•Higher circulating sCD25 level is associated with greater prefrontal Glx/GABA+.•Elevated Glx/GABA+ is linked to pain catastrophizing and evaluative pain ratings.•Elevated Glx/GABA+ is also related ...to anxiodepressive symptoms in chronic pain.•The sCD25-Glx/GABA+ interaction may contribute to pain catastrophizing.
Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance. In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA+ (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC. We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA+. Greater prefrontal Glx/GABA+ was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA+ on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing. Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.
Rationale
Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment.
Objective
This randomized, double-blind, placebo-controlled, incomplete-crossover ...study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males.
Methods
Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements.
Results
The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen’s effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated.
Conclusions
Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.
Anticipating future outcomes is central to decision making and a failure to consider long-term consequences may lead to impulsive choices. Adolescence is a vulnerable period during which ...underdeveloped prefrontal cortical systems may contribute to poor judgment, impulsive choices, and substance abuse. Conversely, substance abuse during this period may alter neural systems involved in decision making and lead to greater impulsivity. Although a broad neural network which supports decision making undergoes extensive change during adolescent development, one region that may be critical is the medial prefrontal cortex. Altered functional integrity of this region may be specifically related to reward perception, substance abuse, and dependence. In the present investigation, we acquired structural magnetic resonance images (MRI), using a 3T Siemens Trio scanner, from 18 cannabis abusing adolescents (CA; 2 female and 16 male subjects; mean age, 17.7 years; range 16-19 years), and 18 healthy controls (HC; 6 female and 12 male subjects; mean age, 17.2 years; range 16-19 years). In order to measure medial orbital prefrontal cortex (moPFC) morphology related to substance abuse and impulsivity, semi-automated cortical reconstruction and volumetric segmentation of MRIs was performed with FreeSurfer. Impulsivity was evaluated with the Barratt Impulsiveness Scale (BIS). Our results indicate that cannabis abusing adolescents have decreased right moPFC volume compared to controls, p = 0.01, d = 0.92, CI(0.95) = 0.21, 1.59. Cannabis abusing adolescents also show decreased future orientation, as indexed by the BIS non-planning subscale, when compared to controls, p = 0.01, d = 0.89, CI(0.95) = 0.23, 1.55. Moreover, total moPFC volume was positively correlated with age of first use r (18) = 0.49, p < 0.03, suggesting that alterations in this region may be related to initiation of cannabis use or that early initiation may lead to reduced moPFC volume.
Despite the high prevalence of obesity, eating disorders, and weight-related health problems in modernized cultures, the neural systems regulating human feeding remain poorly understood. Therefore, ...we applied functional magnetic resonance imaging (fMRI) to study the cerebral responses of 13 healthy normal-weight adult women as they viewed color photographs of food. The motivational salience of the stimuli was manipulated by presenting images from three categories: high-calorie foods, low-calorie foods, and nonedible dining-related utensils. Both food categories were associated with bilateral activation of the amygdala and ventromedial prefrontal cortex. High-calorie foods yielded significant activation within the medial and dorsolateral prefrontal cortex, thalamus, hypothalamus, corpus callosum, and cerebellum. Low-calorie foods yielded smaller regions of focal activation within medial orbitofrontal cortex; primary gustatory/somatosensory cortex; and superior, middle, and medial temporal regions. Findings suggest that the amygdala may be responsive to a general category of biologically relevant stimuli such as food, whereas separate ventromedial prefrontal systems may be activated depending on the perceived reward value or motivational salience of food stimuli.
Abstract Background An increasing body of evidence from neuropsychological and neuroimaging studies suggests that exposure to marijuana throughout adolescence disrupts key cortical maturation ...processes occurring during this developmental phase. GABA-modulating pharmacologic treatments that elevate brain GABA concentration recently have been shown to decrease withdrawal symptoms and improve executive functioning in marijuana-dependent adult subjects. The goal of this study was to investigate whether the lower ACC glutamate previously reported in adolescent chronic marijuana smokers is associated with lower ACC GABA levels. Methods Standard and metabolite-edited proton MRS data were acquired from adolescent marijuana users ( N = 13) and similarly aged non-using controls ( N = 16) using a clinical 3T MRI system. Results The adolescent marijuana-using cohort showed significantly lower ACC GABA levels (−22%, p = 0.03), which paralleled significantly lower ACC glutamate levels (−14%, p = 0.01). Importantly, the lower ACC GABA and glutamate levels detected in the adolescent cohort remained significant after controlling for age and sex. Conclusions The present spectroscopic findings support functional neuroimaging data documenting cingulate dysfunction in marijuana-dependent adolescents. Glutamatergic and GABAergic abnormalities potentially underlie cingulate dysfunction in adolescent chronic marijuana users, and the opportunity for testing suitable pharmacologic treatments with a non-invasive pharmacodynamic evaluation exists.
Aim
Increased oxidative stress in cerebral mitochondria may follow exposure to the systemic hypobaric hypoxia associated with residing at higher altitudes. Because mitochondrial dysfunction is ...implicated in bipolar disorder (BD) pathophysiology, this may impact the cerebral bioenergetics in BD. In this study, we evaluated the cerebral bioenergetics of BD and healthy control (HC) subjects at two sites, located at sea level and at moderate altitude.
Methods
Forty‐three veterans with BD and 33 HC veterans were recruited in Boston (n = 22) and Salt Lake City (SLC; n = 54). Levels of phosphocreatine, β nucleoside triphosphate (βNTP), inorganic phosphate, and pH over total phosphate (TP) were measured using phosphorus‐31 magnetic resonance spectroscopy in the following brain regions: anterior cingulate cortex and posterior occipital cortex, as well as bilateral prefrontal and occipitoparietal (OP) white matter (WM).
Results
A significant main effect of site was found in βNTP/TP (Boston > SLC) and phosphocreatine/TP (Boston < SLC) in most cortical and WM regions, and inorganic phosphate/TP (Boston < SLC) in OP regions. A main effect analysis of BD diagnosis demonstrated a lower pH in posterior occipital cortex and right OP WM and a lower βNTP/TP in right prefrontal WM in BD subjects, compared to HC subjects.
Conclusion
The study showed that there were cerebral bioenergetic differences in both BD and HC veteran participants at two different sites, which may be partly explained by altitude difference. Future studies are needed to replicate these results in order to elucidate the dysfunctional mitochondrial changes that occur in response to hypobaric hypoxia.
Objectives: An increased incidence in white matter abnormalities is among the most frequently reported brain change in patients with bipolar disorder. The objective of the present study was to ...examine white matter tract integrity, using diffusion tensor imaging (DTI), in bipolar patients and healthy comparison subjects.
Methods: Eleven DSM‐IV bipolar I patients and 10 healthy age‐ and sex‐matched controls were studied. DTI data were acquired on a 1.5 Tesla scanner. Fractional anisotropy (FA) and diffusivity (trace) were determined from axial images using region of interest (ROI) analyses. The ROIs were manually placed in the midline and forward projecting arms of the genu (anterior) and the midline of the splenium (posterior) of the corpus callosum.
Results: Bipolar patients had significantly higher FA in the midline of the genu compared with healthy controls. Regional white matter differences were also observed, with significantly lower FA in the genu than forward projecting regions in both groups and lower FA in the genu than the splenium in controls.
Conclusions: Diffusion tensor imaging revealed significant microstructural differences in the genu, as measured by elevated FA in bipolar patients compared with healthy controls. These preliminary findings further support the hypothesis that anomalous frontal brain mechanisms may be associated with bipolar disorder.
Previous functional neuroimaging studies have demonstrated that the amygdala activates in response to fearful faces presented below the threshold of conscious visual perception. Using a backward ...masking procedure similar to that of previous studies, we used functional magnetic resonance imaging (fMRI) to study the amygdala and anterior cingulate gyrus during preattentive presentations of sad and happy facial affect. Twelve healthy adult females underwent blood oxygen level dependent (BOLD) fMRI while viewing sad and happy faces, each presented for 20 ms and “masked” immediately by a neutral face for 100 ms. Masked happy faces were associated with significant bilateral activation within the anterior cingulate gyrus and amygdala, whereas masked sadness yielded only limited activation within the left anterior cingulate gyrus. In a direct comparison, masked happy faces yielded significantly greater activation in the anterior cingulate and amygdala relative to identically masked sad faces. Conjunction analysis showed that masked affect perception, regardless of emotional valence, was associated with greater activation within the left amygdala and left anterior cingulate. Findings suggest that the amygdala and anterior cingulate are important components of a network involved in detecting and discriminating affective information presented below the normal threshold of conscious visual perception.
During the past decade, the pediatric suicide rate has nearly tripled. Yet, little is known about suicide behavior (SB) in children. Identification of risk factors associated with SB during childhood ...may be critical to preventing future attempts. The purpose of this study was to examine the relationship between neurocognitive performance and suicide ideation (SI) in children.
The present study utilized baseline data from 11,875 participants in the Adolescent Brain Cognitive Development (ABCD) study, a longitudinal study that follows 9- and 10-year-old children through late adolescence to examine factors that influence developmental trajectories. Suicidality was assessed by the Kiddie Schedule for Affective Disorder and Schizophrenia (KSADS) suicide module completed by the parent. Neurocognitive ability was assessed using the NIH Toolbox Cognition measures administered to the youth.
Children with a history of SI reported by their parent or concordant parent and youth report of SI demonstrated lower performance on the NIH Toolbox Picture Sequence Memory Test compared to children without SI. The difference in performance on the memory task remained significant when including demographic characteristics, family history of suicide, and internalizing symptoms in the model as covariates.
To our knowledge, this is the first study to identify decreased episodic memory in children with SI. These findings are similar to results from adult and adolescent studies which have reported decreased memory performance among suicide attempters. Deficits in episodic memory may impact a child's ability to problem-solve and generate potential future outcomes, which may increase the risk for SB. Early identification of memory deficits in children may inform suicide prevention and intervention efforts.
Highlights
6% of parents and children reported a history of active suicide ideation in children.
Children with a history of suicide ideation had lower episodic memory performance.
Early identification of memory deficits may inform suicide intervention efforts.
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