Transcranial Magnetic Stimulation Modulates Resting EEG Functional Connectivity Between the Left Dorsolateral Prefrontal Cortex and Limbic Regions in Medicated Patients With Treatment-Resistant Depression.

High-frequency left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to have efficacy in treatment-resistant depression. However, the effects of rTMS on functional connectivity are still not clear. To examine changes in functional connectivity before and after rTMS, resting EEG of 14 patients with treatment-resistant depression was recorded twice at baseline and at week 4, respectively. The EEG data were analyzed using the standardized low-resolution brain electromagnetic tomography (sLORETA). The results reveal that high-frequency left prefrontal rTMS modulates resting EEG functional connectivity between the left dorsolateral prefrontal cortex and limbic regions, including the subgenual cingulate cortex and parahippocampal gyrus.

Effects of essence of chicken on cognitive brain function: a near-infrared spectroscopy study.

The aim of this study was to investigate the effects of the essence of chicken on brain function by near-infrared spectroscopy. Twelve healthy elderly subjects took the essence of chicken or a placebo for 7 d in a double-blind cross-over design study. Changes in oxy-hemoglobin concentrations in the bilateral prefrontal areas of the brain were measured while the subjects performed the simple reaction task, the Groton Maze Learning Test, and the working memory task. In the latter case, there were significant interactions in the changes in oxy-hemoglobin concentrations between treatment and period of intake according to two-way repeated ANOVA. The changes in oxy-hemoglobin concentrations significantly increased in several regions of the prefrontal areas of the brain in those taking essence of chicken for 7 d. These results suggest that essence of chicken is useful as a nutritional supplement to enhance or maintain brain function in the elderly.

Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression.

AIMS: Low-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, and its antidepressant effects have proven to correlate with decreases in cerebral blood flow (CBF) in the orbitofrontal cortex and subgenual cingulate cortex. However, a predictor of treatment response to low-frequency right prefrontal rTMS in depression has not been identified yet. The aim of this study was to estimate regional CBF in the frontal regions and investigate the correlation with treatment response to low-frequency right prefrontal rTMS in depression. METHODS: We examined 26 depressed patients for the correlation between treatment response to rTMS and regional CBF in the frontal regions, by analyzing their brain scans with (99m)Tc-ethyl cysteinate dimer before rTMS treatment. CBF in 16 brain regions was estimated using fully automated region of interest analysis software. Two principal components were extracted from CBF in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization. RESULTS: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions) and ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was not correlated with CBF in the dorsolateral prefrontal cortex, but it was correlated with CBF in the ventromedial prefrontal cortex. CONCLUSION: These findings suggest that CBF in the ventromedial prefrontal cortex may be a potential predictor of low-frequency right prefrontal rTMS, and depressed patients with increased CBF in the ventromedial prefrontal cortex may show a better response.

Public interest and awareness regarding general health, sleep quality and mental wellbeing during the early COVID-19 pandemic period: An exploration using Google trends.

The internet network continues to be a major source of health-related information. Our research provides insights into the online health-seeking behaviors of the general population, and evaluates the potential relationship between the COVID-19 pandemic and public interest and awareness of general sleep health, mental health and wellbeing. Google Trends' weekly relative search volumes (RSVs) were examined during 2020 for searches specifically related to COVID-19 symptoms, and for searches related to general health, sleep and wellbeing, in the United Kingdom, the United States of America, France, Italy and Japan. To obtain insight into the association between the initiation of public restrictions and online search trends, we assessed a six-week period; the 'early pandemic period' (EPP) (01 March 2020 - 11 April 2020). To provide a meaningful pre-pandemic comparison, a similar period during 2019 (03 March - 13 April 2019) was compared for RSV and median difference analysis. The EPP was associated with increased online searches related to COVID-19 symptoms, as compared with those related to more general sleep health, mental health and wellbeing. The latter search terms frequently showed a decrease or minimal change in RSV during the EPP compared with the equivalent period in 2019. This finding illustrates the potential link between the COVID-19 pandemic and online search behavior and corroborates existing findings regarding internet searches during this period. Proactive communication by healthcare professionals during future pandemics and as an ongoing measure could help prevent public neglect of general health and wellbeing symptoms, and encourage reporting and early intervention.

Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression.

AIMS: Low-frequency transcranial magnetic stimulation (TMS) to the right prefrontal cortex has been shown to be effective in treatment-resistant depression. The aim of the present study was to investigate changes in regional cerebral blood flow (rCBF) after low-frequency right prefrontal stimulation (LFRS), and neuroanatomical correlates of therapeutic efficacy of LFRS in treatment-resistant depression. METHODS: Twenty-six patients with treatment-resistant depression received five 60-s 1-Hz trains over the right prefrontal cortex, and 12 treatment sessions were administered during 3 weeks. Brain scans were acquired before and after LFRS using single photon emission computed tomography with (99m) Tc-ethyl cysteinate dimer. Severity of depression was assessed on the Hamilton Depression Rating Scale (HDRS). RESULTS: Significant decreases in rCBF after LFRS were seen in the prefrontal cortex, orbitofrontal cortex, subgenual cingulate cortex, globus pallidus, thalamus, anterior and posterior insula, and midbrain in the right hemisphere. Therapeutic efficacy of LFRS was correlated with decreases in rCBF in the right prefrontal cortex, bilateral orbitofrontal cortex, right subgenual cingulate cortex, right putamen, and right anterior insula. CONCLUSION: The antidepressant effects of LFRS in treatment-resistant depression may be associated with decreases in rCBF in the orbitofrontal cortex and the subgenual cingulate cortex via the right prefrontal cortex.

A 6-month follow-up case report of regional cerebral blood flow changes in treatment-resistant depression after successful treatment with bilateral transcranial magnetic stimulation.

We report a patient with treatment-resistant depression who responded dramatically to bilateral transcranial magnetic stimulation (TMS) and present a 6-month follow-up of changes in regional cerebral blood flow. A 59-year-old man with 4 recurrences of depression came to our outpatient clinic. His current episode had persisted for at least 10 months, although he received several antidepressants. After successful TMS treatment, as compared with normal comparisons, the areas of hypoperfusion in the anterior and subgenual cingulate cortices were almost unchanged but were normalized at month 6. The areas of hyperperfusion in the orbitofrontal cortex were reduced considerably at week 4 and disappeared at month 6. Although there are limitations of a case report, the findings of this case suggest that treatment response to bilateral TMS may be associated with the anterior cingulate, subgenual cingulate, and orbitofrontal cortices.

Changes in hypothalamic-pituitary-thyroid axis following successful treatment with low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression.

Hypothalamic-pituitary-thyroid (HPT) axis abnormalities have been reported in some patients with major depression. To knowledge, however, the effects of low-frequency right prefrontal transcranial magnetic stimulation (TMS) on the HPT axis have not yet been elucidated. The goal of this study was to evaluate alterations in the HPT axis associated with the therapeutic efficacy of TMS treatments. Twenty patients with treatment-resistant depression received five 60-s 1-Hz trains over the right dorsolateral prefrontal cortex. Twelve treatment sessions were administered within a 3-week period (total pulses, 3600). Responders were defined as a > or =50% decrease in the Hamilton Depression Rating Scale (HDRS) score. Serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) were measured, respectively, at pre- and post-treatment. There were no significant changes in fT3 and fT4 levels measured at either pre- or post-treatment in either responders or nonresponders; however, TSH levels of responders elevated significantly after TMS treatments. In addition, there was a significant negative correlation between TSH levels at pretreatment and decrease (%) in the HDRS score. These findings suggest that the HPT axis is associated with antidepressant effects of low-frequency right prefrontal TMS, and indicate that lower TSH levels at pre-treatment are correlated with better therapeutic efficacy.

Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).

Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.

Arachidonic acid supplementation decreases P300 latency and increases P300 amplitude of event-related potentials in healthy elderly men.

In the present study, we examined the effects of arachidonic acid (ARA) on age-related event-related potential (ERP) changes in 25 healthy elderly men. This study was performed using a double-blind crossover design. The subjects were administered 600 mg/day of ARA-enriched triglyceride (SUNTGA40S; containing 240 mg ARA) in capsules or the same amount of olive oil in capsules as an inactive placebo for 1 month. ERPs were measured before capsule administration and after 1 month of administration, and P300 latency and amplitude were also measured. In subjects administered 240 mg/day ARA, P300 latency was significantly shorter, and P300 amplitude was significantly higher than in those administered olive oil capsules, and they exhibited a significant increase in ARA content in serum phospholipids. These findings suggest that supplementation of ARA can improve cognitive function in healthy elderly men.

Fiber tracking of white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex in schizophrenia: a diffusion tensor imaging study.

The goal of this study was to detect abnormalities in white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex using fiber-tracking technique. Diffusion tensor imaging was acquired in 20 patients with schizophrenia and 20 normal comparison subjects. Fiber tracking was performed on the anterior thalamic peduncle, and the tractography was used to determine the cross-sectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy for every step separately in the right and left hemispheres. Compared with normal subjects, patients showed a significant reduction in the cross-sectional area of the left anterior thalamic peduncle. There were no significant differences for the mean fractional anisotropy bilaterally between the two groups, but significant differences for the standard deviation of fractional anisotropy in both hemispheres. Reduction in the cross-sectional area of the left anterior thalamic peduncle suggests the presence of the failure of left-hemisphere lateralization. In schizophrenic patients a significant increase of the standard deviation of fractional anisotropy raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia.

Preliminary Clinical Evaluation of Toxicity and Efficacy of A New Astaxanthin-rich Haematococcus pluvialis Extract.

Astaxanthin (Ax), a carotenoid ubiquitously distributed in microorganisms, fish, and crustaceans, has been known to be a potent antioxidant and hence exhibit various physiological effects. We attempted in these studies to evaluate clinical toxicity and efficacy of long-term administration of a new Ax product, by measuring biochemical and hematological blood parameters and by analyzing brain function (using CogHealth and P300 measures). Ax-rich Haematococcus pluvialis extracts equivalent to 4, 8, 20 mg of Ax dialcohol were administered to 73, 38, and 16 healthy adult volunteers, respectively, once daily for 4 weeks to evaluate safety. Ten subjects with age-related forgetfulness received an extract equivalent to 12 mg in a daily dosing regimen for 12 weeks to evaluate efficacy. As a result, no abnormality was observed and efficacy for age-related decline in cognitive and psychomotor functions was suggested.

Publisher Correction: Fgf10 is essential for limb and lung formation.

In the version of the paper initially published, Fig. 5a was inadvertently duplicated and presented as both Fig. 5a and 5f, and the correct image for Fig. 5f was omitted. Images of the original and corrected figure panels are shown in the correction notice.

Regional cerebral blood flow changes after low-frequency transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in treatment-resistant depression.

Several studies have proved that low-frequency transcranial magnetic stimulation (TMS) of the right dorsolateral prefrontal cortex (DLPFC) showed an antidepressant effect, although its mechanism is still not completely elucidated. The aim of the present study was to clarify the alteration in neuroanatomical function elicited by low-frequency TMS of the right DLPFC in treatment-resistant depression and to detect the difference between responders and nonresponders to TMS. Single-photon emission computed tomography with (99m)Tc-ethyl cysteinate dimer was performed in 14 right-handed male patients with treatment-resistant unipolar depression before and after low-frequency TMS of the right DLPFC. Five 60-second 1-Hz trains were applied and 12 treatment sessions were administered within a 3-week period (total pulses, 3,600). The Hamilton Rating Scale for Depression was administered and the regional cerebral blood flow (rCBF) was analyzed using statistical parametric mapping (SPM2). After TMS treatment in 14 patients, the score on the Hamilton Rating Scale for Depression decreased significantly, and considerable decreases in rCBF were seen in the bilateral prefrontal, orbitofrontal, anterior insula, right subgenual cingulate, and left parietal cortex, but no significant increase in rCBF occurred. Additionally, as compared with 8 nonresponders, 6 responders showed significant increases in rCBF at baseline in the left hemisphere including the prefrontal and limbic-paralimbic regions. These results suggest that the antidepressant effect of low-frequency TMS of the right DLPFC is associated with a decrease in rCBF in the limbic-paralimbic regions via the ipsilateral subgenual cingulate, and increased rCBF at baseline in the left hemisphere may be involved in the response to low-frequency TMS treatment.

Long-chain Polyunsaturated Fatty Acid Supplementation Improves Mood in Elderly Japanese Men.

Although several studies have reported the effects of long-chain polyunsaturated fatty acid (LCPUFA) supplementation on the mood in healthy adults, the effects of LCPUFA on elderly individuals remain unclear. Thus, we hypothesized that LCPUFA supplementation improves mood in the elderly. To address this hypothesis, 115 elderly Japanese men aged 55-64 years were assigned and randomly allocated to the LCPUFA or placebo group. Participants received 4 weeks of supplementation with LCPUFA-containing oil (docosahexaenoic acid (DHA) 300 mg/day, eicosapentaenoic acid (EPA) 100 mg/day, arachidonic acid (ARA) 120 mg/day) or a placebo oil. Mood was assessed using the Profile of Mood States (POMS) before and after supplementation as the secondary outcome in a previously performed randomized controlled trial on cognitive function. A total of 113 participants completed the supplementation period. One hundred participants (LCPUFA, n = 51; placebo, n = 49) who were eligible for evaluation of mood were analyzed. Increases in vigor scores on POMS, reflecting a positive mood, were significantly larger in the LCPUFA group than in the placebo group (LCPUFA, +1.8; placebo, -0.5). No significant differences were observed in changes in other negative mood scores between groups. DHA and ARA content in plasma phospholipids were increased by 0.8% and 0.7%, respectively, in the LCPUFA group, and were significantly larger than those in the placebo group. Dietary DHA, EPA, and ARA intake was unchanged during the study. These results suggest that LCPUFA supplementation may improve vigor (positive mood) in elderly Japanese men.

Low Doses of Long-chain Polyunsaturated Fatty Acids Affect Cognitive Function in Elderly Japanese Men: A Randomized Controlled Trial.

Several studies have reported that the supplementation of long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) improve cognitive function in the elderly. However, the doses used in these studies were higher than general dietary LCPUFA intake levels. This randomized, double-blind, placebo-controlled trial evaluated the effects of low doses of LCPUFA supplementation corresponding to general dietary intake on cognitive function in non-demented elderly Japanese participants. Japanese men aged 55-64 years were enrolled and randomly allocated to the placebo or LCPUFA group. Participants received 4 weeks of supplementation with LCPUFA-containing oil (DHA, 300 mg/day; EPA, 100 mg/day; and ARA, 120 mg/day) or purified olive oil as placebo. Event-related potential P300, reflecting cognitive processes, was measured before and after supplementation. A total of 113 participants completed the supplementation period, and the per-protocol analysis included 69 participants. Changes in P300 latency were significantly different between the placebo group (+13.6 msec) and the LCPUFA group (-1.8 msec) after supplementation. Significant increases in DHA (+0.9%) and ARA (+0.6%) contents in plasma phospholipids were observed in the LCPUFA group; no changes were observed in the placebo group. Dietary DHA, EPA, and ARA intake were in the normal range for Japan participants and remained unchanged during the study. These results suggest that low doses of LCPUFA supplementation have the potential to improve cognitive function in elderly Japanese men.

Structural organization of the mouse neurochondrin gene.

Neurochondrin is a brain and bone specific leucine-rich protein. We previously cloned the two types of mRNAs (neurochondrin-1; 729 amino acids and neurochondrin-2; 712 amino acids) from mouse and human species. As a first step, to better understand the mechanism of the bone and brain specific and developmentally regulated expression of the neruochondrin gene, the genomic organization of murine neurochondrin was determined. It consists of 7 exons and spans about 10 kb; all splice junctions conform to the GT/AG rule. It codes for two alternatively spliced messenger RNAs, neurochondrin-1 containing all 7 exons and neurochondrin-2 lacking exon 1b but containing the other exons. Cap site analysis showed that the major transcription initiation occurs at 765 bp upstream of the ATG start codon of neurochondrin-1. The promoter region has no TATA and CAAT box-like sequence but contains potential AP-1 and SP-1 binding sites. The neurochondrin gene is localized to mouse chromosome 4D1 and rat chromosome 5q36.11.

Arachidonic acid-enriched triacylglycerol improves cognitive function in elderly with low serum levels of arachidonic acid.

Arachidonic acid (ARA) is an n-6 PUFA and is thought to have an important role in various physiological and psychological functions. Recently, supplementation with ARA-enriched TAG was shown to improve age-related decreases in cognitive function in healthy elderly men. To investigate the influence of baseline serum ARA status on cognitive function and its improvement, we analyzed cognitive function stratified by serum ARA level. The stratified analysis was also conducted for the effects of ARA-enriched TAG supplementation on cognitive improvement. Cognitive function was evaluated by measuring event-related potentials (ERPs), including P300 latency and amplitude. When participants were stratified by baseline serum ARA level, P300 latency was significantly longer and P300 amplitude was generally lower in the low-ARA group than in the high-ARA group. No significant difference in P300 components was observed when participants were stratified by serum levels of any other fatty acid. ARA-enriched TAG supplementation significantly shortened P300 latency and increased P300 amplitude in the low-ARA group, although no significant differences were observed in the high-ARA group. These findings suggest that lower serum ARA levels were associated with cognitive function in elderly men and that ARA-enriched TAG supplementation is more effective in improving cognitive function in healthy elderly men with low serum ARA levels than in those with high serum ARA levels.

Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers.

BACKGROUND: Krill oil, rich in n-3 (omega-3) polyunsaturated fatty acids (PUFAs) incorporated in phosphatidylcholine, has been reported to have many effects on physiological function. However, there are few studies using psychophysiological methods published that describe the effects of krill oil on brain function. We investigated the influence of ingestion of krill oil on cognitive function in elderly subjects by using near-infrared spectroscopy and electroencephalography. METHODS: A randomized, double-blind, parallel-group comparative study design was adopted. Forty-five healthy elderly males aged 61-72 years were assigned to receive 12 weeks of treatment with: medium-chain triglycerides as placebo; krill oil, which is rich in n-3 PUFAs incorporated in phosphatidylcholine; or sardine oil, which is abundant in n-3 PUFAs incorporated in triglycerides. Changes in oxyhemoglobin concentrations in the cerebral cortex during memory and calculation tasks were measured. The P300 component of event-related potentials was also measured during a working memory task. RESULTS: During the working memory task, changes in oxyhemoglobin concentrations in the krill oil and sardine oil groups were significantly greater than those in the medium-chain triglyceride group at week 12. The differential value for P300 latency in the krill oil group was significantly lower than that in the medium-chain triglyceride group at week 12. With regard to the calculation task, changes in oxyhemoglobin concentrations in the krill oil group were significantly greater than those in the medium-chain triglyceride group at week 12. CONCLUSION: This study provides evidence that n-3 PUFAs activate cognitive function in the elderly. This is especially the case with krill oil, in which the majority of n-3 PUFAs are incorporated into phosphatidylcholine, causing it to be more effective than sardine oil, in which n-3 PUFAs are present as triglycerides.