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Background Mental burden due to the SARS-CoV-2 pandemic has been widely reported for the general public and specific risk groups like healthcare workers and different patient populations. We aimed to assess its impact on mental health during the early phase by comparing pandemic with prepandemic data and to identify potential risk and protective factors. Methods For this systematic review and meta-analyses, we systematically searched PubMed, PsycINFO, and Web of Science from January 1, 2019 to May 29, 2020, and screened reference lists of included studies. In addition, we searched PubMed and PsycINFO for prepandemic comparative data. Survey studies assessing mental burden by the SARS-CoV-2 pandemic in the general population, healthcare workers, or any patients (eg, COVID-19 patients), with a broad range of eligible mental health outcomes, and matching studies evaluating prepandemic comparative data in the same population (if available) were included. We used multilevel meta-analyses for main, subgroup, and sensitivity analyses, focusing on (perceived) stress, symptoms of anxiety and depression, and sleep-related symptoms as primary outcomes. Results Of 2429 records retrieved, 104 were included in the review (n = 208,261 participants), 43 in the meta-analysis (n = 71,613 participants). While symptoms of anxiety (standardized mean difference [SMD] 0.40; 95% CI 0.15–0.65) and depression (SMD 0.67; 95% CI 0.07–1.27) were increased in the general population during the early phase of the pandemic compared with prepandemic conditions, mental burden was not increased in patients as well as healthcare workers, irrespective of COVID-19 patient contact. Specific outcome measures (eg, Patient Health Questionnaire) and older comparative data (published ≥5 years ago) were associated with increased mental burden. Across the three population groups, existing mental disorders, female sex, and concerns about getting infected were repeatedly reported as risk factors, while older age, a good economic situation, and education were protective. Conclusions This meta-analysis paints a more differentiated picture of the mental health consequences in pandemic situations than previous reviews. High-quality, representative surveys, high granular longitudinal studies, and more research on protective factors are required to better understand the psychological impacts of the SARS-CoV-2 pandemic and to help design effective preventive measures and interventions that are tailored to the needs of specific population groups.

Background: Intimacy is a key psychological problem in anorexia nervosa (AN). Empirical evidence, including neurobiological underpinnings, is however, scarce.Objective: In this study, we evaluated various emotional stimuli including intimate stimuli experienced in patients with AN and non-patients, as well as their cerebral response.Methods: Functional magnetic resonance imaging was conducted using stimuli with positive, neutral, negative and intimate content. Participants (14 AN patients and 14 non-patients) alternated between passive viewing and explicit emotion regulation.Results: Intimate stimuli were experienced less positively in AN patients compared to non-patients. AN patients showed decreased cerebral responses in superior parietal cortices in response to positive and intimate stimuli. Intimate stimuli led to stronger activation of the orbitofrontal cortex, and lower activation of the bilateral precuneus in AN patients. Orbitofrontal responses decreased in AN patients during explicit emotion regulation.Conclusions: These results show that intimate stimuli are of particular importance in AN patients, who show experiential differences compared to non-patients and altered activation of orbitofrontal and parietal brain structures. This supports that AN patients have difficulties with intimacy, attachment, self-referential processing and body perception.LEVEL OF EVIDENCE: Level III, case-control study.

Background Intimacy and psychosexual development represent core problems of anorexia nervosa (AN). Experiential and neurobiological evidence however is scarce. Material and methods Thirty-one female AN patients were compared with 35 non-patients (NP) and 22 recovered participants (REC) by using functional magnetic resonance imaging. Participants viewed pictures of couples in intimate relationships and control stimuli. Results AN patients experienced intimate stimuli with lower valence and dominance. AN showed decreased activation of parietal cortices. NP decreased the prefrontal cortex response, which AN patients did not. REC participants did not differ from NP on a behavioural level, though with regard to the neural signature. Discussion Parietal cortices are related to processing of erotic themes, which seems to be deficient in AN. Dysfunction of prefrontal cortices likely mirrors dysfunctional control in AN. The neural signature does not seem to be state-related considering results of REC.

One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Motor inhibitory control implemented as response inhibition is an essential cognitive function required to dynamically adapt to rapidly changing environments. Despite over a decade of research on the neural mechanisms of response inhibition, it remains unclear, how exactly response inhibition is initiated and implemented. Using a multimodal MEG/fMRI approach in 59 subjects, our results reliably reveal that response inhibition is initiated by the right inferior frontal gyrus (rIFG) as a form of attention-independent top-down control that involves the modulation of beta-band activity. Furthermore, stopping performance was predicted by beta-band power, and beta-band connectivity was directed from rIFG to pre-supplementary motor area (pre-SMA), indicating rIFG’s dominance over pre-SMA. Thus, these results strongly support the hypothesis that rIFG initiates stopping, implemented by beta-band oscillations with potential to open up new ways of spatially localized oscillation-based interventions.

Unexpected and thus surprising events are omnipresent and oftentimes require adaptive behavior such as unexpected inhibition or unexpected action. The current theory of unexpected events suggests that such unexpected events just like global stopping recruit a fronto-basal-ganglia network. A global suppressive effect impacting ongoing motor responses and cognition is specifically attributed to the subthalamic nucleus (STN). Previous studies either used separate tasks or presented unexpected, task-unrelated stimuli during response inhibition tasks to relate the neural signature of unexpected events to that of stopping. Here, we aimed to test these predictions using a within task design with identical stimulus material for both unexpected action and unexpected inhibition using functional magnetic resonance imaging (fMRI) for the first time. To this end, 32 healthy human participants of both sexes performed a cue-informed go/nogo task comprising expected and unexpected action and inhibition trials during fMRI. Using conjunction, contrast, and Bayesian analyses, we demonstrate that unexpected action elicited by an unexpected go signal and unexpected inhibition elicited by an unexpected nogo signal recruited the same fronto-basal-ganglia network which is usually assigned to stopping. Furthermore, the stronger the unexpected action-related activity in the STN region was the more detrimental was the effect on response times. The present results thus complement earlier findings and provide direct evidence for the unified theory of unexpected events while ruling out alternative task and novelty effects.SIGNIFICANCE STATEMENTThis is the first study using functional magnetic resonance imaging (fMRI) to test whether unexpected events regardless of whether they require unexpected action or inhibition recruit a fronto-basal-ganglia network just like stopping. In contrast to previous studies, we used identical stimulus material for both conditions within one task. This enabled us to directly test predictions of the current theory of unexpected events and, moreover, to test for condition-specific neural signatures. The present results underpin that both processes recruit the same neural network while excluding alternative task and novelty effects. The simple task design thus provides an avenue to studying surprise as a pure form of reactive inhibition in neuropsychiatric patients displaying inhibitory deficits who often have a limited testing capacity.

Attention-deficit/hyperactivity disorder (ADHD) and co-existing psychiatric/psychological impairments as well as adverse childhood experiences (ACEs) are common among young offenders. Research on their associations is of major importance for early intervention and crime prevention. Intermittent explosive disorder (IED) warrants specific consideration in this regard. To gain sophisticated insights into the occurrence and associations of ADHD, IED, ACEs, and further psychiatric/psychological impairments in young (male and female) offenders, we used latent profile analysis (LPA) to empirically derive subtypes among 156 young offenders who were at an early stage of crime development based on their self-reported ADHD symptoms, and combined those with the presence of IED. We found four distinct ADHD subtypes that differed rather quantitatively than qualitatively (very low, low, moderate, and severe symptomatology). Additional IED, ACEs, and further internalizing and externalizing problems were found most frequently in the severe ADHD subtype. Furthermore, females were over-represented in the severe ADHD subtype. Finally, ACEs predicted high ADHD symptomatology with co-existing IED, but not without IED. Because ACEs were positively associated with the occurrence of ADHD/IED and ADHD is one important risk factor for on-going criminal behaviors, our findings highlight the need for early identification of ACEs and ADHD/IED in young offenders to identify those adolescents who are at increased risk for long-lasting criminal careers. Furthermore, they contribute to the debate about how to best conceptualize ADHD regarding further emotional and behavioral disturbances.

Highly arousing, affective stimuli have adverse effects on cognition and performance. Perception of affective stimuli is, however, highly subjective and may impact on the interaction of emotion and cognition. Here, we tested the impact of high- versus low-threatening stimuli on response inhibition as a function of perceived threat intensity. Response inhibition was probed using a stop-signal paradigm in 62 healthy adults. We used stop-signals that had previously been paired with an unpleasant electrodermal stimulation (i.e., high-threat stimuli) or that had never been paired with electrodermal stimulation (i.e., low-threat stimuli). High-threat stimuli did not affect stopping performance in general. Only participants who perceived the high-threat stimuli as highly painful showed impaired response inhibition on high-threat trials relative to low-threat trials. Participants who perceived the high-threat as mildly painful, however, showed improved response inhibition on high-threat trials. This effect was not moderated by the current anxious state. This suggests that the impact of negative affective stimuli on cognition critically depends on subjective threat perception. Ratings of affective stimuli should be included in studies probing the emotion-cognition interaction because subjective perception might strongly impact on that interaction. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Jacob et al. (2011) previously reported on intimate picture stimuli for emotion research in females in Psychiatry Research. Difficulties to engage in intimate relations constitute problems of many mental disorders, and intimacy must be differentiated from pure sex drive. Functional neuroimaging is an important tool to understand the pathophysiology of psychiatric disorders. We now studied cerebral activation in response to intimate stimuli in 35 healthy women. Comparison stimuli were taken from the International Affective Picture System. Neuroimaging revealed increased activation in bilateral occipitotemporal, parietal and anterior cingulate cortices extending to the orbitofrontal area. These data reflect cognitive, emotional and motivational compounds congruent with previous neuroimaging data of attachment and long term romantic relationships. Lateral prefrontal, posterior insular regions and the fusiform face area were more active during control images. Our data present a solid basis for use in psychiatric samples.

Like nonaffected adults, individuals with autism spectrum disorders (ASDs) show the entire range of sexual behaviors. However, due to the core symptoms of the disorder spectrum, including deficits in social skills, sensory hypo- and hypersensitivities, and repetitive behaviors, some ASD individuals might develop quantitatively above-average or nonnormative sexual behaviors and interests. After reviewing the relevant literature on sexuality in high-functioning ASD individuals, we present novel findings on the frequency of normal sexual behaviors and those about the assessment of hypersexual and paraphilic fantasies and behaviors in ASD individuals from our own study. Individuals with ASD seem to have more hypersexual and paraphilic fantasies and behaviors than general-population studies suggest. However, this inconsistency is mainly driven by the observations for male participants with ASD. This could be due to the fact that women with ASD are usually more socially adapted and show less ASD symptomatology. The peculiarities in sexual behaviors in ASD patients should be considered both for sexual education and in therapeutic approaches.Al igual que los adultos normales, los sujetos con trastornos del espectro autista (TEA) presentan toda la gama de conductas sexuales. Sin embargo, debido a los síntomas centrales del espectro del trastorno, que incluyen déficits en las destrezas sociales, hiper e hipo sensibilidad sensorial y conductas repetitivas, algunos sujetos con TEA pueden desarrollar intereses y conductas sexuales hipernormales o no habituales. Se revisa la literatura más relevante sobre la sexualidad en sujetos con TEA de alto funcionamiento y se presentan los nuevos hallazgos provenientes de los estudios del grupo de trabajo sobre la frecuencia de las conductas sexuales normales y sobre la evaluación de las conductas y fantasías hipersexuales y parafílicas. Al parecer los sujetos con TEA tienen más conductas y fantasías hipersexuales y parafílicas que lo sugerido por estudios en población general. Sin embargo, esta inconsistencia se debe principalmente a las observaciones realizadas en los hombres con TEA. Esto podría deberse al hecho que las mujeres con TEA están más adaptadas socialmente y presentan menos síntomas del TEA. Las peculiaridades en la conducta sexual de los pacientes con TEA deben ser tomadas en cuenta para la educación sexual y en los abordajes terapéuticos.Comme les adultes non atteints, les personnes ayant un trouble du spectre de l'autisme (TSA) présentent le tableau complet des comportements sexuels. Cependant, certaines personnes ayant un TSA peuvent développer des intérêts et comportements sexuels hypernormaux ou non standard, à cause des symptômes fondamentaux du trouble, comme les déficits de socialisation, les hyposensibilités et hypersensibilités et les comportements répétitifs. Après une analyse de la littérature pertinente sur la sexualité des personnes ayant un TSA de haut niveau, nous présentons des données nouvelles, issues de notre propre étude sur la fréquence des comportements sexuels normaux et sur l'évaluation des comportements et fantasmes hypersexuels et paraphiliques chez les personnes ayant un TSA : celles-ci semblent avoir de tels comportements plus souvent que les études de population générale ne le suggèrent. Cependant, cet écart est principalement le fait des observations des participants masculins ayant un TSA, peut-être parce que les femmes ayant un TSA sont habituellement plus adaptées socialement et moins symptomatiques. Les particularités des comportements sexuels des patients ayant un TSA devraient être prises en charge à la fois pour une éducation sexuelle et des approches thérapeutiques.

In stimulus-selective stop-signal tasks, the salient stop signal needs attentional processing before genuine response inhibition is completed. Differential prefrontal involvement in attentional capture and response inhibition has been linked to the right inferior frontal junction (IFJ) and ventrolateral prefrontal cortex (VLPFC), respectively. Recently, it has been suggested that stimulus-selective stopping may be accomplished by the following different strategies: individuals may selectively inhibit their response only upon detecting a stop signal (independent discriminate then stop strategy) or unselectively whenever detecting a stop or attentional capture signal (stop then discriminate strategy). Alternatively, the discrimination process of the critical signal (stop vs attentional capture signal) may interact with the go process (dependent discriminate then stop strategy). Those different strategies might differentially involve attention- and stopping-related processes that might be implemented by divergent neural networks. This should lead to divergent activation patterns and, if disregarded, interfere with analyses in neuroimaging studies. To clarify this crucial issue, we studied 87 human participants of both sexes during a stimulus-selective stop-signal task and performed strategy-dependent functional magnetic resonance imaging analyses. We found that, regardless of the strategy applied, outright stopping displayed indistinguishable brain activation patterns. However, during attentional capture different strategies resulted in divergent neural activation patterns with variable activation of right IFJ and bilateral VLPFC. In conclusion, the neural network involved in outright stopping is ubiquitous and independent of strategy, while different strategies impact on attention-related processes and underlying neural network usage. Strategic differences should therefore be taken into account particularly when studying attention-related processes in stimulus-selective stopping.SIGNIFICANCE STATEMENTDissociating inhibition from attention has been a major challenge for the cognitive neuroscience of executive functions. Selective stopping tasks have been instrumental in addressing this question. However, recent theoretical, cognitive and behavioral research suggests that different strategies are applied in successful execution of the task. The underlying strategy-dependent neural networks might differ substantially. Here, we show evidence that, regardless of the strategy used, the neural network involved in outright stopping is ubiquitous. However, significant differences can only be found in the attention-related processes underlying those different strategies. Thus, when studying attentional processing of salient stop signals, strategic differences should be considered. In contrast, the neural networks implementing outright stopping seem less or not at all affected by strategic differences.

The occurrence of daily hassles is associated with increased subsequent levels of negative affect. Neuroticism has been found to exacerbate this effect. So far, most research used single-item measures for the assessment of daily hassles or relied on daily diary studies. This study aimed to examine the interrelations of daily hassles, negative affect reactivity, and neuroticism in daily life employing an extensive inventory of daily hassles. Seventy participants (18-30 years; M = 23.9 years, 59% female) completed a 4-week smartphone-based ecological momentary assessment study reporting the occurrence and perceived strain of daily hassles as well as negative affect at five semi-random signals between 9 a.m. and 8 p.m. Multilevel analyses revealed significant associations between elevated levels of negative affect and higher cumulative daily hassle strain ratings per signal in concurrent and time-lagged analyses. Contrary to our expectations, there was no moderation by neuroticism on these associations. The results suggest that daily hassles can accumulate in their impact on mood in daily life and exert a prolonged effect on negative affect. The absence of a significant moderation by neuroticism may be interpreted in the light of methodological specifics of this study.

High rates of adverse childhood experiences (ACEs, e.g., abuse and neglect) have been found in young offenders. Furthermore, ACEs seem to increase the risk of developing relevant mental health problems, in non-offending juveniles and adults. However, this association has only seldomly been addressed in offending juveniles and young adults. The present study aimed at evaluating the prevalence of ACEs and mental health problems as well as their association within a sample of male and female young offenders. Altogether, 161 adolescent and young adult offenders (16.8% females) from the youth detention center Worms (Germany) filled out questionnaires concerning ACEs and mental health problems with a focus on attention-deficit/hyperactivity disorder and intermittent explosive disorder. Considerable rates of mental health problems were found, e.g., a prevalence of 35.9% was found for intermittent explosive disorder. Furthermore, a greater proportion of the female offenders fell into the clinically significant category for somatic complaints, anxiety/depression, and attention problems than the male offenders. Female young offenders also reported more frequently about all forms of ACEs compared to the male offenders. Latent class analysis defined three subtypes of young offenders depending on their individual ACE patterns: (1) low ACEs, (2) mainly neglectful ACEs, and (3) multiple ACEs. ACEs were significantly associated with the occurrence of both internalizing and externalizing mental health disturbances, with the multiple-ACE subtype being most likely to report about significant mental health problems. The results of the present study point towards the relevance to routinely assess ACEs in young offenders to identify possible precursors of mental health problems and of future criminal behaviors.

Initial historical accounts as well as recent data suggest that emotion processing is dysfunctional in conversion disorder patients and that this alteration may be the pathomechanistic neurocognitive basis for symptoms in conversion disorder. However, to date evidence of direct interaction of altered negative emotion processing with motor control networks in conversion disorder is still lacking. To specifically study the neural correlates of emotion processing interacting with motor networks we used a task combining emotional and sensorimotor stimuli both separately as well as simultaneously during functional magnetic resonance imaging in a well characterized group of 13 conversion disorder patients with functional hemiparesis and 19 demographically matched healthy controls. We performed voxelwise statistical parametrical mapping for a priori regions of interest within emotion processing and motor control networks. Psychophysiological interaction (PPI) was used to test altered functional connectivity of emotion and motor control networks. Only during simultaneous emotional stimulation and passive movement of the affected hand patients displayed left amygdala hyperactivity. PPI revealed increased functional connectivity in patients between the left amygdala and the (pre-)supplemental motor area and the subthalamic nucleus, key regions within the motor control network. These findings suggest a novel mechanistic direct link between dysregulated emotion processing and motor control circuitry in conversion disorder., Graphical abstract Image 1, Highlights • We studied emotion processing effects on motor networks in conversion disorder (CD). • Simultaneous motor and emotional stimulation resulted in enhanced amygdala activation. • Left amygdala showed increased functional connectivity with an inhibitory motor loop. • This suggests a direct link of impaired emotion processing and motor networks in CD.

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.

Motivated by the recent replicability crisis we tested replicability of functional magnetic resonance imaging (fMRI) group activations in two independent samples. An identical behavioral and fMRI test battery for the longitudinal investigation of stress resilience mechanisms was developed for the Mainz Resilience Project (MARP) and conducted in a discovery (N = 54) and a replication sample (N = 103). The test battery consisted of a stress reactivity task, a reward sensitivity task, a fear conditioning and extinction paradigm, two volitional reappraisal tasks and an emotional interference inhibition task. Replicability of group activations was tested with the Jaccard index and the Intra Class Correlation (ICC). Overall, we observed good to excellent replicability of activations at the whole brain level. Only a minority of contrasts showed unsatisfactory replicability. Replicability at the level of individual regions of interest (ROIs) was generally lower. Tasks with stronger activation in the discovery sample showed better replicability.

In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented “threat words.” The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian “semantic access network” involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes.

Objectives: Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF). Methods: In 110 MDD patients with executive dysfunctions (percentile Results: Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (F1= 10.18; P = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance. Conclusions: Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96

Threat detection is essential for protecting individuals from adverse situations, in which a network of amygdala, limbic regions and dorsomedial prefrontal cortex (dmPFC) regions are involved in fear processing. Excitability regulation in the dmPFC might be crucial for fear processing, while abnormal patterns could lead to mental illness. Notwithstanding, non-invasive paradigms to measure excitability regulation during fear processing in humans are missing. To address this challenge we adapted an approach for excitability characterization, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS) over the dmPFC during an instructed fear paradigm, to dynamically dissect its role in fear processing. Event-related (ERP) and TMS-evoked potentials (TEP) were analyzed to trace dmPFC excitability. We further linked the excitability regulation patterns to individual MRI-derived gray matter structural integrity of the fear network. Increased cortical excitability was demonstrated to threat (T) processing in comparison to no-threat (NT), reflected by increased amplitude of evoked potentials. Furthermore, TMS at dmPFC enhanced the evoked responses during T processing, while the structural integrity of the dmPFC and amygdala predicted the excitability regulation patterns to fear processing. The dmPFC takes a special role during fear processing by dynamically regulating excitability. The applied paradigm can be used to non-invasively track response abnormalities to threat stimuli in healthy subjects or patients with mental disorders.

Emotion instability in borderline personality disorder (BPD) has been associated with an impaired fronto-limbic inhibitory network. However, functional connectivity (FC) underlying altered emotion regulation in BPD has yet to be established. Here, we used resting-state fMRI to investigate enduring effects of effortful emotion regulation on the amygdala intrinsic FC in BPD. In this multicenter study, resting-state fMRI was acquired before and after an emotion regulation task in 48 BPD patients and 39 non-patient comparison individuals. The bilateral amygdalae were used as a seed in the whole-brain FC analysis and two-way mixed ANOVA to test whether BPD patients exhibited weaker post-task increase in the amygdala intrinsic FC with the prefrontal cortex (PFC), compared to non-patients. Subsequently, we explored whether the results are common for personality disorders characterized by emotional problems, using additional data of 21 cluster-C personality disorder patients. In contrast to non-patients, BPD patients failed to show increased post-task amygdala resting-state FC with the medial, dorsolateral, ventrolateral PFC, and superior temporal gyrus, but surprisingly exhibited decreased FC with the posterior cingulate cortex and increased FC with the superior parietal lobule. In BPD patients, the emotion regulation task failed to increase resting-state amygdala FC with brain regions essential for effortful emotion regulation, which suggests: (a) altered cognitive control typically used to indirectly alleviate distress by reinterpreting the meaning of emotional stimuli; (b) impaired direct regulation of emotional responses, which might be common for personality disorders; (c) avoidance of self-related appraisals induced by social emotional stimuli. Electronic supplementary material The online version of this article (doi:10.1007/s00406-016-0760-z) contains supplementary material, which is available to authorized users.

Impulsivity is a multifaceted construct and an important personality trait in various mental health conditions. Among personality disorders (PDs), especially cluster B PDs are affected. The aims of this review are to summarize the relevant findings of the past 3 years concerning impulsivity in cluster B PDs and to identify those subcomponents of self-reported impulsivity and experimentally measured impulse control that are most affected in these disorders. All studies referred to antisocial (ASPD) or borderline PD (BPD), and none were found for narcissistic or histrionic PD. In ASPD as well as BPD, self-report scales primarily revealed heightened impulsivity compared to healthy controls. In experimental tasks, ASPD patients showed impairments in response inhibition, while fewer deficits were found in delay discounting. BPD patients showed specific impairments in delay discounting and proactive interference, while response inhibition was less affected. However, after inducing high levels of stress, deficits in response inhibition could also be observed in BPD patients. Furthermore, negative affect led to altered brain activation patterns in BPD patients during impulse control tasks, but no behavioral impairments were found. As proposed by the DSM-5 alternative model for personality disorders, heightened impulsivity is a core personality trait in BPD and ASPD, which is in line with current research findings. However, different components of experimentally measured impulse control are affected in BPD and ASPD, and impulsivity occurring in negative emotional states or increased distress seems to be specific for BPD. Future research could be focused on measures that assess impulsive behaviors on a momentary basis as this is a promising approach especially for further ecological validation and transfer into clinical practice.

Objective: We investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, Munchen-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase–derived amyloid precursor protein (APPs-α). Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such as β-amyloid 42 (Aβ 42 ) under treatment conditions. Results: The acitretin group showed a significant increase in CSF APPs-α levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03–0.72, p = 0.035) within this rather short treatment period. The synthetic retinoid acitretin was overall safe and well tolerated. Conclusions: Our pilot study highlights that acitretin is able to enhance the nonamyloidogenic APP processing in human patients. Clinical consequences of this regulation should be investigated in larger and longer trials in patients with AD to evaluate acitretin9s potential to serve as a novel therapeutic drug. Classification of evidence: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.

Objective To determine the functional correlates of vertical gaze palsy and other ocular motor deficits in patients with progressive supranuclear palsy (PSP) using [ 18 F]fluorodeoxyglucose (FDG-)PET. Methods Twenty-six patients with PSP underwent clinical examination of vertical gaze combined with FDG-PET scans to assess regional cerebral glucose metabolism as a marker of neuronal activity. Of these, eighteen PSP patients were also investigated by electrical nystagmography to determine horizontal ocular motor deficits. Statistical parametric mapping analyses were performed to correlate regional neuronal activity with ocular motor functions. Results In categorical comparisons, patients with downward gaze palsy showed a significantly reduced glucose metabolism in bilateral anterior cingulate gyrus and right lingual gyrus compared to those without downward gaze palsy. Maximum velocity of horizontal saccades was positively correlated with glucose metabolism of the rostral vermis and lingual gyrus; regional metabolism of oculomotor vermis was associated with peak velocity of the optokinetic reflex. Analysis of smooth pursuit eye movement amplitude and peak velocity of corrective saccades showed positive correlation with metabolism in bilateral inferior parietal lobe and inferior part of the frontal eye field. All paradigms of smooth pursuit showed positive association with glucose metabolism in V5. Conclusions Ocular motor functions in PSP are correlated with neuronal activity in distinct anatomical regions. These include the anterior cingulate gyrus (downward gaze palsy), rostral cerebellum (saccades), oculomotor vermis (optokinetic reflex) and inferior parietal as well as temporal regions and frontal eye field (smooth pursuit). These findings provide a deeper insight into the pathophysiology of PSP-associated ocular motor abnormalities.

Progressive supranuclear palsy (PSP) is characterized by a symmetric hypokinetic syndrome with early falls and vertical supranuclear gaze palsy. However, clinically asymmetric manifestations occur, resembling idiopathic Parkinson disease or corticobasal degeneration. The aim of this study was to determine the neuronal correlates of patients suffering from PSP with a lateralized disease manifestation (hemi-PSP) in comparison to patients with symmetric clinical presentation (symPSP) and corticobasal degeneration.Twenty-three patients with PSP and 8 patients with corticobasal degeneration according to standard diagnostic criteria underwent F-fluorodeoxyglucose (FDG) PET scans to assess disease-specific patterns of regional cerebral glucose metabolism reflecting neuronal activity. Group differences were analyzed by statistical parametric mapping and region-of-interest analyses.Clinically, 14 patients presented with symPSP while 9 patients were considered as hemi-PSP. Patients with symPSP or hemi-PSP showed similar bilateral medial frontal hypometabolism compared to corticobasal degeneration patients. In contrast, corticobasal degeneration patients exhibited a prominent parietal hypometabolism compared to both symPSP and hemi-PSP patients. SymPSP patients showed no significant hypometabolism compared to hemi-PSP, whereas hemi-PSP patients presented with significant hypometabolism of the motor thalamus, middle cingulate gyrus, and sensorimotor cortex contralateral to the most affected body side compared to symPSP patients.The present study demonstrates that a more pronounced and asymmetric involvement of cortical and subcortical motor areas is associated with a lateralized disease manifestation of PSP. Furthermore, these findings strongly suggest that FDG PET imaging may assist the challenging clinical differentiation between hemi-PSP and corticobasal degeneration by depicting disease-specific patterns of regional cerebral glucose metabolism.

Acting in accord with long-term goals requires control of interfering impulses, the success of which depends on several different processes. Using a structural-equation modeling approach, we investigated 5 behavioral components of impulsivity: the control of stimulus interference, proactive interference, and response interference, as well as decisional and motivational impulsivity. Results support the existence of 5 correlated but separable components of impulsive behavior. The present study is the 1st to demonstrate the separability of stimulus and response interference. It also supports the notion that control of response-related interference is not a unitary construct: Response-selection demands were separable from those of withholding or stopping. Relations between behavioral impulsivity components and self-report measures of impulsivity were largely absent. We conclude that as the construct of impulsivity has been extended to describe an increasingly diverse set of phenomena and processes, it has become too broad to be helpful in guiding future research.

Verbal social interaction plays an important role both in the etiology and treatment of psychiatric disorders. However, the neural basis of social interaction has primarily been studied in the individual brain, neglecting the inter-individual perspective. Here, we show inter-individual neuronal coupling of brain activity during live verbal interaction, by investigating 11 pairs of good female friends who were instructed to speak about autobiographical life events during simultaneous fMRI acquisition. The analysis revealed that the time course of neural activity in areas associated with speech production was coupled with the time course of neural activity in the interlocutor's auditory cortex. This shows the feasibility of the new methodology, which may help elucidate basic reciprocal mechanisms of social interaction and the underpinnings of disordered communication. In particular, it may serve to study the process of psychotherapy on a neuronal level.

We investigated disease-specific cognitive profiles and their neural correlates in Lewy-body diseases (LBD) and tauopathies by CERAD assessment and FDG-PET. Analyses revealed a significant interaction between reduced semantic fluency in tauopathies and impaired verbal learning in LBD. Semantic fluency discriminated between groups with high accuracy (83%). Compared to LBD, tauopathy patients showed bilateral hypometabolism of midbrain, thalamus, middle cingulate gyrus and supplementary motor/premotor cortex. In the reverse contrast, LBD patients exhibited bilateral hypometabolism in posterior parietal cortex, precuneus and inferior temporal gyrus extending into occipital and frontal cortices. In diagnosis-independent voxel-based analyses, verbal learning/memory correlated with left temporal and right parietal metabolism, while fluency was coupled to bilateral striatal and frontal metabolism. Naming correlated with left frontal metabolism and drawing with metabolism in bilateral temporal and left frontal regions. In line with disease-specific patterns of regional glucose metabolism, tauopathies and LBD show distinct cognitive profiles, which may assist clinical differentiation.

BackgroundEmotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI).MethodIn the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS−) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS− were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS− during testing. No UCS was presented.ResultsGroups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS−.ConclusionsDuring IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS−-related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

Despite a large body of research, extant findings on the functional role of left inferior frontal gyrus (LIFG) in phonological and semantic fluency are still controversial. Based on cross-study comparisons, a recent meta-analysis of neuroimaging results suggests that posterior-dorsal (Brodmann area, BA, 44) and anterior-ventral parts (BA 45) of LIFG contribute differentially to processes of phonologically and semantically cued word retrieval, respectively. In contrast, a subsequent functional magnetic resonance imaging experiment failed to validate the proposed dissociation using a within-subjects design. In particular, no evidence for a specific role of BA 45 in semantic fluency was found. Here, we resolve this apparent controversy by showing that the conflicting findings can be accounted for when considering the influence of task demands and individual ability on resulting functional magnetic resonance imaging activation patterns. By comparing phonological versus semantic fluency, higher activation was robustly observed in BA 44. For the opposite comparison, higher activation was found in dorsal BA 45; however, this was more pronounced in posterior-dorsal parts of BA 45 for low-performing subjects and was only apparent in anterior-dorsal parts of BA 45 under high demands on controlled semantic retrieval. Our results thus disclose important determinants for detecting a functional segregation of LIFG in verbal fluency that also have implications for the controversial findings in previous lesion studies. Moreover, the present parcellation of dorsal BA 45 corresponds well with anatomical evidence suggesting a subdivision into an anterior (45A) and posterior part (45B) and may therefore represent evidence for its functional significance in humans.

Attention-Deficit/Hyperactivity Disorder (ADHD) is marked by inhibitory and attentional deficits which can persist into adulthood. Those deficits have been associated with dysfunctional fronto-striatal and fronto-parietal circuits. The present study sought to delineate neural correlates of component specific inhibitory deficits in adult ADHD using functional magnetic resonance imaging (fMRI). 20 adult ADHD patients and 24 matched healthy controls were included. Brain activation was assessed during three stages of behavioral inhibition, i.e. interference inhibition (Simon task), action withholding (Go/no-go task) and action cancelation (Stop-signal task). Behaviorally, ADHD patients were affected in all tasks. Impaired interference inhibition was associated with hypoactivation in parietal and medial frontal regions. During action withholding and cancelation ADHD patients displayed hypoactivation in a fronto-striatal network. These findings support the notion of at least two disturbed neural circuits in ADHD differentially associated with deficits in separate inhibitory subcomponents. Thereby, deficits in inhibitory subcomponents which are closely connected to response interference were related to hypofunction in more attention related circuits, while stopping related deficits were rather associated with hypofunction in inhibitory circuits.

Background Patients with a psychogenic paresis have difficulties performing voluntary movements. Typically, diagnostic interventions are normal. We tested whether patients with a psychogenic lower limb paresis exhibit abnormal motor excitability during motor imagery or movement observation. Methods Transcranial magnetic stimulation (TMS) with single and paired pulses was used to explore motor excitability at rest, during imagination of ankle dorsiflexions and during watching another person perform ankle dorsiflexions. Results obtained in ten patients with a flaccid psychogenic leg paresis were compared with a healthy age-matched control group. In addition, results of two patients with a psychogenic fixed dystonia of the leg are presented. Results During rest, motor excitability evaluated by motor thresholds, size of motor-evoked potentials (MEP) by single pulse TMS, intracortical inhibition and intracortical facilitation tested by paired-pulse TMS were similar in patients and healthy subjects. MEPs recorded in five patients during movement observation were also comparable across the two groups. During motor imagery, patient MEPs were significantly smaller than in the control group and smaller than during rest, indicating an inhibition. Conclusion In patients with motor conversion disorder, the imagination of own body movements induces a reduction of corticospinal motor excitability whereas it induces an excitability increase in healthy subjects. This discrepancy might be the electrophysiological substrate of the inability to move voluntarily. Watching another person perform movements induces a normal excitability increase, indicating a crucial role of the perspective and suggesting that focusing the patient's attention on a different person might become a therapeutic approach.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 –patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies. Trial registration: ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96

Background: Impulsivity is a core feature of borderline personality disorder (BPD). However, previous clinical and experimental studies investigating impulsivity in BPD rendered mixed results. In this study, impulsivity was assessed by self-report scales and behavioral inhibition tasks to compare different data levels. Sampling and Methods: Fifteen women with BPD and 15 matched healthy control subjects (HC) completed the Barratt Impulsiveness Scale, Eysenck’s Impulsivity Questionnaire and the UPPS (Urgency, Lack of Perseverance, Lack of Premeditation and Sensation Seeking) scale, and participated in a Stroop task, an antisaccade task and a stop signal task. Results: Patients with BPD scored significantly higher on self-report measures as compared to HC, but not in behavioral tests. In BPD patients, but not in HC, behavioral inhibition errors were correlated with more intense emotional state. Conclusion: We found a discrepancy between self-report and behavioral data. Further studies need to assess additional possible mechanisms underlying increased impulsivity, their relation to emotional instability, and their neurobiological underpinnings.

Purpose: Recent studies have found age-related BOLD signal changes in several areas of the human brain. We investigated whether such changes also occur in brain areas involved in the processing of motor action observation and imagery. Methods: Functional magnetic resonance imaging with an experimental paradigm in which motor acts had to be observed and/or imagined from a first person perspective was performed in twe nty-six subjects. Results: In line with previous work action observation and imagery induced BOLD signal increases in similar areas, predominantly in the premotor and parietal cortex. In contrast to young subjects the elderly displayed a stronger activity in most acti vated brain areas indicative of compensatory activity for the age-rela ted decline of neural structures. Importantly, activity in the ventrolateral premotor cortex and inferior parietal cortex, seminal area s of the mirror neuron system, did not exhibit activity changes as a function of age. Conclusion: These findings suggest that activity within the mirror neur on system is not age dependent and provide a neural basis for therapeutical interventions and novel rehabilitation treatments such as video therapy.

Many recent studies reported altered functional connectivity within the frontolimbic circuitry in a wide range of neuropsychiatric disorders. However, functional connectivity must rely on structural connections. In this study we applied a novel probabilistic fiber tracking method to assess the structural connectivity between the amygdala and different prefrontal brain regions in vivo. Twenty healthy subjects were investigated with diffusion tensor imaging. Probabilistic fiber tracking was started from the amygdala and different prefrontal brain regions. Resulting probability maps were combined using an extended multiplication of probabilistic maps to identify the most probable anatomical pathways connecting these structures. We found one ventral pathway through the uncinate fascicle, connecting the amygdala and the medial and lateral orbitofrontal cortices. In addition to this ventral pathway, we depicted distinct dorsal pathways (medial and lateral), which connect the amygdala with the anterior cingulate cortex and the dorsolateral prefrontal cortex. The dorso-medial pathway proceeds through the inferior thalamic peduncle, while the dorsolateral pathway travels through the external capsule. We believe that our approach provides a promising tool to assess the integrity of specific structural connections in patients with neuropsychiatric disorders.

Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2×200mg modafinil, 2×20mg methylphenidate, and 2×200mg caffeine or placebo in a 4×4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

Early prognostic stratification is desirable in patients with suspected atypical parkinsonian syndromes (APS) for optimal treatment and counseling. We investigated the prognostic value of imaging disease-specific metabolism patterns with 18F-FDG PET compared to the clinical diagnosis. Methods: Seventy-eight patients with suspected APS at study inclusion underwent a follow-up of up to 5.9 years after prospective 18F-FDG PET imaging. Survival data were analyzed by Kaplan-Meier and Cox regression analyses according to diagnostic classifications provided by 18F-FDG PET at baseline and clinical diagnoses after a median follow-up of 1 year after PET. Results: Forty-four of 78 patients were alive at 4.7±0.6 years after PET. Patients diagnosed with an atypical parkinsonian syndrome (APS) by PET or 1-year clinical follow-up showed a significantly shorter median survival time (4.1 years, age-adjusted hazard ratios [HR]=3.8 for both classifiers) than those diagnosed with Lewy-body diseases (LBD; majority Parkinson’s disease, PD; median survival time not reached). Subgroup classifications of progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) or multisystem atrophy (MSA) by PET and clinical follow-up were associated with significantly shorter survival than PD. Age-adjusted mortality was significantly increased for PSP/CBD (HR=5.2) and MSA (HR=5.6) classified by PET, but only for PSP/CBD diagnosed by clinical follow-up (HR=4.5). Patients with a PET-pattern suggestive of PD with dementia/dementia with Lewy bodies (PDD/DLB) exhibited a trend towards shorter survival than PD (P = 0.07), whereas patients classified as PDD/DLB by clinical follow-up did not (P = 0.65). Conclusion:18F-FDG PET is an early predictor of survival in patients with clinically-suspected APS. Detection of cortical or subcortical hypometabolism by [18F]FDG-PET is an unfavorable predictor. Risk stratification by 18F-FDG PET appears to be at least as predictive as the 1-year follow-up clinical diagnosis. This strongly supports the early inclusion of PET imaging into patient care.

Impulsivity is central to borderline personality disorder (BPD). Response inhibition, addressing the ability to suppress or stop actions, is one aspect of behavioral impulse control which is frequently used to assess impulsivity. BPD patients display deficits in response inhibition under stress condition or negative emotions. We assessed whether response inhibition and its neural underpinnings are impaired in BPD when tested in an emotionally neutral setting and when co-morbid attention-deficit/hyperactivity disorder (ADHD) is excluded. To this end, we studied response inhibition in unmedicated BPD patients and healthy controls (HC) in two independent samples using functional magnetic resonance imaging during Simon-, Go/nogo-, and Stopsignal tasks. BPD patients and HC did not differ significantly in their performance in the Go/nogo and the Stopsignal tasks. Response interference in the Simon task was increased in BPD patients in one sample, but this could not be replicated in the second sample. In both samples, no significant differences in brain activation patterns during any of the tasks were present while the neural impulse control network was robustly activated during the inhibition tasks in both groups. Our results provide evidence that under emotionally neutral conditions response inhibition is not impaired in patients with BPD without co-occurring ADHD.

The Mona Lisa effect describes the phenomenon when the eyes of a portrait appear to look at the observer regardless of the observer's position. Recently, the metaphor of a cone of gaze has been proposed to describe the range of gaze directions within which a person feels looked at. The width of the gaze cone is about five degrees of visual angle to either side of a given gaze direction. We used functional magnetic resonance imaging to investigate how the brain regions involved in gaze direction discrimination would differ between centered and decentered presentation positions of a portrait exhibiting eye contact. Subjects observed a given portrait's eyes. By presenting portraits with varying gaze directions—eye contact (0°), gaze at the edge of the gaze cone (5°), and clearly averted gaze (10°), we revealed that brain response to gaze at the edge of the gaze cone was similar to that produced by eye contact and different from that produced by averted gaze. Right fusiform gyrus and right superior temporal sulcus showed stronger activation when the gaze was averted as compared to eye contact. Gaze sensitive areas, however, were not affected by the portrait's presentation location. In sum, although the brain clearly distinguishes averted from centered gaze, a substantial change of vantage point does not alter neural activity, thus providing a possible explanation why the feeling of eye contact is upheld even in decentered stimulus positions. Hum Brain Mapp 36:619–632, 2015. © 2014 Wiley Periodicals, Inc.

Background and purpose Brain imaging with positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET) and transcranial B-mode sonography (TCS) improves the differential diagnosis of parkinsonism. The diagnostic merits of these approaches in identifying and differentiating atypical parkinsonian syndromes (APS) are compared. Methods Data were included from 36 patients with clinically suspected APS who underwent PET and TCS. FDG-PET scans were analyzed by visual assessment (including voxel-based statistical maps) of a priori defined disease-specific metabolic patterns. Sonographers achieved diagnoses according to pre-defined criteria for echogenicities of the substantia nigra and lenticular nucleus, and third ventricle diameter. Patients with APS were identified and allocated to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Results After a median follow-up period of 9 months, the final clinical diagnoses (reference standard) were Parkinson's disease, n = 15; MSA, n = 9; PSP, n = 7; and CBD, n = 5 (n = 21 APS in total). Six patients (4 APS) showed an insufficient bone window for TCS. In the remaining 30 patients, sensitivity/specificity for diagnosing APS were 82%/100% and 82%/85% for FDG-PET and TCS, respectively. Diagnostic accuracies did not differ between FDG-PET (90%) and TCS (83%; P = 0.69). Likewise, overall accuracy of subgroup classification (non-APS, MSA, PSP and CBD) did not differ between modalities (FDG-PET 87% and TCS 83%; P = 1.00). Conclusions FDG-PET and TCS show comparable accuracies for differential diagnosis of neurodegenerative parkinsonism. This preliminary study supports the use of TCS and warrants further prospective validation.

The prediction of dopaminergic responsiveness in patients with parkinsonism is desirable for effective treatment strategies. We investigated whether striatal dopamine D2/D3 receptor (D2R) binding assessed by 123I-iodobenzamide SPECT is an independent predictor of dopaminergic responsiveness in patients with parkinsonism. Methods: Seventy-eight patients with clinically suspected atypical parkinsonian syndrome (APS) were prospectively recruited for imaging. To quantify striatal D2R binding, 123I-iodobenzamide SPECT datasets were subjected to an observer-independent, regions-of-interest analysis. A final clinical diagnosis of Lewy-body disease (LBD) or APS was made after a mean follow-up of 12 mo. On the basis of follow-up data, dopaminergic responsiveness was classified as 0 (none), 1 (transient), 2 (sustained mild), or 3 (sustained strong). Uni- and multivariate analyses of the relationship between treatment response, D2R binding, and confounding variables were conducted. Results: Sixty patients with clinically verified LBD (n = 28; 22/28 with Parkinson disease) or APS (n = 32), in whom dopaminergic responsiveness could be assessed (n = 19/13/15/13 in categories 0/1/2/3; 18 were excluded because of insufficient dosing), were included in the statistical analysis. Univariate analyses revealed that a sustained treatment response was significantly associated with higher D2R binding, clinical diagnosis of LBD, lower Hoehn and Yahr scores, and younger age. After multivariate correction of D2R binding for diagnosis, age, symptom duration, Hoehn and Yahr score, and dopaminergic pretreatment, no association was found between D2R binding and treatment response, either in the pooled group or in LBD or APS subgroups. Conclusion: Striatal D2R binding assessed by 123I-iodobenzamide SPECT does not provide additional predictive information about treatment response beyond other clinical variables, most notably the clinical diagnosis.

The Stroop interference task is a widely used paradigm to examine cognitive inhibition, which is a key component of goal‐directed behavior. With increasing age, reaction times in the Stroop interference task are usually slowed. However, to date it is still under debate if age‐related increases in reaction times are merely an artifact of general slowing. The current study was conducted to investigate the role of general slowing, as measured by Trail‐Making‐Test‐A, in age‐related alterations of Stroop interference. We applied Diffusion Tensor Imaging (DTI) to determine the topography of neuronal networks underlying Stroop interference under control of general slowing. On the behavioral level, linear regression analysis demonstrated that age accounted for significant variance on Stroop interference, whereas TMT‐A performance did not. Controlling for TMT‐A, DTI based white matter analyses demonstrated a strong association of Stroop interference with integrity measures of genu of corpus callosum, bilateral anterior corona radiata, and bilateral anterior limb of capsula interna. These pathways are associated with frontal brain regions by either connecting the bilateral dorsolateral prefrontal cortex or the anterior cingulate cortex with frontal and subcortical regions or by containing fibers which are part of cortico‐thalamic circuits that cross prefrontal regions. Importantly, results expand our knowledge of the neural basis of Stroop interference and emphasize the importance of white matter integrity of frontal pathways in the modulation of Stroop interference. Combining behavioral and DTI findings our results further suggest that cognitive inhibition, as measured by Stroop task, is a qualitatively distinct cognitive process that declines with age. Hum Brain Mapp 35:2448–2458, 2014. © 2013 Wiley Periodicals, Inc.

Recent studies have begun to carve out a specific role for the rostral part of the dorsal medial prefrontal cortex (dmPFC) and adjacent dorsal anterior cingulate cortex (dACC) in fear/anxiety. Within a novel general framework of dorsal mPFC/ACC areas subserving the appraisal of threat and concomitant expression of fear responses and ventral mPFC/ACC areas subserving fear regulation, the rostral dmPFC/dACC has been proposed to specifically mediate the conscious, negative appraisal of threat situations including, as an extreme variant, catastrophizing. An alternative explanation that has not been conclusively ruled out yet is that the area is involved in fear learning. We tested two different fear expression paradigms in separate fMRI studies (study 1: instructed fear, study 2: testing of Pavlovian conditioned fear) with independent groups of healthy adult subjects. In both paradigms the absence of reinforcement precluded conditioning. We demonstrate significant BOLD activation of an identical rostral dmPFC/dACC area. In the Pavlovian paradigm (study 2), the area only activated robustly once prior conditioning had finished. Thus, our data argue against a role of the area in fear learning. We further replicate a repeated observation of a dissociation between peripheral-physiological fear responding and rostral dmPFC/dACC activation, strongly suggesting the area does not directly generate fear responses but rather contributes to appraisal processes. Although we succeeded in preventing extinction of conditioned responding in either paradigm, the data do not allow us to definitively exclude an involvement of the area in fear extinction learning. We discuss the broader implications of this finding for our understanding of mPFC/ACC function in fear and in negative emotion more generally.

Affective dysregulation is a clinical hallmark of borderline personality disorder (BPD). This study used an instructed fear task combined with functional MRI (fMRI) and skin conductance response (SCR) to test hypotheses about mechanisms of disturbed fronto-limbic neural circuitry underlying dysfunctional emotional processing in BPD.Female BPD patients and matched control subjects were exposed to two visual stimuli during fMRI scanning and SCR recording. Subjects were instructed shortly before scanning that one stimulus (Threat) potentially represents an aversive event whereas another stimulus (Safe) represents safety. The aversive event (electrodermal stimulation) itself was only experienced before this instruction and never occurred during fMRI scanning.Both groups showed stronger SCR to Threat compared to Safe indicating differential fear response which habituated over time. BPD compared to control subjects did not show fMRI signal decrease of amygdala activity or relative ventromedial prefrontal cortex (vmPFC) activity increase over time. Moreover, BPD patients showed increased connectivity of the amygdala with vmPFC but decreased connectivity of subgenual ACC with dorsal ACC compared to control subjects.Prolonged amygdala response and a functional disconnection between ventral and dorsal mPFC regions may be part of the neural mechanisms underlying emotional dysregulation in BPD patients.

Introduction Cigarette smoking is a behavior, which is influenced by genetic, demographic, and psychological factors. A large body of research has examined the association of cigarette smoking variables with individual differences in personality traits. The aim of the current study was to replicate the findings of higher self-reported impulsivity in smokers compared with never-smokers in a German sample using Eysenck´s construct of impulsivity. Furthermore, it was intended to further the knowledge about associations between different self-reported impulsivity components and different smoking variables. Methods We used the Impulsiveness-Venturesomeness-Empathy questionnaire (I7) to measure self-reported impulsiveness and venturesomeness and the Temperament and Character Inventory (TCI) to measure novelty seeking (NS) in a sample of 82 nicotine-dependent smokers and 119 never-smokers. Results Smokers scored higher on impulsiveness, venturesomeness, and NS than never-smokers independent of age, gender, and years of education. We found a significant association between venturesomeness, impulsiveness and smoking status in daily smokers. Conclusions In summary, this study provides evidence that impulsiveness and venturesomeness as well as the novelty-seeking subscale extravagance are significantly associated with smoking status in a German sample of female and male smokers compared with never-smokers.

Bulimia nervosa (BN) is characterized by dysregulation of impulse control, in other words, uncontrolled eating. Functional neuroimaging studies have been sparse and have used variable methodologies.Thirteen medication-free female BN patients and 13 female healthy controls were investigated by functional magnetic resonance imaging using a disease-specific food paradigm. Stimuli were rated after the scanning procedure.Bulimia nervosa patients showed increased fear ratings and a trend for increased disgust. Magnetic resonance imaging data of 10 BN patients could be analysed. Three BN patients had to be excluded from the analysis because of minimal blood oxygen level dependent signals. Compared with healthy controls, BN patients showed less activation of the anterior cingulate cortex, which extended into the lateral prefrontal cortex. Furthermore, the right temporal pole showed decreased reactivity.This study substantiates a key role of lateral prefrontal dysfunction in BN, a brain region involved in impulse control. Furthermore, the anterior cingulate cortex, which plays a key role in emotion processing, is dysfunctional. A major limitation of this study is the small sample size.

Background: In this study we compared the effect of different emotion regulation strategies on positive and negative emotions in patients with borderline personality disorder.Methods: Emotion regulation strategies were a distracting task, individual positive memory imagery, individual soothing imagery, and a neutral comparison condition. During two separate sessions, 17 participants watched either neutral or negative movie segments before using these strategies.Results: All three strategies influenced emotions into a favorable direction as compared to the neutral comparison condition. The positive memory image increased positive emotions significantly stronger than counting colors and distracting.Discussion: Different strategies seem to have similar effects in decreasing negative emotions. Positive emotions may be affected in particular by positive and soothing imagery techniques.

Objective Cerebral grey matter (GM) reduction has repeatedly been shown in anorexia nervosa (AN). Evidence concerning completeness of GM restitution in recovered patients is contradictory. Methods Five long-term recovered patients with AN were compared to symptomatic subjects and healthy controls using voxel-based morphometry. Whole brain GM, white matter and cerebrospinal fluid fractions were studied. Additionally, voxels that had shown significant GM reductions in symptomatic patients were investigated. Results Recovered subjects had been severely affected when symptomatic (mean body mass index: 12.1 kg/m2) and were in remission for a very long time period (>5 years). Whole brain tissue fractions did not differ from controls. Regional analysis showed persistent GM volume reduction, in particular of the precuneus. Conclusions This study further supports the assumption that GM volume restitution is incomplete in subjects, who had previously been severely affected by anorexia nervosa. The meaning of GM reduction in long-term recovered AN patients, that is, its pathophysiological relevance, however, remains unclear. Furthermore, the precise aetiology of GM reduction remains an open question. Copyright © 2010 John Wiley & Sons, Ltd and Eating Disorders Association.

BackgroundCognitive behavioral therapy (CBT) with exposure and response prevention (ERP) is the psychotherapeutic treatment of choice for obsessive–compulsive disorder (OCD). However, little is known about the impact of CBT on frontostriatal dysfunctioning, known to be the neuronal correlate of OCD.MethodA probabilistic reversal learning (RL) task probing adaptive strategy switching capabilities was used in 10 unmedicated patients with OCD and 10 healthy controls during an event-related functional magnetic resonance imaging (fMRI) experiment. Patients were scanned before and after intensive CBT, controls twice at comparable intervals.ResultsStrategy change within the RL task involved activity in a broad frontal network in patients and controls. No significant differences between the groups or in group by time interactions were detected in a whole-brain analysis corrected for multiple comparisons. However, a reanalysis with a more lenient threshold revealed decreased responsiveness of the orbitofrontal cortex and right putamen during strategy change before treatment in patients compared with healthy subjects. A group by time effect was found in the caudate nucleus, demonstrating increased activity for patients over the course of time. Patients with greater clinical improvement, reflected by greater reductions in Yale–Brown Obsessive Compulsive Scale (YBOCS) scores, showed more stable activation in the pallidum.ConclusionsAlthough these findings are preliminary and need to be replicated in larger samples, they indicate a possible influence of psychotherapy on brain activity in core regions that have been shown to be directly involved both in acquisition of behavioral rules and stereotypes and in the pathophysiology of OCD, the caudate nucleus and the pallidum.

The epilepsies have a prevalence of 0.5-1%, which makes them among the most common neuropsychiatric diseases. In contrast to clinical intuition, in highly industrialized countries the peak incidence of epilepsy is observed among those aged over 60 years. This of course is due to demographic change: this section of industrialized societies is steadily growing, especially for women. The clinical presentation, etiology, diagnosis and treatment of elderly patients with epilepsy are summarized in this paper, with a focus on women and the management and health implications of epilepsy for elderly patients. Gender-specific issues such as the influence of perimenopausal hormonal changes, bone health and hormone replacement therapy are discussed.