Substantiating the Therapeutic Effects of Simultaneous Heat Massage Combined with Conventional Physical Therapy for Treatment of Lower Back Pain: A Randomized Controlled Feasibility Trial.

BACKGROUND: There are various therapeutic options for the conservative management of lower back pain (LBP). A combination of two or more treatment options may be more effective in the clinical management of non-specific LBP. In this study, we compared the effects of simultaneous heat massage with conventional physical therapy in patients with subacute LBP. METHODS: A single-center randomized controlled trial in which 40 participants with LBP were allocated to one of two groups: a heat massage group (HMG) and physical therapy group (PTG). The HMG received simultaneous heat massage therapy using a mechanical device (CGM MB-1401, Ceragem, Republic of Korea). The PTG received conventional physical therapy. Both groups received 40 min of therapy once daily, five times a week, for a total of four weeks. Changes in serum cortisol, epinephrine (EP), and norepinephrine (NE) were assessed. The outcomes were measured using the pain numeric rating scale (PNRS), the Oswestry disability index (ODI), the Roland-Morris disability questionnaire (RMDQ), the short-form McGill pain questionnaire (SF-MPQ), the multidimensional fatigue inventory (MFI-20), the Beck depression inventory (BDI), surface EMG (sEMG), and sympathetic skin response (SSR) at baseline (PRE), at 2 (2 W) and 4 weeks (4 W) following the intervention. RESULTS: The serum EP and NE levels in the HMG decreased after treatment. The PNRS, ODI, RMDQ, and SF-MPQ scores improved without significance in both groups. The BDI score showed improvement in the HMG before the PTG. The MFI-20 score improved in both groups, but the results were better in the HMG than in the PTG at 4 W. All the activities of sEMG were significantly decreased in both groups. However, the improvement of the %MVIC in the HMG was better than that in the PTG at 4 W. The SSR latency on sEMG decreased while the amplitude increased in the HMG at 2 W and 4 W, respectively. CONCLUSIONS: Following 4 weeks of combined therapies, heat massage was not superior to conventional physical therapy alone. Both treatments were shown to be effective in improving LBP and pain-related disability. However, heat massage was shown to have a better effect on the control of autonomic nerve function and underlying moods.

Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins.

Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.

Inositol 1,4,5-trisphosphate 3-kinase a functions as a scaffold for synaptic Rac signaling.

Activity-dependent alterations of synaptic contacts are crucial for synaptic plasticity. The formation of new dendritic spines and synapses is known to require actin cytoskeletal reorganization specifically during neural activation phases. Yet the site-specific and time-dependent mechanisms modulating actin dynamics in mature neurons are not well understood. In this study, we show that actin dynamics in spines is regulated by a Rac anchoring and targeting function of inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A), independent of its kinase activity. On neural activation, IP(3)K-A bound directly to activated Rac1 and recruited it to the actin cytoskeleton in the postsynaptic area. This focal targeting of activated Rac1 induced spine formation through actin dynamics downstream of Rac signaling. Consistent with the scaffolding role of IP(3)K-A, IP(3)K-A knock-out mice exhibited defects in accumulation of PAK1 by long-term potentiation-inducing stimulation. This deficiency resulted in a reduction in the reorganization of actin cytoskeletal structures in the synaptic area of dentate gyrus. Moreover, IP(3)K-A knock-out mice showed deficits of synaptic plasticity in perforant path and in hippocampal-dependent memory performances. These data support a novel model in which IP(3)K-A is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism.

Use of a Spinal Thermal Massage Device for Anti-oxidative Function and Pain Alleviation.

Background: Elderly people are vulnerable to a variety of diseases, including chronic pain, which reduces their levels of physical fitness. Thermal massage has been shown to relieve pain and activate antioxidant enzymes. The objective of this study was to determine whether thermal massaging of the spinal column can reduce muscle pain and induce antioxidant function. Methods: This study included participants aged ≥60 years with lower back pain. The participants were assigned to either an experimental group who received spinal column thermal massage and standard rehabilitative treatment or a control group who received standard rehabilitative treatment only. Data from a total of 116 participants (61 and 55 in the control and experimental groups, respectively) were used for analysis. Participants were assessed before treatment and at 4 (POST1) and 8 weeks (POST2) post-treatment, using a pain numeric rating scale (PNRS) and the Roland and Morris Disability Questionnaire (RMDQ), and by measuring the serum levels of superoxide dismutase (SOD), serum glutathione-peroxidase (GPx), and serum catalase (CAT). Results: The extent of pain reduction, as measured by the PNRS, was greater in the experimental group. The RMDQ score in the control group decreased at POST1, but the decrease was not maintained at POST2, whereas the decrease in POST1 in the experimental group continued until POST2. SOD concentrations were significantly higher in the experimental group at POST1 and POST2, and GPx levels were significantly higher in the experimental group at POST2; however, there were no changes in CAT concentrations. Incidentally, there was a significant correlation between antioxidant activity and pain perception in the experimental group. Conclusions: The study findings suggest that spinal column thermal massage reduces pain more effectively, improves self-reported levels of disability, and increases the antioxidant enzyme levels. Thermal massage may, therefore, be useful in the prevention and treatment of diseases associated with oxidation.

The maintenance of specific aspects of neuronal function and behavior is dependent on programmed cell death of adult-generated neurons in the dentate gyrus.

A considerable number of new neurons are generated daily in the dentate gyrus (DG) of the adult hippocampus, but only a subset of these survive, as many adult-generated neurons undergo programmed cell death (PCD). However, the significance of PCD in the adult brain for the functionality of DG circuits is not known. Here, we examined the electrophysiological and behavioral characteristics of Bax-knockout (Bax-KO) mice in which PCD of post-mitotic neurons is prevented. The continuous increase in DG cell numbers in Bax-KO mice resulted in the readjustment of afferent and efferent synaptic connections, represented by age-dependent reductions in the dendritic arborization of DG neurons and in the synaptic contact ratio of mossy fibers with CA3 dendritic spines. These neuroanatomical changes were associated with reductions in synaptic transmission and reduced performance in a contextual fear memory task in 6-month-old Bax-KO mice. These results suggest that the elimination of excess DG neurons via Bax-dependent PCD in the adult brain is required for the normal organization and function of the hippocampus.

The medial prefrontal cortex is involved in spatial memory retrieval under partial-cue conditions.

Brain circuits involved in pattern completion, or retrieval of memory from fragmented cues, were investigated. Using different versions of the Morris water maze, we explored the roles of the CA3 subregion of the hippocampus and the medial prefrontal cortex (mPFC) in spatial memory retrieval under various conditions. In a hidden platform task, both CA3 and mPFC lesions disrupted memory retrieval under partial-cue, but not under full-cue, conditions. For a delayed matching-to-place task, CA3 lesions produced a deficit in both forming and recalling spatial working memory regardless of extramaze cue conditions. In contrast, damage to mPFC impaired memory retrieval only when a fraction of cues was available. To corroborate the lesion study, we examined the expression of the immediate early gene c-fos in mPFC and the hippocampus. After training of spatial reference memory in full-cue conditions for 6 d, the same training procedure in the absence of all cues except one increased the number of Fos-immunoreactive cells in mPFC and CA3. Furthermore, mPFC inactivation with muscimol, a GABA agonist, blocked memory retrieval in the degraded-cue environment. However, mPFC-lesioned animals initially trained in a single-cue environment had no difficulty in retrieving spatial memory when the number of cues was increased, demonstrating that contextual change per se did not impair the behavioral performance of the mPFC-lesioned animals. Together, these findings strongly suggest that pattern completion requires interactions between mPFC and the hippocampus, in which mPFC plays significant roles in retrieving spatial information maintained in the hippocampus for efficient navigation.

Repetitive transcranial magnetic stimulation protects hippocampal plasticity in an animal model of depression.

Despite its therapeutic success in treating mood-related disorders, little is known about the mechanism by which repetitive transcranial magnetic stimulation (rTMS) alters physiological responses of neurons. Using the forced swim test (FST) in rats as a model of depression, we tested the protective effect of rTMS on synaptic plasticity, specifically, on the induction of hippocampal long-term potentiation (LTP). Male Sprague-Dawley rats were subjected to FST to induce immobility, a behavioral symptom of depression. They were subsequently treated with one of the three conditions: rTMS (rTMS: 1000 stimuli at 10Hz), sham rTMS (SHAM: acoustic stimulation only), or an antidepressant drug, fluoxetine (FLX: 10mg/kg, i.p.) for 7 days. There was a significant difference in immobility time between rTMS and SHAM groups after 7 days of treatment, but not after a single day. Following the second swim test on day 7, they were anesthetized and LTP was induced in vivo in the perforant path-dentate gyrus synapses. Another group (NAIVE) that had received no prior treatment was used as a control for LTP. The SHAM or FLX group exhibited little signs of LTP induction. On the contrary, the rTMS and NAIVE group showed a significant increase in field excitatory postsynaptic potentials after LTP induction. These results show that rTMS has an antidepressant-like effect after a relatively short period of treatment, and this effect might be mediated by a cellular process that can potentially reverse the impaired synaptic efficacy caused by the forced swim procedure.

Potential therapeutic mechanism of extremely low-frequency high-voltage electric fields in cells.

The aim of this survey was to provide background theory based on previous research to elucidate the potential pathway by which medical devices using extremely low-frequency high-voltage electric fields (ELF-HVEF) exert therapeutic effects on the human body, and to increase understanding of the AC high-voltage electrotherapeutic apparatus for consumers and suppliers of the relevant devices. Our review revealed that an ELF field as weak as 1-10 µ V/m can induce diverse alterations of membrane proteins such as transporters and channel proteins, including changes in Ca + + binding to a specific site of the cell surface, changes in ion (e.g., Ca + + ) influx or efflux, and alterations in the ligand-receptor interaction. These alterations then induce cytoplasmic responses within cells (Ca + + , cAMP, kinases, etc.) that can have impacts on cell growth, differentiation, and other functional properties by promoting the synthesis of macromolecules. Moreover, increased cytoplasmic Ca + + involves calmodulin-dependent signaling and consequent Ca + + /calmodulin-dependent stimulation of nitric oxide synthesis. This event in turn induces the nitric oxide-cGMP-protein kinase G pathway, which may be an essential factor in the observed physiological and therapeutic responses.

Effects of purinergic and adrenergic antagonists in a rat model of painful peripheral neuropathy.

In previous studies, pain behaviors produced in the spinal nerve ligation rat model of neuropathic pain were partly reduced by surgical lumbar sympathectomy. However, systemic injection of phentolamine, an alpha-adrenoceptor blocker, was not effective in reducing pain behaviors, at least in the Sprague-Dawley strain of rats. This suggests that sympathectomy removes not only adrenoceptor function but also other factors that must contribute importantly to the generation of neuropathic pain behaviors. Since the purinergic substance adenosine 5'-triphosphate (ATP) is known to be co-released with norepinephrine (NE) from the sympathetic nerve terminals, we hypothesized that ATP might be involved in the sympathetic dependency of neuropathic pain. The present study tested this hypothesis by examining the effects of systemic injection of an adrenoceptor blocker (phentolamine), a purinoceptor blocker (suramin), and a combination of these two on behavioral signs of mechanical allodynia in the spinal nerve ligation model of neuropathic pain. The results of the present study showed two novel findings. First, the mechanical hypersensitivity (allodynia) resulting from the L5/6 spinal nerve ligation can be reduced either by sympathetic block accomplished by application of a local anesthetic or by surgical sympathectomy of the L2-L6 sympathetic ganglia. Second, suramin (at 100 mg/kg, i.p.) can reduce mechanical hypersensitivity in neuropathic rats when given in combination with 5 mg/kg of phentolamine. This effect was observed in a subset of neuropathic rats, and the drug responses were consistent in repeated treatments within the animal group. Neither phentolamine nor suramin changed the mechanical sensitivity of neuropathic rats when given alone. The data suggest that the purinergic substance ATP is co-released with NE from sympathetic nerve terminals and these two are together involved, at least in part, in the maintenance of the sympathetically dependent component of pain behaviors in some neuropathic rats.

Non-noxious A fiber afferent input enhances capsaicin-induced mechanical hyperalgesia in the rat.

Intradermal injection of capsaicin induces primary hyperalgesia at the injection site and secondary hyperalgesia in the surrounding undamaged skin. The secondary hyperalgesia is thought to be due to central sensitization of the dorsal horn neurons while primary hyperalgesia is caused by sensitization of nociceptors in the damaged skin. In this study, we asked if additional non-noxious afferent input from the undamaged skin influences the already developed secondary hyperalgesia, which follows an intradermal injection of capsaicin. Capsaicin dissolved in olive oil was injected into the middle of the hind paw of male Sprague-Dawley rats (250-300 g) under gaseous anesthesia. This produced a decrease in the mechanical threshold at the base of the toes for hind limb withdrawals lasting for 1-2h, thus showing a short-lasting (hours) secondary hyperalgesia. When the capsaicin injection was immediately followed by repeated non-noxious mechanical stimuli or weak electrical stimuli (A fiber strength) applied to the area of secondary hyperalgesia (toes) for 30 min, the reduction of the mechanical threshold lasted longer than 24h. These results suggest that non-noxious A fiber afferent input can powerfully modulate central sensitization in the spinal dorsal horn, causing the duration of the secondary hyperalgesia to be greatly extended.

Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain.

Reactive oxygen species (ROS) are free radicals produced in biological systems that are involved in various degenerative brain diseases. The present study tests the hypothesis that ROS also play an important role in neuropathic pain. In the rat spinal nerve ligation (SNL) model of neuropathic pain, mechanical allodynia develops fully 3 days after nerve ligation and persists for many weeks. Systemic injection of a ROS scavenger, phenyl-N-tert-butylnitrone (PBN), relieves SNL-induced mechanical allodynia in a dose-dependent manner. Repeated injections cause no development of tolerance or no loss of potency. Preemptive treatment with PBN is also effective in preventing full development of neuropathic pain behavior. Systemic injection was mimicked by intrathecal injection with a little less efficacy, while intracerebroventricular administration produced a much smaller effect. These data suggest that PBN exerts its anti-allodynic action mainly by spinal mechanisms. Systemic treatment with other spin-trap reagents, 5,5-dimethylpyrroline-N-oxide and nitrosobenzene, showed similar analgesic effects, suggesting that ROS are critically involved in the development and maintenance of neuropathic pain. Thus this study suggests that systemic administration of non-toxic doses of free radical scavengers could be useful for treatment of neuropathic pain.

Spatial learning enhances the expression of inositol 1,4,5-trisphosphate 3-kinase A in the hippocampal formation of rat.

Calcium-mediated signaling is crucial for the synaptic plasticity and long-term memory storage, which requires de novo protein synthesis. Inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A) is an enzyme, which is involved in the maintenance of intracellular calcium homeostasis by converting inositol 1,4,5-trisphosphate (IP(3)) to inositol 1,3,4,5-tetrakisphosphate (IP(4)). Because IP(3)K-A is enriched in the dendritic spines of hippocampal neurons, it has been speculated that this enzyme is involved in the memory formation. In the present study, we demonstrated that the expression of IP(3)K-A is increased in the hippocampal formation of the rats during the Morris water maze training. Immunohistochemical analysis indicated the specific induction of IP(3)K-A protein in the hippocampal formation following 5-day water maze training. Furthermore, in situ hybridization histochemistry showed that the induction of IP(3)K-A mRNA in the hippocampal formation was observed on the first day of training, and the induced level of IP(3)K-A mRNA was maintained until the fifth day of training. These results suggest that IP(3)K-A plays a role in the processing of spatial memory, most likely by regulating the calcium signaling in the dendritic spines of hippocampal formation.

Specific plasticity of parallel fiber/Purkinje cell spine synapses by motor skill learning.

New synapse formation may underlie learning and memory. To examine specific synaptic plasticity by motor learning, we conducted quantitative analysis of synapses between parallel fibers and Purkinje cell dendritic spines in cerebella of rats trained to complete various obstacle courses. Synapses between parallel fibers and Purkinje cell spines were classified into single synapse boutons, multiple synapse boutons, and multiple synapse spines by their different contact features. Acrobat-trained animals had more single and multiple synaptic boutons, without change of multiple synapse spines, than motor control animals. These results may suggest that motor learning induces specific synaptogenesis and Purkinje cell spines are primary sites in motor learning-dependent cerebellar synaptic plasticity.

Is 1/f sound more effective than simple resting in reducing stress response?

BACKGROUND: It has been previously demonstrated that listening to 1/f sound effectively reduces stress. However, these findings have been inconsistent and further study on the relationship between 1/f sound and the stress response is consequently necessary. OBJECTIVE: The present study examined whether sound with 1/f properties (1/f sound) affects stress-induced electroencephalogram (EEG) changes. METHODS: Twenty-six subjects who voluntarily participated in the study were randomly assigned to the experimental or control group. Data from four participants were excluded because of EEG artifacts. A mental arithmetic task was used as a stressor. Participants in the experiment group listened to 1/f sound for 5 minutes and 33 seconds, while participants in the control group sat quietly for the same duration. EEG recordings were obtained at various points throughout the experiment. After the experiment, participants completed a questionnaire on the affective impact of the 1/f sound. RESULTS: The results indicated that the mental arithmetic task effectively induced a stress response measurable by EEG. Relative theta power at all electrode sites was significantly lower than baseline in both the control and experimental group. Relative alpha power was significantly lower, and relative beta power was significantly higher in the T3 and T4 areas. Secondly, 1/f sound and simple resting affected task-associated EEG changes in a similar manner. Finally, participants reported in the questionnaire that they experienced a positive feeling in response to the 1/f sound. CONCLUSIONS: Our results suggest that a commercialized 1/f sound product is not more effective than simple resting in alleviating the physiological stress response.

Identification and characterization of novel activity-dependent transcription factors in rat cortical neurons.

Using gene chip analyses, we have identified novel neuronal activity-dependent genes. Application of 25 mM KCl to mature (14-day culture) rat cortical neurons resulted in more than 1.5-fold induction of 19 genes and reduction of 42 genes among 1200 neural genes. Changes in the overall gene expression profiles appeared to be related to the reduction of excitability and induction of cellular survival signals. Among the genes identified, three transcriptional modulators [encoding Cbp/p300-interacting transactivator with ED-rich tail 2 (CITED2), CCAAT/enhancer binding protein beta (C/EBPbeta) and neuronal orphan receptor-1, (NOR1)] were newly identified as activity-dependent transcription factors, and two of these (CITED2 and NOR1) were found to be influenced by electroconvulsive shock (ECS). NOR1 was induced in specific brain regions by behavioral activation, such as exposure to a novel environment. Because the brain regions that exhibited the induction of these newly identified neuronal activity-dependent transcriptional modulators were distinct from those showing the induction of previously identified activity-dependent genes such as c-fos, these genes might be useful markers for mapping neuronal activity in vivo.

Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats.

Perinatal hypoxia-ischemia is one of the most common risk factors for neonatal mortality and permanent neurodevelopmental disability. Topiramate [2,3:4,5-bis-o-(1-methylethylidene) beta-D-fructo-pyranose sulfamate; TPM] is widely used as an antiepileptic agent with multiple targets. In the present study, we found that treatment with TPM reduced the neuronal damage induced by oxygen-glucose deprivation in vitro with strong inhibition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor. Because perinatal hypoxia is mediated, at least in part, by aberrant glutamatergic excitation, we tested whether treatment with TPM was effective against perinatal brain hypoxia-ischemia. Intraperitoneal or oral pretreatment with TPM was found to reduce the brain damage and subsequent cognitive impairments induced by transient hypoxia-ischemia in perinatal rats. A potent neuroprotective effect of TPM was also observed in a post-treatment regime although post-treatment window appears to be relatively narrow (<2 h). These results suggest that TPM treatment may be beneficial for perinatal hypoxia-ischemia and related damage.

Identification of novel electroconvulsive shock-induced and activity-dependent genes in the rat brain.

Electroconvulsive shock (ECS) has been used as an effective treatment for patients suffering from major depression disorders and schizophrenia. However, the exact mechanisms underlying the action of ECS are poorly understood. Using high-density oligonucleotide microarrays, we identified 60 ECS-induced genes whose gene products are involved in the neuronal signaling, neuritogenesis and tissue remodeling. In situ hybridization and depolarization-dependent expression assay were performed to characterize 4 genes (lysyl oxidase, Ab1-046, SOX11, and T-type calcium channel 1G subunit) which have not yet been reported to be induced by ECS. Interestingly, the induction of these genes was observed mainly in the dentate gyrus of hippocampal formation and piriform cortex, where ECS-induced neural activation is highlighted, and depolarization of cultured cortical neurons also induced the expression of these genes. Taken together, our results suggest that therapeutic actions of ECS may be manifested by the activity-dependent induction of genes related to the plastic changes of the brain such as neuronal signaling neuritogenesis, and tissue remodeling.