What can the psychoneuroimmunology of yoga teach us about depression's psychopathology?

Depression, the most prevailing mental health condition, remains untreated in over 30% of patients. This cluster presents with sub-clinical inflammation. Investigations trialling anti-inflammatory medications had mixed results. The lack of results may result from inflammation's complexity and targeting only a few of depression's abnormal pathways. Mind-body therapies' biological and neuro-imaging studies offer valuable insights into depression psychopathology. Interestingly, mind-body therapies, like yoga, reverse the aberrant pathways in depression. These aberrant pathways include decreased cognitive function, interoception, neuroplasticity, salience and default mode networks connectivity, parasympathetic tone, increased hypothalamic-pituitary-adrenal (HPA) axis activity, and metabolic hyper/hypofunction. Abundant evidence found yogic techniques improving self-reported depressive symptoms across various populations. Yoga may be more effective in treating depression in conjunction with pharmacological and cognitive therapies. Yoga's psychoneuroimmunology teaches us that reducing allostatic load is crucial in improving depressive symptoms. Mind-body therapies promote parasympathetic tone, downregulate the HPA axis, reduce inflammation and boost immunity. The reduced inflammation promotes neuroplasticity and, subsequently, neurogenesis. Improving interoception resolves the metabolic needs prediction error and restores homeostasis. Additionally, by improving functional connectivity within the salience network, they restore the dynamic switching between the default mode and central executive networks, reducing rumination and mind-wandering. Future investigations should engineer therapies targeting the mechanisms mentioned above. The creation of multi-disciplinary health teams offering a combination of pharmacological, gene, neurofeedback, behavioural, mind-body and psychological therapies may treat treatment-resistant depression.

Unraveling the mystery of white matter in depression: A translational perspective on recent advances.

BACKGROUND: Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention. OBJECTIVE: This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype. METHODS: A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression. RESULTS: Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities. CONCLUSION: Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.

"Less is more": A dose-response account of intranasal oxytocin pharmacodynamics in the human brain.

Intranasal oxytocin is attracting attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU), we demonstrate that intranasal oxytocin-induced changes in local regional cerebral blood flow (rCBF) in the amygdala at rest, and in the covariance between rCBF in the amygdala and other key hubs of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects on local rCBF might vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity, which corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain. DATA AVAILABILITY: Participants did not consent for open sharing of the data. Therefore, data can only be accessed from the corresponding author upon reasonable request.

Dopamine multilocus genetic profiles predict sex differences in reactivity of the human reward system.

Sex differences in the neural processing of decision-making are of high interest as they may have pronounced effects on reward- and addiction-related processes. In these, the neurotransmitter dopamine plays a central role by modulating the responsiveness of the reward circuitry. The present functional magnetic resonance imaging study aimed to explore sex and dopamine transmission interactions in decision-making. 172 subjects (111 women) performed a behavioral self-control task assessing reward-related activation during acceptance and rejection of conditioned rewards. Participants were genotyped for six key genetic polymorphisms in the dopamine system that have previously been associated with individual differences in reward sensitivity or dopaminergic transmission in the human striatum, such as rs7118900 (dopamine receptor D2 (DRD2) Taq1A), rs1554929 (DRD2 C957T), rs907094 (DARPP-32), rs12364283 (DRD2), rs6278 (DRD2), and rs107656 (DRD2). The selected polymorphisms were combined in a so-called multilocus genetic composite (MGC) score reflecting the additive effect of different alleles conferring relative increased dopamine transmission in every individual. We successfully demonstrated that reward-related activation in the ventral striatum and ventral tegmental area (VTA) was significantly modulated by biologically informed MGC profiles and sex. When comparing men and women with low MGC profiles that may indicate lower dopamine transmission, only women displayed a reduced down-regulation of activation in the mesolimbic system during reward rejection and additionally, a significant non-linear u-shape relationship between MGC score and VTA activation. Taken together, by integrating neuroimaging and genetics, the present findings contribute to a better understanding of the effects of sex differences on the human brain.

Intranasal Oxytocin Selectively Modulates Large-Scale Brain Networks in Humans.

A growing body of evidence indicates that the neuropeptide oxytocin (OT) alters the neural correlates of socioemotional and salience processing. Yet the effects of OT over important large-scale networks involved in these processes, such as the default mode (DM), ventral attention (VA), and cingulo-opercular (CO) networks, remain unknown. Therefore, we conducted a placebo-controlled crossover study with intranasal 24 IU OT in 38 healthy male subjects using a resting-state functional magnetic resonance imaging paradigm to investigate its impact over these three networks candidates. To understand the underlying mechanisms of the neuropeptide, we compared the intranetwork connectivity for each network candidate and also the internetwork connectivity across all networks between both treatment conditions. Based on the relevance of interindividual factors for OT effects, we correlated individual network changes with behavioral performance in a decision-making task and with impulsivity scores. Our results show that OT mainly alters connectivity in the VA, on one side reducing the coupling to regions that typically form the nodes of DM, an introspective and self-referential network, and on the other side increasing the coupling to the edges of the CO, which is involved in salience processing. The results of the internetwork analyses confirmed the specificity of the OT effects. Indeed, we observed significant correlations with the erroneous performance during decision-making but not with the obtained impulsivity scores. Overall, our data support that the modulation of functional connectivity within the VA is a basic mechanism by which OT directs attentional resources from internal to external cues, preparing the brain for context-dependent salience processing.

Differentiating unipolar and bipolar depression by alterations in large-scale brain networks.

BACKGROUND: Misdiagnosing bipolar depression can lead to very deleterious consequences of mistreatment. Although depressive symptoms may be similarly expressed in unipolar and bipolar disorder, changes in specific brain networks could be very distinct, being therefore informative markers for the differential diagnosis. We aimed to characterize specific alterations in candidate large-scale networks (frontoparietal, cingulo-opercular, and default mode) in symptomatic unipolar and bipolar patients using resting state fMRI, a cognitively low demanding paradigm ideal to investigate patients. METHODS: Networks were selected after independent component analysis, compared across 40 patients acutely depressed (20 unipolar, 20 bipolar), and 20 controls well-matched for age, gender, and education levels, and alterations were correlated to clinical parameters. RESULTS: Despite comparable symptoms, patient groups were robustly differentiated by large-scale network alterations. Differences were driven in bipolar patients by increased functional connectivity in the frontoparietal network, a central executive and externally-oriented network. Conversely, unipolar patients presented increased functional connectivity in the default mode network, an introspective and self-referential network, as much as reduced connectivity of the cingulo-opercular network to default mode regions, a network involved in detecting the need to switch between internally and externally oriented demands. These findings were mostly unaffected by current medication, comorbidity, and structural changes. Moreover, network alterations in unipolar patients were significantly correlated to the number of depressive episodes. CONCLUSION: Unipolar and bipolar groups displaying similar symptomatology could be clearly distinguished by characteristic changes in large-scale networks, encouraging further investigation of network fingerprints for clinical use. Hum Brain Mapp 37:808-818, 2016. © 2015 Wiley Periodicals, Inc.

Asymmetric top-down modulation of ascending visual pathways in pigeons.

Cerebral asymmetries are a ubiquitous phenomenon evident in many species, incl. humans, and they display some similarities in their organization across vertebrates. In many species the left hemisphere is associated with the ability to categorize objects based on abstract or experience-based behaviors. Using the asymmetrically organized visual system of pigeons as an animal model, we show that descending forebrain pathways asymmetrically modulate visually evoked responses of single thalamic units. Activity patterns of neurons within the nucleus rotundus, the largest thalamic visual relay structure in birds, were differently modulated by left and right hemispheric descending systems. Thus, visual information ascending towards the left hemisphere was modulated by forebrain top-down systems at thalamic level, while right thalamic units were strikingly less modulated. This asymmetry of top-down control could promote experience-based processes within the left hemisphere, while biasing the right side towards stimulus-bound response patterns. In a subsequent behavioral task we tested the possible functional impact of this asymmetry. Under monocular conditions, pigeons learned to discriminate color pairs, so that each hemisphere was trained on one specific discrimination. Afterwards the animals were presented with stimuli that put the hemispheres in conflict. Response patterns on the conflicting stimuli revealed a clear dominance of the left hemisphere. Transient inactivation of left hemispheric top-down control reduced this dominance while inactivation of right hemispheric top-down control had no effect on response patterns. Functional asymmetries of descending systems that modify visual ascending pathways seem to play an important role in the superiority of the left hemisphere in experience-based visual tasks.

Active and observational reward learning in adults with autism spectrum disorder: relationship with empathy in an atypical sample.

INTRODUCTION: Autism spectrum disorders (ASDs) are characterised by disturbances in social behaviour. A prevailing hypothesis suggests that these problems are related to deficits in assigning rewarding value to social stimuli. The present study aimed to examine monetary reward processing in adults with ASDs by means of event-related potentials (ERPs). METHODS: Ten individuals with mild ASDs (Asperger's syndrome and high-functioning autism) and 12 healthy control subjects performed an active and an observational probabilistic reward-learning task. RESULTS: Both groups showed similar overall learning performance. With respect to reward processing, subjects with ASDs exhibited a general reduction in feedback-related negativity (FRN) amplitude, irrespective of feedback valence and type of learning (active or observational). Individuals with ASDs showed lower scores for cognitive empathy, while affective empathy did not differ between groups. Correlation analyses revealed that higher empathy (both cognitive and affective) negatively affected performance in observational learning in controls and in active learning in ASDs (only cognitive empathy). No relationships were seen between empathy and ERPs. CONCLUSIONS: Reduced FRN amplitudes are discussed in terms of a deficit in fast reward processing in ASDs, which may indicate altered reward system functioning.