Altered frontolimbic activity during virtual reality-based contextual fear learning in patients with posttraumatic stress disorder.

BACKGROUND: Deficiency in contextual and enhanced responding in cued fear learning may contribute to the development of posttraumatic stress disorder (PTSD). We examined the responses to aversive Pavlovian conditioning with an unpredictable spatial context as conditioned stimulus compared to a predictable context. We hypothesized that the PTSD group would demonstrate less hippocampal and ventromedial prefrontal cortex (vmPFC) activation during acquisition and extinction of unpredictable contexts and an over-reactive amygdala response in the predictable contexts compared to controls. METHODS: A novel combined differential cue-context conditioning paradigm was applied using virtual reality with spatial contexts that required configural and cue processing. We assessed 20 patients with PTSD, 21 healthy trauma-exposed (TC) and 22 non-trauma-exposed (HC) participants using functional magnetic resonance imaging, skin conductance responses, and self-report measures. RESULTS: During fear acquisition, patients with PTSD compared to TC showed lower activity in the hippocampi in the unpredictable and higher activity in the amygdalae in the predictable context. During fear extinction, TC compared to patients and HC showed higher brain activity in the vmPFC in the predictable context. There were no significant differences in self-report or skin conductance responses. CONCLUSIONS: Our results suggest that patients with PTSD differ in brain activation from controls in regions such as the hippocampus, the amygdala, and the vmPFC in the processing of unpredictable and predictable contexts. Deficient encoding of more complex configurations might lead to a preponderance of cue-based predictions in PTSD. Exposure-based treatments need to focus on improving predictability of contextual processing and reducing enhanced cue reactivity.

Structural white and gray matter differences in a large sample of patients with Posttraumatic Stress Disorder and a healthy and trauma-exposed control group: Diffusion tensor imaging and region-based morphometry.

Differences in structural white and gray matter in survivors of traumatic experiences have been related to the development and maintenance of Posttraumatic Stress Disorder (PTSD). However, there are very few studies on diffusion tensor imaging and region based morphometry comparing patients with PTSD to two control groups, namely healthy individuals with or without trauma experience. It is also unknown if differences in white and gray matter are associated. In this cross-sectional study, we examined white- and gray matter differences between 44 patients with PTSD, 49 trauma control and 61 healthy control subjects. We compared the groups applying Tract-Based Spatial Statistics (TBSS) for a whole brain white matter analysis as well as region of interest analyses for white and gray matter. First, trauma control subjects in comparison to patients with PTSD and healthy control subjects showed significantly a) higher fractional anisotropy (FA) in the left corticospinal tract and inferior fronto-occipital fasciculus than patients with PTSD, b) higher FA in the left inferior fronto-occipital-, right inferior- and right superior longitudinal fasciculi, c) higher FA in the forceps minor and d) higher volume of the left and right anterior insulae. Second, we show significant correlations between the FA in the forceps minor and the gray matter volume in the left and right anterior insulae. Third, the mean FA value in the forceps minor correlated negatively with symptom severity of PTSD and depression as well as trait anxiety, whereas the gray matter volume in the left anterior insula correlated negatively with symptom severity in PTSD. Our findings underline the importance of brain structures critically involved in emotion regulation and salience mapping. While previous studies associated these processes primarily to functional and task-based differences in brain activity, we argue that morphometrical white and gray matter differences could serve as targets in neuroscientifically-informed prevention and treatment interventions for PTSD.

White matter correlates of contextual pavlovian fear extinction and the role of anxiety in healthy humans.

Pavlovian contextual fear extinction is viewed as an important mechanism for behavioral adaptation in everyday life, including challenging situations of stress and anxiety. It has frequently been shown to relate to the function of brain areas like the hippocampus and medial prefrontal cortex (mPFC), while the role of structural properties, like white matter tracts in these regions, has been less studied. We employed diffusion tensor imaging to determine structural white matter connectivity (cingulum and uncinate fasciculus) correlates of contextual pavlovian fear extinction indicators measured through functional magnetic resonance imaging, skin conductance responses (SCRs) and self-reports of valence, arousal and contingency in 93 healthy individuals. Higher fractional anisotropy values in the hippocampal cingulum were significantly related to higher SCRs during extinction of contextual conditioned responses (explained variance: 11.2%) as an indicator of extinction deficits on the level of physiological arousal. However, FA was neither related to any of the other fear extinction measures, nor did we find associations with functional extinction responses in the hippocampus or mPFC. Trait anxiety was a significant moderator of the SCR-hippocampal cingulum association (explained variance: 32.09%). The data add evidence for a critical role of the hippocampal formation in contextual pavlovian extinction, and, together with the strong effect of trait anxiety, may have implications for the development of anxiety disorders where contextual extinction learning deficits are observed.

Memory-guided attention: bilateral hippocampal volume positively predicts implicit contextual learning.

Several studies have begun to demonstrate that contextual memories constitute an important mechanism to guide our attention. Although there is general consensus that the hippocampus is involved in the encoding of contextual memories, it is controversial whether this structure can support implicit forms of contextual memory. Here, we combine automated segmentation of structural MRI with neurobehavioral assessment of implicit contextual memory-guided attention to test the hypothesis that hippocampal volume would predict the magnitude of implicit contextual learning. Forty healthy subjects underwent 3T magnetic resonance imaging brain scanning with subsequent automatic measurement of the total brain and hippocampal (right and left) volumes. Implicit learning of contextual information was measured using the contextual cueing task. We found that both left and right hippocampal volumes positively predicted the magnitude of implicit contextual learning. Larger hippocampal volume was associated with superior implicit contextual memory performance. This study provides compelling evidence that implicit contextual memory-guided attention is hippocampus-dependent.

Default mode network connectivity of fear- and anxiety-related cue and context conditioning.

Classical fear conditioning is an important mechanism to adequately respond and adapt to environmental threats and has been related to the development of fear and anxiety. Both cue and context conditioning have been studied but little is known about their relation to relevant resting state networks. The default mode network (DMN) has been reported to be involved in affective learning and described as facilitating a state of readiness in responding to environmental changes. We examined resting state brain connectivity patterns of the default mode network (DMN) in 119 healthy volunteers. Specifically, we carried out correlation analyses between the DMN and skin conductance responses (SCRs) as well as arousal, valence and contingency ratings during learning. In addition, we examined the role of trait anxiety. Two different DMN patterns were identified in which stronger connectivity was linked to lower differential SCRs during fear and anxiety learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. These results were replicated in an independent sample. Functional connectivity of the DMN with these key regions at rest was also predictive of trait anxiety but this association could not be replicated in the second sample. We showed that DMN connectivity is differently associated with cued versus contextual learning mechanisms. Uncovering individual differences in baseline network connectivity of the DMN with these key regions might lead to a better understanding of fear and anxiety. Such findings could indeed help to identify vulnerability factors linked to network alterations at rest with dysregulation of learning processes involved in the pathophysiology of stress and anxiety disorders.

Structural brain correlates of heart rate variability in a healthy young adult population.

The high frequency component of heart rate variability (HRV) has reliably been shown to serve as an index of autonomic inhibitory control and is increasingly considered as a biomarker of adaptability and health. While several functional neuroimaging studies identified associations between regional cerebral blood flow and HRV, studies on structural brain correlates of HRV are scarce. We investigated whether interindividual differences in HRV are related to brain morphology in healthy humans. Thirty participants underwent HRV recording at rest subsequent to structural magnetic resonance imaging. Cortical reconstruction and subcortical volumetry were performed with the Freesurfer image analysis suite. The amount of resting HRV was positively correlated with the cortical thickness of an area within the right anterior midcingulate cortex (aMCC). Consistent with existing studies implicating forebrain regions in cardiac regulation, our findings show that the thickness of the right aMCC is associated with the degree of parasympathetic regulation of heart rate. Evidence for the neural correlates of interindividual differences in HRV may complement our understanding of the mechanisms underlying the association between HRV and self-regulatory capacity.

Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: Implications for psychopathology.

Stress exposure causes a structural reorganization in neurons of the amygdala. In particular, animal models have repeatedly shown that both acute and chronic stress induce neuronal hypertrophy and volumetric increase in the lateral and basolateral nuclei of amygdala. These effects are visible on the behavioral level, where stress enhances anxiety behaviors and provokes greater fear learning. We assessed stress and anxiety levels in a group of 18 healthy human trauma-exposed individuals (TR group) compared to 18 non-exposed matched controls (HC group), and related these measurements to amygdala volume. Traumas included unexpected adverse experiences such as vehicle accidents or sudden loss of a loved one. As a measure of aversive learning, we implemented a cued fear conditioning paradigm. Additionally, to provide a biological marker of chronic stress, we measured the sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis using a dexamethasone suppression test. Compared to the HC, the TR group showed significantly higher levels of chronic stress, current stress and trait anxiety, as well as increased volume of the left amygdala. Specifically, we observed a focal enlargement in its lateral portion, in line with previous animal data. Compared to HC, the TR group also showed enhanced late acquisition of conditioned fear and deficient extinction learning, as well as salivary cortisol hypo-suppression to dexamethasone. Left amygdala volumes positively correlated with suppressed morning salivary cortisol. Our results indicate differences in trauma-exposed individuals which resemble those previously reported in animals exposed to stress and in patients with post-traumatic stress disorder and depression. These data provide new insights into the mechanisms through which traumatic stress might prompt vulnerability for psychopathology.

Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning.

The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.

Amygdalar and hippocampal volume: A comparison between manual segmentation, Freesurfer and VBM.

Automated segmentation of the amygdala and the hippocampus is of interest for research looking at large datasets where manual segmentation of T1-weighted magnetic resonance tomography images is less feasible for morphometric analysis. Manual segmentation still remains the gold standard for subcortical structures like the hippocampus and the amygdala. A direct comparison of VBM8 and Freesurfer is rarely done, because VBM8 results are most often used for voxel-based analysis. We used the same region-of-interest (ROI) for Freesurfer and VBM8 to relate automated and manually derived volumes of the amygdala and the hippocampus. We processed a large manually segmented dataset of n=92 independent samples with an automated segmentation strategy (VBM8 vs. Freesurfer Version 5.0). For statistical analysis, we only calculated Pearsons's correlation coefficients, but used methods developed for comparison such as Lin's concordance coefficient. The correlation between automatic and manual segmentation was high for the hippocampus [0.58-0.76] and lower for the amygdala [0.45-0.59]. However, concordance coefficients point to higher concordance for the amygdala [0.46-0.62] instead of the hippocampus [0.06-0.12]. VBM8 and Freesurfer segmentation performed on a comparable level in comparison to manual segmentation. We conclude (1) that correlation alone does not capture systematic differences (e.g. of hippocampal volumes), (2) calculation of ROI volumes with VBM8 gives measurements comparable to Freesurfer V5.0 when using the same ROI and (3) systematic and proportional differences are caused mainly by different definitions of anatomic boundaries and only to a lesser part by different segmentation strategies. This work underscores the importance of using method comparison techniques and demonstrates that even with high correlation coefficients, there can be still large differences in absolute volume.

Neural Mechanism of a Sex-Specific Risk Variant for Posttraumatic Stress Disorder in the Type I Receptor of the Pituitary Adenylate Cyclase Activating Polypeptide.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a frequent anxiety disorder with higher prevalence rates in female patients than in male patients (2.5:1). Association with a single nucleotide polymorphism (rs2267735) in the gene ADCYAP1R1 encoding the type I receptor (PAC1-R) of the pituitary adenylate cyclase activating polypeptide has been reported with PTSD in female patients. We sought to identify the neural correlates of the described PAC1-R effects on associative learning. METHODS: In a reverse genetic approach, we examined two independent healthy samples (N1 = 112, N2 = 73) using functional magnetic resonance imaging during cued and contextual fear conditioning. Skin conductance responses and verbal self-reports of arousal, valence, and contingency were recorded. RESULTS: We found that PAC1-R modulates the blood oxygenation level-dependent response of the hippocampus. Specifically, we observed decreased hippocampal activity during contextual, but not during cued, fear conditioning in female participants carrying the PAC1-R risk allele. We observed no significant differences in conditionability for skin conductance responses, verbal reports, or activation in other brain regions between the genotype groups in female participants. CONCLUSIONS: Our results suggest that impaired contextual conditioning in the hippocampal formation may mediate the association between PAC1-R and PTSD symptoms. Our findings potentially identify a missing link between the involvement of PAC1-R in PTSD and the well-established structural and functional hippocampal deficits in these patients.

Dissociable roles for hippocampal and amygdalar volume in human fear conditioning.

Fear conditioning is a basic learning process which involves the association of a formerly neutral conditioned stimulus (CS) with a biologically relevant aversive unconditioned stimulus (US). Previous studies conducted in brain-lesioned patients have shown that while the acquisition of autonomic fear responses requires an intact amygdala, a spared hippocampus is necessary for the development of the CS-US contingency awareness. Although these data have been supported by studies using functional neuroimaging techniques in healthy people, attempts to extend these findings to the morphological aspects of amygdala and hippocampus are missing. Here we tested the hypothesis that amygdalar and hippocampal volumes play dissociable roles in determining autonomic responses and contingency awareness during fear conditioning. Fifty-two healthy individuals (mean age 21.83) underwent high-resolution magnetic resonance imaging. We used a differential delay fear conditioning paradigm while assessing skin conductance responses (SCRs), subjective ratings of CS-US contingency, as well as emotional valence and perceived arousal. Left amygdalar volume significantly predicted the magnitude of differential SCRs during fear acquisition, but had no impact on contingency learning. Conversely, bilateral hippocampal volumes were significantly related to contingency ratings, but not to SCRs. Moreover, left amygdalar volume predicted SCRs to the reinforced CS alone, but not those elicited by the US. Our findings bridge the gap between previous lesion and functional imaging studies, by showing that amygdalar and hippocampal volumes differentially modulate the acquisition of conditioned fear. Further, our results reveal that the morphology of these limbic structures moderate learning and memory already in healthy persons.

Functional MRI studies of the hippocampus.

Developments in tasks and imaging techniques applied over the last decades have yielded substantial support for the hypothesized role of the hippocampus in mnemonic processes. Human imaging research has now moved on to disentangle the contributions of the different hippocampal subregions and adjacent cortices, so as to bridge the gap between rodent and human data. Besides the importance of such studies for basic research, the investigation of hippocampal (dys)function has clinical relevance for diseases ranging from neurological disorders such as Alzheimer's disease or epilepsy to mental disorders such as schizophrenia or anxiety disorders. So far, most of the present review articles and books about the hippocampus and its functions focus on traditional declarative memory paradigms and 'encoding versus retrieval'. In this chapter we concentrate on a less travelled, but not less important, route concerning the role of the hippocampus in a well-established associative learning (encoding) paradigm: pavlovian fear conditioning. Fear conditioning is hypothesized to model aversive associative learning on a nonpathological level and is further assumed to recruit the same networks that are relevant for anxiety disorders, with the hippocampus being specific for contextual fear conditioning. We highlight the findings in humans by addressing its role in mediating spatial and temporal aspects of a context, involving different kinds of a fear-conditioning procedure (delay vs. trace conditioning), and its role in extinction, both from a theoretical and clinical perspective.

Bigger is better! Hippocampal volume and declarative memory performance in healthy young men.

The importance of the hippocampus for declarative memory processes is firmly established. Nevertheless, the issue of a correlation between declarative memory performance and hippocampal volume in healthy subjects still remains controversial. The aim of the present study was to investigate this relationship in more detail. For this purpose, 50 healthy young male participants performed the California Verbal Learning Test. Hippocampal volume was assessed by manual segmentation of high-resolution 3D magnetic resonance images. We found a significant positive correlation between putatively hippocampus-dependent memory measures like short-delay retention, long-delay retention and discriminability and percent hippocampal volume. No significant correlation with measures related to executive processes was found. In addition, percent amygdala volume was not related to any of these measures. Our data advance previous findings reported in studies of brain-damaged individuals in a large and homogeneous young healthy sample and are important for theories on the neural basis of episodic memory.

A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.

Activation of the ventral striatum during aversive contextual conditioning in humans.

The goal of this study was to investigate the function of the ventral striatum and brain regions involved in anxiety and learning during aversive contextual conditioning. Functional magnetic resonance imaging was used to assess the hemodynamic brain response of 118 healthy volunteers during a differential fear conditioning paradigm. Concurrently obtained skin conductance responses and self-reports indicated successful context conditioning. Increased hemodynamic responses in the ventral striatum during presentation of the conditioned visual stimulus that predicted the aversive event (CS+) compared to a second stimulus never paired with the aversive event (CS-) were observed in the late acquisition phase. Additionally, we found significant brain responses in the amygdala, hippocampus, insula and medial prefrontal cortex. Our data suggest the involvement of the ventral striatum during contextual fear conditioning, and underline its role in the processing of salient stimuli in general, not only during reward processing.

Hippocampal but not amygdalar volume affects contextual fear conditioning in humans.

Both animal and human studies have identified a critical role of the hippocampus in contextual fear conditioning. In humans mainly functional magnetic resonance imaging has been used. To extend these findings to volumetric properties, 58 healthy participants underwent structural magnetic resonance imaging and participated in a differential fear conditioning paradigm with contextual stimuli. Ratings of emotional valence, arousal, and contingency as well as skin conductance responses (SCRs) were used as indicators of conditioning. Twenty-nine participants with the smallest hippocampal volumes were compared with 29 persons with the largest hippocampal volumes. Persons with larger hippocampal volume (especially on the right side) learned to discriminate between two conditioned contexts, whereas those with small hippocampal volumes did not, as indicated by SCRs. Further analyses showed that these results could not be explained by amygdalar volumes. In contrast, the participant answers on the self-report measures were not significantly influenced by hippocampal or amygdalar, but by total brain volume, suggesting a role of cortical structures in these more cognitive evaluation processes. Reanalysis of the self-report data using partial hippocampal volumes revealed a significant influence of the posterior but not anterior subvolumes, which is in accordance with theories and empirical findings on hippocampal functioning. This study shows the relevance of hippocampal volume for contextual fear conditioning in healthy volunteers and may have important implications for anxiety disorders.

Differential amygdala activation to negative and positive emotional pictures during an indirect task.

The role of the amygdala for the processing of valence and arousal is a matter of debate. Using event-related functional magnetic resonance imaging, we tested valence-specific amygdala effects during attentional distraction. Subjects attended to a matching task in the foreground of neutral pictures, and of negative and positive pictures matched for arousal. Negative pictures elicited stronger amygdala activation than neutral or positive pictures, suggesting valence-specific amygdala responses under attentional load.