Central Institute for Mental Health

Mannheim, Germany

Central Institute for Mental Health

Mannheim, Germany
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Melcher T.,August Research Systems | Winter D.,August Research Systems | Winter D.,Central Institute for Mental Health | Hommel B.,Leiden University | And 4 more authors.
Neuroscience | Year: 2013

Ideomotor theory holds that the perception or anticipatory imagination of action effects activates motor tendencies toward the action that is known to produce these effects, herein referred to as ideomotor response activation (IRA). IRA presupposes that the agent has previously learned which action produces which effects, and that this learning process has created bidirectional associations between the sensory effect codes and the motor codes producing the sensory effects. Here, we refer to this process as ideomotor learning. In the presented fMRI study, we adopted a standard two-phase ideomotor learning paradigm; a mixed between/within-subjects design allowed us to assess the neural substrate of both, IRA and ideomotor learning. We replicated earlier findings of a hand asymmetry in ideomotor processing with significantly stronger IRA by left-hand than right-hand action effects. Crucially, we traced this effect back to more pronounced associative learning for action-contingent effects of the left hand compared with effects of the right hand. In this context, our findings point to the caudate nucleus and the angular gyrus as central structures of the neural network underlying ideomotor learning. © 2012 IBRO.


Millan M.J.,Institute Of Recherche Idr Servier | Andrieux A.,Grenoble Institute des Neurosciences | Bartzokis G.,University of California at Los Angeles | Cadenhead K.,University of California at San Diego | And 21 more authors.
Nature Reviews Drug Discovery | Year: 2016

Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to-and of-this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia. © 2016 Macmillan Publishers Limited. All rights reserved.


Maier S.,Section for Experimental Neuropsychiatry | Perlov E.,Section for Experimental Neuropsychiatry | Graf E.,Albert Ludwigs University of Freiburg | Dieter E.,Section for Experimental Neuropsychiatry | And 8 more authors.
Biological Psychiatry | Year: 2016

Background Gray matter reduction mainly in the anterior cingulate cortex, the basal ganglia, and the cerebellum has been reported in attention-deficit/hyperactivity disorder (ADHD). Yet, respective data remain contradictory and inconclusive. To clarify if structural alteration in these brain areas can be verified in a large cohort of adult patients and if a history of stimulant medication has an effect on brain structure, magnetic resonance imaging was performed in the context of a clinical trial on the efficacy of group psychotherapy, clinical management, methylphenidate, and placebo (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study Trial). Methods Between January 2007 and August 2010, 1480 patients from seven study centers across Germany, aged 18 to 58, were prescreened; 518 were assessed for eligibility; 433 were randomized; and 187 were eligible for neuroimaging. The control group included 121 healthy volunteers. Structural magnetic resonance imaging data sets were acquired. Following strict quality control, 131 patient and 95 control data sets could be analyzed. All patients were unmedicated for at least 6 months. The established method of voxel-based morphometry (VBM8 segmentation and diffeomorphic anatomical registration through exponentiated lie normalization) was used to assess global and regional brain volumes. Results Patients displayed subtle global cerebral volume reductions. There was no evidence of regional gray matter volume abnormalities. The inattentive ADHD subtype was linked to smaller volumes in the left dorsolateral prefrontal cortex. A history of previous medication did not modulate brain volumes. Conclusions ADHD in adulthood is associated with global rather than regional volumetric abnormalities. Previous use of stimulant medication does not seem to modify subsequent brain volumes in a significant way. © 2015 Society of Biological Psychiatry.


Macher K.,Max Planck Institute for Human Cognitive and Brain Sciences | Bohringer A.,Central Institute for Mental Health | Villringer A.,Max Planck Institute for Human Cognitive and Brain Sciences | Villringer A.,Mind and Brain Institute | And 3 more authors.
Journal of Neuroscience | Year: 2014

Previous research has accumulated convincing evidence to show that the human cerebellum contributes to the short-term storage of verbal information, but its specific role in brain networks involved in phonological storage remains uncertain. In a randomized, crossover and sham-controlled design, we here combined transcranial direct current stimulation (tDCS), applied to the right cerebellum, with fMRI to investigate systematically the contribution of the human cerebellum to encoding, maintenance, and retrieval of verbal information. After anodal, but not cathodal, tDCS, we found a reduced item recognition capacity together with an attenuated neural signal from the right cerebellar lobule VIIb, specifically during the late encoding phase. Within this phase, tDCS furthermore affected task-associated functional connections between right cerebellar lobule VIIb and the posterior parietal cortex. These findings suggest that the right cerebellar lobule VIIb interacts with the posterior parietal cortex, specifically during the late stages of verbal encoding, when verbal information enters phonological storage. © 2014 the authors.


Hermann D.,Central Institute for Mental Health | Weber-Fahr W.,Central Institute for Mental Health | Sartorius A.,Central Institute for Mental Health | Hoerst M.,Central Institute for Mental Health | And 10 more authors.
Biological Psychiatry | Year: 2012

Background: In alcoholism, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome and as a key signal for dependence-related neuroplasticity. Our understanding of this pathophysiological mechanism originates largely from animal studies, but human data are needed for translation into successful medication development. Methods: We measured brain glutamate levels during detoxification in alcohol-dependent patients (n = 47) and in healthy control subjects (n = 57) as well as in a rat model of alcoholism by state-of-the-art 1H-magnetic magnetic resonance spectroscopy at 3 and 9.4 T, respectively. Results: We found significantly increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions of treatment-seeking alcoholic patients and alcohol-dependent rats versus respective control subjects. The augmented spectroscopic glutamate signal is likely related to increased glutamatergic neurotransmission because, enabled by the high field strength of the animal scanner, we detected a profoundly elevated glutamate/glutamine ratio in alcohol-dependent rats during acute withdrawal. All dependence-induced metabolic alterations normalize within a few weeks of abstinence in both humans and rats. Conclusions: Our data provide first-time direct support from humans for the glutamate hypothesis of alcoholism, demonstrate the comparability of human and animal magnetic resonance spectroscopy responses, and identify the glutamate/glutamine ratio as potential biomarker for monitoring disease progression. © 2012 Society of Biological Psychiatry.


Skirrow C.,King's College London | Skirrow C.,University College London | Ebner-Priemer U.,Karlsruhe Institute of Technology | Ebner-Priemer U.,Central Institute for Mental Health | And 4 more authors.
Psychological Medicine | Year: 2014

Background. Emotional lability (EL), characterized by negative emotional traits and emotional instability, is frequently reported in children and adults with attention deficit hyperactivity disorder (ADHD). However, EL is primarily assessed using retrospective self-report, which is subject to reporting bias and does not consider the potential influence of positive and negative everyday experiences.Results. The ADHD group reported significantly more frequent bad events, heightened intensity and instability of irritability and frustration, and greater intensity of anger. The results for positive emotions were equivocal or negative. Bad events significantly contributed to the intensity and instability of negative emotions, and showed a stronger influence in the ADHD group. However, covariation for their effect did not eliminate group differences. Small-to-moderate correlations were seen between intensity and instability of negative emotions and the ALS-SF.Conclusions. Adults with ADHD report heightened intensity and instability of negative emotions in daily life. The results suggest two components of EL in ADHD: a reactive component responsive to bad events and an endogenous component, independent of negative everyday events.Method. Ambulatory assessment was carried out in 41 men with ADHD without co-morbidity, current medication or substance abuse, and 47 healthy control participants. Reports of negative and positive emotions (irritability, frustration, anger, happiness, excitement) and the occurrence of bad and good events were completed eight times daily during a working week. Group differences in emotional intensity and instability were investigated using multilevel models, and explored in relation to bad and good events and the Affective Lability Scale - Short Form (ALS-SF), an EL questionnaire. Copyright © 2014 Cambridge University Press.


Spanagel R.,University of Heidelberg | Vengeliene V.,University of Heidelberg | Jandeleit B.,Xenoport | Fischer W.-N.,Xenoport | And 6 more authors.
Neuropsychopharmacology | Year: 2014

Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral - calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking, or relapse-like drinking behavior, we demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence, the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosate-like effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation, we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.


News Article | October 12, 2016
Site: www.nature.com

On an ice-cold day in January, clinical psychologist Emily Holmes picked up a stack of empty diaries and went down to Stockholm’s central train station in search of refugees. She didn’t have to look hard. Crowds of lost-looking young people were milling around the concourse, in clothes too flimsy for the freezing air. “It struck me hard to see how thin some of the young men were,” she says. Holmes, who works at Stockholm’s Karolinska Institute, was seeking help with her research — a pilot project on post-traumatic stress disorder (PTSD), which is all too common in refugees. She wanted to see whether they would be willing to spend a week noting down any flashbacks — fragmented memories of a trauma that rush unbidden into the mind and torment those with PTSD. She easily found volunteers. And when they returned the diaries, Holmes was shocked to see that they reported an average of two a day — many more than the PTSD sufferers she routinely dealt with. “My heart went out to them,” she says. “They managed to travel thousands of kilometres to find their way to safety with this level of symptoms.” Europe is experiencing the largest movement of people since the Second World War. Last year, more than 1.2 million people applied for asylum in the European Union — and those numbers underestimate the scale of the problem. Germany, which has taken in the lion’s share of people, reckons that it received more than a million refugees in 2015, tens of thousands of whom have yet to officially apply for asylum. Most came from Syria, Afghanistan and Iraq. Many have experienced war, shock, upheaval and terrible journeys, and they often have poor physical health. The crisis has attracted global attention and sparked political tension as countries struggle to accommodate and integrate the influx. What hasn’t been widely discussed is the enormous burden of mental-health disorders in migrants and refugees. Clinical psychologist Thomas Elbert from the University of Konstanz in Germany is conducting a local survey of refugees that suggests “more than half of those who arrived in Germany in the last few years show signs of mental disorder, and a quarter of them have a PTSD, anxiety or depression that won’t get better without help”. Previous research shows that refugees and migrants are also at a slightly increased risk of developing schizophrenia. “It is a public-health tragedy — and it’s a scandal that it is not recognized as such, as a physical epidemic would be,” says epidemiologist James Kirkbride of University College London. Doctors and researchers are starting to take action. Holmes and other psychologists and psychiatrists are working with refugees to develop practical, cheap and effective therapies for trauma-related disorders — therapies that could be quickly deployed on this group. Other scientists want to work with local refugees to understand more about how the different types of stresses they suffer play out in their brains, and to learn more about the basic biology of psychiatric disorders. Scientists hope that their studies will help them to deal with other displaced populations, and help policymakers to accommodate the current influx. Politicians have been too slow to consider mental health when they call for refugees to integrate quickly, Elbert says. “It is illusory to think that people can learn a new language and find work when they can’t function properly mentally. If we want quick integration, we need an immediate plan for mental health.” Amira is a clinical psychologist and a refugee from Syria. When the war there started, she worked in camps for Syrian refugees in Jordan. She saw people who had been physically attacked, women who had been raped and children who had been neglected. The symptoms of PTSD were clear, and she knows that many refugees have depression and anxiety, too. She asked that her real name not be used. She arrived in Sweden at the end of December 2015, and wanted to help other refugees but was not allowed to work at first. She tried to make contacts in Stockholm and joined a language course for refugees; she felt very alone but carried on. Now, she has a 6-month position. “I met many children who have experienced war,” she says. “We feel sad, [about] how our children think and how they feel. I have a child and I try to protect him.” Researchers already have a wealth of evidence about the mental health of migrant and refugee populations around the world. (The United Nations defines refugees as people fleeing armed conflict or persecution and migrants as people who choose to move to improve their lives. Asylum seekers are those seeking official refugee status; but sometimes different definitions are used.) A 2005 meta-analysis of studies performed mostly in northern Europe showed that first- and second-generation migrants were at much greater risk of schizophrenia than non-migrants — and that those from developing countries were more at risk than those from developed ones1 . A large cohort study published in March looked at 1.3 million people who had arrived in Sweden before 2011 (see ‘Migrant crisis’). Refugees had a threefold higher incidence of schizophrenia and other psychotic disorders than native-born Swedes, and a 66% higher incidence than migrants who were not refugees2. (The overall risk for refugees and migrants still remains comparatively low, at perhaps 2–3%.) Kirkbride, an author on the study, says that his team’s more recent analysis of UK migration data suggests that the level of increased risk of psychotic disorders may depend on how old people were when they migrated — with children potentially at greater risk. Those who stand out most seem to be particularly vulnerable. The 2005 meta-analysis showed that black migrants in a mostly white population had an almost fivefold increased risk of psychotic disorders1. And the risk is higher for migrants living in neighbourhoods with a low proportion of residents from their own ethnic group compared with those surrounded by many of their own ethnicity3. Psychiatrist Andreas Meyer-Lindenberg from the Central Institute for Mental Health in Mannheim, Germany, is one of those trying to understand the brain mechanisms involved. He has already studied other populations with an above-average risk of psychosis, such as city dwellers4 and ethnic minorities5. The work suggested that the brains of these people are overly sensitive to social stress, such as a stream of disapproving feedback. Thanks to a grant awarded last month from the state government of Baden-Württemberg, Meyer-Lindenberg plans to extend his studies by recruiting 200 refugees and 200 people from the local community. The refugees will use smartphones to note their state of mind — such as feelings of suspiciousness — and they will later receive brain scans. The eventual aim is to find patterns in the data that indicate people with abnormal processing of social stress, who may therefore be at increased risk of mental illness. Jean-Paul Selten, a psychiatrist at Maastricht University in the Netherlands, is also exploring the poisonous nature of social stress. He proposes that pressures such as social exclusion raise the risk of psychosis by changing the brain’s sensitivity to the neurotransmitter dopamine6. Germany’s integration plans, consolidated in a law that came into force in August, involve distributing refugees across the country to avoid the creation of large, isolated ethnic communities. That could be problematic if it increases people’s isolation, but Meyer-Lindenberg says it’s “actually a good policy” — because other people in the community get to know refugees, and this usually reduces xenophobia, another major source of social stress. Politicians consider integration to be essential for security, among other things. A handful of terrorist attacks in Europe over the past two years have been carried out by refugees or others with a migrant background who had been known to have a history of psychiatric problems. But doctors and researchers are extremely wary about making a link between refugees or migrants and terrorist acts, pointing out that very few of those with mental-health problems become violent, regardless of their origins. The security concern simply accentuates the need to help all those with mental-health problems across the population, they say. Psychologists recognize three windows of extreme stress for refugees: the often violent traumas in their home countries that led to their flight; the journey itself; and the arrival, when people are thrust into a foreign country. “The latter ‘post-migration’ phase is becoming increasingly important,” says psychiatrist Malek Bajbouj from the Charité university hospital in Berlin. “Suddenly they realize they have lost everything, have no control over aspects of their lives and no social standing.” In February, Bajbouj — who is of Syrian descent and speaks Arabic — and two colleagues from other departments opened a clearing centre for refugees with mental-health problems, the first of its kind in Germany. It’s a quiet building, a former hospital in the centre of Berlin — but already 1,500 troubled people have passed through its doors. “Refugees may arrive in Germany with great hope, but then find themselves stuck for months in camps with no apparent prospects,” he says. “When we ask them what their greatest stressors are, they typically refer not to their traumatic memories, but to their current frustrations.” The biggest challenge for Bajbouj and others is the sheer volume of people in need of help. They must be assisted quickly and cheaply, in ways that take the pressure off overstretched health professionals. At the clearing centre, three psychiatrists assess visitors rapidly, categorizing them into those who require low-level or more-intensive psychiatric help and those who can be aided by social workers. A lot of effort goes into teaching about stress management and the science behind mental health. “Some people from rural areas hold the Djinn responsible for their moods,” says Bajbouj, “and we teach them that symptoms like sleeplessness and depression are biologically based and can be treated.” Elbert wants to see similar triage systems put in place across Germany. In a paper to be published next month, he and a group of colleagues call for a three-tiered approach. Refugees would initially be helped by bilingual laypeople — ideally migrants or refugees themselves — who are trained to guide people through the German health system (tier one) or to offer trauma counselling (tier two). Those in most need would progress to tier three: qualified psychologists or psychiatrists. Training laypeople seems to work in emergency situations. Elbert, together with Sarah Ayoughi, a clinical psychologist from the psycho­social-care organization Ipso, carried out a randomized controlled study of people with mental-health conditions in north Afghanistan who received psychosocial counselling — a type of talking therapy — conducted by local physicians who had no previous education in psychology or psychiatry, but who were specially trained for the trial. Just 5–8 sessions improved symptoms of depression and anxiety for up to 3 months7. And several studies, including a 2011 randomized controlled trial of former child soldiers in northern Uganda8, show that an approach called narration exposure therapy (NET), carried out by trained lay counsellors, can reduce the severity of PTSD symptoms. Elbert started developing NET with his wife Maggie Schauer, also a clinical psychologist at the University of Konstanz, when they were working with refugees in Kosovo in the late 1990s. It exploits new understanding of how memories are linked with fear circuitry in the brain. A traumatized person works with a therapist or counsellor to construct a narrative of their lives and anchor their traumatic experiences in the correct time and place. Pragmatic as the three-tiered approach may sound, it won’t be simple to introduce in Germany. Professional associations are resistant to allowing people without formal qualifications to help out with psychotherapies, and various regulations could get in the way. But while the federal government ponders what to do, some programmes are starting up with regional government support. Schauer has received €100,000 (US$112,000) to test whether NET works as well on refugees in Germany as it has in war-torn countries. And Ayoughi is organizing the training of refugees in Erfurt in Germany, with additional support from the Google Foundation. Bajbouj thinks that the political desire to get refugees into the workforce fast may end up easing the way for more relaxed rules about psychotherapy. And there is another way to deliver inexpensive mental-health care: through the Internet and apps. He is developing an Arabic-language version of the smartphone app PTSD Coach, which provides education, a personalized emergency plan, self-assessment and 25 different techniques to regulate stress. He is testing it in the Arab Outpatient Centre he opened at the Charité in 2008. In Stockholm, Holmes also hopes that technology can help. The aim of her work is to test whether it’s possible to subdue PTSD-linked emotional flashbacks if a person immediately plays a video game on their phone that competes for cognitive space in the brain — a technique that she has seen work in laboratory tests9. “The important thing now is to develop simple new approaches to therapy that can be scaled up, and to prove that they help,” she says. Sweden, which has taken in a relatively large number of refugees, is also starting mental-health programmes. Early this year, local authorities rolled out a plan to make it easier for refugees to access support: health checks will include more questions about states of mind, and those recognized as being in need will be channelled towards psychological or psychiatric support. The flow of refugees and migrants has eased this year, in part because Turkey has agreed to take back those who illegally entered EU countries from there. But people keep coming. This August, more than 18,000 refugees entered Germany to seek asylum. And even if the current crisis eases, conflict, poverty, natural catastrophe and climate change will inevitably drive fresh waves of migration around the world. “We’ve learnt lessons about mental health from crises in war-torn countries,” says Ayoughi, “and we can apply these in the refugee crisis in Europe now if we get the support.” Then, perhaps, lessons learnt in Europe could feed back to war zones. Bajbouj has been calling for a ‘migration think-tank’, a permanent institution in Germany where scientists of different disciplines can come together to work out what needs to be done. “The challenges are not just about mental health, but about education, integration into the work force and much more,” he says. “But mental health impacts everything.”


Bjork K.,Karolinska Institutet | Hansson A.C.,Central Institute for Mental Health | Sommer W.H.,Central Institute for Mental Health
International Review of Neurobiology | Year: 2010

Much research on experimental animals that is aimed to decipher genetic factors involved in alcoholism has been devoted to either models of innate alcohol-related phenotypes or responses after acute alcohol challenge. Such focus has, however, limitations when it comes to the pathogenetic mechanism underlying alcohol addiction, because the progression into the disorder takes years and genetic as well as environmental factors may exert different influences along this trajectory. Animal models of the neuroadaptations involved in the development of dependence exist, but have been difficult to implement for genetic and genomics analysis. Consequently, currently available data have been difficult to reconcile with the human condition and could be misleading in predicting targets for medication development. This review will illustrate strengths and pitfalls of genomic approaches in rodent models of alcoholism and emphasize the need for convergent lines of evidence to improve the predictive value of such studies. Examples of a convergent research approach include validation studies for Agt, Arrb2, Crhr1, Grin3a, and Npy. © 2010 Elsevier Inc.


Tretter F.,Kompetenzzentrum Sucht | Gebicke-Haerter P.J.,Central Institute for Mental Health
Methods in Molecular Biology | Year: 2012

The classification of psychiatric disorders has always been a problem in clinical settings. The present debate about the major systems in clinical practice, DSM-IV and ICD-10, has resulted in attempts to improve and replace those schemes by some that include more endophenotypic and molecular features. However, these disorders not only require more precise diagnostic tools, but also have to be viewed more extensively in their dynamic behaviors, which require more precise data sets related to their origins and developments. This enormous challenge in brain research has to be approached on different levels of the biological system by new methods, including improvements in electroencephalography, brain imaging, and molecular biology. All these methods entail accumulations of large data sets that become more and more difficult to interpret. In particular, on the molecular level, there is an apparent need to use highly sophisticated computer programs to tackle these problems. Evidently, only interdisciplinary work among mathematicians, physicists, biologists, and clinicians can further improve our understanding of complex diseases of the brain. © 2012 Springer Science+Business Media, LLC.

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