Attachment Security and Cortical Activity Measured by Functional Near-Infrared Spectroscopy During a Working Memory Task in Healthy Young Adults.

Introduction: Attachment style has been associated with socio-emotional outcomes, however little evidence suggests a possible association with executive functioning. Few studies have demonstrated that attachment style mediates working memory and learning relationships. We hypothesized that attachment style affects performance and cortical activity patterns of working memory. Methods: We compared working memory performance and cortical activity in securely and insecurely attached first-year college students (N=49) using three n-back task conditions. Cortical activity was recorded by functional near-infrared spectroscopy during these three conditions of the n-back task. Attachment style was assessed using the Relationship Scale Questionnaire, categorized into four groups. Results: Both study groups showed similar working memory performance. The cortical representation of working memory was different between the two groups. The securely attached group demonstrated higher activity in the right superior frontal and superior-medial frontal areas across all n-back conditions as well as in the right superior frontal cortex during the two-back and three-back conditions. The insecurely attached group displayed higher activity in the bilateral supplementary motor area and the left premotor area only during the three-back condition. Conclusion: These findings emphasize the potential influence of attachment style on the cortical representation of working memory. Different activity maps between the two groups may reflect varying cognitive strategies employed to achieve a comparable working memory performance. Moreover, these results suggest that each style may have a distinct strategy to achieve attachment-relevant and irrelevant neurocognitive tasks.

The Potential Role of POR*28 and CYP1A2*F Genetic Variations and Lifestyle Factors on Clozapine and N-DesmethylClozapine Plasma Levels in Schizophrenia Patients.

BACKGROUND: Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects. RESEARCH DESIGN AND METHODS: As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients. For this purpose, 112 schizophrenia patients receiving CLZ were included in the current study. Plasma CLZ and N-desmethylclozapine (DCLZ) levels were analyzed by using HPLC and genetic variations were identified with the PCR-RFLP method. RESULTS: The patients' CYP1A2 and POR genotypes seemed to not affect plasma CLZ and DCLZ levels whereas in the subgroup analysis, POR *28 genotype significantly influenced simple and adjusted plasma CLZ and DLCZ levels concerning smoking habit and caffeine consumption. CONCLUSIONS: The findings of the present study highlight the importance of both genetic and non-genetic factors (smoking and caffeine consumption) for the individualization of the CLZ treatment. In addition to that, it suggests that the added utility of not only the CLZ metabolizing enzymes but also POR, which is crucial for proper CYP activity, to guide CLZ dosing might be useful for clinical decision-making.

Long Acting Injectable Antipsychotics in the Treatment of Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder (BD) are psychiatric disorders with economic and social effects that cause disability. Treatment non-compliance is one of the major problems faced by clinicians in both schizophrenia and BD. Treatment non-compliance is associated with recurrence and impaired functionality. Treatment compliance increases with long-acting injectable antipsychotics (LAIAs) and recurrence times are prolonged, hospitalization rates decrease compared to those who use an equivalent oral form of the same drug. The use of LAIAs in the maintenance treatment of schizophrenia has also been associated with a low mortality rate, decrease in caregiver burden, and increase in patient satisfaction. Studies show that LAIAs are cost-effective compared to their oral forms. Data on the use of LAIAs in first-episode schizophrenia and BD are relatively limited. The results of studies on the use of LAIAs in patients with first-episode schizophrenia indicate that LAIAs have advantageous in preventing relapse and re-hospitalization compared to oral antipsychotics. In BD, with the use of LAIAs, the rate of hospitalization due to mood episodes and the frequency of manic episodes have been decreased. LAIAs have not been found to be as effective in preventing depressive episodes in BD as manic episodes. Although there are many studies supporting the use of LAIAs in maintenance treatment of schizophrenia and BD, more studies are needed on this issue. In this article, studies on the use of LAIAs in schizophrenia, first episode schizophrenia and BD are reviewed and the place of LAIAs in treatment was discussed.

Cortical activity measured by functional near infrared spectroscopy during a theory of mind task in subjects with schizophrenia, bipolar disorder and healthy controls.

Theory of Mind (ToM) deficits interfere in social cognitive functioning in schizophrenia (SCZ) and are increasingly recognized to do so in bipolar disorder (BD), however their clinical and neurobiological correlates remain unclear. This study represents the first direct comparison of subjects with SCZ (N = 26), BD (N = 26) and healthy controls (N = 33) in cortical activity during the Reading the Mind in the Eyes Task (RMET) using functional Near Infrared Spectroscopy (fNIRS) with the control condition (CC) involving gender identification via the same stimuli. The three groups were compared with a comprehensive ToM battery and assessed in terms of the relationship of ToM performance with clinical symptoms, insight and functioning. The controls scored higher than the SCZ and BD groups in ToM assessments, with SCZ group showing the worse performance in terms of meta-representation and empathy. The SCZ group ToM scores inversely correlated with negative symptom severity and positively correlated with insight; BD group ToM scores negatively correlated with subclinical mania symptoms and projected functioning. Cortical activity was higher during the ToM condition compared to the CC in the pre-motor and supplementary-motor cortices, middle and superior temporal gyri, and the primary somatosensory cortex. Group x Condition interaction was detected whereby activity was higher during the ToM condition among controls with no detected difference between SCZ and BD groups. The results suggest that ToM is represented similarly in cortical activity in SCZ and BD compared to healthy controls pointing to possible neurobiological convergence of SCZ and BD in underlying impairments of social cognition.

Cortical activity during social acceptance and rejection task in social anxiety disorder: A controlled functional near infrared spectroscopy study.

BACKGROUND: The cognitive and emotional vulnerability of individuals with social anxiety disorder (SAD) and their response to repeated experiences of social rejection and social acceptance are important factors for the emergence and maintenance of symptoms of the disorder. Functional neuroimaging studies of SAD reveal hyperactivity in regions involved in the fear circuit such as amygdala, insula, anterior cingulate, and prefrontal cortices (PFC) in response to human faces with negative emotions. Observation of brain activity, however, involving studies of responses to standardized human interaction of social acceptance and social rejection have been lacking. METHODS: We compared a group of index subjects with SAD (N = 22, mean age:26.3 ± 5.4, female/male: 7/15) (SADG) with a group of healthy controls (CG) (N = 21, mean age:28.7 ± 4.5, female/male: 14/7) in measures of cortical activity during standardized experiences of human interaction involving social acceptance (SA) and social rejection (SR) video-simulated handshaking tasks performed by real actors. In a third, control condition (CC), the subjects were expected to press a switch button in an equivalent space. Subjects with a concurrent mood episode were excluded and the severity of subclinical depressive symptoms was controlled. 52-channel functional near-infrared spectroscopy (fNIRS) was used to measure cortical activity. RESULTS: Activity was higher in the SAD subjects compared to healthy controls, in particular in channels that project to middle and superior temporal gyri (STG), frontal eye fields (FEF) and dorsolateral prefrontal cortex (DLPFC) in terms of both SA and SR conditions. Cortical activity during the CC was not different between the groups. Only in the SAD-group, activity in the pre-motor and supplementary motor cortices, inferior and middle temporal gyri and fronto-polar area was higher during the rejection condition than the other two conditions. Anxiety scores were correlated with activity in STG, DLPFC, FEF and premotor cortex, while avoidance scores were correlated with activity in STG and FEF. CONCLUSIONS: SA and SR are represented differently in terms of cortical activity in SAD subjects compared to healthy controls. Higher activity in both social conditions in SAD subjects compared to controls may imply biological sensitivity to these experiences and may underscore the importance of increased cortical activity during social interaction experiences as a putative mediator of vulnerability to SAD. Higher cortical activity in the SADG may possibly indicate stronger need for inhibitory control mechanisms and higher recruitment of theory of mind functions during social stress. Higher activity during the SR compared to the SA condition in the SAD subjects may also suggest distinct processing of social cues, whether they involve acceptance or rejection.

Determination of Mirtazapine and Desmethyl Mirtazapine in Human Plasma by a New Validated HPLC Ultraviolet Method with a Simple and Reliable Extraction Method: Application to Therapeutic Drug Monitoring Study by 62 Real Patient Plasma.

Determination of mirtazapine (MRP) during psychopharmacotherapy in biological fluids is essential to achieve successful therapy, to avoid toxicity related to drug interactions, genetic variability, and poor compliance. A new, rapid, and sensitive high-performance liquid chromatography method has been developed in human plasma for the determination of MRP and N-desmethylmirtazapine (NDM) that is an active metabolite. The separation was achieved on a reverse-phase C18 250 x 4.6 mm i.d., ODS-3 column using programmed gradient elution at 40 °C. 20 mM potassium phosphate buffer (pH 3.9), acetonitrile, and triethylamine (75.0:24.9:0.1, v/v/v) were used as mobile phase A. Mobile phase B consisted of absolute acetonitrile. Clozapine was used as an internal standard. The method showed linearity with good determination coefficients (r2≥0.9981) for each analyte. Intra-day and interday assay precisions (RSD%) were found less than 3.4 and 2.9 for MRP and NDM, respectively. The intra-day and interday accuracy (RE%) of the method were calculated between (-2.8) and 5.5. A new extraction method was used in the study and an excellent recovery (average) values for MRP and NDM (94.4%, 106.6%, respectively) was obtained. The method was specific and sensitive as the limit of detection (LOD) were 0.17 for MRP and 0.15 ng/mL for NDM. This method was applied properly to plasma samples taken from patients receiving MRI (n = 62) treated with 15-30 mg / day. The obtained and statistically evaluated plasma MRP and NDM levels which were 28.6 ± 13.8 and 12.3 ± 6.5 (mean ± SD). The described procedure is relatively simple, precise, and applicable for routine therapeutic drug monitoring especially in psychiatry clinics and toxicology reference laboratories.

The relationship between plasma levels of clozapine and N-desmethyclozapine as well as M1 receptor polymorphism with cognitive functioning and associated cortical activity in schizophrenia.

Studies that examined the effect of clozapine on cognitive functions in schizophrenia provided contradictory results. N-desmethylclozapine (NDMC) is the major metabolite of clozapine and have procognitive effects via agonistic activity in the M1 cholinergic receptors. The rs2067477 polymorphism in the M1 receptors may play role in cognitive profile in schizophrenia. We investigated the association of plasma clozapine (PClz), NDMC (PNdmc) levels and the rs2067477 polymorphism with cognitive functions and cortical activity measured by functional near infrared spectroscopy during the N-Back task in subjects with schizophrenia (N = 50) who are under antipsychotic monotherapy with clozapine. We found that PClz and PNdmc levels were negatively, PNdmc/PClz ratio was positively correlated with immediate recall score in the Rey Auditory Verbal Learning Test. PNdmc/PClz ratio was positively correlated with cortical activity during the N-back task. M1 wild-type group (CC: wild-type) produced higher cortical activity than M1 non wild-type group (CA: heterozygote / AA: mutant) in cortical regions associated with working memory (WM). These results suggest that individual differences in clozapine's effect on short term episodic memory may be associated with PClz and PNdmc. Higher activity in the M1 wild-type group may indicate inefficient use of cortical resources and/or excessive use of certain cognitive strategies during WM performance.

The Association of CYP2D6*4 and POR*28 Polymorphisms on Mirtazapine Plasma Level in Subjects with Major Depressive Disorder and Anxiety Disorders.

AIMS AND OBJECTIVE: The plasma level of mirtazapine (MIR) varies between individuals primarily depending on the differences in metabolism during pharmacotherapy. CYP2D6 takes the role as a major enzyme in MIR metabolism and POR enzyme donates an electron to CYP2D6 for its activity. Single nucleotide polymorphisms in the genes encoding pharmacokinetic enzymes may cause changes in enzyme activity, leading to differences in metabolism of the drug. Our aim was to assess the influence of CYP2D6*4 and POR*28 polymorphisms on MIR plasma levels in Turkish psychiatric patients. MATERIALS AND METHODS: The association between genetic variations and plasma level of MIR was investigated on 54 patients. CYP2D6*4 and POR*28 polymorphisms were analysed using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and plasma MIR levels were measured using HPLC. RESULTS: Allele frequencies of CYP2D6*4 and POR*28 were 0.11 and 0.39, respectively in the study population. The results showed that CYP2D6*4 allele carriers have higher C/D MIR levels while POR*28 allele carriers have lower C/D MIR levels. Combined genotype analyses also revealed that individuals with CYP2D6*1/*1 - POR*28/*28 genotype have a statistically lower C/D MIR level (0.95 ng/ml/dose) when compared with individuals with CYP2D6*1/*1 - POR*1/*1 genotype (1.52 ng/ml/dose). CONCLUSION: Our results indicate that CYP2D6*4 and POR*28 polymorphisms may have a potential in the explanation of differences in plasma levels in MIR treated psychiatric patients. A combination of these variations may be beneficial in increasing drug response and decreasing adverse drug reactions in MIR psychopharmacotherapy.

Attachment Style Predicts Cortical Activity in Temporoparietal Junction (TPJ): An fNIRS Study Using a Theory of Mind (ToM) Task in Healthy University Students.

Results of the behavioral studies suggest that attachment styles may have an enduring effect upon theory of mind (ToM). However biological underpinnings of this relationship are unclear. Here, we compared securely and insecurely attached first grade university students (N = 56) in terms of cortical activity measured by 52 channel Functional Near Infrared Spectroscopy (fNIRS) during the Reading the Mind from the Eyes Test (RMET). The control condition involved gender identification via the same stimuli. We found that the ToM condition evoked higher activity than the control condition particularly in the right hemisphere. We observed higher activity during the ToM condition relative to the control condition in the secure group (SG), whereas the overall cortical activity evoked by the two conditions was indistinguishable in the insecure group (ISG). Higher activity was observed in channels corresponding to right superior temporal and adjacent parietal cortices in the SG relative to the ISG during the ToM condition. Dismissive attachment scores were negatively correlated with activity in channels that correspond to right superior temporal cortex. These results suggest that attachment styles do have an effect on representation of ToM in terms of cortical activity in late adolescence. Particularly, dismissive attachment is represented by lower activity in the right superior temporal cortex during ToM, which might be related to weaker social need and habitual unwillingness for closeness among this group of adolescents.

A Novel Genotyping Method for Detection of the Muscarinic Receptor M1 Gene rs2067477 Polymorphism and Its Genotype/Allele Frequencies in a Turkish Population.

OBJECTIVES: Gene variation in the cholinergic muscarinic receptor 1 (CHRM1) has potential to become a candidate biomarker in the development of several disorders as well as drug response. In this study, a novel polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was developed to determine the C to A single nucleotide polymorphism at position 267 in the CHRM1 gene. MATERIALS AND METHODS: A new reverse primer and a mismatched forward primer were designed to obtain 125 bp PCR products. The PCR products were then digested with the Hae III restriction enzyme to detect the rs2067477 polymorphism that comprises a C to A base change. The novel assay developed was tested in 51 Turkish schizophrenia patients. RESULTS: The genotyping assay was successfully performed in patients with schizophrenia in order to confirm the accuracy and validity of this method. The frequency of CC, CA, and AA genotypes was 72.5%, 25.5%, and 2%, respectively. On the basis of these findings, the allele frequency of C was 0.85 and the allele frequency of A was 0.15. CONCLUSION: This genotyping assay is practical for screening the CHRM1 C267A polymorphism in pharmacogenetic studies. The present polymorphism may be used as a candidate biomarker to determine genetic susceptibility to related diseases and may contribute to the implementation of individualized drug therapy for M1-related diseases.

[Prefrontal Cortex Activity During Facial Affect Processing in Schizophrenia: Association with Clinical Symptoms and Social Cognitive Functions]. / Sizofrenide Yüzdeki Duygu Ifadelerini Tanima Sirasindaki Prefrontal Korteks Aktivitesinin Klinik Belirtiler ve Sosyal Bilis Islevleriyle Iliskisi.

OBJECTIVES: In the present study, we aimed to investigate the prefrontal cortex (PFC) activity during facial affect recognition in schizophrenia, as well as the association of this activity with symptom severity and with the higher order social cognitive functions, namely recognition of false beliefs, faux-pas and hinting. METHOD: Functional near infrared spectroscopy (fNIRS) was used to measure frontal cortical activity during a neuroimaging task prepared with a standard set of pictures of facial affect. The data of the Index Group (IG) consisting of 27 subjects with DSM-IV based diagnoses of schizophrenia and schizophreniform disorder and control group (CG) (N=25) were compared. The control condition was to detect nonaffective changes on a neutral face. Associations with frontal activity during affect recognition and clinical symptoms, false belief recognition, hinting and faux-pas were investigated. RESULTS: Prefrontal activity during both affective and non-affective conditions was higher in the IG than the CG. The IG performed worse than the CG in social cognitive tests. Social cognitive test performance was not correlated with cortical activity. There were no correlations between education status, age and PFC activity in both groups. In the IG, right ventral prefrontal cortex (VPFC) and right medial prefrontal cortex (mPFC) activities were associated with hallucination severity. CONCLUSION: These results suggest the presence of hyperfrontality during face processing in schizophrenia. Results also suggest that schizophrenia patients require more frontal resources to achieve a performance comparable to that of healthy controls in order to detect both affective and non-affective changes on a face. There might be a relationship between facial processing and hallucinations.