Electroceuticals are medical devices that employ electric signals to alter the activity of specific nerve fibers to achieve therapeutic effects. The rapid growth of RF microelectronics has resulted in the development ...Electroceuticals are medical devices that employ electric signals to alter the activity of specific nerve fibers to achieve therapeutic effects. The rapid growth of RF microelectronics has resulted in the development of very small, portable, and inexpensive shortwave and microwave radio frequency (RF) amplifiers, raising the possibility of utilizing these new RF technologies to develop non-contact electroceutical devices. However, the bio-electromagnetics literature suggests that beyond 10 MHz, RF fields cannot influence biological tissue, beyond simple heating, because effective demodulation mechanisms at these frequencies do not exist in the body. However, RF amplifiers operating at or near saturation have non-linear interactions with complex loads, and if body tissue creates a complex loading condition, the opportunity exists for the coupled system to produce non-linear effects, that is, the equivalent of demodulation may occur. Correspondingly, exposure of tissue to pulsed RF energy could result in the creation of low frequency demodulation components capable of influencing tissue activity. Here, we develop a one-dimen- sional, numerical simulation to investigate the complex loading conditions under which such demodulation could arise. Applying these results in a physical prototype device, we show that up to7.5% demodulation can be obtained for a 40 MHz RF field pulsed at 1 KHz. Implications for this research include the possibility of developing wearable, electromagnetic electroceutical de- vices.展开更多
Acute myocardial infarction （AMI） is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. H...Acute myocardial infarction （AMI） is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. However, 25% of patients proceed to develop heart failure （HF） after myocardial infarction （MI） and 50% of these will die within five years. Since the size of the infarct is the major predictor of the outcome, including the development of HF, therapies to improve myocardial salvage have great potential. Over the past three decades, a number of stimuli have been discovered that activate endogenous cardioprotective pathways. In ischemic preconditioning （IPC） and ischemic postconditioning, ischemia within the heart initiates the protection. Brief reversible episodes of ischemia in vascular beds remote from the heart can also trigger cardioprotection when applied before, during, or immediately after myocardial ischemia-- known as remote ischemic pre-, per-, and post-conditioning, respectively. Although the mechanism of remote ischemic preconditioning （RIPC） has not yet been fully elucidated, many mechanistic components are shared with IPC. The discovery of RIPC led to research into the use of remote non-ischemic stimuli including nerve stimulation （spinal and vagal）, and electroacupuncture （EA）. We discovered and, with others, have elucidated mechanistic aspects of a non- ischemic phenomenon we termed remote preconditioning of trauma （RPCT）. RPCT operates via neural stimulation of skin sensory nerves and has similarities and differences to nerve stimulation and EA conducted at acupoints. We show herein that RPCT can be mimicked using electrical stimulation of the abdominal midline （EA-like treatment） and that this modality of activating cardioprotection is powerful as both a preconditioning and a postconditioning stimulus （when applied at reperfusion）. Investigations of these cardioprotective phenomena have led to a more integrative understanding of mechanisms related to cardioprotection, and in the last five to ten years, it has become clear that the mechanisms are similar, whether induced by ischemic or non-ischemic stimuli. Taking together much of the data in the literature, we propose that all of these cardioprotective ＂conditioning＂ phenomena represent activation from different entry points of a cardiac conditioning network that converges upon specific mediators and effectors of myocardial cell survival, including NF-KB, Stat3/5, protein kinase C, bradykinin, and the mitoKA^P channel. Nervous system pathways may represent a novel mechanism for initiating conditioning of the heart and other organs. IPC and RIPC have proven difficult to translate clinically, as they have associated risks and cannot be used in some patients. Because of this, the use of neural and nociceptive stimuli is emerging as a potential non-ischemic and non-traumatic means to initiate cardiac conditioning. Clinical relevance is underscored by the demonstration of postconditioning with one of these modalities, supporting the conclusion that the development of pharmaceuticals and electroceuticals for this purpose is an area ripe for clinical development.展开更多
Background:Synchronization across neural circuits is inextricably associated with brain function and pathology.Although not largely explored,this framework can be applied to baseline anxiety and its disorder,which is ...Background:Synchronization across neural circuits is inextricably associated with brain function and pathology.Although not largely explored,this framework can be applied to baseline anxiety and its disorder,which is characterized by aberrant levels of synchronization between the amygdala nuclei and other areas of the extended amygdala,particularly the bed nucleus of the stria terminalis(BNST)and those outside this complex.Here,we aimed to test the hypothesis that a temporally complex form of electrical stimulation(non-periodic stimulation[NPS])of the amygdala,specifically designed to disrupt hypersynchronous activity in epilepsy,a major comorbidity of pathological anxiety,may reduce its symptoms.Methods:Wistar rats were subjected to a physical restriction protocol model of stress to induce pathological anxiety and were assessed using the gold standard elevated plus maze(EPM)and open field(OF)tests.Result:In all criteria measured by the tests,NPS animals displayed reduced levels of anxiety-related symptoms,back at physiological levels.Conclusions:Considering the known effects and mechanisms of NPS on epileptic phenomena,we hypothesized that the therapeutic effects were achieved by desynchronization(or normalization of synchronism levels)across brain circuits involving the amygdala,BNST,and others.Overall,past and present findings suggest that NPS may be considered as a therapeutic alternative for the treatment of anxiety disorders.展开更多
文摘Electroceuticals are medical devices that employ electric signals to alter the activity of specific nerve fibers to achieve therapeutic effects. The rapid growth of RF microelectronics has resulted in the development of very small, portable, and inexpensive shortwave and microwave radio frequency (RF) amplifiers, raising the possibility of utilizing these new RF technologies to develop non-contact electroceutical devices. However, the bio-electromagnetics literature suggests that beyond 10 MHz, RF fields cannot influence biological tissue, beyond simple heating, because effective demodulation mechanisms at these frequencies do not exist in the body. However, RF amplifiers operating at or near saturation have non-linear interactions with complex loads, and if body tissue creates a complex loading condition, the opportunity exists for the coupled system to produce non-linear effects, that is, the equivalent of demodulation may occur. Correspondingly, exposure of tissue to pulsed RF energy could result in the creation of low frequency demodulation components capable of influencing tissue activity. Here, we develop a one-dimen- sional, numerical simulation to investigate the complex loading conditions under which such demodulation could arise. Applying these results in a physical prototype device, we show that up to7.5% demodulation can be obtained for a 40 MHz RF field pulsed at 1 KHz. Implications for this research include the possibility of developing wearable, electromagnetic electroceutical de- vices.
基金supported by grants from the National Institutes of Health (NIHR01 HL091478) for W.Keith Jonesthe National Natural Science Foundation of China (81470425) for Xiaoping Ren
文摘Acute myocardial infarction （AMI） is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. However, 25% of patients proceed to develop heart failure （HF） after myocardial infarction （MI） and 50% of these will die within five years. Since the size of the infarct is the major predictor of the outcome, including the development of HF, therapies to improve myocardial salvage have great potential. Over the past three decades, a number of stimuli have been discovered that activate endogenous cardioprotective pathways. In ischemic preconditioning （IPC） and ischemic postconditioning, ischemia within the heart initiates the protection. Brief reversible episodes of ischemia in vascular beds remote from the heart can also trigger cardioprotection when applied before, during, or immediately after myocardial ischemia-- known as remote ischemic pre-, per-, and post-conditioning, respectively. Although the mechanism of remote ischemic preconditioning （RIPC） has not yet been fully elucidated, many mechanistic components are shared with IPC. The discovery of RIPC led to research into the use of remote non-ischemic stimuli including nerve stimulation （spinal and vagal）, and electroacupuncture （EA）. We discovered and, with others, have elucidated mechanistic aspects of a non- ischemic phenomenon we termed remote preconditioning of trauma （RPCT）. RPCT operates via neural stimulation of skin sensory nerves and has similarities and differences to nerve stimulation and EA conducted at acupoints. We show herein that RPCT can be mimicked using electrical stimulation of the abdominal midline （EA-like treatment） and that this modality of activating cardioprotection is powerful as both a preconditioning and a postconditioning stimulus （when applied at reperfusion）. Investigations of these cardioprotective phenomena have led to a more integrative understanding of mechanisms related to cardioprotection, and in the last five to ten years, it has become clear that the mechanisms are similar, whether induced by ischemic or non-ischemic stimuli. Taking together much of the data in the literature, we propose that all of these cardioprotective ＂conditioning＂ phenomena represent activation from different entry points of a cardiac conditioning network that converges upon specific mediators and effectors of myocardial cell survival, including NF-KB, Stat3/5, protein kinase C, bradykinin, and the mitoKA^P channel. Nervous system pathways may represent a novel mechanism for initiating conditioning of the heart and other organs. IPC and RIPC have proven difficult to translate clinically, as they have associated risks and cannot be used in some patients. Because of this, the use of neural and nociceptive stimuli is emerging as a potential non-ischemic and non-traumatic means to initiate cardiac conditioning. Clinical relevance is underscored by the demonstration of postconditioning with one of these modalities, supporting the conclusion that the development of pharmaceuticals and electroceuticals for this purpose is an area ripe for clinical development.
基金supported by the Fundaç~ao de Amparo a Pesquisa de Minas Gerais,Brazil(FAPEMIG)(No.APQ 02485-15)the Conselho Narcional de Desenvolvimento Científico e Tecnologico(CNPq)(schol-arship for scientific studies to the first author).
文摘Background:Synchronization across neural circuits is inextricably associated with brain function and pathology.Although not largely explored,this framework can be applied to baseline anxiety and its disorder,which is characterized by aberrant levels of synchronization between the amygdala nuclei and other areas of the extended amygdala,particularly the bed nucleus of the stria terminalis(BNST)and those outside this complex.Here,we aimed to test the hypothesis that a temporally complex form of electrical stimulation(non-periodic stimulation[NPS])of the amygdala,specifically designed to disrupt hypersynchronous activity in epilepsy,a major comorbidity of pathological anxiety,may reduce its symptoms.Methods:Wistar rats were subjected to a physical restriction protocol model of stress to induce pathological anxiety and were assessed using the gold standard elevated plus maze(EPM)and open field(OF)tests.Result:In all criteria measured by the tests,NPS animals displayed reduced levels of anxiety-related symptoms,back at physiological levels.Conclusions:Considering the known effects and mechanisms of NPS on epileptic phenomena,we hypothesized that the therapeutic effects were achieved by desynchronization(or normalization of synchronism levels)across brain circuits involving the amygdala,BNST,and others.Overall,past and present findings suggest that NPS may be considered as a therapeutic alternative for the treatment of anxiety disorders.
