Martin Fungisai Gerchen

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.

Hippocampal–Dorsolateral Prefrontal Coupling as a Species-Conserved Cognitive Mechanism: A Human Translational Imaging Study

Hippocampal–prefrontal cortex (HC–PFC) interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging together with a spatial WM paradigm adapted from rodent research to examine HC–PFC coupling in humans. A PFC–parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral PFC (DLPFC), and right supramarginal gyrus explained one-fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC–DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.

Analyzing Task-Dependent Brain Network Changes by Whole-Brain Psychophysiological Interactions: A Comparison to Conventional Analysis

While fMRI activation studies contrasting task conditions regularly assess the whole brain, this is usually not true for studies analyzing task‐dependent brain connectivity changes by psychophysiological interactions (PPI). Here we combine standard PPI (sPPI) and generalized PPI (gPPI) with a priori brain parcellation by spatially constrained normalized cut spectral clustering (NCUT) to analyze task‐dependent connectivity changes in a whole brain manner, and compare the results to multiseed conventional PPI analyses over all activation peaks in an episodic memory recall task. We show that, depending on the chosen parcellation frame, the whole‐brain PPI approach is able to detect a large amount of the information that is detected by the conventional approach. Over and above, whole‐brain PPI allows identification of several additional task‐modulated connections, particularly from seed regions without significant activation differences between conditions. Hum Brain Mapp 35:5071–5082, 2014.

fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal-limbic brain connectivity.

Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal-limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down-regulation with neurofeedback have not been addressed yet. Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N=16). In contrast, a control group (N=16) receiving sham feedback did not alter amygdala connectivity (Group×Condition t-contrast: p<.05 at cluster-level). Task-dependent increases in amygdala-vmPFC connectivity were predicted by picture arousal (β=.59, p<.05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp=.90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p<.05 at cluster-level). Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation.

Multi-site reproducibility of prefrontal-hippocampal connectivity estimates by stochastic DCM.

This study examined the reproducibility of prefrontal-hippocampal connectivity estimates obtained by stochastic dynamic causal modeling (sDCM). 180 healthy subjects were measured by functional magnetic resonance imaging (fMRI) during a standard working memory N-Back task at three different sites (Mannheim, Bonn, Berlin; each with 60 participants). The reproducibility of regional activations in key regions for working memory (dorsolateral prefrontal cortex, DLPFC; hippocampal formation, HF) was evaluated using conjunction analyses across locations. These analyses showed consistent activation of right DLPFC and deactivation of left HF across all three different sites. The effective connectivity between DLPFC and HF was analyzed using a simple two-region sDCM. For each subject, we evaluated sixty-seven alternative sDCMs and compared their relative plausibility using Bayesian model selection (BMS). Across all locations, BMS consistently revealed the same winning model, with the 2-Back working memory condition as driving input to both DLPFC and HF and with a connection from DLPFC to HF. Statistical tests on the sDCM parameter estimates did not show any significant differences across the three sites. The consistency of both the BMS results and model parameter estimates indicates the reliability of sDCM in our paradigm. This provides a basis for future genetic and clinical studies using this approach.

Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence

According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol‐associated cues, diminished motivation to pursue non‐drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non‐drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol‐dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task‐related brain activation and connectivity. Alcohol‐dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit.

Aberrant activity and connectivity of the posterior superior temporal sulcus during social cognition in schizophrenia

Abstract Schizophrenia is associated with significant impairments in social cognition. These impairments have been shown to go along with altered activation of the posterior superior temporal sulcus (pSTS). However, studies that investigate connectivity of pSTS during social cognition in schizophrenia are sparse. Twenty-two patients with schizophrenia and 22 matched healthy controls completed a social-cognitive task for functional magnetic resonance imaging that allows the investigation of affective Theory of Mind (ToM), emotion recognition and the processing of neutral facial expressions. Moreover, a resting-state measurement was taken. Patients with schizophrenia performed worse in the social-cognitive task (main effect of group). In addition, a group by social-cognitive processing interaction was revealed for activity, as well as for connectivity during the social-cognitive task, i.e., patients with schizophrenia showed hyperactivity of right pSTS during neutral face processing, but hypoactivity during emotion recognition and affective ToM. In addition, hypoconnectivity between right and left pSTS was revealed for affective ToM, but not for neutral face processing or emotion recognition. No group differences in connectivity from right to left pSTS occurred during resting state. This pattern of aberrant activity and connectivity of the right pSTS during social cognition might form the basis of false-positive perceptions of emotions and intentions and could contribute to the emergence and sustainment of delusions.

Hippocampal-Dorsolateral Prefrontal Coupling as a Species-Conserved Cognitive Mechanism: A Human Translational Imaging Study.

Abbreviations: CIU/CSU, chronic idiopathic/spontaneous urticaria; BHR, basophil histamine release; fMLP-N, formylmethionine-leucyl-phenylalanine

Combining task-related activation and connectivity analysis of fMRI data reveals complex modulation of brain networks: Complex Task Modulation of Brain Networks

Task‐related effects in functional magnetic resonance imaging (fMRI) data are usually analyzed with local activation approaches or integrative connectivity approaches, for example, by psychophysiological interaction (PPI) analysis. While both approaches are often applied to the same data set, a systematic combination of the results with a whole‐brain (WB) perspective is rarely conducted and the relationship between task‐dependent activation and connectivity effects is relatively unexplored. Here, we combined brain activation and graph theoretical analysis of WB‐PPI results in an exemplary episodic memory data set of N = 136 healthy human participants and found regions with congruent as well as incongruent activation and connectivity changes between task and control conditions. A comparison with large‐scale resting state networks showed that in congruent as well as incongruent regions task‐positively modulated connections were mainly between‐network connections, especially with the default mode network, while task‐negatively modulated connections were mainly found within resting state networks. Over all regions, the strength of absolute activation effects was associated with the tendency to exhibit task‐positive connectivity changes, mainly driven by a strong relationship in negatively activated regions. These results demonstrate that task demands lead to a complex modulation of brain networks and provide evidence that task‐evoked activation and connectivity effects reflect separable and complementary information on the macroscale brain level assessed by fMRI. Hum Brain Mapp 38:5726–5739, 2017.

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression

Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an animal model of treatment-resistant depression, namely Negative Cognitive State rats. First, an inhibitory light-sensitive ion channel was introduced into the LHb by viral transduction. Subsequently, laser stimulation was performed during fMRI acquisition on a 9.4 Tesla animal scanner. Neural activity and connectivity were assessed, before, during and after laser stimulation. We observed a connectivity decrease in the DMN following laser-induced LHb perturbation. Our data indicate a causal link between LHb downregulation and reduction in DMN connectivity. These findings may advance our mechanistic understanding of LHb inhibition, which had previously been identified as a promising therapeutic principle, especially for treatment-resistant depression.