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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., (© 2021 Fulton et al.; Published by Cold Spring Harbor Laboratory Press.)

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., (Copyright © 2021. Published by Elsevier B.V.)

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., Competing Interests: RG was employed by company Firstox Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Coplan, George, Syed, Rozenboym, Tang, Fulton and Perera.)

Introduction: Pattern separation aids cognitive flexibility by reducing interference between closely related memories. Dentate gyrus (DG) neurogenesis may facilitate pattern separation by blocking memory retrieval via inhibition of non-neurogenic downstream CA3 neurons. We hypothesized that immature adult-born DG neurons would be associated with decreased CA3 activation and increased cognitive flexibility., Method: Two groups of adult male rats were tested either on the place avoidance task (PAT) (unflipped condition) or a subtly altered-PAT (flipped condition). Four weeks prior, the rats were injected with the mitotic marker BrdU. Immature new neurons were detected by the microtubule protein doublecortin (DCX). Cells that took up BrdU and expressed NeuN were identified as relatively more mature neurons. Synaptic activation was determined by c-Fos expression. Adaptation to the flipped versus unflipped condition reflected a measure of cognitive flexibility., Results: CA3 but not DG c-Fos was lower in the flipped versus unflipped condition [p = 0.002]. CA3 c-Fos correlated inversely with flipped task performance and immature (DCX) neurons with primary and secondary but not tertiary dendrites or more mature (BrdU + NeuN) new neurons. CA3 c-Fos was a significant predictor for the flipped versus unflipped condition specifically for DCX versus BrdU-NeuN neurons., Conclusion: Immature new neurons (DCX+) without tertiary dendrites may be preferentially implicated in cognitive flexibility relative to more mature new neurons (BrdU-NeuN). In combination with decreased CA3 activation in the flipped PAT, the functional contribution of these immature DG neurons may involve the inhibition of postsynaptic CA3 neurons containing traces of previously salient conditioned memories., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: 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., Methods: 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., Results: 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, p<0.001). 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 subjects <18 years old compared with those ≥18 years old., Conclusions: 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.

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 1 H-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., (Copyright © 2017. Published by Elsevier B.V.)

Introduction: Using proton magnetic resonance spectroscopy imaging ( 1 H-MRSI), the effects of early life stress (ELS) 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 ELS markers -- cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations, hippocampal volume, body mass and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens (NAcc). We hypothesized that rearing under conditions of ELS [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 ELS markers., Methods: Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent 1 H-MRSI during young adulthood. Voxels were placed over ventral striatum/caudate nucleus (VS/CN) to capture NAcc. Cisternal CSF CRF concentrations, hippocampal volume, body mass and response to a human intruder had been previously determined., Results: VFD-reared monkeys exhibited significantly increased NAA/Cr concentrations in right VS/CN in comparison to normally-reared controls, controlling for multiple comparisons. In comparison to controls, VFD CSF CRF concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN N- acetyl aspartate/creatine (NAA/Cr) 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: ELS produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to ELS 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/NAcc relationship in affective 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., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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."

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 ( 1 H 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.

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=0min, 4h, 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 4h 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 η 2 =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., (Copyright © 2017. Published by Elsevier B.V.)

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive and neuroprotective properties. The hypothalamic-pituitary-adrenal (HPA) 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 IM). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid (CSF) to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand (VFD) 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 CSF cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in CSF but not in serum. Together the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occurs in the face of HPA axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompts exploration of protective measures against glucocorticoid-induced neurotoxicity.

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 < 0.05) was observed when controlled for age, sex, body weight and crown-rump length whereas ejection fraction (EF) (p = 0.037) was greater in VFD-reared versus non-VFD subjects. Pulse pressure was lower in VFD versus non-VFD females (p < 0.05). Male timidity in response to a human intruder was associated with reduced LVEDD (p < 0.05)., Conclusions: ELS is associated with both structural and functional reductions of left ventricular measures, potentially implying a body-wide thrifty phenotype. Parallel "thrift" adaptations may occur in key brain areas following ELS and may play an unexplored role in mood and anxiety disorder susceptibility.

Background: 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., Purpose: 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., Methods: Ventricular lactate was assessed in vivo with proton magnetic resonance spectroscopic imaging ( 1 H MRSI) with the results normed across the 2 studies in which the data were collected., Results: Mean 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., Conclusion: 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.

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., (Published by Elsevier B.V.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models: (1) "the avoidance model"; (2) "the intolerance of uncertainty model"; (3) "the meta-cognitive model"; (4) "the emotion dysregulation model"; and (5) "the acceptance based model". For depression, the following theoretical models are explicated: (1) "the cognitive model"; (2) "the behavioral activation model"; and (3) "the interpersonal model". Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines (BZDs) are an important "bridging strategy" to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-à-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors (e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a "stacking approach" not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression.

Unlabelled: 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 (F1,37 = 22.11, P < .0001, partial η(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 (F1,18 = 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., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 ((1)H 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., (Published by Elsevier B.V.)

Background: Chronic stress may conceivably require plasticity of maternal physiology and behavior to cope with the conflicting primary demands of infant rearing and foraging for food. In addition, social rank may play a pivotal role in mandating divergent homeostatic adaptations in cohesive social groups. We examined cerebrospinal fluid (CSF) oxytocin (OT) levels and hypothalamic-pituitary adrenal (HPA) axis regulation in the context of maternal social stress and assessed the contribution of social rank to dyadic distance as reflective of distraction from normative maternal-infant interaction., Methods: Twelve socially housed mother-infant bonnet macaque dyads were studied after variable foraging demand (VFD) exposure compared to 11 unstressed dyads. Dyadic distance was determined by behavioral observation. Social ranking was performed blindly by two observers. Post-VFD maternal plasma cortisol and CSF OT were compared to corresponding measures in non-VFD-exposed mothers., Results: High-social rank was associated with increased dyadic distance only in VFD-exposed dyads and not in control dyads. In mothers unexposed to VFD, social rank was not related to maternal cortisol levels, whereas VFD-exposed dominant versus subordinate mothers exhibited increased plasma cortisol. Maternal CSF OT directly predicted maternal cortisol only in VFD-exposed mothers. CSF OT was higher in dominant versus subordinate mothers. VFD-exposed mothers with "high" cortisol specifically exhibited CSF OT elevations in comparison to control groups., Conclusion: Pairing of maternal social rank to dyadic distance in VFD presumably reduces maternal contingent responsivity, with ensuing long-term sequelae. VFD-exposure dichotomizes maternal HPA-axis response as a function of social rank with relatively reduced cortisol in subordinates. OT may serve as a homeostatic buffer during maternal stress exposure.

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.

Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals., Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years)., Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: "high" cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls., Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.

First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying "treatment resistant depression (TRD)" with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by "flooding" 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario - presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder - each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for "stacked" interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.

Purpose: To determine whether short-term pressure elevation affects complement gene expression in the retina in vitro and in vivo., Methods: Muller cell (TR-MUL5) cultures and organotypic retinal cultures from adult mice and monkeys were subjected to either 24-h or 72-h of pressure at 0, 15, 30, and 45 mmHg above ambient. C57BL/6 mice were subjected to microbead-induced intraocular pressure (IOP) elevation for 7 days. RNA and protein were extracted and used for analysis of expression levels of complement component genes and complement component 1, q subcomponent (C1q) and complement factor H (CFH) immunoblotting., Results: mRNA levels of complement genes and C1q protein levels in Muller cell cultures remained the same for all pressure levels after exposure for either 24 or 72 h. In primate and murine organotypic cultures, pressure elevation did not produce changes in complement gene expression or C1q and CFH protein levels at either the 24-h or 72-h time points. Pressure-related glial fibrillary acidic protein (GFAP) mRNA expression changes were detected in primate retinal organotypic cultures (analysis of variance [ANOVA]; p<0.05). mRNA expression of several other genes changed as a result of time in culture. Eyes subjected to microbead-induced IOP elevation had no differences in mRNA expression of complement genes and C1q protein levels (ANOVA; p>0.05 for both) with contralateral control and naïve control eyes., Conclusions: Short-term elevation of pressure in vitro as well as short-term (1 week) IOP elevation in vivo does not seem to dramatically alter complement system gene expression in the retina. Prolonged expression to elevated pressure may be necessary to affect the complement system expression.

Objective: We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis - a form of neuroplasticity - and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS)., Methods: We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging ((1)H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables., Results: Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA., Conclusion: Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge-high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

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<0.001) scores after intervention. Mean scores for the treatment-first group did not change significantly at the 3-month follow-up. Among participants with depression diagnosed at baseline, 89% in the treatment-first group were not depressed at the end of treatment compared with 38% in the wait-list group (Fisher's exact test, P=0.01). Furthermore, the treatment-first group experienced greater improvements in quality of life, assessed with the Kidney Disease Quality of Life Short Form (P=0.04), and interdialytic weight gain (P=0.002) than the wait-list group, although no effect on compliance was evident at follow-up. In summary, CBT led to significant improvements in depression, quality of life, and prescription compliance in this trial, and studies should be undertaken to assess the long-term effects of CBT on morbidity and mortality in patients with ESRD.

Objectives: Although hippocampal neurogenesis has been implicated in mood disorders, the precise role new neurons play in mood regulation is not fully elucidated. Here we examine whether neurogenesis improves mood by facilitating segregation of novel experiences that conflict with older maladaptive memories., Methods: Study 1: Four groups (N = 9 each) of adult male rats (exposed to stress or control conditions plus antidepressant or placebo) underwent active training on the place-avoidance task (PAT) on week 0; tested on recalling the "Initial PAT" on weeks 4 and 8; learning a subtly "Altered PAT" on week 8; and euthanazed on week 9. Study-2: Two groups (N = 12 each) rats tested either on the Initial-PAT or Altered-PAT 3 days post-training and immediately euthanized., Results: Stressed subjects treated with placebo were slower in learning the week 8 Altered Task and had lower neurogenesis rates than non-stressed animals and Stressed subjects given drug (Study 1). Synaptic activation of mature hippocampal neurons inversely correlated with Altered-PAT performance and with neurogenesis rates (Study 2)., Conclusions: Increasing neurogenesis enhances acquisition of novel experiences possibly by suppressing activation of mature hippocampal neurons that mediate established, conflicting memories. Therefore, antidepressants may improve mood by stimulating new hippocampal neurogenesis that facilitate detection of positive experiences while suppressing interference from recurring depressogenic thought patterns.

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 naïve 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., (© 2013 Wiley Periodicals, Inc.)

Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n=7) or non-remitters (n=6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21)=6.55, p=0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final-baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r=0.81, p=0.002], with no significant association in healthy subjects [Fisher r-to-z p=0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman=0.62, p=0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ's and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.

Epigenetic marks (e.g., DNA 5-methylcytosine [5mC] content or CpG methylation) within specific gene regulatory regions have been demonstrated to play diverse roles in stress adaptation and resulting health trajectories following early adversity. Yet the developmental programming of the vast majority of the epigenome has not yet been characterized, and its role in the impact of early stress largely unknown. In the present study, we investigated the relationships among early life stress, whole-epigenome and candidate stress pathway gene (serotonin transporter, 5-HTT) methylation patterns, and adult behavioral stress adaptation in a non-human primate model. Early in life, experimental variable foraging demand (VFD) stress or control conditions were administered to two groups each of 10 female bonnet macaques (Macaca radiata) and their mothers. As adults (3-13 years of age), these females were assessed for behavioral adaptation to stress across four conditions of increasing intensity. Blood DNA 5-HTT 5mC status was determined using sodium bisulfite pyrosequencing and total 5mC content was determined using ELISA. Neither stress reactivity nor DNA methylation differed based on early life stress. However, we found that both greater 5-HTT and whole-genome 5mC was associated with enhanced behavioral stress reactivity following early life stress, but not control conditions. Therefore, regardless of developmental origin, greater DNA methylation conferred a genomic background of "risk" in the context of early stress. We suggest that this may arise from constrained plasticity in gene expression needed for stress adaptation early in development. This risk may have wider implications for psychological and physical stress adaptation and health., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls., Methods: Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators., Results: Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right>left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right>left shift in hippocampal NAA concentrations, controlling for age and denominator., Conclusion: Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels., Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation., Conclusion: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

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 3 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 (G×E) interaction., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM.

Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010), but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX), and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2), but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein). This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA)-an amino acid considered reflective of neuronal density/functional integrity-using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N=10) or control rearing conditions (N=9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC. We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter. VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter. Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

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 ((1)H 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 ( 1)H 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

The role of the prefrontal cortex as an executive oversight of posterior brain regions raises the question of the extent to which the anterior regions of the brain interconnect with the posterior regions. The aim of this study is to test the complexity of rostral white matter tracts, which connect anterior and posterior brain regions, in comparison to caudal white matter tracts and the corpus callosum. Diffusion tensor imaging (DTI) is a modality that measures fractional anisotropy (FA). Higher white matter complexity could result in a decrease of FA, possibly through denser intersection of fiber tracts. DTI was used to determine regional FA in 9 healthy bonnet macaques (Macaca radiata). Four regions of interest were included: anterior and posterior limbs of the internal capsule, the occipital lobe white matter, and the corpus callosum. FA of the anterior limbs of the internal capsule was lowest compared to all other regions of interest (Newman-Keuls (N-K); p<0.0001), whereas FA of the corpus callosum was highest (N-K; p<0.0001). The posterior limbs of the internal capsule and the occipital white matter were not distinguishable but exhibited intermediate FA in comparison to the former (N-K; p<0.0001) and the latter (N-K; p<0.0001). The current study demonstrates that FA, a measure of white matter complexity, can vary markedly as a function of region of interest. Moreover, validation of these findings using neurohistological studies and replication in human samples appears warranted., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

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 (50mM) 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.

Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T(1)-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging ((1)H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ. Mean lateral ventricular lactate concentrations measured by (1)H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate. CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.