Center for Behavioral Brain Sciences

The development of magnetic resonance imaging (MRI) techniques has defined modern neuroimaging. Since its inception, tens of thousands of studies using techniques such as functional MRI and diffusion weighted imaging have allowed for the non-invasive study of the brain. Despite the fact that MRI is routinely used to obtain data for neuroscience research, there has been no widely adopted standard for organizing and describing the data collected in an imaging experiment. This renders sharing and reusing data (within or between labs) difficult if not impossible and unnecessarily complicates the application of automatic pipelines and quality assurance protocols. To solve this problem, we have developed the Brain Imaging Data Structure (BIDS), a standard for organizing and describing MRI datasets. The BIDS standard uses file formats compatible with existing software, unifies the majority of practices already common in the field, and captures the metadata necessary for most common data processing operations.

Abstract Developmental changes were examined in the associations among physical and relational aggression, and sociometric and perceived popularity based on peer nominations. Participating in the longitudinal study were 905 children (440 girls, 465 boys) from ages 10 to 14. Associations between the forms of status and between the forms of aggression decreased over time. Relational aggression increasingly predicted high social prominence but low social preference; physical aggression was increasingly less disliked but decreasingly predictive of prominence. The effect of relational aggression on perceived popularity was strong for girls. Perceived popularity preceded physical and relational aggression for both genders. Implications for the attainment of high status, processes of peer influence on antisocial behavior, and gender differences in the meaning of status are discussed.

Successful goal-directed behavior requires not only correct action selection, planning, and execution but also the ability to flexibly adapt behavior when performance problems occur or the environment changes. A prerequisite for determining the necessity, type, and magnitude of adjustments is to continuously monitor the course and outcome of one's actions. Feedback-control loops correcting deviations from intended states constitute a basic functional principle of adaptation at all levels of the nervous system. Here, we review the neurophysiology of evaluating action course and outcome with respect to their valence, i.e., reward and punishment, and initiating short- and long-term adaptations, learning, and decisions. Based on studies in humans and other mammals, we outline the physiological principles of performance monitoring and subsequent cognitive, motivational, autonomic, and behavioral adaptation and link them to the underlying neuroanatomy, neurochemistry, psychological theories, and computational models. We provide an overview of invasive and noninvasive systemic measures, such as electrophysiological, neuroimaging, and lesion data. We describe how a wide network of brain areas encompassing frontal cortices, basal ganglia, thalamus, and monoaminergic brain stem nuclei detects and evaluates deviations of actual from predicted states indicating changed action costs or outcomes. This information is used to learn and update stimulus and action values, guide action selection, and recruit adaptive mechanisms that compensate errors and optimize goal achievement.

Magnetic resonance imaging and spectroscopic techniques are widely used in humans both for clinical diagnostic applications and in basic research areas such as cognitive neuroimaging. In recent years, new human MR systems have become available operating at static magnetic fields of 7 T or higher (≥300 MHz proton frequency). Imaging human-sized objects at such high frequencies presents several challenges including non-uniform radiofrequency fields, enhanced susceptibility artifacts, and higher radiofrequency energy deposition in the tissue. On the other side of the scale are gains in signal-to-noise or contrast-to-noise ratio that allow finer structures to be visualized and smaller physiological effects to be detected. This review presents an overview of some of the latest methodological developments in human ultra-high field MRI/MRS as well as associated clinical and scientific applications. Emphasis is given to techniques that particularly benefit from the changing physical characteristics at high magnetic fields, including susceptibility-weighted imaging and phase-contrast techniques, imaging with X-nuclei, MR spectroscopy, CEST imaging, as well as functional MRI. In addition, more general methodological developments such as parallel transmission and motion correction will be discussed that are required to leverage the full potential of higher magnetic fields, and an overview of relevant physiological considerations of human high magnetic field exposure is provided.

For cognitive processes to function well, it is essential that the brain is optimally supplied with oxygen and blood. In recent years, evidence has emerged suggesting that cerebral oxygenation and hemodynamics can be modified with physical activity. To better understand the relationship between cerebral oxygenation/hemodynamics, physical activity, and cognition, the application of state-of-the art neuroimaging tools is essential. Functional near-infrared spectroscopy (fNIRS) is such a neuroimaging tool especially suitable to investigate the effects of physical activity/exercises on cerebral oxygenation and hemodynamics due to its capability to quantify changes in the concentration of oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin (deoxyHb) non-invasively in the human brain. However, currently there is no clear standardized procedure regarding the application, data processing, and data analysis of fNIRS, and there is a large heterogeneity regarding how fNIRS is applied in the field of exercise⁻cognition science. Therefore, this review aims to summarize the current methodological knowledge about fNIRS application in studies measuring the cortical hemodynamic responses during cognitive testing (i) prior and after different physical activities interventions, and (ii) in cross-sectional studies accounting for the physical fitness level of their participants. Based on the review of the methodology of 35 as relevant considered publications, we outline recommendations for future fNIRS studies in the field of exercise⁻cognition science.

PURPOSE: Relaxation times, transmit homogeneity, signal-to-noise ratio (SNR) and parallel imaging g-factor were determined in the human brain at 3T, 7T, and 9.4T, using standard, tight-fitting coil arrays. METHODS: The same human subjects were scanned at all three field strengths, using identical sequence parameters and similar 31- or 32-channel receive coil arrays. The SNR of three-dimensional (3D) gradient echo images was determined using a multiple replica approach and corrected with measured flip angle and T2 (*) distributions and the T1 of white matter to obtain the intrinsic SNR. The g-factor maps were derived from 3D gradient echo images with several GRAPPA accelerations. RESULTS: As expected, T1 values increased, T2 (*) decreased and the B1 -homogeneity deteriorated with increasing field. The SNR showed a distinctly supralinear increase with field strength by a factor of 3.10 ± 0.20 from 3T to 7T, and 1.76 ± 0.13 from 7T to 9.4T over the entire cerebrum. The g-factors did not show the expected decrease, indicating a dominating role of coil design. CONCLUSION: In standard experimental conditions, SNR increased supralinearly with field strength (SNR ∼ B0 (1.65) ). To take full advantage of this gain, the deteriorating B1 -homogeneity and the decreasing T2 (*) have to be overcome.

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n=21) or to a control group (indoor progressive-muscle relaxation/stretching, n=19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here.

OBJECTIVE: We previously reported an unexpectedly high seroprevalence (~10%) of N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1) autoantibodies (AB) in healthy and neuropsychiatrically ill subjects (N = 2,817). This finding challenges an unambiguous causal relationship of serum AB with brain disease. To test whether similar results would be obtained for other brain antigen-directed AB previously connected with pathological conditions, we systematically screened serum samples of 4,236 individuals. METHODS: Serum samples of healthy (n = 1,703) versus neuropsychiatrically ill subjects (schizophrenia, affective disorders, stroke, Parkinson disease, amyotrophic lateral sclerosis, personality disorder; total n = 2,533) were tested. For analysis based on indirect immunofluorescence, we used biochip mosaics of frozen brain sections (rat, monkey) and transfected HEK293 cells expressing respective recombinant target antigens. RESULTS: Seroprevalence of all screened AB was comparable in healthy and ill individuals. None of them, however, reached the abundance of NMDAR1 AB (again ~10%; immunoglobulin [Ig] G ~1%). Appreciable frequency was noted for AB against amphiphysin (2.0%), ARHGAP26 (1.3%), CASPR2 (0.9%), MOG (0.8%), GAD65 (0.5%), Ma2 (0.5%), Yo (0.4%), and Ma1 (0.4%), with titers and Ig class distribution similar among groups. All other AB were found in ≤0.1% of individuals (anti-AMPAR-1/2, AQP4, CV2, Tr/DNER, DPPX-IF1, GABAR-B1/B2, GAD67, GLRA1b, GRM1, GRM5, Hu, LGl1, recoverin, Ri, ZIC4). The predominant Ig class depended on antigen location, with intracellular epitopes predisposing to IgG (chi-square = 218.91, p = 2.8 × 10(-48) ). INTERPRETATION: To conclude, the brain antigen-directed AB tested here are comparably detectable in healthy subjects and the disease groups studied here, thus questioning an upfront pathological role of these serum AB.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

BACKGROUND: During the aging process, physical capabilities (e.g., muscular strength) and cognitive functions (e.g., memory) gradually decrease. Regarding cognitive functions, substantial functional (e.g., compensatory brain activity) and structural changes (e.g., shrinking of the hippocampus) in the brain cause this decline. Notably, growing evidence points towards a relationship between cognition and measures of muscular strength and muscle mass. Based on this emerging evidence, resistance exercises and/or resistance training, which contributes to the preservation and augmentation of muscular strength and muscle mass, may trigger beneficial neurobiological processes and could be crucial for healthy aging that includes preservation of the brain and cognition. Compared with the multitude of studies that have investigated the influence of endurance exercises and/or endurance training on cognitive performance and brain structure, considerably less work has focused on the effects of resistance exercises and/or resistance training. While the available evidence regarding resistance exercise-induced changes in cognitive functions is pooled, the underlying neurobiological processes, such as functional and structural brain changes, have yet to be summarized. Hence, the purpose of this systematic review is to provide an overview of resistance exercise-induced functional and/or structural brain changes that are related to cognitive functions. METHODS AND RESULTS: A systematic literature search was conducted by two independent researchers across six electronic databases; 5957 records were returned, of which 18 were considered relevant and were analyzed. SHORT CONCLUSION: Based on our analyses, resistance exercises and resistance training evoked substantial functional brain changes, especially in the frontal lobe, which were accompanied by improvements in executive functions. Furthermore, resistance training led to lower white matter atrophy and smaller white matter lesion volumes. However, based on the relatively small number of studies available, the findings should be interpreted cautiously. Hence, future studies are required to investigate the underlying neurobiological mechanisms and to verify whether the positive findings can be confirmed and transferred to other needy cohorts, such as older adults with dementia, sarcopenia and/or dynapenia.

Progress in neuroscience relies on new techniques for investigating the complex dynamics of neuronal networks. An ongoing challenge is to achieve minimally invasive and high-resolution observations of neuronal activity in vivo inside deep brain areas. Recently introduced methods for holographic control of light propagation in complex media enable the use of a hair-thin multimode optical fibre as an ultranarrow imaging tool. Compared to endoscopes based on graded-index lenses or fibre bundles, this new approach offers a footprint reduction exceeding an order of magnitude, combined with a significant enhancement in resolution. We designed a compact and high-speed system for fluorescent imaging at the tip of a fibre, achieving a resolution of 1.18 ± 0.04 µm across a 50-µm field of view, yielding 7-kilopixel images at a rate of 3.5 frames/s. Furthermore, we demonstrate in vivo observations of cell bodies and processes of inhibitory neurons within deep layers of the visual cortex and hippocampus of anaesthetised mice. This study paves the way for modern microscopy to be applied deep inside tissues of living animal models while exerting a minimal impact on their structural and functional properties.

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC.

The topic of investigating how mindfulness meditation training can have antidepressant effects via plastic changes in both resting state and meditation state brain activity is important in the rapidly emerging field of neuroplasticity. In the present study, we used a longitudinal design investigating resting state fMRI both before and after 40 days of meditation training in 13 novices. After training, we compared differences in network connectivity between rest and meditation using common resting state functional connectivity methods. Interregional methods were paired with local measures such as Regional Homogeneity. As expected, significant differences in functional connectivity both between states (rest versus meditation) and between time points (before versus after training) were observed. During meditation, the internal consistency in the precuneus and the temporoparietal junction increased, while the internal consistency of frontal brain regions decreased. A follow-up analysis of regional connectivity of the dorsal anterior cingulate cortex further revealed reduced connectivity with anterior insula during meditation. After meditation training, reduced resting state functional connectivity between the pregenual anterior cingulate and dorsal medical prefrontal cortex was observed. Most importantly, significantly reduced depression/anxiety scores were observed after training. Hence, these findings suggest that mindfulness meditation might be of therapeutic use by inducing plasticity related network changes altering the neuronal basis of affective disorders such as depression.

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

The demographic change in industrial countries, with increasingly sedentary lifestyles, has a negative impact on mental health. Normal and pathological aging leads to cognitive deficits. This development poses major challenges on national health systems. Therefore, it is necessary to develop efficient cognitive enhancement strategies. The combination of regular physical exercise with cognitive stimulation seems especially suited to increase an individual’s cognitive reserve, i.e. his/her resistance to degenerative processes of the brain. Here, we outline insufficiently explored fields in exercise-cognition research and provide a classification approach for different motor-cognitive training regimens. We suggest to classify motor-cognitive training in two categories, (I) sequential motor-cognitive training (the motor and cognitive training are conducted time separated) and (II) simultaneous motor-cognitive training (motor and cognitive training are conducted sequentially). In addition, simultaneous motor-cognitive training may be distinguished based on the specific characteristics of the cognitive task. If successfully solving the cognitive task is not a relevant prerequisite to complete the motor-cognitive task, we would consider this type of training as (IIa) motor-cognitive training with additional cognitive task. In contrast, in ecologically more valid (IIb) motor cognitive training with incorporated cognitive task, the cognitive tasks is a relevant prerequisite to solve the motor-cognitive task. We speculate that incorporating cognitive tasks into motor tasks, rather than separate training of mental and physical functions, is the most promising approach to efficiently enhance cognitive reserve. Further research investigating the influence of motor(-cognitive) exercises with different quantitative and qualitative characteristics on cognitive performance is urgently needed.

Animal research indicates that a combination of physical activity and sensory enrichment has the largest and the only sustaining effect on adult neuroplasticity. Dancing has been suggested as a human homologue to this combined intervention as it poses demands on both physical and cognitive functions. For the present exploratory study, we designed an especially challenging dance program in which our elderly participants constantly had to learn novel and increasingly difficult choreographies. This six-month-long program was compared to conventional fitness training matched for intensity. An extensive pre/post-assessment was performed on the 38 participants (63-80 y), covering general cognition, attention, memory, postural and cardio-respiratory performance, neurotrophic factors and-most crucially-structural MRI using an exploratory analysis. For analysis of MRI data, a new method of voxel-based morphometry (VBM) designed specifically for pairwise longitudinal group comparisons was employed. Both interventions increased physical fitness to the same extent. Pronounced differences were seen in the effects on brain volumes: Dancing compared to conventional fitness activity led to larger volume increases in more brain areas, including the cingulate cortex, insula, corpus callosum and sensorimotor cortex. Only dancing was associated with an increase in plasma BDNF levels. Regarding cognition, both groups improved in attention and spatial memory, but no significant group differences emerged. The latter finding may indicate that cognitive benefits may develop later and after structural brain changes have taken place. The present results recommend our challenging dance program as an effective measure to counteract detrimental effects of aging on the brain.

The thalamus, a crucial node in the well-described cortico-striatal-thalamo-cortical circuits, has been the focus of functional and structural imaging studies investigating human emotion, cognition and memory. Invasive work in animals and post-mortem investigations have revealed the rich cytoarchitectonics and functional specificity of the thalamus. Given current restrictions in the spatial resolution of non-invasive imaging modalities, there is, however, a translational gap between functional and structural information on these circuits in humans and animals as well as between histological and cellular evidence and their relationship to psychological functioning. With the advance of higher field strengths for MR approaches, better spatial resolution is now available promising to overcome this conceptual problem. We here review these two levels, which exist for both neuroscientific and clinical investigations, and then focus on current attempts to overcome conceptual boundaries of these observations with the help of ultra-high resolution imaging.

Accumulating evidence from animal and human studies supports the notion that physical exercise can enhance neuroplasticity and thus reduce the risk of several neurodegenerative diseases (e.g., dementia). However, the underlying neurobiological mechanisms of exercise induced neuroplasticity are still largely unknown. One potential mediator of exercise effects is the neurotrophin BDNF, which enhances neuroplasticity via different pathways (e.g., synaptogenesis, neurogenesis, long-term potentiation). Current research has shown that (i) increased peripheral lactate levels (following high intensity exercise) are associated with increased peripheral BDNF levels, (ii) lactate infusion at rest can increase peripheral and central BDNF levels and (iii) lactate plays a very complex role in the brain's metabolism. In this review, we summarize the role and relationship of lactate and BDNF in exercise induced neuroplasticity.