Training intervention effects on cognitive performance and neuronal plasticity-A pilot study.

Studies suggest that people suffering from chronic pain may have altered brain plasticity, along with altered functional connectivity between pain-processing brain regions. These may be related to decreased mood and cognitive performance. There is some debate as to whether physical activity combined with behavioral therapy (e.g. cognitive distraction, body scan) may counteract these changes. However, underlying neuronal mechanisms are unclear. The aim of the current pilot study with a 3-armed randomized controlled trial design was to examine the effects of sensorimotor training for nonspecific chronic low back pain on (1) cognitive performance; (2) fMRI activity co-fluctuations (functional connectivity) between pain-related brain regions; and (3) the relationship between functional connectivity and subjective variables (pain and depression). Six hundred and sixty two volunteers with non-specific chronic low back pain were randomly allocated to a unimodal (sensorimotor training), multidisciplinary (sensorimotor training and behavioral therapy) intervention, or to a control group within a multicenter study. A subsample of patients (n = 21) from one study center participated in the pilot study presented here. Measurements were at baseline, during (3 weeks, M2) and after intervention (12 weeks, M4 and 24 weeks, M5). Cognitive performance was measured by the Trail Making Test and functional connectivity by MRI. Pain perception and depression were assessed by the Von Korff questionnaire and the Hospital and Anxiety. Group differences were calculated by univariate and repeated ANOVA measures and Bayesian statistics; correlations by Pearson's r. Change and correlation of functional connection were analyzed within a pooled intervention group (uni-, multidisciplinary group). Results revealed that participants with increased pain intensity at baseline showed higher functional connectivity between pain-related brain areas used as ROIs in this study. Though small sample sizes limit generalization, cognitive performance increased in the multimodal group. Increased functional connectivity was observed in participants with increased pain ratings. Pain ratings and connectivity in pain-related brain regions decreased after the intervention. The results provide preliminary indication that intervention effects can potentially be achieved on the cognitive and neuronal level. The intervention may be suitable for therapy and prevention of non-specific chronic low back pain.

Regular Physical Activity, Short-Term Exercise, Mental Health, and Well-Being Among University Students: The Results of an Online and a Laboratory Study.

The health benefits of regular physical activity and aerobic exercise are undisputed in the literature. The present series of pilot studies had two major objectives: (a) examine mental health, well-being, and regular physical activity of university students and (b) explore the potential health benefits of short-term aerobic exercise on university students in an online and a laboratory study. Mental health and well-being were measured before (Time 1, T1) and after (Time 2, T2) a 6 week (online study) and 2 week (laboratory study) low- to moderate-intensity aerobic exercise intervention. Mental health and well-being were assessed using standardized self-report measures of depression, anxiety, positive and negative affect, perceived stress and coping strategies, body dissatisfaction, and quality of life. The effects of the aerobic exercise were compared to a cognitive non-exercise control condition (online study), motor coordination exercise (laboratory study), and a waiting list (online and laboratory). A total of 185 university students were recruited from German universities at T1. Further, 74 (women: n = 67) students completed the 6-week intervention. Similarly, 32 (women: n = 30) participants completed the 2 week intervention (laboratory study). At T1, 36.6% of the students (women and men) reported experiencing depressive symptoms. 41.83% of them (women and men) had high levels of state anxiety. All the students reported experiencing stress (e.g., due to uncertainty related to factors such as their finances, job, and social relationships). At T1, regular physical activity was negatively correlated with self-reported depression, anxiety, and perceived psychosomatic stress and positively correlated with quality of life and positive affect. Among women, cardiovascular fitness (operationalized as resting heart rate variability) was negatively correlated with self-reported anxiety (state) and depression at T1 (laboratory study). The 6 week aerobic exercise intervention resulted in significant improvements in self-reported depression, overall perceived stress, and perceived stress due to uncertainty. The present results confirm that there is a relationship between regular physical activity, cardiovascular fitness, mental health, and well-being among university students. They support the hypothesis that short-term aerobic exercise interventions can act as buffer against depression and perceived stress in university students after 6 weeks of aerobic exercise of low to moderate intensity.

Anticipatory feelings: Neural correlates and linguistic markers.

This review introduces anticipatory feelings (AF) as a new construct related to the process of anticipation and prediction of future events. AF, defined as the state of awareness of physiological and neurocognitive changes that occur within an oganism in the form of a process of adapting to future events, are an important component of anticipation and expectancy. They encompass bodily-related interoceptive and affective components and are influenced by intrapersonal and dispositional factors, such as optimism, hope, pessimism, or worry. In the present review, we consider evidence from animal and human research, including neuroimaging studies, to characterize the brain structures and brain networks involved in AF. The majority of studies reviewed revealed three brain regions involved in future oriented feelings: 1) the insula; 2) the ventromedial prefrontal cortex (vmPFC); and 3) the amygdala. Moreover, these brain regions were confirmed by a meta-analysis, using a platform for large-scale, automated synthesis of fMRI data. Finally, by adopting a neurolinguistic and a big data approach, we illustrate how AF are expressed in language.

Stress and Alterations in the Pain Matrix: A Biopsychosocial Perspective on Back Pain and Its Prevention and Treatment.

The genesis of chronic pain is explained by a biopsychosocial model. It hypothesizes an interdependency between environmental and genetic factors provoking aberrant long-term changes in biological and psychological regulatory systems. Physiological effects of psychological and physical stressors may play a crucial role in these maladaptive processes. Specifically, long-term demands on the stress response system may moderate central pain processing and influence descending serotonergic and noradrenergic signals from the brainstem, regulating nociceptive processing at the spinal level. However, the underlying mechanisms of this pathophysiological interplay still remain unclear. This paper aims to shed light on possible pathways between physical (exercise) and psychological stress and the potential neurobiological consequences in the genesis and treatment of chronic pain, highlighting evolving concepts and promising research directions in the treatment of chronic pain. Two treatment forms (exercise and mindfulness-based stress reduction as exemplary therapies), their interaction, and the dose-response will be discussed in more detail, which might pave the way to a better understanding of alterations in the pain matrix and help to develop future prevention and therapeutic concepts.

Vascular-metabolic and GABAergic Inhibitory Correlates of Neural Variability Modulation. A Combined fMRI and PET Study.

Neural activity varies continually from moment to moment. Such temporal variability (TV) has been highlighted as a functionally specific brain property playing a fundamental role in cognition. We sought to investigate the mechanisms involved in TV changes between two basic behavioral states, namely having the eyes open (EO) or eyes closed (EC) in vivo in humans. To these ends we acquired BOLD fMRI, ASL, and [18F]-fluoro-deoxyglucose PET in a group of healthy participants (n = 15), along with BOLD fMRI and [18F]-flumazenil PET in a separate group (n = 19). Focusing on an EO- vs EC-sensitive region in the occipital cortex (identified in an independent sample), we show that TV is constrained in the EO condition compared to EC. This reduction is correlated with an increase in energy consumption and with regional GABAA receptor density. This suggests that the modulation of TV by behavioral state involves an increase in overall neural activity that is related to an increased effect from GABAergic inhibition in addition to any excitatory changes. These findings contribute to our understanding of the mechanisms underlying activity variability in the human brain and its control.

Negative childhood experiences alter a prefrontal-insular-motor cortical network in healthy adults: A preliminary multimodal rsfMRI-fMRI-MRS-dMRI study.

Research in humans and animals has shown that negative childhood experiences (NCE) can have long-term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brain's resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion-related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion-related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter-related brain systems. In particular, they highlight the role of a prefrontal-insular-motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs.

Neural activity during interoceptive awareness and its associations with alexithymia-An fMRI study in major depressive disorder and non-psychiatric controls.

OBJECTIVE: Alexithymia relates to difficulties recognizing and describing emotions. It has been linked to subjectively increased interoceptive awareness (IA) and to psychiatric illnesses such as major depressive disorder (MDD) and somatization. MDD in turn is characterized by aberrant emotion processing and IA on the subjective as well as on the neural level. However, a link between neural activity in response to IA and alexithymic traits in health and depression remains unclear. METHODS: A well-established fMRI task was used to investigate neural activity during IA (heartbeat counting) and exteroceptive awareness (tone counting) in non-psychiatric controls (NC) and MDD. Firstly, comparing MDD and NC, a linear relationship between IA-related activity and scores of the Toronto Alexithymia Scale (TAS) was investigated through whole-brain regression. Secondly, NC were divided by median-split of TAS scores into groups showing low (NC-low) or high (NC-high) alexithymia. MDD and NC-high showed equally high TAS scores. Subsequently, IA-related neural activity was compared on a whole-brain level between the three independent samples (MDD, NC-low, NC-high). RESULTS: Whole-brain regressions between MDD and NC revealed neural differences during IA as a function of TAS-DD (subscale difficulty describing feelings) in the supragenual anterior cingulate cortex (sACC; BA 24/32), which were due to negative associations between TAS-DD and IA-related activity in NC. Contrasting NC subgroups after median-split on a whole-brain level, high TAS scores were associated with decreased neural activity during IA in the sACC and increased insula activity. Though having equally high alexithymia scores, NC-high showed increased insula activity during IA compared to MDD, whilst both groups showed decreased activity in the sACC. CONCLUSIONS: Within the context of decreased sACC activity during IA in alexithymia (NC-high and MDD), increased insula activity might mirror a compensatory mechanism in NC-high, which is disrupted in MDD.

Increase in glutamate/glutamine concentration in the medial prefrontal cortex during mental imagery: A combined functional mrs and fMRI study.

Recent functional magnetic resonance spectroscopy (fMRS) studies have shown changes in glutamate/glutamine (Glx) concentrations between resting-state and active-task conditions. However, the types of task used have been limited to sensory paradigms, and the regions from which Glx concentrations have been measured limited to sensory ones. This leaves open the question as to whether the same effect can be seen in higher-order brain regions during cognitive tasks. Cortical midline structures, especially the medial prefrontal cortex (MPFC), have been suggested to be involved in various such cognitive tasks. We, therefore set out to use fMRS to investigate the dynamics of Glx concentrations in the MPFC between resting-state and mental imagery task conditions. The auditory cortex was used as a control region. In addition, functional magnetic resonance imaging was used to explore task-related neural activity changes. The mental imagery task consisted of imagining swimming and was applied to a large sample of healthy participants (n = 46). The participants were all competitive swimmers, ensuring proficiency in mental-swimming. Glx concentrations in the MPFC increased during the imagery task, as compared to resting-state periods preceding and following the task. These increases mirror BOLD activity changes in the same region during the task. No changes in either Glx concentrations or BOLD activity were seen in the auditory cortex. These findings contribute to our understanding of the biochemical basis of generating or manipulating mental representations and the MPFC's role in this.

Interoception in insula subregions as a possible state marker for depression-an exploratory fMRI study investigating healthy, depressed and remitted participants.

BACKGROUND: Interoceptive awareness (iA), the awareness of stimuli originating inside the body, plays an important role in human emotions and psychopathology. The insula is particularly involved in neural processes underlying iA. However, iA-related neural activity in the insula during the acute state of major depressive disorder (MDD) and in remission from depression has not been explored. METHODS: A well-established fMRI paradigm for studying (iA; heartbeat counting) and exteroceptive awareness (eA; tone counting) was used. Study participants formed three independent groups: patients suffering from MDD, patients in remission from MDD or healthy controls. Task-induced neural activity in three functional subdivisions of the insula was compared between these groups. RESULTS: Depressed participants showed neural hypo-responses during iA in anterior insula regions, as compared to both healthy and remitted participants. The right dorsal anterior insula showed the strongest response to iA across all participant groups. In depressed participants there was no differentiation between different stimuli types in this region (i.e., between iA, eA and noTask). Healthy and remitted participants in contrast showed clear activity differences. CONCLUSIONS: This is the first study comparing iA and eA-related activity in the insula in depressed participants to that in healthy and remitted individuals. The preliminary results suggest that these groups differ in there being hypo-responses across insula regions in the depressed participants, whilst non-psychiatric participants and patients in remission from MDD show the same neural activity during iA in insula subregions implying a possible state marker for MDD. The lack of activity differences between different stimulus types in the depressed group may account for their symptoms of altered external and internal focus.

Associations of regional GABA and glutamate with intrinsic and extrinsic neural activity in humans­a review of multimodal imaging studies.

The integration of multiple imaging modalities is becoming an increasingly well used research strategy for studying the human brain. The neurotransmitters glutamate and GABA particularly lend themselves towards such studies. This is because these transmitters are ubiquitous throughout the cortex, where they are the key constituents of the inhibition/excitation balance, and because they can be easily measured in vivo through magnetic resonance spectroscopy, as well as with select positron emission tomography approaches. How these transmitters underly functional responses measured with techniques such as fMRI and EEG remains unclear though, and was the target of this review. Consistently shown in the literature was a negative correlation between GABA concentrations and stimulus-induced activity within the measured region. Also consistently found was a positive correlation between glutamate concentrations and inter-regional activity relationships, both during tasks and rest. These findings are outlined along with results from populations with mental disorders to give an overview of what brain imaging has suggested to date about the biochemical underpinnings of functional activity in health and disease. We conclude that the combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key methodological and interpretive issues be addressed before can meet its potential.

How to investigate neuro-biochemical relationships on a regional level in humans? Methodological considerations for combining functional with biochemical imaging.

There is an increasing interest in combining different imaging modalities to investigate the relationship between neural and biochemical activity. More specifically, imaging techniques like MRS and PET that allow for biochemical measurement are combined with techniques like fMRI and EEG that measure neural activity in different states. Such combination of neural and biochemical measures raises not only technical issues, such as merging the different data sets, but also several methodological issues. These methodological issues ­ ranging from hypothesis generation and hypothesis-guided use of technical facilities to target measures and experimental measures ­ are the focus of this paper. We discuss the various methodological problems and issues raised by the combination of different imaging methodologies in order to investigate neuro-biochemical relationships on a regional level in humans. For example, the choice of transmitter and scan type is discussed, along with approaches to allow the establishment of particular specificities (such as regional or biochemical) to in turn make results fully interpretable. An algorithm that can be used as a form of checklist for designing such multimodal studies is presented. The paper concludes that while several methodological and technical caveats needs to be overcome and addressed, multimodal imaging of the neuro-biochemical relationship provides an important tool to better understand the physiological mechanisms of the human brain.

External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18)F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders.

GABA in the insula - a predictor of the neural response to interoceptive awareness.

The insula has been identified as a key region involved in interoceptive awareness. Whilst imaging studies have investigated the neural activation patterns in this region involved in intero- and exteroceptive awareness, the underlying biochemical mechanisms still remain unclear. In order to investigate these, a well-established fMRI task targeting interoceptive awareness (heartbeat counting) and exteroceptive awareness (tone counting) was combined with magnetic resonance spectroscopy (MRS). Controlling for physiological noise, neural activity in the insula during intero- and exteroceptive awareness was confirmed in an independent data sample using the same fMRI design. Focussing on MRS values from the left insula and combining them with neural activity during intero- and exteroceptive awareness in the same healthy individuals, we demonstrated that GABA concentration in a region highly involved in interoceptive processing is correlated with neural responses to interoceptive stimuli, as opposed to exteroceptive stimuli. In addition, both GABA and interoceptive signal changes in the insula predicted the degree of depressed affect, as measured by the Beck Hopelessness Scale. On the one hand, the association between GABA concentration and neural activity during interoceptive awareness provides novel insight into the biochemical underpinnings of insula function and interoception. On the other, through the additional association of both GABA and neural activity during interoception with depressed affect, these data also bear potentially important implications for psychiatric disorders like depression and anxiety, where GABAergic deficits, altered insula function and abnormal affect coincide.

Glutamate concentration in the medial prefrontal cortex predicts resting-state cortical-subcortical functional connectivity in humans.

Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex--specifically the medial prefrontal cortex (mPFC)--and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc), dorsomedial thalamus (DMT), and periaqueductal grey (PAG). It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia.

Neuroimaging in pedophilia.

Paraphilia is a set of disorders characterized by abnormal sexual desires. Perhaps most discussed amongst them, pedophilia is a complex interaction of disturbances of the emotional, cognitive and sexual experience. Using new imaging techniques such as functional magnetic resonance imaging, neural correlates of emotional, sexual and cognitive abnormalities and interactions have been investigated. As described on the basis of current research, altered patterns of brain activity, especially in the frontal areas of the brain, are seen in pedophilia. Building on these results, the analysis of neural correlates of impaired psychological functions opens the opportunity to further explore sexual deviances, which may contribute ultimately to the development of tools for risk assessment, classification methods and new therapeutic approaches.

GABAA receptors predict aversion-related brain responses: an fMRI-PET investigation in healthy humans.

The perception of aversive stimuli is essential for human survival and depends largely on environmental context. Although aversive brain processing has been shown to involve the sensorimotor cortex, the neural and biochemical mechanisms underlying the interaction between two independent aversive cues are unclear. Based on previous work indicating ventromedial prefrontal cortex (vmPFC) involvement in the mediation of context-dependent emotional effects, we hypothesized a central role for the vmPFC in modulating sensorimotor cortex activity using a GABAergic mechanism during an aversive-aversive stimulus interaction. This approach revealed differential activations within the aversion-related network (eg, sensorimotor cortex, midcingulate, and insula) for the aversive-aversive, when compared with the aversive-neutral, interaction. Individual differences in sensorimotor cortex signal changes during the aversive-aversive interaction were predicted by GABAA receptors in both vmPFC and sensorimotor cortex. Together, these results demonstrate the central role of GABA in mediating context-dependent effects in aversion-related processing.

GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation.

Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [(18)F]Flumazenil PET to measure GABA(A) receptor binding potentials. It was demonstrated that the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABA(A) receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity.

Involvement of glutamate in rest-stimulus interaction between perigenual and supragenual anterior cingulate cortex: a combined fMRI-MRS study.

The brain shows a high degree of activity at rest. The significance of this activity has come increasingly into focus. At present, however, the interaction between this activity and stimulus-induced activity is not well defined. The interaction between a task-negative (perigenual anterior cingulate cortex, pgACC) and task-positive (supragenual anterior cingulate cortex, sgACC) region during a simple task was thus investigated using a combination of fMRI and MRS. Negative BOLD responses in the pgACC were found to show a unidirectional effective connectivity with task-induced positive BOLD responses in the sgACC. This connectivity was shown to be related specifically with glutamate levels in the pgACC. These results demonstrate an interaction between deactivation from resting-state and resting-state glutamate levels in a task-negative region (pgACC), and task-induced activity in a task-positive region (sgACC). This provides insight into the neuronal and biochemical mechanisms by means of which the resting state activity of the brain potentially impacts upon subsequent stimulus-induced activity.

Are emotions associated with activity during rest or interoception? An exploratory fMRI study in healthy subjects.

Imaging studies investigating the default-mode network (DMN) of the brain revealed the phenomenon of elevated neural responses during periods of rest. This effect has been shown to be abnormally elevated in regions of the DMN concerning mood disorders like major depressive disorder (MDD). Since these disorders are accompanied by impaired emotional functioning, this leads to the suggestion of an association between activity during rest conditions and emotions, which remains to be demonstrated in a healthy and clinical population. Controlling for interoceptive processing, a process often closely connected to emotional functioning, we here demonstrate in an fMRI study of 30 healthy subjects the connection between activity during rest conditions in regions of the DMN and emotions in a psychologically, regionally, and stimulus specific way. Our findings provide further insight into the psychological functions underlying rest activity. Our findings in healthy subjects may also have future implications for a better understanding of mood disorders.

The 'resting-state hypothesis' of major depressive disorder-a translational subcortical-cortical framework for a system disorder.

Major depressive disorder (MDD) has traditionally been characterized by various psychological symptoms, involvement of diverse functional systems (e.g., somatic, affect, cognition, reward, etc.), and with progress in neuroscience, an increasing number of brain regions. This has led to the general assumption that MDD is a stress-responsive brain 'system disorder' where either one or several alterations infiltrate a large number of functional systems in the brain that control the organism's somatic, affective, and cognitive life. However, while the effects or consequences of the abnormal changes in the functional systems of, for instance affect, cognition or reward have been investigated extensively, the underlying core mechanism(s) underlying MDD remain unknown. Hypotheses are proliferating rapidly, though. Based on recent findings, we will entertain an abnormality in the resting-state activity in MDD to be a core feature. Based on both animal and human data, we hypothesize that abnormal resting-state activity levels may impact stimulus-induced neural activity in medially situated core systems for self-representation as well as external stimulus (especially stress, specifically separation distress) interactions. Moreover, due to nested hierarchy between subcortical and cortical regions, we assume 'highjacking' of higher cortical affective and cognitive functions by lower subcortical primary-process emotional systems. This may account for the predominance of negative affect in somatic and cognitive functional system operations with the consecutive generation of the diverse symptoms in MDD. We will here focus on the neuroanatomical and biochemical basis of resting-state abnormalities in MDD including their linkage to the diverse psychopathological symptoms in depression. However, our 'resting-state hypothesis' may go well beyond that by being sufficiently precise to be linked to genetic, social, immunological, and endocrine dimensions and hypotheses as well as to clinical dimensions like endophenotypes and various diagnostic-prognostic biomarkers. Taken together, our 'resting-state hypothesis' may be considered a first tentative framework for MDD that integrates translational data, the various dimensions, and subcortical-cortical systems while at the same time providing the link to the clinical level of symptoms, endophenotypes and biomarkers.