Long-term, repeated doses of intravenous autologous mesenchymal stem cells for a patient with Parkinson's disease: a case report.

Parkinson's disease (PD) is a neurodegenerative disease that involves the loss of dopaminergic neurons in the substantia nigra pars compacta of the basal ganglia. Clinically, patient presentation involves a combination of motor and non-motor symptoms characterized by progressive worsening over time and significant decreases in overall quality-of-life. Despite there being no fully restorative cure for PD, Mesenchymal Stem Cell (MSC) therapy offers promising therapeutic potential. Here, we report a case of a 77-year-old female, living with idiopathic Parkinson's Disease for over 17 years. The patient received multiple infusions of autologous Hope Biosciences adipose-derived MSCs (HB-adMSCs). A total of 26 infusion treatments of HB-adMSCs were administered over the course of ~2 years that resulted in marked improvements in her typical Parkinsonian symptoms, as demonstrated by the decreases in her UPDRS (Unified Parkinson's Disease Rating Scale) scores. Changes in clinical scores mirrored concurrent changes in regional brain metabolism as quantified by FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography), compared to baseline. Long-term, multiple infusions of HB-adMSCs were safely tolerated by the patient without any serious adverse events. Further research is needed to evaluate the safety and efficacy of HB-adMSC therapy for the treatment of PD patients.

PET imaging of microglia using PBR28suv determines therapeutic efficacy of autologous bone marrow mononuclear cells therapy in traumatic brain injury.

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of rats: Sham, CCI-alone and CCI-BMMNCs (AUTO). One hundred twenty days after injury, rodents were imaged with PBR28 and their cognitive behavior assessed utilizing the Morris Water Maze. Subsequent ex vivo analysis included brain volume and immunohistochemistry. BMMNCs therapy attenuated PBR28suv in comparison to CCI alone and it improved spatial learning as measured by the Morris Water Maze. Ex vivo analysis demonstrated preservation of brain volume, a decrease in amoeboid-shaped microglia in the dentate gyrus and an increase in the ratio of ramified to amoeboid microglia in the thalamus. PBR28suv is a viable option to measure efficacy of BMMNCs therapy after TBI.

Feasibility of a meditation intervention for stroke survivors and informal caregivers: a randomized controlled trial.

BACKGROUND: Depressive symptoms are a significant psychological complication of stroke, impacting both survivors and informal caregivers of survivors. Randomized controlled trials are needed to determine optimal non-pharmacological strategies to prevent or ameliorate depressive symptoms in stroke survivors and their informal caregivers. METHODS: A prospective, randomized, parallel-group, single-center, feasibility study. Participants were assigned to a 4-week meditation intervention or expressive writing control group. The intervention comprised four facilitator-led group meditation sessions, one session per week and building upon prior session(s). Descriptive statistics were used to examine the proportion of eligible individuals who enrolled, retention and adherence rates, and the proportion of questionnaires completed. Data were collected at baseline, immediately after the 4-week intervention period, and 4 and 8 weeks after the intervention period. Secondary analysis tested for changes in symptoms of depression (Center for Epidemiologic Studies-Depression [CES-D]), anxiety [State-Trait Anxiety Inventory for Adults (STAI)], and pain (Brief Pain Inventory-Short Form) in the intervention group via paired t tests. Linear mixed models were used to compare longitudinal changes in the measures between the groups. Intervention and trial design acceptability were preliminary explored. RESULTS: Seventy-one (77%) individuals enrolled and 26 (37%) completed the study (baseline and 8-week post-intervention visits completed). Forty-two (66%) participants completed baseline and immediate post-intervention visits. Mean questionnaire completion rate was 95%. The median meditation group session attendance rate for the intervention group was 75.0%, and the mean attendance rate was 55%. Non-significant reductions in CES-D scores were found. Paired t tests for stroke survivors indicated a significant reduction from baseline through week 8 in BPI-sf severity scores (p = 0.0270). Repeated measures analysis with linear mixed models for informal caregivers indicated a significant reduction in in STAI-Trait scores (F [3,16.2] = 3.28, p = 0.0479) and paired t test showed a significant reduction from baseline to week 4 in STAI-Trait scores (mean = - 9.1250, 95% CI [- 16.8060 to 1.4440], p = 0.0262). No between-group differences were found. CONCLUSIONS: Future trials will require strategies to optimize retention and adherence before definitive efficacy testing of the meditation intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03239132. Registration date: 03/08/2017.

Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission.

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain µ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = -3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a chronic, life threatening injury for which few effective interventions are available. Evidence in animal models suggests un-checked immune activation may contribute to the pathophysiology. Changes in regional density of active brain microglia can be quantified in vivo with positron emission topography (PET) with the relatively selective radiotracer, peripheral benzodiazepine receptor 28 (11 C-PBR28). Phenotypic assessment (activated vs resting) can subsequently be assessed (ex vivo) using morphological techniques. To elucidate the mechanistic contribution of immune cells in due to TBI, we employed a hybrid approach involving both in vivo (11 C-PBR28 PET) and ex vivo (morphology) to elucidate the role of immune cells in a controlled cortical impact (CCI), a rodent model for TBI. Density of activated brain microglia/macrophages was quantified 120 hours after injury using the standardized uptake value (SUV) approach. Ex vivo morphological analysis from specific brain regions using IBA-1 antibodies differentiated ramified (resting) from amoeboid (activated) immune cells. Additional immunostaining of PBRs facilitated co-localization of PBRs with IBA-1 staining to further validate PET data. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated density of amoeboid microglia/macrophages in the ipsilateral dentate gyrus, corpus callosum, thalami and injury penumbra of injured animals compared to sham animals. PBR co-stained with amoeboid microglia/macrophages in the injury penumbra and not with astrocytes. These data suggest the technologies evaluated may serve as bio-signatures of neuroinflammation following severe brain injury in small animals, potentially enabling in vivo tracking of neuroinflammation following TBI and cellular-based therapies.

Out of the Mouths of Babes: Links Between Linguistic Structure of Loss Narratives and Psychosocial Functioning in Parentally Bereaved Children.

This study examined links between the language bereaved children use to describe the death of their caregiver and children's psychological/behavioral functioning and coping strategies. Participants included 44 children (54.5% male) aged 7 to 12 (M = 9.05) years who were bereaved by the death of a caregiver. Children were assessed via self- and caregiver-report measures and an in-person interview regarding the loss of their caregiver. Children's loss narratives gathered through in-person interviews were transcribed and subjected to textual analysis. Linguistic categories included pronouns and verb tense. Drawing from linguistic and self-distancing theories, we hypothesized that children's use of language reflecting self-distancing (third-person pronouns and past tense) or social connectedness (first-person plural pronouns) would be negatively associated with psychological/behavioral distress and avoidant coping. Similarly, we expected that children's use of self-focused language (first-person singular pronouns and present tense) would be positively associated with psychological/behavioral distress and avoidant coping. As hypothesized, preliminary findings suggest that children who employed more self-distancing language and used more social connectedness words reported less avoidant coping, rs = .40-.42. Also as hypothesized, children who employed more self-focused language had higher levels of self-reported posttraumatic stress symptoms, r = .54, and avoidant coping, r = .54, and higher parent-reported psychological/behavioral distress, r = .43. Implications for theory-building, risk screening, and directions for future research with bereaved youth are discussed.

Functional TSPO polymorphism predicts variance in the diurnal cortisol rhythm in bipolar disorder.

INTRODUCTION: Psychosocial stress contributes to onset/exacerbation of mood episodes and alcohol use, suggesting dysregulated diurnal cortisol rhythms underlie episodic exacerbations in Bipolar Disorder (BD). However, mechanisms underlying dysregulated HPA rhythms in BD and alcohol use disorders (AUD) are understudied. Knowledge of associated variance factors have great clinical translational potential by facilitating development of strategies to reduce stress-related relapse in BD and AUD. Evidence suggests structural changes to mitochondrial translocator protein (TSPO) (a regulator of steroid synthesis) due to the single nucleotide polymorphism rs6971, may explain much of this variance. However, whether rs6971 is associated with abnormal HPA rhythms and clinical exacerbation in humans is unknown. METHODS: To show this common TSPO polymorphism impacts HPA rhythms in BD, we tested whether rs6971 (dichotomized: presence/absence of polymorphism) predicted variance in diurnal cortisol rhythm (saliva: morning and evening for 3 days) in 107 BD (50 with and 57 without AUD) and 28 healthy volunteers of similar age and ethno-demographic distribution. RESULTS: Repeated measures ANOVA confirmed effects BD (F5,525 = 3.0, p = 0.010) and AUD (F5,525 = 2.9, p = 0.012), but not TSPO polymorphism (p > 0.05). Interactions were confirmed for TSPO × BD (F5,525 = 3.9, p = 0.002) and for TSPO × AUD (F5,525 = 2.8, p = 0.017). DISCUSSION: We identified differences in diurnal cortisol rhythm depending on presence/absence of common TSPO polymorphism in BD volunteers with or without AUD and healthy volunteers. These results have wide ranging implications but further validation is needed prior to optimal clinical translation.

Ketamine potentiates oxidative stress and influences behavior and inflammation in response to lipolysaccharide (LPS) exposure in early life.

Immune activation (IA) during the early neonatal period is a risk factor for the development of schizophrenia. Lipopolysaccharide (LPS) injected in neonates lead to behavioral and brain changes that persist to adult life. We investigated oxidative stress, levels of cytokines, and the locomotor activity of IA in a schizophrenia animal model in which neonatal male Wistar rats were administered with an injection of LPS (50µg/kg) on postnatal day 3 and different doses of ketamine (5, 15 and 25mg/kg) for 7days during adulthood. Rats LPS-induced did not have locomotor activity alterations. Locomotor activity was elevated in neonatally saline-injected in the higher dose ketamine-treated animals. Carbonyl protein in the prefrontal cortex (PFC), hippocampus and striatum were increased in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Lipid damage occurred in the PFC, striatum and hippocampus in the LPS- and saline-induced in the ketamine (15 and 25mg/kg) -treated animals. In the hippocampus the superoxide dismutase (SOD) was decreased in the LPS- and saline-induced in the ketamine-treated with the dose of 25mg/kg. In the PFC SOD was reduced in the LPS-induced in the ketamine (25mg/kg)-treated animals. Catalase in the PFC and hippocampus was reduced in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Pro- and anti-inflammatory cytokines were lower in the brains of LPS-induced in the higher dose ketamine-treated rats. IA influences the locomotor activity and cytokine levels induced by ketamine, and it has a negative effect in potentiating the oxidative stress by higher doses of ketamine in the brain.

Bipolar disorder moderates associations between linoleic acid and markers of inflammation.

Dietary polyunsaturated fatty acids (PUFA) and inflammatory proteins associate with immune activation and have been implicated in the pathophysiology of mood disorders. We have previously reported that individuals with bipolar disorder (BPD) have decreased PUFA intake, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA); and decreased PUFA concentration of plasma EPA and linoleic acid (LA). We have also reported an association between plasma LA and its metabolites and burden of disease measures in BPD. In the current cross-sectional study we collected blood samples and diet records from both bipolar (n = 91) and control subjects (n = 75) to quantify plasma cytokine concentrations and dietary LA intake, respectively. Using multiple linear regression techniques, we tested for case control differences in plasma cytokine levels and associations between cytokines and dietary LA intake, adjusting for sex, age, BMI, and total energy intake. We found significantly higher plasma levels of interleukin 18 (IL-18) (p = 0.036), IL-18 binding protein (IL-18BP) (p = 0.001), soluble tumor necrosis factor receptor (sTNFR) 1 (p = 0.006), and sTNFR2 (p = 0.007) in BPD compared with controls. Moreover, BPD significantly moderated the associations of dietary LA intake with plasma levels of IL-18, sTNFR1 and sTNFR2, which were inverse associations in bipolar individuals and positive associations in controls (p for dietary LA x BPD diagnosis interaction < 0.05 for all three). These findings suggest potential dysregulation of LA metabolism in BPD, which may extend to a modified influence of dietary LA on specific inflammatory pathways in individuals with BPD compared to healthy controls.

Reduced Inhibitory Control Mediates the Relationship Between Cortical Thickness in the Right Superior Frontal Gyrus and Body Mass Index.

Unhealthy eating behaviors often develop in the setting of inadequate inhibitory control, a function broadly ascribed to the prefrontal cortex (PFC). Regulation of inhibitory control by the PFC and its anatomical components and their contribution to increasing body mass index (BMI) are poorly understood. To study the role of PFC in the regulation of inhibitory control and body weight, we examined measures of cortical thickness in PFC sub-regions, inhibitory control (color-word interference task (CWIT)), and BMI in 91 healthy volunteers. We tested the predictive effect of PFC sub-regional cortical thickness on BMI and mediation by inhibitory control measured with CWIT. Measures of depression (BDI-II), anxiety (STAI-T) and trauma-related symptoms (TSC-40) were collected; the disinhibition scale of the three-factor eating questionnaire (TFEQ) was used to assess disinhibited eating. We then tested the relationship between BD-II, STAI-T, TSC-40, TFEQ, CWIT, and BMI with correlation analyses. Right superior frontal gyrus cortical thickness significantly predicted BMI (ß=-0.91; t=-3.2; p=0.002). Mediation analysis showed a significant indirect effect of cortical thickness on BMI mediated by inhibitory control (95% CI=-6.1, -0.67). BMI was unrelated to BDI-II, STAI-T, TSC-40, or TFEQ scores. We found an inverse relationship between cortical thickness in the right-superior frontal gyrus and BMI, which was fully mediated by inhibitory control neurocognitive performance. Our results suggest possible targets for neuromodulation in obesity (ie superior frontal gyrus) and a quantifiable mediator of their effects (ie inhibitory control).

Peripheral inflammation during abnormal mood states in bipolar I disorder.

BACKGROUND: Bipolar disorder carries a substantive morbidity and mortality burden, particularly related to cardiovascular disease. Abnormalities in peripheral inflammatory markers, which have been commonly reported in case-control studies, potentially link these co-morbidities. However, it is not clear whether inflammatory markers change episodically in response to mood states or are indicative of chronic pro-inflammatory activity, regardless of mood, in bipolar disorder. METHODS: Investigations focused on comparing concentrations of specific inflammatory cytokines associated with immune activation status (primary outcome=tumor necrosis factor alpha (TNF-α)) in 37 participants with bipolar disorder across 3 mood states (mania N=15, depression N=9, normal mood N=13) and 29 controls without a psychiatric disorder (total N=66). Cytokine levels were also compared to T1ρ, a potential neuroimaging marker for inflammation, in select brain regions in a subsample (N=39). RESULTS: Participants with bipolar disorder and healthy controls did not differ significantly in inflammatory cytokine concentrations. However, compared to cases with normal mood, cases with abnormal mood states (mania and depression) had significantly elevated levels of TNF-α, its soluble receptors (sTNFR1/sTNFR2), other macrophage-derived cytokines (interleukin 1ß (IL-1ß), IL-6, IL-10, and IL-18) in addition to IL-4, interferon-γ, monocyte chemotactic protein-1, fibroblast growth factor ß, and vascular endothelial growth factor. Cytokine levels were not correlated with signals from T1ρ imaging in selected structures (amygdalae, hippocampi, hypothalamus, anterior cingulate gyrus, and middle frontal gyrus). LIMITATIONS: Participants were not followed prospectively across mood states. CONCLUSION: Activation of inflammatory markers was found in abnormal mood states of bipolar disorder. Longitudinal study of individuals with mood disorders is needed to confirm these findings and to elucidate the time course of any such changes.

Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans.

Evidence in animal models suggests IL-1 family cytokines interact with central endogenous opioid neurotransmitter systems, inducing or perpetuating pathological states such as persistent pain syndromes, depression, substance use disorders, and their comorbidity. Understanding these interactions in humans is particularly relevant to understanding pathological states wherein this neurotransmitter system is implicated (ie, persistent pain, mood disorders, substance use disorders, etc). Here, we examined relationships between IL-1ß, IL-1ra, and functional measures of the endogenous opioid system in 34 healthy volunteers, in the absence and presence of a standardized sustained muscular pain challenge, a psychophysical challenge with emotionally and physically stressful components. Mu-opioid receptor availability in vivo was examined with [(11)C]carfentanil positron emission tomography (PET) scanning. Sex and neuroticism impacted IL-1 family cytokines; higher baseline IL-1ß and IL-1ra was identified in females with lower neuroticism. Higher baseline IL-1ß was also associated with reduced µ-opioid receptor availability (amygdala) and greater pain sensitivity. The pain challenge increased IL-1ß in females with high neuroticism. Strong associations between IL-1ra (an anti-nociceptive cytokine) and µ-opioid receptor activation (VP/NAcc) were identified during the pain challenge and the resulting analgesic effect of µ-opioid receptor activation was moderated by changes in IL-1ß whereby volunteers with greater pain induced increase in IL-1ß experienced less endogenous opioid analgesia. This study demonstrates the presence of relationships between inflammatory factors and a specific central neurotransmitter system and circuitry, of relevance to understanding interindividual variations in regulation of responses to pain and other physical and emotional stressors.

Psychological and environmental correlates of HPA axis functioning in parentally bereaved children: preliminary findings.

This study examined bereaved children's HPA-axis functioning (cortisol awakening response; CAR) in relation to psychological distress, coping, and surviving parents' grief reactions. Participants included 38 children (20 girls) with recent parental loss (previous 6 months) and 28 of their surviving caregivers (23 women) who were assessed using self-report instruments and in-person, semistructured interviews. Interviews involved discussions about the child's thoughts and feelings related to the loss. Participants provided 3 saliva samples at home (awakening, 30 minutes later, and evening) over 3 successive days, beginning on the day following the interview. Results show a significant relation between dampening of the child's Day 1 CAR and more symptoms of anxiety (r = -.45), depression (r = -.40), posttraumatic stress (r = -.45), and maladaptive grief (r = -.43), as well as higher levels of avoidant coping (r = -.53). Higher levels of parental maladaptive grief were also associated (r = -.47) with a dampening of the child's Day 1 CAR. Our results raise the possibility that blunted CAR may be a result of accumulating allostatic load and/or a result of emotionally challenging events (discussions regarding the deceased) and their subsequent processing (or lack thereof) within the family, which may be particularly stressful for those bereaved children experiencing high levels of psychological distress, avoidant coping, and parental maladaptive grief.

A pilot study investigating tumor necrosis factor-α as a potential intervening variable of atypical antipsychotic-associated metabolic syndrome in bipolar disorder.

BACKGROUND: Strong associations exist between tumor necrosis factor-α (TNF-α) and metabolic syndrome (MetS). Although TNF-α is associated with bipolar depression (BD), its role in atypical antipsychotic (AAP)-associated MetS in BD is unclear. Here, we investigate the potential intervening role of TNF-α in the indirect relationship between AAP treatment and MetS in BD. MATERIALS AND METHODS: Using a cross-sectional design, 99 euthymic BD volunteers were stratified by the presence or the absence of MetS (National Cholesterol Education Program Adult Treatment Panel III). Serum TNF-α concentration, determined via chemiluminescent immunometric assays, was compared between groups (ie, MetS or no MetS). We investigated the intervening effect of TNF-α on the relation between AAP treatment and MetS in BD using regression techniques. RESULTS: Treatment with those antipsychotics believed associated with a higher risk for MetS (ie, AAPs: olanzapine, quetiapine, risperidone, paliperidone, clozapine) was found to be associated with significantly greater TNF-α (F 1,88 = 11.2, P = 0.001, mean difference of 1.7 ± 0.51) and a higher likelihood of MetS (F 1,88 = 4.5, P = 0.036) than in those not receiving treatment with an AAP. Additionally, TNF-α was greater (trending toward significance; T 52 = 2.0, P = 0.05) in BD volunteers with MetS and was found to have a statistically significant effect on the indirect relationship between AAP treatment and elevated waist circumference in these BD volunteers. DISCUSSION: These results identify TNF-α as a potential intervening variable of AAP-associated MetS in BD, not previously identified in this population. Future prospective studies could assess the predictive potential of TNF-α in determining risk of AAP-associated MetS in BD. Given previous evidence relating TNF-α and mood state in BD, this study increases the importance in understanding the role of TNF-α in "mind-body" interactions and renews discussions of the utility of research into the clinical efficacy of TNF-α antagonist treatment in mood disorders.

Association of plasma ω-3 and ω-6 lipids with burden of disease measures in bipolar subjects.

Omega-3 (n-3) fatty acids have been implicated in mood disorders, yet clinical trials supplementing n-3 fats have shown mixed results. However, the predominant focus of this research has been on the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We used an unbiased approach to assay plasma n-3 and omega-6 (n-6) species that interact at the level of biosynthesis and down-stream processing, to affect brain function and, potentially, mood. We used lipomic technology to assay plasma levels of n-3 and n-6 fatty acids from 40 bipolar and 18 control subjects to investigate differences in plasma levels and associations with the burden of disease markers, neuroticism and global assessment of function (GAF) and mood state (Hamilton Depression Scale (HAM-D)). Most significantly, we found the levels of dihomo-gamma-linolenic acid (DGLA) to positively correlate with neuroticism and HAM-D scores and negatively correlate with GAF scores; and HAM-D to negatively correlate with linoleic acid (LA) and positively correlate with fatty acid desaturase 2 (FADS2) activity, an enzyme responsible for converting LA to gamma-linolenic acid (GLA). These associations remained significant following Bonferroni multiple testing correction. These data suggest that specific n-6 fatty acids and the enzymes that control their biosynthesis may be useful biomarkers in measurements of depressive disorders and burden of disease, and that they should be considered when investigating the roles of n-3s.

Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects.

Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n-6 PUFA in serum. We found positive associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6, arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters. The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and disease outcome in bipolar subjects and supports the need for further investigations into individualized specific modulations of lipid profiles to add adjunctive value to treatment paradigms.

Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol. METHOD: Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined. RESULTS: A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups. LIMITATIONS: The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account. CONCLUSIONS: Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.

Association of plasma interleukin-18 levels with emotion regulation and µ-opioid neurotransmitter function in major depression and healthy volunteers.

BACKGROUND: Alterations in central neurotransmission and immune function have been documented in major depression (MDD). Central and peripheral endogenous opioids are linked to immune functioning in animal models, stress-activated, and dysregulated in MDD. We examined the relationship between µ-opioid receptor (OR)-mediated neurotransmission and a proinflammatory cytokine (interleukin [IL]-18). METHODS: We studied 28 female subjects (14 MDDs, 14 control subjects) with positron emission tomography and [(11)C] carfentanil (µ-OR selective) during neutral and sadness states. With a simple regression model in SPM2 (Wellcome Trust, London, England) we identified brain regions where baseline µ-OR availability (nondisplaceable binding potential [BP(ND)]) and sadness-induced changes in µ-OR BP(ND) were associated with baseline IL-18. RESULTS: Baseline IL-18 was greater in MDDs than control subjects [t(25) = 2.13, p = .04]. In control subjects IL-18 was correlated with negative emotional ratings at baseline and during sadness induction. In MDDs, IL-18 was positively correlated with baseline regional µ-OR BP(ND) and with sadness-induced µ-opioid system activation in the subgenual anterior cingulate, ventral basal ganglia, and amygdala. CONCLUSIONS: This study links plasma IL-18 with sadness-induced emotional responses in healthy subjects, the diagnosis of MDD, and µ-opioid functioning, itself involved in stress adaptation, emotion regulation, and reward. This suggests that IL-18 represents a marker associated with emotion regulation/dysregulation at least in part through central opioid mechanisms.

A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder.

BACKGROUND: Lithium is an effective treatment for Bipolar Disorder (BD) and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania. RESULTS: Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes. CONCLUSIONS: We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel hypotheses for validation in future work, we prioritized SNPs near genes in the network based on functional annotation. We also developed a "concept signature" for the genes in the network and identified additional candidate genes that may influence the system because they are significantly associated with the signature.

Dysregulation of regional endogenous opioid function in borderline personality disorder.

OBJECTIVE: Borderline personality disorder is characterized by a lack of effective regulation of emotional responses. The authors investigated the role of the endogenous opioid system and mu-opioid receptors in emotion regulation in borderline personality disorder. METHOD: Mu-opioid receptor availability in vivo (nondisplaceable binding potential, or BP(ND)) was measured with positron emission tomography and the selective radiotracer [(11)C]carfentanil during neutral and sustained sadness states in 18 unmedicated female patients with borderline personality disorder and 14 healthy female comparison subjects. RESULTS: Patients showed greater regional mu-opioid BP(ND) than did comparison subjects at baseline (neutral state) bilaterally in the orbitofrontal cortex, caudate, and nucleus accumbens and in the left amygdala, but lower BP(ND) in the posterior thalamus. Sadness induction was associated with greater reductions in BP(ND) (endogenous opioid system activation) in the patient group than in the comparison group in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex. Patients showed evidence of endogenous opioid system deactivation in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects. Correlations of baseline measures with the Dissociative Experiences Scale and endogenous opioid system activation with the Barratt Impulsiveness Scale did not remain significant after correction for multiple comparisons. CONCLUSIONS: Differences exist between patients with borderline personality disorder and comparison subjects in baseline in vivo mu-opioid receptor concentrations and in the endogenous opioid system response to a negative emotional challenge that can be related to some of the clinical characteristics of patients with borderline personality disorder. The regional network involved is implicated in the representation and regulation of emotion and stress responses.