Individual and additive effects of neuromodulators on the slow components of afterhyperpolarization currents in layer V pyramidal cells of the rat medial prefrontal cortex.

The effects of 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine (DA) and the muscarinic receptor agonist carbachol (CCh) on the voltage step-induced outward currents underlying afterhyperpolarization (AHP), consisting of a medium (I(mAHP)) and slow (I(sAHP)) component, were investigated in layer V pyramidal cells of the rat medial prefrontal cortex (mPFC). Whole-cell voltage clamp recordings were performed in vitro to quantitatively measure I(mAHP) and I(sAHP) and to examine their functional link to spike-frequency adaptation in the presence of agonists. CCh, 5-HT and NA all reduced the I(sAHP) and the spike adaptation, and, in some cells, replaced the I(sAHP) by the slow inward currents (I(sADP)) underlying the slow afterdepolarization (sADP). DA, however, failed to increase the frequency despite its comparable inhibition of the I(sAHP) over a range of concentrations. In order to test the neuromodulator agonists to see if they have additive actions on the I(sAHP), the effects of co-application of two agonists that increased spike-frequency, 5-HT+NA, 5-HT+CCh and CCh+NA, all at the concentration 30 microM were examined. Specific combinations that included CCh showed additive effects on the slow afterpolarization currents, possibly via both inhibition of I(sAHP) and generation of I(sADP). These findings suggest that neuromodulators have differential effects on the link between the I(sAHP) modulation and spike-frequency adaptation, and that they could exert additive effects on the slow aftercurrents following a strong excitation and, therefore, regulate the repetitive firing properties of the output cells of the rat mPFC.

Reduced frontopolar activation during verbal fluency task associated with poor social functioning in late-onset major depression: Multi-channel near-infrared spectroscopy study.

AIM: Functional neuroimaging studies to date have indicated prefrontal dysfunction in late-onset major depression (LOD). The relationships between prefrontal dysfunction and clinical characteristics including social functioning, however, have been unclear. The objective of the present study was to evaluate prefrontal hemodynamic response related to an executive task in LOD and to assess the relationship between activation in the prefrontal regions and clinical characteristics including social functioning. METHODS: Twenty-four subjects with LOD and 30 age- and gender-matched healthy subjects were recruited for the present study. Hemoglobin concentration changes in the prefrontal and superior temporal cortical surface area were measured during verbal fluency task (VFT) using 52-channel near-infrared spectroscopy (NIRS), which enables real-time monitoring of cerebral blood volume (CBV) in the cortical surface area. RESULTS: The two groups had a distinct spatiotemporal pattern of oxy-hemoglobin concentration change; LOD patients had less activation in a broad area covering both prefrontal and superior temporal cortices than healthy controls. In addition, reduced activation of the frontopolar region had a significant positive correlation with lower self-assessment of social functioning scores in the patient group. CONCLUSION: Reduced frontopolar cortical activation was associated with social functioning impairment in patients with LOD, and NIRS may be an efficient clinical tool for monitoring these characteristics.

Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients.

Plasma levels of ACTH, cortisol and monoamines were examined in 23 depressed patients and 31 healthy subjects. Patients showed increased plasma cortisol levels, but not plasma adrenocorticotropic hormone (ACTH) levels. The plasma levels of a dopamine metabolite, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), were significantly decreased in the patients. In contrast, the plasma levels of a serotonin (5-HT) metabolite, hydroxyindoleacetic acid (5-HIAA), and 5-HT turnover (5-HIAA/5-HT) were increased in the depressed patients. Therefore, plasma levels of HVA and 5-HIAA are proven to be dissociable. Furthermore, plasma levels of 5-HIAA and L-DOPA have positive relationships with severity of depression. On the basis of this and the previous studies, we speculate that an increase in the plasma 5-HIAA levels might be a compensatory mechanism for stress, whereas 5-HT turnover might reflect depressive state. Taken together, plasma levels of HVA and 5-HIAA, and 5-HT turnover (5-HIAA/5-HT) could be good markers for evaluating depression.

Correlation between plasma levels of glutamate, alanine and serine with severity of depression.

The goal of this study was to evaluate the utility of using plasma levels of amino acids as an indicator of the severity of depression. The samples were collected from 23 depressed patients receiving antidepressant medication, and were compared to 31 healthy subjects. The plasma levels of amino acids were determined using HPLC with fluorometric detection. The severity of depression was evaluated using the Hamilton Depression Rating Scale (HAM-D) scores. Plasma levels of glutamate, glutamine, glycine and taurine were significantly increased in the depressed patients compared to the controls. Statistical analysis indicated a positive correlation between glutamate and alanine levels and HAM-D scores and a negative correlation of L-serine with HAM-D scores. The results indicate that plasma level of glutamate, alanine and L-serine could reflect the severity of depression rather than glutamine, glycine and taurine.

Suicidal ideation is associated with reduced prefrontal activation during a verbal fluency task in patients with major depressive disorder.

BACKGROUND: Despite the known relationship between prefrontal function and increased suicidality during major depressive episodes, the links between prefrontal function and suicidality remain unclear in major depressive disorder (MDD). Suicidal ideation usually precedes a suicide attempt. If prefrontal cortex (PFC) activity is a biomarker for suicidal ideation in depression, monitoring it could be useful for suicide prevention. Therefore, in this study, we assessed the association between prefrontal function and suicidal ideation in MDD. METHODS: Prefrontal function in 67 patients with MDD (31 with suicidal ideation and 36 without) and 67 age-, gender-, and intelligence quotient-matched healthy controls (HCs) was evaluated using near-infrared spectroscopy (NIRS) during a verbal fluency task (VFT). Suicidal ideation was assessed using item 3 of the Hamilton Depression Rating Scale (HAMD). RESULTS: Regional hemodynamic changes were significantly smaller in patients with MDD than in HCs in prefrontal and temporal regions. Hemodynamic changes in the right dorsolateral PFC (DLPFC), orbitofrontal cortex (OFC), and right frontopolar cortex (FPC) regions in patients with MDD with suicidal ideation were significantly smaller than in those without suicidal ideation. In addition, hemodynamic changes correlated negatively with the severity of suicidal ideation in the DLPFC, OFC, and FPC in patients with MDD. LIMITATIONS: Further studies with a larger sample size are required to verify our findings. CONCLUSIONS: These results suggest that the DLPFC, OFC, and FPC are brain substrates of suicidal ideation in depressive states in patients with MDD, and that NIRS data can be employed as a clinically useful biomarker for the assessment of suicide risk.

Relationship between hypothalamic-pituitary-adrenal axis dysregulation and insulin resistance in elderly patients with depression.

Cortisol dysregulation has been proposed to be involved in depression. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with major depressive disorder (MDD) was previously reported to be higher in the elderly. Furthermore, insulin resistance and the prevalence of type 2 diabetes are known to increase with aging. The aim of the present study was to determine whether a relationship existed between plasma cortisol levels following the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test and insulin resistance evaluated by the homeostasis model assessment of insulin resistance (HOMA-R) in elderly MDD subjects. Fifteen unmedicated MDD inpatients and 17 age- and sex-matched healthy controls participated in this study. After overnight fasting, blood samples were collected to measure plasma glucose and insulin concentrations, estimate HOMA-R, and perform the DEX/CRH test to evaluate HPA axis function. The value of the area under the time curve of plasma cortisol concentrations (CortAUC) and peak cortisol values (Cortpeak) following the administration of DEX/CRH both correlated with HOMA-R in MDD group. In contrast, neither CortAUC nor Cortpeak correlated with HOMA-R in controls. This is the first study to directly demonstrate the relationship between HPA axis dysregulation assessed with the DEX/CRH test and the index of insulin resistance estimated as HOMA-R in elderly MDD patients.

Association between social functioning and prefrontal hemodynamic responses in elderly adults.

Social functioning has received widespread attention as one of the most important outcomes in psychiatric disorders and has been related to cognitive functioning and the underlying brain activity. Cognitive decline, however, appears not only in the psychiatric population but also in aged individuals. In our previous study, we demonstrated a significant relationship between social functioning and prefrontal cortex (PFC) activity in patients with depression. However, it has not been shown whether the above relationship could be extended to healthy populations. The purpose of the present study was to investigate a possible association between social functioning and prefrontal hemodynamic responses in healthy elderly adults by using a non-invasive and low-constraint functional neuroimaging technique, near-infrared spectroscopy (NIRS). Study subjects included 55 healthy, elderly volunteers. We measured hemodynamic responses over prefrontal cortical (PFC) areas during the verbal fluency task by using multi-channel NIRS and analyzed the relationship between task-associated hemodynamic responses and social functioning as measured by the social adaptation self-evaluation scale (SASS). A significant positive relationship was observed between the SASS total score and PFC activation. Our findings suggest that PFC activation is associated with social functioning in healthy elderly adults. Furthermore, hemodynamic responses assessed using non-invasive NIRS could be a useful biological marker of these characteristics.

Relationship between prefrontal function during a cognitive task and social functioning in male Japanese workers: a multi-channel near-infrared spectroscopy study.

To investigate whether prefrontal function during a cognitive task reflects the social functioning of male Japanese workers, prefrontal function during a working memory task in 181 male workers was measured by multi-channel near-infrared spectroscopy (NIRS). Social functioning was assessed using the Social Adaptation Self-Evaluation Scale (SASS). The results indicated that cortical oxygenation level increases in dorsolateral prefrontal region showed significant positive correlations with the interest and motivation factor scores on the SASS. These results suggest that dorsolateral prefrontal function is associated with the interest and motivation factor in social functioning in male workers and that NIRS could be an addition to the medical tools for monitoring these characteristics on mental health examination.

Fish consumption is positively associated with social functioning: a cross-sectional study in male Japanese workers.

This study investigated the association of fish consumption with social functioning. One hundred forty male Japanese workers completed the social adaptation self-evaluation scale (SASS) and their customary fish consumption was assessed. The total, interest, and motivation factor scores on SASS showed significant positive correlations with fish consumption.

Reduced prefrontal cortex activation during the working memory task associated with poor social functioning in late-onset depression: multi-channel near-infrared spectroscopy study.

A number of studies have demonstrated impairment of working memory (WM) in patients with major depressive disorder (MDD). However, the relationship between the underlying brain activity associated with impairment of WM function in MDD patients and their clinical characteristics is not yet clear. The objective of this study is to evaluate prefrontal hemodynamic response related to a WM task in patients with late-onset depression (LOD) and to assess the relationship between activation in the prefrontal cortex and clinical characteristics. Thirty-six patients with LOD and 35 age- and gender-matched healthy controls were recruited for the present study. We measured hemoglobin concentration changes in the prefrontal and temporal regions during a WM (2-back, letter version) task using 52-channel near-infrared spectroscopy (NIRS). LOD patients were associated with reduced increase in prefrontal and temporal activation compared with healthy controls. Moreover, reduced activation in the prefrontal and temporal regions was significantly related to lower scores on the Social Adaptation Self-Evaluation Scale (SASS) in the patient group. More specifically, the reduced hemodynamic response in the frontopolar region was associated with functional impairment related to interpersonal relationship factor scores on the SASS. These findings suggest that hemodynamic response in prefrontal and temporal regions during a WM task may act as a biological marker of social functioning in LOD patients.

The relationship between the prefrontal activation during a verbal fluency task and stress-coping style in major depressive disorder: a near-infrared spectroscopy study.

This study aimed to identify coping styles used by patients with major depressive disorder (MDD) in comparison with those used by healthy controls, and to explore their association with prefrontal hemodynamic response related to a cognitive task. Regional hemodynamic changes were monitored during a verbal fluency task (VFT) using a 52-channel near-infrared spectroscopy (NIRS) apparatus in 26 MDD patients in depressive state and 30 matched healthy controls, and their correlation with coping styles assessed by Coping Inventory for Stressful Situations (CISS) were examined. We found the Emotion-oriented coping style was significantly higher, whereas the Task-oriented coping and Avoidance-oriented coping style were lower in the MDD group compared with controls. Emotion-oriented coping style positively correlated with subjective assessment of depression severity. Regional hemodynamic changes were significantly smaller in the MDD group than in the control group in prefrontal and temporal regions, and positively correlated with Task-oriented coping (adaptive coping) in the bilateral ventrolateral and dorsolateral prefrontal cortex, and the midline fronto-polar and bilateral orbitofrontal cortex regions. These findings suggest coping styles may be considered an important source of knowledge for patients who struggle with the illness and for mental health professionals who work with MDD patients, and that hemodynamic response in the ventrolateral and dorsolateral prefrontal cortex, midline fronto-polar, and orbitofrontal cortex regions during a VFT may reflect the adaptive coping (Task-oriented coping) style in MDD patients in depressive state.

A multi-channel near-infrared spectroscopy study of prefrontal cortex activation during working memory task in major depressive disorder.

Many neuropsychological studies demonstrate impairment of working memory in patients with major depressive disorder (MDD). However, there are not enough functional neuroimaging studies of MDD patients seeking for the underlying brain activity relevant to working memory function. The objective of this study is to evaluate prefrontal hemodynamic response related to working memory function in patients with MDD. Twenty-four subjects with MDD and 26 age- and gender-matched healthy subjects were recruited for the present study. We measured hemoglobin concentration changes in the prefrontal and superior temporal cortical surface areas during the execution of working memory task (WM; 2-back, letter version) using 52-channel near-infrared spectroscopy (NIRS), which enables real-time monitoring of task-related changes in cerebral blood volumes in the cortical surface areas. MDD patients showed a smaller increase in lateral prefrontal and superior temporal cortex activation during the 2-back task and associated poorer task performance than healthy controls. The results coincided with previous findings in terms of working memory deficits and prefrontal cortex dysfunction in MDD patients, but contradicted with some previous fMRI studies that suggested increased cortical activity during the working memory task in patients with depression. The contradiction may, in part, be explained by a relatively low level of cognitive demand imposed on the subjects in the present study.

Effects of cyclohexanonic long-chain fatty alcohol, tCFA15 on amino acids in diabetic rat brain: a preliminary study.

The aim of this study was to evaluate the effects of streptozotocin-induced type 1diabetes and a subchronic treatment with cyclohexanonic long-chain fatty alcohol, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (tCFA15) on contents of amino acids including aspartate, glutamate, glutamine, GABA, glycine, taurine, alanine, serine, threonine, and arginine in the prefrontal cortex, hippocampus and striatum. Levels of glutamate, threonine, taurine, alanine, arginine, and the ratio of glutamate/glutamine were altered region-differently in the brain of diabetic rats. However, tCFA15 region-specifically antagonized the changes in taurine and arginine levels and the ratio of glutamate/glutamine. The alteration in glutamate/glutamine ratio may indicate that experimental models of type 1 diabetes have abnormalities of neuron-gria interaction in brain.