Nothingness Is All There Is: An Exploration of Objectless Awareness During Sleep.

Recent years have seen a heightened focus on the study of minimal forms of awareness during sleep to advance the study of consciousness and understand what makes a state conscious. This focus draws on an increased interest in anecdotical descriptions made by classic Indian philosophical traditions about unusual forms of awareness during sleep. For instance, in the so-called state of witnessing-sleep or luminosity sleep, one is said to reach a state that goes beyond ordinary dreaming and abide in a state of just awareness, a state in which one is not aware of anything else other than one's own awareness. Moreover, for these traditions, this state is taken to be the essence or background of consciousness. Reports on such a state opens the door to exciting new lines of research in the study of consciousness, such as inquiry into the so-called objectless awareness during sleep-states of awareness that lack an ordinary object of awareness. In this two-staged research project, we attempted to find the phenomenological blueprints of such forms of awareness during sleep in 18 participants by conducting phenomenological interviews, informed by a novel tool in qualitative research, the micro-phenomenological interview (MPI) method. Following a phenomenological analysis, we isolated a similar phase across 12 reported experiences labeled as "nothingness phase" since it described what participants took to be an experience of "nothingness." This common phase was characterized by minimal sense of self-a bodiless self, yet experienced as being "somewhere"-, the presence of non-modal sensations, relatively pleasant emotions, an absence of visual experience, wide and unfocused attention, and an awareness of the state as it unfolded.

Long-term Effects of a Brief Mindfulness Intervention Versus a Health Enhancement Program for Treating Depression and Anxiety in Patients Undergoing Hemodialysis: A Randomized Controlled Trial.

Background: Depression and anxiety affect approximately 50% of patients with kidney failure receiving hemodialysis and are associated with decreased quality of life and increased risk of hospitalization and mortality. A Brief Mindfulness Intervention (BMI) may be promising in treating depressive and anxiety symptoms in this population, but the long-term sustainability of the intervention's effects is unknown. Objective: We previously conducted a randomized controlled trial (RCT; n = 55) comparing an 8-week BMI with an active control (Health Enhancement Program [HEP]) for patients receiving dialysis, with depression and/or anxiety. Here, we examine the 6-month follow-up data to determine the long-term sustainability of BMI versus HEP in reducing (1) depressive symptoms, (2) anxiety symptoms, and (3) the efficacy of BMI versus HEP in reducing the likelihood of hospitalization. Design: In this study, we analyzed 6-month follow-up data from an 8-week assessor-blinded parallel RCT, which evaluated the efficacy of a BMI against an active control, HEP, in patients receiving hemodialysis with symptoms of depression and/or anxiety. Setting: The study took place at hemodialysis centers in 4 tertiary-care hospitals in Montreal, Canada. Participants: Participants included adults aged ≥18 years who were receiving in-center hemodialysis 3 times per week and had symptoms of depression and/or anxiety as indicated by a score ≥6 on the Patient Health Questionnaire-9 (PHQ-9) and/or the General Anxiety Disorder-7 (GAD-7). Methods: Participants were randomized to the treatment arm (BMI) or the active control arm (HEP) and completed assessments at baseline, 8 weeks, and 6-month follow-up. Depression was assessed using the PHQ-9, and anxiety was assessed by the GAD-7. Hospitalization rates were assessed using medical chart information. Results: We observed significant decrease in depression scores over 6 months in both BMI and HEP groups, with no significant difference between groups. Anxiety scores significantly decreased over 6 months, but only in the BMI group. Brief Mindfulness Intervention and Health Enhancement Program were comparable in terms of hospitalization rates. Limitations: The limitations of our study include the modest sample size and lack of a third arm such as a waitlist control. Conclusions: Our results suggest that the beneficial effects of BMI and HEP for improving mood disorder symptoms in patients receiving dialysis persist at 6-month follow-up. Both interventions showed sustained effects for depressive symptoms, but BMI may be more useful in this population given its efficacy in reducing anxiety symptoms as well. Trial registration: Prior to recruitment, the trial had been registered (ClinicalTrials.gov Identifier: NCT03406845).

Contexte: La dépression et l'anxiété touchent environ 50% des patients atteints d'insuffisance rénale sous hémodialyse et sont associées à une diminution de la qualité de vie et à un risque accru d'hospitalisation et de mortalité. Une brève intervention basée sur la pleine conscience pourrait s'avérer prometteuse pour le traitement des symptômes liés à l'anxiété et à la dépression dans cette population. On ignore toutefois la viabilité à long terme des effets d'une telle intervention. Objectifs: Nous avons précédemment mené un essai contrôlé randomisé (n = 55) comparant une brève intervention de pleine conscience (IPC) de huit semaines à un témoin actif (Programme d'amélioration de la santé [PAmS]) chez les patients sous dialyse présentant des symptômes de dépression et/ou d'anxiété. Nous examinons ici les données après six mois de suivi pour déterminer la viabilité à long terme de l'IPC par rapport au PAmS sur la réduction (1) des symptômes dépressifs, (2) des symptômes d'anxiété, et (3) l'efficacité de l'IPC par rapport au PAmS à réduire la probabilité d'hospitalisation. Type d'étude: Un essai contrôlé randomisé, d'une durée de huit semaines, mené en parallèle et en aveugle pour l'évaluateur, lequel évaluait l'efficacité d'une IPC par rapport au témoin actif (PAmS) chez les patients sous hémodialyse présentant des symptômes de dépression et/ou d'anxiété. Cadre: L'étude a eu lieu dans les centres d'hémodialyse de quatre hôpitaux de soins tertiaires de Montréal (Canada). Participants: Des adultes qui recevaient des traitements d'hémodialyse en centre 3x/semaine et qui présentaient des symptômes de dépression et/ou d'anxiété tels que définis par un score ≥6 au questionnaire sur la santé des patients (PHQ-9) et/ou sur le trouble général d'anxiété-7 (GAD-7). Méthodologie: Les participants ont été répartis aléatoirement dans le groupe de traitement (IPC) ou le groupe témoin actif (PAmS) et ont répondu aux questionnaires au début de l'étude, après huit semaines et après six mois de suivi. La dépression a été évaluée à l'aide du PHQ-9 et l'anxiété par le GAD-7. Les taux d'hospitalisation ont été évalués à l'aide des dossiers médicaux. Résultats: Nous avons observé une diminution significative des scores de dépression sur six mois dans les groupes IPC et PAmS, sans différence significative entre les groupes. Seul le groupe IPC a montré une diminution significative des scores d'anxiété sur six mois. Les taux d'hospitalisation étaient comparables dans les deux groupes. Limites: Taille modeste de l'échantillon et absence d'un troisième bras tel un groupe témoin constitué de patients sur une liste d'attente. Conclusion: Nos résultats suggèrent que les effets bénéfiques de l'IPC et du PAmS sur les symptômes des troubles de l'humeur des patients sous dialyse persistent après six mois de suivi. Les deux interventions ont montré des effets durables sur les symptômes dépressifs, mais l'IPC pourrait s'avérer plus pertinente dans cette population puisqu'elle a également montré une efficacité à réduire les symptômes d'anxiété. Enregistrement de l'essai: L'essai avait été enregistré avant le recrutement (ClinicalTrials.gov Identificateur : NCT03406845).

Do Brief Mindfulness Interventions (BMI) and Health Enhancement Programs (HEP) Improve Sleep in Patients in Hemodialysis with Depression and Anxiety?

(1) Objective: to determine if a brief mindfulness intervention (BMI) and a health education program (HEP) could improve measures of insomnia in patients undergoing hemodialysis. (2) Methods: this was a planned secondary analysis of a randomized controlled trial of BMI vs. HEP for hemodialysis patients with depression and/or anxiety symptoms. The primary outcome for the analysis was the Athens Insomnia Scale (AIS). The secondary outcome was consolidation of daily inactivity (ConDI), an actigraphy measure that describes sleep continuity and is based on a sleep detection algorithm validated by polysomnography. We also explored whether changes in AIS and ConDI were associated with changes in depression, anxiety, and quality of life scores over 8-week follow-up. (3) Results: BMI and HEP groups did not differ significantly from one another. Exposure to BMI or HEP improved sleep quality (baseline AIS 9.9 (±5.0) vs. 8-week follow-up 6.4 (±3.9), (V = 155.5, p = 0.015)), but not ConDI. Improvements in AIS were associated with lower depression scores (Rho = 0.57, p = 0.01) and higher quality-of-life scores (Rho = 0.46, p = 0.04). (4) Conclusions: mindfulness and HEP may be helpful interventions to improve self-reported sleep quality in patients undergoing hemodialysis. Decreases in insomnia scores were associated with decreased depression symptoms and increased quality of life scores.

Brief Mindfulness Intervention vs. Health Enhancement Program for Patients Undergoing Dialysis: A Randomized Controlled Trial.

BACKGROUND: Between 20-50% of patients undergoing maintenance dialysis for end-stage kidney disease experience symptoms of depression and/or anxiety, associated with increased mortality, greater health care utilization, and decreased quality of life. It is unknown whether mindfulness-based interventions can improve depression and anxiety symptoms in patients receiving this treatment. METHODS: We conducted an 8-week multicenter randomized controlled trial comparing a brief mindfulness intervention (BMI) vs. an active control (Health Enhancement Program [HEP]) in 55 patients receiving dialysis with symptoms of depression and/or anxiety. The primary outcome was change in Patient Health Questionnaire-9 (PHQ-9) depression scores, with a primary analysis in participants with baseline PHQ-9 ≥ 10, and a secondary analysis including all participants. The secondary outcome was change in Generalized Anxiety Disorder-7 (GAD-7) anxiety scores with corresponding primary and secondary analyses. RESULTS: Both BMI and HEP reduced depressive symptoms, with no difference between trial arms (PHQ-9 change = -7.0 vs. -6.1, p = 0.62). BMI was more effective than HEP in reducing anxiety (GAD-7 change = -8.7 vs. -1.4, p = 0.01). Secondary analyses revealed no differences between arms. CONCLUSIONS: For patients undergoing dialysis, both BMI and HEP may be helpful interventions for depression symptoms, and BMI may be superior to HEP for anxiety symptoms. Mindfulness-based and other psychosocial interventions may be further evaluated in those undergoing dialysis as treatment options for symptoms of depression and anxiety.

Extrasynaptic Communication.

Streams of action potentials or long depolarizations evoke a massive exocytosis of transmitters and peptides from the surface of dendrites, axons and cell bodies of different neuron types. Such mode of exocytosis is known as extrasynaptic for occurring without utilization of synaptic structures. Most transmitters and all peptides can be released extrasynaptically. Neurons may discharge their contents with relative independence from the axon, soma and dendrites. Extrasynaptic exocytosis takes fractions of a second in varicosities or minutes in the soma or dendrites, but its effects last from seconds to hours. Unlike synaptic exocytosis, which is well localized, extrasynaptic exocytosis is diffuse and affects neuronal circuits, glia and blood vessels. Molecules that are liberated may reach extrasynaptic receptors microns away. The coupling between excitation and exocytosis follows a multistep mechanism, different from that at synapses, but similar to that for the release of hormones. The steps from excitation to exocytosis have been studied step by step for the vital transmitter serotonin in leech Retzius neurons. The events leading to serotonin exocytosis occur similarly for the release of other transmitters and peptides in central and peripheral neurons. Extrasynaptic exocytosis occurs commonly onto glial cells, which react by releasing the same or other transmitters. In the last section, we discuss how illumination of the retina evokes extrasynaptic release of dopamine and ATP. Dopamine contributes to light-adaptation; ATP activates glia, which mediates an increase in blood flow and oxygenation. A proper understanding of the workings of the nervous system requires the understanding of extrasynaptic communication.

Effects of Mindfulness-Based Cognitive Therapy on Peripheral Markers of Stress and Inflammation in Older-Adults With Depression and Anxiety: A Parallel Analysis of a Randomized Controlled Trial.

Background: Depression and anxiety are prevalent in older-adults and often difficult to treat: up to 55% of patients are unresponsive to pharmacotherapy. Mindfulness-Based Cognitive Therapy (MBCT) is a promising treatment, however, its biological mechanisms remain unknown in older-adults. Methods: We examined if, in older-adults, decreased depression and anxiety symptoms after MBCT are associated with changes in the expression levels of C-reactive protein, Interleukin-1ß, Monocyte chemoattractant protein-1 and mineralocorticoid receptor compared to treatment as usual (TAU). Older-adults (age ≥60) with depression and anxiety were randomized to MBCT or treatment as usual. Gene expression levels from blood samples were measured using quantitative polymerase chain reaction (n = 37) at baseline and after 8-weeks of MBCT or TAU. Results: As previously published, we found a significant reduction in symptoms of depression F (1, 35) = 10.68, p = 0.002, partial η2 = 0.23 and anxiety F (1, 35) = 9.36, p = 0.004, partial η2 = 0.21 in geriatric participants following MBCT compared to TAU. However, the expression levels of measured genes were not significantly different between groups and were not associated with changes in depression and anxiety symptoms. Conclusion: Our results suggest that the symptom reduction following MBCT in older-adults may not be accompanied by changes in the stress-response and inflammatory pathways. Future research should address other potential biological alterations associated to MBCT that may be responsible for the reduction of symptoms.

Continuation Sessions of Mindfulness-Based Cognitive Therapy (MBCT-C) vs. Treatment as Usual in Late-Life Depression and Anxiety: An Open-Label Extension Study.

OBJECTIVES: Mindfulness-based cognitive therapy (MBCT) is a novel treatment for depression. Our published randomized controlled trial shows that MBCT improves symptoms of late-life depression (LLD) and anxiety (LLA). We now examine whether continuation sessions of MBCT (MBCT-C) can prevent LLD/LLA symptom recurrence. METHODS/DESIGN: Following an 8-week MBCT intervention, we compared patients who attended open-label weekly 1-hour MBCT-C for another 26 weeks (n = 10) vs those who did not (n = 17) for change in depressive and anxiety symptoms. RESULTS: While there were no significant differences between groups on depressive or anxiety symptom severities between 8- and 34- weeks (Cohen's d = 0.045), we observed a small clinical effect of MBCT-C on symptoms of anxiety (d = 0.29). CONCLUSIONS: These preliminary results suggest that MBCT-C may be somewhat beneficial for symptoms of LLA, but not for LLD. Healthcare providers should consider what is clinically feasible before investing time and resources into MBCT-C in older adults with depression and/or anxiety.

Early Clinical Exposure to Geriatric Psychiatry and Medical Students' Interest in Caring for Older Adults: A Randomized Controlled Trial.

OBJECTIVE: In the next 25 years, the population aged 65 and older will nearly double in many countries, with few new doctors wishing to care for older adults. The authors hypothesize that early clinical exposure to elderly patient care could increase student interest in caring for older adults during their future career. METHODS: The authors conducted a pragmatic medical education randomized controlled trial (RCT) at the Jewish General Hospital and the Douglas Mental Health Institute, McGill University, in Montreal, Canada. Third-year medical students undergoing their mandatory 16-week half-time clerkship rotation in psychiatry were randomly assigned to the equivalent of 2-4 weeks of full-time exposure to clinical geriatric psychiatry (n = 84). RESULTS: Being randomly assigned to geriatric psychiatry exposure (n = 44 of 84) was associated with increased "comfort in working with geriatric patients and their families" at 16-week follow-up (59.1% versus 37.5%, χ2 (1) = 3.9; p = 0.05). However, there was no significant association found between geriatric psychiatry exposure and change "in interest in caring for older adults," or change in "interest in becoming a geriatric psychiatrist." CONCLUSION: The results of this pragmatic education RCT suggest that exposing third-year medical students to 2-4 weeks of geriatric psychiatry did not increase their interest to care for older adults or become a geriatric psychiatrist. However, it did increase their comfort level in working with older adults and their families. However, more research is necessary to identify potential interventions that could inspire and increase medical student interest in caring for older adults as part of their future careers.

Mind-Body Interventions in Late-Life Mental Illnesses and Cognitive Disorders: A Narrative Review.

BACKGROUND: Current pharmacological treatments and psychotherapeutic approaches often have adverse effects or are ineffective in late-life cognitive and mental illnesses. Mind-body interventions offer a holistic approach and are of interest because of potential patient acceptability and scalability. OBJECTIVE: To synthesize current evidence on mind-body interventions in treating or preventing mental illnesses and cognitive disorders in older adults. SEARCH STRATEGY: A search was conducted using Ovid MEDLINE, EMBASE, and PsycINFO articles published from 1993 to 2017. SELECTION CRITERIA: 1) Randomized controlled trials, 2) involving older adults (>60 years old), 3) suffering from mental illness or cognitive decline, 4) comparing mind-body interventions with a control group. Mind-body interventions included: imagery, meditation, prayer, autogenic training, tai chi & variants, and yoga. Control group included: health education, other non-pharmacological interventions, treatment as usual, or no treatment at all. DATA COLLECTION AND ANALYSIS: Data included number of patients, age, psychiatric diagnoses, type of intervention, frequency andduration, control conditions, outcomes measures and treatment results. RESULTS: 3916 articles were reviewed and ten met inclusion criteria. Six were on Tai Chi and four assessed meditation-based therapies. Clinically significant improvement in depressive and anxiety symptoms were reported, as well as improvement insomedomains of cognition and reduced risk of cognitive deterioration. CONCLUSION: There is increasing evidence that mind-body interventions may potentially be useful in the treatment or prevention of geriatric mental illnesses and cognitive disorders. There are important methodological limitations of the current literature such as small sample sizes, heterogeneous study populations, and varying clinical outcomes.

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial.

BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

End-of-Life Care Preferences in Patients with Severe and Persistent Mental Illness and Chronic Medical Conditions: A Comparative Cross-Sectional Study.

OBJECTIVES: Physicians rarely engage severe and persistent mental illness (SPMI) patients in end-of-life care discussion despite an increased risk of debilitating medical illnesses and mortality. Access to quality palliative care and medical assistance in dying (MAID) has become a priority in Canada and many jurisdictions. In this study, we compared SPMI and chronic medically ill (CMI) patients' end-of-life care preferences and comfort level with end-of-life care discussion, and identified potential predictors of interest in MAID. DESIGN: Comparative cross-sectional study. SETTING: Hospital-based. PARTICIPANTS: We recruited 106 SPMI and 95 CMI patients at the Jewish General Hospital, Canada. Patients aged ≥40 years, without severe cognitive impairment, able to communicate in English or French and provide written informed consent were included. MEASUREMENTS: Attitudes towards pain management, palliative sedation, MAID, and artificial life support were collected with the Health Care Preferences Questionnaire. Adjusted odd ratios (aOR) were calculated for each end-of-life care intervention. Comfort with discussion was rated on a Likert scale. A stepwise regression analysis was performed to identify predictors of interest in MAID. RESULTS: SPMI was not correlated to any end-of-life care intervention, except for MAID where SPMI patients were less likely to support its use (aOR: 0.48, 95% CI: 0.25-0.94, p = 0.03). Religiosity was also correlated with interest in MAID (aOR: 0.14, 95% CI: 0.06-0.31, p < 0.001). Patients in both groups were comfortable talking about end-of-life care. CONCLUSIONS: SPMI patients are able to voice their end-of-life care preferences, and contrary to some fears, do not want MAID more than CMI patients.

Repression of Astrocytic Connexins in Cortical and Subcortical Brain Regions and Prefrontal Enrichment of H3K9me3 in Depression and Suicide.

Background: Major depressive disorder has been associated with dysfunctional astrocytic networks. The underlying causes, extent, and consequences of such dysfunctions remain to be characterized. Astrocyte-astrocyte communication occurs principally through gap junction channels primarily formed by connexin 30 and 43 (CX30 and CX43). We previously reported decreased connexin expression in the prefrontal cortex of depressed suicides. In the present study, we investigated whether these changes are mediated by epigenetic regulation, and expanded gene expression quantifications to other cortical and subcortical regions to assess the regional distribution of connexion disruptions in depressed suicides. Methods: The expression of CX30 and CX43 was measured by real-time PCR in samples of neocortex (Brodmann areas 4 and 17), cerebellar cortex, mediodorsal thalamus, and caudate nucleus of 22 depressed suicides and 22 matched sudden-death controls. Chromatin immunoprecipitation was used to measure enrichment levels of the repressive chromatin mark H3K9me3 in the prefrontal cortex. Results: We found a consistent downregulation of connexin genes in all regions examined, except in the cerebellum where an increase in the expression of CX30 was measured and using chromatin immunoprecipitation we observed an enrichment of H3K9me3 for both Cx30 and Cx43 in the prefrontal cortex. Conclusions: Our study shows widespread astrocytic CX gene repression in depressed suicides that is mediated, at least in part, through epigenetic mechanisms. Taken together, these findings support the notion of widespread cerebral astrocytic dysfunction in major depressive disorder.

Excitatory Inputs Determine Phase-Locking Strength and Spike-Timing of CA1 Stratum Oriens/Alveus Parvalbumin and Somatostatin Interneurons during Intrinsically Generated Hippocampal Theta Rhythm.

UNLABELLED: Theta oscillations are essential for learning and memory, and their generation requires GABAergic interneurons. To better understand how theta is generated, we explored how parvalbumin (PV) and somatostatin (SOM) interneurons in CA1 stratum oriens/alveus fire during hippocampal theta and investigated synaptic mechanisms underlying their behavior. Combining the use of transgenic mice to visually identify PV and SOM interneurons and the intact hippocampal preparation that can generate theta oscillations in vitro without cholinergic agonists, we performed simultaneous field and whole-cell recordings. We found that PV interneurons uniformly fire strongly phase-locked to theta, whereas SOM neurons are more heterogeneous with only a proportion of cells displaying tight phase-locking. Differences in phase-locking strength could be explained by disparity in excitatory inputs received; PV neurons received significantly larger EPSCs compared with SOM neurons, and the degree of phase-locking in SOM neurons was significantly correlated with the size of EPSCs. In contrast, IPSC amplitude did not differ between cell types. We determined that the local CA1 rhythm plays a more dominant role in driving CA1 interneuron firing than afferent inputs from the CA3. Last, we show that PV and strongly phase-locked SOM neurons fire near the peak of CA1 theta, under the tight control of excitatory inputs that arise at a specific phase of each theta cycle. These results reveal a fundamental mechanism of neuronal phase-locking and highlight an important role of excitation from the local network in governing firing behavior during rhythmic network states. SIGNIFICANCE STATEMENT: Rhythmic activity in the theta range (3-12 Hz) is important for proper functioning of the hippocampus, a brain area essential for learning and memory. To understand how theta rhythm is generated, we investigated how two types of inhibitory neurons, those that express parvalbumin and somatostatin, fire action potentials during theta in an in vitro preparation of the mouse hippocampus. We found that the amount of excitatory input they receive from the local network determines how closely their spikes follow the network theta rhythm. Our findings reveal an important role of local excitatory input in driving inhibitory neuron firing during rhythmic states and may have implications for diseases, such as epilepsy and Alzheimer's disease, which affect the hippocampus and related areas.

Cellular and Molecular Inflammatory Profile of the Choroid Plexus in Depression and Suicide.

The inflammatory hypothesis of depression is one of the main theories that endeavors to explain and describe the underlying biological mechanisms of depression and suicide. While mounting evidence indicates altered peripheral and central inflammatory profiles in depressed patients and suicide completers, little is known about how peripheral and central inflammation might be linked in these contexts. The choroid plexus (ChP), a highly vascularized tissue that produces cerebrospinal fluid (CSF) and lacks a blood-brain-barrier, is an interface between peripheral and central immune responses. In the present study, we investigated the cellular and molecular inflammatory profile of the ChP of the lateral ventricle in depressed suicides and psychiatrically healthy controls. Gene expression of macrophages, pro- and anti-inflammatory cytokines, and various factors implicated in immune cell trafficking were measured; and density of ionized calcium-binding adaptor molecule 1-positive (Iba1+) macrophages associated with the ChP epithelial cell layer (ECL) was examined. Significant downregulations of the genes encoding interleukin 1ß (IL1ß), a pro-inflammatory acute-phase protein; intercellular cell adhesion molecule 1 (ICAM1), a protein implicated in immune cell trafficking in the ChP; and IBA1, a monocyte/macrophage marker; were detected in depressed suicides as compared to controls. No difference in the density of Iba1+ macrophages associated with the ChP ECL was observed. While interpretation of these findings is challenging in the absence of corroborating data from the CSF, peripheral blood, or brain parenchyma of the present cohort, we hypothesize that the present findings reflect a ChP compensatory mechanism that attenuates the detrimental effects of chronically altered pro-inflammatory signaling caused by elevated levels of pro-inflammatory cytokines, such as IL-1ß, peripherally and/or centrally. Together, these findings further implicate neuroimmune processes in the etiology of depression and suicide.

Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors.

OBJECTIVE: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder. METHOD: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate ≤5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex. RESULTS: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes. CONCLUSIONS: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways.

Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides.

Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified ("resting") microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.

Morphometric characterization of microglial phenotypes in human cerebral cortex.

BACKGROUND: Microglia can adopt different morphologies, ranging from a highly ramified to an amoeboid-like phenotype. Although morphological properties of microglia have been described in rodents, little is known about their fine features in humans. The aim of this study was to characterize the morphometric properties of human microglia in gray and white matter of dorsal anterior cingulate cortex (dACC), a region implicated in behavioral adaptation to neuroinflammation. These properties were compared to those of murine microglia in order to gain a better appreciation of the differences displayed by these cells across species. METHODS: Postmortem dACC samples were analyzed from 11 individuals having died suddenly without any history of neuroinflammatory, neurodegenerative, nor psychiatric illness. Tissues were sectioned and immunostained for the macrophage marker Ionized calcium binding adaptor molecule 1 (IBA1). Randomly selected IBA1-immunoreactive (IBA1-IR) cells displaying features corresponding to commonly accepted microglial phenotypes (ramified, primed, reactive, amoeboid) were reconstructed in 3D and all aspects of their morphologies quantified using the Neurolucida software. The relative abundance of each morphological phenotype was also assessed. Furthermore, adult mouse brains were similarly immunostained, and IBA1-IR cells in cingulate cortex were compared to those scrutinized in human dACC. RESULTS: In human cortical gray and white matter, all microglial phenotypes were observed in significant proportions. Compared to ramified, primed microglia presented an average 2.5 fold increase in cell body size, with almost no differences in branching patterns. When compared to the primed microglia, which projected an average of six primary processes, the reactive and amoeboid phenotypes displayed fewer processes and branching points, or no processes at all. In contrast, the majority of microglial cells in adult mouse cortex were highly ramified. This was also the case following a postmortem interval of 43 hours. Interestingly, the morphology of ramified microglia was strikingly similar between species. CONCLUSIONS: This study provides fundamental information on the morphological features of microglia in the normal adult human cerebral cortex. These morphometric data will be useful for future studies of microglial morphology in various illnesses. Furthermore, this first direct comparison of human and mouse microglia reveals that these brain cells are morphologically similar across species, suggesting highly conserved functions.

Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides.

Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression.