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Millimeter Wave Effects on Electrical Responses of the Sural Nerve In Vivo
Abstract
Millimeter wave (MMW, 42.25 GHz)-induced changes in electrical activity of the murine sural nerve were studied in vivo using external electrode recordings. MMW were applied to the receptive field of the sural nerve in the hind paw. We found two types of responses of the sural nerve to MMW exposure. First, MMW exposure at the incident power density >/=45 mW/cm(2) inhibited the spontaneous electrical activity. Exposure with lower intensities (10-30 mW/cm(2)) produced no detectable changes in the firing rate. Second, the nerve responded to the cessation of MMW exposure with a transient increase in the firing rate. The effect lasted 20-40 s. The threshold intensity for this effect was 160 mW/cm(2). Radiant heat exposure reproduced only the inhibitory effect of MMW but not the transient excitatory response. Depletion of mast cells by compound 48/80 eliminated the transient response of the nerve. It was suggested that the cold sensitive fibers were responsible for the inhibitory effect of MMW and radiant heat exposures. However, the receptors and mechanisms involved in inducing the transient response to MMW exposure are not clear. The hypothesis of mast cell involvement was discussed.
... Neuronal activity is a particularly good marker for gauging stimulus thresholds since the neuronal membrane is optimised for sensing and in conducting electrical impulses with millisecond temporal response. Several research groups [8][9][10][11][12][13][14][15][16][17][18] have noted significant impact on neuronal activity induced in vivo by modest levels of millimetre-wave exposure (40-130 GHz, 1 -100 mW/cm 2 , seconds to minutes) that are not much higher than the MPE. Synchronisation of the firing rate of neurons in the hypothalamus of both rabbit and rat was observed at and below 10 mW/cm 2 [8,9]. ...
... Even at 2-3mW/cm 2 , at certain frequencies between 40 and 52 GHz, an isolated frog sciatic nerve showed measureable changes in the amplitude and latency of its compound action potential [11]. Higher levels of millimetre-wave power (10 -100mW/cm 2 ), which tend to raise the temperature of the exposed sample, have been shown to produce changes in neuronal activity that sometimes do, and sometimes do not, correlate with broadband radiant heating [12][13][14][15]. For example, changes in action potential firing rates in skate skin exposed to 130mW/cm 2 at 54 GHz were anti-correlated with those produced by radiant heating [12]. ...
... Similar results, correlating millimetre-wave exposure (62 and 75 GHz) and direct temperature rise, were also reported for the changes induced in ionic currents in these neurons [14]. Most recently, the electrical response of an exposed frog sural nerve (.45mW/cm 2 at 42 GHz) showed threshold effects and transient behaviour that were not well reproduced by broadband radiant heating [15]. Additional studies have focused on millimetre-wave induced changes in cell membrane permeability. ...
Investigations on the biological impact of low levels of millimetre-wave energy date back to the first experiments on the generation and detection of these high-frequency signals by Sir Jagadis Chunder Bose at the end of the 19th century. Slightly more than a hundred years later, millimetre-wave transmission has become a ubiquitous commercial reality. Despite the widespread use of millimetre-wave transmitters for communications, radar and even non-lethal weapons systems, only a handful of researchers have funded programmes focusing on millimetre-wave interactions with biological systems. As such, there is a growing need for a better understanding of the mechanisms of these interactions and their possible adverse and therapeutic implications. Independent of the health impact of long-term exposure to high doses of millimetre-wave energy on whole organisms, there exists the potential for subtle effects on specific tissues or organs which can best be quantified in studies which examine real-time changes in cellular function as energy is applied. In this Letter, a series of experiments are presented which show changes in cell membrane potential and the action potential firing rate of cortical neurons under short (1 min) exposures to continuous-wave 60 GHz radiation at W/cm2 power levels, more than 1000 times below the US government maximum permissible exposure. The findings have implications for non-contact stimulation and control of neurologic function, and might prove useful in a variety of health applications from suppression of peripheral neuropathic pain to the treatment of central neurological disorders.
... Yet with no dedicated funding from U.S. Civilian Federal Agencies, very few research groups are willing to undertake these studies. Several investigations [4][5][6][7][8][9][10][11][12][13][14][15][16], mainly outside the U.S., have noted significant impact on neuronal activity from modest level millimeter wave exposures (40-130 GHz, 1-100 mW/cm 2 , seconds to minutes) that are not much higher than the Federal Communications Commission-established maximum permissible exposure (MPE) limits of 1 mW/cm 2 for 6 minutes in the 30-300 GHz frequency regime [17]. Synchronization of the firing rate of neurons in the hypothalamus of both rabbit and rat was observed at and below 10 mW/cm 2 [4,5]. ...
... Even at 2-3mW/cm 2 , at certain frequencies between 40 and 52 GHz an isolated frog sciatic nerve showed measureable changes in the amplitude and latency of its compound action potential [7]. Higher levels of millimeter-wave power (10-100mW/cm 2 ), which tend to raise the temperature of the exposed sample, have been shown to produce changes in neuronal activity that sometimes do, and sometimes don't correlate with broadband radiant heating [8][9][10][11]. For example, changes in action potential firing rates in skate skin exposed to 130mW/cm 2 at 54 GHz were anticorrelated with those produced by radiant heating [8]. In another study, however, exposure of snail pacemaker neurons to 75 GHz radiation at levels sufficient to raise the temperature several degrees in a few seconds showed changes in firing rate that matched those produced by radiant heating [9]. ...
... Similar results correlating millimeter wave exposure (62 and 75 GHz) and direct temperature rise were also reported for the changes induced in ionic currents in these neurons [10]. Most recently, the electrical response of an exposed frog sural nerve (>45mW/cm 2 at 42 GHz) showed threshold effects and transient behavior that were not well reproduced by broadband radiant heating [11]. Additional studies have focused on millimeter-wave induced changes in cell membrane permeability. ...
As the application and commercial use of millimeter- and submillimeter-wavelength radiation become more widespread, there is a growing need to understand and quantify both the coupling mechanisms and the impact of this long wavelength energy on biological function. Independent of the health impact of high doses of radio frequency (RF) energy on full organisms, which has been extensively investigated, there exists the potential for more subtle effects, which can best be quantified in studies which examine real-time changes in cellular functions as RF energy is applied. In this paper we present the first real time examination of RF induced changes in cellular activity at absorbed power levels well below the existing safe exposure limits. Fluorescence microscopy imaging of immortalized epithelial and neuronal cells in vitro indicate increased cellular membrane permeability and nanoporation after short term exposure to modest levels (10-50 mW/cm2) of RF power at 60 GHz. Sensitive patch clamp measurements on pyramidal neurons in cortical slices of neonatal rats showed a dramatic increase in cellular membrane permeability resulting either in suppression or facilitation of neuronal activity during exposure to sub-μW/cm2 of RF power at 60 GHz. Non-invasive modulation of neuronal activity could prove useful in a variety of health applications from suppression of peripheral neuropathic pain to treatment of central neurological disorders.
... Many studies have shown that spontaneous electrical activities, namely human brain sleep patterns, respiration, heart rate generation and regulation, motor control, and sensory information are responsible for almost 80 percent of metabolic energy consumption in the brain (Alekseev et al., 2010;Bortolotto et al., 2019;Dipalo et al., 2017;Friesen, 1989;Gu et al., 1994;Mazzoni et al. 2007;Moshtagh-Khorasani et al., 2013;Napoli & Obeid, 2016). Some patterns of periodic spontaneous activity such as respiration and heart rate generation accompany us throughout life. ...
... Bashkirtseva et al. (Bashkirtseva et al., 2020) showed spontaneous electrical activity of neuronal networks from order to chaos, and some experimental studies observed corruptive impacts of electromagnetic fields on spontaneous chaotic behaviors. In (Alekseev et al., 2010), the rat sural nerve was exposed to electromagnetic radiation, and inhibitory effects of the field on spontaneous activities of this nerve were observed. Regarding the bifurcation analysis in Fig. 2, we also found that the presence of electromagnetic induction suppressed the development of the spontaneous chaotic activities in a neuronal network. ...
The interaction between neurons in a neuronal network develops spontaneous electrical activities. But the effects of electromagnetic radiation on these activities have not yet been well explored. In this study, a ring of three coupled 1-dimensional Rulkov neurons and the generated electromagnetic field (EMF) are considered to investigate how the spontaneous activities might change regarding the EMF exposure. By employing the bifurcation analysis and time series, a comprehensive view of neuronal behavioral changes due to electromagnetic inductions is provided. The main findings of this study are as follows: 1) When a neuronal network is showing a spontaneous chaotic firing manner (without any external stimuli), a generated magnetic field inhibits this type of behavior. In fact, EMF completely eliminated the chaotic intrinsic behaviors of the neuronal loop. 2) When the network is exhibiting regular period-3 spiking patterns, the generated magnetic field changes its firing pattern to chaotic spiking, which is similar to epileptic seizures. 3) With weak synaptic connections, electromagnetic radiation inhibits and suppresses neuronal activities. 4) If the external magnetic flux has a high amplitude, it can change the shape of the induction current according to its shape 5) when there are weak synaptic connections in the network, a high-frequency external magnetic flux engenders high-frequency fluctuations in the membrane voltages. On the whole, electromagnetic radiation changes the pattern of the spontaneous activities of neuronal networks in the brain according to synaptic strengths and initial states of the neurons.
... I danni diretti delle radiazioni elettromagnetiche ai mammiferi, a livello biologico, neuro-muscolare e neuro-comportamentale sono stati ampiamente dimostrati per ratti e topi di laboratorio (Millenbaugh et al., 2008;Alekseev et al., 2010;Sypniewska et al., 2010;Kumar et al., 2012;Barthelemy et al., 2016;Kim et al., 2017;Sepehrimanesh et al., 2017) e possono essere estesi ai micro-mammiferi selvatici, molti dei quali protetti. ...
... L'attuale inadeguatezza normativa è resa ancora più grave dalle considerazioni espresse nel paragrafo precedente sulla reale utilità degli standard ICNIRP ai fini di garantire un'efficace tutela della salute pubblica e dalle evidenze scientifiche preliminari che documentano la potenziale pericolosità dell'esposizione alle frequenze del 5G che utilizzeranno, in parte, onde millimetriche. (Gordon et al., 1969;Alekseev et al., 1997Alekseev et al., , 2010Pakhomov et al., 1997;, Pikov et al., 2010Shapiro et al., 2013), ed è in grado di modulare la sintesi di proteine coinvolte in processi infiammatori e immunologici (Sypniewska et al. 2010), con possibili effetti sistemici anche se l'assorbimento è limitato agli strati più superficiali della cute. L'esposizione a onde millimetriche è anche in grado di indurre aneuploidia e alterazioni cromosomiche in fibroblasti umani fetali e adulti e tali eventi sono riconosciuti come predisponenti alla trasformazione cellulare maligna (Franchini et al., 2018). ...
Il problema dell’invasività e dei rischi dei campi elettromagnetici ad alta frequenza è già stato trattato dalle nostre Associazioni. Nel corso degli anni si sono accumulate numerose evidenze sull’effetto nefasto di questa forma di inquinamento sulla salute umana e sull’ambiente.
Nell’ultimo decennio sono state diffuse risoluzioni scientifiche e governative, consensi scientifici e documenti di posizione, rapporti di gruppi di scienziati indipendenti e appelli ai governi per invitare a limitare la diffusione dell’uso di tecnologie di comunicazione promuovendo standard di sicurezza per i campi elettromagnetici basati su evidenze biologiche.
Alle raccomandazioni provenienti dal mondo scientifico, purtroppo, come nel caso dei pesticidi, delle emissioni in atmosfera e degli inquinanti organici persistenti (POP), è generalmente seguita una notevole inerzia normativa sia a livello europeo che nazionale. Ancora di più è trascurato, a livello politico e amministrativo, l’effetto sinergico di queste fonti di inquinamento, così come il Principio di Precauzione che dovrebbe guidare qualsiasi scelta in ambito gestionale.
Nel frattempo i campi elettromagnetici artificiali e l’inquinamento diffuso hanno continuato ad aumentare significativamente per motivazioni più legate a interessi economici privati che a effettive necessità o al concreto interesse per la salute pubblica e la tutela ambientale.
Negli ultimi tempi una notevole inquietudine si è diffusa anche presso i non addetti ai lavori per la nuova tecnologia 5G che minaccia, in un quadro già pericoloso almeno a livello locale, un ulteriore incremento dei campi elettromagnetici artificiali e l’utilizzo di frequenze mai utilizzate su così ampia scala in assenza di regole adeguate e di efficaci sistemi di monitoraggio dell’esposizione pubblica.
Per questi motivi e per porre, ancora una volta, all’attenzione pubblica e ai mass media i rischi correlati a queste tecnologie abbiamo trattato in maniera per quanto possibile sintetica le informazioni provenienti dalla ricerca scientifica, offrendo al lettore una notevole bibliografia con la quale aumentare la propria conoscenza e farsi una propria idea della situazione presente, a nostro parere già inquietante.
Le conclusioni a cui siamo giunti è che, se è vero che non si possono bloccare le innovazioni tecnologiche, esse devono essere tuttavia impiegate su larga scala solo dopo averne compiutamente considerato i possibili impatti ambientali e sanitari e solo dopo un efficace adeguamento delle normative in relazione alle conoscenze scientifiche, privilegiando la salute e l’ambiente prima di qualsiasi interesse economico.
Per tutelare la salute pubblica si rende indispensabile recepire gli studi scientifici più recenti ed attuare quanto indicato dalla Raccomandazione 1815 dell’Assemblea Plenaria del Consiglio d’Europa del 2011, volta ad abbassare i limiti di esposizione alle radiofrequenza in relazione all’uso privato di telefoni mobili, telefoni DECT (cordless), WiFi, WLAN e WIMAX per computer, Baby Phones a 0,2 V/m sul “lungo termine”, mentre secondo il rapporto Bionitiative 2012 sulla base delle evidenze sperimentali e del principio di precauzione deve essere portato a 0,6 V/m nell’immediato.
In relazione al 5G, fermi restando i presupposti di cui sopra, è necessaria una moratoria per valutare adeguatamente gli effetti sulla salute e sull’ambiente delle frequenze utilizzate, anche in relazione alla loro prevista onni-pervadenza. Vanno inoltre valutati i possibili effetti sulla sempre più folta comunità degli Elettrosensibili e sui soggetti potenzialmente più vulnerabili, come i bambini.
Riteniamo inoltre doveroso, sulla base delle evidenze disponibili, il divieto di installazione di reti Wi-Fi negli asili e nelle scuole frequentate da bambini e ragazzi al di sotto dei 16 anni e il divieto di posizionamento di ripetitori di radiotelefonia in prossimità degli stessi luoghi..
Vi deve essere obbligo, per le Agenzie di Salute Pubblica, di valutare i rischi per la salute connessi alle radiofrequenze, selezionando studi scientifici indipendenti ed escludendo quelli finanziati dall’industria delle telecomunicazioni o da fondazioni ed enti finanziati dalla stessa.
Riteniamo che debba essere sottoposto a Valutazione Ambientale Strategica l’intera Strategia per le Telecomunicazioni. Ricordiamo che il processo di VAS impone criteri ampi di partecipazione, tutela degli interessi legittimi e trasparenza del processo decisionale, attraverso il coinvolgimento e la consultazione dei soggetti competenti in materia ambientale e del pubblico che in interessato dall’iter decisionale.
Auspichiamo la promozione di investimenti pubblici e detassazione per la connettività in fibra ottica e via cavo, che è la tecnologia più efficiente e sicura per la salute e per l’ambiente.
Su questi presupposti siamo lieti di offrire al pubblico il nostro rapporto, svolto in modo del tutto indipendente.
Gradiamo costruttivi feedback per migliorare ulteriormente la conoscenza di base e la divulgazione delle problematiche correlate all’incremento dei campi elettromagnetici artificiali e alla necessità di un adeguata normativa e di processi per quanto possibile trasparenti e partecipati di valutazione degli impatti delle nuove tecnologie.
... I danni diretti delle radiazioni elettromagnetiche ai mammiferi, a livello biologico, neuro-muscolare e neuro-comportamentale sono stati ampiamente dimostrati per ratti e topi di laboratorio (Millenbaugh et al., 2008;Alekseev et al., 2010;Sypniewska et al., 2010;Kumar et al., 2012;Barthelemy et al., 2016;Kim et al., 2017;Sepehrimanesh et al., 2017) e possono essere estesi ai micro-mammiferi selvatici, molti dei quali protetti. ...
... L'attuale inadeguatezza normativa è resa ancora più grave dalle considerazioni espresse nel paragrafo precedente sulla reale utilità degli standard ICNIRP ai fini di garantire un'efficace tutela della salute pubblica e dalle evidenze scientifiche preliminari che documentano la potenziale pericolosità dell'esposizione alle frequenze del 5G che utilizzeranno, in parte, onde millimetriche. (Gordon et al., 1969;Alekseev et al., 1997Alekseev et al., , 2010Pakhomov et al., 1997;, Pikov et al., 2010Shapiro et al., 2013), ed è in grado di modulare la sintesi di proteine coinvolte in processi infiammatori e immunologici (Sypniewska et al. 2010), con possibili effetti sistemici anche se l'assorbimento è limitato agli strati più superficiali della cute. L'esposizione a onde millimetriche è anche in grado di indurre aneuploidia e alterazioni cromosomiche in fibroblasti umani fetali e adulti e tali eventi sono riconosciuti come predisponenti alla trasformazione cellulare maligna (Franchini et al., 2018). ...
Il problema dell’invasività e dei rischi dei campi elettromagnetici ad alta frequenza è già stato trattato dalle nostre Associazioni. Nel corso degli anni si sono accumulate numerose evidenze sull’effetto nefasto di questa forma di inquinamento sulla salute umana e sull’ambiente.
Nell’ultimo decennio sono state diffuse risoluzioni scientifiche e governative, consensi scientifici e documenti di posizione, rapporti di gruppi di scienziati indipendenti e appelli ai governi per invitare a limitare la diffusione dell’uso di tecnologie di comunicazione promuovendo standard di sicurezza per i campi elettromagnetici basati su evidenze biologiche.
Alle raccomandazioni provenienti dal mondo scientifico, purtroppo, come nel caso dei pesticidi, delle emissioni in atmosfera e degli inquinanti organici persistenti (POP), è generalmente seguita una notevole inerzia normativa sia a livello europeo che nazionale. Ancora di più è trascurato, a livello politico e amministrativo, l’effetto sinergico di queste fonti di inquinamento, così come il Principio di Precauzione che dovrebbe guidare qualsiasi scelta in ambito gestionale.
Nel frattempo i campi elettromagnetici artificiali e l’inquinamento diffuso hanno continuato ad aumentare significativamente per motivazioni più legate a interessi economici privati che a effettive necessità o al concreto interesse per la salute pubblica e la tutela ambientale.
Negli ultimi tempi una notevole inquietudine si è diffusa anche presso i non addetti ai lavori per la nuova tecnologia 5G che minaccia, in un quadro già pericoloso almeno a livello locale, un ulteriore incremento dei campi elettromagnetici artificiali e l’utilizzo di frequenze mai utilizzate su così ampia scala in assenza di regole adeguate e di efficaci sistemi di monitoraggio dell’esposizione pubblica.
Per questi motivi e per porre, ancora una volta, all’attenzione pubblica e ai mass media i rischi correlati a queste tecnologie abbiamo trattato in maniera per quanto possibile sintetica le informazioni provenienti dalla ricerca scientifica, offrendo al lettore una notevole bibliografia con la quale aumentare la propria conoscenza e farsi una propria idea della situazione presente, a nostro parere già inquietante.
Le conclusioni a cui siamo giunti è che, se è vero che non si possono bloccare le innovazioni tecnologiche, esse devono essere tuttavia impiegate su larga scala solo dopo averne compiutamente considerato i possibili impatti ambientali e sanitari e solo dopo un efficace adeguamento delle normative in relazione alle conoscenze scientifiche, privilegiando la salute e l’ambiente prima di qualsiasi interesse economico.
Per tutelare la salute pubblica si rende indispensabile recepire gli studi scientifici più recenti ed attuare quanto indicato dalla Raccomandazione 1815 dell’Assemblea Plenaria del Consiglio d’Europa del 2011, volta ad abbassare i limiti di esposizione alle radiofrequenza in relazione all’uso privato di telefoni mobili, telefoni DECT (cordless), WiFi, WLAN e WIMAX per computer, Baby Phones a 0,2 V/m sul “lungo termine”, mentre secondo il rapporto Bionitiative 2012 sulla base delle evidenze sperimentali e del principio di precauzione deve essere portato a 0,6 V/m nell’immediato.
In relazione al 5G, fermi restando i presupposti di cui sopra, è necessaria una moratoria per valutare adeguatamente gli effetti sulla salute e sull’ambiente delle frequenze utilizzate, anche in relazione alla loro prevista onni-pervadenza. Vanno inoltre valutati i possibili effetti sulla sempre più folta comunità degli Elettrosensibili e sui soggetti potenzialmente più vulnerabili, come i bambini.
Riteniamo inoltre doveroso, sulla base delle evidenze disponibili, il divieto di installazione di reti Wi-Fi negli asili e nelle scuole frequentate da bambini e ragazzi al di sotto dei 16 anni e il divieto di posizionamento di ripetitori di radiotelefonia in prossimità degli stessi luoghi..
Vi deve essere obbligo, per le Agenzie di Salute Pubblica, di valutare i rischi per la salute connessi alle radiofrequenze, selezionando studi scientifici indipendenti ed escludendo quelli finanziati dall’industria delle telecomunicazioni o da fondazioni ed enti finanziati dalla stessa.
Riteniamo che debba essere sottoposto a Valutazione Ambientale Strategica l’intera Strategia per le Telecomunicazioni. Ricordiamo che il processo di VAS impone criteri ampi di partecipazione, tutela degli interessi legittimi e trasparenza del processo decisionale, attraverso il coinvolgimento e la consultazione dei soggetti competenti in materia ambientale e del pubblico che in interessato dall’iter decisionale.
Auspichiamo la promozione di investimenti pubblici e detassazione per la connettività in fibra ottica e via cavo, che è la tecnologia più efficiente e sicura per la salute e per l’ambiente.
Su questi presupposti siamo lieti di offrire al pubblico il nostro rapporto, svolto in modo del tutto indipendente.
Gradiamo costruttivi feedback per migliorare ulteriormente la conoscenza di base e la divulgazione delle problematiche correlate all’incremento dei campi elettromagnetici artificiali e alla necessità di un adeguata normativa e di processi per quanto possibile trasparenti e partecipati di valutazione degli impatti delle nuove tecnologie.
... Early studies on invertebrate neurons [7] revealed that MMW exposure, despite accompanying sample heating, caused suppression (rather than the expected thermal enhancement) of electrophysiological activity. Similar studies [3,10,11] conducted on leech neural ganglia demonstrated different effects from MMW radiation and equivalent conductive heating -suppression vs. acceleration of action potential (AP) spiking. ...
... Our model shows that even at significantly increased temperatures, caused by MMW energy absorption, an induced increase in membrane capacitance leads to AP suppression rather than the AP enhancement normally seen through simple thermal conduction. Our results agree with findings from studies conducted on actual neurons [2,3,7,[9][10][11]. Fig. 1. ...
Heating is the most obvious effect that exposure to millimeter-wave-to-terahertz (MMW-THz) radiation has on living tissue. It is expected that the resulting increase in temperature causes up regulation of cellular mechanisms, e.g. increased rate of action potential (AP) generation. However, some studies have demonstrated the opposite. Here we show, using a simple computer model of a neuron, the passive cell parameters (affected by MMW exposure) that might be responsible for the suppression of action potentials (AP) even with temperature increases of as much as 10 °C.
... Despite MMW have been suggested for biomedical applications (Zhadobov et al., 2015) (also considering their hypoalgesic effects (Radzievsky et al., 2001;Usichenko et al., 2006;Usichenko et al., 2003;Ziskin, 2013)), specific preliminary evidences showed as the exposure to frequency over 30 GHz could alter gene expression Le Quement et al., 2012;Le Quement et al., 2014;Millenbaugh et al., 2008;Soubere Mahamoud et al., 2016), increase the temperature of the skin (Zhadobov et al., 2015), stimulate cell proliferation (Li et al., 2010;Li et al., 2014), alter the functions of cell membrane (Cosentino et al., 2013;Di Donato et al., 2012) and neuro-muscular systems (Alekseev et al., 2010;Alekseev et al., 1997;Gordon et al., 1969;Khramov et al., 1991;Pakhomov et al., 1997;Pikov et al., 2010;Shapiro et al., 2013). ...
... Studies in animal models suggest neurologic outcomes following MMW exposure, in terms of EEG alterations secondary to MMW-induced stress reactions (due to the increase in skin temperature) (Xie et al., 2011) and altered neuronal and neuromuscular functions (Alekseev et al., 2010;Alekseev et al., 1997;Gordon et al., 1969;Khramov et al., 1991;Pakhomov et al., 1997;Pikov et al., 2010;Shapiro et al., 2013). ...
The spread of radiofrequency electromagnetic fields (RF-EMF) is rising and health effects are still under investigation. RF-EMF promote oxidative stress, a condition involved in cancer onset, in several acute and chronic diseases and in vascular homeostasis. Although some evidences are still controversial, the WHO IARC classified RF-EMF as "possible carcinogenic to humans", and more recent studies suggested reproductive, metabolic and neurologic effects of RF-EMF, which are also able to alter bacterial antibiotic resistance. In this evolving scenario, although the biological effects of 5G communication systems are very scarcely investigated, an international action plan for the development of 5G networks has started, with a forthcoming increment in devices and density of small cells, and with the future use of millimeter waves (MMW). Preliminary observations showed that MMW increase skin temperature, alter gene expression, promote cellular proliferation and synthesis of proteins linked with oxidative stress, inflammatory and metabolic processes, could generate ocular damages, affect neuro-muscular dynamics. Further studies are needed to better and independently explore the health effects of RF-EMF in general and of MMW in particular. However, available findings seem sufficient to demonstrate the existence of biomedical effects, to invoke the precautionary principle, to define exposed subjects as potentially vulnerable and to revise existing limits. An adequate knowledge of pathophysiological mechanisms linking RF-EMF exposure to health risk should also be useful in the current clinical practice, in particular in consideration of evidences pointing to extrinsic factors as heavy contributors to cancer risk and to the progressive epidemiological growth of noncommunicable diseases.
... This particular MMW effect involves activation of the peripheral neural system and changes in endogenous opioid content in the central nervous system [Radzievsky et al., 2008]. The hypothesis of involvement of TRPV channels in the activation of sensory nerves by MMW has already been issued, but no clear data have supported it [Alekseev et al., 2010]. As electromagnetic energy provided by MMW exposure can reach free nerve endings within the skin [Ziskin, 2013], we wanted to assess the possible impact of these waves on a neuronal cellular model (Neuroscreen-1 cells). ...
... Involvement of ion channels has often been proposed to enlighten the potential effects of electromagnetic fields [Alekseev et al., 2010;Pall, 2013]. In this study, we have shown that MMW exposure at high power density (10 mW/cm 2 ) for 24 h modifies neither the expression level, nor recycling of representative nociceptive channel-receptors. ...
Millimeter waves (MMW) will be increasingly used for future wireless telecommunications. Previous studies on skin keratinocytes showed that MMW could impact the mRNA expression of Transient Receptor Potential cation channel subfamily Vanilloid, member 2 (TRPV2). Here, we investigated the effect of MMW exposure on this marker, as well as on other membrane receptors such as Transient Receptor Potential cation channel subfamily Vanilloid, member 1 (TRPV1) and purinergic receptor P2X, ligand-gated ion channel, 3 (P2 × 3). We exposed the Neuroscreen-1 cell line (a PC12 subclone), in order to evaluate if acute MMW exposures could impact expression of these membrane receptors at the protein level. Proteotoxic stress-related chaperone protein Heat Shock Protein 70 (HSP70) expression level was also assessed. We used an original high-content screening approach, based on fluorescence microscopy, to allow cell-by-cell analysis and to detect any cell sub-population responding to exposure. Immunocytochemistry was done after 24 h MMW exposure of cells at 60.4 GHz, with an incident power density of 10 mW/cm2 . Our results showed no impact of MMW exposure on protein expressions of HSP70, TRPV1, TRPV2, and P2 × 3. Moreover, no specific cell sub-populations were found to express one of the studied markers at a different level, compared to the rest of the cell populations. However, a slight insignificant increase in HSP70 expression and an increase in protein expression variability within cell population were observed in exposed cells, but controls showed that this was related to thermal effect.
... These radiations, generally in association with other treatments, gave positive clinical results in the cure of miscellaneous diseases, such as ulcers, pain relief, cardiovascular diseases, wound healing, bronchial asthma, skin disorders or cancers [12]. Meanwhile, it was demonstrated that MMW may have medical effect on inflammatory [13,14,15] and analgesic [16,17,18] responses. The mechanism involved in MMW biological effects remains to be elucidated, especially because these radiations have a shallow penetration (,1 mm) [19]. ...
... As a consequence of the MMW shallow penetration, the electromagnetic energy is absorbed by low quantity of biological material, leading to relatively high levels of the specific absorption rates (SAR), compared to the lower part of the RF spectrum. As MMW belong to the microwave family, this energy transfer induces a heat effect for the incident power densities (IPD) above 5 mW/cm 2 [18,19,20]. This thermal effect is currently the main well-established biological effect and served as a basis for the definition of the MMW exposure standards and guidelines by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). ...
Radiofrequency radiations constitute a new form of environmental pollution. Among them, millimeter waves (MMW) will be widely used in the near future for high speed communication systems. This study aimed therefore to evaluate the biocompatibility of MMW at 60 GHz. For this purpose, we used a whole gene expression approach to assess the effect of acute 60 GHz exposure on primary cultures of human keratinocytes. Controls were performed to dissociate the electromagnetic from the thermal effect of MMW. Microarray data were validated by RT-PCR, in order to ensure the reproducibility of the results. MMW exposure at 20 mW/cm2, corresponding to the maximum incident power density authorized for public use (local exposure averaged over 1 cm2), led to an increase of temperature and to a strong modification of keratinocyte gene expression (665 genes differentially expressed). Nevertheless, when temperature is artificially maintained constant, no modification in gene expression was observed after MMW exposure. However, a heat shock control did not mimic exactly the MMW effect, suggesting a slight but specific electromagnetic effect under hyperthermia conditions (34 genes differentially expressed). By RT-PCR, we analyzed the time course of the transcriptomic response and 7 genes have been validated as differentially expressed: ADAMTS6, NOG, IL7R, FADD, JUNB, SNAI2 and HIST1H1A. Our data evidenced a specific electromagnetic effect of MMW, which is associated to the cellular response to hyperthermia. This study raises the question of co-exposures associating radiofrequencies and other environmental sources of cellular stress.
... Furthermore, it was shown that MMW treatment may have an analgesic effect in both human and animal models [Radzievsky et al., 1999;Rojavin et al., 2000]. This hypoalgesia can result from a direct effect of MMW on nerve cells [Radzievsky et al., 2008;Alekseev et al., 2010]. ...
... TRPV2 is a widely expressed calcium channel. In neurons of the peripheral nervous system, TRPV2 is involved in heat sensing and has been proposed as a candidate for the mediation of MMW effects in pain therapy [Alekseev et al., 2010]. ...
The main purpose of this study is to investigate potential responses of skin cells to millimeter wave (MMW) radiation increasingly used in the wireless technologies. Primary human skin cells were exposed for 1, 6, or 24 h to 60.4 GHz with an average incident power density of 1.8 mW/cm(2) and an average specific absorption rate of 42.4 W/kg. A large-scale analysis was performed to determine whether these exposures could affect the gene expression. Gene expression microarrays containing over 41,000 unique human transcript probe sets were used, and data obtained for sham and exposed cells were compared. No significant difference in gene expression was observed when gene expression values were subjected to a stringent statistical analysis such as the Benjamini-Hochberg procedure. However, when a t-test was employed to analyze microarray data, 130 transcripts were found to be potentially modulated after exposure. To further quantitatively analyze these preselected transcripts, real-time PCR was performed on 24 genes with the best combination of high fold change and low P-value. Five of them, namely CRIP2, PLXND1, PTX3, SERPINF1, and TRPV2, were confirmed as differentially expressed after 6 h of exposure. To the best of our knowledge, this is the first large-scale study reporting on potential gene expression modification associated with MMW radiation used in wireless communication applications. Bioelectromagnetics. © 2011 Wiley-Liss, Inc.
... In most of these works, cells, animals, or humans have been locally exposed by a horn antenna. In contrast to lowpower exposures, these induce a superficial heating (typically 1-2 8C, depending on the antenna and exposure area [Alekseev et al., 2010]), which is partly compensated by the blood flow in in vivo models. The local exposure of the skin at millimeter waves has been extensively investigated from electromagnetic and thermodynamic points of view [Alekseev et al., 2008a,b;Alekseev and Ziskin, 2009a,b]. ...
... Moreover, several experimental techniques have been introduced to quantify thermal effects resulting from millimeter-wave exposure; they are summarized in Zhadobov et al. [2011]. In addition, some recent studies have demonstrated that high-power millimeter-wave exposures (160 mW/cm 2 ) may result in biological effects that are different from those observed for equivalent temperature increments induced by infrared heating [Alekseev et al., 2010]. ...
Due to the expected mass deployment of millimeter-wave wireless technologies, thresholds of potential millimeter-wave-induced biological and health effects should be carefully assessed. The main purpose of this study is to propose, optimize, and characterize a near-field exposure configuration allowing illumination of cells in vitro at 60 GHz with power densities up to several tens of mW/cm(2) . Positioning of a tissue culture plate containing cells has been optimized in the near-field of a standard horn antenna operating at 60 GHz. The optimal position corresponds to the maximal mean-to-peak specific absorption rate (SAR) ratio over the cell monolayer, allowing the achievement of power densities up to 50 mW/cm(2) at least. Three complementary parameters have been determined and analyzed for the exposed cells, namely the power density, SAR, and temperature dynamics. The incident power density and SAR have been computed using the finite-difference time-domain (FDTD) method. The temperature dynamics at different locations inside the culture medium are measured and analyzed for various power densities. Local SAR, determined based on the initial rate of temperature rise, is in a good agreement with the computed SAR (maximal difference of 5%). For the optimized exposure setup configuration, 73% of cells are located within the ±3 dB region with respect to the average SAR. It is shown that under the considered exposure conditions, the maximal power density, local SAR, and temperature increments equal 57 mW/cm(2) , 1.4 kW/kg, and 6 °C, respectively, for the radiated power of 425 mW.
... The outermost layer of the organism's skin will absorb almost all of the MMW exposure, while the dermis and epidermis of the skin surface are highly dominated by the nervous system [91]. An initial investigation demonstrated that MMW at 41.34 GHz frequency can markedly influence the refractory period characteristics of nerves. ...
This comprehensive review critically examines the current state of research on the biological effects of millimeter-wave (MMW) therapy and its potential implications for disease treatment. By investigating both the thermal and non-thermal impacts of MMWs, we elucidate cellular-level alterations, including changes in ion channels and signaling pathways. Our analysis encompasses MMW’s therapeutic prospects in oncology, such as inducing apoptosis, managing pain, and modulating immunity through cytokine regulation and immune cell activation. By employing a rigorous methodology involving an extensive database search and stringent inclusion criteria, we emphasize the need for standardized protocols to enhance the reliability of future research. Although MMWs exhibit promising therapeutic potential, our findings highlight the urgent need for further elucidation of non-thermal mechanisms and rigorous safety assessments, considering the intricate nature of MMW interactions and inconsistent study outcomes. This review underscores the importance of focused research on the biological mechanisms of MMWs and the identification of optimal frequencies to fully harness their therapeutic capabilities. However, we acknowledge the challenges of variable study quality and the necessity for advanced quality control measures to ensure the reproducibility and comparability of future investigations. In conclusion, while MMW therapy holds promise as a novel therapeutic modality, further research is imperative to unravel its complex biological effects, establish safety profiles, and optimize treatment protocols before widespread clinical application.
... Kesari et al. (2) reported that 50 GHz-MMW exposure induced DNA double-strand breaks and chronically increased the apoptosis rate of cells during spermatogenesis (3) in rats. Other research groups have also showed that MMW exposure induces circulatory failure (4), hemorrhage and congestion of blood vessels (5), a decrease in the firing rate of the sural nerve (6), and gene expression of stress-induced transcription factors and heat-shock proteins (7). In contrast, Habauzit et al. (8) failed to find alterations in gene expression in rat skin after chronic exposure to 94 GHz-MMW. ...
Introduction
Limited information is available on the biological effects of whole-body exposure to quasi-millimeter waves (qMMW). The aim of the present study was to determine the intensity of exposure to increase body temperature and investigate whether thermoregulation, including changes in skin blood flow, is induced in rats under whole-body exposure to qMMW.
Methods
The backs of conscious rats were extensively exposed to 28 GHz qMMW at absorbed power densities of 0, 122, and 237 W/m² for 40 minutes. Temperature changes in three regions (dorsal and tail skin, and rectum) and blood flow in the dorsal and tail skin were measured simultaneously using fiber-optic probes.
Results
Intensity-dependent temperature increases were observed in the dorsal skin and the rectum. In addition, skin blood flow was altered in the tail but not in the dorsum, accompanied by an increase in rectal temperature and resulting in an increase in tail skin temperature.
Discussion
These findings suggest that whole-body exposure to qMMW drives thermoregulation to transport and dissipate heat generated on the exposed body surface. Despite the large differences in size and physiology between humans and rats, our findings may be helpful for discussing the operational health-effect thresholds in the standardization of international exposure guidelines.
... Bashkirtseva et al. (Bashkirtseva et al. 2020) showed spontaneous electrical activity of neuronal networks from order to chaos, and some experimental studies observed corruptive impacts of electromagnetic elds on spontaneous chaotic behaviors. In (Alekseev et al. 2010), the rat sural nerve was exposed to electromagnetic radiation, and inhibitory effects of the eld on spontaneous activities of this nerve were observed. Regarding the bifurcation analysis in Fig. 2, we also found that the presence of electromagnetic induction suppressed the development of the spontaneous chaotic activities in a neuronal network. ...
The interaction between neurons in a neuronal network develops spontaneous electrical activities. But the effects of electromagnetic radiation on these activities have not yet been well explored. In this study, a ring of three coupled 1-dimensional Rulkov neurons is considered and then exposed to an electromagnetic field (EMF) to investigate how its spontaneous activities might change regarding the EMF exposure. By employing the bifurcation analysis and time series, a comprehensive view of neuronal behavioral changes due to electromagnetic radiations is provided. It is demonstrated that exposure to these EMFs may inhibit chaotic neuronal behaviors when the neuronal network is supposed to develop a chaotic behavior spontaneously. In fact, EMFs completely eliminated the chaotic intrinsic behaviors of the neuronal loop. On the other hand, due to this exposure, the development of chaotic regimes is seen when the network is supposed to show regular spiking behaviors. Furthermore, it is observed that with weaker synaptic couplings, electromagnetic radiation inhibits and suppresses neuronal activities. On the whole, electromagnetic radiation may change the pattern of the spontaneous activities of neuronal networks in the brain according to synaptic strengths and initial states of the neurons.
... In this study we adopted a raster scan setup for MMW exposure to prevent focused heating effects as previous reports have shown the absorption of high power MMWs can cause thermal changes in the skin [12,15,[38][39][40][41][42]. We confirmed via experimental measurements and computational modelling there was negligible associated heating (∆T max ∼ +1.2°C) for the exposure time in our experimental setup (Supplement 1, Fig. S1). ...
As millimetre wave (MMW) frequencies of the electromagnetic spectrum are increasingly adopted in modern technologies such as mobile communications and networking, characterising the biological effects is critical in determining safe exposure levels. We study the exposure of primary human dermal fibroblasts to MMWs, finding MMWs trigger genomic and transcriptomic alterations. In particular, repeated 60 GHz, 2.6 mW cm⁻², 46.8 J cm⁻² d⁻¹ MMW doses induce a unique physiological response after 2 and 4 days exposure. We show that high dose MMWs induce simultaneous non-thermal alterations to the transcriptome and DNA structural dynamics, including formation of G-quadruplex and i-motif secondary structures, but not DNA damage.
... Applications using high-power millimeter waves already exist, implying that people using these technologies may be inadvertently exposed. Several publications have studied some peculiar frequencies used in millimeter range such as at 30, 42, 60 GHz and now 94 GHz (11,(13)(14)(15)(16)(17)(18)(19). All of these frequencies may be studied as the main difference in the physical action on skin is the penetration depth. ...
Millimeter waves (MMW) are broadband frequencies that have recently been used in several applications in wireless communications, medical devices and nonlethal weapons [i.e., the nonlethal weapon, Active Denial Systems, (ADS) operating at 94–95 GHz, CW]. However, little information is available on their potential effects on humans. These radiofrequencies are absorbed and stopped by the first layer of the skin. In this study, we evaluated the effects of 94 GHz on the gene expression of skin cells. Two rat populations consisting of 17 young animals and 14 adults were subjected to chronic long-term 94 GHz MMW exposure. Each group of animals was divided into exposed and sham subgroups. The two independent exposure experiments were conducted for 5 months with rats exposed 3 h per day for 3 days per week to an incident power density of 10 mW/cm ² , which corresponded to twice the ICNIRP limit of occupational exposure for humans. At the end of the experiment, skin explants were collected and RNA was extracted. Then, the modifications to the whole gene expression profile were analyzed with a gene expression microarray. Without modification of the animal's temperature, long-term chronic 94 GHz-MMW exposure did not significantly modify the gene expression of the skin on either the young or adult rats.
... In the 40.1-50 GHz frequency group, 26 studies were identified, 13 in vivo [16,17,26,48,49,51,53,65,69,74,80,84,98] and 13 in vitro [29][30][31]62,64,86,89,92,93,100,105,107] with nine studies showing responses. A large number of studies have tested cell biology endpoints such as cell proliferation, gene or protein expression, and changes in oxidative stress. ...
The introduction of the fifth generation (5G) of wireless communication will increase the number of high-frequency-powered base stations and other devices. The question is if such higher frequencies (in this review, 6–100 GHz, millimeter waves, MMW) can have a health impact. This review analyzed 94 relevant publications performing in vivo or in vitro investigations. Each study was characterized for: study type (in vivo, in vitro), biological material (species, cell type, etc.), biological endpoint, exposure (frequency, exposure duration, power density), results, and certain quality criteria. Eighty percent of the in vivo studies showed responses to exposure, while 58% of the in vitro studies demonstrated effects. The responses affected all biological endpoints studied. There was no consistent relationship between power density, exposure duration, or frequency, and exposure effects. The available studies do not provide adequate and sufficient information for a meaningful safety assessment, or for the question about non-thermal effects. There is a need for research regarding local heat developments on small surfaces, e.g., skin or the eye, and on any environmental impact. Our quality analysis shows that for future studies to be useful for safety assessment, design and implementation need to be significantly improved.
... Recently, similar mechanisms were proposed as an explanation of the effects of low intensity EHF-EMF on nervous tissue involving a direct interaction with the neuronal plasma membrane 7 . Further non-thermal mechanisms were also suggested to explain the transient response of high frequency EMF on the electrical activity of the sural nerve in vivo, which appears to be specific to the field because the radiant heating did not reproduce this effect 34 . Thus our results suggest subtle specific effects, which do not depend on the thermal energy imparted by the EHF-EMF on the axon model. ...
Among the many biological effects caused by low intensity extremely high frequency electromagnetic fields (EHF-EMF) reported in the literature, those on the nervous system are a promising area for further research. The mechanisms by which these fields alter neural activity are still unclear and thus far there appears to be no frequency dependence regarding neuronal responses. Therefore, proper in vitro models for preliminary screening studies of the interaction between neural cells with EMF are needed. We designed an artificial axon model consisting of a series of parallel RC networks. Each RC network contained an aqueous solution of lipid vesicles with a gradient of potassium (K+) concentration as the functional element. We investigated the effects of EHF-EMF (53.37 GHz-39 mW) on the propagation of the electric impulse. We report that exposure to the EHF-EMF increases the amplitude of electrical signal by inducing a potassium efflux from lipid vesicles. Further, exposure to the EHF-EMF potentiates the action of valinomycin - a K+ carrier - increasing the extent of K+ transport across the lipid membrane. We conclude that exposure to the EHF-EMF facilitates the electrical signal propagation by increasing transmembrane potassium efflux, and that the model presented is promising for future screening studies of different EMF frequency spectrum bands.
... Altogether these studies indicate that MMW-related effects could be mediated via interaction with cell membrane interphase structures like superficial water and/or the Guy-Chapman layers. A decrease in neuron input resistance upon low-intensity (mW) MMW exposure was recently reported for rat cortical slices [87] and spontaneous electrical in the murine sural nerve is inhibited upon application of 45 mW cm 22 , 42.25 GHz MMW irradiation [88]. In experiments with mice treated by anticancer chemotherapy, the utilization of MMW radiation resulted in an increased level of CD69 expression compared to the control group [89]. ...
Since regular radio broadcasts started in the 1920s, the exposure to humanmade electromagnetic fields has steadily increased. These days we are not only exposed to radio waves but also other frequencies from a variety of sources, mainly from communication and security devices. Considering that nearly all biological systems interact with electromagnetic fields, understanding the affects is essential for safety and technological progress. This
paper systematically reviews the role and effects of static and pulsed radio frequencies (100–109 Hz), millimetre waves (MMWs) or gigahertz (109– 1011 Hz), and terahertz (1011–1013 Hz) on various biomolecules, cells and tissues. Electromagnetic fields have been shown to affect the activity in cell membranes (sodium versus potassium ion conductivities) and non-selective channels, transmembrane potentials and even the cell cycle. Particular attention is given to millimetre and terahertz radiation due to their increasing utilization and, hence, increasing human exposure. MMWs are known to alter active transport across cell membranes, and it has been reported that terahertz radiation may interfere with DNA and cause genomic instabilities. These and other phenomena are discussed along with the discrepancies and controversies from published studies.
... 17 Both of these were shown to be involved in the mechanisms of MW analgesia. 1,2,10,15,16 The interpretation of the data is limited because of methodological issues: CPT may not be sensitive enough for weak analgesic intervention; and the objectivity of the acquisition of verbal reports by the investigator using a stopwatch might be imprecise because of variability in reac- tion times. This could have influenced the measured onsets of sensations. ...
Background:
The hypoalgesic effect of electromagnetic millimeter waves (MW) is well studied in animal model; however, the results of human research are controversial. The aim of this study was to evaluate the effects of various frequency ranges of MW on hypoalgesia using the cold pressor test (CPT).
Methods:
Experimental pain was induced using standardized CPT protocols in 20 healthy male volunteers. The skin of the lower part of sternum was exposed to MW with a frequency of 42.25 GHz (active generator); MW within 50-75 GHz frequency range (noise generator); or an inactive MW device (placebo generator) in a random crossover double-blinded manner. Pain threshold, measured using the CPT, was the primary outcome. Other CPT parameters, heart rate, blood pressure, incidence of subjective sensations (paresthesia) during exposure, as well as quality of volunteers' blinding were also recorded. The end points of the condition with exposure to 42.25 GHz, were compared with baseline; exposure to noise 50-75 GHz; and placebo generators.
Results:
Pain threshold increased during exposure to the 42.25 GHz generator when compared with baseline: median difference (MD), 1.97 seconds (95% confidence interval [CI], 0.35-3.73) and noise generator: MD, 1.27 seconds (95% CI, 0.05-2.33) but not compared with the placebo generator. Time to onset of cold and increasing pain sensations as well as diastolic blood pressure increased under the exposure to the 42.25 GHz generator when compared with baseline and noise generator. Other outcome measures were comparable among the study conditions.
Conclusions:
We were able to partially confirm the previously suggested hypoalgesic effects of low-intensity electromagnetic MW. However, the effect was indistinguishable from the placebo condition in our investigation.
... E-mail: maxim.zhadobov@univ-rennes1.fr biological cells. Recently, several in vivo and in vitro studies have reported their potential biological and health effects [Pakhomov et al., 1998;Nicolas Nicolaz et al., 2009;Zhadobov et al., 2009;Alekseev et al., 2010]. Most of these studies demonstrated that: ...
... If the cells are modeled as small spheres and the culture medium is homogeneous, the dielectric permittivity of the cells can be calculated from measurements of pure culture medium and cell suspension permittivities using equation (5). (1) Network analyzer, (2) coaxial cable, (3) wooden block, (4) coaxial probe, (5) adjustable clamp, (6) metal rod, (7) stand, (8) dual adjustable clamp, (9) shorting block, (10) water beaker, (11) cell suspension. ...
The objective of this paper was to test and evaluate an experimental procedure for providing data on the complex permittivity of different cell lines in the 2–50-GHz range at room temperature, for the purpose of future dosimetric studies. The complex permittivity measurements were performed on cells suspended in culture medium using an open-ended coaxial probe. Maxwell’s mixture equation then allows the calculation of the permittivity profiles of the cells from the difference in permittivity between the cell suspensions and pure culture medium. The open-ended coaxial probe turned out to be very sensitive to disturbances affecting the measurements, resulting in poor precision. Permittivity differences were not large in relation to the spread of the measurements and repeated measurements were performed to improve statistics. The 95% confidence intervals were computed for the arithmetic means of the measured permittivity differences in order to test the statistical significance. The results showed that for bone cells at the lowest tested concentration (33 500/ml), there were significance in the real part of the permittivity at frequencies above 30 GHz, and no significance in the imaginary part. For the second lowest concentration (67 000/ml) there was no significance at all. For a medium concentration of bone cells (135 000/ml) there was no significance in the real part, but there was significance in the imaginary part at frequencies below about 25 GHz. The cell suspension with a concentration of 1 350 000/ml had significance in the real part for both high (above 30 GHz) and low (below 15 GHz) frequencies. The imaginary part showed significance for frequencies below 25 GHz. In the case of an osteosarcoma cell line with a concentration of 2 700 000/ml, only the imaginary part showed significance, and only for frequencies below 15 GHz. For muscle cells at a concentration of 743 450/ml, there was only significance in the imaginary part for frequen- ies below 5 GHz. The experimental data indicated that the complex permittivity of the culture medium may be used for modeling of cell suspensions.
... 17 Both of these were shown to be involved in the mechanisms of MW analgesia. 1,2,10,15,16 The interpretation of the data is limited because of methodological issues: CPT may not be sensitive enough for weak analgesic intervention; and the objectivity of the acquisition of verbal reports by the investigator using a stopwatch might be imprecise because of variability in reaction times. This could have influenced the measured onsets of sensations. ...
The hypoalgesic effect of millimeter waves (MW) was studied using experimental pain model of Cold Pressor Test (CPT) in healthy volunteers. Skin of the lower part of sternum of each volunteer was exposed to either source of MW with 42.25 GHz ("fixed frequency" generator), 50-75 GHz ("noise frequency" generator) or inactive device ("placebo" generator) in a random order. Pain threshold, pain tolerance and diastolic blood pressure within CPT increased under the exposure to "frequency generator" as compared to baseline and to "noise" generator, but not vs. placebo.
... [26]). The state of the art power limits are delivered by military systems (up to several MW at 94 GHz) [27]; however, the output power of the generators used for the research purposes at 60 GHz is typically limited to several watts [26,28,29]. ...
The biocompatibility of millimeter-wave devices and systems is an important issue due to the wide number of emerging body-centric wireless applications at millimeter waves. This review article provides the state of knowledge in this field and mainly focuses on recent results and advances related to the different aspects of millimeter-wave interactions with the human body. Electromagnetic, thermal, and biological aspects are considered and analyzed for exposures in the 30-100 GHz range with a particular emphasis on the 60-GHz band. Recently introduced dosimetric techniques and specific instrumentation for bioelectromagnetic laboratory studies are also presented. Finally, future trends are discussed.
... E-mail: maxim.zhadobov@univ-rennes1.fr biological cells. Recently, several in vivo and in vitro studies have reported their potential biological and health effects [Pakhomov et al., 1998;Nicolas Nicolaz et al., 2009;Zhadobov et al., 2009;Alekseev et al., 2010]. Most of these studies demonstrated that: ...
The main purpose of this study is to provide experimental data on the complex permittivity of some biological solutions in the 2-67 GHz range at room and human body temperatures. The permittivity measurements are performed using an open-ended coaxial probe. Permittivity spectra of several representative monomolecular solutions of proteins, amino acids, nucleic acids, and carbohydrates are analyzed and compared. Furthermore, measurements have also been performed for complex biomolecular solutions, including bovine serum albumin (BSA)-DNA-glucose mixture, culture medium, and yeast extract solution. The results demonstrate that for concentrations below 1%, the permittivity spectra of the solutions do not substantially differ from that of distilled water. Measurements carried out for 4% and 20% BSA solutions show that the presence of proteins results in a decrease in permittivity. For highly concentrated RNA solutions (3%), a slight increase in the imaginary part of the permittivity is observed below 10 GHz. Experimental data show that free water permittivity can be used for modeling of the culture medium above 10 GHz. However, at lower frequencies a substantial increase in the imaginary part of the permittivity due to ionic conductivity should be carefully taken into account. A similar increase has also been observed for the yeast extract solution in the lower frequency region of the considered spectrum. Above 10 GHz, the high concentration of proteins and other low-permittivity components of the yeast extract solution results in a decrease in the complex permittivity compared to that of water. Obtained data are of utmost importance for millimeter-wave dosimetry studies. Bioelectromagnetics. © 2011 Wiley Periodicals, Inc.
Objective. Electrical stimulation of the auricular vagus nerve is a non-invasive neuromodulation technique that has been used for various conditions, including depression, epilepsy, headaches, and cerebral ischemia. However, unwanted non-vagal nerve stimulations can occur because of diffused stimulations. The objective of this study is to develop a region-specific non-invasive vagus nerve stimulation (VNS) technique using the millimeter wave (MMW) as a stimulus for the auricular branch of the vagus nerve (ABVN).Approach. A numerical simulation was conducted to ascertain whether the MMW could excite the ABVN in the human outer-ear with a millimeter-scale spatial resolution. Additionally, MMW-induced neuronal responses in seven mice were evaluated. Transcutaneous auricular VNS (ta-VNS) was applied to the cymba conchae innervated by the AVBN using a 60-GHz continuous wave (CW). As a control, the auricle's exterior margin was stimulated and referred to as transcutaneous auricular non-vagus nerve stimulation (ta-nonVNS). During stimulation, the local field potential (LFP) in the nucleus tractus solitarii (NTS), an afferent vagal projection site, was recorded simultaneously.Main results. The ta-VNS with a stimulus level of 13 dBm showed a significant increase in the LFP power in the NTS. The mean increases in power (n = 7) in the gamma high and gamma very high bands were 8.6 ± 2.0% and 18.2 ± 5.9%, respectively. However, the ta-nonVNS with a stimulus level of 13 dBm showed a significant decrease in the LFP power in the NTS. The mean decreases in power in the beta and gamma low bands were 11.0 ± 4.4% and 10.8 ± 2.8%, respectively. These findings suggested that MMW stimulation clearly induced a different response according to the presence of ABVN.Significance. Selective auricular VNS is feasible using the MMW. This study provides the basis for the development of a new clinical treatment option using the stimulation of the ta-VNS with a square millimeter spatial resolution.
Here, we studied changes in pain sensitivity in rats subjected to low-intensity millimeter-wavelength electromagnetic radiation (EMR MM) of 7.1 mm and 0.1 mW/cm2 in the occipital-collar region with daily exposure of 30 min over 21 days. As well, this radiation was combined with moderate electromagnetic shielding (EMS) which had the following parameters. The shielding coefficients of the constant component of the magnetic field along the vertical and horizontal constituents were 4.4- and 20-fold, respectively, with an exposure of 22 h/day over 21 days. The pain sensitivity was estimated with algometric tests, that is, the hot plate, flick-tail, and algesimeter-pincher tests; these allowed observation of the pain impulse at different regulatory levels. The algological effects of both individual and combined EMR MM and EMS were demonstrated. It was shown that EMR MM has an antinociceptive property when combined with EMS, as well as a modulation effect caused by shielding during hyperalgesia. At the same time, shielding reduces the antinociceptive effect of EMR MM.
The currently ongoing deployment if the fifth generation of the wireless communication technology, the 5G technology, has reignited the health debate around the new kind of radiation that will be used/emitted by the 5G devices and networks – the millimeter-waves. The new aspect of the 5G technology, that is of concern to some of the future users, is that both, antennas and devices will be continuously in a very close proximity of the users’ bodies. Skin is the only organ of the human body, besides the eyes, that will be directly exposed to the mm-waves of the 5G technology. However, the whole scientific evidence on the possible effects of millimeter-waves on skin and skin cells, currently consists of only some 99 studies. This clearly indicates that the scientific evidence concerning the possible effects of millimeter-waves on humans is insufficient to devise science-based exposure limits and to develop science-based human health policies. The sufficient research has not been done and, therefore, precautionary measures should be considered for the deployment of the 5G, before the sufficient number of quality research studies will be executed and health risk, or lack of it, scientifically established.
A joint metabolomic and lipidomic workflow is used to account for a potential effect of millimeter waves (MMW) around 60 GHz on biological tissues. For this purpose, HaCaT human keratinocytes were exposed at 60.4 GHz with an incident power density of 20 mW/cm², this value corresponding to the upper local exposure limit for general public in the context of a wide scale deployment of MMW technologies and devices. After a 24h-exposure, endo- and extracellular extracts were recovered to be submitted to an integrative UPLC-Q-Exactive metabolomic and lipidomic workflow. R-XCMS data processing and subsequent statistical treatment led to emphasize a limited number of altered features in lipidomic sequences and in intracellular metabolomic analyses, whatever the ionization mode (i.e 0 to 6 dysregulated features). Conversely, important dysregulations could be reported in extracellular metabolomic profiles with 111 and 99 frames being altered upon MMW exposure in positive and negative polarities, respectively. This unexpected extent of modifications can hardly stem from the mild changes that could be reported throughout transcriptomics studies, leading us to hypothesize that MMW might alter the permeability of cell membranes, as reported elsewhere.
Realizing a minimally-invasive interface with the brain for treating neurological disorders represents a considerable challenge for modern medicine. Implantable neuromodulation devices have been successfully used for treating a variety of neurological disorders, such as Parkinson's disease, dystonia, epilepsy, chronic pain, and migraine. However, the implantation trauma and the risks associated with chronic presence of the implant in the nervous tissue have limited the widespread use of these devices. Minimally-invasive technologies based on the surface electrical stimulation and transcranial magnetic stimulation have been developed to modulate the neuronal excitability in the brain, but their spatial resolution, limited to several centimeters, is insufficient for selective stimulation of millimeter-scale neuronal populations in the brain. Here, we describe some unique benefits afforded by a novel non-contact neuromodulation technique that employs millimeter waves. Using the leech ganglion preparation, we demonstrate a profound suppression of neuronal excitability induced by a low-power millimeter wave exposure. Based on these findings, we discuss the possible mechanisms and implications for developing a minimally-invasive neuromodulation therapy.
Interactions between millimeter waves (MMWs) and biological systems have received increasing attention due to the growing use of MMW radiation in technologies ranging from experimental medical devices to telecommunications and airport security. Studies have shown that MMW exposure alters cellular function, especially in neurons and muscles. However, the bio-physical mechanisms underlying such effects are still poorly understood. Due to the high aqueous absorbance of MMW, thermal mechanisms are likely. However, nonthermal mechanisms based on resonance effects have also been postulated. We studied MMW stimulation in a simplified preparation comprising Xenopus laevis oocytes expressing proteins that underlie membrane excitability. Using electrophysiological recordings simultaneously with 60 GHz stimulation, we observed changes in the kinetics and activity levels of voltage-gated potassium and sodium channels and a sodium-potassium pump that are consistent with a thermal mechanism. Furthermore, we showed that MMW stimulation significantly increased the action potential firing rate in oocytes coexpressing voltage-gated sodium and potassium channels, as predicted by thermal terms in the Hodgkin-Huxley model of neurons. Our results suggest that MMW stimulation produces significant thermally mediated effects on excitable cells via basic thermodynamic mechanisms that must be taken into account in the study and use of MMW radiation in biological systems.
Millimetre waves correspond to the range of frequencies located between 30 and 300 GHz. Many applications exist and are emerging in this band, including wireless telecommunications, imaging and monitoring systems. In addition, some of these frequencies are used in therapy in Eastern Europe, suggesting that interactions with the human body are possible. This review aims to summarise current knowledge on interactions between millimetre waves and living matter. Several representative examples from the scientific literature are presented. Then, possible mechanisms of interactions between millimetre waves and biological systems are discussed.RésuméLes ondes millimétriques correspondent à la gamme des fréquences comprises entre 30 et 300 GHz. De nombreuses applications existent et émergent actuellement dans ce domaine, notamment en télécommunications, imagerie et surveillance. De plus, certaines de ces fréquences sont utilisées en thérapie en Europe de lʼEst, ce qui suggère que des interactions avec lʼorganisme sont possibles. Cette revue vise à résumer lʼétat des connaissances actuelles sur les interactions ondes millimétriques/matière vivante. Plusieurs exemples représentatifs de la littérature scientifique sont présentés. Enfin, les différents mécanismes potentiellement impliqués dans les effets biologiques des ondes millimétriques seront discutés.
Interactions between millimeter waves (MMWs) and biological systems have received increasing attention due to the growing use of MMW radiation in technologies ranging from experimental medical devices to telecommunications and airport security. Studies have shown that MMW exposure alters cellular function, especially in neurons and muscles. However, the biophysical mechanisms underlying such effects are still poorly understood. Due to the high aqueous absorbance of MMW, thermal mechanisms are likely. However, nonthermal mechanisms based on resonance effects have also been postulated. We studied MMW stimulation in a simplified preparation comprising Xenopus laevis oocytes expressing proteins that underlie membrane excitability. Using electrophysiological recordings simultaneously with 60 GHz stimulation, we observed changes in the kinetics and activity levels of voltage-gated potassium and sodium channels and a sodium-potassium pump that are consistent with a thermal mechanism. Furthermore, we showed that MMW stimulation significantly increased the action potential firing rate in oocytes coexpressing voltage-gated sodium and potassium channels, as predicted by thermal terms in the Hodgkin-Huxley model of neurons. Our results suggest that MMW stimulation produces significant thermally mediated effects on excitable cells via basic thermodynamic mechanisms that must be taken into account in the study and use of MMW radiation in biological systems.
As millimeter waves (MMWs) are being increasingly used in communications and military applications, their potential effects on biological tissue has become an important issue for scientific inquiry. Specifically, several MMW effects on the whole-nerve activity were reported, but the underlying neuronal changes remain unexplored. This study used slices of cortical tissue to evaluate the MMW effects on individual pyramidal neurons under conditions mimicking their in vivo environment. The applied levels of MMW power are three orders of magnitude below the existing safe limit for human exposure of 1 mW cm(-2). Surprisingly, even at these low power levels, MMWs were able to produce considerable changes in neuronal firing rate and plasma membrane properties. At the power density approaching 1 microW cm(-2), 1 min of MMW exposure reduced the firing rate to one third of the pre-exposure level in four out of eight examined neurons. The width of the action potentials was narrowed by MMW exposure to 17% of the baseline value and the membrane input resistance decreased to 54% of the baseline value across all neurons. These effects were short lasting (2 min or less) and were accompanied by MMW-induced heating of the bath solution at 3 degrees C. Comparison of these results with previously published data on the effects of general bath heating of 10 degrees C indicated that MMW-induced effects cannot be fully attributed to heating and may involve specific MMW absorption by the tissue. Blocking of the intracellular Ca(2+)-mediated signaling did not significantly alter the MMW-induced neuronal responses suggesting that MMWs interacted directly with the neuronal plasma membrane. The presented results constitute the first demonstration of direct real-time monitoring of the impact of MMWs on nervous tissue at a microscopic scale. Implication of these findings for the therapeutic modulation of neuronal excitability is discussed.
This protocol details methods to identify and record from cutaneous primary afferent axons in an isolated mammalian skin-saphenous nerve preparation. The method is based on extracellular recordings of propagated action potentials from single-fiber receptive fields. Cutaneous nerve endings show graded sensitivities to various stimulus modalities that are quantified by adequate and controlled stimulation of the superfused skin with heat, cold, touch, constant punctate pressure or chemicals. Responses recorded from single-fibers are comparable with those obtained in previous in vivo experiments on the same species. We describe the components and the setting-up of the basic equipment of a skin-nerve recording station (few days), the preparation of the skin and the adherent saphenous nerve in the mouse (15-45 min) and the isolation and recording of neurons (approximately 1-3 h per recording). In addition, stimulation techniques, protocols to achieve single-fiber recordings, issues of data acquisition and action potential discrimination are discussed in detail.
Afferent activity of single facial cold receptors was extracellularly recorded from infraorbital nerve fibers in the rat, and the response properties of 28 receptors to thermal stimulation were quantitatively studied. Generally, on repeated stimulation, the afferent activity was highly reproducible and was not dependent on previous adapting temperatures. At constant temperatures, a periodic pattern was apparent in the discharges of 24 receptors; in the remaining 4 receptors periodic elements could not reliably be detected. The temperature dependence of the cyclic pattern corresponded to that observed in other mammalian cold receptor populations: we observed regular impulse groups (bursts) at lower and beating activity at higher adapting temperatures. Rapid changes of temperature induced transient alterations of activity. The dynamic response to cooling was biphasic, indicating a complex sequence of receptor events. A transient acceleration of impulse frequency was followed by a dynamic burst discharge which was characterized by longer pauses and a greater number of impulses per burst compared with the steady-state activity at the same temperature. This indicates a deceleration of the periodic receptor events during the adaptation process following dynamic responses, which is accompanied by a concomitant shift of these processes to a more pronounced suprathreshold condition. In an additional series of experiments, parameters of the periodic activity in the rat were compared with corresponding data of facial and lingual cold receptors in the cat. Whereas the number of impulses per cycle was similar in the 3 receptor populations, the frequency of the periodic pattern proved to be considerably higher in the rat than in the cat.
The response characteristics of facial thermoreceptors of the common vampire bat and of the mouse have been quantitatively studied. Cold receptors were identified in bat and mouse; warm receptors were only established in the bat. Cold and warm receptor populations of the two species share most of their properties with facial thermoreceptor populations of various mammalian species investigated so far. The temporal pattern of activity of cold receptors of the mouse corresponded to that observed in cats, dogs and monkeys: impulse groups at lower, and beating activity at higher temperatures. At maintained temperature, no impulse groups were initiated in cold receptors of the bat. However, cooling steps from various initial temperatures induced a transient grouped discharge in both cold receptor populations. A discharge in regular groups of impulses was occasionally generated in warm receptors of the bat at maintained temperatures and following warming steps. The data indicate that the temperature dependence of periodic activity in warm receptors is not as uniform as it is in cold receptors. It is concluded that cyclic processes are involved in sensory transduction of both warm and cold receptors, and that this cyclic behavior seems to be a general property of thermoreceptors of presumably all vertebrate species.
The effect of menthol on the discharge pattern of feline nasal and lingual cold receptors was analyzed in order to elucidate the underlying sensory transducer mechanism. A repetitive beating activity and burst (grouped) discharges were observed in both cold receptor populations at constant temperatures and after rapid cooling. An analysis of the impulse activity revealed a cyclic pattern of impulse generation, which suggested the existence of an underlying receptor potential oscillation that initiates impulses in the afferent nerve when it exceeds a threshold value. The frequency and amplitude of the periodic impulse-inducing receptor processes were characterized by the burst frequency, which increased with warming, and by the average number of impulses generated during each cycle, which increased with cooling. Menthol at micromolar concentrations induced an acceleration of the burst frequency at higher temperatures, but reduced the burst frequency in the midtemperature range. At temperatures above 25 degrees C, menthol increased the number of impulses elicited during each cycle and induced bursting in previously repetitively discharging fibers. At low temperatures, menthol suppressed bursting and finally inhibited all cold receptor activity. The impulse pattern at constant temperatures and during the dynamic response to rapid cooling was comparably affected by menthol. Calcium application completely abolished the stimulating menthol effect. Since, in equal concentrations, menthol specifically impairs neuronal calcium currents, the results are consistent with the conjecture that in cold receptors, menthol reduces the activation of a calcium-stimulated outward current by an impeding effect on a calcium conductance, thereby inducing depolarization and a modification of bursting behavior. The data confirm the hypothesis of a calcium-controlled outward conductance being involved in the generation of cyclic afferent activity in cold receptors.
Static and dynamic discharge patterns of bursting cold fibers in the lingual nerve of the cat were analysed at temperatures between 10 and 40°C. The period of the static burst discharge depends only on temperature and is not affected by the number of spikes per burst. The termination of an intraburst sequence of impulses can be predicted by the duration of the intraburst intervals. Irregular impulse patterns at low static temperatures show a unimodal interval distribution, whereas the interval histograms from irregular spike sequences at high temperatures have multiple peaks with nearly equal distances.
The relationship between exposure to electromagnetic fields (EMFs) and human health is more and more in focus. This is mainly because of the rapid increasing use of such EMFs within our modern society. Exposure to EMFs has been linked to different cancer forms, e.g. leukemia, brain tumors, neurological diseases, such as Alzheimer's disease, asthma and allergy, and recently to the phenomena of 'electrosupersensitivity' and 'screen dermatitis'. There is an increasing number of reports about cutaneous problems as well as symptoms from internal organs, such as the heart, in people exposed to video display terminals (VDTs). These people suffer from subjective and objective skin and mucosa-related symptoms, such as itch, heat sensation, pain, erythema, papules and pustules. In severe cases, people can not, for instance, use VDTs or artificial light at all, or be close to mobile telephones. Mast cells (MCs), when activated, release a spectrum of mediators, among them histamine, which is involved in a variety of biological effects with clinical relevance, e.g. allergic hypersensitivity, itch, edema, local erythema and many types of dermatoses. From the results of recent studies, it is clear that EMFs affect the MC, and also the dendritic cell, population and may degranulate these cells. The release of inflammatory substances, such as histamine, from MCs in the skin results in a local erythema, edema and sensation of itch and pain, and the release of somatostatin from the dendritic cells may give rise to subjective sensations of on-going inflammation and sensitivity to ordinary light. These are, as mentioned, the common symptoms reported from patients suffering from 'electrosupersensitivity'/'screen dermatitis'. MCs are also present in the heart tissue and their localization is of particular relevance to their function. Data from studies made on interactions of EMFs with the cardiac function have demonstrated that highly interesting changes are present in the heart after exposure to EMFs. One could speculate that the cardiac MCs are responsible for these changes due to degranulation after exposure to EMFs. However, it is still not known how, and through which mechanisms, all these different cells are affected by EMFs. In this article, we present a theoretical model, based upon observations on EMFs and their cellular effects, to explain the proclaimed sensitivity to electric and/or magnetic fields in humans.
The increasing use of transgenic mice for the study of pain mechanisms necessitates comprehensive understanding of the murine somatosensory system. Using an in vivo mouse preparation, we studied response properties of tibial nerve afferent fibers innervating glabrous skin. Recordings were obtained from 225 fibers identified by mechanical stimulation of the skin. Of these, 106 were classed as A beta mechanoreceptors, 51 as A delta fibers, and 68 as C fibers. A beta mechanoreceptors had a mean conduction velocity of 22.2 +/- 0.7 (SE) m/s (13.8--40.0 m/s) and a median mechanical threshold of 2.1 mN (0.4--56.6 mN) and were subclassed as rapidly adapting (RA, n = 75) or slowly adapting (SA, n = 31) based on responses to constant force mechanical stimuli. Conduction velocities ranged from 1.4 to 13.6 m/s (mean 7.1 +/- 0.6 m/s) for A delta fibers and 0.21 to 1.3 m/s (0.7 +/- 0.1 m/s) for C fibers. Median mechanical thresholds were 10.4 and 24.4 mN for A delta and C fibers, respectively. Responses of A delta and C fibers evoked by heat (35--51 degrees C) and by cold (28 to -12 degrees C) stimuli were determined. Mean response thresholds of A delta fibers were 42.0 +/- 3.1 degrees C for heat and 7.6 +/- 3.8 degrees C for cold, whereas mean response thresholds of C fibers were 40.3 +/- 0.4 degrees C for heat and 10.1 +/- 1.9 degrees C for cold. Responses evoked by heat and cold stimuli increased monotonically with stimulus intensity. Although only 12% of tested A delta fibers were heat sensitive, 50% responded to cold. Only one A delta nociceptor responded to both heat and cold stimuli. In addition, 40% of A delta fibers were only mechanosensitive since they responded neither to heat nor to cold stimuli. Thermal stimuli evoked responses from the majority of C fibers: 82% were heat sensitive, while 77% of C fibers were excited by cold, and 68% were excited by both heat and cold stimuli. Only 11% of C fibers were insensitive to heat and/or cold. This in vivo study provides an analysis of mouse primary afferent fibers innervating glabrous skin including new information on encoding of noxious thermal stimuli within the peripheral somatosensory system of the mouse. These results will be useful for future comparative studies with transgenic mice.
Sensations of cold are mediated by specific thermoreceptor nerve endings excited by low temperature and menthol. Here we identify a population of cold-sensitive cultured mouse trigeminal ganglion neurons with a unique set of biophysical properties. Their impulse activity during cooling and menthol application was similar to that of cold thermoreceptor fibers in vivo. We show that cooling closes a background K+ channel, causing depolarization and firing that is limited by the slower reduction of a cationic inward current (Ih). In cold-insensitive neurons, firing is prevented by a slow, transient, 4-AP-sensitive K+ current (IKD) that acts as an excitability brake. In addition, pharmacological blockade of IKD induced thermosensitivity in cold-insensitive neurons, a finding that may explain cold allodynia in neuropathic pain. These results suggest that cold sensitivity is not associated to a specific transduction molecule but instead results from a favorable blend of ionic channels expressed in a small subset of sensory neurons.
An in vitro preparation of the guinea-pig cornea was used to study the effects of changing temperature on nerve terminal impulses recorded extracellularly from cold-sensitive receptors. At a stable holding temperature (31-32.5 degrees C), cold receptors had an ongoing periodic discharge of nerve terminal impulses. This activity decreased or ceased with heating and increased with cooling. Reducing the rate of temperature change reduced the respective effects of heating and cooling on nerve terminal impulse frequency. In addition to changes in the frequency of activity, nerve terminal impulse shape also changed with heating and cooling. At the same ambient temperature, nerve terminal impulses were larger in amplitude and faster in time course during heating than those recorded during cooling. The magnitude of these effects of heating and cooling on nerve terminal impulse shape was reduced if the rate of temperature change was slowed. At 29, 31.5, and 35 degrees C, a train of 50 electrical stimuli delivered to the ciliary nerves at 10-40 Hz produced a progressive increase in the amplitude of successive nerve terminal impulses evoked during the train. Therefore, it is unlikely that the reduction in nerve terminal impulse amplitude observed during cooling is due to the activity-dependent changes in the nerve terminal produced by the concomitant increase in impulse frequency. Instead, the differences in nerve terminal impulse shape observed at the same ambient temperature during heating and cooling may reflect changes in the membrane potential of the nerve terminal associated with thermal transduction.
The ability to detect changes in temperature is a fundamental sensory mechanism for every species and provides organisms with a detailed view of the environment. This review focuses on what is known of the neuronal and molecular substrates for thermosensation across species, focusing on the three robust model systems extensively used to study sensory signaling, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the laboratory mouse. Nematodes migrate to thermal climes that are amenable to their survival, a behavior that is regulated primarily through a single sensory neuron. Additionally, nematodes "learn" to seek out this temperate zone based upon their prior experience, a robust model of learning and memory. Drosophila larvae also prefer select thermal zones that are optimal for growth and have also developed vigorous mechanisms to avoid unfavorable conditions. In mammals, the transduction mechanisms for thermosensation have been identified primarily due to the fact that naturally occurring plant products evoke distinct psychophysical sensation of temperature change. More remarkably, the elucidation of the molecular sensors in mammals, along with those in Drosophila, has demonstrated conservation in the molecular mediators of temperature sensation across diverse species.
The experimental results on the central nervous system reactions of a healthy man to a peripheral (the right or left hands) action of low-intensity (non-thermal) electromagnetic fields of the extremely low frequency and extremely high frequency band are presented. The studies have been carried out using the methods of sensory indication and electroencephalography. The obtained differences in the reactions show that mechanisms of biological action in these two cases are different. In the first case, the lemniscus system takes part mainly in the radiation-stimulus, and in the second case, the non-specific somatomensory system primarily participates.
The effect of menthol on the discharge pattern of feline nasal and lingual cold receptors was analyzed in order to elucidate the underlying sensory transducer mechanism. A repetitive beating activity and burst (grouped) discharges were observed in both cold receptor populations at constant temperatures and after rapid cooling. An analysis of the impulse activity revealed a cyclic pattern of impulse generation, which suggested the existence of an underlying receptor potential oscillation that initiates impulses in the afferent nerve when it exceeds a threshold value. The frequency and amplitude of the periodic impulse-inducing receptor processes were characterized by the burst frequency, which increased with warming, and by the average number of impulses generated during each cycle, which increased with cooling. Menthol at micromolar concentrations induced an acceleration of the burst frequency at higher temperatures, but reduced the burst frequency in the midtemperature range. At temperatures above 25 degrees C, menthol increased the number of impulses elicited during each cycle and induced bursting in previously repetitively discharging fibers. At low temperatures, menthol suppressed bursting and finally inhibited all cold receptor activity. The impulse pattern at constant temperatures and during the dynamic response to rapid cooling was comparably affected by menthol. Calcium application completely abolished the stimulating menthol effect. Since, in equal concentrations, menthol specifically impairs neuronal calcium currents, the results are consistent with the conjecture that in cold receptors, menthol reduces the activation of a calcium-stimulated outward current by an impeding effect on a calcium conductance, thereby inducing depolarization and a modification of bursting behavior. The data confirm the hypothesis of a calcium-controlled outward conductance being involved in the generation of cyclic afferent activity in cold receptors.
Effects of low-intensity millimeter waves (MMW) were studied in isolated frog nerve using a high-rate stimulation (HRS) functional test. Irradiation was performed in 3 frequency bands (41.1441.54, 45.89–45.93, and 50.8-51.0 GHz), at 5 frequencies in each band. The incident power density was 2.5 m W/cm2 for the 45.8945.93 GHz band and 10-fold less for the other two bands. Each nerve underwent a single 38-min MMW or sham exposure accompanied by an HRS train (20 paired stimuli/s for 17 min). The second stimulus in each pair was delivered during the relative refractory period, 9 ms after the first one. HRS caused a temporary and reversible decrease of the amplitude and conduction velocity of compound action potentials. MMW irradiation attenuated these changes; the MMW effect on the conduction velocity could be caused by microwave heating, while the effect on the amplitude apparently was not thermal. The amplitude changed significantly only in the test action potential (the one evoked during the refractory period), thus testifying to an improvement of the nerve refractory properties. This effect depended on MMW frequency rather than intensity and reached maximum at 41.34 GHz. A 100-MHz deviation from this frequency (to 41.24 or 41.44 GHz) reduced the effect more than twofold, and a 200-MHz deviation eliminated it. The results provided further evidence for the existence of frequency-specific, resonance-type mechanisms of MMW interaction with biological systems.
1. The purpose of the present study was to compare the responsiveness unmyelinated cutaneous units in vivo and in vitro and to determine the proportion of primary afferents innervating the rat hairy skin that do not respond to transient mechanical or thermal stimuli. We have adopted electrical search strategies to locate the terminal arborization of unmyelinated fibers before testing the sensitivity to adequate stimuli. 2. A total of 144 unmyelinated units were studied, of which 31 were obtained from in vivo and 113 from in vitro experiments. 55 afferents were investigated after chronic surgical sympathectomy. Units recorded from sympathectomized rats did not differ in their conduction velocity, electrical thresholds, or receptive properties from units in intact animals. 3. There were only minor differences between the properties of units recorded in vivo and in vitro. This probably reflects technical differences of the setups rather than biological changes introduced by the in vitro conditions. Except for a higher prevalence of mechano-cold sensitive units in vitro, there was no significant difference between the distributions of receptor types. 4. Eight of 31 units (26%) recorded in vivo and 17 of 113 units (15%) obtained from in vitro experiments failed to respond to transient mechanical or thermal stimuli. In vivo, one of eight initially unresponsive units was activated by repeated mechanical and thermal stimulation. Two further units became responsive after topical application of mustard oil. In vitro, 2 of 17 unresponsive units were activated by repeated stimulation. Ten of the remaining unresponsive units were treated with a combination of inflammatory mediators. Four of these units were activated: three developed ongoing activity, and two of them also became responsive to mechanical and/or heat stimuli. The fourth unit responded to probing but was not spontaneously active. 5. We conclude that transient mechanical or thermal stimuli can excite the majority of unmyelinated cutaneous units. However, in vivo and in vitro, part of unmyelinated units are initially unresponsive even to noxious forms of stimulation. Because those unresponsive units were also encountered in sympathectomized preparations, and because some units can be recruited with repeated noxious stimuli or inflammatory agents, it is unlikely that all of them are sympathetic efferents. The same substances that cause sensitization of "normal" nociceptors are capable of recruiting initially unresponsive unmyelinated afferents.
Electrical stimulation (ES) of sensory nerves causes increased vascular permeability and vasodilatation, a process known as neurogenic inflammation. The purpose of this study was to assess the role of mast cells in neurogenic inflammation induced by ES of sensory nerves. ES of the rat saphenous nerve for 1, 3, 5, 15, or 30 min induced a 166 to 436% increase in the amount of 125I-albumin deposited in the skin. Through the initial 15 min of ES, the histamine content of the skin remained unchanged. However, 30 min of ES caused a 22.1% decrease in skin histamine (p less than 0.05). ES for 5 min followed by measurement of vascular permeability from 0 to 30 min thereafter resulted in maximal increases in 125I-albumin in the skin immediately after cessation of the pulse of ES. When skin histamine was measured at various intervals after a 5-min pulse of ES, no change in the histamine content was observed through the subsequent 30 min. When mast cell degranulation was assessed histologically, 5 min of ES failed to stimulate mast cell degranulation. However, 30 min of ES caused a significant increase in the proportion of degranulating mast cells. When draining venous plasma histamine was monitored before, during and after ES, no change in plasma histamine was observed. In contrast, the intradermal injection of 5 micrograms of compound 48/80 produced a significant increase in plasma histamine. In order to examine the possibility that histamine might be released but remain in the skin after ES, skin "blisters" were developed by intradermal injections of saline. There was a significant increase in the amount of 125I-albumin extravasated into blister fluid measured after 3, 5, and 10 min of ES and a significant increase in histamine after 5 or 10 min. Therefore, prolonged ES of sensory nerves can cause mast cell degranulation. However, ES causes increased vascular permeability at times when no mast cell activation can be observed. These data suggest that the initial phases of neurogenic inflammation are independent of mast cell activation.
A close spatial relationship between serotonin-containing mast cells and substance P-containing nerves was shown by immunohistochemistry using a combination of antisera specific for serotonin and substance P. This supports earlier morphological results suggesting an innervation of mast cells and pharmacological studies which postulate an influence of substance P on the release of histamine from mast cells.
1. Cutaneous thermoreceptors were examined electrophysiologically in primates (monkey, baboon) and in sub‐primates (dog and rat) by recording from single units dissected from peripheral nerves.
2. Thermal stimuli were delivered from thermodes in contact with the skin.
3. Primate ‘cold’ receptors had spot‐like receptive fields and were found in both hairy and glabrous skin. The conduction velocities of the axons ranged from 0·6 to 15·3 m/sec.
4. The discharge from the primate receptors characteristically appeared in bursts with intervals of silence within the range temperatures of 18‐40° C. Static and dynamic sensitivity curves were established, with maxima about 30° C.
5. Cold receptors in the lip of the dog had maximal sensitivity at 31‐37° C. The axons were myelinated with conduction velocities less than 20 m/sec.
6. ‘Warm’ receptors, with maximal sensitivity at 40° C and non‐myelinated axons, were abundant in the scrotal nerve of the rat. The ‘cold’ receptors had maximal responses at 23‐28° C.
7. The ‘spurious’ thermoreceptor behaviour of slowly adapting mechanoreceptors is described and the way in which they may distort integrated potential records from whole nerves is analysed.
The responses of sensory nerve fibres to capsaicin solution topically applied to their cutaneous receptive fields were studied using the rat saphenous nerve. The polymodal nociceptors responded to capsaicin with discharge and subsequent densensitization to chemical, mechanical and thermal stimuli. Other types of C fibres, and A beta and A delta fibres, showed no response to capsaicin.
Low intensity millimeter-wave electromagnetic radiation of less than 10 mW cm-2 power intensity has a nonthermal effect on the body and it is widely used in medical practice for treatment of various diseases. Nevertheless, the effect of EMR on biological tissues is not understood. The skin and its sensory receptors are considered to be responsible for EMR reception, but this has yet to be confirmed. The present experiments were designed to study the effect of millimeter-wave electromagnetic radiation on the ampullae of Lorenzini in skates, which are very sensitive to weak electrical stimuli at low frequency. Reception of low-intensity millimeter-wave electromagnetic radiation at 37-55 GHz by the electroreceptors (ampullae of Lorenzini) in the skate has been shown. At a power intensity of 1-5 mW cm-2 irradiating the duct opening at 1-20 mm distance caused a transient increase in the firing rate of a single afferent unit. When the power intensity was increased inhibitory responses were also observed. Some receptors responded with a prolonged excitatory activity lasting up to 30 min to the irradiation of the duct opening. Direct irradiation of the sensory cells produced only an inhibition, probably due to a rise in temperature. It is proposed that millimeter-wave electromagnetic radiation generates a d.c. potential at the vicinity of duct opening which can be detected by the electroreceptors.
To prove the existence of human intraepidermal nerve fibers at the electron microscopic level, we used both conventional and immunohistochemical ultrastructural techniques. Specimens were obtained from skin of the back, one of the most densely innervated areas of the human epidermis. The immunohistochemical marker protein gene product 9.5 was chosen because it is highly potent in labeling nerves. Thin nerve fibers were found in the basal, spinous, and granular layers of the epidermis with both techniques used, although it was more difficult to identify the nervous structures with the conventional method. The nerves appeared in the intercellular spaces and contacted keratinocyte cell bodies or cilia by membrane-membrane apposition, but without any specialized structures. Nerve fibers in the very superficial part of the vital human epidermis have not been described before at the ultrastructural level.
A preparation of the hindpaw-skin together with the saphenous nerve from the adult rat was maintained in vitro. This was used to characterize the properties of sensory receptors with slowly conducting nerve fibres (C- and A delta) and to evaluate the effects of capsaicin and the capsaicin antagonist, capsazepine. Mechano-heat sensitive C-fibres were the most sensitive to capsaicin (threshold < 0.3 microM) applied to the receptive field. Other types of C-fibres were less sensitive (mechano-cold sensitive fibres threshold 1 microM) or insensitive (high- and low-threshold mechano-sensitive fibres). Mechano-heat and mechano-cold sensitive A delta-receptors were also activated by capsaicin but high- and low-threshold mechano-sensitive A delta-fibres were insensitive to capsaicin (maximum concentration 3 microM). The capsaicin-induced activation of mechano-heat sensitive C-fibres was concentration dependent with an EC50 = 350 nM. Responses to capsaicin, administered at submaximal concentrations were highly reproducible when administrations were separated by 30 min. Administrations at greater frequency reduced responsiveness to capsaicin. This was accompanied by a slowing of conduction velocity or production of a conduction blockade which was reversible after a few minutes. The activation of mechano-heat sensitive C-fibres by capsaicin could be prevented by capsazepine, indicating the involvement of specific capsaicin receptor-sites. These data show that fine afferents in the rat hindpaw-skin retain receptive properties when maintained in vitro. These fibres exhibit differential sensitivity to capsaicin; mechano-heat sensitive C-fibres being the most sensitive. The activation of this class of fibre was mediated via a specific capsaicin-receptor.
1. A total of 574 cutaneous afferent units in the sural and plantar nerves supplying the skin of the rat foot was examined: 399 A beta-units, 55 A delta-units, and 120 C-units. Their receptive-field (RF) properties were similar to those described in other mammals. However, the receptor type composition of units was different between the two nerves. 2. The sural A beta-fiber sample (n = 160) consisted of G-hair (41%), field (11%), rapidly adapting (RA; 6%), slowly adapting type I (SA-I; 7%), and type II (SA-II; 35%) mechanoreceptors. The plantar A beta-fiber sample (n = 239) was composed of G-hair (3%), RA (35%), SA-I (30%), SA-II (24%), and Pacinian corpuscle (PC; 8%) mechanoreceptors. 3. The RFs of SA-II units were located on both hairy and glabrous skin overlying the foot joints. Many of the SA-II units responded to movement of the foot joints. The RFs of both SA-I and RA units were small in size and located in high density on the toe tips and footpads. PC units were very sensitive to vibration and had extremely large RFs as in other species, although they were rare and found only in the plantar nerve. Field units were similar to SA-II units in response properties and RF distribution. 4. The sural A delta-fiber sample (n = 44) included nociceptors (68%), D-hair (27%), and cold (5%) receptors. All sampled plantar A delta-fibers (n = 11) were nociceptors. Of A delta-nociceptor units, A delta-mechanical nociceptors (73%) were dominant. 5. The sural C-fiber sample (n = 85) included nociceptors (44%), C-mechanoreceptors (33%), and cold receptors (21%). The plantar C-fiber sample (n = 35) included nociceptors (77%) and cold receptors (23%). No warm units were found among either the sural or plantar nerve fibers. Of C-nociceptors, C-mechanoheat nociceptors (80%) were dominant. 6. The results indicate that all well-known types of cutaneous receptors, except warm receptors, exist in the foot skin of the rat. On the basis of the fact that RFs of RA and SA-I units are in high density on the toe tips and footpads, it is suggested that those regions may have a spatial discriminating capacity. It is also suggested that SA-II receptors may play a role in proprioception, because they have RFs on the skin over foot joints and respond to joint movement.(ABSTRACT TRUNCATED AT 400 WORDS)
The effects of millimeter waves (mm-waves, 75 GHz) and temperature elevation on the firing rate of the BP-4 pacemaker neuron of the pond snail Lymnaea stagnalis were studied by using microelectrode techniques. The open end to a rectangular waveguide covered with a thin Teflon film served as a radiator. Specific absorption rates (SARs), measured in physiological solution at the radiator outlet, ranged from 600 to 4,200 W/kg, causing temperatures rises from 0.3 to 2.2 degrees C, respectively. Irradiation at an SAR of 4200 W/kg caused a biphasic change in the firing rate, i.e., a transient decrease in the firing rate (69 +/- 22% below control) followed by a gradual increase to a new level that was 68 +/- 21% above control. The biphasic changes in the firing rate were reproduced by heating under the condition that the magnitude (2 degrees C) and the rate of temperature rise (0.96 degrees C/s) were equal to those produced by the irradiation (for an SAR of 4,030 W/kg). The addition of 0.05 mM of ouabain caused the disappearance of transient responses of the neuron to the irradiation. It was shown that the rate of temperature rise played an important role in the development of a transient neuronal response. The threshold stimulus for a transient response of the BP-4 neuron found in warming experiments was a temperature rise of 0.0025 degrees C/s.
Effects of a short-term exposure to millimeter waves (CW, 40-52 GHz, 0.24-3.0 mW/cm2) on the compound action potential (CAP) conduction were studied in an isolated frog sciatic nerve preparation. CAPs were evoked by either a low-rate or a high-rate electrical stimulation of the nerve (4 and 20 paired pulses/s, respectively). The low-rate stimulation did not alter the functional state of the nerve, and the amplitude, latency, and peak latency of CAPs could stay virtually stable for hours. Microwave irradiation for 10-60 min at 0.24-1.5 mW/cm2, either at various constant frequencies or with a stepwise frequency change (0.1 or 0.01 GHz/min), did not cause any detectable changes in CAP conduction or nerve refractoriness. The effect observed under irradiation at a higher field intensity of 2-3 mW/cm2 was a subtle and transient reduction of CAP latency and peak latency along with a rise of the test CAP amplitude. These changes could be evoked by any tested frequency of the radiation; they reversed shortly after cessation of exposure and were both qualitatively and quantitatively similar to the effect of conventional heating of 0.3-0.4 degree C. The high-rate electrical stimulation caused gradual and reversible decrease of the amplitude of conditioning and test CAPs and increased their latencies and peak latencies. These changes were essentially the same with and without irradiation (2.0-2.7 or 0.24-0.28 mW/cm2), except for attenuation of the decrease of the test CAP amplitude. This effect was observed at both field intensities, but was statistically significant only for certain frequencies of the radiation. Within the studied limits, this effect appeared to be dependent on the frequency rather than on the intensity of the radiation, but this observation requires additional experimental confirmation.
Close contacts between mast cells (MC) and nerve fibers have previously been demonstrated in normal and inflamed skin by light and electron microscopy. A key step for any study in MC-nerve interactions in situ is to simultaneously visualize both communication partners, preferably with the option of double labelling the nerve fibers. For this purpose, we developed the following triple-staining technique. After paraformaldehyde-picric acid perfusion fixation, cryostat sections of back skin from C57BL/6 mice were incubated with a primary rat monoclonal antibody to substance P (SP), followed by incubation with a secondary goat-anti-rat TRITC-conjugated IgG. A rabbit antiserum to CGRP was then applied, followed by a secondary goat-anti-rabbit FITC-conjugated IgG. MCs were visualized by incubation with AMCA-labelled avidin, or (for a more convenient quantification of close MC-nerve fiber contacts) with a mixture of TRITC- and FITC-labelled avidins. Using this simple, novel covisualization method, we were able to show that MC-nerve associations in mouse skin are, contrary to previous suggestions, highly selective for nerve fiber types, and that these interactions are regulated in a hair cycle-dependent manner: in telogen and early anagen skin, MCs preferentially contacted CGRP-immunoreactive (IR) or SP/CGRP-IR double-labelled nerve fibers. Compared with telogen values, there was a significant increase in the number of close contacts between MCs and tyrosine hydroxylase-IR fibers during late anagen, and between MCs and peptide histidine-methionine-IR and choline acetyl transferase-IR fibers during catagen.
Using an in vitro nerve skin preparation and controlled mechanical or thermal stimuli, we analyzed the receptive properties of 277 mechanosensitive single primary afferents with myelinated (n = 251) or unmyelinated (n = 26) axons innervating the hairy skin in adult or 2-wk-old mice. Afferents were recorded from small filaments of either sural or saphenous nerves in an outbred mice strain or in the inbred Balb/c strain. On the basis of their receptive properties and conduction velocity, several receptor types could be distinguished. In adult animals (>6 wk old), 54% of the large myelinated fibers (Abeta, n = 83) showed rapidly adapting (RA) discharges to constant force stimuli and probably innervated hair follicles, whereas 46% displayed a slowly adapting (SA) response and probably innervated Merkel cells in touch domes. Among thin myelinated fibers (Adelta, n = 91), 34% were sensitive D hair receptors and 66% were high-threshold mechanoreceptors (AM fibers). Unmyelinated fibers had high mechanical thresholds and nociceptive functions. All receptor types had characteristic stimulus-response functions to suprathreshold force stimuli. Noxious heat stimuli (15-s ramp from 32 to 47 degrees C measured at the corium side of the skin) excited 26% (5 of 19) of AM fibers with a threshold of 42.5 +/- 1.4 degrees C (mean +/- SE) and an average discharge of 15.8 +/- 9.7 action potentials and 41% (7 of 17) C fibers with a mean threshold of 37.6 +/- 1.9 degrees C and an average discharge of 22.0 +/- 6.0 action potentials. Noxious cold stimuli activated 1 of 10 AM fibers and 3 of 10 C fibers. One of 10 C units responded to both heat and cold stimuli. All types of afferent fibers present in adult mice could readily be recognized in mice at postnatal day 14. However, fibers had reduced conduction velocities and the stimulus-response function to mechanical stimuli was more shallow in all fibers except for the D hairs. In juvenile mice, 22% of RA units also displayed an SA response at high stimulus intensities; these units were termed RA/SA units. We conclude that all types of cutaneous afferent fibers are already committed to their phenotype 2 wk after birth but undergo some maturation over the following weeks. This preparation has great potential for the study of transgenic mice with targeted mutations of genes that code factors that are involved in the specification of sensory neuron phenotypes.
Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
To find out if millimeter waves can decrease experimental pain response in mice using cold water tail flick test.
Male Swiss albino mice (15 mice per group) were exposed to continuous millimeter waves at a frequency of 61.22 GHz with incident power densities (IPD) ranging from 0.15 to 5.0 mW/cm2 for 15 min or sham exposed. Latency of tail withdrawal in a cold water (1 +/- 0.5 degrees C) tail flick test was measured before the exposure (baseline) and then four times after the exposure with 15 min breaks.
The mean latency of the tail flick response in mice exposed to millimeter waves was more than twice that of sham-exposed controls (p<0.05). This effect was proportional to the power of millimeter waves and completely disappeared at an IPD level of < or = 0.5 mW/cm2. Pretreatment of mice with the opioid antagonist naloxone (1 mg/kg i.p.) blocked the effect of millimeter waves.
Results suggest that the antinociceptive effect of millimeter waves is mediated through endogenous opioids.
Based on a hypothesis of neural system involvement in the initial absorption and further processing of the millimeter electromagnetic waves (MW) signal, we reproduced, quantitatively assessed and compared the analgesic effect of a single MW treatment, exposing areas of skin possessing different innervation densities. The cold water tail flick test (cTFT) was used to assess experimental pain in mice. Three areas of exposure were used: the nose, the glabrous skin of the right footpad, and the hairy skin of the mid back at the level of T5-T10. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15mW/cm2; and duration = 15 min. The maximum hypoalgesic effect was achieved by exposing to MW the more densely innervated skin areas--the nose and the footpad. The hypoalgesic effect in the cTFT after MW exposure to the murine back, which is less densely innervated, was not statistically significant. These results support the hypothesis of neural system involvement in the systemic response to MW.
Transduction in cutaneous cold receptors is poorly understood at present. We have studied this question using dorsal root ganglion (DRG) neurones in primary culture as a model of the otherwise inaccessible receptor terminal. Whole-cell recordings during cooling from 32 to 20 degrees C revealed a large depolarization (>8mV) in 22 of 88 DRG neurones (25%), sometimes accompanied by action potentials. In cold-sensitive neurones cooling inhibited a time-independent background K+ current (Icold) which was resistant to tetraethylammonium and 4-aminopyridine. Ouabain elicited a substantially smaller depolarization than cooling, and no action potentials. We conclude that excitation by cooling in this model is primarily due to inhibition of Icold and that the previously suggested role of the Na+/K+ adenosine triphosphatase is secondary. We suggest that Icold may underlie cold transduction in cutaneous thermoreceptors.
In a series of blind experiments, using the cold water tail-flick test (cTFT) as a quantitative indicator of pain, the hypoalgesic effect of a single exposure of mice to low power electromagnetic millimeter waves (MW) was studied. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15 mW/cm2; and duration = 15 min. MW treatment was applied to the glabrous skin of the footpad. Exposure of an intact murine paw to the MW resulted in a statistically significant hypoalgesia as measured in the cTFT. These mice were able to resist cold noxious stimulation in the cTFF more than two times longer than animals from the sham-exposed group. A unilateral sciatic nerve transection was used to deafferent the area of exposure in animals from one of the experimental groups. This surgery, conducted six days before the MW treatment, completely abolished the hypoalgesic effect of the exposure to MW. The results obtained support the conclusion that the MW-skin nerve endings interaction is the essential step in the initiation of biological effects caused by MW. Based on our past and present results we recommend that in order to obtain a maximum therapeutic effect, densely innervated skin areas (head, hands) need to be used preferentially for exposure to MW in clinical practice.
The aim of this study was to determine whether the iontophoretic administration of the mast cell degranulator compound 48/80 influences axon reflex vasodilatation in the skin of the human forearm. In stage 1, compound 48/80 was administered by iontophoresis to a circular site in the forearm of 9 healthy men and 8 healthy women on four occasions spread over 24 h. Two control sites were also prepared by passing the iontophoretic current through 0.9% saline. Large wheals initially developed at the compound 48/80 site in 8 of the males and in 2 of the females, but wheals were minimal in all subjects by the fourth administration. In stage 2, compound 48/80 iontophoresis provoked substantial flaring at the first control site, whereas saline iontophoresis induced only minor flaring at the second control site, indicating that compound 48/80 induced axon reflex vasodilatation. However, prior treatment with compound 48/80 inhibited flaring to compound 48/80 in subjects who initially developed wheals, consistent with mast cell degranulation. In stage 3, flaring after iontophoresis of histamine was investigated at the site of compound 48/80 pretreatment and at the second control site in 12 subjects. Flaring was impaired only slightly in 6 subjects who initially developed wheals to compound 48/80. The persistence of flaring indicates that repeated administrations of compound 48/80 did not abolish neurogenic inflammation. Transcutaneous iontophoresis of compound 48/80 may be an attractive alternative to intradermal injection in studies that aim at clarifying the function of mast cells in healthy and diseased skin.
Heating rates of human skin exposed locally to 42.25 GHz mm waves, coming from a waveguide (WG) opening or a YAV device designed for therapeutic application, were studied in vivo using infrared (IR) thermography. For both radiators, the power density distribution was described by a circularly symmetrical Gaussian type function on the exposed skin surface. Insertion of a small thermocouple (d = 0.1 mm) in the exposed area did not produce any significant artifact, either in the power density distribution or kinetics measurement, providing it was perpendicular to the E vector. The heating kinetics in the skin exposed with either the WG opening or the YAV device were well fitted to solutions of the 2-D bio-heat transfer equation for homogeneous tissue. Changes in irradiating beam size (1-8 mm) had no detectable effect on the initial (0.3-3.0 s) phase of the heating kinetics. However, the amplitude of the kinetics decreased substantially with decreasing the beam size. As the temperature rise in the time interval necessary for reliable measurement of the initial temperature rise rate was very small, an accurate experimental determination of specific absorption rate (SAR) becomes practically impossible at the low intensities normally used in our experiments. The correct SAR values may be found from fitting of the model to the heating kinetics. Bioelectromagnetics 24:571-581, 2003.
We investigated the influence of blood perfusion on local heating of the forearm and middle finger skin following 42.25 GHz exposure with an open ended waveguide (WG) and with a YAV mm wave therapeutic device. Both sources had bell-shaped distributions of the incident power density (IPD) with peak intensities of 208 and 55 mW/cm(2), respectively. Blood perfusion was changed in two ways: by blood flow occlusion and by externally applied vasodilator (nonivamide/nicoboxil) cream to the skin. For thermal modeling, we used the bioheat transfer equation (BHTE) and the hybrid bioheat equation (HBHE) which combines the BHTE and the scalar effective thermal conductivity equation (ETCE). Under normal conditions with the 208 mW/cm(2) exposure, the cutaneous temperature elevation (DeltaT) in the finger (2.5 +/- 0.3 degrees C) having higher blood flow was notably smaller than the cutaneous DeltaT in the forearm (4.7 +/- 0.4 degrees C). However, heating of the forearm and finger skin with blood flow occluded was the same, indicating that the thermal conductivity of tissue in the absence of blood flow at both locations was also the same. The BHTE accurately predicted local hyperthermia in the forearm only at low blood flow. The HBHE made accurate predictions at both low and high perfusion rates. The relationship between blood flow and the effective thermal conductivity (k(eff)) was found to be linear. The heat dissipating effect of higher perfusion was mostly due to an apparent increase in k(eff). It was shown that mm wave exposure could result in steady state heating of tissue layers located much deeper than the penetration depth (0.56 mm). The surface DeltaT and heat penetration into tissue increased with enlarging the irradiating beam area and with increasing exposure duration. Thus, mm waves at sufficient intensities could thermally affect thermo-sensitive structures located in the skin and underlying tissue.
Temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels are critical contributors to normal pain and temperature sensation and therefore represent attractive targets for pain therapy. When these channels were first discovered, most attention was focused on their potential contributions to direct thermal activation of peripheral sensory neurons. However, recent anatomical, physiological, and behavioral studies have provided evidence that TRPV channels expressed in skin epithelial cells may also contribute to thermosensation in vitro and in vivo. Here, we review these studies and speculate on possible communication mechanisms from cutaneous epithelial cells to sensory neurons.
The abilities to sense environmental and internal temperatures are required for survival, both for maintenance of homeostasis and for avoidance of tissue-damaging noxious temperatures. Vertebrates can sense external physical stimuli via specialized classes of neurons in the peripheral nervous system that project to the skin. Temperature-sensitive neurons can be divided into two classes: innocuous thermosensors (warm or cool) and noxious thermonociceptors (hot or cold). ThermoTRPs, a subset of the transient receptor potential family of ion channels, which are expressed in sensory nerve endings and in skin, respond to distinct thermal thresholds. In this review, we examine the extent to which thermoTRPs are responsible for providing a molecular basis for thermal sensation.
Sensory neurons innervating the skin encode the familiar sensations of temperature, touch and pain. An explosion of progress has revealed unanticipated cellular and molecular complexity in these senses. It is now clear that perception of a single stimulus, such as heat, requires several transduction mechanisms. Conversely, a given protein may contribute to multiple senses, such as heat and touch. Recent studies have also led to the surprising insight that skin cells might transduce temperature and touch. To break the code underlying somatosensation, we must therefore understand how the skin's sensory functions are divided among signalling molecules and cell types.
To identify the mechanisms of biological effects of mm waves it is important to develop accurate methods for evaluating absorption and penetration depth of mm waves in the epidermis and dermis. The main characteristics of mm wave skin dosimetry were calculated using a homogeneous unilayer model and two multilayer models of skin. These characteristics included reflection, power density (PD), penetration depth (delta), and specific absorption rate (SAR). The parameters of the models were found from fitting the models to the experimental data obtained from measurements of mm wave reflection from human skin. The forearm and palm data were used to model the skin with thin and thick stratum corneum (SC), respectively. The thin SC produced little influence on the interaction of mm waves with skin. On the contrary, the thick SC in the palm played the role of a matching layer and significantly reduced reflection. In addition, the palmar skin manifested a broad peak in reflection within the 83-277 GHz range. The viable epidermis plus dermis, containing a large amount of free water, greatly attenuated mm wave energy. Therefore, the deeper fat layer had little effect on the PD and SAR profiles. We observed the appearance of a moderate SAR peak in the therapeutic frequency range (42-62 GHz) within the skin at a depth of 0.3-0.4 mm. Millimeter waves penetrate into the human skin deep enough (delta = 0.65 mm at 42 GHz) to affect most skin structures located in the epidermis and dermis.
Millimeter wave treatment (MMWT) is based on the systemic biological effects that develop following local skin exposure to low power electromagnetic waves in the millimeter range. In the present set of experiments, the hypoalgesic effect of this treatment was analyzed in mice. The murine nose area was exposed to MMW of "therapeutic" frequencies: 42.25, 53.57, and 61.22 GHz. MMWT-induced hypoalgesia was shown to be frequency dependent in two experimental models: (1) the cold water tail-flick test (chronic non-neuropathic pain), and (2) the wire surface test (chronic neuropathic pain following unilateral constriction injury to the sciatic nerve). Maximum hypoalgesic effect was obtained when the frequency was 61.22 GHz. Other exposure parameters were: incident power density = 13.3 mW/cm(2), duration of each exposure = 15 min. Involvement of delta and kappa endogenous opioids in the MMWT-induced hypoalgesia was demonstrated using selective blockers of delta- and kappa-opioid receptors and the direct ELISA measurement of endogenous opioids in CNS tissue. Possible mechanisms of the effect and the perspectives of the clinical application of MMWT are discussed.
A morphometric analysis of hypothalamic cells containing c-Fos-like protein detected by an indirect immunoperoxidase method was carried out to clarify the responses to movement restriction and skin electromagnetic high frequency (EHF) irradiation (7.1mm, 42.2GHz, 20mW output power) simultaneously to three acupuncture projection areas. The morphometry of c-Fos-protein positive neurons by their number and type was analyzed. Movement restriction (40min) induced c-Fos protein expression primarily in cells with 10-50mum(2) sizes (associative type neurons) only in anterior hypothalamic nucleus and lateral hypothalamic area; while additional EHF-irradiation of acupuncture projection areas (under movement restriction) induced c-Fos expression in all hypothalamic structures and mostly in cells with 70-150mum(2) sizes (relay type neurons), i.e. changed the pattern of activated cell type distribution. In conclusion, the findings show that modest stress under which experimental animals often are exposed increase c-Fos protein expression in hypothalamic centers and skin EHF-irradiation of acupuncture projection areas seem to increase that.
Studies of the pattern of activation of hypothalamic cells in conditions of electrical pain stimulation demonstrated an increase in the proportion of c-Fos-positive cells (to 72.02-98.95%), predominantly affecting cells of size 10-50 microm2. UHF irradiation of the skin activated hypothalamic cells of size 10-70 microm2 in the paraventricular and dorsomedial nuclei and in the periforniceal zone of the lateral hypothalamic field. Combined action of UHF irradiation of the skin and electrical pain stimulation led to decreases in the proportions of cells activated as a result of pain stimulation in the anterior hypothalamic field, the ventromedial nucleus, and the basal part of the lateral hypothalamic field. Changes in the distribution of activated cells by size (mainly a reduction in the proportion of cells of area 10-30 microm2 and an increase in the proportion of larger cells) were detected in the ventromedial nucleus and the basal part of the lateral field. UHF irradiation of the skin was found to have a modifying effect, consisting of a reduction in the degree of activation of hypothalamic cells evoked by electrical pain stimulation.
Sensor and subsensor reactions of a healthy man to peripheral effect of low‐intensity millimeter waves
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Peculiarities of white rat skin afferent activity resulting from exposure to low-intensity millimeter electromagnetic waves. Digest of papers of international symposium “Non-Thermal Intensity Millimeter Waves in Medicine
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