Effects of Antioxidant Supplements (BioPQQ™) on Cerebral Blood Flow and Oxygen Metabolism in the Prefrontal Cortex.

Pyrroloquinoline quinone (PQQ) is a quinone compound originally identified in methanol-utilizing bacteria and is a cofactor for redox enzymes. At the Meeting of the International Society on Oxygen Transport to Tissue (ISOTT) 2014, we reported that PQQ disodium salt (BioPQQ™) improved cognitive function in humans, as assessed by the Stroop test. However, the physiological mechanism of PQQ remains unclear. In the present study, we measured regional cerebral blood flow (rCBF) and oxygen metabolism in prefrontal cortex (PFC), before and after administration of PQQ, using time-resolved near-infrared spectroscopy (tNIRS). A total of 20 healthy subjects between 50 and 70 years of age were administered BioPQQ™ (20 mg) or placebo orally once daily for 12 weeks. Hemoglobin (Hb) concentration and absolute tissue oxygen saturation (SO2) in the bilateral PFC were evaluated under resting conditions using tNIRS. We found that baseline concentrations of hemoglobin and total hemoglobin in the right PFC significantly increased after administration of PQQ (p < 0.05). In addition, decreases in SO2 level in the PFC were more pronounced in the PQQ group than in the placebo group (p < 0.05). These results suggest that PQQ causes increased activity in the right PFC associated with increases in rCBF and oxygen metabolism, resulting in enhanced cognitive function.

Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus.

We examined the effects of silymarin, which was extracted from Silybum marianum, on delayed neuronal cell death in the rat hippocampus. Rats were divided into four groups: sham-operated rats (sham group), rats which underwent ischemic surgery (control group), rats which were treated with silymarin before and after ischemic surgery (pre group), and rats which were treated with silymarin after ischemic surgery only (post group). We performed the ischemic surgery by occluding the bilateral carotid arteries for 20min and sacrificed the rats one week after the surgery. Silymarin was administered orally at 200mg/kg body weight. Smaller numbers of delayed cell deaths were noted in the rat CA1 region of the pre- and post-groups, and no significant difference was observed between these groups. There were few apoptotic cell deaths in all groups. Compared to the control group, significantly fewer cell deaths by autophagy were found in the pre- and post-group. We concluded that silymarin exerts a preservation effect on delayed neuronal cell death in the rat hippocampus and this effect has nothing to do with the timing of administering of silymarin.

Influence of Pleasant and Unpleasant Auditory Stimuli on Cerebral Blood Flow and Physiological Changes in Normal Subjects.

The prefrontal cortex (PFC) plays an important role in emotion and emotional regulation. The valence asymmetry hypothesis, proposes that the left/right asymmetry of the PFC activity is correlated with specific emotional responses to stressors. However, this hypothesis still seems to leave room for clarifying neurophysiological mechanisms. The purpose of the present study was to investigate the effects of stimuli with positive and negative valence sounds (hereafter PS, NS) selected from the International Affective Digitized Sounds-2 on physiological and physiological responses, including PFC activity in normal participants. We studied the effect of both stimuli using 12 normal subjects (mean age 26.8 years) on cerebral blood oxygenation in the bilateral PFC by a multi-channel NIRS, alpha wave appearance rate in theta, alpha, beta by EEG, autonomic nervous function by heart rate, and emotional conditions by the State-Trait Anxiety Inventory (STAI) and the visual analogue scale (VAS). PS was selected over 7.00 and NS were fewer than 3.00 in the Pleasure values. Sounds were recorded during 3 s and reproduced at random using software. Every task session was designed in a block manner: seven rests with Brown Noise (30 s) and six tasks (30 s) blocks. All participants performed each session in random order with eyes closed. A paired Student's t-test was used for comparisons (P<0.05). PFC activity showed increases bilaterally during both stimuli with a greater activation of the left side in PS and a tendency of more activation by NS in the right PFC. Significantly greater alpha wave intensity was obtained in PS. Heart rate tended to show smaller values in PS. The STAI level tended to show smaller values in PS, and a significantly greater VAS score was obtained in PS which indicated 'pleasant'. Despite the limitations of this study such as the low numbers of the subjects, the present study indicated that PS provided pleasant psychological and physiological responses and NS unpleasant responses. The PFC was activated bilaterally, implying a valence effect with the possibility of a dominant side.

Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQ™) on Cognitive Functions.

Pyrroloquinoline quinone (PQQ) is a quinone compound first identified in 1979. It has been reported that rats fed a PQQ-supplemented diet showed better learning ability than controls, suggesting that PQQ may be useful for improving memory in humans. In the present study, a randomized, placebo-controlled, double-blinded study to examine the effect of PQQ disodium salt (BioPQQ™) on cognitive functions was conducted with 41 elderly healthy subjects. Subjects were orally given 20 mg of BioPQQ™ per day or placebo, for 12 weeks. For cognitive functions, selective attention by the Stroop and reverse Stroop test, and visual-spatial cognitive function by the laptop tablet Touch M, were evaluated. In the Stroop test, the change of Stroop interference ratios (SIs) for the PQQ group was significantly smaller than for the placebo group. In the Touch M test, the stratification analyses dividing each group into two groups showed that only in the lower group of the PQQ group (initial score<70), did the score significantly increase. Measurements of physiological parameters indicated no abnormal blood or urinary adverse events, nor adverse internal or physical examination findings at any point in the study. The preliminary experiment using near-infrared spectrometry (NIRS) suggests that cerebral blood flow in the prefrontal cortex was increased by the administration of PQQ. The results suggest that PQQ can prevent reduction of brain function in aged persons, especially in attention and working memory.

Ginkobiloba extract improves working memory performance in middle-aged women: role of asymmetry of prefrontal cortex activity during a working memory task.

In order to clarify the mechanism through which extract of Ginkgo biloba leaves (EGb) improves cognitive function, we examined the effects of EGb on cerebral blood oxygenation in the prefrontal cortex (PFC) and on performance during a working memory task, using near-infrared spectrometry (NIRS). First, we evaluated differences in behavioral performance of the Sternberg working memory test (ST) and in the activation pattern of the PFC during ST between 15 young and 19 middle-aged healthy women. Then, we examined the effect of EGb (120 mg/day for 6 weeks) on ST performance and PFC activation pattern in the middle-aged group. The middle-aged group exhibited a longer reaction time (RT) in ST than the young group and showed a different PFC activation pattern during ST, i.e., the middle-aged group showed bilateral activation while the young group showed right-dominant activation. In the middle-aged group, administration of EGb for 6 weeks shortened the RT of ST and changed the PFC activation pattern to right-dominant, like that in the young group. The results indicate the PFC plays a role in the physiological cognitive function-enhancing effect of EGb. EGb might improve working memory function in middle-aged individuals by counteracting the occurrence of aging-related hemispheric asymmetry reduction.

NIRS-based neurofeedback learning systems for controlling activity of the prefrontal cortex.

The aim of this study was to develop a NIRS-based neurofeedback system to modulate activity in the prefrontal cortex (PFC). We evaluated the effectiveness of the system in terms of separability of changes in oxy-Hb and its derivative. Training with neurofeedback resulted in higher separability than training without neurofeedback or no training, suggesting that the neurofeedback system could enhance self-control of PFC activity. Interestingly, the dorsolateral PFC exhibited enhanced activity and high separability after neurofeedback training. These observations suggest that the neurofeedback system might be useful for training subjects to regulate emotions by self-control of dorsolateral PFC activity.

Effects of acupuncture on autonomic nervous function and prefrontal cortex activity.

Acupuncture is helpful in treating various diseases, including autonomic nervous system (ANS) dysfunction caused by mental stress. On the other hand, the frontal lobe is suggested to play an important role in stress responses by modulating the ANS. The aim of the study was to evaluate the effects of acupuncture on ANS and frontal lobe activities. We investigated 18 normal adults. We measured the activity of prefrontal cortex (PFC) caused by real acupuncture (WHO-LI4) and sham acupuncture, employing optical topography. To evaluate ANS function, we analyzed heart rate variability (HRV). Analysis of HRV revealed a decrease of the LF/HF ratio, and an increase of the HF power by real acupuncture, indicating a shift to parasympathetic dominancy. Acupuncture also caused cerebral blood oxygenation changes in both directions, that is, an increase and/or a decrease of oxyhemoglobin (Oxy-Hb) in the bilateral PFC. However, the Oxy-Hb change was not correlated with HRV parameters in the majority of cases. One of the possible explanations of the poor correlations might be that the PFC activity induced by acupuncture is not closely linked with ANS function.

Effects of fragrance administration on stress-induced prefrontal cortex activity and sebum secretion in the facial skin.

Although fragrances have long been known to influence stress-induced psychosomatic disorders, the neurophysiological mechanism remains unclear. We evaluated the effect of fragrance on the relation between the level of sebum secretion in the facial skin and the stress-induced prefrontal cortex (PFC) activity, which regulates the activity of the hypothalamic-pituitary-adrenal axis. Employing near infrared spectroscopy, we measured hemoglobin concentration changes in the bilateral PFC during a mental arithmetic task in normal adults (n=31), and evaluated asymmetry of the PFC activity in terms of the laterality index (i.e., [(right-left)/(right+left)]) of oxyhemoglobin concentration changes (LI-oxyHb). We measured the level of sebum secretion in the facial skin before the task performance. There was a significant positive correlation between the LI-oxyHb and the level of sebum secretion (r=+0.44, p=0.01). We selected the subjects who exhibited high levels of sebum secretion and right-dominant PFC activity for the study on the fragrance effect (n=12). Administration of fragrance for four weeks significantly reduced the level of sebum (p=0.02) in the fragrance group (n=6). In addition, the LI-oxyHb decreased significantly from 0.11+/-0.07 to -0.10+/-0.18 (p=0.01), indicating that the dominant side of the stress-induced PFC activity changed from the right to left side. In contrast, neither LI-oxyHb nor the levels of sebum secretion changed significantly in the control group (n=6). These results suggest that administration of fragrance reduced the level of sebum secretion by modulating the stress-induced PFC activity. The PFC may be involved in the neurophysiological mechanism of fragrance effects on systemic response to mental stress.

Auditory-evoked cerebral oxygenation changes in hypoxic-ischemic encephalopathy of newborn infants monitored by near infrared spectroscopy.

Recent neuronal activation studies have demonstrated the presence of regional cerebral blood flow (rCBF) increases in response to neuronal activation in normal newborns. In the present study, using near infrared spectroscopy (NIRS), we evaluated the evoked cerebral blood oxygenation (CBO) changes in hypoxic-ischemic encephalopathy (HIE) of newborns. We studied 20 normal newborns and 22 HIE newborns; mild HIE (n=9), moderate HIE (n=7), and severe HIE (n=6). The babies were from 1 to 3 days postdelivery. We measured the concentration changes of deoxyhemoglobin (Deoxy-Hb), oxyhemoglobin (Oxy-Hb), and total hemoglobin (Total-Hb) induced by auditory stimulation in the frontal lobes. The normal and HIE groups showed different Oxy-Hb and Total-Hb responses. In normal newborns, 19 out of 20 normal subjects showed increases of Oxy-Hb and Total-Hb, whereas 14 out of 22 subjects showed decreases of Oxy-Hb and Total-Hb during the stimulation (chi(2)=19.95, p<0.001). In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb (r=-0.73, p<0.001). These results suggest that infants with HIE have decreased rCBF in the frontal lobes during auditory stimulation.