New publication in Brain Stimulation

Alternate sessions of transcranial direct current stimulation (tDCS) reduce chronic pain in women affected by chikungunya. A randomized clinical trial

Clécio Gabriel de Souza, Rodrigo Pegado, Jardson Fausto da Costa, Edgard Morya, Abrahão Baptista, Gozde Unal, Marom Bikson, & Alexandre Hideki Okano

Brain Stimulation | (2021) | https://doi.org/10.1016/j.brs.2021.02.015

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Abstract:

Context

Thousands of people worldwide have been infected by the chikungunya virus (CHIKV), and the persistence of joint pain symptoms has been considered the main problem. The mechanisms of neuropathic pain include cortical areas. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) act on brain areas involved in the processing of chronic pain. It was previously demonstrated that tDCS for five consecutive days significantly reduced pain in the chronic phase of chikungunya (CHIK).

Objective

To analyze the effect of alternate tDCS sessions on pain and functional capacity in individuals affected by CHIK.

Methods

In a randomized clinical trial, 58 women in the chronic phase of CHIK were divided into two groups: active tDCS (M1-S0, 2mA, 20 minutes) and sham. The Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI) were used to assess pain, while the Health Assessment Questionnaire (HAQ) assessed functional capacity. These scales were used before and after six sessions of tDCS in nonconsecutive days on the primary motor cortex, and at follow-up consultation 7 and 15 days after the last session. A repeated measures mixed-model ANOVA was used for comparison between groups (significant p-values < 0.05).

Results

A significant pain reduction (Z[3, 171] = 14.303; p < 0.0001) was observed in the tDCS group compared to the sham group; no significant difference in functional capacity was observed (Z[1.57] = 2.797; p = 0.1).

Conclusion

Our results suggest that six nonconsecutive sessions of active tDCS on M1 reduce pain in chronic CHIKV arthralgia.

Forouzan V. Farahani, a PhD student in the lab of Dr. Lucas Parra will present her defense of her research proposal on Tuesday, March 9, 2021 at 9:30am. A copy of her abstract is below. If you would like to attend, please contact Forouzan at fvasheg000@citymail.cuny.edu for the Zoom meeting ID.

Abstract

Transcranial direct current stimulation (tDCS) involves low-intensity electrical current applied to the brain via electrodes placed over the scalp. This technique has gained attention due to putative improvements in brain function and the potential to treat brain-related disorders. Various aspects of tDCS, including safety, simplicity, and affordability, have drawn interest as an alternative treatment. Nonetheless, the efficacy of this technique is open to discussion. An important question about the effectiveness of tDCS is whether its effects can last after the period of stimulation. The lasting effects of this technique are thought to be mediated by synaptic plasticity. Several studies have found DCS-induced effects on synaptic plasticity in animal models. Yet, there is no direct evidence associating neuronal excitability to synaptic plasticity.

One promising application of tDCS is the modulation of motor excitability and motor learning. Functional and structural changes in the primary motor cortex (M1) have been associated with motor skill learning. Therefore, human and animal tDCS studies have targeted this region to modulate motor learning. However, there are ongoing debates about the efficacy of low-intensity tDCS, the underlying mechanism explaining the results, and the importance of online versus offline tDCS with learning. This dissertation provides the first direct in vitro evidence linking the effects of DCS on neuronal membrane potential and excitability to Hebbian synaptic plasticity. While this mechanism now has some support, we also uncovered that it could not fully account for the effects of DCS on plasticity. We propose that DCS also affects plasticity via the propagation of its effects over recurrent excitatory connections combined with a homeostatic plasticity mechanism. We plan to study the effect of anodal tDCS on enhancing motor skill learning in rats in vivo. We will investigate whether the effects are due to sensation or stress. Moreover,

Neuromodulation techniques for Alzheimer’s disease and age-related cognitive decline.

By Marom Bikson (City College of New York)

Even as the societal burden of Alzheimer’s disease and related dementias increases, pharmaceutical trials targeting the associated toxic protein aggregates have disappointed. Neuromodulation devices apply energy (eg, electrical or ultrasound) to the brain to promote the recovery of function. As an alternative to pharmacologic interventions (drug therapies), neuromodulation therapies are non-systemic and can directly target brain regions with stimulation waveforms designed to boost specific brain processes.

Neuromodulation devices can be surgically implanted or used non-invasively (on the scalp). Noninvasive neuromodulation treatments can involve repeated visits to a clinic, whereas some devices can be used at home. Neuromodulation therapies are established for indications such as depression, pain, epilepsy, and Parkinson’s disease, and include patients who were not responsive to drug therapies. Neuromodulation trials show promise in maintaining, and even reversing, cognitive decline in Alzheimer’s and related neurodegenerative disorders.

A neuromodulation technique using “shockwave” ultrasound received regulatory medical CE approval for use in Alzheimer’s disease and mild-to-moderate dementia. Patients who received this noninvasive, painless treatment at outpatient clinics over the course of six visits within 2 weeks showed neuropsychological improvements lasting at least 3 months. (1) Not to be confused with transcranial focused ultrasound stimulation, “shockwave” ultrasound applies isolated acoustic pulses that in turn enhance neurovascular function. (2)

A wearable neuromodulation technique called transcranial direct current stimulation (tDCS) is also actively trialed for Alzheimer’s and age-related cognitive decline. tDCS is suitable even for at-home use (it could be made available over the counter) and may provide unique therapeutic potency by “cleansing the brain.”

More plaques versus less clearance in Alzheimer’s disease: chicken and egg

A key question in Alzheimer’s disease research is: how much of the accumulation of toxic protein aggregates reflect abnormal production versus disrupted clearance  mechanisms? (3) Therapeutically, this is a moot point unless we have treatments that can boost brain clearance.

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles is the pathologic hallmark of Alzheimer’s disease; however, drug trials targeting these proteins have been unsuccessful.

Because they remove cellular waste products and deliver nutrients to the interstitial space (the space around neurons), the clearance systems of the brain are critical for normal brain function. Brain interstitial fluid clearance systems become disrupted with Alzheimer’s disease progression.(4)

Interstitial fluid clearance mechanisms may also be generally compromised with age, which may further be linked to the role of clearance during sleep.(5,6)

How transcranial direct current stimulation works

Go with the (blood) flow

Transcranial direct current stimulation (tDCS) applies a low fixed-intensity (direct current) electrical current to the brain through electrodes placed on the scalp. Powered by a 9-volt battery, tDCS is painless, safe, and can be administered at home. (7,8)

Like most other treatments of brain disease, neurons are the de facto target of tDCS.

Adverse effects of tDCS are very mild, including tingling or itching sensations that resolve as stimulation ends, and skin reddening (erythema) that can persist a while longer. Given this sign of profound change in blood flow at the scalp by tDCS, one may ask: could changes in neurovascular function also be occurring?

In fact, there is extensive brain imaging data of the brain vascular response to tDCS. However, as is typically the case with brain imaging techniques that rely on hemodynamic response (eg, blood-oxygen-level-dependent imaging functional MRI), this vascular response is considered an epiphenomenon, which means the detection of vascular action is presumed to be secondary to neuronal stimulation.

This makes sense based on the underlying principle of neurovascular coupling: cerebral blood supply is increased in response to neuronal metabolic activity, as well as to remove toxic byproducts from the interstitial space. But could tDCS swap the regular order of neurovascular coupling: activating blood flow first, which then leads to secondary neuronal modulation? These questions are hard to answer, precisely because neuronal activity and brain vasculature are intimately linked. To convincingly show a primary vascular response, one would require a “brain” consisting of vasculature but no neurons.

Blood vessel walls, including those making up neuronal vasculature, are formed by endothelial cells, which are the barrier between the brain’s interstitial space and circulating blood. This blood–brain-barrier (BBB) is an exceptionally regulated barrier as a result of tight bonds between endothelial cells, known as tight junctions. Cultured endothelial cells on a filter form a BBB model, which can be absent of other cells types. Using such a model, we showed that direct current stimulation directly activates endothelial cells, thereby providing direct evidence of how brain vasculature could respond to  tDCS. (9)

We showed that the neurovascular endothelial cells that make up the BBB are a direct cellular target of tDCS, which supports ongoing trials where activating brain blood flow can support recovery of function (eg, in acute  stroke). (10)

Further analyses of the mechanism’s underlying BBB stimulation led us to a novel therapeutic pathway for Alzheimer’s disease: boosting brain clearance.

Flush and rinse

Direct current stimulation drove water transport across the BBB model through the mechanism of electro-osmosis, which occurs when electrical current flowing through a network of cells produces an associated drag on water. The smaller the gap between cells, the more electro-osmosis, and the BBB is exceptionally tight. Moreover, when the current flow is in a sustained direction, as is the case for tDCS, so is the water flow.

Along with water flow, we showed boosting of specific molecule transport and endothelial-cell gene activation. We reproduced our finding that tDCS boosts transport across the BBB in an intact animal model.(11)

We made a further striking discovery: in addition to enhancing transport across the BBB, tDCS also increased diffusivity within the brain interstitial space.(12)

Taken together, this indicates that tDCS, a noninvasive neuromodulation technique with minimal side effects, could boost brain clearance by both driving water across the BBB and enhancing transport around neurons.

Ongoing and future clinical trials: treating Alzheimer’s disease with tDCS

In patients with Alzheimer’s disease or age-related atypical cognitive impairment, clinical trials with tDCS treatment have been completed, and expanded trials are ongoing. The National Institutes of Health (NIH)-funded study Augmenting Cognitive Training in Older Adults (ACT) is a Phase 3, definitive, multi-site, randomized clinical trial of 360 older adults to establish the benefit of delivering tDCS to remediate age-related cognitive decline. (13)

The randomized controlled Prevention of Alzheimer’s dementia with Cognitive remediation plus tDCS in Mild cognitive impairment and Depression (PACt-MD) study includes 375 older participants with either atypical cognitive impairment and/or major depression.(14)

While most trials evaluate in-clinical treatment, an NIH-funded, randomized, double-blind trial study at Albert Einstein College of Medicine, Bronx, NY, will evaluate the effects of 6 months of at-home tDCS in 100 patients with mild-to-moderate Alzheimer's disease.(15)

The Veterans Administration and NIH are supporting two double-blind, randomized, controlled trials in patients with mild cognitive impairment (146 patients) or Alzheimer’s disease (100 patients) using High-Definition tDCS, a form of tDCS that can focally target brain regions.(16,17)

These studies will further use imaging to evaluate changes in both cerebral blood and amyloid and tau plaque severity.

Clinical trials of tDCS around the world are recruiting hundreds more older adults with mild cognitive impairment, Alzheimer’s disease, and related dementia. These trials were founded on the established actions of tDCS on neurons, including promoting synaptic plasticity. But tDCS may also be boosting brain vascular function and driving brain clearance mechanisms. Even as definitive clinical data on the treatment of age-related cognitive decline continue to emerge, further work characterizing these special mechanisms of tDCS can be used to optimize therapies.

Key points

• Neuromodulation devices are non-drug therapies designed to boost specific therapeutic mechanisms.

• Transcranial direct current stimulation (tDCS) is a wearable device that is actively trialed for the treatment of Alzheimer’s disease and mild cognitive impairment.

• In addition to stimulating neurons, tDCS enhances brain blood flow and clearance mechanisms.

• The boosting of brain clearance mechanism by tDCS is a powerful mechanism to reverse the build-up of toxic proteins associated with Alzheimer’s disease.

References

1. Beisteiner R, Matt E, Fan C, et al. Transcranial pulse stimulation with ultrasound in Alzheimer's disease–a new navigated focal brain therapy. Adv Sci (Weinh). 2019;7:1902583.

2. Hatanaka K, Ito K, Shindo T, et al. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. Am J Physiol Cell Physiol. 2016;311:C378-385.

3. Tarasoff-Conway JM, Carare RO, Osorio L, et al. Clearance systems in the brain–implications for Alzheimer disease. Nat Rev Neurol. 2015;11:457-470.

4. Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis. 2016;93:215-225.

5. Kress BT, Iliff JJ, Xia M, Wang M, et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014;76:845-861.

6. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373-377.

7. Bikson M, Grossman P, Thomas C, et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul. 2016;9:641-661. PDF

8. Charvet LE, Kasschau M, Datta A, et al. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols. Front Syst Neurosci. 2015;9:26.

9. Cancel LM, Arias K, Bikson M, Tarbell JM. Direct current stimulation of endothelial monolayers induces a transient and reversible increase in transport due to the electroosmotic effect. Sci Rep. 2018;8:9265. PDF

10. NCT03574038. Transcranial direct current stimulation as a neuroprotection in acute stroke (TESSERACT).https://clinicaltrials.gov/ct2/show/NCT03574038.Accessed November 28, 2020.

11. Shin DW, Fan J, Luu E, et al. In vivo modulation of the blood-brain barrier permeability by transcranial direct current stimulation (tDCS). Ann Biomed Eng. 2020;48:1256-1270.

12. Xia Y, Khalid W, Yin Z, Huang G, Bikson M, Fu BM. Modulation of solute diffusivity in brain tissue as a novel mechanism of transcranial direct current stimulation (tDCS). Sci Rep. 2020;10:18488.

13. NCT02851511. Augmenting cognitive training in older adults (ACT).https://clinicaltrials.gov/ct2/show/NCT02851511. Accessed November 28, 2020.

14. NCT02386670. Prevention of Alzheimer's disease with CR plus tDCS in mild cognitive impairment and depression (PACt-MD) (PACt-MD).https://www.clinicaltrials.gov/ct2/show/NCT02386670. Accessed November 28, 2020.

15. NCT04404153. NeurostImulation for cognitive enhancement in Alzheimer's disease (NICE-AD).https://clinicaltrials.gov/ct2/show/NCT04404153. Accessed November 28, 2020.

16. NCT02155946. Promoting adaptive neuroplasticity in mild cognitive impairment.https://clinicaltrials.gov/ct2/show/NCT02155946. Accessed November 28, 2020.

17. NCT03875326. Stimulation to improve memory (STIM).https://clinicaltrials.gov/ct2/show/NCT03875326. Accessed November 28, 2020.

New publication in Physiology & Behavior

Effect of tDCS on well-being and autonomic function in professional male players after official soccer matches

Alexandre Moreira, Daniel Gomes da Silva Machado, Luciane Moscaleski, Marom Bikson, Gozde Unal, Paul S Bradley, Abrahão F Baptista, Edgard Morya, Thais Cevada, Lucas Marques, Vinicius Zanetti, & Alexandre Hideki Okano

Physiology & Behavior | (2021) | https://doi.org/10.1016/j.physbeh.2021.113351

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Abstract: This study aimed to examine the effect of transcranial direct current stimulation (tDCS) used as a recovery strategy, on heart rate (HR) measures and perceived well-being in 12 male professional soccer players. tDCS was applied in the days after official matches targeting the left dorsolateral prefrontal cortex (DLPFC) with 2 mA for 20 min (F3-F4 montage). Participants were randomly assigned to anodal tDCS (a-tDCS) or sham tDCS sessions. Players completed the Well-Being Questionnaire (WBQ) and performed the Submaximal Running Test (SRT) before and after tDCS. HR during exercise (HRex) was determined during the last 30 s of SRT. HR recovery (HRR) was recorded at 60 s after SRT. The HRR index was calculated from the absolute difference between HRex and HRR. A significant increase was observed for WBQ (effect of time; p<0.001; ηp2=0.417) with no effect for condition or interaction. A decrease in HRR (p=0.014; ηp2=0.241), and an increase in HRR index were observed (p=0.045; ηp2=0.168), with no effect for condition or interaction. No change for HRex was evident (p>0.05). These results suggest that a-tDCS over the DLPFC may have a positive effect on enhancing well-being and parasympathetic autonomic markers, which opens up a possibility for testing tDCS as a promising recovery-enhancing strategy targeting the brain in soccer players. The findings suggest that brain areas related to emotional and autonomic control might be involved in these changes with a possible interaction effect of tDCS by placebo-related effects, but more research is needed to verify this effect.

Dr. Marom Bikson speaks on Jan 15th 2020 at the North American Neuromodulation Society (NANS) anual meeting (online).

“Spinal Cord Stimulation (SCS): Subthreshold Actions” Slides PDF

Dr. Bikson also serves on the Scientific Program Committee for NANS 2020 and organizes / chairs several sessions around engineering and basic science topics.

Dr. Marom Bikson writes an Expert Point of View for Neurodiem on “Wearable neuromodulation devices that flush the brain: a promising tool against Alzheimer’s disease”

Read the paper here (free sign up may be required)

Key points in article

• Neuromodulation devices are nondrug therapies designed to boost specific therapeutic mechanisms.

• Transcranial direct current stimulation (tDCS) is a wearable device that is actively trialed for the treatment of Alzheimer’s disease and mild cognitive impairment.

• In addition to stimulating neurons, tDCS enhances brain blood flow and clearance mechanisms.

• The boosting of brain clearance mechanism by tDCS is a powerful mechanism to reverse the build-up of toxic proteins associated with Alzheimer’s disease.

Engineering principles of SCS and DBS: Foundations, industry updates, and emerging concepts

on: Thursday January 14, 2021 10am – 6:30pm ET

As free conference/ Information and registation here

The conference is co-chaired by Marom Bikson and Scott Lempka.

Dr. Bikson will also lecture on “Neurostimulation fundamentals: Dose, current flow, and neural activation” Download slides.

New publication in Neuromodulation: Technology at the Neural Interface

Neurocapillary‐Modulation

Niranjan Khadka and Marom Bikson.

Neuromodulation: Technology at the Neural Interface 2020. DOI: https://doi.org/10.1111/ner.13338

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Abstract

Objectives

We consider two consequences of brain capillary ultrastructure in neuromodulation. First, blood‐brain barrier (BBB) polarization as a consequence of current crossing between interstitial space and the blood. Second, interstitial current flow distortion around capillaries impacting neuronal stimulation.

Materials and Methods

We developed computational models of BBB ultrastructure morphologies to first assess electric field amplification at the BBB (principle 1) and neuron polarization amplification by the presence of capillaries (principle 2). We adapt neuron cable theory to develop an analytical solution for maximum BBB polarization sensitivity.

Results

Electrical current crosses between the brain parenchyma (interstitial space) and capillaries, producing BBB electric fields (EBBB) that are >400x of the average parenchyma electric field (ĒBRAIN), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λBBB) and wall thickness (dth‐BBB), the analytical solution for maximal BBB electric field (EABBB) is given as: (ĒBRAIN × λBBB)/dth‐BBB. Electrical current in the brain parenchyma is distorted around brain capillaries, amplifying neuronal polarization. Specifically, capillary ultrastructure produces ~50% modulation of the ĒBRAIN over the ~40 μm inter‐capillary distance. The divergence of EBRAIN (Activating function) is thus ~100 kV/m2 per unit ĒBRAIN.

Conclusions

BBB stimulation by principle 1 suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Whereas the spatial profile of EBRAIN is traditionally assumed to depend only on macroscopic anatomy, principle 2 suggest a central role for local capillary ultrastructure—which impact forms of neuromodulation including deep brain stimulation (DBS), spinal cord stimulation (SCS), transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and transcranial electrical stimulation (tES)/transcranial direct current stimulation (tDCS).

. Application of neurocapillary-modulation in neuromodulation simulations of tES, DBS, and SCS.

New publication in the Journal of Behavioral Addictions

Effects of transcranial direct current stimulation on addictive behavior and brain glucose metabolism in problematic online gamers

Hyeonseok Jeong , Jin Kyoung Oh, Eun Kyoung Choi, Jooyeon Jamie Im, Sujung Yoon, Helena Knotkova, Marom Bikson, In-Uk Song, Sang Hoon Lee, & Yong-An Cho

Journal of Behavioral Addictions | (2020) | https://doi.org/10.1556/2006.2020.00092

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Abstract: Background and aims: Some online gamers may encounter difficulties in controlling their gaming behavior. Previous studies have demonstrated beneficial effects of transcranial direct current stimulation (tDCS) on various kinds of addiction. This study investigated the effects of tDCS on addictive behavior and regional cerebral metabolic rate of glucose (rCMRglu) in problematic online gamers. Methods: Problematic online gamers were randomized and received 12 sessions of either active (n 5 13) or sham tDCS (n 5 13) to the dorsolateral prefrontal cortex over 4 weeks (anode F3/cathode F4, 2 mA for 30 min, 3 sessions per week). Participants underwent brain 18F-fluoro-2-deoxyglucose positron emission tomography scans and completed questionnaires including the Internet Addiction Test (IAT), Brief Self-Control Scale (BSCS), and Behavioral Inhibition System/Behavioral Activation System scales (BIS/ BAS) at the baseline and 4-week follow-up. Results: Significant decreases in time spent on gaming (P 5 0.005), BIS (P 5 0.03), BAS-fun seeking (P 5 0.04), and BAS-reward responsiveness (P 5 0.01), and increases in BSCS (P 5 0.03) were found in the active tDCS group, while decreases in IAT were shown in both groups (P < 0.001). Group-by-time interaction effects were not significant for these measures. Increases in BSCS scores were correlated with decreases in IAT scores in the active group (b 5
0.85, P < 0.001). rCMRglu in the left putamen, pallidum, and insula was increased in the active group compared to the sham group (P for interaction < 0.001). Discussion and conclusions: tDCS may be beneficial for problematic online gaming potentially through changes in self-control, motivation, and striatal/insular metabolism. Further larger studies with longer follow-up period are warranted to confirm our findings.

The CCNY Neural Engineering group, including the Bikson lab, Parra lab, and Dmochowski lab, contributed centrally to the NYC Neuromodulation 2020 conference. This is the fourth NYC Neuromodulation 2020 conference since it was founded by Prof. Marom Bikson in 2013, and run in 2015, in 2017, in 2018 with the North American Neuromodulaiton Society (NANS), and in 2019 with Neurovations. Prof. Bikson has served as co-chair of all NYC Neuromodulaiton conferences.

Because of the COVID-19 pandemic the NYC Neuromodulaiton 2020 conference was held online in two separate sessions: oral talks session on April 20-22, 2020 and a poster session on Dec 18-22, 2020. The NYC Neuromodulation conference series is recognized as as among the preeminent meetings presenting advanced neurotechnolgy with a focus on brain stimulation (neuromodulation) approaches such as transcranial Direct Current Stimulation, Transcranial Magnetic Stimulation, Deep Brain Stimulation, and Spinal Cord Stimulation. The CCNY Neural Engineering group is among the most productive and recognized R&D labs in the worlds, making NYC Neuromodulation a natural showcase for its work.

The NYC Neuromodulation conferences are produced through Neuromodec, a broader initiative supported by CCNY Neural Engineering which includes conference productions and listings, job and clinician search tools, and informational pages such as “What is Spinal Cord Stimulation?” and “What is Transcranial Magnetic Stimulation?”

New publication in eNeuro

Zeinab Esmaeilpour, Mark Jackson, Greg Kronberg, Rosana Esteller, Brad Hershey, and Marom Bikson

eNeuro 16th December 2020, ENEURO. 0368-20.2020;

Abstract

Understanding the cellular mechanisms of kHz electrical stimulation is of a broad interest in neuromodulation including forms of transcranial electrical stimulation (tES), interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in response to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most studied systems in neuroscience and exhaustively characterized in screening the effects of electrical stimulation. High-frequency electric fields of varied amplitudes (1-150 V/m), waveforms (sinusoidal, symmetrical pule, asymmetrical pulse), and frequencies (1 and10 kHz) were tested. Changes in single or paired-pulse field excitatory postsynaptic potentials (fEPSP) in CA1 were measured in response to radial- and tangential-directed electric fields, with a brief (30 s) or long (30 min) application times. The effects of kHz stimulation on ongoing endogenous network activity were tested in carbachol-induced gamma oscillation of CA3a and CA3c. Across 23 conditions evaluated, no significant changes in fEPSP were resolved, while responses were detected for within-slice control DC fields. 1 kHz sinusoidal and pulse stimulation (≥60 V/m), but not 10 kHz induced changes in an oscillating neuronal network. We thus report no responses to low-amplitude 1 kHz or any 10 kHz fields, suggesting that any brain sensitivity to these fields is via yet-to-be-determined mechanism(s) of action which was not identified in our experimental preparation.

SIGNIFICANCE STATEMENT There a large mismatch between enthusiasm for clinical treatments using kHz frequency electrical stimulation and the understanding of kHz mechanisms of action. Indeed, the well-established low-pass properties of cell membranes should attenuate any response to kHz stimulation. This study presents the largest and broadest characterization of the cellular effects of kHz stimulation using the most established animal model to detect CNS sensitivity to electric fields: Our work systematically evaluated sensitivity of hippocampal synaptic function and oscillatory network activity in response to kHz. Only at low kHz (1 kHz but not 10 kHz) with high intensity and during oscillations responses were detected. These systematic and largely negative experimental series suggest kHz neuromodulation operates via yet to be determined mechanisms.

The CCNY Neural Engineering lab will support the organization of NYC Neuromodulation 2020 poster session. The conference is co-chaired by Dr. Marom Bikson, and Zeinab Esmaeilpour and Nigel Gebodh serve on the conference abstract committee.

It will be a virtual poster session designed around a “home” page for each accepted poster. That homepage will include a long abstract, the poster, a presenting author bio and professional hyperlinks, and (optional) a short video. See example homepage here >>. You have until December 15th, 2020 at 11:59 PM (ET) to upload, review, and edit your submission (your abstract home page). Submission will be reviewed by the abstract committee on December 16th, 2020 and notices will be sent out to accepted authors.

On December 18th, 2020 at 9 AM (ET), all accepted abstracts will be publicly available, and will remain so indefinitely. Only from Dec 18th, 2020 9 AM (ET) until Dec 22, 2020 5 PM (ET) there will be a comment session open. Anyone who creates an account can post a comment and the author (or other commentators) can respond. These comments will be independently moderated (author may bring inappropriate comments to the attention of moderator for review/ removal) for professional content and frozen on Dec 22, 2020 5 PM (ET).

All accepted abstracts will be citable through the conference. Authors may select to have their abstract also published in Brain Stimulation journal. Abstracts selected for this process must contain at least some new analysis, new data, and/or new discussion. Abstracts selected for this process will be subject to secondary review by Brain Stimulation (which will occur after Dec 22, 2020).

For full event details and abstract submission go here

New publication in Frontiers in Human Neuroscience

Update on the Use of Transcranial Electrical Brain Stimulation to Manage Acute and Chronic COVID-19 Symptoms

Giuseppina Pilloni, Marom Bikson, Bashar W. Badran, Mark S. George, Steven A. Kautz, Alexandre Hideki Okano, Abrahão Fontes Baptista & Leigh E. Charvet

Frontiers in Human Neuroscience | (2020) 14:595567 | https://doi.org/10.3389/fnhum.2020.595567

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Abtract: The coronavirus disease 19 (COVID-19) pandemic has resulted in the urgent need to develop and deploy treatment approaches that can minimize mortality and morbidity. As infection, resulting illness, and the often prolonged recovery period continue to be characterized, therapeutic roles for transcranial electrical stimulation (tES) have emerged as promising non-pharmacological interventions. tES techniques have established therapeutic potential for managing a range of conditions relevant to COVID-19 illness and recovery, and may further be relevant for the general management of increased mental health problems during this time. Furthermore, these tES techniques can be inexpensive, portable, and allow for trained self-administration. Here, we summarize the rationale for using tES techniques, specifically transcranial Direct Current Stimulation (tDCS), across the COVID-19 clinical course, and index ongoing efforts to evaluate the inclusion of tES optimal clinical care.

New publication in Frontiers in Neurology

Applications of Non-invasive Neuromodulation for the Management of Disorders Related to COVID-19

Abrahão Fontes Baptista, Adriana Baltar, Alexandre Hideki Okano, Alexandre Moreira, Ana Carolina Pinheiro Campos, Ana Mércia Fernandes, André Russowsky Brunoni, Bashar W. Badran, Clarice Tanaka, Daniel Ciampi de Andrade, Daniel Gomes da Silva Machado, Edgard Morya, Eduardo Trujillo, Jaiti K. Swami, Joan A. Camprodon, Katia Monte-Silva, Katia Nunes Sá, Isadora Nunes, Juliana Barbosa Goulardins, Marom Bikson, Pedro Sudbrack-Oliveira, Priscila de Carvalho, Rafael Jardim Duarte-Moreira, Rosana Lima Pagano, Samuel Katsuyuki Shinjo & Yossi Zana

Frontiers in Neurology | (2020) 11:573718 | https://doi.org/10.3389/fneur.2020.573718

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Abstract:

Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19.

Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders.

Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders.

Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway.

Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19.

Prof. Marom Bikson gives seminar to the Johns Hopkins University Translational Neuroengineering Technologies Network on “The Ins and Outs of tDCS”

Nov 24, 2020 (online)

Link to TNT program

Slides PDF

New publication Physics in Medicine & Biology

Role of skin tissue layers and ultra-structure in transcutaneous electrical stimulation including tDCS

Niranjan Khadka & Marom Bikson

Physics in Medicine & Biology | (2020) 65:22 | https://doi.org/10.1088/1361-6560/abb7c1

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Abstract: Background. During transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), current density concentration around the electrode edges that is predicted by simplistic skin models does not match experimental observations of erythema, heating, or other adverse events. We hypothesized that enhancing models to include skin anatomical details, would alter predicted current patterns to align with experimental observations. Method. We develop a high-resolution multi-layer skin model (epidermis, dermis, and fat), with or without additional ultra-structures (hair follicles, sweat glands, and blood vessels). Current flow patterns across each layer and within ultra-structures were predicted using finite element methods considering a broad range of modeled tissue parameters including 78 combinations of skin layer conductivities (S m–1): epidermis (standard: 1.05 × 10−5; range: 1.05 × 10−6 to 0.465); dermis (standard: 0.23; range: 0.0023 to 23), fat (standard: 2 × 10−4; range: 0.02 to 2 × 10−5). The impact of each ultra-structures in isolation and combination was evaluated with varied basic geometries. An integrated final model is then developed. Results. Consistent with prior models, current flow through homogenous skin was annular (concentrated at the electrode edges). In multi-layer skin, reducing epidermis conductivity and/or increasing dermis conductivity decreased current near electrode edges, however no realistic tissue layer parameters produced non-annular current flow at both epidermis and dermis. Addition of just hair follicles, sweat glands, or blood vessels resulted in current peaks around each ultrastructure, irrespective of proximity to electrode edges. Addition of only sweat glands was the most effective approach in reducing overall current concentration near electrode edges. Representation of blood vessels resulted in a uniform current flow across the vascular network. Finally, we ran the first realistic model of current flow across the skin. Conclusion. We confirm prior models exhibiting current concentration near hair follicles or sweat glands, but also exhibit that an overall annular pattern of current flow remains for realistic tissue parameters. We model skin blood vessels for the first time and show that this robustly distributes current across the vascular network, consistent with experimental erythema patterns. Only a state-of-the-art precise model of skin current flow predicts lack of current concentration near electrode edges across all skin layers.

New Publication in Clinical Neurophysiology

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines

Simone Rossi, Andrea Antal, Sven Bestmann, Marom Bikson, Carmen Brewer, Jürgen Brockmöller, Linda L. Carpenter, Massimo Cincotta, Robert Chen, Jeff D. Daskalakis, Vincenzo Di Lazzaro, Michael D. Fox, Mark S. George, Donald Gilbert, Vasilios K. Kimiskidis, Giacomo Koch, Risto J. Ilmoniemi, Jean Pascal Lefaucheur, Letizia Leocani, Sarah H. Lisanby, Carlo Miniussi, Frank Padberg, Alvaro Pascual-Leone, Walter Paulus, Angel V. Peterchev, Angelo Quartarone, Alexander Rotenberg, John Rothwell, Paolo M. Rossini, Emiliano Santarnecchi, Mouhsin M. Shafi, Hartwig R. Siebner, Yoshikatzu Ugawa, Eric M. Wassermann, Abraham Zangen, Ulf Ziemann, & Mark Hallett

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Abstract: This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects.

New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy).

An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

2020 Neurotech Leaders Forum, November 16-17, 2020

Embassy Suites, San Francisco Airport Waterfront and Online, Program details

Dr. Marom Bikson to join panel on “Repelling the Invasion: Surface Stimulation Makes a Comeback” to speak on “Non-invasive Neuromodulation. Going home (in the time of COVID).”

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New publication in Brain Stimulation

Temporal interference stimulation targets deep brain regions by modulating neural oscillations

Zeinab Esmaeilpour, Greg Kronberg, Davide Reato, Lucas C. Parra, & Marom Bikson

Brain Stimulation | (2020) 11(7) | https://doi.org/10.1016/j.brs.2020.11.007

Abstract:

Background

Temporal interference (TI) stimulation of the brain generates amplitude-modulated electric fields oscillating in the kHz range with the goal of non-invasive targeted deep brain stimulation. Yet, the current intensities required in human (sensitivity) to modulate deep brain activity and if superficial brain region are spared (selectivity) at these intensities remains unclear.

Objective

We developed an experimentally constrained theory for TI sensitivity to kHz electric field given the attenuation by membrane low-pass filtering property, and for TI selectivity to deep structures given the distribution of modulated and unmodulated electric fields in brain.

Methods

The electric field threshold to modulate carbachol-induced gamma oscillations in rat hippocampal slices was determined for unmodulated 0.05-2 kHz sine waveforms, and 5 Hz amplitude-modulated waveforms with 0.1-2 kHz carrier frequencies. The neuronal effects are replicated with a computational network model to explore the underlying mechanisms, and then coupled to a validated current-flow model of the human head.

Results

Amplitude-modulated electric fields are stronger in deep brain regions, while unmodulated electric fields are maximal at the cortical regions. Both experiment and model confirmed the hypothesis that spatial selectivity of temporal interference stimulation depends on the phasic modulation of neural oscillations only in deep brain regions. Adaptation mechanism (e.g. GABAb) enhanced sensitivity to amplitude modulated waveform in contrast to unmodulated kHz and produced selectivity in modulating gamma oscillation (i.e. Higher gamma modulation in amplitude modulated vs unmodulated kHz stimulation). Selection of carrier frequency strongly affected sensitivity to amplitude modulation stimulation. Amplitude modulated stimulation with 100 Hz carrier frequency required ∼5 V/m (corresponding to ∼13 mA at the scalp surface), whereas, 1 kHz carrier frequency ∼60 V/m (∼160 mA) and 2 kHz carrier frequency ∼80 V/m (∼220 mA) to significantly modulate gamma oscillation. Sensitivity is increased (scalp current required decreased) for theoretical neuronal membranes with faster time constants.

Conclusion

The TI sensitivity (current required at the scalp) depends on the neuronal membrane time-constant (e.g. axons) approaching the kHz carrier frequency. TI selectivity is governed by network adaption (e.g. GABAb) that is faster than the amplitude-modulation frequency. Thus, we show neuronal and network oscillations time-constants determine the scalp current required and the selectivity achievable with TI in humans.

New publication in Brain Stimulation

Comparison of cortical network effects of high-definition and conventional tDCS during visuomotor processing

Pejman Sehatpour, Clément Dondé, Devin Adair, Johanna Kreither, Javier Lopez-Calderon, Michael Avissar, Marom Bikson, & Daniel C. Javitt

Brain Stimulation | (2021) 14(1):33-35 | https://doi.org/10.1016/j.brs.2020.11.004

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