Abstract The forced swim test (FST) is a behavioral test in rodents which was developed in 1978 by Porsolt and colleagues as a model for predicting the clinical efficacy of antidepressant drugs. A ...modified version of the FST added the classification of active behaviors into swimming and climbing, in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. The FST is now widely used in basic research and the pharmaceutical screening of potential antidepressant treatments. It is also one of the most commonly used tests to assess depressive-like behavior in animal models. Despite the simplicity and sensitivity of the FST procedure, important differences even in baseline immobility rates have been reported between different groups, which complicate the comparison of results across studies. In spite of several methodological papers and reviews published on the FST, the need still exists for clarification of factors which can influence the procedure. While most recent reviews have focused on antidepressant effects observed with the FST, this one considers the methodological aspects of the procedure, aiming to summarize issues beyond antidepressant action in the FST. The previously published literature is analyzed for factors which are known to influence animal behavior in the FST. These include biological factors, such as strain, age, body weight, gender and individual differences between animals; influence of preconditioning before the FST: handling, social isolation or enriched environment, food manipulations, various kinds of stress, endocrine manipulations and surgery; schedule and routes of treatment, dosage and type of the drugs as well as experimental design and laboratory environmental effects. Consideration of these factors in planning experiments may result in more consistent FST results.
Research into environmental factors associated with suicide has historically focused on meteorological variables. Recently, a heightened risk of suicide related to short-term exposure to airborne ...particulate matter was reported. Here, we examined the associations between short-term exposure to nitrogen dioxide, particulate matter, and sulfur dioxide and completed suicide in Salt Lake County, Utah (n = 1,546) from 2000 to 2010. We used a time-stratified case-crossover design to estimate adjusted odds ratios for the relationship between suicide and exposure to air pollutants on the day of the suicide and during the days preceding the suicide. We observed maximum heightened odds of suicide associated with interquartile-range increases in nitrogen dioxide during cumulative lag 3 (average of the 3 days preceding suicide; odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.04, 1.39) and fine particulate matter (diameter ≤2.5 μm) on lag day 2 (day 2 before suicide; OR = 1.05, 95% CI: 1.01, 1.10). Following stratification by season, an increased suicide risk was associated with exposure to nitrogen dioxide during the spring/fall transition period (OR = 1.35, 95% CI: 1.09, 1.66) and fine particulate matter in the spring (OR = 1.28, 95% CI: 1.01, 1.61) during cumulative lag 3. Findings of positive associations between air pollution and suicide appear to be consistent across study locations with vastly different meteorological, geographical, and cultural characteristics.
Childhood overweight/obesity has been associated with negative consequences related to brain function and may involve alterations in white matter pathways important for cognitive and emotional ...processing. Aerobic physical activity is a promising lifestyle factor that could restore white matter alterations. However, little is known about either regional white matter alterations in children with overweight/obesity or the effects of aerobic physical activity targeting the obesity-related brain alterations in children. Using a large-scale cross-sectional population-based dataset of US children aged 9 to 10 years (n = 8019), this study explored the associations between overweight/obesity and microstructure of limbic white matter tracts, and examined whether aerobic physical activity may reduce the overweight/obesity-related white matter alterations in children. The primary outcome measure was restriction spectrum imaging (RSI)-derived white matter microstructural integrity measures. The number of days in a week that children engaged in aerobic physical activity for at least 60 minutes per day was assessed. We found that females with overweight/obesity had lower measures of integrity of the fimbria-fornix, a major limbic-hippocampal white matter tract, than their lean peers, while this difference was not significant in males. We also found a positive relationship between the number of days of aerobic physical activity completed in a week and integrity measures of the fimbria-fornix in females with overweight/obesity. Our results provide cross-sectional evidence of sex-specific microstructural alteration in the fimbria-fornix in children with overweight/obesity and suggest that aerobic physical activity may play a role in reducing this alteration. Future work should examine the causal direction of the relationship between childhood overweight/obesity and brain alterations and evaluate potential interventions to validate the effects of aerobic physical activity on this relationship.
Abstract The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the ...DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x = − 2, y = 54, z = − 12; SZ: x =−2, y = 22, z = 18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition.
•Trauma exposure in veterans may be associated with lower GABA/H2O in the dorsal ACC.•Trauma exposure in veterans may be associated with lower glutamine/H2O in the dorsal ACC.•Dorsal ACC GABA/H2O and ...sleep problems were negatively correlated in the PTSD group.
Trauma-related diagnoses such as posttraumatic stress disorder (PTSD) are prevalent in veterans. The identification of mechanisms related to stress vulnerability and development of PTSD specifically in a veteran population may aid in the prevention of PTSD and identification of novel treatment targets.
Veterans with PTSD (n = 27), trauma-exposed veterans with no PTSD (TEC, n = 18) and non-trauma-exposed controls (NTEC, n = 28) underwent single-voxel proton (1H) magnetic resonance spectroscopy (MRS) at 3 Tesla in the dorsal anterior cingulate cortex (dACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence in addition to completing a clinical battery.
The PTSD and TEC groups demonstrated lower gamma-amino butyric acid (GABA)/H2O (p = 0.02) and glutamine (Gln)/H2O (p = 0.02) in the dACC as compared to the NTEC group. The PTSD group showed a trend towards higher Glu/GABA (p = 0.053) than the NTEC group. Further, GABA/H2O in the dACC correlated negatively with sleep symptoms in the PTSD group (p = 0.03) but not in the TEC and NTEC groups.
Cross-sectional study design, concomitant medications, single voxel measurement as opposed to global changes, absence of measure of childhood or severity of trauma and objective sleep measures, female participants not matched for menstrual cycle phase.
Exposure to trauma in veterans may be associated with lower GABA/H2O and Gln/H2O in the dACC, suggesting disruption in the GABA-Gln-glutamate cycle. Further, altered Glu/GABA in the dACC in the PTSD group may indicate an excitatory-inhibitory imbalance. Further, lower GABA/H2O in the ACC was associated with poor sleep in the PTSD group. Treatments that restore GABAergic balance may be particularly effective in reducing sleep symptoms in PTSD.
Bupropion has been used in the treatment of patients with substance dependence based on its weak inhibition of dopamine and norepinephrine reuptake. We hypothesized that 6 weeks of bupropion ...sustained release (SR) treatment would decrease craving for Internet game play as well as video game cue-induced brain activity in patients with Internet video game addiction (IAG). Eleven subjects who met criteria for IAG, playing StarCraft (>30 hr/week), and eight healthy comparison subjects (HC) who had experience playing StarCraft (<3 days/week and <1 hr/day). At baseline and at the end of 6 weeks of bupropion SR treatment, brain activity in response to StarCraft cue presentation was assessed using 1.5 Tesla functional MRI. In addition, symptoms of depression, craving for playing the game, and the severity of Internet addiction were evaluated by Beck Depression Inventory, self-report of craving on a 7-point visual analogue scale, and Young's Internet Addiction Scale, respectively. In response to game cues, IAG showed higher brain activation in left occipital lobe cuneus, left dorsolateral prefrontal cortex, and left parahippocampal gyrus than HC. After a 6 week period of bupropion SR, craving for Internet video game play, total game play time, and cue-induced brain activity in dorsolateral prefrontal cortex were decreased in the IAG. We suggest that bupropion SR may change craving and brain activity in ways that are similar to those observed in individuals with substance abuse or dependence.
•The mechanisms underlying conditioned pain modulation are multifaceted.•During cold, application-specific cerebral activations were found in precuneus and left insula.•Conditioned suppression of ...insula test-pain response was related to hypoalgesia.•The insular changes are predicted by early prefrontal response to cold conditioning.•Smaller early prefrontal response predicts heterotopic noxious hyperalgesia.
The mechanisms underlying conditioned pain modulation (CPM) are multifaceted. We searched for a link between individual differences in prefrontal cortex activity during multi-trial heterotopic noxious cold conditioning and modulation of the cerebral response to phasic heat pain.
In 24 healthy female subjects, we conditioned laser heat stimuli to the left hand by applying alternatively ice-cold or lukewarm compresses to the right foot. We compared pain ratings with cerebral fMRI BOLD responses. We also analyzed the relation between CPM and BOLD changes produced by the heterotopic cold conditioning itself, as well as the impact of anxiety and habituation of cold-pain ratings.
Specific cerebral activation was identified in precuneus and left posterior insula/SII, respectively, during early and sustained phases of cold application. During cold conditioning, laser pain decreased (n=7), increased (n=10) or stayed unchanged (n=7). At the individual level, the psychophysical effect was directly proportional to the cold-induced modulation of the laser-induced BOLD response in left posterior insula/SII. The latter correlated with the BOLD response recorded 80s earlier during the initial 10-s phase of cold application in anterior cingulate, orbitofrontal and lateral prefrontal cortices.
High anxiety and habituation of cold pain were associated with greater laser heat-induced pain during heterotopic cold stimulation. The habituation was also linked to the early cold-induced orbitofrontal responses.
We conclude that individual differences in conditioned pain modulation are related to different levels of prefrontal cortical activation by the early part of the conditioning stimulus, possibly due to different levels in trait anxiety.
As adjuvant therapy for enhancing the effects of stimulants and thereby minimizing medication doses, we hypothesized that aerobic exercise might be an effective adjunctive therapy for enhancing the ...effects of methylphenidate on the clinical symptoms, cognitive function, and brain activity of adolescents with attention deficit hyperactivity disorder (ADHD).
Thirty-five adolescents with ADHD were randomly assigned to one of two groups in a 1/1 ratio; methylphenidate treatment + 6-wk exercise (sports-ADHD) or methylphenidate treatment + 6-wk education (edu-ADHD). At baseline and after 6 wk of treatment, symptoms of ADHD, cognitive function, and brain activity were evaluated using the Dupaul attention deficit hyperactivity disorder rating scale--Korean version (K-ARS), the Wisconsin Card Sorting Test, and 3-T functional magnetic resonance imaging, respectively.
The K-ARS total score and perseverative errors in the sports-ADHD group decreased compared with those in the edu-ADHD group. After the 6-wk treatment period, the mean β value of the right frontal lobe in the sports-ADHD group increased compared with that in the edu-ADHD group. The mean β value of the right temporal lobe in the sports-ADHD group decreased. However, the mean β value of the right temporal lobe in the edu-ADHD group did not change. The change in activity within the right prefrontal cortex in all adolescents with ADHD was negatively correlated with the change in K-ARS scores and perseverative errors.
The current results indicate that aerobic exercise increased the effectiveness of methylphenidate on clinical symptoms, perseverative errors, and brain activity within the right frontal and temporal cortices in response to the Wisconsin card sorting test stimulation.
The focus of this review is to provide a synthesis of the current literature on the role of brain choline, as measured by proton magnetic resonance spectroscopy (1H-MRS), in major depressive disorder ...(MDD). The most recent 1H-MRS literature review took place over 10 years ago and, reflecting the high level of research on this topic, much has been learned since then. Higher brain choline levels have been linked to an increase in depression, and a cholinergic model for MDD development has been postulated. However, current 1H-MRS studies have been inconclusive regarding the role of choline in depression. Data from eighty-six peer-reviewed studies were analyzed for a random-effects model meta-analysis. Two significant findings are reported. Papers that did not report segmentation had a significant, moderate effect size. Higher choline concentrations in the frontal lobe were found in depressed patients, both in those who responded to treatment and those who did not, after treatment with psychiatric medication, repetitive transcranial magnetic stimulation, or electroconvulsive therapy. Findings from this review may add to existing information regarding the role of brain choline in MDD. This may provide a future target for treatment and drug development. It also may serve as a biomarker for treatment progress.
•In proton magnetic resonance spectroscopy, choline may vary by voxel tissue content.•In proton magnetic resonance spectroscopy, measured choline concentrations may be dependent on the type of measurement used.•Increased choline in the frontal lobe is associated with depression treatment.
After participating in this activity, learners should be better able to:• Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide• ...Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan.
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