may lead to a sustained alleviation of depression. This may be accomplished by the disruption of a facial feedback loop, which potentially mitigates the experience of negative emotions. Accordingly, glabellar BTX injection can attenuate amygdala activity in response to emotional stimuli. A prototypic condition with an excess of negative emotionality and impulsivity accompanied by elevated amygdala reactivity to emotional stimuli is borderline personality disorder (BPD). In order to improve the understanding of how glabellar BTX may affect the processing of emotional stimuli and impulsivity, we conducted a functional magnetic resonance imaging (fMRI) study. Our hypotheses were (1) glabellar BTX leads to increased activation in prefrontal areas during inhibition performance and (2) BTX decreases amygdala activity during the processing of emotional stimuli in general. Using an emotional go-/no-go paradigm during fMRI, the interference of emotion processing and impulsivity in a sample of n = 45 women with BPD was assessed. Subjects were randomly assigned to BTX treatment or serial acupuncture (ACU) of the head. After 4 weeks, both treatments led to a reduction in the symptoms of BPD. However, BTX treatment was specifically associated with improved inhibition performance and increased activity in the motor cortex. In addition, the processing of negative emotional faces was accompanied by a reduction in right amygdala activity. This study provides the first evidence that glabellar BTX injections may modify central neurobiological and behavioural aspects of BPD. Since the control treatment produced similar clinical effects, these neurobiological findings may be specific to BTX and not a general correlate of symptomatic improvement.

Laterality in simple multiplication: Assessing hemispheric specialization of arithmetic fact retrieval in a visual hemifield paradigm.

The prominent view in numerical cognition is that highly overlearned arithmetic facts are verbally mediated and unilaterally processed in a left-hemispheric network, including language areas. However, this view has recently been challenged. Here, we evaluated the hemispheric specialization of verbal arithmetic fact retrieval and number magnitude processing using two verification tasks (i.e., multiplication and number magnitude comparison) in a divided hemifield paradigm in healthy participants (n = 35). In the number comparison task, we replicated bilateral processing advantages for the unit-decade compatibility effect. Magnitude processing was facilitated after bilateral compared with a unilateral presentation. In the multiplication task, lateralized presentation to the left hemisphere yielded processing advantages in arithmetic fact retrieval when the required interhemispheric transitions from the input, processing, and output stages were considered. Crucially, we observed a systematic processing advantage in left visual hemifield stimuli presentation (i.e., initial right-hemisphere processing). Our findings corroborate the assumption that arithmetic fact retrieval is subserved by left-lateralized verbal/linguistic processing. Thereby, they suggest a distinction between unilateral left-hemispheric linguistic processing of arithmetic fact retrieval and bilateral number magnitude processing. Interestingly, however, our data present right-hemispheric processing advantages in identifying early processed visual symbolic numerical stimuli. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Clinical effects of glabellar botulinum toxin injections on borderline personality disorder: A randomized controlled trial.

BACKGROUND: Inhibition of frowning via injections of botulinum toxin A (BTX) into the glabellar region has shown beneficial effects in the treatment of major depression. Preliminary research suggests that improvements in the affective domain are not depression-specific, but may also translate to other psychiatric disorders. AIM: This 16-week, single-blind, two-center randomized controlled trial investigated the influence of BTX on clinical symptoms of borderline personality disorder (BPD). METHODS: Fifty-four patients with BPD were randomly assigned to treatment with BTX (n = 27) or a minimal acupuncture (ACU) control condition (n = 27). Clinical outcomes were followed at 2, 4, 6, 8, 12, and 16 weeks. Primary endpoint was the relative score change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) 8 weeks after baseline relative to the control group and adjusted for treatment center. Secondary and additional outcome variables were self-rated borderline symptoms, comorbid symptoms of depression, psychological distress, and clinical global impression. RESULTS: Participants showed significant improvements at the primary efficacy endpoint in both treatment groups (BTX: M = -0.39, SD = 0.39; ACU: M = -0.35, SD = 0.42), but no superior effect of the BTX condition in comparison with the control intervention was found-F(1,5323) = 0.017, p = 0.68). None of the secondary or additional outcomes yielded significant group differences. Side effects were mild and included headache, transient skin or muscle irritations, and dizziness. CONCLUSION: Evidence regarding the efficacy of BTX for BDP remains limited, and the design of adequate control conditions presents an opportunity for further research.ClinicalTrials.gov registry: Botulinum Toxin A for Emotional Stabilization in Borderline Personality Disorder (BPD), NCT02728778, https://clinicaltrials.gov/ct2/show/NCT02728778.

T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas.

PURPOSE: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy. EXPERIMENTAL DESIGN: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single-cell T-cell receptor (TCR) sequencing from established T-cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T-cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor-targeting guide RNAs. RESULTS: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic MHC class II (MHCII)-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHCII-restricted mutation-specific T-cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert antitumor responses against CICR215W-expressing syngeneic gliomas. CONCLUSIONS: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T-cell adoptive therapy.

Mode effect: An issue of perspective? Writing mode differences in a spelling assessment in German children with and without developmental dyslexia.

Digital technology has an increasing influence on writing processes. In this context, the question arises whether changes in writing mode (i.e., handwriting vs. computer-keyboard typing) also require changes in writing assessments. However, data directly comparing writing mode influences in children with and without developmental writing deficits are scarce. This study investigated the influence of writing mode in German-speaking, typically developing children and children with developmental dyslexia (DD) from two different levels. Results showed on a general level that writing mode influenced overall spelling accuracy, writing time, and self-corrections comparably in children with and without DD. On a rule-specific level, outcomes for writing time and self-corrections substantiated these findings. However, as regards spelling accuracy, a mode effect was only apparent for capitalization, whereas other spelling rules were resistant to writing mode influences. Present findings suggest that a mode effect is present only for typing specific aspects (e.g., capitalization) rather than reflecting a general influence on orthographic principles (e.g., grapheme-phoneme assignment, morphologic principles). These mode-specific aspects seem to comparably affect the writing performance of typically developing children and children with DD. We recommend writing assessments to consider that different writing modes may influence individual spelling rules differently.

Mental Health, Sense of Coherence, and Interpersonal Violence during the COVID-19 Pandemic Lockdown in Germany.

Preliminary data indicates that the Coronavirus SARS-CoV-2 disease (COVID-19) pandemic may have a substantial impact on mental health and well-being. We assessed mental health in response to the lockdown in Germany between 1 April 2020 and 15 April 2020 using a cross-sectional online survey (n = 3545) with a mixed-methods approach. We found increased levels of psychosocial distress (Patient Health Questionnaire (PHQ) stress module), anxiety, depressive symptoms (PHQ-4), irritability, and a decrease in overall well-being (WHO-Five Well-Being Index (WHO-5)), sense of coherence (Short Form of the Sense of Coherence Scale (SOC-L9)), sexual contentment, and sleep quality. The four-week-prevalence of interpersonal violence was yet at 5% and included verbal, physical, and sexual violence. Participants reported finding comfort in family, friends, conversation, exercise, and activity. Findings are also in line with research showing that women seem to have more trouble coping with the pandemic and lockdown measures. Our observations demonstrate that the COVID-19 pandemic and related measures lead to a mental health burden even in a highly developed Western country and should, therefore, be taken seriously. The findings for interpersonal violence are alarming. Thus, we should sharpen our focus on the matter and activate and enhance supporting systems to help protect those affected.

Hemispheric Lateralization of Arithmetic Facts and Magnitude Processing for Two-Digit Numbers.

In the human brain, a (relative) functional asymmetry (i.e., laterality; functional and performance differences between the two cerebral hemispheres) exists for a variety of cognitive domains (e.g., language, visual-spatial processing, etc.). For numerical cognition, both bi-lateral and unilateral processing has been proposed with the retrieval of arithmetic facts postulated as being lateralized to the left hemisphere. In this study, we aimed at evaluating this claim by investigating whether processing of multiplicatively related triplets in a number bisection task (e.g., 12_16_20) in healthy participants (n = 23) shows a significant advantage when transmitted to the right hemisphere only as compared to transmission to the left hemisphere. As expected, a control task revealed that stimulus presentation to the left or both visual hemifields did not increase processing disadvantages of unit-decade incompatible number pairs in magnitude comparison. For the number bisection task, we replicated the multiplicativity effect. However, in contrast to the hypothesis deriving from the triple code model, we did not observe significant hemispheric processing asymmetries for multiplicative items. We suggest that participants resorted to keep number triplets in verbal working memory after perceiving them only very briefly for 150 ms. Rehearsal of the three numbers was probably slow and time-consuming so allowing for interhemispheric communication in the meantime. We suggest that an effect of lateralized presentation may only be expected for early effects when the task is sufficiently easy.

Hierarchical Development of Early Visual-Spatial Abilities - A Taxonomy Based Assessment Using the MaGrid App.

Visual-spatial abilities (VSA) are considered a building block of early numerical development. They are intuitively acquired in early childhood and differentiate in further development. However, when children enter school, there already are considerable individual differences in children's visual-spatial and numerical abilities. To better understand this diversity, it is necessary to empirically evaluate the development as well as the latent structure of early VSA as proposed by the 2 by 2 taxonomy of Newcombe and Shipley (2015). In the present study, we report on a tablet-based assessment of VSA using the digital application (app) MaGrid in kindergarten children aged 4-6 years. We investigated whether the visual-spatial tasks implemented in MaGrid are sensitive to replicate previously observed age differences in VSA and thus a hierarchical development of VSA. Additionally, we evaluated whether the selected tasks conform to the taxonomy of VSA by Newcombe and Shipley (2015) applying a confirmatory factor analysis (CFA) approach. Our results indicated that the hierarchical development of VSA can be measured using MaGrid. Furthermore, the CFA substantiated the hypothesized factor structure of VSA in line with the dimensions proposed in the taxonomy of Newcombe and Shipley (2015). Taken together, the present results advance our knowledge to the (hierarchical) development as well as the latent structure of early VSA in kindergarten children.

Genetic and chemical diversity of the toxic herb Jacobaea vulgaris Gaertn. (syn. Senecio jacobaea L.) in Northern Germany.

Tansy ragwort, Jacobaea vulgaris Gaertn. (syn. Senecio jacobaea L.), is a common Asteraceae in Europe and Asia and known to be an invasive pest in several regions in the world. Recently it is also spreading immensely in native regions like Northern Germany. Pyrrolizidine alkaloids (PAs), which are found in high amounts in Jacobaea vulgaris, are toxic for humans and potentially lethal for grazing animals. In this study we investigated 27 populations of tansy ragwort in Northern Germany for their PA concentration and composition using liquid chromatography coupled to high resolution mass spectrometry. Furthermore, we investigated the genetic structure of selected populations using amplified length polymorphism markers. We detected 98 different PAs in the samples and considerable differences of PA composition between populations. In contrast, PA content of populations did not differ significantly. Genetic (4%) differentiation among populations was low while average genetic diversity was high (0.35). There was no correlation between genetic and geographic distance. Neither genetic markers nor chemical composition revealed any connection to the geographic pattern. As we could not detect any pattern in genetic or chemical diversity, we suggest that the existence of this diversity is a result of a broad interaction with the environment rather than that of evolutionary constraints in the current selection process driving PA composition in J. vulgaris in certain chemotypes.

Clinical characteristics associated with paedophilia and child sex offending - Differentiating sexual preference from offence status.

Contrary to public perception, child sex offending (CSO) and paedophilia are not the same. Only half of all cases of CSO are motivated by paedophilic preference, and a paedophilic preference does not necessarily lead to CSO. However, studies that investigated clinical factors accompanying and contributing to paedophilia so far mainly relied on paedophiles with a history of CSO. The aim of this study was to distinguish between factors associated with sexual preference (paedophile versus non-paedophile) and offender status (with versus without CSO). Accordingly, a 2 (sexual preference) × 2 (offender status) factorial design was used for a comprehensive clinical assessment of paedophiles with and without a history of CSO (n = 83, n = 79 respectively), child sex offenders without paedophilia (n = 32) and healthy controls (n = 148). Results indicated that psychiatric comorbidities, sexual dysfunctions and adverse childhood experiences were more common among paedophiles and child sex offenders than controls. Offenders and non-offenders differed in age, intelligence, educational level and experience of childhood sexual abuse, whereas paedophiles and non-paedophiles mainly differed in sexual characteristics (e.g., additional paraphilias, onset and current level of sexual activity). Regression analyses were more powerful in segregating offender status than sexual preference (mean classification accuracy: 76% versus 68%). In differentiating between offence- and preference-related factors this study improves clinical understanding of both phenomena and may be used to develop scientifically grounded CSO prevention and treatment programmes. It also highlights that some deviations are not traceable to just one of these two factors, thus raising the issue of the mechanism underlying both phenomena.

Effects of Intranasal Oxytocin Administration on Sexual Functions in Healthy Women: A Laboratory Paradigm.

PURPOSE: The neuropeptide oxytocin (OXT) has a variety of physiological functions in maternal behavior and attachment including sexual behavior. Based on animal research and our previous human studies, we set out to investigate intranasal administration of OXT and hypothesized that OXT should be able to modulate sexual function in women. METHODS: In a double-blind, placebo-controlled, crossover laboratory setting, the acute effects of intranasal administered OXT (24 international units) on sexual drive, arousal, orgasm, and refractory aspects of sexual behavior were analyzed in 27 healthy females (mean age ± SD, 27.52 ± 8.04) together with physiological parameters using vaginal photoplethysmography. FINDINGS: Oxytocin administration showed no effect on subjective sexual parameters (eg, postorgasmic tension; P = 0.051). Physiological parameters (vaginal photoplethysmography amplitude and vaginal blood volume) showed a response pattern towards sexual arousal but were not affected by OXT. IMPLICATIONS: Using a well-established laboratory paradigm, we did not find that intranasal OXT influences female sexual parameters. Also, sexual drive and other functions were not affected by OXT. These findings indicate that OXT is not able to significantly increase subjective and objective parameters of sexual function in a setting with high internal validity; however, this might be different in a more naturalistic setting.

Botulinum Toxin as a Treatment for Depression in a Real-world Setting.

OBJECTIVES: A series of randomized controlled trials have shown the efficacy of glabellar botulinum toxin (BTX) injection as a treatment for depression in women. We wanted to extend these findings and assess how they may be translated to a real-world setting. METHODS: For that purpose, 42 patients with severe, in most cases chronic and treatment-resistant depression received adjunctive treatment with BTX in private practice. Depression severity was rated before and 3 weeks after the treatment using the Hamilton Depression Rating Scale, the Montgomery Åsberg Depression Rating Scale, and the Beck Depression Inventory. RESULTS: Almost all of the patients improved clinically, with depression scores dropping by 27% on all 3 scales in the sample as a whole. These changes were highly significant (P<0.001, paired t test or Wilcoxon test) and the absolute prepost score differences were similar to those observed in previous randomized controlled trials. Importantly, treatment effects did not differ between male (n=23) and female (n=19) patients. CONCLUSIONS: These findings suggest that glabellar BTX injection may also be effective in the treatment of severe depression and in the treatment of depression in men, when treatment is carried out not just in clinical trials but in real-world settings.

Lack of Increase in Sexual Drive and Function After Dopaminergic Stimulation in Women.

Human and animal data indicate that the dopaminergic system plays a crucial role in sexual drive and function. Using a double-blind, placebo-controlled crossover design, this prototype study investigated the effect of the D2 dopamine agonist cabergoline on sexual parameters in 13 healthy women. Cardiovascular and genital parameters were monitored continuously. Sexual drive and function were measured using self-report sexual experience scales. In contrast to previous theories and assumptions, we found that cabergoline did not alter objective and subjective sexual parameters in healthy women. This finding suggests that there may be sex differences in the influence of the dopaminergic system on human sexual functioning.

The New Hamburg-Hannover Agitation Scale in Clinical Samples: Manifestation and Differences of Agitation in Depression, Anxiety, and Borderline Personality Disorder.

BACKGROUND/AIMS: Agitation is a burdening phenomenon that occurs in a variety of psychiatric disorders. The aim of this study was to give a first direction for agitation occurrence in depression, anxiety disorder, and borderline personality disorder (BPD) as well as in healthy controls with and without psychiatric record. METHODS: Using the Hamburg-Hannover Agitation Scale (H2A), an instrument that allows for the measurement of agitation independently of the presence of a specific disorder, a patient sample (n = 158) and a healthy control group (n = 685) with (n = 94) and without (n = 591) psychiatric record were examined. The data were mainly analysed using ANOVAs and post hoc tests. RESULTS: Patients showed significantly higher H2A agitation levels than healthy controls. Within the clinical sample, BPD patients exhibited the strongest manifestation of agitation, scoring significantly higher than the depression and the anxiety disorder sample, while these two subgroups did not significantly differ from each other. Moreover, healthy subjects with a psychiatric record experienced a significantly stronger agitation than subjects without a psychiatric record. CONCLUSION: Further studies are needed with larger, more balanced, and differentiated sample sizes including a wider range of clinical pictures. The results demonstrate that agitation occurs and differs in psychiatric patients as well as in healthy controls.

Differing Connectivity of Exner's Area for Numbers and Letters.

There is a growing body of evidence indicating a crucial role of Exner's area in (hand-) writing symbolic codes such as letters and words. However, a recent study reported a patient with a lesion affecting Broca's and Exner's area, who suffered from severe peripheral agraphia for letters but not for Arabic digits. The authors suggested a speculative account postulating differential connectivity of Exner's area for numbers and letters in order to explain this dissociation. In the present study, we evaluated this account, employing atlas-based tractography for the patient's anatomy, deterministic fiber-tracking as well as an automated toolkit to investigate the connectivity of Exner's area in healthy adults. In particular, fiber pathways connecting Exner's area with areas associated with language processing (e.g., the arcuate fascicle, ventral pathways encompassing the external/extreme capsule system) reached the inferior part of Exner's area, while fronto-parietal fibers (e.g., the superior longitudinal fascicle) connected the upper part of Exner's area with the intraparietal sulcus typically involved in number processing. Our results substantiated the differential connectivity account for Exner's area by identifying the neural connections between fiber tracts and cortex areas of interest. Our data strongly suggest that white matter connectivity should be taken into account when investigating the neural underpinnings of impaired and intact human cognition.