Functional connectivity profile of the human inferior frontal junction: involvement in a cognitive control network

Background: The human inferior frontal junction area (IFJ) is critically involved in three main component processes of cognitive control (working memory, task switching and inhibitory control). As it overlaps with several areas in established anatomical labeling schemes, it is considered to be underreported as a functionally distinct location in the neuroimaging literature. While recent studies explicitly focused on the IFJ´s anatomical organization and functional role as a single brain area, it is usually not explicitly denominated in studies on cognitive networks. However based on few analyses in small datasets constrained by specific a priori assumptions on its functional specialization, the IFJ has been postulated to be part of a cognitive control network. Goal of this meta-analysis was to establish the IFJ’s connectivity profile on a high formal level of evidence by aggregating published implicit knowledge about its co-activations. We applied meta-analytical connectivity modeling (MACM) based on the activation likelihood estimation (ALE) method without specific assumptions regarding functional specialization on 180 (reporting left IFJ activity) and 131 (right IFJ) published functional neuroimaging experiments derived from the BrainMap database. This method is based on coordinates in stereotaxic space, not on anatomical descriptors. Results: The IFJ is significantly co-activated with areas in the dorsolateral and ventrolateral prefrontal cortex, anterior insula, medial frontal gyrus / pre-SMA, posterior parietal cortex, occipitotemporal junction / cerebellum, thalamus and putamen as well as language and motor areas. Results are corroborated by an independent resting-state fMRI analysis. Conclusions: These results support the assumption that the IFJ is part of a previously described cognitive control network. They also highlight the involvement of subcortical structures in this system. A direct line is drawn from works on the functional significance of brain activity located at the IFJ and its anatomical definition to published results related to distributed cognitive brain systems. The IFJ is therefore introduced as a convenient starting point to investigate the cognitive control network in further studies

Towards literature-based feature selection for diagnostic classification: A meta-analysis of resting-state fMRI in depression

Information derived from functional magnetic resonance imaging (fMRI) during wakeful rest has been introduced as a candidate diagnostic biomarker in unipolar major depressive disorder (MDD). Multiple reports of resting state fMRI in MDD describe group effects. Such prior knowledge can be adopted to pre-select potentially discriminating features for diagnostic classification models with the aim to improve diagnostic accuracy. Purpose of this analysis was to consolidate spatial information about alterations of spontaneous brain activity in MDD, primarily to serve as feature selection for multivariate pattern analysis techniques (MVPA). Thirty two studies were included in final analyses. Coordinates extracted from the original reports were assigned to two categories based on directionality of findings. Meta-analyses were calculated using the non-additive activation likelihood estimation approach with coordinates organized by subject group to account for non-independent samples. Converging evidence revealed a distributed pattern of brain regions with increased or decreased spontaneous activity in MDD. The most distinct finding was hyperactivity/hyperconnectivity presumably reflecting the interaction of cortical midline structures (posterior default mode network components including the precuneus and neighboring posterior cingulate cortices associated with self-referential processing and the subgenual anterior cingulate and neighboring medial frontal cortices) with lateral prefrontal areas related to externally-directed cognition. Other areas of hyperactivity/hyperconnectivity include the left lateral parietal cortex, right hippocampus and right cerebellum whereas hypoactivity/hypoconnectivity was observed mainly in the left temporal cortex, the insula, precuneus, superior frontal gyrus, lentiform nucleus and thalamus. Results are made available in two different data formats to be used as spatial hypotheses in future studies, particularly for diagnostic classification by MVPA

Deutsche biomedizinische Forschung: auf beiden Augen geschlechterblind?!

Gegenstand dieses Beitrags ist die Integration der Geschlechterperspektive in die biomedizinische Forschung. Es wird der Frage nachgegangen, ob und inwieweit ein Geschlechterbewusstsein, das beiden Geschlechtern (männlichen und weiblichen Individuen) gerecht wird, in den Fachorganisationen der biomedizinischen Forschung, in den Fachgesellschaften, Förderorganisationen und Fachzeitschriften verbreitet ist. Dadurch hat dieser Beitrag auch eine wissenschaftspolitische Bedeutung und Zielsetzung. Wir haben die Situation einer geschlechterdifferenzierenden biomedizinischen Forschung in Deutschland mithilfe einer anonymen Umfrage bei den relevanten Fachorganisationen analysiert. Diese Untersuchung ergab, dass Fachgesellschaften, Förderorganisationen und Fachzeitschriften die Integration der Geschlechterperspektive in die biomedizinische Forschung als wichtig erachten. In der Praxis planen sie jedoch weder gegenwärtig noch in Zukunft eine Änderung der Leitlinien für die Forschenden. Dementsprechend ergab eine Analyse von Veröffentlichungen des vom BMBF geförderten "Nationalen Bernstein Netzwerks Computational Neuroscience", die sich mit neurowissenschaftlichen Studien am Menschen beschäftigten, dass keine geschlechterdifferenzierte Datenauswertung stattfand. Die Begutachtungsrichtlinien für Forschungsanträge und Publikationen der Förderorganisationen und Zeitschriften mit Sitz in Deutschland müssen daher verändert werden. Auf lange Sicht gesehen wird nur eine frühzeitige Integration von geschlechterdifferenzierten Forschungsbefunden in die grundständige Lehre der Medizin und Naturwissenschaften zu einem Umdenken bei den Forschenden führen.This article focuses on the process of integrating the gender perspective into biomedical research. We aim to investigate the level of sex/ gender awareness in specialist associations, research funding agencies and trade journals. The results of this article thus also have an impact on science policy. The status quo of sex/ gender awareness in these organizations was assessed by means of an anonymous survey. We found that even though integrating sex and gender into biomedical research was claimed to be of importance, none of the organizations surveyed intends to include sex/ gender aspects in its guidel ines and policies - either now or in the future. Accordingly, an analysis of neuroscientific studies of human subjects stemming from research conducted by the National Bernstein Network for Computational Neuroscience, which is funded by the German Federal Ministry of Education and Research, revealed that sex/ gender-differentiated data evaluation was not performed. As a consequence, guidelines for evaluating research grant applications as well as for reviewing papers for publication need to be revised in the German research landscape. In the long run only integrating sex/ gender issues in basic and clinical teaching in medicine and the life sciences will lead to change in medical and biomedical research

Human Fear Conditioning and Extinction in Neuroimaging: A Systematic Review

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending o

Geschlechtsspezifische Unterschiede bei chronischem Pruritus

Chronischer Juckreiz ist mit einer Lebenszeitprävalenz von ca. 23 % ein sehr häufiges Symptom, das durch zahlreiche dermatologische, internistische, neurologische und auch psychische Erkrankungen ausgelöst werden kann. Während bei jüngeren Patientinnen und Patienten eher der entstellende Aspekt der durch Kratzen beschädigten Haut eine Rolle spielt, leiden ältere Patientinnen und Patienten oftmals unter einem schwer zu behandelbaren Juckreiz unterschiedlichster Ursache. Obwohl der chronische Pruritus als Volkssymptom angesehen werden kann, liegen bisher nur sehr wenige Studien zu geschlechtsspezifischen Unterschieden vor. Diese zeigen, dass Frauen und Männer eine unterschiedliche Pruritus- Wahrnehmung haben – Frauen nehmen das Symptom intensiver wahr. Dies führt bei Frauen nicht nur zu einer höheren psychischen Belastung, sondern auch zu einem unterschiedlichen Verhalten – Frauen kratzen vermehrt. Aber auch die Qualitäten des Symptoms sind unterschiedlich, Frauen empfinden beispielsweise vermehrt einen brennenden Juckreiz, was u. a. auf die Aktivierung von schmerzleitenden Nervenfasern (neuropathische Komponente) hindeutet. Dies deutet auf eine unterschiedliche Verarbeitung von Pruritus im Gehirn hin. Die geschlechtsspezifischen Unterschiede hinsichtlich der Juckempfindung sollten dringend weiter untersucht werden, um eine geschlechtsadaptierte Diagnostik und möglicherweise auch Therapie anbieten zu können und somit zur verbesserten Behandlung der Betroffenen beitragen zu können

Geschlechtsspezifische Unterschiede bei chronischem Pruritus

"Chronischer Juckreiz ist mit einer Lebenszeitprävalenz von ca. 23 % ein sehr häufiges Symptom, das durch zahlreiche dermatologische, internistische, neurologische und auch psychische Erkrankungen ausgelöst werden kann. Während bei jüngeren Patientinnen und Patienten eher der entstellende Aspekt der durch Kratzen beschädigten Haut eine Rolle spielt, leiden ältere Patientinnen und Patienten oftmals unter einem schwer zu behandelbaren Juckreiz unterschiedlichster Ursache. Obwohl der chronische Pruritus als Volkssymptom angesehen werden kann, liegen bisher nur sehr wenige Studien zu geschlechtsspezifischen Unterschieden vor. Diese zeigen, dass Frauen und Männer eine unterschiedliche Pruritus- Wahrnehmung haben - Frauen nehmen das Symptom intensiver wahr. Dies führt bei Frauen nicht nur zu einer höheren psychischen Belastung, sondern auch zu einem unterschiedlichen Verhalten - Frauen kratzen vermehrt. Aber auch die Qualitäten des Symptoms sind unterschiedlich, Frauen empfinden beispielsweise vermehrt einen brennenden Juckreiz, was u. a. auf die Aktivierung von schmerzleitenden Nervenfasern (neuropathische Komponente) hindeutet. Dies deutet auf eine unterschiedliche Verarbeitung von Pruritus im Gehirn hin. Die geschlechtsspezifischen Unterschiede hinsichtlich der Juckempfindung sollten dringend weiter untersucht werden, um eine geschlechtsadaptierte Diagnostik und möglicherweise auch Therapie anbieten zu können und somit zur verbesserten Behandlung der Betroffenen beitragen zu können." (Autorenreferat)"Chronicitch is a common symptom with a life-time prevalence of around 23% which is provoked by numerous dermatological, internal, neurological and mental disorders. While the disfiguring resulting from skin being damaged by scratching plays an important role in younger patients, older patients often suffer from a difficult-to-treat pruritus of various causes. Although chronic pruritus can be considered as a widespread disease, there are only a few studies which have examined sex-/ gender-specific differences. These studies have indicated that females and males have a different pruritus perception: females experience the symptom more intensively. This not only leads to a greater psychological burden in females, but results in a different behaviour, because females scratch more. Women also experience different symptoms, for example more women experience a burning itch, which indicates a stronger involvement of nerve fibres (neuropathic component). Women not only experience greater itch intensity, they are also more distracted by the itching than men are. This indicates a different cerebral perception and modulation. Sex-/genderspecific differences in regard to itching need further investigation in order to be able to offer sex-/gender-specific diagnostics and tailor therapy to improve the clinical situation of the affected patients." (Autorenreferat

Probing the relevance of the hippocampus for conflict-induced memory improvement

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction

Early Affective Processing in Patients with Acute Posttraumatic Stress Disorder: Magnetoencephalographic Correlates

Background: In chronic PTSD, a preattentive neural alarm system responds rapidly to emotional information, leading to increased prefrontal cortex (PFC) activation at early processing stages (<100 ms). Enhanced PFC responses are followed by a reduction in occipito-temporal activity during later processing stages. However, it remains unknown if this neuronal pattern is a result of a long lasting mental disorder or if it represents changes in brain function as direct consequences of severe trauma.Methodology: The present study investigates early fear network activity in acutely traumatized patients with PTSD. It focuses on the question whether dysfunctions previously observed in chronic PTSD patients are already present shortly after trauma exposure. We recorded neuromagnetic activity towards emotional pictures in seven acutely traumatized PTSD patients between one and seven weeks after trauma exposure and compared brain responses to a balanced healthy control sample. Inverse modelling served for mapping sources of differential activation in the brain.Principal Findings: Compared to the control group, acutely traumatized PTSD patients showed an enhanced PFC response to high-arousing pictures between 60 to 80 ms. This rapid prefrontal hypervigilance towards arousing pictorial stimuli was sustained during 120–300 ms, where it was accompanied by a reduced affective modulation of occipito-temporal neural processing.Conclusions: Our findings indicate that the hypervigilance-avoidance pattern seen in chronic PTSD is not necessarily a product of an endured mental disorder, but arises as an almost immediate result of severe traumatisation. Thus, traumatic experiences can influence emotion processing strongly, leading to long-lasting changes in trauma network activation and expediting a chronic manifestation of maladaptive cognitive and behavioral symptoms

Sex Differences in Itch Perception and Modulation by Distraction – an fMRI Pilot Study in Healthy Volunteers

Background: Even though itch is a common syndrome of many diseases there is only little knowledge about sex and gender differences in pruritus, especially in central itch perception and modulation. To our knowledge, this is the first fMRI study examining sex differences in perception and its modulation by distraction. Methods: Experimental itch was induced by application of histamine (0.1 mM) via microdialysis fibers twice at the left forearm and twice at the left lower leg in 33 healthy volunteers (17 females, 16 males). The brain activation patterns were assessed by fMRI during itch without and with distraction (Stroop task). Between the various conditions, subjects were asked to rate itch intensity, desire to scratch and pain intensity. In a second experiment in 10 of the 33 volunteers histamine was replaced by saline solution to serve as control for the ‘Stroop’ condition. Results: Women generally presented higher itch intensities compared to men during itch over the course of the experiment. A more specific analysis revealed higher itch intensities and desire to scratch in women during experimental induced itch that can be reduced by distraction at the lower legs when itch is followed by ‘Stroop’. In contrast, men depicted significant reduction of ‘itch’ by ‘Stroop’ at the forearms. Women depicted higher brain activation of structures responsible for integration of sensory, affective information and motor integration/planning during ‘itch’ and ‘Stroop’ condition when compared to men. No sex differences were seen in the saline control condition. Conclusion: Women and men exhibited localisation dependent differences in their itch perception with women presenting higher itch intensities and desire to scratch. Our findings parallel clinical observations of women reporting higher itch intensities depending on itch localisation and suffering more from itch as compared to men

Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus

BackgroundChronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch–scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification.AimThe aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli.MethodsAnalyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch.ResultsAnalysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification.ConclusionOur results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch