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.

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.

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.