No evidence from a negative mood induction fMRI task for frontal functional asymmetry as a suitable neurofeedback target.

Frontal functional asymmetry (FA) has been proposed as a potential target for neurofeedback (NFB) training for mental disorders but most FA NFB studies used electroencephalography while the investigations of FA NFB in functional magnetic resonance imaging (fMRI) are rather limited. In this study, we aimed at identifying functional asymmetry effects in fMRI and exploring its potential as a target for fMRI NFB studies by re-analyzing an existing data set containing a resting state measurement and a sad mood induction task of n = 30 participants with remitted major depressive disorder and n = 30 matched healthy controls. We applied low-frequency fluctuations (ALFF), fractional ALFF, and regional homogeneity and estimated functional asymmetry in both a voxel-wise and regional manner. We assessed functional asymmetry during rest and negative mood induction as well as functional asymmetry changes between the phases, and associated the induced mood change with the change in functional asymmetry. Analyses were conducted within as well as between groups. Despite extensive analyses, we identified only very limited effects. While some tests showed nominal significance, our results did not contain any clear identifiable patterns of effects that would be expected if a true underlying effect would be present. In conclusion, we do not find evidence for FA effects related to negative mood in fMRI, which questions the usefulness of FA measures for real-time fMRI neurofeedback as a treatment approach for affective disorders.

Effects of Rumination and Mindful Self-Focus Inductions During Daily Life in Patients With Remitted Depression: An Experimental Ambulatory Assessment Study.

Rumination has been proposed as an important risk factor for depression, whereas mindful attention is considered a protective form of self-focusing. Experimental studies have demonstrated differential effects of these modes when induced in the lab. However, their impact on daily life processes is poorly understood, particularly in individuals vulnerable to depressive relapses. The aim of our study was to examine short- and longer-term effects of repeated brief rumination and mindful self-focus inductions during daily life on momentary mood, cognitions, and cortisol in patients with remitted depression (rMDD) as well as in healthy individuals, and to identify their potential differential effects in these groups. The study involved repeated short ambulatory inductions of a ruminative or a mindful self-focus during daily life with additional assessments of momentary mood, rumination, self-acceptance, and cortisol over 4 consecutive days in a sample of patients with rMDD (n = 32, ≥2 lifetime episodes, age 19-55 years) and matched healthy controls (n = 32, age 21-54 years). Multilevel models revealed differential immediate effects of the two induction modes on all momentary mood and cognitive outcomes (all p's < .001), but not on cortisol. Detrimental effects of rumination over mindful self-focus inductions were particularly strong for cognitions in the patient group. Longer-term effects of the inductions over the day were lacking. This study underlines immediate deteriorating effects of an induced ruminative compared to a mindful self-focus on momentary mood and cognitions during daily life in patients with rMDD and in healthy individuals. The observed stronger rumination-related reactivity in patients suggests heightened cognitive vulnerability. Understanding rumination- and mindfulness-based mechanisms of action in real-life settings can help to establish mechanism-based treatment options for relapse prevention in depression.

Feasibility of training the dorsolateral prefrontal-striatal network by real-time fMRI neurofeedback.

Real-time fMRI neurofeedback (rt-fMRI NF) is a promising non-invasive technique that enables volitional control of usually covert brain processes. While most rt-fMRI NF studies so far have demonstrated the ability of the method to evoke changes in brain activity and improve symptoms of mental disorders, a recently evolving field is network-based functional connectivity (FC) rt-fMRI NF. However, FC rt-fMRI NF has methodological challenges such as respirational artefacts that could potentially bias the training if not controlled. In this randomized, double-blind, yoke-controlled, pre-registered FC rt-fMRI NF study with healthy participants (N = 40) studied over three training days, we tested the feasibility of an FC rt-fMRI NF approach with online global signal regression (GSR) to control for physiological artefacts for up-regulation of connectivity in the dorsolateral prefrontal-striatal network. While our pre-registered null hypothesis significance tests failed to reach criterion, we estimated the FC training effect at a medium effect size at the end of the third training day after rigorous control of physiological artefacts in the offline data. This hints at the potential of FC rt-fMRI NF for the development of innovative transdiagnostic circuit-specific interventional approaches for mental disorders and the effect should now be confirmed in a well-powered study.

Using mind control to modify cue-reactivity in AUD: the impact of mindfulness-based relapse prevention on real-time fMRI neurofeedback to modify cue-reactivity in alcohol use disorder: a randomized controlled trial.

BACKGROUND: Alcohol Use Disorder is a severe mental disorder affecting the individuals concerned, their family and friends and society as a whole. Despite its high prevalence, novel treatment options remain rather limited. Two innovative interventions used for treating severe disorders are the use of real-time functional magnetic resonance imaging neurofeedback that targets brain regions related to the disorder, and mindfulness-based treatments. In the context of the TRR SFB 265 C04 "Mindfulness-based relapse prevention as an addition to rtfMRI NFB intervention for patients with Alcohol Use Disorder (MiND)" study, both interventions will be combined to a state-of-the art intervention that will use mindfulness-based relapse prevention to improve the efficacy of a real-time neurofeedback intervention targeting the ventral striatum, which is a brain region centrally involved in cue-reactivity to alcohol-related stimuli. METHODS/DESIGN: After inclusion, N = 88 patients will be randomly assigned to one of four groups. Two of those groups will receive mindfulness-based relapse prevention. All groups will receive two fMRI sessions and three real-time neurofeedback sessions in a double-blind manner and will regulate either the ventral striatum or the auditory cortex as a control region. Two groups will additionally receive five sessions of mindfulness-based relapse prevention prior to the neurofeedback intervention. After the last fMRI session, the participants will be followed-up monthly for a period of 3 months for an assessment of the relapse rate and clinical effects of the intervention. DISCUSSION: The results of this study will give further insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback interventions for the treatment of Alcohol Use Disorder. Additionally, the study will provide further insight on neurobiological changes in the brain caused by the neurofeedback intervention as well as by the mindfulness-based relapse prevention. The outcome might be useful to develop new treatment approaches targeting mechanisms of Alcohol Use Disorder with the goal to reduce relapse rates after discharge from the hospital. TRIAL REGISTRATION: This trial is pre-registered at clinicaltrials.gov (trial identifier: NCT04366505; WHO Universal Trial Number (UTN): U1111-1250-2964). Registered 30 March 2020, published 29 April 2020.

Just a very expensive breathing training? Risk of respiratory artefacts in functional connectivity-based real-time fMRI neurofeedback.

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI NFB) is a promising method for targeted regulation of pathological brain processes in mental disorders. But most NFB approaches so far have used relatively restricted regional activation as a target, which might not address the complexity of the underlying network changes. Aiming towards advancing novel treatment tools for disorders like schizophrenia, we developed a large-scale network functional connectivity-based rtfMRI NFB approach targeting dorsolateral prefrontal cortex and anterior cingulate cortex connectivity with the striatum. In a double-blind randomized yoke-controlled single-session feasibility study with N â€‹= â€‹38 healthy controls, we identified strong associations between our connectivity estimates and physiological parameters reflecting the rate and regularity of breathing. These undesired artefacts are especially detrimental in rtfMRI NFB, where the same data serves as an online feedback signal and offline analysis target. To evaluate ways to control for the identified respiratory artefacts, we compared model-based physiological nuisance regression and global signal regression (GSR) and found that GSR was the most effective method in our data. Our results strongly emphasize the need to control for physiological artefacts in connectivity-based rtfMRI NFB approaches and suggest that GSR might be a useful method for online data correction for respiratory artefacts.

Mindfulness-based focused attention training versus progressive muscle relaxation in remitted depressed patients: Effects on salivary cortisol and associations with subjective improvements in daily life.

Major Depression is a stress-related disorder characterized by altered hypothalamic-pituitary-adrenal axis function. Mindfulness-based interventions have shown to improve subjective parameters of stress and to reduce relapse rates in depressed patients. However, research on their effects on diurnal patterns of cortisol and associations with subjective outcomes is lacking. The present Ambulatory Assessment study investigated possible changes in daily rhythm cortisol parameters (cortisol awakening response (CAR), daily slope, total cortisol) in currently remitted individuals with recurrent depression who were randomized to a four-week mindfulness-based focused attention training (MBAT, n = 39) or a progressive muscle relaxation training (PMR, n = 39). A second aim was to investigate whether changes in cortisol were linked to improvements in affective and cognitive daily life states. On three weekdays before and after the intervention, seven saliva cortisol samples per day were collected. For analysis, multilevel models were applied. Results revealed no group-specific or general change in CAR and daily slopes from pre- to postintervention. In contrast, total cortisol increased across groups, which was however moderated by group and subjective improvement status. While cortisol increased irrespective of subjective improvement in PMR participants, MBAT participants with larger reductions in negative affect and rumination maintained their initial cortisol levels, whereas those with lower improvement paralleled the PMR group. Thereby, MBAT appeared to buffer an increase in overall cortisol secretion over time, but only in patients showing marked improvements in those affective and cognitive states that constitute core elements for depressive relapses in the vulnerability model of mindfulness-based cognitive therapy.

The NeMo real-time fMRI neurofeedback study: protocol of a randomised controlled clinical intervention trial in the neural foundations of mother-infant bonding.

INTRODUCTION: Most mothers feel an immediate, strong emotional bond with their newborn. On a neurobiological level, this is accompanied with the activation of the brain reward systems, including the striatum. However, approximately 10% of all mothers report difficulties to bond emotionally with their infant and display impaired reward responses to the interaction with their infant which might have long-term negative effects for the child's development. As previous studies suggest that activation of the striatal reward system can be regulated through functional MRI (fMRI)-based neurofeedback (NFB), we have designed and investigate fMRI-NFB training to treat maternal bonding difficulties. METHODS AND ANALYSIS: In the planned trial, mothers will be presented pictures of their infant and real-time fMRI (rtfMRI), peripheral measures, neural, endocrine, psychophysiological and behavioural measures will be assessed. Mothers with bonding difficulties (n=68) will be randomised to one of two double-blind intervention groups at 4-6 months postpartum. They will participate in three repeated NFB training sessions with rtfMRI-NFB training to increase activation of (a) the ventral striatum or (b) the anterior cingulate. Interview data and real-time mother-infant interaction behaviour pre-intervention, post-intervention and at follow-up will serve as clinical outcome measures. ETHICS AND DISSEMINATION: Study procedures are in line with the recommendations of the World Medical Association (revised Declaration of Helsinki) and were approved by the Ethics Committee of the Medical Faculty, s-450/2017, Heidelberg University. All participants will provide written informed consent after receiving a detailed oral and written explanation of all procedures and can withdraw their consent at any time without negative consequence. Results will be internationally published and disseminated, to further the discussion on non-pharmacological treatment options in complex mental disorders. TRIAL REGISTRATION NUMBER: DRKS00014570; Pre-results.

The SyBil-AA real-time fMRI neurofeedback study: protocol of a single-blind randomized controlled trial in alcohol use disorder.

BACKGROUND: Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study. METHODS: N = 100 patients with Alcohol Use Disorder will be randomized to 5 parallel groups in a single-blind fashion and receive real-time functional magnetic resonance imaging neurofeedback while they are presented pictures of alcoholic beverages. The groups will either downregulate the ventral striatum, upregulate the right inferior frontal gyrus, negatively modulate the connectivity between these regions, upregulate, or downregulate the auditory cortex as a control region. After receiving 3 sessions of neurofeedback training within a maximum of 2 weeks, participants will be followed up monthly for a period of 3 months and relapse rates will be assessed as the primary outcome measure. DISCUSSION: The results of this study will provide insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback training in the treatment of Alcohol Use Disorder as well as in the involved brain systems. This might help to identify predictors of successful neurofeedback treatment which could potentially be useful in developing personalized treatment approaches. TRIAL REGISTRATION: The study was retrospectively registered in the German Clinical Trials Register (trial identifier: DRKS00010253 ; WHO Universal Trial Number (UTN): U1111-1181-4218) on May 10th, 2016.

From the neurobiological basis of comorbid alcohol dependence and depression to psychological treatment strategies: study protocol of a randomized controlled trial.

BACKGROUND: Alcohol use disorder and depression occur commonly in the community. Even though this high-prevalence comorbidity is associated with poorer posttreatment outcomes and greater utilization of costly treatment services, existing treatment trials often exclude patients with comorbid depressive and alcohol use disorders. Past research suggests that symptoms such as craving and anhedonia might be associated with alterations within the reward circuit, while emotion regulation deficits are related to disruptions within the default mode network. The aim of this clinical neuroimaging study is to transfer previous research about the reward circuit and default mode network underlying alcohol use disorder and depression to achieve a better understanding of neural signatures characterizing their comorbidity. In addition, the neurobiological results will be used to test whether two psychotherapeutic intervention programs, mindfulness-based training and behavioral activation training, are able to positively influence the identified pathomechanisms. METHODS: By means of functional magnetic resonance imaging (fMRI), 60 comorbid alcohol dependent and depressed patients are compared to 30 patients with depression only, 30 patients with alcohol use disorder only and 30 healthy control participants. Comorbid patients are randomized to either receive a behavioral activation or mindfulness based training and asked to participate in a second fMRI session and 3 month follow-up assessment. Thereby, we plan to explore whether these brief group psychotherapeutic intervention programs are able to positively influence the identified neurobiological pathomechanisms. The primary outcomes are reward and default mode network activity and connectivity evoked by paradigms measuring different facets of reward and emotion processing. Secondary outcome measures include craving and depression scores, as well as relapse rates. Predictors include participants' characteristics, personality traits and indicators of mental health. DISCUSSION: The objective of the project is to identify common and/or distinct neural signatures underlying the comorbidity of alcohol dependence and depression. If the neurobiological understanding of alcohol addiction and depression is improved, this could potentially serve as a key predictor of treatment response to specific types of behavioral or mindfulness therapies hypothesized to alter reward and resting state systems. TRIAL REGISTRATION: German Clinical Trial Register DRKS00010249 . The trial was registered January 23th 2017.

Real-time functional magnetic resonance imaging neurofeedback can reduce striatal cue-reactivity to alcohol stimuli.

It has been shown that in alcoholic patients, alcohol-related cues produce increased activation of reward-related brain regions like the ventral striatum (VS), which has been proposed as neurobiological basis of craving. Modulating this activation might be a promising option in the treatment of alcohol addiction. One approach might be real-time functional magnetic resonance imaging neurofeedback (rtfMRI NF). This study was set up to implement and evaluate a rtfMRI approach in a group of non-addicted heavy social drinkers. Thirty-eight heavy drinking students were assigned to a real feedback group (rFB, n = 13), a yoke feedback group (yFB, n = 13) and a passive control group (noFB, n = 12). After conducting a reward task as functional localizer to identify ventral striatal regions, the participants viewed alcohol cues during three NF training blocks in a 3 T MRI scanner. The rFB group received feedback from their own and the yFB from another participants' VS. The noFB group received no feedback. The rFB and the yFB groups were instructed to downregulate the displayed activation. Activation of the VS and prefrontal control regions was compared between the groups. We found significant downregulation of striatal regions specifically in the rFB group. While the rFB and the yFB groups showed significant activation of prefrontal regions during feedback, this activation was only correlated to the reduction of striatal activation in the rFB group. We conclude that rtfMRI NF is a suitable method to reduce striatal activation to alcohol cues. It might be a promising supplement to the treatment of alcoholic patients.

Simultaneous EEG and fMRI reveals a causally connected subcortical-cortical network during reward anticipation.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been used to study the neural correlates of reward anticipation, but the interrelation of EEG and fMRI measures remains unknown. The goal of the present study was to investigate this relationship in response to a well established reward anticipation paradigm using simultaneous EEG-fMRI recording in healthy human subjects. Analysis of causal interactions between the thalamus (THAL), ventral-striatum (VS), and supplementary motor area (SMA), using both mediator analysis and dynamic causal modeling, revealed that (1) THAL fMRI blood oxygenation level-dependent (BOLD) activity is mediating intermodal correlations between the EEG contingent negative variation (CNV) signal and the fMRI BOLD signal in SMA and VS, (2) the underlying causal connectivity network consists of top-down regulation from SMA to VS and SMA to THAL along with an excitatory information flow through a THAL→VS→SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Induced ruminative and mindful attention in everyday life: an experimental ambulatory assessment study.

BACKGROUND AND OBJECTIVES: Rumination has been proposed as a risk factor for depression, while mindful attention might be protective. Differential effects of these attention foci have so far only been examined in the laboratory. Therefore, we conducted an experimental ambulatory assessment study using ruminative and mindful attention inductions in everyday life to examine their effects in a natural context. METHODS: Fifty young adults carried palmtops over three weekdays (rumination induction day, mindful attention induction day, noninduction day; randomized cross-over design). Ten times a day, participants rated ruminative self-focus and mood. On the induction days, they were additionally subjected to 3-min inductions of ruminative or mindful attention at each assessment. RESULTS: The two induction modes exhibited differential immediate effects on ruminative self-focus and mood. While induced rumination immediately deteriorated valence and calmness, induced mindful attention specifically enhanced calmness. Depressive symptoms did not moderate these effects. While overall longer term effects of the inductions were missing, the mindful attention day was associated with slightly increasing positive valence over the day. LIMITATIONS: The results need to be replicated in high-risk and patient samples to demonstrate the clinical significance of identified effects. CONCLUSIONS: Results confirm the emotional relevance of rumination and mindful attention in real world settings. Future work may test whether adaptive attention-focusing instructions delivered in daily life can support clinical interventions.

Erotic and disgust-inducing pictures--differences in the hemodynamic responses of the brain.

The aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.