The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders.

BACKGROUND: Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample. METHODS: Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length. RESULTS: Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group. CONCLUSIONS: This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.

The Relationship between Negative Symptoms and Both Emotion Management and Non-social Cognition in Schizophrenia Spectrum Disorders.

OBJECTIVE: There is ongoing debate regarding the relationship between clinical symptoms and cognition in schizophrenia spectrum disorders (SSD). The present study aimed to explore the potential relationships between symptoms, with an emphasis on negative symptoms, and social and non-social cognition. METHOD: Hierarchical cluster analysis with k-means optimisation was conducted to characterise clinical subgroups using the Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms in n = 130 SSD participants. Emergent clusters were compared on the MATRICS Consensus Cognitive Battery, which measures non-social cognition and emotion management as well as demographic and clinical variables. Spearman's correlations were then used to investigate potential relationships between specific negative symptoms and emotion management and non-social cognition. RESULTS: Four distinct clinical subgroups were identified: 1. high hallucinations, 2. mixed symptoms, 3. high negative symptoms, and 4. relatively asymptomatic. The high negative symptom subgroup was found to have significantly poorer emotion management than the high hallucination and relatively asymptomatic subgroups. No further differences between subgroups were observed. Correlation analyses revealed avolition-apathy and anhedonia-asociality were negatively correlated with emotion management, but not non-social cognition. Affective flattening and alogia were not associated with either emotion management or non-social cognition. CONCLUSIONS: The present study identified associations between negative symptoms and emotion management within social cognition, but no domains of non-social cognition. This relationship may be specific to motivation, anhedonia and apathy, but not expressive deficits. This suggests that targeted interventions for social cognition may also result in parallel improvement in some specific negative symptoms.

Working Memory and Attention Influence Antisaccade Error Rate in Schizophrenia.

Objectives: Antisaccade error rate has been proposed to be one of the most promising endophenotypes for schizophrenia. Increased error rate in patients has been associated with working memory, attention and other executive function impairments. The relationship between antisaccade error rate and other neuropsychological processes in patients compared to healthy controls has not been explored in depth. This study aimed to replicate the finding of heightened antisaccade error rate in patients and determine which cognitive processes were most strongly associated with antisaccade error rate in both patients and controls. In addition, the study investigated whether different antisaccade task paradigms engage different cognitive processes. Methods: One hundred and ninety-one participants (54 patients with schizophrenia/schizoaffective disorder and 137 controls) completed the antisaccade task, which included both gap and step task parameters. Neuropsychological measures were obtained using the MCCB and the Stroop task. Results: The current study replicated a pronounced antisaccade error rate deficit in patients. In patients, working memory variance was most significantly associated with antisaccade errors made during the step condition, while attentional processes were most associated with errors made during the gap condition. In controls, overall global cognitive performance was most associated with antisaccade rates for both gap and step conditions. Conclusions: The current study demonstrates that in schizophrenia patients, but not controls, elevated antisaccade error rate is associated with attention and working memory, but not with global cognitive impairment or psychopathological processes. Our novel findings demonstrate that the gap and step conditions of the antisaccade task engage different cognitive processes. (JINS, 2019, 25, 174-183).

Exploring Heterogeneity on the Wisconsin Card Sorting Test in Schizophrenia Spectrum Disorders: A Cluster Analytical Investigation.

OBJECTIVES: The Wisconsin Card Sorting Test (WCST) is a complex measure of executive function that is frequently employed to investigate the schizophrenia spectrum. The successful completion of the task requires the interaction of multiple intact executive processes, including attention, inhibition, cognitive flexibility, and concept formation. Considerable cognitive heterogeneity exists among the schizophrenia spectrum population, with substantive evidence to support the existence of distinct cognitive phenotypes. The within-group performance heterogeneity of individuals with schizophrenia spectrum disorder (SSD) on the WCST has yet to be investigated. A data-driven cluster analysis was performed to characterise WCST performance heterogeneity. METHODS: Hierarchical cluster analysis with k-means optimisation was employed to identify homogenous subgroups in a sample of 210 schizophrenia spectrum participants. Emergent clusters were then compared to each other and a group of 194 healthy controls (HC) on WCST performance and demographic/clinical variables. RESULTS: Three clusters emerged and were validated via altered design iterations. Clusters were deemed to reflect a relatively intact patient subgroup, a moderately impaired patient subgroup, and a severely impaired patient subgroup. CONCLUSIONS: Considerable within-group heterogeneity exists on the WCST. Identification of subgroups of patients who exhibit homogenous performance on measures of executive functioning may assist in optimising cognitive interventions. Previous associations found using the WCST among schizophrenia spectrum participants should be reappraised. (JINS, 2019, 25, 750-760).

A New Angle on Transcranial Magnetic Stimulation Coil Orientation: A Targeted Narrative Review.

Transcranial magnetic stimulation (TMS) is used to treat several neuropsychiatric disorders including depression, where it is effective in approximately one half of patients for whom pharmacological approaches have failed. Treatment response is related to stimulation parameters such as the stimulation frequency, pattern, intensity, location, total number of pulses and sessions applied, and target brain network engagement. One critical but underexplored component of the stimulation procedure is the orientation or yaw angle of the commonly used figure-of-eight TMS coil, which is known to impact neuronal response to TMS. However, coil orientation has remained largely unchanged since TMS was first used to treat depression and continues to be based on motor cortex anatomy, which may not be optimal for the dorsolateral prefrontal cortex treatment site. In this targeted narrative review, we evaluate experimental, clinical, and computational evidence indicating that optimizing coil orientation may improve TMS treatment outcomes. The properties of the electric field induced by TMS, the changes to this field caused by the differing conductivities of head tissues, and the interaction between coil orientation and the underlying cortical anatomy are summarized. We describe evidence that the magnitude and site of cortical activation, surrogate markers of TMS dosing and brain network targeting considered central in clinical response to TMS, are influenced by coil orientation. We suggest that coil orientation should be considered when applying therapeutic TMS and propose several approaches to optimizing this potentially important treatment parameter.

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

Menstrual Cycle in Trauma-Related Disorders: A Mini-Review.

Fluctuations of sex hormones across the menstrual cycle have been linked to exacerbation of symptoms of psychiatric disorders. Women diagnosed with trauma-related disorders such as post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) have reported worsening of mood symptoms at various phases of their menstrual cycle. There is also considerable overlap between PTSD, BPD, and complex-PTSD (cPTSD) symptoms, suggesting similar biological underpinnings. This mini-review examines the influence of sex hormones and the menstrual cycle on PTSD, BPD, and cPTSD symptoms, and discusses the involvement of the hypothalamic-pituitary-adrenal (HPA) axis. We review literature showing that PTSD and BPD symptoms fluctuate with the menstrual cycle, though the effect of the menstrual cycle phase appears to be inconsistent, warranting future research. Based on the reported phasic vulnerability in individuals with PTSD and BPD, it is plausible to assume that women diagnosed with the newly introduced cPTSD may experience similar difficulties. However, no study to date has addressed this. This review highlights the importance of considering an individual's trauma history as it may influence symptom severity and diagnosis, and the phase of the menstrual cycle at the time of diagnosis. This review also highlights that additional work is needed to clarify the influence of estradiol and progesterone fluctuations on trauma-related symptoms, especially in cPTSD. Continued research on menstrual cycle vulnerability and trauma will lead to better informed management and treatment of PTSD, BPD, and cPTSD.

Gender Differences in the Correlations between Childhood Trauma, Schizotypy and Negative Emotions in Non-Clinical Individuals.

Early life trauma has a negative impact on the developing brain, and this can lead to a wide range of mental illnesses later in life. Childhood trauma is associated with increased psychotic symptoms and negative emotions such as depressive, anxiety, and stress symptoms in adulthood. Childhood trauma has also been shown to influence sub-clinical 'schizotypy' characteristics of psychosis in the general population. As it has been reported that mental health outcomes after early life trauma exposure are influenced by gender, the current study aimed to investigate the gender differences in the relationship between childhood trauma, schizotypy and negative emotions. Sixty-one non-clinical participants (33 men and 28 women) aged between 18 and 45 completed self-report questionnaires to measure early life trauma, schizotypy and negative emotions. Despite similar levels of childhood trauma in men and women, early life trauma in women was associated with increased schizotypy personality characteristics (Cognitive Disorganisation) and increased depression, anxiety and stress later in life, but no correlations were observed in men. Our findings suggest that the sociocultural and biological processes affected by early life adversities may differ between the genders. Women may be more vulnerable to the influence of childhood trauma, which may be associated with increased psychopathology later in life.

The prevalence of early life trauma in premenstrual dysphoric disorder (PMDD).

Early life trauma is a risk factor for many mental disorders; however, there is a lack of research exploring early life trauma in Premenstrual Dysphoric Disorder (PMDD), a debilitating form of Premenstrual Syndrome (PMS). This descriptive study aimed to determine the prevalence of early life trauma in women with PMDD and characterise type and age of trauma experience. Data for 100 women diagnosed with PMDD was extracted from the Monash Alfred Women's Mental Health Clinic Database. Experience of early life trauma was subclassified into four types (Physical abuse, sexual abuse, emotional abuse and/or neglect) and four age groups (0-5, 6-10, 11-14 and/or 15-18 years old). Prevalence of early life trauma was calculated and compared with Australian population estimates. Eighty-three percent of women with PMDD had experienced early life trauma, with emotional abuse being the most common (71%). All types of trauma were more common amongst PMDD women than the general Australian population. Trauma prevalence was similar across the four age groups, ranging from 59 to 66%. Of note, 51.8% women experienced trauma across all age groups. Our results suggest a strong association between early life trauma and PMDD. Emotional abuse and/or chronic trauma across childhood may be most strongly associated with PMDD.

Evidence that a working memory cognitive phenotype within schizophrenia has a unique underlying biology.

It is suggested studying phenotypes within the syndrome of schizophrenia will accelerate understanding the complex molecular pathology of the disorder. Supporting this hypothesis, we have identified a sub-group within schizophrenia with impaired working memory (WM) and have used Affymetrix™ Human Exon 1.0 ST Arrays to compare their blood RNA levels (n=16) to a group of with intact WM (n=18). Levels of 72 RNAs were higher in blood from patients with impaired WM, 11 of which have proven links to the maintenance of different aspects of working memory (cognition). Overall, changed gene expression in those with impaired WM could be linked to cognition through glutamatergic activity, olfaction, immunity, inflammation as well as energy and metabolism. Our data gives preliminary support to the hypotheses that there is a working memory deficit phenotype within the syndrome of schizophrenia with has a biological underpinning. In addition, our data raises the possibility that a larger study could show that the specific changes in gene expression we have identified could prove to be the biomarkers needed to develop a blood test to identify those with impaired WM; a significant step toward allowing the use of personalised medicine directed toward improving their impaired working memory.

Sex hormones and cognition in aging.

Hormones of the hypothalamic-pituitary-gonadal axis that regulate reproductive function are also potent neurosteriods that have multiple effects on the development, maintenance and function of the brain. There is a growing body of evidence linking sex hormones to cognitive functioning across the lifespan. Both subjective and objective cognitive changes can occur with aging. For women, cognitive complains are commonly associated with the menopause transition-a time of significant hormone flux. Sex differences in neurodegenerative conditions associated with cognitive dysfunction, such as Alzheimer's disease and Parkinson's disease, suggest a potential link between sex hormones and cognitive decline. Evidence for the effects of hormone therapy on cognition is growing, but remains inconclusive. This chapter provides an overview of sex hormones and cognition in association with healthy aging, including a focus on the menopause transition, as well as reviewing findings linking sex hormones to cognitive decline associated with Alzheimer's disease and Parkinson's disease. An overview of hormone therapy and cognition is also provided.

Schizotypy, neuroticism, and saccadic eye movements: New data and meta-analysis.

Deficits on saccade tasks, particularly antisaccade performance, have been reliably reported in schizophrenia. However, less evidence is available on saccade performance in relation to schizotypy, a personality constellation harboring risk for schizophrenia. Here, we report a large empirical study of the associations of schizotypy and neuroticism with antisaccade and prosaccade performance (Study I). Additionally, we carried out meta-analyses of the association between schizotypy and antisaccade error rate (Study II). In Study I, N = 526 healthy individuals from the general population aged 18-54 years completed prosaccade and antisaccade tasks as well as the Schizotypal Personality Questionnaire (SPQ). Schizotypy was significantly associated with increased antisaccade error rate, with the disorganized dimension emerging as strongest predictor (ß = .118, p = .007). Neuroticism emerged as a significant predictor for prosaccade gain (ß = .103, p = .023) and antisaccade latency (ß = .101, p = .025). In Study II, random-effects meta-analyses were performed on the published data and those from Study I. Meta-analyses revealed significant associations (all p ≤ .003) of antisaccade error rate with positive (g = 0.37), negative (g = 0.26), disorganized (g = 0.36) and overall schizotypy (g = 0.37). Overall, the present work replicates the association between antisaccade direction errors and schizotypy. Significant findings from meta-analyses provide further evidence of the antisaccade error rate as a putative schizophrenia spectrum marker.

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial.

INTRODUCTION: Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established. METHODS: We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4. RESULTS: The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680). CONCLUSION: This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.

Peak saccadic eye velocity across menstrual phases in naturally cycling women; A pilot study.

Peak saccadic eye velocity (pSEV) has been investigated in studies that characterise the pathophysiology of menstrual cycle related mood disorders, such as premenstrual dysphoric disorder (PMDD). pSEV is a stable and sensitive measure of gamma-aminobutyric acid A (GABAA) receptor function. Dysregulation of the GABA pathway has been associated with the onset of PMDD. Despite a growing number of studies utilising pSEV as an outcome measure in interventional drug studies for menstrual cycle related mood disorders, there are no reported studies that have investigated whether pSEV is sensitive to hormone fluctuations across the natural menstrual cycle. To address this gap, this pilot study aimed to characterise pSEV in women across the menstrual cycle. Participants were monitored across two menstrual cycles and saccadic eye movements were measured in both luteal and follicular phases. Seven participants completed the full study and were included in the final analysis. Results revealed luteal phase pSEV was significantly less than follicular phase pSEV. This finding is novel and forms a stepping-stone for further understanding the associations between menstrual hormone profiles and GABAA receptors.

The effects of a muscarinic receptor 1 gene variant on executive and non-executive cognition in schizophrenia spectrum disorders.

Individuals with schizophrenia who are homozygous at the c.267C > A (rs2067477) single nucleotide polymorphism within the muscarinic M1 receptor gene have been reported to perform less well on the Wisconsin Card Sorting Test (WCST). We investigated if rs2067477 genotype variation influenced WCST performance and non-executive cognition cross-diagnostically in a sample of 147 schizophrenia spectrum participants (SSD) and 294 healthy controls. We were unable to detect any significant differences in executive and non-executive cognitive performance across genotype. A broader genetic focus should be considered when investigating the association between the muscarinic system and cognition in SSD.

The influence of the glutamatergic system on cognition in schizophrenia: A systematic review.

Previous literature showing the role of the glutamatergic system on cognition in schizophrenia has been inconclusive. 44 relevant pharmacological, candidate gene and neuroimaging studies were identified through systematic search following PRISMA guidelines. To be included, studies must have observed at least one objective measure of cognitive performance in patients with schizophrenia and either manipulated or measured the glutamatergic system. Of the cognitive domains observed, memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway. In addition, evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signalling appears to be involved in working memory. In addition, it appears that the glutamatergic pathway is particularly involved in cognitive flexibility and learning potential in regards to executive functioning. The glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains. This review demonstrates the necessity for cognition to be examined by domain as opposed to globally.