Csilla Szabó

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.

Blood biomarkers of depression track clinical changes during cognitive-behavioral therapy

BACKGROUND Results from convergent genomics indicated new peripheral biomarkers for mood states. We sought to investigate the clinical utility of the BioM-10 Mood Panel, a peripheral biomarker set of low vs. high mood states, in the diagnosis of major depressive episode and to monitor the effectiveness of cognitive-behavioral therapy (CBT). METHOD 44 patients with a first episode of major depression and 30 healthy control subjects participated in the study. The BioM-10 panel׳s gene expression profile was measured from whole peripheral blood with the Affymetrix Human Genome U133 Plus 2.0 Gene Chips, focusing on 10 top genes related to high mood states (MBP, EDG2, FZD3, ATXN1, and EDNRB) and low mood states (FGFR1, MAG, PMP22, UGT8, and ERBB3). We studied gene expression before and after CBT. RESULTS The BioM-10 prediction score discriminated patients and controls with high sensitivity (84%) and specificity (90%). There was an increase in the BioM-10 prediction score after CBT relative to the pretreatment value. Clinical improvement was associated with higher prediction scores reflecting a greater ratio of high mood markers relative to low mood markers. LIMITATIONS Sample size was small for a genome-wide microarray study. Convergent genomic studies have not been conducted in major depressive disorder. More evidence is needed from patients with severe, recurrent, and chronic forms of depression. CONCLUSIONS The BioM-10 panel is a promising tool as a biomarker setup for the evaluation of low and high mood states across diagnostic categories. The panel includes genes related to growth factor pathways and myelination, which may provide new insights into the pathophysiology of mood dysregulation.

Low-grade inflammation disrupts structural plasticity in the human brain

Increased low-grade inflammation is thought to be associated with several neuropsychiatric disorders characterized by decreased neuronal plasticity. The purpose of the present study was to investigate the relationship between structural changes in the human brain during cognitive training and the intensity of low-grade peripheral inflammation in healthy individuals (n=56). A two-month training (30 min/day) with a platformer video game resulted in a significantly increased volume of the right hippocampal formation. The number of stressful life events experienced during the past year was associated with less pronounced enlargement of the hippocampus. However, the main predictor of hippocampal volume expansion was the relative peripheral expression of Nuclear Factor-κB (NF-κB), a transcription factor playing a central role in the effect of pro-inflammatory cytokines. Interleukin-6 (IL-6) and C-reactive protein levels were not related to hippocampal plasticity when NF-κB was taken into consideration. These results suggest that more intensive peripheral inflammation is associated with weaker neuronal plasticity during cognitive training.

Changes in FKBP5 expression and memory functions during cognitive-behavioral therapy in posttraumatic stress disorder: A preliminary study

Posttraumatic stress disorder (PTSD) is characterized by hyperarousal, flashbacks, avoidance, and memory dysfunctions. Although psychotherapy improves the clinical symptoms, its effect on memory has not been explored. In addition, there is no information about gene expression changes related to hippocampal functions. We assessed PTSD patients (n=20) using the Wechsler Memory Scale-Revised (WAIS-R) and a paired associates learning (PAL) test, as well as changes in blood FK506 binding protein (FKBP5) mRNA expression before and after cognitive behavioral therapy (CBT). Results revealed that before CBT PTSD patients were impaired on WAIS-R delayed recall, attention/concentration, and PAL compared with trauma-exposed control subjects (n=20). These memory dysfunctions showed a significant improvement after CBT. Better performance on the PAL test correlated with enhanced blood FKBP5 mRNA expression. These results suggest that elevated FKBP5 expression during CBT is related to improved associative memory linked to the hippocampal formation.

Antipsychotics influence Toll-like receptor (TLR) expression and its relationship with cognitive functions in schizophrenia.

Increasing evidence suggests that altered immune functions are related to the pathophysiology of schizophrenia. Relatively little information is available on Toll-like receptors (TLRs), which are implicated in the recognition of molecular patterns associated with pathogens and internal cellular damage signals. By using immunophenotyping and flow cytometry, we investigated TLRs in CD14+ monocytes, CD4+CD25+Foxp3+ regulatory T cells (Treg), and CD3+CD4+CD25+ activated T cells (Tact) in 35 drug-naïve patients with schizophrenia before and after an 8-week period of antipsychotic treatment with risperidone or olanzapine. As compared with 30 healthy control individuals, drug-naïve patients with schizophrenia exhibited an increased percentage of TLR4+ and TLR5+ monocytes and TLR5+ Treg/Tact cells. At the end of the treatment period, we observed normalized TLR4+ monocytes and an up-regulation of TLR2+ monocytes and Treg/Tact cells. Mean fluorescent intensity values, indicating receptor density, were consistent with these findings. In the drug-naïve state, but not after treatment, higher percentages of TLR4+ and TLR5+ monocytes were correlated with more severe cognitive deficits. Positive, negative, and general clinical symptoms were not associated with TLRs. There were no significant differences between patients receiving olanzapine and risperidone. These results indicate that abnormal expression of TLRs can be detected in the earliest stage of schizophrenia, which is modulated by antipsychotics. Immunological alterations in unmedicated schizophrenia patients may be linked to cognitive deficits.

Uniting the neuro developmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.

Ethical sensitivity in obsessive-compulsive disorder and generalized anxiety disorder: The role of reversal learning

BACKGROUND AND OBJECTIVES In obsessive-compulsive disorder (OCD), amplified moral sensitivity may be related to the orbitofrontal-striatal circuit, which is also critical in reversal learning. This study examined three questions: (1) What aspects of ethical sensitivity is altered in OCD?; (2) What is the relationship between ethical sensitivity and reversal learning?; (3) Are potential alterations in ethical sensitivity and reversal learning present in generalized anxiety disorder (GAD)? METHODS Participants were 28 outpatients with OCD, 21 individuals with GAD, and 30 matched healthy controls. Participants received the ethical sensitivity scale questionnaire (ESSQ), rating scales for clinical symptoms, a reversal learning task, and the Wisconsin Card Sorting Test (WCST). RESULTS We found higher ethical sensitivity scores in OCD compared with healthy controls in the case of generating interpretations and options and identifying the consequences of actions. Individuals with OCD displayed prolonged reaction times on probabilistic errors without shift and final reversal errors. Participants with GAD did not differ from healthy controls on the ESSQ, but they were slower on reversal learning relative to nonpatients. In OCD, reaction time on final reversal errors mediated the relationship between ethical sensitivity and compulsions. WCST performance was intact in OCD and GAD. LIMITATIONS Small sample size, limited neuropsychological assessment, self-rating scale for ethical sensitivity. CONCLUSION Prolonged reaction time at switching reinforcement contingencies is related to increased ethical sensitivity in OCD. Slow affective switching may link ethical sensitivity and compulsions.

Acute response to psychological trauma and subsequent recovery: No changes in brain structure

We used magnetic resonance imaging to study brain structure in acute stress disorder (ASD) following a psychological trauma and after 4 weeks in remission. Whole-brain voxel-based morphometry and FreeSurfer analysis of the hippocampal formation and amygdala revealed no structural changes in ASD (n=75) compared with trauma-exposed individuals without ASD (n=60) and community controls (n=60). These results suggest that ASD, in contrast to posttraumatic stress disorder, is not characterized by structural brain alterations.