Einat Levy-Gigi

Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.

BACKGROUND Posttraumatic stress disorder (PTSD) is characterized by a reduced expression of FKBP5, a key modulator of the glucocorticoid receptor. Smaller hippocampal volume has also been documented in PTSD. We explored possible changes in FKBP5 gene expression and brain structure in patients with PTSD after cognitive behavioral therapy (CBT). METHODS We measured peripheral FKBP5 RNA and volumes of the hippocampus, amygdala, and medial orbitofrontal cortex in 39 patients with PTSD before and after CBT. The control subjects were 31 trauma-exposed individuals without PTSD who were also assessed twice. Gene expression changes were screened with a microarray toolkit, which was followed by quantitative polymerase chain reaction for FKBP5 RNA. Brain volumes were measured using FreeSurfer. RESULTS At baseline, patients with PTSD showed lower FKBP5 gene expression and smaller hippocampal and medial orbitofrontal cortex, but not amygdala, volumes relative to control subjects. At follow-up, we found significantly increased FKBP5 expression and increased hippocampal volume in patients with PTSD. At follow-up, patients did not differ from control subjects in hippocampal volume. Improvement in PTSD symptoms was predicted by increased FKBP5 expression and increased hippocampal volume, but the primary predictor was FKBP5 expression. The most significantly altered gene expression in patients with PTSD relative to control subjects was found for ribosomal protein S6 kinase, which did not change after CBT and did not correlate with hippocampal volume. CONCLUSIONS Clinical improvement in individuals with PTSD was associated with increased expression of FKBP5 and increased hippocampal volume, which were positively correlated.

Reduced hippocampal volume is associated with overgeneralization of negative context in individuals with PTSD.

OBJECTIVE Previous studies demonstrated reduced hippocampal volume in individuals with posttraumatic stress disorder (PTSD). However, the functional role the hippocampus plays in PTSD symptomatology is still unclear. The aim of the present study was to explore generalization learning and its connection to hippocampal volume in individuals with and without PTSD. Animal and human models argue that hippocampal deficit may result in failure to process contextual information. Therefore we predicted associations between reduced hippocampal volume and overgeneralization of context in individuals with PTSD. METHOD We conducted MRI scans of bilateral hippocampal and amygdala formations as well as intracranial and total brain volumes. Generalization was measured using a novel-learning paradigm, which separately evaluates generalization of cue and context in conditions of negative and positive outcomes. RESULTS As expected, MRI scans indicated reduced hippocampal volume in PTSD compared to non-PTSD participants. Behavioral results revealed a selective deficit in context generalization learning in individuals with PTSD, F(1, 43) = 8.27, p < .01, η(p)² = .16. Specifically, as predicted, while generalization of cue was spared in both groups, individuals with PTSD showed overgeneralization of negative context. Hence, they could not learn that a previously negative context is later associated with a positive outcome, F(1, 43) = 7.33, p = .01, η(p)² = .15. Most importantly, overgeneralization of negative context significantly correlated with right and left hippocampal volume (r = .61, p = .000; r = .5, p = .000). Finally, bilateral hippocampal volume provided the strongest prediction of overgeneralization of negative context. CONCLUSIONS Reduced hippocampal volume may account for the difficulty of individuals with PTSD to differentiate negative and novel conditions and hence may facilitate reexperiencing symptoms.

The Effect of Dopamine Agonists on Adaptive and Aberrant Salience in Parkinson's Disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinsons disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus–reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus–reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus–reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

Emotion regulatory flexibility sheds light on the elusive relationship between repeated traumatic exposure and posttraumatic stress disorder symptoms

Conventional wisdom suggests that repeated traumatic exposure should strongly relate to increased posttraumatic stress disorder (PTSD) symptoms. However, research with first responders, who are repeatedly exposed to traumatic events, finds inconsistent links to PTSD. Although recent studies explored associations between general self-reported emotion-regulation and PTSD, the present study was the first to test the moderating role of regulatory choice flexibility, the ability to choose regulatory options that suit contextual demands. A total of 69 firefighters with differing duty-related traumatic-exposure were tested on an innovative performance-based regulatory choice flexibility paradigm and evaluated for PTSD symptoms using clinical interviews. We predicted and found that firefighters with low but not high regulatory choice flexibility showed a significant positive correlation between traumatic exposure and PTSD symptoms. This moderation was specific to PTSD symptoms and contributed above and beyond other well-established correlates of PTSD. The results suggest that regulatory choice flexibility can intersect the deleterious link between traumatic exposure and PTSD symptoms.

Interpersonal distance and social anxiety in autistic spectrum disorders: A behavioral and ERP study

An inherent feature of social interactions is the use of social space or interpersonal distance—the space between one individual and another. Because social deficits are core symptoms of Autistic Spectrum Disorder (ASD), we hypothesized that individuals on this spectrum will exhibit abnormal interpersonal distance preferences. The literature on interpersonal distance in ASD is not conclusive. While some studies show preferences for closer distances among this group, others show preferences for farther distances than controls. A common symptom of ASD that may explain the variance in responses to interpersonal distance in this population is social anxiety (SA), which has been shown to correlate with interpersonal distance preferences. In the current study, we investigated interpersonal distance preferences in a group of individuals with ASD using both behavioral and ERP measures. We found greater variance in interpersonal distance preferences in the ASD group than in the control group. Furthermore, we showed that this variance can be explained by differences in SA level and can be predicted by the N1 amplitude, an early ERP component related to attention and discrimination processes. These results hint at the early sensory and attentional processes that may be affecting higher social behaviors, both in subclinical and in clinical populations.

The hidden price of repeated traumatic exposure

Abstract Neuroimaging studies have demonstrated reduced hippocampal volume in trauma-exposed individuals without posttraumatic stress disorder (PTSD). However, the implications of such a deficit in this non-clinical population are still unclear. Animal and human models of PTSD suggest that hippocampal deficit may result in impaired learning and use of associations between contextual information and aversive events. Previous study has shown that individuals with PTSD have a selective impairment in reversing the negative outcome of context-related information. The aim of this study was to test whether non-PTSD individuals who are repeatedly exposed to traumatic events display similar impairment. To that end, we compared the performance of active-duty firefighters who are frequently exposed to traumatic events as part of their occupational routine and civilian matched-controls with no history of trauma-exposure. We used a novel cue–context reversal paradigm, which separately evaluates reversal of negative and positive outcomes of cue and context-related information. As predicted, we found that while both trauma-exposed firefighters and unexposed matched-controls were able to acquire and retain stimulus-outcome associations, firefighters struggled to learn that a previously negative context is later associated with a positive outcome. This impairment did not correlate with levels of PTSD, anxiety or depressive symptoms. The results suggest that similar to individuals with PTSD, highly exposed individuals fail to associate traumatic outcomes with their appropriate context. This impairment may reflect a possible hidden price of repeated traumatic exposure, which is not necessarily associated with PTSD diagnosis, and may affect the way highly exposed individuals interpret and react to their environment.

The role of empathy in the neural responses to observed human social touch.

One of the ways in which individuals convey feelings and thoughts to one another is through touch. Although the neural responses to felt and observed tactile stimuli between an inanimate object and a part of the human body have been vastly explored, the neural responses to observed human interaction involving touch are not well understood. Considering that the observation of social touch involves vicarious sharing of emotions, we hypothesized that levels of empathic traits modulate the neural responses to observed touch and focused on the attenuation in the mu\alpha rhythm (8–13Hz), a neural marker that has been related to sensorimotor resonance. Fifty-four participants observed photos depicting social touch, nonsocial touch, or no touch while their electroencephalography (EEG) activity was recorded. Results showed that interindividual differences in levels of empathic traits modulated both behavioral and electrophysiological responses to human social touch, such that highly empathic participants evaluated human social touch as inducing more pleasant emotions and exhibited greater mu suppression upon observation of human social touch compared to less empathic participants. Specifically, both the behavioral and the electrophysiological responses to observed social touch were predicted by levels of personal distress, a measure of emotional contagion. These findings indicate that the behavioral and electrophysiological responses to observed social touch are modulated by levels of empathy.

Neuropsychological functions and visual contrast sensitivity in schizophrenia: The potential impact of comorbid posttraumatic stress disorder (PTSD)

Previous studies have revealed a high prevalence of posttraumatic stress disorder (PTSD) in patients with other severe mental disorders, including schizophrenia. However, the neuropsychological and psychophysical correlates of comorbid PTSD are less exactly defined. The purpose of the present study was to assess immediate and delayed memory, attention, visuospatial skills, language, and basic visual information processing in patients with schizophrenia with or without PTSD. We recruited 125 patients with schizophrenia and 70 healthy controls matched for visual acuity, age, gender, education, and socioeconomic status. Twenty-one of patients with schizophrenia exhibited comorbid PTSD. We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and visual contrast sensitivity tasks for low spatial/high temporal frequency (0.3 cycle/degree and 18 Hz) and high spatial/low temporal frequency (10 cycles/degree and 1Hz) sinusoidal gratings. All patients were clinically stable and received antipsychotic medications. Results revealed that relative to healthy controls, patients with schizophrenia exhibited significant and generalized neuropsychological dysfunctions and reduced visual contrast sensitivity, which was more pronounced at low spatial/high temporal frequency. When we compared schizophrenia patients with and without PTSD, we found that patients with comorbid PTSD displayed lower scores for RBANS attention, immediate and delayed memory, and visuospatial scores. Schizophrenia patients with or without PTSD displayed similar visual contrast sensitivity. In conclusion, comorbid PTSD in schizophrenia may be associated with worse neuropsychological functions, whereas it does not affect basic visual information processing.

The hidden price and possible benefit of repeated traumatic exposure.

Abstract There is a growing evidence showing that first-responders who are frequently exposed to traumatic events as part of their occupational routine may pay a hidden price. Although they display low to moderate levels of post-traumatic stress disorder (PTSD) symptoms, similar to individuals with full-blown PTSD, they show impaired ability to process and react according to contextual demands. We aimed to test whether this impairment affects performance on simple unrelated tasks and its association with cumulative traumatic exposure and level of PTSD symptoms. Thirty-nine trauma-exposed criminal scene investigator police and 35 unexposed civilians matched for age, gender, and education performed a simple discrimination task in the presence of aversive pictures with low or high intensity. We predicted and found that trauma-exposed individuals failed to modify their behavior in accordance with levels of negative intensity. Hence they were equally distracted in both low and high negative intensity conditions, compared to unexposed controls who showed improved performance in low intensity conditions. Importantly, performance of trauma-exposed individuals on conditions of low intensity negatively correlated with their levels of PTSD symptoms. These results highlight the maladaptive tendency of individuals with repeated traumatic exposure to maintain the same behavior in low-intensity contextual conditions when it is no longer adequate. Interestingly however, in high-intensity conditions trauma-exposed individuals outperformed unexposed controls. Specifically, when completing simple tasks in high intensity conditions. The results suggest that repeated traumatic exposure has both positive and negative consequences on the way individuals interpret and react to their environment.

The hidden price of repeated traumatic exposure: different cognitive deficits in different first-responders

Studies on first responders who are repeatedly exposed to traumatic events report low levels of PTSD symptoms and diagnosis. However, neuroimaging and behavioral studies show that traumatic exposure is associated with brain and cognitive dysfunctions. Taking together it may suggest that traumatic exposure have a price, which is not sufficiently defined by the standard PTSD measures. In a recent study we revealed that similar to individuals with PTSD, non-PTSD highly exposed firefighters display a selective impairment in hippocampal related functions. In the current study we aimed to test whether different first responders display a similar impairment. We concentrated on unique populations of active duty firefighters and criminal scene-investigators (CSI) police, who are frequently exposed to similar levels and types of traumatic events, and compared them to civilian matched-controls with no history of trauma-exposure. We used a hippocampal dependent cue-context reversal paradigm, which separately evaluates reversal of negative and positive outcomes of cue and context related information. We predicted and found that all participants were equally able to acquire and retain stimulus-outcome associations. However, there were significant differences in reversal learning between the groups. Performance among firefighters replicated our prior findings; they struggled to learn that a previously negative context is later associated with a positive outcome. CSI police on the other hand showed a selective impairment in reversing the outcome of a negative cue. Hence after learning that a specific cue is associated with a negative outcome, they could not learn that later it is associated with a positive outcome. Performance in both groups did not correlate with levels of PTSD, anxiety, depression or behavioral inhibition symptoms. The results provide further evidence of the hidden price of traumatic exposure, suggesting that this price may differ as a function of occupation.