Functional connectivity abnormalities during processing of predictive stimuli in patients with major depressive disorder.

The study investigated the underlying mechanisms associated with the ability of patients with major depressive disorder (MDD) to utilize predictive contextual information in order to facilitate detection of predictable versus random targets. To this end we evaluated EEG event-related functional connectivity during the processing of predictive stimuli in MDD and control subjects. A target detection task was used where targets were either preceded by randomized sequences of standards, or by sequences that included a predictive sequence. Functional connectivity was evaluated using synchronization likelihood and graph theory. The cluster coefficient and local efficiency values were greater in MDD compared to controls, during the processing of the three stimuli consisting of the predictive sequence, in the beta frequency band, suggesting an increased structured network organization. These changes were associated with increased functional connectivity within frontal networks in MDD patients compared to controls. However, no significant functional connectivity group-changes were observed for target conditions or randomized standards. These findings suggest that MDD is associated with context-specific functional connectivity abnormalities during the processing of predictive stimuli.

Participation of the left inferior frontal gyrus in human originality.

Human creative cognition is commonly described as a twofold cyclic process that involves an idea generation phase and an idea evaluation phase. Although the evaluation phase makes a crucial contribution to originality, its underlying mechanisms have not received sufficient research attention. Here, we suggest that the left inferior frontal gyrus (lIFG) plays a major role in the interplay between the evaluation and generation networks and that inhibiting this region's activity may have an effect on "releasing" the generation neural network, resulting in greater originality. To examine the neural networks that mediate the generation and evaluation of ideas, we conducted an fMRI experiment on a group of healthy human participants (Study 1), in which we compared an idea generation task to an idea evaluation task. We found that evaluating the originality of ideas is indeed associated with a relative increase in lIFG activation, as opposed to generating original ideas. We further showed that temporarily inhibiting the lIFG using continuous theta-burst stimulation (Study 2) results in less strict evaluation on the one hand and increased originality scores on the other. Our findings provide converging evidence from multiple methods to show that the lIFG participates in evaluating the originality of ideas.

Secondary Prevention of Chronic PTSD by Early and Short-Term Administration of Escitalopram: A Prospective Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE: Prospective studies have not identified a viable pharmacologic strategy for secondary prevention of posttraumatic stress disorder (PTSD). The authors examined whether preventive intervention via early and short-term administration of a selective serotonin reuptake inhibitor (SSRI), within 1 month of exposure to a traumatic event (before diagnosis of PTSD could be made), may reduce the severity of PTSD symptoms according to DSM-IV at 13 months' follow-up. METHODS: Over 25,000 screening calls to patients referred to an emergency department for a traumatic event performed between June 2006 and December 2008 yielded 353 participants who were recruited within the month following a traumatic event . Participants were randomly assigned in a double-blind design to escitalopram (n = 176) or placebo (n = 177). The per-protocol analysis comprised 198 participants (escitalopram, n = 102; placebo, n = 96) who received treatment for 12 to 24 weeks and were available for follow-up at week 56. RESULTS: The primary outcome measure, the Clinician Administered PTSD Scale (CAPS), revealed no prevention effect. However, a secondary outcome, the Pittsburgh Sleep Quality Inventory (PSQI), showed better results for the SSRI group than for the placebo group. For a subset of participants who experienced intentional trauma (missile attacks, rape, or physical assault; n = 50), the prevention effect was found on both primary and secondary measures (CAPS, PSQI and measures of depression and global illness severity). CONCLUSIONS: Early and short-term administration of escitalopram was not shown to prevent PTSD, although it did improve sleep quality. In a subgroup of participants who experienced intentional trauma, however, this early-treatment approach may be effective as secondary prevention. This large study is the first to investigate the preventive effect of early administration of escitalopram on PTSD. It highlights the relevance of the type of trauma (intentional vs unintentional) to the outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00300313​​.

The role of oxytocin in empathy in PTSD.

OBJECTIVE: Although impairments in social skills are common in posttraumatic stress disorder (PTSD), only a handful of studies have investigated the empathic abilities of patients with PTSD. The first aim of this study was to characterize emotional and cognitive empathy deficits among patients with PTSD. Furthermore, intranasal oxytocin (OT) has been reported as possibly improving emotional empathy, and it has recently been suggested that patients with PTSD may suffer from abnormal functioning of the oxytocinergic system. Therefore, the second aim of this study was to investigate whether intranasal OT may enhance empathic abilities in these patients. METHOD: Using a randomized, double-blind, placebo-controlled crossover design, we administered 24 International Units of oxytocin and placebo at a 1-week interval to 32 patients with PTSD and to 30 matched healthy controls and then measured participants' emotional and cognitive empathy. RESULTS: Patients with PTSD exhibited deficits in both emotional and cognitive empathy, and these deficits were associated with the severity of their PTSD symptoms. The administration of OT did not improve empathic abilities in our sample, although it did tend to selectively enhance the ability of men with PTSD to recognize body motions of anger. CONCLUSIONS: These results indicate that patients with PTSD have deficits in both emotional and cognitive empathic abilities and that their empathic difficulties may underlie their impairments in social and interpersonal skills. (PsycINFO Database Record

Oxytocin improves compassion toward women among patients with PTSD.

Although impairments in social skills, including empathic abilities, are common in post-traumatic stress disorder (PTSD), the ability to feel compassion-a pro-social behavior that is based on empathy and drives us to help others-has never been assessed among these patients. The first aim of this study was to examine whether patients with PTSD suffer from deficits in compassion and to examine the association between the clusters of PTSD symptoms and these deficits. Furthermore, given that intranasal oxytocin (OT) has been suggested to possibly modulate social behaviors, the second aim of this study was to investigate whether intranasal OT may enhance compassion in these patients. Using a randomized, double-blind, placebo-controlled crossover design, we administered 24 IU of OT and placebo at a one-week interval to 32 patients with PTSD and to 30 matched healthy control participants. The results indicate that patients with PTSD exhibit deficits in compassion and that the numbing cluster emerged as the key predictor of those deficits. Moreover, the results indicate that a single intranasal dose of OT enhances compassion toward women (but not towards men), both in patients with PTSD and in controls. These results offer support for recent suggestions that intranasal OT may potentially be an effective pharmacological intervention for patients with PTSD.

The role of branched chain amino acid and tryptophan metabolism in rat's behavioral diversity: Intertwined peripheral and brain effects.

Previously, we showed that a transient early-in-life interference with the expression of multiple genes by mithramycin (MTR) followed by later-in-life exposure to chronic stress, leads to a "daring" and novelty seeking behavior in rats. In this study we searched for molecular changes that contribute to this behavioral alteration. We applied a non-hypothesis driven strategy using whole genome cDNA array analysis (WGA) followed by Genome Scale Metabolic modeling analysis (GSMM). Gene expression validation was performed by qRT-PCR and immunoblotting. Brain and serum amino acids levels were measured by HPLC. WGA data directed us towards metabolic pathways and GSMM pointed at branched chain amino acids (BCAA) pathway. Out of 21 amino acids analyzed in the prefrontal cortex of MTR+Stress rats only tryptophan, whose brain levels depend on serum BCAA levels, showed a significant decrease. No change was observed in serotonin or kynurenine levels. However, a significant reduction in mRNA and protein levels of the large neutral amino acid transporter (LAT1), which transports BCAA and tryptophan into the brain, as well as in serum levels of tryptophan/BCAA ratio were observed. The latter may be attributed to the failure to increase serum insulin, following stress, in rats pre-exposed to mithramycin. Finally, significant correlations were observed between the anxiety index and tryptophan and between T-maze errors and LAT1. This study shows a specific behavioral pattern, which is linked to modulations in fluxes of amino acids both peripheral and central, which converge and reciprocally interact, and may thus be equally important targets for therapeutic intervention.

A prospective, randomized, three arm, open label study comparing the safety and efficacy of PP110, a novel treatment for hemorrhoids to preparation-H® maximum strength cream in the treatment of grade 2-3 hemorrhoids.

BACKGROUND: Hemorrhoids are a common disorder that affects the quality of life of millions of people worldwide. The effectiveness of OTC medication is limited and they mainly provide symptomatic relief. In order to treat this ailment, we formulated PP110 Gel and Wipes, as a novel treatment for hemorrhoids. PP110 is based on known active ingredients with a topical film-forming agent designed to provide physical protection and prolonged tissue contact with the active ingredients. METHODS: PP110 Gel, PP110 Wipes and the comparator Preparation-H® were used on three patient cohorts. Treatment was administered once daily for PP110, and three-four times daily for Preparation-H®, for 14 days. Six different clinical parameters relating to common symptoms of hemorrhoids were monitored. RESULTS: PP110 Gel was significantly better than Preparation-H® in reducing bleeding (Δ = 6 %), providing pain relief (Δ = 10 %) and controlling itching (Δ = 11 %). These three parameters are considered as the most common distressing symptoms for hemorrhoids patients, demonstrating that PP110 is superior to conventional treatment. CONCLUSION: This study demonstrated the efficacy of the PP110 Gel in treating hemorrhoids and its superiority to conventional treatments. The PP110 film-based formulation provides a slow-release mechanism and as a consequence, a prolonged therapeutic window. PP110 was both more effective in reducing hemorrhoids symptoms and more convenient to use, in that it only required application once per day.

Cultural Perspectives on the Aftereffects of Combat Trauma: Review of a Community Study of Bedouin IDF Servicemen and Their Families.

Combat trauma may affect servicemen from indigenous, traditional communities in ways that warrant special attention. The Bedouins, who enlist in the Israel Defense Forces (IDF) voluntarily, represent a unique, closed, collectivist cultural minority, potentially in a predicament in light of ongoing sociopolitical events. This paper summarizes findings and lessons learned from a community study of Bedouin IDF servicemen and their families residing in Israel's Western Galilee. This is the only research endeavor to have addressed trauma exposure and posttraumatic reactions in this community. The sampling strategies and interview schedule were designed in consideration of participation barriers typical of hard-to-reach populations. Data collection followed an extended phase of liaising with key informants and building trust. Study limitations are discussed in terms of the challenges presented by this type of research. Interviews conducted with 317 men, 129 wives, and 67 mothers revealed high levels of trauma exposure and posttraumatic stress disorder (PTSD) in the men, and related distress in wives and mothers, but not in the children. The role of aggression in mediating the impact of PTSD and concepts such as shame, the loss of personal resources, and beliefs about retribution are highlighted as key issues for a culturally relevant understanding of traumatized indigenous communities.

Oxytocin increases empathy to pain when adopting the other- but not the self-perspective.

There is growing evidence that the neuropeptide oxytocin (OT) facilitates various forms of sensitivity to others, but the mechanism by which OT enhances empathy in humans is unclear. In this study, we examined whether OT increases empathy by the way of blurring the distinction between self and other, or by enhancing the difference between self and other. In this double-blind, placebo-controlled, within-subject crossover design, empathic responses of healthy participants were compared when imagining oneself (i.e., self-perspective empathy) versus when imagining the other (i.e., other-perspective empathy) in painful and nonpainful situations. Under OT treatment, participants expressed more empathy when imagining others than when imagining oneself in pain. This was in contrast to the placebo condition where there were no differences between the empathic responses during the self- and the other-perspective. We propose that the modulatory effect of OT on empathy when taking the other-perspective may be mediated by its role in self- and other-distinctiveness and corollary by its role in increasing salience to social agents and cues.

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study.

BACKGROUND: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent and long lasting effects on cortical excitability. In a previous open study, we demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) in major depression (MD). The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using a double-blind, sham-controlled design. METHODS: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n=15) or sham cTBS (n=14) for 10 consecutive work days. After the 10th session, patients who received sham TBS were crossed over to active cTBS which consisted of 10 daily sessions. Patients who received active cTBS continued with the same treatment protocol for additional 10 treatments. Each treatment session consisted of 3600 stimuli at an intensity of 100% of the active motor threshold. Severity of depression was assessed weekly. RESULTS: Overall, there was no significant difference in the degree of clinical improvement between active and sham cTBS groups. However, in patients whose medication status remained unchanged before the trial (n=8) and in those who were medication-free (n=3), active cTBS resulted in a significantly greater reduction of Hamilton depression scores as compared to sham cTBS. LIMITATIONS: A small sample size, confounding effect of medication and short treatment period. CONCLUSIONS: Our results suggest that the antidepressant effect of cTBS is modest, yet it might be beneficial to patients nonresponsive to ongoing pharmacological treatment. A direct comparison between cTBS and conventional rTMS protocols is warranted.

Intranasal administration of oxytocin increases compassion toward women.

It has been suggested that the degree of compassion-the feeling of warmth, understanding and kindness that motivates the desire to help others, is modulated by observers' views regarding the target's vulnerability and suffering. This study tested the hypothesis that as compassion developed to protect vulnerable kinships, hormones such as oxytocin, which have been suggested as playing a key role in 'tend-and-befriend' behaviors among women, will enhance compassion toward women but not toward men. Thirty subjects participated in a double-blind, placebo-controlled, within-subject study. Following administration of oxytocin/placebo, participants listened to recordings of different female/male protagonists describing distressful emotional conflicts and were then asked to provide compassionate advice to the protagonist. The participants' responses were coded according to various components of compassion by two clinical psychologists who were blind to the treatment. The results showed that in women and men participants oxytocin enhanced compassion toward women, but did not affect compassion toward men. These findings indicate that the oxytocinergic system differentially mediates compassion toward women and toward men, emphasizing an evolutionary perspective that views compassion as a caregiving behavior designed to help vulnerable individuals.

Local contextual processing in major depressive disorder.

OBJECTIVE: The study investigated local contextual processing in patients with major depressive disorder (MDD). This was defined as the ability to utilize predictive contextual information to facilitate detection of predictable versus random targets. METHOD: We recorded EEG in 15 MDD patients and 14 age-matched controls. Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences of standards that included a predictive sequence signaling the occurrence of a subsequent target event. RESULTS: Both MDD patients and age-matched controls demonstrated a significant reaction time (RT) and P3b latency differences between predicted and random targets. However, patients demonstrated a specific prolongation of these measures during processing of predicted targets, as well as an attenuation of P3b amplitudes for the predictive sequence. In addition, patients target N1 amplitudes were attenuated compared with controls. CONCLUSION: MDD patients were able to utilize predictive context in order to facilitate processing of deterministic targets, however, this ability was limited compared to controls, as demonstrated by context-dependent P3b deficits. SIGNIFICANCE: These findings suggest that patients with major depression have altered processing of local contextual processing.

Entacapone augmentation of antipsychotic treatment in schizophrenic patients with negative symptoms; a double-blind placebo-controlled study.

Negative symptoms in schizophrenia are associated with decreased dopaminergic activity in the prefrontal cortex (PFC). It is hypothesized that increasing dopamine levels would alleviate negative symptoms. Termination of dopamine activity in the PFC is mainly via catechol-O-methyl tranferase (COMT) activity. Hence, inhibition of COMT activity with entacapone should reverse PFC dopaminergic transmission. To assess the efficacy of entacapone addition to antipsychotic treatment in patients with residual schizophrenia, we conducted a double-blind, randomised, placebo-controlled study for 12 wk of treatment with entacapone or placebo. Clinical measures (PANSS, CGI and QLS) were obtained at baseline and at weeks 4, 8 and 12 and cognitive functions were assessed by the RBANSS. Significant improvement over time in PANSS and QLS scores was observed in both groups. However, entacapone did not demonstrate a beneficial effect compared to placebo. Therefore, this study does not support a therapeutic role for entacapone in residual schizophrenia.

Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with ß-arrestin.

Antidepressant medication is the standard treatment for major depression disorder (MDD). However, the response to these treatments is often incomplete and many patients remain refractory. In the present study, we show that the glucocorticoid receptor (GR) agonist dexamethasone (DEX) increased MAPK/ERK1/2 signaling in the presence of the noradrenergic antidepressant, desipramine (DMI), while no such effect was induced by DEX or DMI alone in human neuroblastoma SH-SY5Y cells. This enhancement was dependent on the activation of both α(2) adrenergic receptors (AR) and GR. The timing of MAPK/ERK1/2 activation as well as DEX-induced reduction in membranous α(2) AR suggests the involvement of a ß-arrestin-dependent mechanism. In line with the latter, DEX increased cytosolic and decreased membranous levels of ß-arrestin. Concomitantly, DEX induced a time-dependent increase in cytosolic α(2) AR-ß-arrestin interaction and a decrease in ß-arrestin interaction with Mdm2 E3 ubiquitin ligase. All of these effects of DEX were prevented by the GR antagonist RU486. Our data suggest an additional intracellular role for DEX, in which activation of GR interferes with the trafficking and degradation of ß-arrestin-α2c-AR complex. We suggest that such an interaction in the presence of DMI can enhance MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes, which is impaired in MDD, while stimulated by antidepressants.

Possible association of Toll-like receptor 9 polymorphisms with cytokine levels and posttraumatic symptoms in individuals with various types of orthopaedic trauma: early findings.

BACKGROUND: Although TLR9 polymorphisms may be associated with cytokine dysregulation, its role in regulation of cytokines due to bodily trauma or in relation to acute stress symptoms or posttraumatic stress symptoms (ASS/PTS) has not been evaluated. AIMS: To assess serum cytokine levels and levels of ASS and PTS in relation to four common TLR9 single-nucleotide polymorphisms (SNPs) in individuals with various types of orthopaedic trauma. METHODS: Forty-eight accident-injured individuals, aged 20-60 years were studied. Serum cytokine levels and TLR9 SNPS (1486T/C, 1237T/C, 1174G/A and 2848G/A) were assessed together with intensity of ASS and PTS symptoms. RESULTS: Statistically significant higher serum levels of IL-12 and IL-1ß (p<.05) were found in individuals heterozygous for TLR9-1237 (TC) than in individuals expressing the most common TLR9-1237 type (TT), while differences in levels of IL-6 were not significant. Also, marginally significant levels of IL-6 were found in individuals expressing the common TLR9-1174 (GG) compared with individuals homozygous (AA) or heterozygous (GA) for this SNP. They also had non-significant higher intensity of ASS symptoms. A trend of higher PTS levels in individuals expressing the most common type TLR9-1174 (GG) was found, contrary to homozygous (AA) and heterozygous individuals (GA). CONCLUSIONS: The results of this pilot study suggest that accident-injured individuals with certain TLR9 polymorphisms express higher levels of pro-inflammatory cytokines (IL-1ß, IL-6 and IL-12). The associations of TLR9 SNPSs with increased risk of ASS or PTS should be further studied in larger groups of such patients.

Face or body? Oxytocin improves perception of emotions from facial expressions in incongruent emotional body context.

The neuropeptide oxytocin (OT) has been repeatedly reported to play an essential role in the regulation of social cognition in humans in general, and specifically in enhancing the recognition of emotions from facial expressions. The later was assessed in different paradigms that rely primarily on isolated and decontextualized emotional faces. However, recent evidence has indicated that the perception of basic facial expressions is not context invariant and can be categorically altered by context, especially body context, at early perceptual levels. Body context has a strong effect on our perception of emotional expressions, especially when the actual target face and the contextually expected face are perceptually similar. To examine whether and how OT affects emotion recognition, we investigated the role of OT in categorizing facial expressions in incongruent body contexts. Our results show that in the combined process of deciphering emotions from facial expressions and from context, OT gives an advantage to the face. This advantage is most evident when the target face and the contextually expected face are perceptually similar.

Early postnatal interference with the expression of multiple Sp1 regulated genes leads to disparate behavioral response to sub-chronic and chronic stress in rats.

BACKGROUND: It is currently accepted that complex behavior and mental disorder results from a combination of biological susceptibility and exposure to environmental stimuli. Most of the gene-environment interaction models focus on the interaction between the stimuli and a single candidate gene. We suggest that an alternative approach is interference with the expression of multiple genes followed by exposure to environmental insults. METHODS: Early interference with gene transcription was performed by treatment of 7 days old Wistar male rats for 4 days with the Sp1/DNA binding inhibitor, mithramycin. Environmental insult was mimicked by exposing these rats during adulthood (34 days) to sub-chronic (12 days, n=30) or chronic stress (28 days, n=48). The effects of mithramycin and stress treatment on the behavioral response and serum corticosterone concentration were assessed. RESULTS: Exposure of mithramycin treated rats to sub-chronic stress led to anxious behavior in the open field test, high startle response, low sucrose preference, indifference to novel objects and high serum corticosterone concentration. However, exposure to chronic stress resulted in normal sucrose preference, startle response and serum corticosterone, novelty seeking behavior and reduced anxiety. In saline treated rats the extension of stress duration led to behavioral and hormonal adaptation to stress. CONCLUSION: Our study suggests that postnatal temporal interference with multiple gene expression can lead to hyper-responsiveness to environmental stimuli, the features of which affects the phenotypic outcomes. Such a paradigm may be used to model gene-environmental interaction in the etiology of behavioral disorders.

The neurocognitive basis of insight into illness in anorexia nervosa: a pilot metacognitive study.

The primary goal of the present study was to explore the neuropsychological basis of insight into illness in anorexia nervosa by evaluating its differential and joint links with cognitive vs. metacognitive performance. Participants in the study were 25 women with anorexia nervosa (AN) and 25 healthy comparisons (HC). All participants completed a computerized version of the Wisconsin Card Sorting Task (WCST) and the Computerized Body-Size Discrimination task (CBSD). In addition to the standard administration of the tasks, subjects were also asked to rate their level of confidence in the correctness of each sort and to choose whether they wanted each sort to be "counted" toward their overall performance score on the test. Insight into illness in the AN group was assessed with the Scale of Unawareness of Mental Disorder (SUMD). Prediction of poor insight was significantly improved when adding the new, free-choice metacognitive measures to the conventional measures in both tasks, but not the other way around. These preliminary results suggest that metacognition might be an important mediator between basic cognitive deficits and poor insight and that it might be even more relevant to poor insight than cognitive deficits per se.

ß-endorphin degradation and the individual reactivity to traumatic stress.

Reactivity to traumatic stress varies between individuals and only a minority of those exposed to trauma develops stress-induced psychopathologies. Currently extensive effort is made to unravel the specific mechanisms predisposing to vulnerability vs. resilience to stress. We investigated in rats the role of ß-endorphin metabolism in vulnerability to acute traumatic stress. Responders (showing extreme anxiety; n=7) and resilient non-responders (not differing from the non-stressed individuals; n=8) to traumatic foot-shock stress were compared for their blood levels of stress hormones as well as brain levels and activity of two opioid-degrading enzymes. ß-endorphin is a substrate to insulin degrading enzyme, which also degrades insulin. Therefore, the effects of insulin application on behavioral and hormonal responses and on ß-endorphin degradation were tested. Pre- and post-stress levels of serum corticosterone, and post-stress plasma ß-endorphin concentration differentiated between the responders and the non-responders. In brain, responders showed enhanced degradation rates of ß-endorphin, assessed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), in hippocampal and amygdalar slices as compared to non-responders. Application of insulin to the amygdala, prior to exposure to traumatic stress, reduced post-stress anxiety and serum corticosterone levels only in the responders. In parallel, amygdalar ß-endorphin degradation rate was also reduced by insulin. These results suggest that slowing down ß-endorphin degradation rate may constitute an integral part of the normal stress-response, upon a failure of which an extreme anxiety develops. Modulation of opioid degradation may thus present a potential novel target for interference with extreme anxiety.