Unraveling the link between childhood maltreatment and depression: Insights from the role of ventral striatum and middle cingulate cortex in hedonic experience and emotion regulation.

Childhood maltreatment is an established risk factor for psychopathology. However, it remains unclear how childhood traumatic events relate to mental health problems and how the brain is involved. This study examined the serial mediation effect of brain morphological alterations and emotion-/reward-related functions on linking the relationship from maltreatment to depression. We recruited 156 healthy adolescents and young adults and an additional sample of 31 adolescents with major depressive disorder for assessment of childhood maltreatment, depressive symptoms, cognitive reappraisal and anticipatory/consummatory pleasure. Structural MRI data were acquired to identify maltreatment-related cortical and subcortical morphological differences. The mediation models suggested that emotional maltreatment of abuse and neglect, was respectively associated with increased gray matter volume in the ventral striatum and greater thickness in the middle cingulate cortex. These structural alterations were further related to reduced anticipatory pleasure and disrupted cognitive reappraisal, which contributed to more severe depressive symptoms among healthy individuals. The above mediating effects were not replicated in our clinical group partly due to the small sample size. Preventative interventions can target emotional and reward systems to foster resilience and reduce the likelihood of future psychiatric disorders among individuals with a history of maltreatment.

A Sensitive LC-MS/MS Method for the Determination of Afatinib in Human Plasma and Its Application to a Bioequivalence Study.

A high performance liquid chromatography-tandem mass spectrometry assay for the determination of afatinib (AFT) in human plasma was established. A simple sample preparation of protein precipitation was used and separation was achieved on a C18 column by the gradient mixture of mobile Phase A of water (containing 0.1% ammonia) and the mobile Phase B of acetonitrile and water (V:V = 95:5, containing 0.2% ammonia). The multiple reaction monitoring mode was used to monitor the precursor-to-production transitions of m/z 486.2 â†’ m/z 371.4 for AFT and m/z 492.2 â†’ m/z 371.3 for AFT-d6 (internal standard) at positive ionization mode. The calibration curve ranged from 0.100 to 25.0 ng·mL-1 and the correlation coefficient was greater than 0.99. The intra- and inter-batch precision was less than or equal to 10.0%. Accuracy determined at four concentrations was in the range of 92.3-103.3%. In summary, our method was sensitive, simple and reliable for the quantification of AFT and was successfully applied to a bioequivalence study.

Mouse strain-specific responses of mitochondrial respiratory function and cardiac hypertrophy to isoproterenol treatment.

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O2 consumption at state III with either complex I substrates or complex II substrate, compared with those from FVB/nJ mice. ISO treatment did not affect mitochondrial respiratory control rate (RCR), but significantly suppressed the ADP/O ratio generated from the complex II substrate in both strains. The ADP/O ratio generated from the complex I substrates in A/J mice declined by 50% after ISO treatment, whereas FVB/nJ mice were not affected. These results suggest that, compared with FVB/nJ mice, A/J mice possesses a poor integrity of mitochondrial respiratory chain that might contribute to its vulnerability to ISO-induced cardiac hypertrophy.

Simultaneous determination and determination of sildenafil and its active metabolite in human plasma using LC-MS/MS method.

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.

A trend toward smaller optical angles and medial-ocular distance in schizophrenia spectrum, but not in bipolar and major depressive disorders.

Minor physical anomalies (MPAs) are subtle signs of fetal developmental abnormalities that have been considered to be among the most replicated risk markers for schizophrenia-spectrum disorders. However, quantitative approaches are needed to measure craniofacial MPAs. The present study adopted an imaging-based quantitative approach to examine craniofacial MPAs across the spectrum of schizophrenia and affective disorders, to address their sensitivity and specificity. We sampled 31 patients with schizophrenia, 30 of their unaffected relatives, and 30 individuals with schizotypal personality traits, as well as 37 non-schizotypal controls. We also examined 17 patients with bipolar disorder and 19 patients with major depressive disorder. Five craniofacial MPAs were measured on anterior-posterior commissure-aligned T1-weighted images of an individual's native brain space: medial-ocular distance, lateral-ocular distance, optical angle, maximum skull length, and skull-base width. Compared to non-schizotypal controls, patients with schizophrenia and their relatives showed a trend toward having smaller optical angles and medial-ocular distance, while no difference was found in patients with bipolar or major depressive disorders, suggesting some degree of specificity to schizophrenia. Our approach may benefit future research on craniofacial MPAs as risk markers for schizophrenia-spectrum disorders, and may eventually be useful in strategies to enhance risk stratification using multiple risk markers.

Multivariate Neural Representations of Value during Reward Anticipation and Consummation in the Human Orbitofrontal Cortex.

The role of the orbitofrontal cortex (OFC) in value processing is a focus of research. Conventional imaging analysis, where smoothing and averaging are employed, may not be sufficiently sensitive in studying the OFC, which has heterogeneous anatomical structures and functions. In this study, we employed representational similarity analysis (RSA) to reveal the multi-voxel fMRI patterns in the OFC associated with value processing during the anticipatory and the consummatory phases. We found that multi-voxel activation patterns in the OFC encoded magnitude and partial valence information (win vs. loss) but not outcome (favourable vs. unfavourable) during reward consummation. Furthermore, the lateral OFC rather than the medial OFC encoded loss information. Also, we found that OFC encoded values in a similar way to the ventral striatum (VS) or the anterior insula (AI) during reward anticipation regardless of motivated response and to the medial prefrontal cortex (MPFC) and the VS in reward consummation. In contrast, univariate analysis did not show changes of activation in the OFC. These findings suggest an important role of the OFC in value processing during reward anticipation and consummation.

Differential mesolimbic and prefrontal alterations during reward anticipation and consummation in positive and negative schizotypy.

Schizotypy is associated with anhedonia. However, previous findings on the neural substrates of anhedonia in schizotypy are mixed. In the present study, we measured the neural substrates associated with reward anticipation and consummation in positive and negative schizotypy using functional MRI. The Monetary Incentive Delay task was administered to 33 individuals with schizotypy (18 positive schizotypy (PS),15 negative schizotypy (NS)) and 22 healthy controls. Comparison between schizotypy individuals and controls were performed using two-sample T tests for contrast images involving gain versus non-gain anticipation condition and gain versus non-gain consummation condition. Multiple comparisons were corrected using Monte Carlo Simulation correction of p<.05. The results showed no significant difference in brain activity between controls and schizotypy individuals as a whole during gain anticipation or consummation. However, during the consummatory phase, NS individuals rather than PS individuals showed diminished left amygdala and left putamen activity compared with controls. We observed significantly weaker activation at the left ventral striatum during gain anticipation in NS individuals compared with controls. PS individuals, however, exhibited enhanced right ventral lateral prefrontal activity. These findings suggest that different dimensions of schizotypy may be underlied by different neural dysfunctions in reward anticipation and consummation.

Production of Bioactive Recombinant Bovine Chymosin in Tobacco Plants.

Chymosin (also known as rennin) plays an essential role in the coagulation of milk in the cheese industry. Chymosin is traditionally extracted from the rumen of calves and is of high cost. Here, we present an alternative method to producing bovine chymosin from transgenic tobacco plants. The CYM gene, which encodes a preprochymosin from bovine, was introduced into the tobacco nuclear genome under control of the viral 35S cauliflower mosaic promoter. The integration and transcription of the foreign gene were confirmed with Southern blotting and reverse transcription PCR (RT-PCR) analyses, respectively. Immunoblotting analyses were performed to demonstrate expression of chymosin, and the expression level was quantified by enzyme-linked immunosorbent assay (ELISA). The results indicated recombinant bovine chymosin was successfully expressed at an average level of 83.5 ng/g fresh weight, which is 0.52% of the total soluble protein. The tobacco-derived chymosin exhibited similar native milk coagulation bioactivity as the commercial product extracted from bovine rumen.

Neural evidence for the use of digit-image mnemonic in a superior memorist: an fMRI study.

Some superior memorists demonstrated exceptional memory for reciting a large body of information. The underlying neural correlates, however, are seldom addressed. C.L., the current holder of Guinness World Record for reciting 67,890 digits in π, participated in this functional magnetic resonance imaging (fMRI) study. Thirteen participants without any mnemonics training were included as controls. Our previous studies suggested that C.L. used a digit-image mnemonic in studying and recalling lists of digits, namely associating 2-digit groups of "00" to "99" with images and generating vivid stories out of them (Hu et al., 2009). Thus, 2-digit condition was included, with 1-digit numbers and letters as control conditions. We hypothesized that 2-digit condition in C.L. should elicit the strongest activity in the brain regions which are associated with his mnemonic. Functional MRI results revealed that bilateral frontal poles (FPs, BA10), left superior parietal lobule (SPL), left premotor cortex (PMC), and left dorsolateral prefrontal cortex (DLPFC), were more engaged in both the study and recall phase of 2-digit condition for C.L. relative to controls. Moreover, the left middle/inferior frontal gyri (M/IFG) and intraparietal sulci (IPS) were less engaged in the study phase of 2-digit condition for C.L. (vs. controls). These results suggested that C.L. relied more on brain regions that are associated with episodic memory other than verbal rehearsal while he used his mnemonic strategies. This study supported theoretical accounts of restructured cognitive mechanisms for the acquisition of superior memory performance.

Abnormal functional connectivity of the amygdala-based network in resting-state FMRI in adolescents with generalized anxiety disorder.

BACKGROUND: We aimed to investigate the disruptions of functional connectivity of amygdala-based networks in adolescents with untreated generalized anxiety disorder (GAD). MATERIAL AND METHODS: A total of 26 adolescents with first-episode GAD and 20 normal age-matched volunteers underwent resting-state and T1 functional magnetic resonance imaging (fMRI). We analyzed the correlation of fMRI signal fluctuation between the amygdala and other brain regions. The variation of amygdala-based functional connectivity and its correlation with anxiety severity were investigated. RESULTS: Decreased functional connectivity was found between the left amygdala and left dorsolateral prefrontal cortex. An increased right amygdala functional connectivity with right posterior and anterior lobes of the cerebellum, insula, superior temporal gyrus, putamen, and right amygdala were found in our study. Negative correlations between GAD scores and functional connectivity of the right amygdala with the cerebellum were also observed in the GAD adolescents. CONCLUSIONS: Adolescents with GAD have abnormalities in brain regions associated with the emotional processing pathways.

Neurobiological changes of schizotypy: evidence from both volume-based morphometric analysis and resting-state functional connectivity.

The current study sought to examine the underlying brain changes in individuals with high schizotypy by integrating networks derived from brain structural and functional imaging. Individuals with high schizotypy (n = 35) and low schizotypy (n = 34) controls were screened using the Schizotypal Personality Questionnaire and underwent brain structural and resting-state functional magnetic resonance imaging on a 3T scanner. Voxel-based morphometric analysis and graph theory-based functional network analysis were conducted. Individuals with high schizotypy showed reduced gray matter (GM) density in the insula and the dorsolateral prefrontal gyrus. The graph theoretical analysis showed that individuals with high schizotypy showed similar global properties in their functional networks as low schizotypy individuals. Several hubs of the functional network were identified in both groups, including the insula, the lingual gyrus, the postcentral gyrus, and the rolandic operculum. More hubs in the frontal lobe and fewer hubs in the occipital lobe were identified in individuals with high schizotypy. By comparing the functional connectivity between clusters with abnormal GM density and the whole brain, individuals with high schizotypy showed weaker functional connectivity between the left insula and the putamen, but stronger connectivity between the cerebellum and the medial frontal gyrus. Taken together, our findings suggest that individuals with high schizotypy present changes in terms of GM and resting-state functional connectivity, especially in the frontal lobe.

Acute aerobic exercise increases cortical activity during working memory: a functional MRI study in female college students.

There is increasing evidence that acute aerobic exercise is associated with improved cognitive function. However, neural correlates of its cognitive plasticity remain largely unknown. The present study examined the effect of a session of acute aerobic exercise on working memory task-evoked brain activity as well as task performance. A within-subjects design with a counterbalanced order was employed. Fifteen young female participants (M = 19.56, SD = 0.81) were scanned using functional magnetic resonance imaging while performing a working memory task, the N-back task, both following an acute exercise session with 20 minutes of moderate intensity and a control rest session. Although an acute session of exercise did not improve behavioral performance, we observed that it had a significant impact on brain activity during the 2-back condition of the N-back task. Specifically, acute exercise induced increased brain activation in the right middle prefrontal gyrus, the right lingual gyrus, and the left fusiform gyrus as well as deactivations in the anterior cingulate cortexes, the left inferior frontal gyrus, and the right paracentral lobule. Despite the lack of an effect on behavioral measures, significant changes after acute exercise with activation of the prefrontal and occipital cortexes and deactivation of the anterior cingulate cortexes and left frontal hemisphere reflect the improvement of executive control processes, indicating that acute exercise could benefit working memory at a macro-neural level. In addition to its effects on reversing recent obesity and disease trends, our results provide substantial evidence highlighting the importance of promoting physical activity across the lifespan to prevent or reverse cognitive and neural decline.

Neural correlates of prospective memory in individuals with schizotypal personality features.

OBJECTIVE: Prospective memory (PM) refers to the ability to remember to perform actions in the future. Schizophrenia spectrum disorders show impairments in PM but neural correlates of these impairments remain unclear. The present study aimed to examine brain activation during PM to identify impairments in individuals with schizotypal personality features. METHOD: Nineteen participants with schizotypal features and 22 healthy controls participated in a functional MRI experiment while performing a PM task. RESULTS: Results showed that the prefrontal cortex (including Brodmann Area [BA] 10), middle temporal gyrus, and precuneus were activated when performing the PM task compared with baseline. The schizotypal and control groups did not differ in behavioral PM performance. However, participants with schizotypal features showed decreased activations in the inferior and medial frontal lobes (BA 45, and 8). CONCLUSIONS: These results confirmed that the PM network involves prefrontal cortex, including BA 10. The lower activation in prefrontal cortex of individuals with schizotypal features when performing a PM task indicates brain activation abnormality. Notably, this abnormality may occur in the absence of any behavioral manifestation. Our findings support the hypothesis of frontal lobe involvement in PM deficits observed in individuals with schizotypal features.

Interferon-γ improves renal interstitial fibrosis and decreases intrarenal vascular resistance of hydronephrosis in an animal model.

OBJECTIVES: To investigate the effect of interferon (IFN)-γ administration on renal interstitial fibrosis (RIF) and intrarenal vascular resistance of diseased kidneys in a reversible unilateral ureteral obstruction (RUUO) animal model. METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three groups: RUUO with intramuscular IFN-γ treatment (400 IU/d; RUUO + IFN), RUUO with vehicle treatment, and sham operation. RUUO was induced by clamping the left ureter using a small polyethylene tube. The obstruction was reversed seven days after the operation by removing the tube. Six animals in each group were killed at days 7 and 14. The intrarenal resistive index (RI) of diseased kidneys was measured by colored Doppler flow imaging. RIF was evaluated using Masson's trichrome staining. RESULTS: The obstruction was successfully reversed in all animals. At day 7, the RIF scores were 32.1 ± 3.1 and 40.3 ± 3.1 in the RUUO + IFN group and the RUUO group, respectively. The RI increased by 87% in the RUUO group and by 64% in the RUUO + IFN group compared with sham. At day 14, the RIF scores decreased to 24.6 ± 3.9 in the RUUO + IFN group, but increased to 50.8 ± 4.4 in the RUUO group. The increase of RI was reduced to 64% in the RUUO group and to 20% in the RUUO + IFN group. Ureteral obstruction induced few lesions in the contralateral kidneys, and IFN-γ administration had no significant effect on them, although it exerted an antifibrotic effect on the obstructed kidneys. CONCLUSIONS: IFN-γ administration restored or preserved renal histology and hemodynamics in an animal model of renal fibrosis after surgical reversal of hydronephrosis.