Brain stimulation patterns emulating endogenous thalamocortical input to parvalbumin-expressing interneurons reduce nociception in mice.

BACKGROUND: The bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated. OBJECTIVE: We investigated the role of cortical parvalbumin expressing (PV) interneurons within the TC circuit in gating nociception and their selective response to TC burst patterns. We then tested if transcranial magnetic stimulation (TMS) patterned on endogenous nociceptive TC bursting modulate nociceptive behaviors. METHODS: The switching of TC neurons between tonic (single spike) and burst (high frequency spikes) firing modes may be a critical component in modulating nociceptive signals. Deep brain electrical stimulation of TC neurons and immunohistochemistry were used to examine the differential influence of each firing mode on cortical PV interneuron activity. Optogenetic stimulation of cortical PV interneurons assessed a direct role in nociceptive modulation. A new TMS protocol mimicking thalamic burst firing patterns, contrasted with conventional continuous and intermittent theta burst protocols, tested if TMS patterned on endogenous TC activity reduces nociceptive behaviors in mice. RESULTS: Immunohistochemical evidence confirmed that burst, but not tonic, deep brain stimulation of TC neurons increased the activity of PV interneurons in the cortex. Both optogenetic activation of PV interneurons and TMS protocol mimicking thalamic burst reduced nociceptive behaviors. CONCLUSIONS: Our findings suggest that burst firing of TC neurons recruits PV interneurons in the cortex to reduce nociceptive behaviors and that neuromodulation mimicking thalamic burst firing may be useful for modulating nociception.

Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface.

We present non-invasive means that detect unilateral hand motor brain activity from one individual and subsequently stimulate the somatosensory area of another individual, thus, enabling the remote hemispheric link between each brain hemisphere in humans. Healthy participants were paired as a sender and a receiver. A sender performed a motor imagery task of either right or left hand, and associated changes in the electroencephalogram (EEG) mu rhythm (8-10 Hz) originating from either hemisphere were programmed to move a computer cursor to a target that appeared in either left or right of the computer screen. When the cursor reaches its target, the outcome was transmitted to another computer over the internet, and actuated the focused ultrasound (FUS) devices that selectively and non-invasively stimulated either the right or left hand somatosensory area of the receiver. Small FUS transducers effectively allowed for the independent administration of stimulatory ultrasonic waves to somatosensory areas. The stimulation elicited unilateral tactile sensation of the hand from the receiver, thus establishing the hemispheric brain-to-brain interface (BBI). Although there was a degree of variability in task accuracy, six pairs of volunteers performed the BBI task in high accuracy, transferring approximately eight commands per minute. Linkage between the hemispheric brain activities among individuals suggests the possibility for expansion of the information bandwidth in the context of BBI.

Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.

BACKGROUND: Transcranial focused ultrasound (FUS) is gaining momentum as a novel non-invasive brain stimulation method, with promising potential for superior spatial resolution and depth penetration compared to transcranial magnetic stimulation or transcranial direct current stimulation. We examined the presence of tactile sensations elicited by FUS stimulation of two separate brain regions in humans-the primary (SI) and secondary (SII) somatosensory areas of the hand, as guided by individual-specific functional magnetic resonance imaging data. RESULTS: Under image-guidance, acoustic stimulations were delivered to the SI and SII areas either separately or simultaneously. The SII areas were divided into sub-regions that are activated by four types of external tactile sensations to the palmar side of the right hand-vibrotactile, pressure, warmth, and coolness. Across the stimulation conditions (SI only, SII only, SI and SII simultaneously), participants reported various types of tactile sensations that arose from the hand contralateral to the stimulation, such as the palm/back of the hand or as single/neighboring fingers. The type of tactile sensations did not match the sensations that are associated with specific sub-regions in the SII. The neuro-stimulatory effects of FUS were transient and reversible, and the procedure did not cause any adverse changes or discomforts in the subject's mental/physical status. CONCLUSIONS: The use of multiple FUS transducers allowed for simultaneous stimulation of the SI/SII in the same hemisphere and elicited various tactile sensations in the absence of any external sensory stimuli. Stimulation of the SII area alone could also induce perception of tactile sensations. The ability to stimulate multiple brain areas in a spatially restricted fashion can be used to study causal relationships between regional brain activities and their cognitive/behavioral outcomes.

Oldenlandia diffusa Promotes Antiproliferative and Apoptotic Effects in a Rat Hepatocellular Carcinoma with Liver Cirrhosis.

Oldenlandia diffusa (OD) is commonly used with various diseases such as cancer, arthritis, and autoimmune disease. Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). Here, we show that the therapeutic effect of OD, which was investigated both in vitro and chemically, induced HCC model. OD significantly enhanced apoptosis and antiproliferative activity and reduced migration ability of HCC cells. In vivo, OD was treated twice a day for 28 days after confirmed HCC model through 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) imaging. The survival in OD treated groups was shown to have a greater therapeutic effect than the control group. 28 days after OD treatment, OD treated groups resulted in a significant reduction in tumor number, size, (18)F-FDG uptake, and serum levels such as alanine transaminase, aspartate transaminase, and alkaline phosphate compared to the control group. Also, proliferated cells in tumor sites by OD were reduced compared to the control group. Furthermore, several rats in OD treated group survived over 60 days and liver morphology of these rats showed the difference between tumor mass and normal tissue. These results suggest that OD may have antiproliferative activity, inhibition of metastasis, and apoptotic effects in chemically induced HCC model and can have the potential use for clinical application as anticancer drug of the herbal extract.

Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.

Focused ultrasound (FUS) has recently been investigated as a new mode of non-invasive brain stimulation, which offers exquisite spatial resolution and depth control. We report on the elicitation of explicit somatosensory sensations as well as accompanying evoked electroencephalographic (EEG) potentials induced by FUS stimulation of the human somatosensory cortex. As guided by individual-specific neuroimage data, FUS was transcranially delivered to the hand somatosensory cortex among healthy volunteers. The sonication elicited transient tactile sensations on the hand area contralateral to the sonicated hemisphere, with anatomical specificity of up to a finger, while EEG recordings revealed the elicitation of sonication-specific evoked potentials. Retrospective numerical simulation of the acoustic propagation through the skull showed that a threshold of acoustic intensity may exist for successful cortical stimulation. The neurological and neuroradiological assessment before and after the sonication, along with strict safety considerations through the individual-specific estimation of effective acoustic intensity in situ and thermal effects, showed promising initial safety profile; however, equal/more rigorous precautionary procedures are advised for future studies. The transient and localized stimulation of the brain using image-guided transcranial FUS may serve as a novel tool for the non-invasive assessment and modification of region-specific brain function.

A Pilot Study for the Neuroprotective Effect of Gongjin-dan on Transient Middle Cerebral Artery Occlusion-Induced Ischemic Rat Brain.

In this study, we investigated whether gongjin-dan improves functional recovery and has neuroprotective effects on reducing the infarct volume after transient middle cerebral artery occlusion (MCAo). Infarct volume was measured using TTC staining and glucose utilization by F-18 FDG PET. Functional improvement was evaluated with the Rota-rod, treadmill, Garcia score test, and adhesive removal test. At 14 days after MCAo, neuronal cell survival, astrocytes expansion, and apoptosis were assessed by immunohistofluorescence staining in the peri-infarct region. Also, the expression of neurotrophic factors and inflammatory cytokines such as VEGF, BDNF, Cox-2, TNF-α, IL-1ß, and IL-1α was measured in ischemic hemisphere regions. The gongjin-dan-treated group showed both reduced infarct volume and increased glucose utilization. Behavior tests demonstrated a significant improvement compared to the control. Also in the gongjin-dan treated group, NeuN-positive cells were increased and number of astrocytes, microglia, and apoptotic cells was significantly decreased compared with the control group in the ischemic peri-infarct area. Furthermore, the expression of VEGF and BDNF was increased and level of Cox-2, TNF-α, IL-1ß, and IL-1α was decreased. These results suggest that gongjin-dan may improve functional outcome through the rapid restoration of metabolism and can be considered as a potential neuroprotective agent.

Electroacupuncture enhances motor recovery performance with brain-derived neurotrophic factor expression in rats with cerebral infarction.

OBJECTIVE: Electroacupuncture (EA) is a traditional medicine in patients with post-stroke rehabilitation. Brain-derived neurotrophic factor (BDNF) is a potent growth factor involved in recovery following cerebral injury. The aim of the present study was to investigate whether EA increases BDNF levels and facilitates functional recovery. METHODS: Occlusion of the middle cerebral artery was performed in rats (N=12) followed by reperfusion. EA was applied at the GV20 (Baihui) acupoint. Motor and sensory functions were monitored on the Garcia scale for 2 weeks. Expressions of BDNF and receptor tyrosine kinase B (trkB) were determined by immunoblotting and immunohistochemistry. RESULTS: Improvement of Garcia scores, particularly in motor performance, were noted in the group with EA stimulation (p<0.05). With EA application, BDNF was elevated in the ischaemic hemisphere with increased numbers of BDNF(+) cells. Increased expression of trkB was also detected. CONCLUSION: These results indicate that EA at GV20 improves motor recovery and stimulates BDNF/trkB expression in rats with cerebral ischaemia.

Changes in brain FDG metabolism induced by acupuncture in healthy volunteers.

BACKGROUND: With the aid of newly developed functional brain imaging studies, studies are ongoing to see if acupuncture first acts on specific brain areas to induce effects on the human body. PURPOSE: To examine if stimulation at specific acupuncture points changes brain glucose metabolism patterns, including the limbic system and specific brain areas related to the acupuncture effect in healthy volunteers using fluorodeoxyglucose positron emission tomography combined computed tomography (FDG-PET/CT). MATERIAL AND METHODS: Twenty healthy volunteers (11 men and 9 women; mean age 49.1+/-7.3 years, age range 35-62 years) were included. Two sets of PET/CT scans were obtained from each volunteer, with and without stimulation by acupuncture. Two classic acupoints, LR3 (liver meridian) and ST44 (stomach meridian) were tested at the same time, using disposable sterile stainless steel needles. After initial acupuncture, the needle was kept in place without further stimulation. FDG-PET/CT scan of the brain began 45 min after FDG injection (185-222 MBq). RESULTS: After stimulation of LR3 and ST44 by acupuncture, glucose metabolism in the brain was increased in the left insula (BA 13), bilateral thalami, superior frontal region of the right frontal lobe, and the inferior frontal region of left frontal lobe compared with baseline. On the other hand, glucose metabolism was decreased after acupuncture in the cingulate and parahippocampal (BA 36) regions of the left limbic lobe. CONCLUSION: Changes of glucose metabolism in specific brain areas following stimulation by acupuncture on LR3 and ST44 were documented using FDG-PET/CT.

Effect of combination therapy with sodium ozagrel and panax ginseng on transient cerebral ischemia model in rats.

Sodium ozagrel (SO) prevents platelet aggregation and vasoconstriction in the cerebral ischemia. It plays an important role in the prevention of brain damage induced by cerebral ischemia/reperfusion. Recently, many animal studies have suggested that the Panax ginseng (PG) has neuroprotective effects in the ischemic brain. In this study, we assessed the neuroprotective effects that come from a combination therapy of SO and PG in rat models with middle cerebral artery occlusion (MCAO). Animals with MCAO were assigned randomly to one of the following four groups: (1) control (Con) group, (2) SO group (3 mg/kg, intravenously), (3) PG group (200 mg/kg, oral feeding), and (4) SO + PG group. The rats were subjected to a neurobehavior test including adhesive removal test and rotarod test at 1, 3, 7, 10, and 15 days after MCAO. The cerebral ischemic volume was quantified by Metamorph imaging software after 2-3-5-triphenyltetrazolium (TTC) staining. The neuronal cell survival and astrocytes expansion were assessed by immunohistofluorescence staining. In the adhesive removal test, the rats of PG or SO + PG group showed significantly better performance than those of the control group (Con: 88.1 ± 24.8, PG: 43.6 ± 11, SO + PG: 11.8 ± 7, P < .05). Notably, the combination therapy group (SO + PG) showed better performance than the SO group alone (SO: 56 ± 12, SO + PG: 11.8 ± 7, P < .05). In TTC staining for infarct volume, cerebral ischemic areas were also significantly reduced in the PG group and SO + PG group (Con: 219 ± 32, PG: 117 ± 8, SO + PG: 99 ± 11, P < .05). Immunohistofluorescence staining results showed that the group which received SO + PG group therapy had neuron cells in the normal range. They also had a low number of astrocytes and apoptotic cells compared with the control or SO group in the peri-infarction area. During astrocytes staining, compared to the SO + PG group, the PG group showed only minor differences in the number of NeuN-positive cells and quantitative analysis of infarct volume. In conclusion, these studies showed that in MCAO rat models, the combination therapy with SO and PG may provide better neuroprotective effects such as higher neuronal cell survival and inhibition of astrocytes expansion than monotherapy with SO alone.

Regional cerebral blood flow in patients with alcohol-related dementia: a SPECT study.

The purpose of this study was to investigate regional cerebral blood flow (rCBF) changes using 1110 MBq of Tc-99m ECD SPECT in alcohol-related dementia (ARD) patients. Twenty-five patients with ARD and 22 healthy control subjects were included in the study. Mini-Mental Status Examination was applied to the patients and controls. The ARD patients showed drastically reduced rCBF in the frontal cortices, basal ganglia, and thalami. The results indicate that ARD is associated with hypoperfusion in both cortical and subcortical regions. These findings support previous studies suggesting the association with both cortical and subcortical neuropathology in ARD patients.

The clinical value of dacryoscintigraphy in the selection of surgical approach for patients with functional lacrimal duct obstruction.

PURPOSE: Dacryoscintigraphy is widely known to be an effective modality in diagnosing abnormalities of the lacrimal system that cause epiphora (pathological overflow of tear). However, dacryoscintigraphy rarely serves beyond the simple diagnostic use for lacrimal duct obstruction. In our study, dacryoscintigraphy results of patients with functional lacrimal duct obstruction are newly classified into three types, the effects and prognoses of silicone tube intubation are noted according to each type, and the role of dacryoscintigraphy in determining appropriate surgical approaches is evaluated. METHODS: Subjects were 36 eyes of 29 patients complaining of epiphora who had increased tear meniscus, but showed no sign of obstruction on duct syringing. Impression of functional lacrimal duct obstruction was made through dacryoscintigraphy, and silicone tubes were inserted. RESULTS: Patients were classified according to the results of dacryoscintigraphy; those with delayed secretion in the distal nasolacrimal duct were typed as class I; those with delays in the proximal nasolacrimal duct class II; and delayed secretion from the pre-lacrimal sac to the lacrimal sac as class III. All patients had silicone tube intubations together with selective punctoplasty. Symptomatic improvement was observed in all 6 cases of distal nasolacrimal duct obstruction (100%), 14 of 18 proximal obstruction cases (77.8%), and 8 of 12 pre-lacrimal obstructions (66.7%). CONCLUSIONS: Functional lacrimal duct obstruction is easily diagnosed with dacryoscintigraphy. Furthermore, its may be classified by types of obstruction to predict post-operative results of silicone tube insertion. Cases suspicious of pre-lacrimal sac obstructions in particular may achieve better operative results with adjuvant treatments in addition to silicone tube insertion.