Anna Linda Krause

Dissociation of glutamate and cortical thickness is restricted to regions subserving trait but not state markers in major depressive disorder

BACKGROUND The anterior cingulate cortex (ACC) plays an important role in the neuropathology of major depressive disorder (MDD). So far, the effect of local cortical alteration on metabolites in multiple subdivisions of ACC has not been studied. We aimed to investigate structural and biochemical changes and their relationship in the pregenual ACC (pgACC), dorsal ACC (dACC) in MDD. METHODS We obtained magnetic resonance spectroscopy (MRS) in two investigated regions for 24 depressed patients and matched controls. In each region, cortical thickness (CTh) was calculated within a template mask based on its MRS voxel. We investigated neurotransmitter concentrations of Glx, N-acetyl aspartate (NAA), and myo-inositol (m-Ins) in two investigated regions, as well as their relationships with CTh in depressed individuals and healthy controls. RESULTS Patients showed significantly lower cortical thickness in dACC compared to controls. Glx in dACC significantly correlated with CTh in healthy controls but not MDD patients, while NAA and CTh in dACC significantly correlated in both groups. A marginal decrease of Glx in pgACC was found in the subgroup of more severely depressive patients, compared to the mildly depressed patients. LIMITATIONS Modest sample size and lack of episodes of depression may limit the generalizability of our findings. CONCLUSION Our results indicate an abolished CTh-MRS relation in dACC-associated with structural decline-but not in pgACC, where acute MRS alterations prevailed. Our study provides the first evidence of a neurochemical basis explaining some of the inter-individual variability in CTh in MDD.

Richness in Functional Connectivity Depends on the Neuronal Integrity within the Posterior Cingulate Cortex

The brains connectivity skeleton—a rich club of strongly interconnected members—was initially shown to exist in human structural networks, but recent evidence suggests a functional counterpart. This rich club typically includes key regions (or hubs) from multiple canonical networks, reducing the cost of inter-network communication. The posterior cingulate cortex (PCC), a hub node embedded within the default mode network, is known to facilitate communication between brain networks and is a key member of the “rich club.” Here, we assessed how metabolic signatures of neuronal integrity and cortical thickness influence the global extent of a functional rich club as measured using the functional rich club coefficient (fRCC). Rich club estimation was performed on functional connectivity of resting state brain signals acquired at 3T in 48 healthy adult subjects. Magnetic resonance spectroscopy was measured in the same session using a point resolved spectroscopy sequence. We confirmed convergence of functional rich club with a previously established structural rich club. N-acetyl aspartate (NAA) in the PCC is significantly correlated with age (p = 0.001), while the rich club coefficient showed no effect of age (p = 0.106). In addition, we found a significant quadratic relationship between fRCC and NAA concentration in PCC (p = 0.009). Furthermore, cortical thinning in the PCC was correlated with a reduced rich club coefficient after accounting for age and NAA. In conclusion, we found that the fRCC is related to a marker of neuronal integrity in a key region of the cingulate cortex. Furthermore, cortical thinning in the same area was observed, suggesting that both cortical thinning and neuronal integrity in the hub regions influence functional integration of at a whole brain level.

Graph theory reveals hyper-functionality in visual cortices of Seasonal Affective Disorder patients

Abstract Objectives. Seasonal affective disorder (SAD) is a subtype of recurrent unipolar or bipolar depressive disorder with a higher prevalence in winter than in summer. The biological underpinnings of SAD are so far poorly understood. Studies examining SAD have found disturbances between the molecular and connectivity scales. The aim of the study was to explore changes in functional connectivity typical for SAD. Methods. We investigated unmedicated, untreated SAD patients and healthy controls using resting-state functional magnetic resonance imaging (rs-fMRI) utilizing graph theory, a data driven and hypothesis free approach, to model functional networks of the brain. Results. Comparing whole brain network properties using graph theory we observed globally affected network topologies with increasing pathlength in SAD. Nodal changes, however, were highly restricted to bilateral inferior occipital cortex. Interestingly, we found a lateralization where hyper-connectedness was restricted to right inferior occipital cortex and hyper-efficiency was found in the left inferior occipital cortex. Furthermore, we found these nodes became more “hub like” in patients, suggesting a greater functional role. Conclusions. Our work stresses the importance of abnormal intrinsic processing during rest, primarily affecting visual areas and subsequently changing whole brain networks, and thus providing an important hint towards potential future therapeutic approaches.

Dynamic disconnection of the supplementary motor area after processing of dismissive biographic narratives

To understand the interplay between affective social information processing and its influence on mental states we investigated changes in functional connectivity (FC) patterns after audio exposure to emotional biographic narratives.

Dismissing Attachment Characteristics Dynamically Modulate Brain Networks Subserving Social Aversion

Attachment patterns influence actions, thoughts and feeling through a person’s “inner working model”. Speech charged with attachment-dependent content was proposed to modulate the activation of cognitive-emotional schemata in listeners. We performed a 7 Tesla rest-task-rest functional magnetic resonance imaging (fMRI)-experiment, presenting auditory narratives prototypical of dismissing attachment representations to investigate their effect on 23 healthy males. We then examined effects of participants’ attachment style and childhood trauma on brain state changes using seed-based functional connectivity (FC) analyses, and finally tested whether subjective differences in responsivity to narratives could be predicted by baseline network states. In comparison to a baseline state, we observed increased FC in a previously described “social aversion network” including dorsal anterior cingulated cortex (dACC) and left anterior middle temporal gyrus (aMTG) specifically after exposure to insecure-dismissing attachment narratives. Increased dACC-seeded FC within the social aversion network was positively related to the participants’ avoidant attachment style and presence of a history of childhood trauma. Anxious attachment style on the other hand was positively correlated with FC between the dACC and a region outside of the “social aversion network”, namely the dorsolateral prefrontal cortex, which suggests decreased network segregation as a function of anxious attachment. Finally, the extent of subjective experience of friendliness towards the dismissing narrative was predicted by low baseline FC-values between hippocampus and inferior parietal lobule (IPL). Taken together, our study demonstrates an activation of networks related to social aversion in terms of increased connectivity after listening to insecure-dismissing attachment narratives. A causal interrelation of brain state changes and subsequent changes in social reactivity was further supported by our observation of direct prediction of neuronal responses by individual attachment and trauma characteristics and reversely prediction of subjective experience by intrinsic functional connections. We consider these findings of activation of within-network and between-network connectivity modulated by inter-individual differences as substantial for the understanding of interpersonal processes, particularly in clinical settings.

Self-directedness and the susceptibility to distraction by saliency

ABSTRACT People with low Self-directedness (SD) tend to explain their behaviour as being significantly influenced by events in the external environment. One important dimension of external cues is their level of salience: highly salient external stimuli are more likely to capture attention, even when such stimuli are not relevant to goals. We examined whether adults reporting low SD would exhibit greater susceptibility to distraction by highly salient external stimuli. Fifty-four (42 males) subjects completed the Attention Modulation by Salience Task (AMST) measuring reaction times to early- or late-onset auditory stimuli in the presence of high- or low-salience visual distractors. SD was assessed via self-report, and analyses tested the relationship between SD and performance on the AMST. Results showed a slowed early response to auditory cues during high salience compared to low salience. Indeed, individuals reporting low SD showed stronger salience interference, suggesting that external causality attribution is accompanied by a subconscious perceptual deficit.

Novelty seeking and reward dependence-related large-scale brain networks functional connectivity variation during salience expectancy: Variations During Salience Expectancy

A salience network (SN) anchored in the anterior insula (AI) and dorsal anterior cingulate cortex (dACC) plays a key role in switching between brain networks during salience detection and attention regulation. Previous fMRI studies have associated expectancy behaviors and SN activation with novelty seeking (NS) and reward dependence (RD) personality traits. To address the question of how functional connectivity (FC) in the SN is modulated by internal (expectancy‐related) salience assignment and different personality traits, 68 healthy participants performed a salience expectancy task using functional magnetic resonance imaging, and psychophysiological interaction analysis (PPI) was conducted to determine salience‐related connectivity changes during these anticipation periods. Correlation was then evaluated between PPI and personality traits, assessed using the temperament and character inventory of 32 male participants. During high salience expectancy, SN‐seed regions showed reduced FC to visual areas and parts of the default mode network, but increased FC to the central executive network. With increasing NS, participants showed significantly increasing disconnection between right AI and middle cingulate cortex when expecting high‐salience pictures as compared to low‐salience pictures, while increased RD also predicted decreased right dACC and caudate FC for high salience expectancy. Our findings suggest a direct link between personality traits and internal salience processing mediated by differential network integration of the SN. SN activity and coordination may therefore be moderated by novelty seeking and reward dependency personality traits, which are associated with risk of addiction. Hum Brain Mapp 38:4064–4077, 2017.

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial

Abstract Background The increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects. Methods Blood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX). Results Systolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005). Conclusions Subanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.

Metabolic mapping reveals sex dependent involvement of default mode and salience network in alexithymia

Alexithymia, a personality construct marked by difficulties in processing ones emotions, has been linked to the altered activity in the anterior cingulate cortex (ACC). Although longitudinal studies reported sex differences in alexithymia, what mediates them is not known. To investigate sex-specific associations of alexithymia and neuronal markers, we mapped metabolites in four brain regions involved differentially in emotion processing using a point-resolved spectroscopy MRS sequence in 3 Tesla. Both sexes showed negative correlations between alexithymia and N-acetylaspartate (NAA) in pregenual ACC (pgACC). Women showed a robust negative correlation of the joint measure of glutamate and glutamine (Glx) to NAA in posterior cingulate cortex (PCC), whereas men showed a weak positive association of Glx to NAA in dorsal ACC (dACC). Our results suggest that lowered neuronal integrity in pgACC, a region of the default mode network (DMN), might primarily account for the general difficulties in emotional processing in alexithymia. Association of alexithymia in women extends to another region in the DMN-PCC, while in men a region in the salience network (SN) was involved. These observations could be representative of sex specific regulation strategies that include diminished internal evaluation of feelings in women and cognitive emotion suppression in men.

Functional connectivity changes following interpersonal reactivity

Attachment experiences substantially influence emotional and cognitive development. Narratives comprising attachment‐dependent content were proposed to modulate activation of cognitive‐emotional schemata in listeners. We studied the effects after listening to prototypical attachment narratives on wellbeing and countertransference‐reactions in 149 healthy participants. Neural correlates of these cognitive‐emotional schema activations were investigated in a 7 Tesla rest‐task‐rest fMRI‐study (23 healthy males) using functional connectivity (FC) analysis of the social approach network (seed regions: left and right Caudate Nucleus, CN). Reduced FC between left CN and bilateral dorsolateral prefrontal cortex (DLPFC) represented a general effect of prior auditory stimulation. After presentation of the insecure‐dismissing narrative, FC between left CN and bilateral temporo‐parietal junction, and right dorsal posterior Cingulum was reduced, compared to baseline. Post‐narrative FC‐patterns of insecure‐dismissing and insecure‐preoccupied narratives differed in strength between left CN and right DLPFC. Neural correlates of the moderating effect of individual attachment anxiety were represented in a reduced CN‐DLPFC FC as a function of individual neediness‐levels. These findings suggest specific neural processing of prolonged mood‐changes and schema activation induced by attachment‐specific speech patterns. Individual desire for interpersonal proximity was predicted by attachment anxiety and furthermore modulated FC of the social approach network in those exposed to such narratives.