Creating a new tool for Post-Traumatic Disorder treatment

The first article on real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback was published in 2003 (Weiskopf et al., 2003) with the aim to enable the subject to learn to control activation in rostral-ventral and dorsal anterior cingulate cortex (ACC). Rt-fMRI neurofeedback involves data collection of neural activity, real-time data preprocessing, online statistical analysis, providing the results back to the participant, and active effort of participant in order to either up- and/or down-regulate the target region’s activation. In the last 16 years the topic attracted great attention from different labs around the world and many different brain regions were regulated with the help of rt-fMRI neurofeedback. Nevertheless it had the most distinct impact in the clinical research as it could be used with clinical population in order to normalize their abnormal neural activity. The dissertation focused on the implementation of the rt-fMRI neurofeedback to the Post-Traumatic Stress Disorder (PTSD) patients. PTSD is developed as a result of experiencing a traumatic event in first hand or hearing that a close one experienced it. PTSD has a high prevalence (Kessler et al., 2005) and also high impact on the patient’s life quality (Warshaw et al., 1993). Unfortunately the response rate to the therapy is around 50% (Bradley et al., 2005; Stein et al., 2006). Hence, there is a need for a new treatment tool for PTSD. The neurocircuitry model of PTSD indicate that there is increased activity in amygdala, decreased activity in ventromedial prefrontral cortex (vmPFC)/rostral ACC (rACC) and hippocampus (Rauch et al., 2006). Animal model of PTSD revealed that stimulating rACC led to increase in extinction learning and rats exhibited less PTSD symptoms (Milad & Quirk, 2002). Following these findings, we decided to implement rACC rt-fMRI neurofeedback to PTSD patients. The first study focused to develop a new paradigm to target rACC and tested it with healthy population. We used Ekman faces as functional localizer in order to locate the rACC. Experimental design constituted of four functional runs in one session. The main aim was to assess the methods effectiveness in one session. Surprisingly eight out of sixteen female participants learned to regulate their rACC, whereas only four out of sixteen male participants were able to regulate their rACC at will. Interestingly the learner/non-learners are not widely reported in the rt-fMRI literature and no gender difference has been reported so far. As a result we decided to implement it with only one sex in PTSD group. In the second study we tested the paradigm with the female PTSD patients. Eight out of sixteen PTSD patients gained control over their rACC. We also found that PTSD patients recruited more brain regions, especially multi-sensory brain regions for the upregulation of rACC in comparison to healthy subjects. We failed to find a single factor to predict rACC control success across groups. There is a need for further study to identify the predictor factors. As a result we concluded that the best practice of rt-fMRI with PTSD patients would be to use it as a supportive tool to psychotherapy in order to identify the best working strategy for their treatment. Further research recommendations are discussed below

Probing fMRI brain connectivity and activity changes during emotion regulation by EEG neurofeedback

Despite the existence of several emotion regulation studies using neurofeedback, interactions among a small number of regions were evaluated, and therefore, further investigation is needed to understand the interactions of the brain regions involved in emotion regulation. We implemented electroencephalography (EEG) neurofeedback with simultaneous functional magnetic resonance imaging (fMRI) using a modified happiness-inducing task through autobiographical memories to upregulate positive emotion. Then, an explorative analysis of whole brain regions was done to understand the effect of neurofeedback on brain activity and the interaction of whole brain regions involved in emotion regulation. The participants in the control and experimental groups were asked to do emotion regulation while viewing positive images of autobiographical memories and getting sham or real (based on alpha asymmetry) EEG neurofeedback, respectively. The proposed multimodal approach quantified the effects of EEG neurofeedback in changing EEG alpha power, fMRI blood oxygenation level-dependent (BOLD) activity of prefrontal, occipital, parietal, and limbic regions (up to 1.9% increase), and functional connectivity in/between prefrontal, parietal, limbic system, and insula in the experimental group. New connectivity links were identified by comparing the brain functional connectivity between experimental conditions (Upregulation and View blocks) and also by comparing the brain connectivity of the experimental and control groups. Psychometric assessments confirmed significant changes in positive and negative mood states in the experimental group by neurofeedback. Based on the exploratory analysis of activity and connectivity among all brain regions involved in emotion regions, we found significant BOLD and functional connectivity increases due to EEG neurofeedback in the experimental group, but no learning effect was observed in the control group. The results reveal several new connections among brain regions as a result of EEG neurofeedback which can be justified according to emotion regulation models and the role of those regions in emotion regulation and recalling positive autobiographical memories

Evaluating self-regulation in adolescents with conduct problems or severe disruptive behavior disorders - possible neural targets for future interventions

Disruptive behavior is a common phenomenon in human nature and frequently occurs during adolescence. It is associated with conduct problems (CP) in healthy as well as clinical populations. When CP exceed the normal range and disruptive behaviors are severe, Disruptive Behavior Disorder (DBD), including Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD), is often diagnosed. Individuals who fulfill diagnostic criteria of DBD also frequently display a conspicuous pattern of behavior that is characterized by a callous, uncaring and unemotional interpersonal style, including deficits in empathy, emotional affectivity and conscientiousness. These behaviors have been labeled the affective dimension of psychopathy or callous-unemotional traits (CU traits) in research. Overall, evidence-based psychological treatments for DBD (with and without increased CU traits) only reach small to moderate effect sizes and there is currently not enough evidence to support one specific form of treatment over another. To date, real-time functional magnetic resonance imaging (rtfMRI-NF) is increasingly considered as a promising tool for the training of brain self-regulation in order to treat psychiatric conditions. It has already been applied to train self-regulation of compromised inhibitory or emotional brain regions, and of emotion regulation strategies in adult psychopaths and adolescents diagnosed with ADHD. For the purpose of investigating and evaluating new innovative forms of treatments for adolescents with DBD, this thesis followed a two-way approach. First (study 1), a large dataset of healthy young adolescents (mean age: 14.44 (0.41), range 13.08-15.72 years) with varying level of CP was analyzed with respect to possible neural correlates of frontal control over CP during affective processing of negative facial emotions. Second (study 2), an individualized rtfMRI-NF training aiming at the learning of self-regulation of emotional processing regions (amygdala or insula) and, as a result, at the improvement of affective processing was conducted with adolescent patients (mean age: 14.62 (1.64), range: 12.04-17.99 years) diagnosed with DBD and elevated CU traits (ICU total score >20 in self-rating and/or >24 in parent-rating) over a course of 10 weeks and compared with a clinical TAU group. In study 1, we observed no significant differences in brain responses to negative facial affect in adolescents with high versus low CP. However, regression analyses along the CP dimension across the groups revealed a significant nonlinear effect: left orbitofrontal cortex (OFC) responses increased with increasing CP up to the clinical range, and, decreased again only for the highest CP range. This increasing left OFC activity found during affective processing in an epidemiological adolescent sample with low to clinically relevant levels of CP might represent frontal control mechanisms preventing the outbreak of disruptive or conduct disorder despite conduct problems. In study 2, the NF and the TAU group showed comparable and significant clinical improvement on DBD-related behavioral scales over time, in line with non-inferiority. Within the NF group, successful learning of self-regulation in the target region was found for NF of the amygdala, but not for NF of the insula. The data suggest that the self-regulation of emotional processing regions might be more promising when receiving feedback from the amygdala (as compared to the insula). Additional exploratory analyses also suggested involvement of prefrontal areas in the learning of self-regulation of emotion processing regions. However, clinical improvement in NF was not specific to the amygdala group. In the emotion matching task, both treatment groups showed decreased activities after treatment in prefrontal emotion-regulation related areas, potentially indicating higher efficiency of processing affective stimuli after treatment. The results suggest clinical improvement and non-inferiority of rtfMRI-NF training compared to other treatment options for adolescents with diagnosis of DBD, but further studies are needed to clarify underlying mechanisms and cost effectiveness. As a future perspective, further investigation of the role of structural and functional connections between subcortical and prefrontal areas with respect to the cognitive regulation of affective arousal might be fruitful for the development of future specific treatment strategies aiming at the improvement of adaptive reactivity, emotion regulation and social behavior. Also, the OFC could form a promising target for further NF approaches aiming at the control of emotions

Probing fMRI brain connectivity and activity changes during emotion regulation by EEG neurofeedback

Despite the existence of several emotion regulation studies using neurofeedback, interactions among a small number of regions were evaluated, and therefore, further investigation is needed to understand the interactions of the brain regions involved in emotion regulation. We implemented electroencephalography (EEG) neurofeedback with simultaneous functional magnetic resonance imaging (fMRI) using a modified happiness-inducing task through autobiographical memories to upregulate positive emotion. Then, an explorative analysis of whole brain regions was done to understand the effect of neurofeedback on brain activity and the interaction of whole brain regions involved in emotion regulation. The participants in the control and experimental groups were asked to do emotion regulation while viewing positive images of autobiographical memories and getting sham or real (based on alpha asymmetry) EEG neurofeedback, respectively. The proposed multimodal approach quantified the effects of EEG neurofeedback in changing EEG alpha power, fMRI blood oxygenation level-dependent (BOLD) activity of prefrontal, occipital, parietal, and limbic regions (up to 1.9% increase), and functional connectivity in/between prefrontal, parietal, limbic system, and insula in the experimental group. New connectivity links were identified by comparing the brain functional connectivity between experimental conditions (Upregulation and View blocks) and also by comparing the brain connectivity of the experimental and control groups. Psychometric assessments confirmed significant changes in positive and negative mood states in the experimental group by neurofeedback. Based on the exploratory analysis of activity and connectivity among all brain regions involved in emotion regions, we found significant BOLD and functional connectivity increases due to EEG neurofeedback in the experimental group, but no learning effect was observed in the control group. The results reveal several new connections among brain regions as a result of EEG neurofeedback which can be justified according to emotion regulation models and the role of those regions in emotion regulation and recalling positive autobiographical memories

Real-time fMRI-based neurofeedback in depression

Depression is one of the leading causes of disability worldwide. Currently available treatment methods are not always effective in improving depression. There is thus a pressing need for the development of novel treatment methods. Neurofeedback training can potentially alleviate symptoms of depression. By providing depressed patients with feedback about the ongoing processes in their brain via functional magnetic resonance imaging (fMRI), patients can be trained to increase the activation in positive emotion processing areas by engaging in positive imagery. The advantages of this method are that it is non-invasive, offers an individually tailored approach without any side-effects and has the capability to target the neurobiological and cognitive pathways putatively mediating depression. The main aim of this thesis was to elaborate on pilot findings that fMRI-neurofeedback has potential as an add-on treatment tool for depression (Linden et al., 2012). In doing so, this thesis does not focus on confirming that fMRI-neurofeedback can improve symptoms of depression as the dataset employed here is part of a larger dataset of a currently still running clinical trial. Instead this work investigated the feasibility of a control group receiving feedback from a scene processing area and assessed whether fMRI-neurofeedback can indeed affect emotion processing areas that function abnormally in depression and enhance perceived self-efficacy. Sixteen moderately to severely depressed patients took part in a course of five neurofeedback training sessions in which all patients learned to up-regulate the activation in their individually localised target areas. The patients that had received feedback from a positive emotion area influenced the activity in a wider emotion regulation network than just their target area. Additionally, the acquisition of self-regulation skills significantly improved scores on a self-efficacy scale. These findings confirmed the ability of neurofeedback to target biological and cognitive pathways putatively mediating depression