scholarly journals Dose-Dependent Effects of Transcranial Alternating Current Stimulation on Spike Timing in Awake Nonhuman Primates

2019 ◽  
Author(s):  
Luke Johnson ◽  
Ivan Alekseichuk ◽  
Jordan Krieg ◽  
Alex Doyle ◽  
Ying Yu ◽  
...  
Keyword(s):  
Electric Fields ◽  
Nonhuman Primates ◽  
Brain Activity ◽  
Alternating Current ◽  
Spike Timing ◽  
Novel Treatments ◽  
Dose Dependent Fashion ◽  
Transcranial Alternating Current Stimulation ◽  
Dose Dependent

ABSTRACTWeak extracellular electric fields can influence spike timing in neural networks. Approaches to impose such fields on the brain in a noninvasive manner have high potential for novel treatments of neurological and psychiatric disorders. One of these methods, transcranial alternating current stimulation (TACS), is hypothesized to affect spike timing and cause neural entrainment. However, the conditions under which these effects occur in-vivo are unknown. Here, we show that TACS modulates spike timing in awake nonhuman primates (NHPs) in a dose-dependent fashion. Recording single-unit activity from pre-and post-central gyrus regions in NHPs during TACS, we found that a larger population of neurons became entrained to the stimulation waveform for higher stimulation intensities. Performing a cluster analysis of changes in interspike intervals, we identified two main types of neural responses to TACS – increased burstiness and phase entrainment. Our results demonstrate the ability of TACS to affect spike-timing in the awake primate brain and identify fundamental neural mechanisms. Concurrent electric field recordings demonstrate that spike-timing changes occur with stimulation intensities readily achievable in humans. These results suggest that novel TACS protocols tailored to ongoing brain activity may be a potent tool to normalize spike-timing in maladaptive brain networks and neurological disease.

scholarly journals Dose-dependent effects of transcranial alternating current stimulation on spike timing in awake nonhuman primates

2020 ◽  
Vol 6 (36) ◽  
pp. eaaz2747 ◽  
Author(s):  
Luke Johnson ◽  
Ivan Alekseichuk ◽  
Jordan Krieg ◽  
Alex Doyle ◽  
Ying Yu ◽  
...  
Keyword(s):  
Electric Fields ◽  
Nonhuman Primates ◽  
Therapeutic Potential ◽  
Brain Activity ◽  
Alternating Current ◽  
Spike Timing ◽  
Transcranial Alternating Current Stimulation ◽  
Neural Entrainment ◽  
Dose Dependent

Weak extracellular electric fields can influence spike timing in neural networks. Approaches to noninvasively impose these fields on the brain have high therapeutic potential in neurology and psychiatry. Transcranial alternating current stimulation (TACS) is hypothesized to affect spike timing and cause neural entrainment. However, the conditions under which these effects occur in vivo are unknown. Here, we recorded single-unit activity in the neocortex in awake nonhuman primates during TACS and found dose-dependent neural entrainment to the stimulation waveform. Cluster analysis of changes in interspike intervals identified two main types of neural responses to TACS—increased burstiness and phase entrainment. Our results uncover key mechanisms of TACS and show that the stimulation affects spike timing in the awake primate brain at intensities feasible in humans. Thus, novel TACS protocols tailored to ongoing brain activity may be a tool to normalize spike timing in maladaptive brain networks and neurological disease.

scholarly journals Transcranial Alternating Current Stimulation (tACS) Entrains Alpha Oscillations by Preferential Phase Synchronization of Fast-Spiking Cortical Neurons to Stimulation Waveform

2019 ◽  
Author(s):  
Ehsan Negahbani ◽  
Iain M. Stitt ◽  
Marshall Davey ◽  
Thien T. Doan ◽  
Moritz Dannhauer ◽  
...  
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Cortical Neurons ◽  
Posterior Parietal Cortex ◽  
Phase Synchronization ◽  
Alternating Current ◽  
Arnold Tongue ◽  
Transcranial Alternating Current Stimulation ◽  
Neuronal Oscillators

SummaryModeling studies predict that transcranial alternating current stimulation (tACS) entrains brain oscillations, yet direct examination has been lacking or potentially contaminated by stimulation artefact. Here we first demonstrate how the posterior parietal cortex drives primary visual cortex and thalamic LP in the alpha-band in head-fixed awake ferrets. The spike-field synchrony is maximum within alpha frequency, and more prominent for narrow-spiking neurons than broad-spiking ones. Guided by a validated model of electric field distribution, we produced electric fields comparable to those in humans and primates (< 0.5 mV/mm). We found evidence to support the model-driven predictions of how tACS entrains neural oscillations as explained by the triangular Arnold tongue pattern. In agreement with the stronger spike-field coupling of narrow-spiking cells, tACS more strongly entrained this cell population. Our findings provide the firstin vivoevidence of how tACS with electric field amplitudes used in human studies entrains neuronal oscillators.

scholarly journals Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation

2014 ◽  
Vol 16 (1) ◽  
pp. 93-102 ◽  
Keyword(s):  
Electric Fields ◽  
Brain Stimulation ◽  
Rational Design ◽  
Brain Activity ◽  
Field Potential ◽  
Alternating Current ◽  
Noninvasive Brain Stimulation ◽  
Starting Point ◽  
Recent Developments ◽  
Transcranial Alternating Current Stimulation

Synchronized neuronal activity in the cortex generates weak electric fields that are routinely measured in humans and animal models by electroencephalography and local field potential recordings. Traditionally, these endogenous electric fields have been considered to be an epiphenomenon of brain activity. Recent work has demonstrated that active cortical networks are surprisingly susceptible to weak perturbations of the membrane voltage of a large number of neurons by electric fields. Simultaneously, noninvasive brain stimulation with weak, exogenous electric fields (transcranial current stimulation, TCS) has undergone a renaissance due to the broad scope of its possible applications in modulating brain activity for cognitive enhancement and treatment of brain disorders. This review aims to interface the recent developments in the study of both endogenous and exogenous electric fields, with a particular focus on rhythmic stimulation for the modulation of cortical oscillations. The main goal is to provide a starting point for the use of rational design for the development of novel mechanism-based TCS therapeutics based on transcranial alternating current stimulation, for the treatment of psychiatric illnesses.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

Enhancement of FSH bioactivity in vivo using site-specific antisera

1997 ◽  
Vol 152 (3) ◽  
pp. 355-363 ◽  
Author(s):  
L Ferasin ◽  
G Gabai ◽  
J Beattie ◽  
G Bono ◽  
A T Holder
Keyword(s):  
Biological Activity ◽  
Treatment Period ◽  
Ovarian Function ◽  
Day Treatment ◽  
Site Specific ◽  
Dose Dependent Fashion ◽  
Snell Dwarf ◽  
Fsh Bioactivity ◽  
Dose Dependent

The ability of site-specific antipeptide antisera to enhance the biological activity of ovine FSH (oFSH) in vivo was investigated using hypopituitary Snell dwarf mice. These animals were shown to respond to increasing doses of oFSH (3·3–90 μg/day), administered in two daily injections over a 5-day treatment period, in a highly significant dose-dependent fashion. The responses measured were increases in uterine weight, ovarian weight and the index of keratinisation in vaginal smears. The dose-dependent response to oFSH confirmed the suitability of this animal model for these investigations and suggested the suboptimal dose of oFSH (20 μg/day) for use in enhancement studies. Five peptides derived from the β subunit of bovine FSH (bFSH) (A, residues 33–47; B, 40–51; C, 69–80; D, 83–94; E, 27–39) were used to generate polyclonal antipeptide antisera. Of these peptides, only A and B produced an antiserum (raised in sheep) capable of recognising 125I-bFSH in a liquid phase RIA. Antisera prepared against peptide A or peptide B were found to significantly enhance the biological activity of 20 μg oFSH/day over a 5-day treatment period. The response to antipeptide antisera alone did not differ significantly from that observed in PBS-injected control animals, neither did the response to FSH alone differ from that observed in animals treated with FSH plus preimmune serum. Thus the enhanced responses are dependent upon the presence of FSH plus antipeptide antiserum. Peptides A and B are located in a region thought to be involved in receptor recognition, this may have implications for the mechanism underlying this phenomenon and/or the structure/function relationships of FSH. That FSH-enhancing antisera can be generated by immunisation of animals with peptides A and B suggests that it may be possible to develop these peptides as vaccines capable of increasing reproductive performance, such as ovulation rate. The high degree of sequence homology between ovine, bovine and porcine (and to a lesser extent human and equine) FSH in the region covered by peptides A and B suggests that these peptides could also be used to promote and regulate ovarian function in all of these species. Journal of Endocrinology (1997) 152, 355–363

Changes in TMS measures of cortical excitability induced by transcranial direct and alternating current stimulation

2021 ◽  
Author(s):  
Michael A. Nitsche ◽  
Walter Paulus ◽  
Gregor Thut
Keyword(s):  
Brain Stimulation ◽  
Cortical Excitability ◽  
Brain Activity ◽  
Alternating Current ◽  
Transcranial Electrical Stimulation ◽  
Electrical Currents ◽  
After Effects ◽  
Brain Physiology ◽  
Transcranial Alternating Current Stimulation ◽  
Oscillatory Brain Activity

Brain stimulation with weak electrical currents (transcranial electrical stimulation, tES) is known already for about 60 years as a technique to generate modifications of cortical excitability and activity. Originally established in animal models, it was developed as a noninvasive brain stimulation tool about 20 years ago for application in humans. Stimulation with direct currents (transcranial direct current stimulation, tDCS) induces acute cortical excitability alterations, as well as neuroplastic after-effects, whereas stimulation with alternating currents (transcranial alternating current stimulation, tACS) affects primarily oscillatory brain activity but has also been shown to induce neuroplasticity effects. Beyond their respective regional effects, both stimulation techniques have also an impact on cerebral networks. Transcranial magnetic stimulation (TMS) has been pivotal to helping reveal the physiological effects and mechanisms of action of both stimulation techniques for motor cortex application, but also for stimulation of other areas. This chapter will supply the reader with an overview about the effects of tES on human brain physiology, as revealed by TMS.

scholarly journals Interleukin-6 is a potent thrombopoietic factor in vivo in mice

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1241-1244 ◽  
Author(s):  
T Ishibashi ◽  
H Kimura ◽  
Y Shikama ◽  
T Uchida ◽  
S Kariyone ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Serum Levels ◽  
In Vivo Studies ◽  
Time Intervals ◽  
Platelet Counts ◽  
Striking Increase ◽  
Biologic Activity ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract To determine the biologic activity of interleukin-6 (IL-6) on megakaryocytopoiesis and thrombocytopoiesis in vivo, the cytokine was administered intraperitoneally to mice every 12 hours at varying doses for five days or for varying time intervals, based on the kinetic analysis of IL-6 serum levels indicating the peak of 40 minutes following injection, with no detection at 150 minutes. A dose-response experiment showed that IL-6 increased platelet counts in a dose- dependent fashion at a plateau stimulation level of 5 micrograms. Administration of 5 micrograms of IL-6 reproducibly elevated platelet counts at five days by approximately 50% to 60% of increase. Moreover, a striking increase in megakaryocytic size in response to IL-6 was elicited by the treatment, but no change in megakaryocyte numbers; whereas IL-6 administration did not expand CFU-MK numbers. The in vivo studies in this manner had negligible effects on other hematologic parameters, with the minor exception of monocyte levels. These data show that IL-6 acts on maturational stages in megakaryocytopoiesis and promotes platelet production in vivo in mice, suggesting that IL-6 functions as thrombopoietin.

scholarly journals Transcranial alternating current stimulation attenuates BOLD adaptation and increases functional connectivity

2020 ◽  
Vol 123 (1) ◽  
pp. 428-438 ◽  
Author(s):  
Kohitij Kar ◽  
Takuya Ito ◽  
Michael W. Cole ◽  
Bart Krekelberg
Keyword(s):  
Functional Connectivity ◽  
Electric Fields ◽  
Full Range ◽  
Region Of Interest ◽  
Alternating Current ◽  
Human Motion ◽  
Dependent Manner ◽  
Bold Imaging ◽  
Transcranial Alternating Current Stimulation ◽  
The Brain

Transcranial alternating current stimulation (tACS) is used as a noninvasive tool for cognitive enhancement and clinical applications. The physiological effects of tACS, however, are complex and poorly understood. Most studies of tACS focus on its ability to entrain brain oscillations, but our behavioral results in humans and extracellular recordings in nonhuman primates support the view that tACS at 10 Hz also affects brain function by reducing sensory adaptation. Our primary goal in the present study is to test this hypothesis using blood oxygen level-dependent (BOLD) imaging in human subjects. Using concurrent functional magnetic resonance imaging (fMRI) and tACS, and a motion adaptation paradigm developed to quantify BOLD adaptation, we show that tACS significantly attenuates adaptation in the human motion area (hMT+). In addition, an exploratory analysis shows that tACS increases functional connectivity of the stimulated hMT+ with the rest of the brain and the dorsal attention network in particular. Based on field estimates from individualized head models, we relate these changes to the strength of tACS-induced electric fields. Specifically, we report that functional connectivity (between hMT+ and any other region of interest) increases in proportion to the field strength in the region of interest. These findings add support for the claim that weak 10-Hz currents applied to the scalp modulate both local and global measures of brain activity. NEW & NOTEWORTHY Concurrent transcranial alternating current stimulation (tACS) and functional MRI show that tACS affects the human brain by attenuating adaptation and increasing functional connectivity in a dose-dependent manner. This work is important for our basic understanding of what tACS does, but also for therapeutic applications, which need insight into the full range of ways in which tACS affects the brain.

scholarly journals CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1175-1183 ◽  
Author(s):  
Brian Kavanagh ◽  
Shaun O'Brien ◽  
David Lee ◽  
Yafei Hou ◽  
Vivian Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Effector T Cells ◽  
Activated T Cells ◽  
Ctla4 Blockade ◽  
Dose Dependent Fashion ◽  
Dose Dependent

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.

Sign in / Sign up

Export Citation Format

Share Document