Efficacy of Kami Guibi-tang as an Add-On Therapy to Acetylcholinesterase Inhibitor for Cognitive Function in Mild Alzheimer's Disease: A Pilot Study.

Background: Kami Guibi-tang (KGT), a traditional Korean herbal medicine is mainly used to treat insomnia and nervousness. Acetylcholinesterase inhibitors (AChEIs) are the main treatments for mild Alzheimer's disease (AD), a degenerative brain disease. However, currently no drug can fundamentally treat AD or reverse the advanced cognitive decline. This clinical study explored the efficacy and safety of adding KGT to AChEI for cognitive function in mild AD. Methods: This was a pilot study for a larger randomized, double-blind, placebo-controlled trial. Participants between 55-90 years diagnosed with mild AD were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea. They were randomized to receive either KGT or placebo for 24 weeks, in addition to their regular AChEI. The primary outcome was treatment efficacy, as assessed by the relative amount of change over the study period in total scores on the Dementia version of the Seoul Neuropsychological Screening Battery (SNSB-D). Changes in SNSB subscores were assessed as secondary outcomes. Safety parameters, including adverse events and abnormalities in blood tests, electrocardiograms, and brain magnetic resonance imaging were also monitored. Results: Between March 2018 and November 2020, seven participants each in the KGT group and the placebo group completed the 24-week trial. There were no significant changes in SNSB-D total or subindex scores for either group (p = 0.69 and 0.63, respectively), and no significant differences were observed between them (p=0.71). No adverse events related to KGT were reported. We also compared and analyzed the results of a previous pilot study conducted on amnestic mild cognitive impairment (aMCI) using protocol of this study. The aMCI group showed a significant improvement in the total SNSB-D score, especially in the memory domain, compared to the mild AD group (p = 0.04 and 0.02, respectively). The Korean Mini-Mental State Exam and Korean Instrumental Activities of Daily Living scores also significantly improved in the aMCI group (p = 0.01 and 0.02, respectively). Conclusions: Compared to placebo, adding KGT to AChEI did not significantly improve cognitive function in SNSB in patients with mild AD. We suggest that KGT would have a positive effect on patients with early stages of cognitive impairment such as aMCI. The findings could assist design larger, longer-term clinical trials of KGT use in elderly patients with mild AD. This study was registered in the Korean Clinical Trial Registry on December 26, 2017, with the CRIS approval number KCT0002904.

Effects of Kami Guibi-tang in patients with mild cognitive impairment: study protocol for a phase III, randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is often considered a precursor to Alzheimer's disease (AD) and represents a key therapeutic target for early intervention of AD. However, no treatments have been approved for MCI at present. Our previous pilot study has shown that Kami Guibi-tang (KGT), a traditional herbal prescription widely used in Korean medicine for treating amnesia, might be beneficial for improving general cognitive function of aMCI patients. We will conduct a larger-scale clinical trial to validate the findings of our pilot study and further examine the efficacy and safety of KGT in aMCI. METHODS: This trial is designed as a randomized, double-blind, placebo-controlled clinical trial. A total of 84 aMCI patients will be recruited and randomized into the treatment and control groups. Participants will be administered either KGT or placebo granules for 24 weeks, with a follow-up period of 12 weeks after the last treatment. Primary outcomes will include changes in cognitive performance assessed using a neuropsychological test battery, called the Seoul Neuropsychological Screening Battery, between the baseline, post-intervention visit, and follow-up visit (24th and 36th week, respectively). Secondary outcomes will involve the rate of progression to AD, changes in neuroimaging signals assessed using structural magnetic resonance imaging (MRI), resting-state functional MRI (rs-fMRI), and task-based fMRI, and changes in blood biomarkers measured by the ratio of plasma amyloid-ß 42/40 levels (Aß42/Aß40) between the baseline and post-intervention visit (24th week). For safety assessments, blood chemistry tests and electrocardiograms (ECG) will also be performed. DISCUSSION: This study aims to provide confirmatory evidence of the effect of the Korean herbal medicine, KGT, on improving cognitive function in patients with aMCI. We will identify the possible mechanisms underlying the effects of KGT using neuroimaging signals and blood biomarkers. TRIAL REGISTRATION: Korean Clinical Trial Registry ( https://cris.nih.go.kr/cris/search/detailSearch.do/16918; Registration number: KCT0007039; Date of registration: February 24, 2022).

Ultrasensitive probeless capacitive biosensor for amyloid beta (Aß1-42) detection in human plasma using interdigitated electrodes.

Progressive aggregation and protein misfolding are the initial fundamental indicators of neurodegenerative disorders such as Alzheimer's disease (AD). In this study, a highly sensitive and novel method to detect amyloid beta (Aß) biomarkers, which are a hallmark of AD, using an immunoassay platform-based interdigitated capacitive biosensor, has been explored. For several decades, aptamers have classified as a novel class of molecular recognition probes comprising single-stranded complementary DNA sequences that bind to their identified targets with high specificity and affinity by an in vitro technique called SELEX (systematic evolution of exponential and enrichment). Aptamers, often referred to as "chemical antibodies", possess several highly obvious features for clinical use. The proposed sensing bio-device was fabricated and glazed with oligomeric Aß (oAß) aptamer and anti-oAß antibody, functionalized onto a Pt/Ti-featured SiO2 substrate. Subsequently, analytical studies were conducted to confirm that the specificity, sensitivity, and selective detection of the oAß-based bioengineered surfaces facilitate a label-free approach. The bionic capacitive sensor achieved real-time detection within 5 s (faster response than ELISA) under the femto-molar range concentrations of oAß peptide in plasma using anti-oAß antibody and oAß aptamer with ultra-high affinity. Furthermore, the prepared capacitive biochip was selective against plasma-borne antigens and standby for 100 days at 4 °C. The developed biosensor is suitable for point-of-care (POC) diagnostic applications owing to its portability and scalability. Furthermore, the superior efficacy of oAß in identifying AD has huge potential for biomedical applications.

Efficacy and safety of Kami-guibi-tang for mild cognitive impairment: a pilot, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Mild cognitive impairment (MCI) is considered an intermediate phase between normal aging and dementia. As the majority of cases of amnestic MCI (aMCI) progress to Alzheimer's disease (AD), it is considered the prodromal stage of AD, and a treatment target for prevention of further cognitive decline. However, no medications have been shown to have symptomatic or preventive benefits in MCI. Kami-guibi-tang (KGT) is a traditional herbal formula used in Korean medicine to treat amnesia, which is reported to increase acetylcholine levels via activation of choline acetyltransferase. The objective of this study was to evaluate the efficacy and safety of KGT in patients with aMCI. METHODS: This study was designed as a single-center, randomized, double-blind, placebo-controlled pilot study. Participants diagnosed with aMCI were randomized to receive either KGT or placebo granules for 24 weeks. The efficacy measure was a change in the Seoul Neuropsychological Screening Battery (SNSB) score. The safety measures included the occurrence of adverse events and abnormalities in vital signs and blood chemistry, electrocardiogram (ECG), and brain magnetic resonance imaging (MRI) findings. RESULTS: A total of 16 patients in the KGT group and 14 patients in the placebo group were investigated in the study. The mean score of Clinical Dementia Rating-Sum of Boxes (CDR-SB) significantly improved from 1.53 (0.64) points to 1.13 (0.62) points in the KGT group (p = 0.010), whereas it worsened from 1.61 (0.88) points to 1.75 (0.94) points in the placebo group. There was a significant difference in the CDR-SB scores between the two groups after the intervention (p = 0.045). The total SNSB-D scores and the scores in the memory domain after the treatment were significantly higher than the baseline values in the KGT group, but not in the placebo group. The frequency of adverse events was not significantly different between the two groups, and there were no abnormalities in vital signs or blood test, ECG, and brain MRI findings after the intervention. CONCLUSIONS: KGT may provide a safe and effective treatment option for patients with aMCI. Further studies with a larger sample size are needed to validate the findings. TRIAL REGISTRATION: Korean Clinical Trial Registry, ID: KCT0002407; Registered on March 30, 2017, http://cris.nih.go.kr/.

Treatment evaluation of Kami Guibi-tang on participants with amnestic mild cognitive impairment using magnetic resonance imaging on brain metabolites, gamma-aminobutyric acid, and cerebral blood flow.

PURPOSE: To evaluate the effectiveness of Kami Guibi-tang (KGT) in the treatment of mild cognitive impairment (MCI) using magnetic resonance imaging (MRI) on brain metabolites, neurotransmitter, and cerebral blood flow (CBF). METHODS: We randomly allocated a total of 30 MCI patients to a KGT (N = 16) or a placebo (N = 14) group and performed MRI scans before and after 24 weeks of treatment. The participants underwent brain magnetic resonance spectroscopy and MRI scans to obtain brain metabolites using Point-RESolved Spectroscopy (PRESS) single-voxel spectroscopy, gamma-aminobutyric acid (GABA) neurotransmitter using Mescher-Garwood PRESS, and CBF using pseudocontinuous arterial spin labeling sequences using a 3.0 Tesla MRI system. We analyzed metabolite and neurotransmitter levels and CBF using repeated-measure analysis of variance to evaluate between-subject group effect, within-subject treatment condition effect, and interaction of group by condition (group x condition). RESULTS: The GABA+/creatine (Cr) ratio values were not significantly different between the before and after treatment conditions. The glutamate complex/Cr ratio difference before and after treatment was lower in the KGT group than in the placebo group, but was not statistically significant (p = 0.077). The result of region of interest-based CBF measurement showed that CBF values were significantly lower after treatment at Cluster 2 for the KGT group (p = 0.003) and the placebo group (p = 0.011), at hippocampus for the KGT group (p = 0.004) and the placebo group (p = 0.008), and at the fusiform gyrus for the KGT group (p = 0.002). Furthermore, the absolute CBF difference before and after treatment in the fusiform gyrus was significantly lower in the KGT group than in the placebo group (p = 0.024). CONCLUSIONS: Although a KGT treatment of 24 weeks showed some significant impact on the level of CBF, the Korean version of the mini-mental state examination score was not significantly different between before and after treatment conditions, indicating that there was no memory function improvement after treatment in amnestic MCI patients. Therefore, further studies should be performed with a relatively larger population and extending the duration of the KGT treatment.

The effectiveness and safety of Kami Guibi-tang for mild cognitive impairment: study protocol of a pilot, randomized, placebo-controlled, double-blind trial.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate phase between normal aging and dementia. Since a majority of amnestic MCI (aMCI) cases progress to Alzheimer's disease (AD), it is considered the prodromal stage of AD and, therefore, a treatment target for the prevention of further cognitive decline. However, there is no approved treatment for MCI at present. Kami Guibi-tang (KGT) is a herbal drug used in Korean medicine to treat amnesia, insomnia, loss of appetite, and depression. We will explore the effectiveness and safety of KGT in amnestic MCI in this trial. METHODS/DESIGN: The study will be a single-center, randomized, placebo-controlled, double-blind trial. Eligible participants diagnosed with amnestic MCI will be randomly allocated to a treatment or control group. Participants will take KGT or placebo granules, three times a day, for 24 weeks. The primary outcomes will be changes in Seoul Neuropsychological Screening Battery (SNSB) scores, and magnetic resonance imaging (MRI) measurements including those of brain metabolites, neurotransmitters, and cerebral blood flow. The secondary outcomes will include the safety assessment, measured by changes in blood chemistry, changes in blood protein and cholesterol levels related to AD pathology, and a comparison of MRI changes between the two groups, using age and genotype as covariates. DISCUSSION: This study will be the first clinical trial to identify the therapeutic potential of Kami Guibi-tang for amnestic MCI. The findings will provide insight into the feasibility of large-scale trials to gather evidence for KGT as a treatment for MCI. TRIAL REGISTRATION: Korean Clinical Trial Registry, ID: KCT0002407 . Registered on 30 March 2017.

Effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica: protocol for a randomized, patient-assessor blind, sham-controlled clinical trial.

BACKGROUND: Sciatica is a relatively frequent illness that easily becomes a chronic and relapsing condition. Although numerous systematic reviews have analyzed various therapies for sciatica, the validity of their included studies is limited. Considering the limitations of conventional treatment options for sciatica, acupuncture is a possible option; however, evidence supporting its efficacy and mechanism in patients with sciatica is lacking. The aim of this proposed protocol is to investigate the effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica. METHODS/DESIGN: This study is a randomized, patient-assessor blind, two-arm, parallel, non-penetrating, sham-controlled clinical trial. Eligible participants will include adults (aged 19-70 years old) with a clinical diagnosis of chronic sciatica (40 mm or more of a 100-mm visual analog scale (VAS) for bothersomeness) blinded to the treatment received. Patients will be randomly allocated into the acupuncture treatment group (manual acupuncture plus electroacupuncture (EA), n = 34) or the sham acupuncture control group (sham acupuncture plus placebo EA without electrical stimulation, n = 34). Groups will receive treatment twice a week for a total of eight sessions over 4 weeks. Functional magnetic resonance imaging will be implemented at baseline and endpoint to investigate the mechanism of acupuncture. The primary outcome measure is the VAS for bothersomeness and secondary outcomes include the VAS for pain intensity, Oswestry Disability Index, EuroQol 5-Dimension, Coping Strategy Questionnaire, Beck's Depression Inventory, and State-Trait Anxiety Inventory. Adverse events will be assessed at every visit. DISCUSSION: The results of this trial (which will be available in 2020) should provide important clinical evidence for the effect of acupuncture and demonstrate how acupuncture can be helpful for the treatment of chronic sciatica. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03350789 . Registered on 15 November 2017.

Phantom Acupuncture Induces Placebo Credibility and Vicarious Sensations: A Parallel fMRI Study of Low Back Pain Patients.

Although acupuncture is an effective therapeutic intervention for pain reduction, the exact difference between real and sham acupuncture has not been clearly understood because a somatosensory tactile component is commonly included in the existing sham acupuncture protocols. In an event-related fMRI experiment, we implemented a novel form of sham acupuncture, phantom acupuncture, that reproduces the acupuncture needling procedure without somatosensory tactile stimulation while maintaining the credibility of the acupuncture treatment context. Fifty-six non-specific low back pain patients received either real (REAL) or phantom (PHNT) acupuncture stimulation in a parallel group study. The REAL group exhibited greater activation in the posterior insula and anterior cingulate cortex, reflecting the needling-specific components of acupuncture. We demonstrated that PHNT could be delivered credibly. Interestingly, the PHNT-credible group exhibited bilateral activation in SI/SII and also reported vicarious acupuncture sensations without needling stimulation. The PHNT group showed greater activation in the bilateral dorsolateral/ventrolateral prefrontal cortex (dlPFC/vlPFC). Moreover, the PHNT group exhibited significant pain reduction, with a significant correlation between the subjective fMRI signal in the right dlPFC/vlPFC and a score assessing belief in acupuncture effectiveness. These results support an expectation-related placebo analgesic effect on subjective pain intensity ratings, possibly mediated by right prefrontal cortex activity.

A pilot study of differential brain activation to suicidal means and DNA methylation of CACNA1C gene in suicidal attempt patients.

Suicide is a serious public health problem. In this study, we investigated functional brain changes to novel visual stimuli of suicidal means, DNA methylation status, and the relationship between the two markers. 14 suicidal attempt patients (SAs) and 22 healthy controls were included. Pictures of facial expressions and suicidal means were shown to subjects during fMRI scanning. 11 CpG sites within transcription factor binding site of CACNA1C gene were selected. In knives (K) vs. natural landscape (NL) condition, left middle frontal gyrus (Brodmann's area, BA 6 and 46) and left inferior frontal gyrus (BA 9) were shown to be significantly higher brain activation in the SAs than the controls (p<0.001). DNA methylation percentages of CpG site 4 (p=0.005) and 6 (p=0.037) were found to be related to the SAs. In the SAs, methylation degree of site 4 and site 6 was positively correlated with signal intensity of K vs. NL condition in left thalamus. The degree of site 4 was positively correlated with signal intensity in left middle and inferior frontal gyri in SAs. The possibility that these findings might be involved in the neurobiology of suicidal behavior is suggested.

Uhwang Chungsim Won decreases blood oxygen level-dependent fMRI signal response to a motor stimulation task.

OBJECTIVES: To evaluate the effect of Uhwang Chungsim Won [UC, Niuhuang Qingxin Pill ()] on the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal response to a motor stimulation task using a hand grasping paradigm. METHODS: Ten healthy right-handed male volunteers were recruited. Their BOLD fMRI signal characteristics during hand grasping were determined before and 1 h after consuming UC. RESULTS: With the administration of UC, BOLD responses to the right hand motor task showed a decrease in both hemispheres including the right cerebellar culmen, right and left medial frontal gyrus, right parahippocampal gyrus, right and left sublobar insula, right and left posterior cingulate, left precuneus, and right precentral gyrus. Decreased BOLD responses to the left hand motor task were shown in the right lingual gyrus, right cerebellar culmen, left superior temporal gyrus, right and left middle frontal gyrus, and right precentral gyrus after UC administration. Increased BOLD responses to the left hand motor task were shown in the left and right posterior cingulate, while there was no increased response to the right hand motor task after UC administration. CONCLUSIONS: UC administration significantly decreased fMRI BOLD signal responses to hand grasping in most of the brain areas including the primary motor cortex, but it is not clear whether these decreased responses were caused by a decrease in neuronal activities or by an increase in cerebral blood flow due to the cerebral vasodilatory effects of UC. Further studies using positron emission tomography or single photon emission computed tomography are needed to fully elucidate these findings.

Acupuncture on GB34 activates the precentral gyrus and prefrontal cortex in Parkinson's disease.

BACKGROUND: Acupuncture is increasingly used as an additional treatment for patients with Parkinson's disease (PD). METHODS: In this functional magnetic resonance imaging study, brain activation in response to acupuncture in a group of 12 patients with PD was compared with a group of 12 healthy participants. Acupuncture was conducted on a specific acupoint, the right GB 34 (Yanglingquan), which is a frequently used acupoint for motor function treatment in the oriental medical field. RESULTS: Acupuncture stimulation on this acupoint activates the prefrontal cortex, precentral gyrus, and putamen in patients with PD; areas that are known to be impaired in patients with PD. Compared with healthy participants, patients with PD showed significantly higher brain activity in the prefrontal cortex and precentral gyrus, especially visible in the left hemisphere. CONCLUSIONS: The neuroimaging results of our study suggest that in future acupuncture research; the prefrontal cortex as well as the precentral gyrus should be treated for symptoms of Parkinson's disease and that GB 34 seems to be a suitable acupoint. Moreover, acupuncture evoked different brain activations in patients with Parkinson's disease than in healthy participants in our study, stressing the importance of conducting acupuncture studies on both healthy participants as well as patients within the same study, in order to detect acupuncture efficacy. TRIAL REGISTRATION: KCT0001122 at cris.nih.go.kr (registration date: 20140530).

Differential Localization of Pain-Related and Pain-Unrelated Neural Responses for Acupuncture at BL60 Using BOLD fMRI.

The objective of this study was to differentiate between pain-related and pain-unrelated neural responses of acupuncture at BL60 to investigate the specific effects of acupuncture. A total of 19 healthy volunteers were evaluated. fMRI was performed with sham or verum acupuncture stimulation at the left BL60 before and after local anesthesia. To investigate the relative BOLD signal effect for each session, a one-sample t-test was performed for individual contrast maps, and a paired t-test to investigate the differences between the pre- and post-anesthetic signal effects. Regarding verum acupuncture, areas that were more activated before local anesthesia included the superior, middle, and medial frontal gyri, inferior parietal lobule, superior temporal gyrus, thalamus, middle temporal gyrus, cingulate gyrus, culmen, and cerebellar tonsil. The postcentral gyrus was more deactivated before local anesthesia. After local anesthesia, the middle occipital gyrus, inferior temporal gyrus, postcentral gyrus, precuneus, superior parietal lobule, and declive were deactivated. Pre-anesthetic verum acupuncture at BL60 activated areas of vision and pain transmission. Post-anesthetic verum acupuncture deactivated brain areas of visual function, which is considered to be a pain-unrelated acupuncture response. It indicates that specific effects of acupoint BL60 are to control vision sense as used in the clinical setting.

Neural pathway interference by retained acupuncture: a functional MRI study of a dog model of Parkinson's disease.

OBJECTIVE: The aims of this study were to investigate the interference of the brain activation during a passive movement task (PMT) by retained acupuncture at the ST 36 acupoint and to compare these effects between normal brain and Parkinson's disease (PD) brain. METHODS: Functional magnetic resonance imaging (fMRI) techniques have been used to study neurophysiology in animals. Eight healthy beagle dogs were divided into two groups of four dogs each, a normal control group and a PD model group. PD was induced by intravenous injection of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-HCl. During fMRI, the PMT was performed in the right tarsal joint during three different sessions, which consisted of PMT only, PMT while an acupuncture needle was inserted at the ST 36 acupoint, and PMT while needle was inserted at a sham point. RESULTS AND DISCUSSION: Standard veterinary neurological examination was performed on dogs with MPTP-induced PD. A homogeneous grade similar to human PD patients was evident in all dogs. The fMRI study showed that insertion of the acupuncture needle at acupoint ST 36 significantly affected the proprioceptive brain activation by decreasing blood oxygenation level-dependent signal intensity in basal ganglia, limbic system, and cerebellum. Compared with normal and PD brain, we suggest that acupuncture at ST 36 has different modulation effects depending on the pathologic condition of the brain. The study provides evidence of the potential clinical applications of retained acupuncture at ST 36 for rehabilitation therapy of PD patients.

A comparison of brain activity between healthy subjects and stroke patients on fMRI by acupuncture stimulation.

OBJECTIVE: To investigate brain activity patterns during acupuncture in stroke patients, and to compare the result with normal subjects using functional magnetic resonance imaging (fMRI). METHODS: A total of 11 stroke patients with motor weakness and 10 healthy subjects were studied. fMRI was performed during acupuncture on the left side at points Quchi (LI11) and Zusanli (ST36). Data were analyzed using statistical parametric maps of brain activation induced by acupuncture stimulation. RESULTS: The results showed that stimulation of both LI11 and ST36 produced significantly different brain activation patterns between the two groups. The normal group showed a greater overall activation than the stroke group. In the normal group, parts of the frontal lobe, parietal lobe, sub-lobar, cerebellum and midbrain regions were activated by acupuncture at the left LI11. On the other hand, only the right side of the inferior parietal lobule region was activated in the stroke patients. When the left ST36 was stimulated in the normal group, both sides of the frontal lobe, parietal lobe, temporal lobe, and sub-lobar, and the left side of occipital lobe, and the right side of cerebellum and midbrain regions were activated. For the same stimulation in the stroke group, only both sides of the inferior parietal lobule and cerebellum regions were activated (P<0.05, cluster level). Deactivation pattern was not noted during any acupuncture stimulation in both groups. CONCLUSION: Brain signal activations during the same acupuncture were different between the healthy and the stroke patients, and the effects showed a correlation of different acupuncture points.

Neural substrates of acupuncture in the modulation of cravings induced by smoking-related visual cues: an fMRI study.

RATIONALE: Cue reactivity is a key factor in modulating motivational and goal-directed behaviors associated with compulsive drug intake and relapse. Smoking-associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward. OBJECTIVES: We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges. METHODS: After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue × Session × Group). RESULTS: After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus. CONCLUSIONS: These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase.

Brain activity associated with memory and cognitive function during jaw-tapping movement in healthy subjects using functional magnetic resonance imaging.

OBJECTIVE: To determine whether jaw-tapping movement, a classically described as an indication of personal well-being and mental health, stimulates the memory and the cognitive regions of the brain and is associated with improved brain performance. METHODS: Twelve healthy right-handed female subjects completed the study. Each patient performed a jaw-tapping task and an n-back task during functional magnetic resonance imaging (fMRI). The subjects were trained to carry out the jaw-tapping movement at home twice a day for 4 weeks. The fMRI was repeated when they returned. RESULTS: During the first and second jaw-tapping session, both sides of precentral gyrus and the right middle frontal gyrus (BA 6) were activated. And during the second session of the jaw-tapping task, parts of frontal lobe and temporal lobe related to memory function were more activated. In addition, the total percent task accuracy in n-back task significantly increased after 4 weeks of jawtapping movement. After jaw-tapping training for 4 weeks, brain areas related to memory showed significantly increased blood oxygen level dependent signals. CONCLUSION: Jaw-tapping movement might be a useful exercise for stimulating the memory and cognitive regions of the brain.

Acupuncture stimulation on GB34 activates neural responses associated with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a degenerative brain disorder that is caused by neural defects in the substantia nigra. Numerous studies have reported that acupuncture treatment on GB34 (Yanglingquan) leads to significant improvements in patients with PD and in PD animal models. Studies using functional magnetic resonance imaging (fMRI) have shown that patients with PD, compared to healthy participants, have lower neural responses in extensive brain regions including the putamen, thalamus, and the supplementary motor area. OBJECTIVE: This study investigated the reported association between acupuncture point GB34 and PD. METHODS: Using fMRI, neural responses of 12 patients with PD and 12 healthy participants were examined before and after acupuncture stimulation. RESULTS: Acupuncture stimulation increased neural responses in regions including the substantia nigra, caudate, thalamus, and putamen, which are impaired caused by PD. CONCLUSIONS: Areas associated with PD were activated by the acupuncture stimulation on GB34. This shows that acupuncture treatment on GB34 may be effective in improving the symptoms of PD. Although more randomized controlled trials on the topic will be needed, this study shows that acupuncture may be helpful in the treatment of symptoms involving PD.

Differential localization of pain-related neural responses during acupuncture stimulation using Blood Oxygen Level Dependent (BOLD) fMRI in a canine model.

The objective of this study was to differentiate the neuronal responses, which was related or unrelated, to pain associated with acupuncture stimulation, and to localize the brain regions with response to stimulation that is unrelated to pain by using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI). BOLD fMRI was performed in six normal healthy beagle dogs, during placebo and verum acupuncture stimulations, at the right side of BL60 (KunLun) acupoint before and after local anesthesia of the acupoint. The order of the four sessions was placebo; verum acupuncture stimulation; before local anesthesia; and followed by the same stimulation after local anesthesia. One-sample t-test analysis was performed to localize the activated or deactivated areas, during both pre-anesthesia and post-anesthesia. In order to compare the pre-anesthesia to post-anesthetic responses, and placebo to verum acupuncture stimulation, within-subject analysis was performed. The post-anesthetic verum acupuncture stimulation resulted in increased activations in the left somatic afferent area I and II, right visual and auditory association area, and the descending reticular activating system of the brainstem. In addition, differential areas during post-anesthesia compared to that of the pre-anesthesia were in the left olfactory peduncle and descending reticular activating system of the brainstem. These results indicate that the areas of specific neural pathway are considered to be unrelated to the pain response during acupuncture stimulation.

Investigation of the delayed neuronal effects of acupuncture manipulations.

OBJECTIVES: The aim of this study was to investigate the delayed neuronal effects of acupuncture manipulations by observing blood oxygen level-dependent (BOLD) signal intensities. SUBJECTS: Fifteen (15) healthy, acupuncture-naive, right-handed subjects (all males; mean age, 23 years; range, 21-24 years) participated in this study. DESIGN AND INTERVENTIONS: Each subject was scanned in eight sessions that consisted of two repeated baseline scans (Period 1), two repeated scans with acupuncture stimulation at right LR2 (Period 2), two repeated scans with retention (Period 3), and two repeated scans after removal of the needle (Period 4). OUTCOME MEASURES: Sixteen (16) regions of interest (ROI) were defined. The BOLD signals for each session were obtained for each ROI. A mixed-effects analysis of variance (ANOVA) test was performed in order to investigate the BOLD signal differences of the Periods in the 16 ROIs. RESULTS: The BOLD signal intensities increased in Periods 2 and 3, and then started to decrease in Period 4 in the right amygdala, supramarginal gyrus, temporal pole, and superior temporal gyrus. However, the BOLD signal intensity in Period 4 was significantly higher than that of Period 1. Especially, BOLD signal intensity was elevated promptly in the insula and the parahippocampal gyrus, whereas it was persistently elevated (delayed effect) in the amygdala. CONCLUSIONS: BOLD signals were persistently elevated for at least 8 minutes after removal of the acupuncture needle or for at least 19 minutes after rotation of an acupuncture needle in some specific brain areas previously linked with LR2. In those specific brain ROIs, neuronal activation accompanying and following acupuncture showed both prompt and delayed effects.

fMRI study of effect on brain activity according to stimulation method at LI11, ST36: painful pressure and acupuncture stimulation of same acupoints.

OBJECTIVES: The objective of this study was to assess differences in brain responses between pressure and acupuncture stimulation at the same acupoint using functional magnetic resonance imaging (fMRI). SUBJECTS: A total of 10 healthy right-handed volunteers were studied. DESIGN: fMRI was performed with two different paradigms; namely, pressure and acupuncture stimulation at acupuncture points LI11 and ST36 on the left. fMRI data were analyzed using SPM2. RESULTS: In comparison with the left LI11 pressure stimulation, both sides of the parahippocampal gyrus, cerebellum, left side of thalamus, and right side of posterior cingulate regions were more activated by the left LI11 acupuncture stimulation. In comparison with the left ST36 pressure stimulation, the secondary motor cortex, limbic system (cingulate gyrus, posterior cingulate), primary visual cortex, pons, and medulla regions were more activated by left ST36 acupuncture stimulation. In comparison with the left ST36 pressure stimulation, both side of BA 4 and BA 6 were more activated by the LI11 pressure stimulation. In comparison with the left LI11 acupuncture stimulation, left BA 6, BA 8, and anterior cingulate cortex (ACC) were more activated by the left ST36 acupuncture stimulation. CONCLUSIONS: In conclusion, brain signal activation patterns according to the stimulation methods and acupoints were observed to differ. Acupuncture stimulation activated more regions than pressure at the same acupoint. In particular, acupuncture stimulation activated the limbic system, such as the parahippocampal gyrus and ACC.