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Background: Early-life stress is associated with alterations in telomere length, a marker of accumulated stress and aging, and a risk factor for psychiatric disorders. Nonhuman primate maternal variable foraging demand (VFD) is a validated early-life stress model, resulting in anxiety- and depressive-like symptoms in offspring. Previous studies reported increased plasma glucagon-like peptide 1 (pGLP-1) along with insulin resistance in this model. We investigated whether VFD rearing related to adult telomere length and to these neuroendocrine markers. Methods: Adult leukocyte telomere length was measured in VFD-reared (12 males, 13 females) and non-VFD–reared (9 males, 26 females) bonnet macaques. Associations between adult telomere length and adolescent fasting pGLP-1 or insulin resistance in VFD-reared versus non-VFD–reared groups were examined using regression modeling, controlling for sex, weight, and age. Results: VFD subjects had relatively longer telomeres than non-VFD subjects (p = .017), and females relatively longer than males (p = .0004). Telomere length was positively associated with pGLP-1 (p = .0009) and with reduced insulin sensitivity (p < .0001) in both sexes, but not as a function of rearing group. Conclusions: Unexpectedly, VFD was associated with longer adult telomere length. Insulin resistance may lead to higher pGLP-1 levels in adolescence, which could protect telomere length in VFD offspring as adults. Associations between adult telomere length and adolescent insulin resistance and high pGLP-1 may reflect an adaptive, compensatory response after early-life stress exposure.

Protein kinase Mζ (PKMζ) maintains long-term potentiation (LTP) and long-term memory through persistent increases in kinase expression. Early-life adversity is a precursor to adult mood and anxiety disorders, in part, through persistent disruption of emotional memory throughout life. Here we subjected 10- to 16-wk-old male bonnet macaques to adversity by a maternal variable-foraging demand paradigm. We then examined PKMζ expression in their ventral hippocampi as 7- to 12-yr-old adults. Quantitative immunohistochemistry reveals decreased PKMζ in dentate gyrus, CA1, and subiculum of subjects who had experienced early-life adversity due to the unpredictability of maternal care. Adult animals with persistent decrements of PKMζ in ventral hippocampus express timid rather than confrontational responses to a human intruder. Persistent down-regulation of PKMζ in the ventral hippocampus might reduce the capacity for emotional memory maintenance and contribute to the long-lasting emotional effects of early-life adversity.

ALPIM (anxiety, laxity, pain, immune, and mood) syndrome has been previously described in adults. The authors aimed to identify its occurrence in adolescents and confirm its existence in adults. Given the association of the disorder with somatic symptoms, separation anxiety disorder (SAD) was explored as an ALPIM comorbidity.Medical records of patients aged 11-34 with a diagnosis of depression or anxiety (panic disorder, SAD, social anxiety or generalized anxiety disorder) seen during a 1-year period were reviewed. Data were collected on the presence of ALPIM comorbidities. Analyses were conducted to detect their co-occurrence and evaluate possible predictors of the ALPIM syndrome.Inclusion criteria were met by 185 patient charts. A significant association was observed between the ALPIM comorbidities with 20 study subjects (10.8%) meeting criteria for ALPIM syndrome (patients with one or more diagnoses from each ALPIM domain). Patients with SAD had increased odds of being diagnosed with ALPIM (odds ratio=7.14, 95% CI=2.48-20.54, p0.001). Neither major depression nor generalized anxiety disorder was found to be predictive of ALPIM syndrome. There was no difference in the prevalence of ALPIM-related comorbidities between study subjects18 years old compared with those ≥18 years old.These findings reestablish the association of distinct psychiatric and nonpsychiatric conditions described as the ALPIM syndrome. Furthermore, the syndrome may present during adolescence. SAD may be an independent predictive factor for the occurrence of ALPIM syndrome. Patients with individual ALPIM comorbidities should be assessed for the syndrome, especially if they have a history of SAD.

Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only (r = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.

Introduction: Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology and/or resistance to antidepressant treatment. While early-life adversity and the short variant (‘s’) of the serotonin transporter gene's long polymorphic region (5-HTTLPR) are suggested as interacting risk factors for affective disorders, no studies have examined whether their superposed risk effectuates neurogenic changes into adulthood. Similarly, it is not established whether reduced hippocampal volume in adolescence, variously identified as a marker and antecedent of affective disorders, anticipates diminished adult neurogenesis. We investigate these potential developmental precursors of neurogenic alterations using a bonnet macaque model. Methods: Twenty-five male infant bonnet macaques were randomized to stressed [variable foraging demand (VFD)] or normative [low foraging demand (LFD)] rearing protocols and genotyped for 5-HTTLPR polymorphisms. Adolescent MRI brain scans (mean age 4.2y) were available for 14 subjects. Adult-born neurons were detected post-mortem (mean age 8.6y) via immunohistochemistry targeting the microtubule protein doublecortin (DCX). Models were adjusted for age and weight. Results: A putative vulnerability group (VG) of VFD-reared ‘s’-carriers (all ‘s/l’) exhibited reduced neurogenesis compared to non-VG subjects. Neurogenesis levels were positively predicted by ipsilateral hippocampal volume normalized for total brain volume, but not by contralateral or raw hippocampal volume. Limitations: No ‘s’-carriers were identified in LFD-reared subjects, precluding a 2×2 factorial analysis. Conclusion: The ‘s’ allele (with adverse rearing) and low adolescent hippocampal volume portend a neurogenic deficit in adult macaques, suggesting persistent alterations in hippocampal plasticity may contribute to these developmental factors’ affective risk in humans.

Introduction The neurometabolism underlying the cognitive and affective symptoms associated with generalized anxiety disorder (GAD) remain poorly understood. After we have linked worry to intelligence in patients with GAD, we hypothesized that aberrant neurometabolic correlations between hippocampus and neocortical regions may underlie a shared substrate in GAD patients for both anxiety sensitivity and intelligence. Methods GAD patients (n = 16; F = 11) and healthy volunteers (n = 16; F = 10) were assessed using 1H-MRSI. Co-axial planes I [hippocampus (HIPP)] and co-axial plane III [dorsolateral prefrontal cortex (DLPFC), central gyrus (CG)] were examined. Using general linear models, we examined resting metabolite concentrations using HIPP as a hub to CG and DLPFC. Neocortical ROIs were related to Anxiety Sensitivity Index (ASI) and Full Scale IQ (FSIQ) in GAD patients versus controls. Results Right hippocampal Cho/Cr directly predicted left DLPFC Cho/Cr in GAD (r = 0.75), an effect distinguishable (p = 0.0004) from controls. Left HIPP Cho/Cr positively predicted left CG Cho/Cr in GAD, an effect distinguishable from controls. In patients, both left and right DLPFC Cho/Cr positively predicted ASI but only left DLPFC Cho/Cr inversely predicted IQ. By contrast, IQ in controls correlated directly with left CG Cho/Cr. Limitations Small sample size precluded us from investigating how gender and FSIQ subscales related to neurochemical correlations in the ROIs examined. Conclusions Aberrant resting state neurochemical correlation between left DLPFC and right HIPP may contribute to GAD symptomatology. Unlike controls, in GAD, IQ and worry may share a common yet inverse neurometabolic substrate in left DLPFC.

Background: Early life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a “thrifty phenotype” throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced “behavioral plasticity”, which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations. Methods: 14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters. Results: Reduced LVESD (p

Introduction Early life stress (ELS) has been shown to play a role in establishing persistent maladaptive HPA axis modifications that may contribute to the pathogenesis of mood and anxiety disorders. Central glucocorticoid receptor (GR) messenger RNA (mRNA) expression may facilitate (mal)adaptive responsivity to ELS. The role of adult monocytic GR mRNA expression, a putative CNS proxy, during acute stress exposure was explored as well as the ELS marker, juvenile cerebrospinal fluid (CSF) corticotropin-releasing factor. Methods Six adult macaques (three of which were exposed to variable foraging demand, a form of ELS) underwent acute restraint. Baseline GR expression and plasma cortisol concentrations were separately measured followed by subsequent measurements following stress completion (t = 0 min, 4 h, 5 days and 7 days). Juvenile CSF CRF concentrations were available in five subjects to determine their developmental association with GR expression in response to stress. Results As expected acute restraint stress produced a significant increase in plasma cortisol concentrations most robustly observed at 4 h post-stress time point. There was a significant juvenile CSF CRF concentration x time interaction in predicting adult GR mRNA expression in response to stress (partial η2 = 0.80). During acute stress juvenile CRF concentrations negatively predicted GR expression and during recovery, “flipped” to positively predict expression. Juvenile CSF CRF concentrations positively correlated with the volatility of adult GR mRNA expression. Conclusions During acute stress, relatively high CSF CRF concentrations are associated with relatively rapid reductions in GR expression. Return to an ambient post-stress state was characterized by a direct relationship, consistent with increased HPA axis restraint in high CRF subjects. An ELS-associated allostatic adaptation suggests relative elevations of juvenile CSF CRF concentration set the stage for a relative hyper-volatility of adult GR mRNA expression in response to acute stress with potential long-term implications for HPA axis regulation.

Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy (1H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen’s d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) frequently have overlapping symptoms, leading to the suggestion that the same disease processes may underpin the two disorders - the unitary hypothesis. However, studies investigating the two disorders have reported substantial clinical and/or biological differences between them, suggesting distinct pathophysiological underpinnings.The purpose of this study was to further add to the body of evidence favoring different disease processes in CFS and FM by comparing ventricular cerebrospinal fluid lactate levels among patients with CFS alone, FM alone, overlapping CFS and FM symptoms, and healthy control subjects.Ventricular lactate was assessedMean CSF lactate levels in CFS, FM and CFS+FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects.While patients with CFS, FM and comorbid CFS and FM can be differentiated from healthy subjects based on measures of CFS lactate, this neuroimaging outcome measure is not a viable biomarker for differentiating CFS from FM or from patients in whom symptoms of the two disorders overlap.

Background The rostral prefrontal cortex (RPFC) is involved in reflective thought processes such as self-knowledge and person perception. We hypothesized that childhood emotional abuse, which is disruptive of emotional regulation, would differentially impact neurometabolite concentrations of the RPFC, and related neocortical areas, in adults with generalized anxiety disorder (GAD) versus healthy controls. Methods GAD patients ( n =16; females=11) and medically healthy volunteers ( n =16; F =10) were assessed using the Childhood Trauma Questionnaire (CTQ), specifically the emotional abuse category. Proton magnetic resonance spectroscopy imaging examined 3 regions of interest (ROI) from the most rostral slice from the Duyn et al. (1993) multivoxel imaging modality: rostral prefrontal cortex (BA 10,9), premotor cortex (BA 6,8) and secondary somatosensory and associated parietal cortex (BA 5,7). Metabolites included N -acetyl-aspartate, creatine, and choline. Results GAD patients reported higher emotional abuse scores versus controls. An omnibus general linear model including 3 ROI, 3 metabolites, and laterality as dependent variables revealed a significant diagnosis by CTQ emotional abuse score interactive effect. In controls, all 3 ROI for all 3 metabolites on both sides demonstrated a significant inverse relationship with emotional abuse scores; none were significant in GAD patients. Limitations A major limitation is the uneven distribution of emotional abuse scores between the controls and GAD patients, with GAD patients reporting higher scores. Conclusion Unlike controls, GAD patients appear compromised in forming a molecular representation reflective of magnitude of childhood emotional abuse. The neurometabolites in GAD patients appear non-aligned to childhood emotional abuse, suggesting potential consequences for normative “theory of mind” processes and emotional function in certain anxiety disorders.

Background Maternal response to allostatic overload during infant rearing may alter neurobiological measures in grown offspring, potentially increasing susceptibility to mood and anxiety disorders. We examined maternal cerebrospinal fluid (CSF) glutamate response during exposure to variable foraging demand (VFD), a bonnet macaque model of allostatic overload, testing whether activation relative to baseline predicted concomitant CSF elevations of the stress neuropeptide, corticotropin-releasing factor. We investigated whether VFD-induced activation of maternal CSF glutamate affects maternal–infant attachment patterns and offspring CSF 5-hydroxyindoleacetic acid concentrations. Methods Mother–infant dyads were exposed to the “VFD stressor,” a paradigm in which mothers experience 16 weeks of foraging uncertainty while rearing their infant offspring. Through staggering the infant age of VFD onset, both a cross-sectional design and a longitudinal design were used. Maternal CSF glutamate and glutamine concentrations post-VFD exposure were cross-sectionally compared to maternal VFD naive controls. Proportional change in concentrations of maternal glutamate (and glutamine), a longitudinal measure, was evaluated in relation to VFD-induced elevations of CSF corticotropin-releasing factor. The former measure was related to maternal–infant proximity scores obtained during the final phases of VFD exposure. Maternal glutamatergic response to VFD exposure was used as a predictor variable for young adolescent offspring CSF metabolites of serotonin, dopamine, and norepinephrine. Results Following VFD exposure, maternal CSF glutamate concentrations correlated positively with maternal CSF CRF concentrations. Activation relative to baseline of maternal CSF glutamate concentrations following VFD exposure correlated directly with a) increased maternal-infant proximity during the final phases of VFD and b) offspring CSF concentrations of monoamine metabolites including 5-hydroxyindoleacetic acid, which was elevated relative to controls. Conclusions Activation of maternal CSF glutamate in response to VFD-induced allostasis is directly associated with elevations of maternal CSF corticotropin-releasing factor. Maternal CSF glutamate alterations induced by VFD potentially compromise serotonin neurotransmission in grown offspring, conceivably modeling human vulnerability to treatment-resistant mood and anxiety disorders.

Objective The Research Domain Criteria (RDoC) project was initiated to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. This article reviews the rationale behind the RDoC program, its goals, and central tenets; discusses application of an RDoC framework to research with maltreated children; and highlights some clinical implications of this work. Method Published RDoC papers were reviewed, together with relevant preclinical and clinical studies that guide our work on risk and resilience in maltreated children. Results The ultimate long-term goal of the RDoC initiative is precision medicine in psychiatry. In the interim, the RDoC initiative provides a framework to organize research to help develop the database required to derive a new psychiatric nomenclature that can appropriately match treatments to patients. The primary focus of RDoC is on neural circuitry, with levels of analyses that span from molecules to behavior. There has been some concern that the RDoC framework is reductionist, with an overemphasis on neural circuits and genetics; however, the briefly reviewed, burgeoning literature on neuroplasticity and epigenetics highlights that this concern is unwarranted, as one cannot study neural circuits and genetics without considering experience. Conclusion The study of maltreated children has a number of advantages for the RDoC project, including the following: study of a subset of patients who are often not responsive to standard interventions; examination of a relatively homogenous sample with onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established, relevant animal models to facilitate translational research.

The authors describe a spectrum disorder comprising a core anxiety (A) disorder and four domains: joint laxity (L), chronic pain syndromes (P), immune disorders (I), and mood disorders (M)-dubbed the ALPIM syndrome. This study examined 76 consecutive outpatients with an anxiety disorder plus at least one somatic condition from three domains. More than 80% of the patients had panic attacks, fibromyalgia, and major depressive episodes. Associations were found between joint laxity and bipolar III, headache with bipolar II, and bipolar II with chronic fatigue syndrome. Significant relationships were demonstrated within and between domains, validating ALPIM as a syndrome.

Low ankle-brachial index (ABI) is a marker of peripheral arterial disease associated with higher cardiovascular risk. ABI has been found to be influenced by left ventricular ejection fraction (LVEF), but this relation is confounded by atherosclerosis. Objectives: Since nonhuman primates have a low incidence of atherosclerosis, we sought to evaluate the effect of LVEF on ABI in 24 healthy female bonnet macaques (age 83 ± 21 months). Methods: LVEF was determined by echocardiography during anesthesia with ketamine. ABI was determined using automatic blood pressure cuff. Results: Mean LVEF was 73 ± 6%. Mean ABI was 1.03 (range 0.78-1.17) with similar right and left lower limb values (p = 0.78). On univariate analysis, mean ABI was significantly correlated with LVEF (r = 0.58, p = 0.003) but not with age, crown-rump length or weight. Mean LVEF increased in a stepwise manner from lowest to highest ABI tertile (68 ± 6 vs. 73 ± 4 vs. 77 ± 5%, p = 0.008). On ordinal regression and forced multivariate linear analyses, ABI status was independently related to LVEF. Conclusions: ABI is influenced by left ventricular systolic function but not age, height, weight or mass index in bonnet macaques. Left ventricular systolic function should be accounted for when considering ABI measurements.

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive, and neuroprotective properties. The hypothalamic-pituitary-adrenal axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques ( Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg intramuscular). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand conditions. Since there were no rearing effects at baseline or for any of the conditions tested—either for cortisol or TGF-β—the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and cerebrospinal fluid cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in cerebrospinal fluid but not in serum. Together, the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occur in the face of hypothalamic-pituitary-adrenal axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompt exploration of protective measures against glucocorticoid-induced neurotoxicity.

Introduction Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.”

Functional imaging studies have implicated the orbitofrontal cortex (OFC) in the pathophysiology of borderline personality disorder (BPD). To date, however, volume-based magnetic resonance imaging (MRI) studies have yielded mixed results. We used a surface-based processing approach that allowed us to measure five morphometric cortical features of the OFC, including volumetric (cortical thickness and surface area) and geometric (mean curvature, depth of sulcus, and metric distortion – three indicators of cortical folding) parameters. Participants comprised 25 female BPD patients with no other current psychiatric comorbidity and 25 age- and gender-matched healthy controls who received structural MRI scans. Images were processed using the Freesurfer package. All BPD patients had a history of comorbid psychiatric disorder(s) and were currently on medications. Compared with controls, the BPD group showed reduced cortical thickness, surface area, mean curvature, depth of sulcus, and metric distortion in the right medial OFC. In the left medial OFC, the BPD group had reduced cortical thickness and mean curvature, but increased metric distortion. This study confirmed the utility of surface-based analysis in the study of BPD cortical structures. In addition, we observed extensive structural abnormalities in the medial OFC of female subjects with BPD, findings that were most pronounced in the right OFC, with preliminary data suggesting hemispheric asymmetry.

Patients with ESRD have high rates of depression, which is associated with diminished quality of life and survival. We determined whether individual cognitive behavioral therapy (CBT) reduces depression in hemodialysis patients with elevated depressive affect in a randomized crossover trial. Of 65 participants enrolled from two dialysis centers in New York, 59 completed the study and were assigned to the treatment-first group (n=33) or the wait-list control group (n=26). In the intervention phase, CBT was administered chairside during dialysis treatments for 3 months; participants were assessed 3 and 6 months after randomization. Compared with the wait-list group, the treatment-first group achieved significantly larger reductions in Beck Depression Inventory II (self-reported, P=0.03) and Hamilton Depression Rating Scale (clinician-reported, P

Background There is a paucity of information on the risks and clinical characteristics of tardive dyskinesia with atypical antipsychotic agents in patients with mood and anxiety disorders in clinical practice. Methods: The authors retrospectively screened the charts of 268 patients with a mood or anxiety disorder treated with atypical antipsychotic agents from a psychiatric practice. Fifteen patients who developed tardive dyskinesia were identified and further data was collected on these patients. Results Tardive dyskinesia occurred in 5.9% of patients after exposure to an atypical antipsychotic agent for a mean of 28.7 months (range: 1–83). The average dosage of the offending agent in chlorpromazine equivalents was 350 mg/day (range: 67–969). All patients experienced oral-buccal-lingual stereotypy, which was frequently severe in nature, but completely resolved in all but one patient. Most patients (90.9%) who consented to a second trial of an atypical antipsychotic did not experience a relapse of TD. Limitations: All patients were treated in a clinical practice setting by a single psychiatrist, which may limit the generalizability of the findings. Conclusions The observed rate of TD represents a real world estimate of the risk of TD with atypical antipsychotic agents in patients with mood disorders. Fortunately, with early recognition symptoms appear to be reversible and further treatment with another atypical antipsychotic does not necessarily lead to relapse.

Stress coping is an important part of mammalian life, influencing somatic and mental health, social integration, and reproductive success. The experience of early psychological stress helps shape lifelong stress coping strategies. Recent studies have shown that the effects of early stress may not be restricted to the affected generation, but may also be transmitted to offspring. Understanding whether early stress influences development in subsequent generations may help us understand somewhat why many stress-related traits and diseases, for which little genetic basis has been discovered, run in families. Experimental early life “variable foraging demand” (VFD) stress has been associated with behavioral hypo-responsiveness to stress in infant and adolescent bonnet macaques. The present study examined the behavioral effects of experimental early VFD stress in adult bonnet macaques, and further investigated whether non-exposed adolescent offspring of VFD macaques were also affected. Thirty female bonnet macaques from four rearing histories were observed for behavioral response during stress: adults which had been VFD reared as infants (n = 11), adults which had been Control reared as infants (n = 9), and foraging demand naive adolescents whose mothers were VFD (n = 4) or Control reared (n = 6). Subjects were observed for behavioral response during two experimental stressor conditions, including: (1) relocation to a novel environment; and (2) relocation with exposure to a “human intruder” making eye contact. Factor analysis yielded five factors that described categories of behavior across stress conditions. While adult VFD and Control reared females unexpectedly did not differ significantly, non-exposed adolescent offspring of VFD reared mothers displayed significant hypo-responsiveness in all behavioral categories compared with non-exposed adolescent offspring of Control females. We suggest that stress hypo-responsiveness previously observed in adolescent VFD reared animals may abate with age, but is nonetheless observed in the next generation. We conclude that VFD stress affects behavioral development of subsequent generations in non-human primates. Am. J. Primatol. 75:509-517, 2013. © 2013 Wiley Periodicals, Inc.

Hippocampal neurogenesis continues throughout the lifespan of adult mammals, but the rates decline dramatically with increasing age. Among the factors that have been shown to affect neurogenesis, aging has been shown to be one of its most potent regulators in mice. The mechanism for the decline in neurogenesis with age is thought to be related to age-dependent changes in local and systemic neuroendocrinology and neurochemistry, as well as internal changes to precursor cells that result in decreased reactivity to normal stimuli. Since most of the data about neurogenesis and age were established from rodent studies, we sought to study this relationship in nonhuman primates in five previously studied cohorts of bonnet monkeys (Macaca radiata). In the present study, we statistically analyze the relationship of age and hippocampal neurogenesis rates, as measured by the number of DCX expressing cells in the subgranular zone of the dentate gyrus in 71 subjects with ages ranging from 3.5 to 17 years. We observed a non-significant relationship between age and doublecortin for subjects less than nine years old (corresponding to young and full adulthood) but a linear significant decline for subjects 9 years or greater (middle age and senescence). In contrast to previous studies that show neurogenesis to decline linearly throughout the lifespan, this study shows that neurogenesis occurs steadily throughout adulthood and begins to decline in middle age in bonnet macaques.

Background To investigate the mechanism underlying the anxiolytic properties of riluzole, a glutamate-modulating agent, we previously studied the effect of this drug on hippocampal N-acetylaspartate (NAA) and volume in patients with generalized anxiety disorder (GAD). In the same cohort, we now extend our investigation to the occipital cortex, a brain region that was recently implicated in the antidepressant effect of riluzole. Methods Fourteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. The healthy group did not receive riluzole treatment. Both groups underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) were used as the primary and secondary outcome measures, respectively. Results At baseline, we found clusters of increased cortical thickness in the occipital region in GAD compared to healthy subjects. In the right hemisphere, 8 weeks of treatment reduced occipital cortical thickness in the GAD group ( t = 3.67, p = 0.004). In addition, the improvement in HAM-A scores was negatively correlated with post-treatment right occipital NAA ( r = −0.68, p = 0.008), and with changes in NAA levels ( r = −0.53, p = 0.051). In the left hemisphere, we found positive associations between changes in occipital cortical thickness and improvement in HAM-A ( r = 0.60, p = 0.04) and PSWQ ( r = 0.62, p = 0.03). Conclusion These pilot findings implicate the occipital cortex as a brain region associated with pathology and clinical improvement in GAD. In addition, the region specific effect of riluzole implies a distinct pathophysiology in the occipital cortex – compared to other, previously studied, frontolimbic brain structures.

Introduction Functional neuroimaging studies report global prefrontal dysconnectivity in mood disorders, supporting the notion of widespread disruptions in brain networks. Microscopic alterations in white matter (WM) tracts – which possess neuroplastic properties and play a central role in brain connectivity – are interrogated herein in the context of brain dysconnectivity. Early life stress (ELS), an antecedent to human mood disorders, induces WM alterations in volumetrics and integrity. We hypothesized that nonhuman primate infants exposed to ELS would exhibit persistent impairments in both frontal and posterior concordance of WM integrity, therefore contributing to global brain dysconnectivity. Methods Using a 3T MRI, diffusion tensor imaging (DTI) was performed on 21 adult male Bonnet macaques, 12 of whom had been raised under variable foraging demand (VFD) conditions and nine of whom had been raised under normative conditions (Non-VFD). As representative of anterior regions, fractional anisotropy (FA) concordance between anterior corpus callosum (ACorpusC) and anterior limb of the internal capsule (ALIC) was examined. For posterior regions, FA concordance between posterior corpus callosum (PCorpusC) and posterior limb of the internal capsule (PLICA) and between PCorpusC and occipital WM was examined. Examination of posterior FA was explored in the context of frontal markers of neuroplasticity. Results A concordant relationship for FA between left ALIC and ACorpusC was evident in Non-VFD-reared subjects, but significantly absent in VFD-reared subjects. For left posterior regions, FA concordance between PLICA and PCorpusC and occipital WM and PCorpusC was evident in VFD-reared and not Non-VFD-reared subjects. The posterior concordance in VFD was significantly distinguishable from the deficit in anterior concordance FA in VFD. Conclusions The findings support the view that disrupted emotional integrity of the maternal-infant attachment process affects normative synchronous development of frontal white matter tracts but creates errant posterior concordance and also disrupts an inverse relationship between posterior white matter tracts and markers of neuroplasticity. We provide preliminary evidence that a concordant relationship between capsular–callosal FA may become discordant, providing a putative mechanism for prefrontal functional brain dysconnectivity.

Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N-acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

Lactate uses an unknown mechanism to induce panic attacks in people and panic-like symptoms in rodents. We tested whether intraperitoneal (IP) lactate injections act peripherally or centrally to induce panic-like symptoms in rats by examining whether IP lactate directly affects the CNS. In Long-Evans rats, IP lactate (2 mmol/kg) injection increased lactate levels in the plasma and the cerebrospinal fluid. IP lactate also induced tachycardia and behavioral freezing suggesting the production of panic-like behavior. To enter intermediate metabolism, lactate is oxidized by lactate dehydrogenase (LDH) to pyruvate with co-reduction of NAD + to NADH. Therefore, we measured the ratio of NADH/NAD + to test whether IP lactate altered lactate metabolism in the CNS. Lactate metabolism was studied in the hippocampus, a brain region believed to contribute to panic-like symptoms. IP lactate injection lowered the ratio of NADH/NAD + without altering the total amount of NADH and NAD + suggesting oxidation of hippocampal redox state. Lactate oxidized hippocampal redox since intrahippocampal injection of the LDH inhibitor, oxamate (50 mM) prevented the oxidation of NADH/NAD + by IP lactate. In addition to oxidizing hippocampal redox, IP lactate rapidly increased the firing rate of hippocampal neurons. Similar IP pyruvate injections had no effect. Neural discharge also increased following intrahippocampal lactate injection suggesting that increased discharge was a direct action of lactate on the hippocampus. These studies show that oxidation of brain redox and increased hippocampal firing are direct actions of lactate on the CNS that may contribute to the production of lactate-induced panic.

The neural basis of generalized anxiety disorder (GAD) is poorly characterized. The effect of chronic administration (12 weeks) of paroxetine, a selective serotonin reuptake inhibitor, on N-acetylaspartate (NAA), a marker of neuronal viability, was evaluated in adults with GAD using proton magnetic resonance spectroscopic imaging (1H MRSI) at 1.5 T. We hypothesized that, pretreatment abnormalities in hippocampal NAA/creatine (NAA/Cr) would normalize with symptomatic improvement. Nine GAD patients (mean age = 41.7 year; 4 females) received 12 weeks of open-label paroxetine treatment, flexibly dosed up to 60 mg/day. Clinical outcome was assessed with the Hamilton Anxiety Rating Scale (HAM-A). Multislice 1H MRSI scans were performed at unmedicated baseline and following 6 and 12 weeks of treatment. Ten untreated healthy volunteers (HVs) (mean age = 37.1 year; 4 females) received scans at the same intervals. All patients achieved remission (HAM-A ≤ 7) by week 12. Compared to HVs, GAD patients showed persistently lower levels of bilateral hippocampal NAA/Cr (17.7% mean decrease; Cohen’s d = 1.29) that were maintained across all three time points, despite marked symptom improvement. This pilot study failed to support an association between a hippocampal neuronal marker and anxiolytic response to paroxetine, and suggests further investigation of potential trait-like hippocampal abnormalities in GAD.

Background and objectives: There is growing identification of the need to seriously study the psychiatric presentations of end-stage renal disease patients treated with hemodialysis. This study reports on the course of depression and anxiety diagnoses and their impact on quality of life and health status. Design, setting, participants, & measurements: The 16-mo course of psychiatric diagnoses in 50 end-stage renal disease patients treated with hemodialysis was measured by structured clinical interview. Results: Three different pathways were identified: one subset of patients not having a psychiatric diagnosis at either baseline or 16-mo follow-up (68% for depression, 51% for anxiety), one group having an intermittent course (21% for depression, 34% for anxiety), and one group having a persistent course (11% for depression, 15% for anxiety), with diagnoses at both time 1 and time 2. For depression, the people with the persistent course showed marked decreases in quality of life and self-reported health status compared with the nondepressed and intermittently depressed cohorts. The most powerful predictor of depression at time 2 is degree of depressive affect at time 1(P < 0.05). Conclusions: Patients at risk for short- and long-term complications of depression can be potentially identified by high levels of depressive affect even at a single time point. As nearly 20% of the sample had chronic depression or anxiety, identifying a psychiatric diagnosis in hemodialysis patients and then offering treatment are important because, in the absence of intervention, psychiatric disorders are likely to persist in a substantial proportion of patients.

Background Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging ( 1 H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N -acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. Methods Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by 1 H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders ( n = 9) or nonresponders ( n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures. Results A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety. Conclusions These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted.

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

Depression is well established as a prevalent mental health problem for people with ESRD and is associated with morbidity and mortality. However, depression in this population remains difficult to assess and is undertreated. Current estimates suggest a 20 to 30% prevalence of depression that meets diagnostic criteria in this population. The extent of other psychopathology in patients with ESRD is largely unknown. The aim of this study was to expand the research on psychiatric complications of ESRD and examine the prevalence of a broad range of psychopathology in an urban hemodialysis center and their impact on quality of life. With the use of a clinician-administered semistructured interview in this randomly selected sample of 70 predominately black patients, >70% were found to have a psychiatric diagnosis. Twenty-nine percent had a current depressive disorder: 20% had major depression, and 9% had a diagnosis of dysthymia or depression not otherwise specified. Twenty-seven percent had a current major anxiety disorder. A current substance abuse diagnosis was found in 19%, and 10% had a psychotic disorder. The mean Beck Depression Inventory score was 12.1 +/- 9.8. Only 13% reported being in current treatment by a mental health provider, and only 5% reported being prescribed psychiatric medication by their physician. A total of 7.1% had compound depression or depression coexistent with another psychiatric disorder. The construct of depression was also disentangled from the somatic effects of poor medical health by demonstrating a unique relationship between depressive affect and depression diagnosis, independent of health status. This study also suggests the utility of cognitive variables as a meaningful way of understanding the differences between patients who have ESRD with clinical depression or other diagnoses and those who have no psychiatric comorbidity. The findings of both concurrent and isolated anxiety suggest that the prevalence of psychopathology in patients with ESRD might be higher than previously expected, and the disorders may need to be treated independently. In addition, the data suggest that cognitive behavioral therapeutic techniques may be especially advantageous in this population of patients who are treated with many medications.

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F 1,37 = 22.11, P 2 = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing. At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F 1,18 = 8.18, P = .01, partial η 2 = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo ( P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation. Perspective Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy (1H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p < 0.001) and HC (p = 0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p = 0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p = 0.05) and HC groups (p = 0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes.

We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects , conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA). Methods: When infants were 2-6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD. Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Golgi impregnation is unique in its ability to display the dendritic trees of large numbers of individual neurons. However, its reputation for inconsistency leaves many investigators reluctant to embrace this methodology, particularly for the study of formalin-fixed human brain tissue. After reviewing the literature, testing a variety of technical variations, and discussing the procedure with experienced practitioners, we have concluded that much of the unpredictability can be removed by matching the Golgi technique to the conditions that were used for fixation of the tissue. Briefly fixed tissues worked best with the rapid Golgi technique, which includes osmium during the initial chromation step, and with the Golgi-Cox method, which includes mercuric chloride during chromation. For tissues that have been fixed for several years or even for several decades, superior results are obtained with the Golgi-Kopsch technique, using multiple changes of a chromation solution that contains paraformaldehyde. In the Golgi-Kopsch technique, pH should be used to monitor the reduction of Cr6+ to Cr3+, which is a crucial determinant of successful chromation. With any Golgi technique, agitation throughout the impregnation helps to avoid precipitates and to improve the quality of impregnation. When the appropriate method is chosen, Golgi impregnation is a useful technique for the neuropathologist.

Background Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. Methods Bonnet macaque ( Macaca radiata ) mother–infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). Results In anterior cingulate, VFD-reared subjects displayed significantly decreased N -acetylaspartate (NAA) resonance and significantly increased glutamate–glutamine–γ-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated ( r = −.638, p = .014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. Conclusions These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

The two neuropeptides corticotropin-releasing-factor (CRF) and oxytocin (OT) may produce opposing behavioral effects — elevations of the former have been associated with anxiety and social vigilance and reductions of the latter with reduced social affiliation. We sought to test the hypothesis that, within the primate macaque genus, the more gregarious, affiliative, and affectively stable bonnet species ( Macaca radiata ) would exhibit lower cerebrospinal fluid (CSF) CRF and higher CSF OT concentrations in comparison to its close relative, the temperamentally volatile and socially distant pigtail ( Macaca nemestrina ). Cisternal CSF samples were obtained from young adult male and female pigtail and bonnet macaques, and CRF and OT concentrations were measured by radioimmunoassay. Pigtail macaques exhibited significantly higher concentrations of CSF CRF and significant lower concentrations of CSF OT than bonnet macaques. Results were not attributable to age or sex differences in group composition. When included together in a multiple regression, CRF and OT showed a multiple R of 0.76, accounting for more than half of the species variance. Although species differences in the bioeffectiveness of these peptides may possibly confound the observed biobehavioral relationships, in the absence of any existing data to that effect, the current findings appear in accordance with the hypothesis and consistent with previously reported species–typical behaviors observed in these macaques.