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.

Deficient fear extinction memory in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) might be maintained by deficient extinction memory. We used a cued fear conditioning design with extinction and a post-extinction phase to provoke the return of fear and examined the role of the interplay of amygdala, hippocampus and prefrontal regions. METHODS: We compared 18 PTSD patients with two healthy control groups: 18 trauma-exposed subjects without PTSD (nonPTSD) and 18 healthy controls (HC) without trauma experience. They underwent a three-day ABC-conditioning procedure in a functional magnetic resonance imaging scanner. Two geometric shapes that served as conditioned stimuli (CS) were presented in the context of virtual reality scenes. Electric painful stimuli were delivered after one of the two shapes (CS+) during acquisition (in context A), while the other (CS-) was never paired with pain. Extinction was performed in context B and extinction memory was tested in a novel context C. RESULTS: The PTSD patients showed significantly higher differential skin conductance responses than the non-PTSD and HC and higher differential amygdala and hippocampus activity than the HC in context C. In addition, elevated arousal to the CS+ during extinction and to the CS- throughout the experiment was present in the PTSD patients but self-reported differential valence or contingency were not different. During extinction recall, differential amygdala activity correlated positively with the intensity of numbing and ventromedial prefrontal cortex activity correlated positively with behavioral avoidance. CONCLUSIONS: PTSD patients show heightened return of fear in neural and peripheral measures. In addition, self-reported arousal was high to both danger (CS+) and safety (CS-) cues. These results suggest that a deficient maintenance of extinction and a failure to identify safety signals might contribute to PTSD symptoms, whereas non-PTSD subjects seem to show normal responses.

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.

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.