Exploration of the biological mechanisms in neuropsychiatric disorders using multimodal imaging

The present doctoral thesis focused on the multimodal imaging investigation of brain mechanisms in neuropsychiatric disorders, emphasizing on the research questions of whether and how neurochemistry is associated with brain anatomical structures and brain functions. The aim of the thesis is to provide a biochemical insight underlying the altered brain morphology and functions in the two disorders studied, which might ultimately offer evidence for novel therapeutic implications. There are two brain imaging projects included in this thesis. In project I, the first aim was to explore the mechanism of partial volume recovery during the first two weeks of abstinence from alcohol at a whole-brain level. The hippocampus was then chosen as a seed region, to investigate the abstinence-induced neurochemical changes and whether the hyperglutamatergic state induced by alcohol withdrawal may affect GM volume recovery in the hippocampus. We found cortical thickness alteration corresponds to the partial cortical volumetric recovery. Moreover, alcohol differentially impacts on sulci and gyri of the neocortex. Sulci are more susceptive to excessive alcohol consumption and abstinence-induced recovery. Lower subcortical volume was found in alcohol dependent patients at withdrawal, and no subcortical volume regain was observed during the initial two weeks of abstinence. In support of a ‘hyperglutamatergic state’ induced by withdrawal, our rat model demonstrated elevated Glu/Gln ratios during acute withdrawal (12h and 60h after stopping alcohol intake) and a trend towards an increase in Glu levels at 12h compared to control rats. The main novel finding of this study was that in both species a negative association was found between Glu markers and GM volume in the hippocampus after alcohol withdrawal (but not during withdrawal), suggesting that this tissue damage is a consequence of withdrawal and results from withdrawal-induced hyperglutamatergic neurotoxicity. In project II, the study emphasized the additional value of multimodal imaging analyses to unravel group differences between BPD patients and HCs which could not be detected by BOLD response and ACC GABA levels per se. The superior aim was to explore the interrelationship between GABA, neural correlates of interference inhibition, and impulsivity traits in BPD. We found task-related functional connectivity and the association of fMRI measures with MRS derived GABA levels are significantly different between the two groups. These analyses give support for a disconnection of the fronto-striatal network during interference inhibition in BPD patients that is related to elevated impulsivity ratings, specifically the UPPS sensation seeking score. Our hierarchical analyses also give first evidence for the hypothesis that the fronto-striatal network during inhibitory control serves to mediate the association between ACC GABA levels and impulsivity symptomatology in patients with BPD. In other words, GABAergic transmission in the ACC drives the inhibitory-related fronto-striatal brain network, whereas the disruption of fronto-striatal connectivity is of core relevance to the sensation seeking symptom in BPD patients. Taken together, multimodal imaging fusion analysis of neurobiochemistry - structure/function relationship can offer opportunities to deepen our understanding of neurobiological mechanisms of brain disorders

Repetitive Transcranial Magnetic Stimulation Treating Impulsivity in Borderline Personality Disorder and Attention Deficit/Hyperactivity Disorder

The need for novel treatment approaches that target impulsivity symptoms in neuropsychiatric disorders is clear. Repetitive transcranial magnetic stimulation (rTMS) allows selective neuromodulation of regions involved in the functional neuroanatomy of neuropsychiatric disorders. This chapter presents impulsivity in psychiatry, especially in borderline personality disorder (BPD) and attention-deficit hyperactivity disorder (ADHD), its neural underpinnings, and its possible treatment by rTMS. We reviewed available studies on rTMS in impulsivity in BPD and ADHD published before August 13, 2017, systematically searching in the PubMed, Web of Science, and Scopus databases. The results are discussed in the context of the latest neuropsychological models of impulsivity and their underlying functional neuroanatomy. rTMS treatment of impulsivity in BPD and ADHD seems to be a plausible approach. The functional neuroanatomy of processes related to impulsive behavior and decision making in these disorders is linked with abnormalities in the fronto-limbic structures that can be targeted and modulated by rTMS. Although limited evidence is available, rTMS seems to be a safe and potentially effective method of impulsivity treatment in patients with BPD and ADHD. However, more studies are needed to determine the most efficient cortical location and design for rTMS treatment of impulsivity

Effect of Pharmacological Interventions on the Fronto-Cingulo-Parietal Cognitive Control Network in Psychiatric Disorders: A Transdiagnostic Systematic Review of fMRI Studies

Executive function deficits such as working memory, decision-making, and attention problems are a common feature of several psychiatric disorders for which no satisfactory treatment exists. Here, we transdiagnostically investigate the effects of pharmacological interventions (other than methylphenidate) on the fronto-cingulo-parietal cognitive control network, in order to identify functional brain markers for future pro-cognitive pharmacological interventions. 29 manuscripts investigated the effect of pharmacological treatment on executive function-related brain correlates in psychotic disorders (n=11), depression (n=4), bipolar disorder (n=4), ADHD (n=4), OCD (n=2), smoking dependence (n=2), alcohol dependence (n=1) and pathological gambling (n=1). In terms of impact on the fronto-cingulo-parietal networks, the preliminary evidence for catechol-o-methyl-transferase inhibitors, nicotinic receptor agonists and atomoxetine suggested was relatively consistent, the data for atypical antipsychotics and anticonvulsants moderate, and interpretation of the data for antidepressants was hampered by the employed study designs. Increased activity in task-relevant areas and decreased activity in task-irrelevant areas were the most common transdiagnostic effects of pharmacological treatment. These markers showed good positive and moderate negative predictive value. It is concluded that fronto-cingulo-parietal activity changes can serve as a marker for future pro-cognitive interventions. Future recommendations include the use of randomized double-blind designs and selective cholinergic and glutamatergic compounds

Disentangling Brain Networks in Adult ADHD: Studies with fMRI and TMS

Attention Deficit/ Hyperactivity Disorder (ADHD) is not only limited to young patients. It is increasingly diagnosed in adults. Although the estimated prevalence in Europe ranges between 2 and 3% (48), the knowledge about adult ADHD pathophysiology and its neurobiological basis developed only in the past two decades, primarily stimulated by the rapid developments in modern genetic and imaging techniques. ADHD in adulthood leads to an array of major psychosocial problems such as social maladaptation, academic underachieving, antisocial and aggressive behaviour, relation problems, high risk sexual behaviour and car accidents (11,12;55;67;66). These factors in total lead to a negative impact on social and economic well-being of the individual

The relationship between impulsivity, affect and a history of psychological adversity: a cognitive-affective neuroscience approach

There is increasing evidence that trauma exposure is associated with impulsive behaviour and difficulties regulating affect. The findings of recent studies implicate the disruption of neurobiological mechanisms, particularly those involving the neurotransmitter serotonin, in both impulsivity and affect regulation

GABA, glutamate and neural activity: a systematic review with meta-analysis of multimodal ¹H-MRS-fMRI studies

Multimodal neuroimaging studies combining proton magnetic resonance spectroscopy ( H-MRS) to quantify GABA and/or glutamate concentrations and functional magnetic resonance imaging (fMRI) to measure brain activity non-invasively have advanced understanding of how neurochemistry and neurophysiology may be related at a macroscopic level. The present study aimed to perform a systematic review and meta-analysis of available studies examining the relationship between H-MRS glutamate and/or GABA levels and task-related fMRI signal in the healthy brain. Ovid (Medline, Embase, and PsycINFO) and Pubmed databases were systematically searched to identify articles published until December 2019. The primary outcome of interest was the association between resting levels of glutamate or GABA and task-related fMRI. Fifty-five papers were identified for inclusion in the systematic review. A further 22 studies were entered into four separate meta-analyses. These meta-analyses found evidence of significant negative associations between local GABA levels and (a) fMRI activation to visual tasks in the occipital lobe, and (b) activation to emotion processing in the medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC). However, there was no significant association between mPFC/ACC glutamate levels and fMRI activation to cognitive control tasks or to emotional processing, with the relationship to emotion processing related neural activity narrowly missing significance. Moreover, our systematic review also found converging evidence of negative associations between GABA levels and local brain activity, and positive associations between glutamate levels and distal brain activity, outside of the H-MRS sampling region. Albeit less consistently, additional relationships between GABA levels and distal brain activity and between glutamate levels and local brain activity were found. It remains unclear if the absence of effects for other brain regions and other cognitive-emotional domains reflects study heterogeneity or potential confounding effects of age, sex, or other unknown factors. Advances in H-MRS methodology as well as in the integration of H-MRS readouts with other imaging modalities for indexing neural activity hold great potential to reveal key aspects of the pathophysiology of mental health disorders involving aberrant interactions between neurochemistry and neurophysiology such as schizophrenia. 1 1 1 1

Implications from social and non-social task-based and task-free neuroimaging studies

Research on the effects of oxytocin on social cognition and behavior is constantly growing. Moreover, oxytocin is already discussed to be used as a drug supporting common therapies for a range of disorders displaying deficits in social cognition. Although, the knowledge about its neurophysiological mechanisms lacks in particular regarding its functioning in the non-social domain of behavior, cognition and related brain responses. Therefore, the present thesis had the aim to explore whether the neuropeptide oxytocin has an effect on non-social cognitive processes and their underlying neural correlates, how the neural mechanisms of oxytocin are modulated by additional social input and which basal changes are driven by the effects of oxytocin. I addressed these questions by the use of functional magnetic resonance imaging (fMRI) with task-based and resting-state designs and with a neuroimaging genetics approach. Oxytocin is synthesized in subnuclei of the hypothalamus and was originally known for its involvement in inducing labor. The oxytocin receptor is distributed largely across the brain, covering areas of the mesolimbic system such as the ventral striatum (vStr), the ventral tegmental area (VTA) and the amygdala, but also frontal areas and regions which are not prominently involved in social cognition. Generally, oxytocin is thought to affect social behavior and cognition, including parenting, affiliative behavior, but also emotion-regulation. It is also assumed to be sensitive for context, gender and personality characteristics. Whereas many studies explored the impact of oxytocin on socio-emotional actions such as on emotion-processing in the amygdala, only very few studies focused on the non-socioemotional domain, as for example memory processing or reward-related decision-making. With regard to the aims of this thesis, two of the three experiments employed a non-social decision making paradigm to reveal effects of oxytocin on non-social behavior and related brain activity. Indeed, oxytocin also modulated neural circuits during non-social tasks and even during the resting-state paradigm in the third experiment. This indicates that a social context might not be required to observe changes in neural activity and connectivity by oxytocin. Several theories have been proposed to explain the mechanisms by which oxytocin might function. The social cognition theory suggests that oxytocin might modulate prosocial affiliative behaviors and self-referential processing, the fear/stress approach emphasized its anxiolytic and stress reducing effects, the general approach-avoidance hypothesis of oxytocin assumes that oxytocin acts on approach and avoidance motivation and the social salience hypothesis implies that oxytocin regulates the salience of social stimuli. In conclusion, currently there is no general theory accounting for all the social and non-social effects of oxytocin as described in the literature. In the same perspective, the overall results from the current thesis contradict aspects of each theory, while specific patterns of effects may be best reconciliated with the framework of the approach-avoidance theory and the social salience hypothesis. In the first study a neuroimaging genetics approach was applied to investigate whether common variants of the oxytocin receptor gene influenced behavior and neural responses in a non-social reward-based decision-making paradigm. Specifically, due to dopaminergic-oxytocinergic interactions oxytocin-induced changes were expected in bottom-up reward-related and in top-down cognitive control-related activity. Two of the three candidate single-nucleotide-polymorphism (SNP) of the oxytocin receptor gene (OXTR) were associated with a modulation of reward-related activity during desire and reason situations in the paradigm used. The desire context was formed by allowing to obtain a presented reward, whereas in the reason context the same reward had to be rejected. Participants who were homozygous for the major allele of the OXTR SNP rs1042778 expressed more bottom-up related activity in the vStr in the desire context. In contrast to this, minor allele carriers showed a greater suppression of the reward-related activity in the reason context. This might have led to better cognitive control and therefore to significantly better performance in the rejection of reward stimuli in reason situations. According to this, major allele carriers had a stronger coupling between the vStr and the VTA in desire contexts. Moreover, minor allele carriers displayed an enhanced connectivity between the vStr and the anteroventral prefrontal cortex (avPFC) in reason situations. For the OXTR SNP rs237897 an interaction of gender with the activity in the VTA could be detected. Female participants, homozygous for the major genotype, presented more activation in the left VTA compared to males. Altogether, this study could show that OXTR polymorphisms are able to modulate reward-related as well as control-related activity even in a non-social decision-making paradigm. In study 2 a neuroimaging experiment was performed with the application of intranasal oxytocin and a modified reward-based decision-making paradigm including non-social as well as social stimuli. The main question was whether exogenous oxytocin alters behavioral and neural processes during the non-social condition in this task. Additionally, I was interested in possible changes of oxytocin effects by the presentation of emotional stimuli. Furthermore, by the additional use of both positive and fearful stimuli, I wanted to shed light on the ongoing discussion whether oxytocin acts valence-dependent or irrespective of valence on the activity of the amygdala. An opposite modulation of activity and functional connectivity regarding non-social compared with social context was shown after oxytocin treatment. In the non-social desire situation oxytocin reduced bottom-up activity within the vStr, probably by enhancing top-down control due to strengthening the negative coupling to a frontal region. In contrast, in non-social reason contexts the vStr was less deactivated, maybe due to decreased top-down control. By presenting fearful faces in the social condition, the pattern of neural responses and functional connectivity reversed. In this condition, oxytocin increased the activation in the vStr in desire situations, while it reduced the activation in reason situations. This change in activity was paralleled by stronger positive coupling in the desire context and less coupling as well as negative coupling in the reason context. Furthermore, depending on valence oxytocin decreased amygdala activation for fearful faces and increased amygdala activation for positive faces. The altered activity within the reward system by oxytocin might be the reason for an impaired performance during both desire and reason trials. After oxytocin treatment participants were less accurate in selecting target stimuli than in rejecting the reward stimulus and vice versa for the placebo. This suggests rather an impaired working memory than disturbed stimulus-association learning. To sum up, the comparison between the effects of oxytocin in the non-social and social condition yielded that oxytocin influences corticomesolimbic regions in a context-sensitive manner. The last study used a resting-state fMRI technique with additional administration of intranasal oxytocin. Of particular interest was the possible alteration of functional connectivity within and between large-scale networks by oxytocin. The analysis focused on functional networks indicated to play a major role in salience processing (the salience network - CO), social cognition and self-referential processing (the default mode network - DM) and attention processing (the ventral attentional network - VA). Thereby, basal changes by which oxytocin might influence neuronal responses were shown providing results for the ongoing debate on the underlying function of oxytocin. Although, I expected significant changes of functional connectivity within the DM network. The modulation of the CO and the VA networks were seen. Indeed, oxytocin changed the functional connectivity within and between large-scale networks even without engagement in a task. Oxytocin mainly influenced the VA by decreasing the cross-talk to regions typically part of the DM nodes; and oxytocin strengthened the functional connectivity to the edges of the CO, involving regions linked to salience processing. Additionally, oxytocin directly impacted the functional connectivity within the CO. Therefore, one basic effect of oxytocin might be to redirect attention (VA) from self-referential processing (DM) to the external environment, preparing for reception of salient information (CO). Taken together, the purpose of the present thesis was to extend the knowledge about the effects of oxytocin as well as basic mechanisms of oxytocin’s influence on cognition, behavior and neural activation and connectivity in non-social, social and task-free conditions. The results clearly demonstrated effects on neural activation, functional connectivity and on behavior in all three studies; supporting the claim that oxytocin does not only play an important role in socio-emotional processing