Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo

Background: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy (1H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect.

Objective: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo.

Methods: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo-inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership.

Results: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels.

Conclusion: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD.

Associations between early adrenarche, affective brain function and mental health in children

Early timing of adrenarche, associated with relatively high levels of Dehydroepiandrosterone (DHEA) in children, has been associated with mental health and behavioral problems. However, little is known about effects of adreneracheal timing on brain function. The aim of this study was to investigate the effects of early adrenarche (defined by high DHEA levels independent of age) on affective brain function and symptoms of psychopathology in late childhood (N = 83, 43 females, M age 9.53 years, s.d. 0.34 years). Results showed that higher DHEA levels were associated with decreased affect-related brain activity (i) in the mid-cingulate cortex in the whole sample, and (ii) in a number of cortical and subcortical regions in female but not male children. Higher DHEA levels were also associated with increased externalizing symptoms in females, an association that was partly mediated by posterior insula activation to happy facial expressions. These results suggest that timing of adrenarche is an important moderator of affect-related brain function, and that this may be one mechanism linking early adrenarche to psychopathology.

Increased premotor cortex activation in high functioning autism during action observation

The mirror neuron (MN) hypothesis of autism has received considerable attention, but to date has produced inconsistent findings. Using functional MRI, participants with high functioning autism or Asperger's syndrome were compared to typically developing individuals (n=12 in each group). Participants passively observed hand gestures that included waving, pointing, and grasping. Concerning the MN network, both groups activated similar regions including prefrontal, inferior parietal and superior temporal regions, with the autism group demonstrating significantly greater activation in the dorsal premotor cortex. Concerning other regions, participants with autism demonstrated increased activity in the anterior cingulate and medial frontal gyrus, and reduced activation in calcarine, cuneus, and middle temporal gyrus. These results suggest that during observation of hand gestures, frontal cortex activation is affected in autism, which we suggest may be linked to abnormal functioning of the MN system.

Association between serotonin transporter genotype, brain structure and adolescent onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13–19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy

Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research.

Brain substrates of social decision-making in dual diagnosis: cocaine dependence and personality disorders

Cocaine dependence frequently co-occurs with personality disorders, leading to increased interpersonal problems and greater burden of disease. Personality disorders are characterised by patterns of thinking and feeling that divert from social expectations. However, the comorbidity between cocaine dependence and personality disorders has not been substantiated by measures of brain activation during social decision-making. We applied functional magnetic resonance imaging to compare brain activations evoked by a social decision-making task-the Ultimatum Game-in 24 cocaine dependents with personality disorders (CDPD), 19 cocaine dependents without comorbidities and 19 healthy controls. In the Ultimatum Game participants had to accept or reject bids made by another player to split monetary stakes. Offers varied in fairness (in fair offers the proposer shares ~50 percent of the money; in unfair offers the proposer shares <30 percent of the money), and participants were told that if they accept both players get the money, and if they reject both players lose it. We contrasted brain activations during unfair versus fair offers and accept versus reject choices. During evaluation of unfair offers CDPD displayed lower activation in the insula and the anterior cingulate cortex and higher activation in the lateral orbitofrontal cortex and superior frontal and temporal gyri. Frontal activations negatively correlated with emotion recognition. During rejection of offers CDPD displayed lower activation in the anterior cingulate cortex, striatum and midbrain. Dual diagnosis is linked to hypo-activation of the insula and anterior cingulate cortex and hyper-activation of frontal-temporal regions during social decision-making, which associates with poorer emotion recognition.

Fibromyalgia and bipolar disorder: emerging epidemiological associations and shared pathophysiology

Fibromyalgia (FM) is a prevalent disorder defined by the presence of chronic widespread pain in association with fatigue, sleep disturbances and cognitive dysfunction. Recent studies indicate that bipolar spectrum disorders frequently co-occur in individuals with FM. Furthermore, shared pathophysiological mechanisms anticipate remarkable phenomenological similarities between FM and BD. A comprehensive search of the English literature was carried out in the Pubmed/MEDLINE database through May 10th, 2015 to identify unique references pertaining to the epidemiology and shared pathophysiology between FM and bipolar disorder (BD). Overlapping neural circuits may underpin parallel clinical manifestations of both disorders. Fibromyalgia and BD are both characterized by functional abnormalities in the hypothalamic-pituitary-adrenal axis, higher levels of inflammatory mediators, oxidative and nitrosative stress as well as mitochondrial dysfunction. An over-activation of the kynurenine pathway in both illnesses drives tryptophan away from the production of serotonin and melatonin, leading to affective symptoms, circadian rhythm disturbances and abnormalities in pain processing. In addition, both disorders are associated with impaired neuroplasticity (e.g., altered brain-derived neurotrophic factor signaling). The recognition of the symptomatic and pathophysiological overlapping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.

Cocaine-specific neuroplasticity in the ventral striatum network is linked to delay discounting and drug relapse

AIMS: To contrast functional connectivity on ventral and dorsal striatum networks in cocaine dependence relative to pathological gambling, via a resting-state functional connectivity approach; and to determine the association between cocaine dependence-related neuroadaptations indexed by functional connectivity and impulsivity, compulsivity and drug relapse. DESIGN: Cross-sectional study of 20 individuals with cocaine dependence (CD), 19 individuals with pathological gambling (PG) and 21 healthy controls (HC), and a prospective cohort study of 20 CD followed-up for 12 weeks to measure drug relapse. SETTING AND PARTICIPANTS: CD and PG were recruited through consecutive admissions to a public clinic specialized in substance addiction treatment (Centro Provincial de Drogodependencias) and a public clinic specialized in gambling treatment (AGRAJER), respectively; HC were recruited through community advertisement in the same area in Granada (Spain). MEASUREMENTS: Seed-based functional connectivity in the ventral striatum (ventral caudate and ventral putamen) and dorsal striatum (dorsal caudate and dorsal putamen), the Kirby delay-discounting questionnaire, the reversal-learning task and a dichotomous measure of cocaine relapse indicated with self-report and urine tests. FINDINGS: CD relative to PG exhibit enhanced connectivity between the ventral caudate seed and subgenual anterior cingulate cortex, the ventral putamen seed and dorsomedial pre-frontal cortex and the dorsal putamen seed and insula (P≤0.001, kE=108). Connectivity between the ventral caudate seed and subgenual anterior cingulate cortex is associated with steeper delay discounting (P≤0.001, kE=108) and cocaine relapse (P≤0.005, kE=34). CONCLUSIONS: Cocaine dependence-related neuroadaptations in the ventral striatum of the brain network are associated with increased impulsivity and higher rate of cocaine relapse.

Neural correlates of impaired self-awareness of apathy, disinhibition and dysexecutive deficits in cocaine-dependent individuals

Cocaine addiction is characterized by impaired self-awareness about cognitive and motivational deficits, leading to poor treatment outcomes. However, there is still limited understanding of the neurophysiological underpinnings of this impairment. We aimed to establish if impaired self-awareness is underpinned by brain structural phenotypes among cocaine-dependent individuals (CDI). Sixty-five CDI and 65 designated informants completed the Frontal Systems Behavior Scale, and a subsample of 40 CDI were scanned via magnetic resonance imaging. We applied multiple regression models to establish the association between levels of self-awareness indexed by Frontal Systems Behavior Scale's discrepancy scores (i.e. informant ratings minus self-reports of apathy, disinhibition and dysexecutive deficits) and gray matter volumes indexed by magnetic resonance imaging voxel-based measures within five brain regions of interest: anterior cingulate cortex, orbitofrontal cortex (OFC), striatum, insula and dorsolateral prefrontal cortex (DLPFC). We also examined the neural underpinnings of underestimation versus overestimation of deficits, by splitting the CDI group according to the positive or negative value of their discrepancy scores. We found that poorer self-awareness of apathy deficits was associated with greater gray matter volume in the dorsal striatum, and poorer self-awareness of disinhibition deficits was associated with greater gray matter volume in the OFC in the whole sample. More underestimation and more overestimation of executive deficits were linked to lower DLPFC volume. We show that impaired self-awareness of cognitive and motivational deficits in cocaine addiction has a neural underpinning, implicating striatum, OFC and DLPFC structural phenotypes.

Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex

High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200μA; 90μs) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIα/β), glycogen synthase kinase 3 (GSK3α/β) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100μg/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIα/β and GSK3α/β significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIα/β, GSK3α/β, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIα/β, and GSK3α/β in the LHb together with the downregulation of CaMKIIα/β, GSK3α/β, and AMPK in the IL, contribute to the antidepressant actions of DBS.

Examination of EMG normalisation methods for the study of the posterior and posterolateral neck muscles in healthy controls

The purpose of this study was to examine the reliability of normalisation methods used in the study of the posterior and posterolateral neck muscles in a group of healthy controls. Six asymptomatic male subjects performed a total of 12 maximum voluntary isometric contractions (MVIC) and 60%-submaximal isometric contractions (60%-MVIC) against the torque arm of an isokinetic dynamometer whilst surface and intramuscular electromyography (EMG) was recorded unilaterally from representative posterior and posterolateral locations. Reliability was calculated using intra-class correlation coefficient (ICC), relative standard error of measurement (%SEM) and relative coefficient of variation (%CV). Maximal torque output was found to be highly reliable in the directions of extension and right lateral bending when the first of three MVIC contractions was excluded. When averaged across contraction direction, high reliability was found for both surface (MVIC: ICC = 0.986, %SEM = 7.5, %CV = 9.2; 60%-MVIC: ICC = 0.975, %SEM = 10, %CV = 13.7) and intramuscular (MVIC: ICC = 0.910, %SEM = 20, %CV = 19.1; 60%-MVIC: ICC = 0.952, %SEM = 16.5, %CV = 13.5) electrodes. Intramuscular electrodes displayed the least reliability in right lateral bending. The use of visual feedback markedly increased the reliability of 60%-MVIC contractions.

Cerebral cortex : an MRI-based study of volume and variance with age and sex

The aim of the present study was to examine quantitative differences in lobar cerebral cortical volumes in a healthy adult population. Quantitative volumetric MRI of whole brain, cerebral and cerebellar volumes was performed in a cross-sectional analysis of 97 normal volunteers, with segmented frontal, temporal, parietal and occipital cortical volumes measured in a subgroup of 60 subjects, 30 male and 30 female, matched for age and sex. The right cerebral hemisphere was larger than the left across the study group with a small (<1%) but significant difference in symmetry (P < 0.001). No difference was found between volumes of right and left cerebellar hemispheres. Rightward cerebral cortical asymmetry (right larger than left) was found to be significant across all lobes except parietal. Males had greater cerebral, cerebellar and cerebral cortical lobar volumes than females. Larger male cerebral cortical volumes were seen in all lobes except for left parietal. Females had greater left parietal to left cerebral hemisphere and smaller left temporal to left cerebral hemisphere ratios. There was a mild reduction in cerebral volumes with age, more marked in males. This study confirms and augments past work indicating underlying structural asymmetries in the human brain, and provides further evidence that brain structures in humans are differentially sensitive to the effects of both age and sex.

Effects of lifetime loading history on cortical bone density and its distribution in middle-aged and older men

We have reported previously that long-term participation of weight-bearing exercise is associated with increased QCT-derived cortical bone size and strength in middle-aged and older men, but not whole bone cortical volumetric BMD. However, since bone remodeling and the distribution of loading-induced strains within cortical bone are non-uniform, the aim of this study was to examine the effects of lifetime loading history on cortical bone mass distribution and bone shape in healthy community dwelling middle-aged and older men. We used QCT to assess mid-femur and mid-tibia angular bone mass distribution around its center (polar distribution), the bone density distribution through the cortex (radial distribution), and the ratio between the maximum and minimum moments of inertia (I_max/I_min ratio) in 281 men aged 50 to 79 years. Current (> 50 years) and past (13–50 years) sport and leisure time activity was assessed by questionnaire to calculate an osteogenic index (OI) during adolescence and adulthood. All men were then categorized into a high (H) or low/non impact (L) group according to their OI scores in each period. Three contrasting groups were then formed to reflect weight-bearing impact categories during adolescence and then adulthood: H–H, H–L and L–L. For polar bone mass distribution, bone deposition in the anterolateral, medial and posterior cortices were 6–10% greater at the mid-femur and 9–24% greater at mid-tibia in men in the highest compared to lowest tertile of lifetime loading (p < 0.01– < 0.001). When comparing the influence of contrasting loading history during adolescence and adulthood, there was a graded response between the groups in the distribution of bone mass at the anterior-lateral and posterior regions of the mid-tibia (H–H > H–L > L–L). For radial bone density distribution, there were no statistically significant effects of loading at the mid-femur, but a greater lifetime OI was associated with a non-significant 10–15% greater bone density near the endocortical region of the mid-tibia. In conclusion, a greater lifetime loading history was associated with region-specific adaptations in cortical bone density.