Executive dysfunction in bipolar disorder and borderline personality disorder.

OBJECTIVE: The boundary between bipolar disorder (BD) and borderline personality disorder is a controversial one. Despite the importance of the topic, few studies have directly compared these patient groups. The aim of the study was to compare the executive functioning profile of BD and BPD patients. METHOD: Executive functioning (sustained attention, problem-solving, planning, strategy formation, cognitive flexibility and working memory) was assessed in BD (n=30) and BPD outpatients (n=32) using a computerized assessment battery (Cambridge Neuropsychological Test Automated Battery, CANTAB). The groups were compared to one another as well as to healthy controls. RESULTS: BD patients showed deficits in strategy formation and in planning (indicated by longer execution time in the ToL task) in comparison to BPD patients and healthy controls. BPD patients showed deficits in planning (short deliberation time in the ToL task) in comparison to BD patients and in comparison to healthy controls. In comparison to healthy controls, BPD patients displayed deficits in problem-solving. CONCLUSIONS: Differences in executive dysfunction between BD and BPD patients suggest that this cognitive dimension may be relevant for the clarification of the boundary between the disorders.

I think therefore I am: Rest-related prefrontal cortex neural activity is involved in generating the sense of self.

The sense of self has always been a major focus in the psychophysical debate. It has been argued that this complex ongoing internal sense cannot be explained by any physical measure and therefore substantiates a mind-body differentiation. Recently, however, neuro-imaging studies have associated self-referential spontaneous thought, a core-element of the ongoing sense of self, with synchronous neural activations during rest in the medial prefrontal cortex (PFC), as well as the medial and lateral parietal cortices. By applying deep transcranial magnetic stimulation (TMS) over human PFC before rest, we disrupted activity in this neural circuitry thereby inducing reports of lowered self-awareness and strong feelings of dissociation. This effect was not found with standard or sham TMS, or when stimulation was followed by a task instead of rest. These findings demonstrate for the first time a critical, causal role of intact rest-related PFC activity patterns in enabling integrated, enduring, self-referential mental processing.

The role of oxytocin in empathy to the pain of conflictual out-group members among patients with schizophrenia.

BACKGROUND: Oxytocin (OT) is associated with our ability to empathize and has been shown to play a major role in mediating social behaviors within the context of intergroup dynamics. Schizophrenia is associated with impaired empathy, and with a dysfunctional oxytocinergic system. The effect of OT on the empathic responses of patients with schizophrenia within the context of intergroup relationships has not been studied. The present study examined the effect of OT on the patients' empathic responses to pain experienced by in-group, conflictual out-group and neutral out-group members. METHOD: In a double-blind, placebo-controlled, within-subject cross-over design, the responses on the Pain Evaluation Task of 28 male patients with schizophrenia were compared to 27 healthy male controls. All participants received a single intranasal dose of 24 IU OT or placebo, 1 week apart. RESULTS: OT induced an empathy bias in the healthy controls towards the conflictual out-group members. Although this effect was absent in the patient group, OT seems to heighten an empathic bias in the patient group towards the in-group members when rating non-painful stimuli. CONCLUSIONS: The study demonstrates that the administration of OT can result in empathic bias towards adversary out-group members in healthy controls but not in patients with schizophrenia. However, the OT-induced bias in both the patients (in the no-pain condition towards the in-group members) and the healthy controls (in the no-pain and pain conditions towards the adversary out-group) suggests that OT enhances the distinction between conflictual in-group and out-group members.

Improving social perception in schizophrenia: the role of oxytocin.

Previous research has shown that patients with schizophrenia are impaired in a wide range of social cognitive abilities, including emotion recognition, empathy for others, and mental perspective-taking. Recent studies suggest that a dysfunction of the oxytocinergic system contributes to the social impairment in schizophrenia. Accordingly, the present study sought to examine whether patients with schizophrenia would improve in a social perception task after taking a single dose of oxytocin, as compared to a placebo. Thirty-five patients diagnosed with schizophrenia were compared with 46 psychologically healthy matched controls on their recognition of kinship and intimacy, using the Interpersonal Perception Task. All participants received a single intranasal dose of 24 IU oxytocin or placebo, one week apart. Overall, the participants were more accurate in judging intimacy and kinship following the administration of oxytocin, as opposed to a placebo. However, when comparing patients with controls, only the recognition of kinship improved significantly in the patient group, whereas no such effect was observed in the control group or in the recognition of intimacy in either group. This is one of the first studies to demonstrate that social perception in schizophrenia can be improved by the administration of oxytocin and that patients show a greater treatment effect than controls.

Guilt and depression: two different factors in individuals with negative symptoms of schizophrenia.

OBJECTIVE: Depression is common among schizophrenia patients and constitutes a major risk factor for suicide. Calgary Depression Scale (CDSS) is the most widely used instrument for measuring depression in schizophrenia. CDSS has never been examined in patients with predominant negative symptoms, thus possibly hindering both accurate assessment and understanding of the underlying mechanisms. The current study is the first to examine CDSS' structure in this population. METHODS: We conducted Principal Component Analysis (n=184) for the CDSS items. Thereafter, we correlated emerging factors with psychopathological, demographic and side effect variables. We assessed internal consistency and reliability of the emerging factors, as well as demographic correlations. RESULTS: The analysis yielded two factors: depression-hopelessness and guilt. Factors distinctly correlated with separate variables. Removal of item #7 (early waking) improved internal consistency. The depression-hopelessness factor had an inverse correlation with negative symptoms, and positive correlation with neuroleptic side effects. CONCLUSIONS: CDSS structure indicated of two separate factors, i.e., depression-hopelessness and guilt, suggesting separate underlying processes. The validity of the scale might benefit from a two-fold structure and the removal/replacement of item #7 (early waking). A noteworthy inverse correlation was found between the depression factor and negative symptoms, as well as a positive correlation between depression factor and neuroleptic side effects.

Remission of positive symptoms according to the "remission in Schizophrenia Working Group" criteria: a longitudinal study of cognitive functioning.

Schizophrenia patients in positive symptomatic remission (PSR; n=39) were assessed using a longitudinal research design. The patients were found to exhibit widespread cognitive impairments that were stable over the three-year follow-up period. The findings support a generalized and stable cognitive impairment profile among schizophrenia patients in partial symptomatic remission.

Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder.

UNLABELLED: Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosylmethionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD. OBJECTIVES: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. METHODS: Forty-six serotonin-reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment. RESULTS: There was a greater improvement in the ability to recall information (P=0.04) and a trend towards statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance. CONCLUSIONS: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication.

Neurocognitive functions of heavy cannabis using schizophrenia patients.

This current study assessed neurocognitive functioning in a carefully selected sample of schizophrenia patients with and without heavy cannabis use and healthy controls. All subjects were negative for any other substance use. Schizophrenia subjects had impaired neurocognitive functions across a wide range of tasks compared to healthy controls. Cannabis using schizophrenia patients had focused impairments on tasks of attention, and the findings suggest an impulsive pattern of response among these patients.

Transcranial magnetic stimulation of the ventromedial prefrontal cortex impairs theory of mind learning.

Imaging and lesion studies indicate that the prefrontal cortex plays a prominent role in mediating theory of mind (ToM) functioning. Particularly, the ventromedial prefrontal cortex (VMPFC) appears to be involved in mediating ToM functioning. This study utilized slow repetitive transcranial magnetic stimulation (rTMS) over the VMPFC in 13 healthy subjects in order to test whether normal functioning of the VMPFC is necessary for ToM functioning. We found that rTMS to the VMPFC, but not sham-rTMS, significantly disrupted ToM learning. Performance on a control task, not involving affective ToM functioning, was not significantly altered after applying rTMS to the VMPFC or sham-rTMS. In an additional experiment, rTMS to the vertex did not significantly affect ToM learning, confirming specificity of the VMPFC region. These findings indicate that the VMPFC is critical for intact ToM learning and shed further light on the concept and localization of ToM in particular and empathic functioning in general.

Comparison of insight among schizophrenia and bipolar disorder patients in remission of affective and positive symptoms: analysis and critique.

BACKGROUND: Schizophrenia and bipolar disorder are associated with impairments in insight, leading to a poorer clinical outcome and functioning. Earlier studies comparing the two disorders on the basis of insight included inpatients or patients who were clinically symptomatic. The current study therefore assessed patients in remission of affective symptoms and positive symptoms of schizophrenia. METHODS: Schizophrenia and bipolar disorder patients (n=32, n=34; respectively) underwent clinical and functional evaluations. Insight was assessed using the Scale to assess Unawareness of Mental Disorder (SUMD) and the positive and negative syndrome scale (PANSS). Attention was assessed using a continuous performance task (CANTAB's rapid visual information processing). RESULTS: Schizophrenia patients displayed poorer insight into having a mental disorder and into the social consequences thereof compared to the bipolar disorder patients. They were also less aware of their anhedonia-asociality. Age, however, was significantly correlated with insight and differences in insight between the patient groups became nonsignificant when age was used as a covariate in the statistical analyses. Age was not a moderating variable of the relationship between diagnosis and insight. CONCLUSIONS: Significant differences in insight held by the two patient groups might be related to age disparities between patient groups. Earlier studies did not adequately address these age differences, their cause and their potential effects on findings. These issues are explored with regard to the findings of the current study, as well as earlier studies, emphasizing the need for further research of the relationship between age and insight.

Effectiveness of a second deep TMS in depression: a brief report.

OBJECTIVES: Deep transcranial magnetic stimulation (DTMS) is an emerging and promising treatment for major depression. In our study, we explored the effectiveness of a second antidepressant course of deep TMS in major depression. We enrolled eight patients who had previously responded well to DTMS but relapsed within 1 year in order to evaluate whether a second course of DTMS would still be effective. METHODS: Eight depressive patients who relapsed after a previous successful deep TMS course expressed their wish to be treated again. Upon their request, they were recruited and treated with 20 daily sessions of DTMS at 20 Hz using the Brainsway's H1 coil. The Hamilton depression rating scale (HDRS), Hamilton anxiety rating scale (HARS) and the Beck depression inventory (BDI) were used weekly to evaluate the response to treatment. RESULTS: Similar to the results obtained in the first course of treatment, the second course of treatment (after relapse) induced significant reductions in HDRS, HARS and BDI scores, compared to the ratings measured prior to treatment. The magnitude of response in the second course was smaller relative to that obtained in the first course of treatment. CONCLUSIONS: Our results suggest that depressive patients who previously responded well to deep TMS treatment are likely to respond again. However, the slight reduction in the magnitude of the response in the second treatment raises the question of whether tolerance or resistance to this treatment may eventually develop.

Positive effects of repetitive transcranial magnetic stimulation on attention in ADHD Subjects: a randomized controlled pilot study.

OBJECTIVES: Repetitive transcranial stimulation (rTMS) affects dopaminergic secretion in the prefrontal cortex. Attention deficit hyperactivity disorder (ADHD) had been suggested to involve dopaminergic prefrontal abnormalities. METHODS: In this crossover double-blind randomized, sham-controlled pilot study, patients diagnosed as having adult ADHD received either a single session of high-frequency rTMS directed to the right prefrontal cortex (real rTMS) or a single session of sham rTMS. RESULTS: A total of 13 patients (seven males, six females) who fulfilled the criteria for adult ADHD, according to DSM-IV criteria gave informed consent and were enrolled. There was a specific beneficial effect on attention 10 minutes after a real rTMS course. The post-real rTMS attention score improved significantly (M=3.56, SD=0.39) compared to the pre-real rTMS attention score (M=3.31, SD=0.5) [t(12)=2.235, P < 0.05]. TMS had no effect on measures of mood and anxiety. The sham rTMS had no effect whatsoever. CONCLUSIONS: Our findings should encourage future research on the possibility of amelioration of attention difficulties in patients suffering from ADHD by using high frequency rTMS directed to the right dorsolateral prefrontal cortex. (NIH registry NCT00825708).

The effect of intranasal administration of oxytocin on fear recognition.

The oxytocinergic system has recently been placed amongst the most promising targets for various psychiatric treatments due to its role in prosocial behavior and anxiety reduction. Although recent studies have demonstrated a general effect of administration of oxytocin on emotion recognition, no study to date has examine the effect of oxytocin on each emotion separately. In the present study, a double-blind placebo-controlled crossover design was used in a dynamic facial expression task, in order to assess the effects of administration of oxytocin on emotion recognition. A single dose of oxytocin or a placebo was administered intranasally to 27 healthy male subjects 45 min prior to task performance. The results showed that a single intranasal administration of oxytocin, as opposed to the placebo, improved the subjects' ability to recognize fear, but not other emotions. These results suggest a specific role for oxytocin in fear recognition, which could be relevant for clinical disorders that manifest deficits in processing emotional facial expressions, particularly fear.

The effect of Ondansetron on memory in schizophrenic patients.

It has been well established that patients with schizophrenia have impaired cognitive function on neuropsychological tasks related to memory. Previous studies also suggest serotonin's central role in memory. This double-blind crossover study aimed to explore the effect of Ondansetron, a selective serotonin 3 receptor (5-HT(3)) antagonist, on a variety of memory tasks in schizophrenic patients. Clozapine-treated schizophrenic patients in remission (N=21) were randomly treated with Ondansetron or placebo and then evaluated at three consecutive points. These evaluations included clinical measures (including Positive and Negative Syndrome Scale for Schizophrenia, Clinical Global Impression and Extrapyramidal Symptoms Rating Scale) and neuropsychological measures (including Digit Span, Paired Association, Rey-Osterich Complex Figure Test, Digit Symbol and the Rivermead Behavioral Memory Tests). Ondansetron, when compared with placebo, did not affect the above clinical measures and most of the neuropsychological tests. Short-term administration of Ondansetron, however, was associated with significantly improved visuo-spatial memory as measured by the Rey-Osterich Complex Figure Test. These preliminary results suggest Ondansetron's possible role in enhancement of memory function in schizophrenia.

Perception of dyadic relationship and emotional states in patients with affective disorder.

BACKGROUND: Previous research has shown that interpersonal processes play a significant role in the development and maintenance of affective disorders. In this study, this claim was further investigated by comparing the perception of the dyadic relationship and judgment of other's emotions in affective disorder patients. METHOD: The sample included 39 couples (n=39 couples) with one of the partners suffering from an affective disorder and currently either in an acute or remitted depressive state. All participants completed four instruments, measuring the perceived quality of the dyadic relationship and the perception of other's emotions as reflected by judgments of facial expressions line drawings. RESULTS: While the level of marital satisfaction was found to be lower in the acute than in the remitted group both for ill partners and their spouses, spouses in both the acute and remitted group tended to be more critical of their ill partners. Patients who were depressed judged facial expressions significantly less positively than did remitted patients. Judgments of negative emotions were highly correlated between partners in the acute group, but uncorrelated in the remitted group. Acutely depressed patients were less sensitive to invitation than remitted patients, while their spouses displayed the opposite pattern. CONCLUSION: The present results shed further light on the interpersonal dynamics between depressed patients and their spouses by underscoring differences between couples with a remitted vs. acutely depressed partner in their perception of the dyadic unit and their judgments of facial emotions. LIMITATIONS: Longitudinal research is needed, in which the same patients are tested during periods of remission and acute episodes, as well as research investigating the role of patient gender in the perception of facial expressions of emotions.

A dominant negative inhibitor of the Egr family of transcription regulatory factors suppresses cerebellar granule cell apoptosis by blocking c-Jun activation.

To investigate the role of the Egr family of transcription regulatory factors in neuronal apoptosis, we examined the effect of a dominant negative Egr inhibitor construct in a well characterized in vitro paradigm, cerebellar granule cell death induced by withdrawal of depolarizing concentrations of extracellular potassium. We found that this apoptotic stimulus increases the activity of a reporter gene driven by the Egr response element and that a dominant negative inhibitor of Egr-mediated transcription blocks granule cell apoptosis. In contrast, apoptosis of immature granule cells induced by cytosine arabinoside is not inhibited by the Egr inhibitor construct. Because activation of c-Jun is an essential step in granule cell death induced by potassium deprivation, but not cytosine arabinoside, we asked whether the Egr inhibitor acts by influencing c-Jun activation or its ability to induce apoptosis. We found that the Egr inhibitor does not block the ability of a constitutively active c-Jun construct to induce apoptosis in these cells but does suppress activation of c-Jun-mediated transcription induced by lowering extracellular potassium concentration. Furthermore, the Egr inhibitor blocks the ability of MEKK1 [mitogen-activated protein kinase (MAPK) kinase kinase 1], an upstream kinase capable of stimulating the JNK (c-Jun N-terminal protein kinase)-c-Jun pathway, to induce apoptosis and activate c-Jun. Together, these studies indicate that the Egr family of transcription factors plays a critical role in neuronal apoptosis and identify c-Jun activation as an important downstream target of the Egr family in this process.

Post-psychotic depression in schizophrenia.

Although a depressive state is known to occur following the resolution of an acute psychotic episode, little research has investigated its etiology, course, prognosis and treatment. Very often the depression is mistaken for an extrapyramidal-like syndrome--the secondary effect of antipsychotic medication--as a sense of inevitability assails both the patient and therapist. Post-psychotic depression, far from being an obscure and undefined clinical picture, has the characteristics of a clear-cut syndrome. Nevertheless, it was only recently referred to as a distinct entity in psychiatric classification systems. As a result, different researchers used varying criteria for the definition of the phenomenon, and the data collected in the different studies are therefore difficult to compare. We present a critical review of the data published to date, with emphasis on the importance of early recognition and treatment of post-psychotic depression.

Transcranial magnetic stimulation and antidepressive drugs share similar cellular effects in rat hippocampus.

Transcranial magnetic stimulation (TMS) has been proposed as a safe and efficient treatment of human clinical depression. Although its antidepressive mechanism of action remained unknown, our previous studies indicate that TMS has a long-lasting effect on neuronal excitability in the hippocampus. We now compare the effects of chronic TMS with those of the antidepressant drugs desipramine and mianserin. The three treatments did not affect basal conduction in the perforant path to the dentate gyrus, but markedly suppressed paired-pulse and frequency-dependent inhibition, resulting from a reduction in local circuit inhibition in the dentate gyrus. Concomitantly, these treatments enhanced the expression of long-term potentiation in the perforant path synapse in the dentate gyrus. Finally, chronic TMS as well as mianserin suppressed the serotonin-dependent, potentiating action of fenfluramine on population spike in the dentate gyrus. Thus, TMS, mianserin, and desipramine are likely to affect the same neuronal populations, which may be relevant to their antidepressant action.

Aging affects transcranial magnetic modulation of hippocampal evoked potentials.

Transcranial magnetic stimulation (TMS) is being proposed as a method of choice for the treatment of clinical depression, yet its action in the brain is still not well understood. In previous studies we found that TMS has a long-term effect on reactivity of the hippocampus to perforant path stimulation. Since the efficacy of antidepressants is highly age-dependent, we studied possible age-related effects of TMS on hippocampal evoked responses. Young adult (3 months), aging (10 months) and aged (24-26 months) awake rats were subjected to daily TMS for one week, followed by measurements of several parameters of reactivity to perforant path stimulation in the anesthetized rat. TMS did not affect responses of the hippocampus to single perforant path stimulation, but reduced drastically paired-pulse and frequency dependent depression in the young and aging but not the old rats. Likewise, TMS increased LTP expression in the young but not the old rats, and reduced the efficacy of serotonin modulation of reactivity of the hippocampus, in the young but not the old rats. Thus, long term effects of chronic TMS on local GABAergic inhibition are highly age dependent.