5th International Network of tES-fMRI (INTF) Webinar on Individually Optimized Non-Invasive Brain Stimulation

May 27th, 2021 for a two-hour webinar on individually optimized non-invasive brain stimulation co-hosted by Marom Bikson and Hamed Ekhtiari.

Registation and full details here

(Dr. Bikson’s presentation slides on “Closed looped stimulation: Why bother?” PDF)

In this online INTF Webinar exploring the Fundamentals & Challenges of Individually Optimized Non-Invasive Brain Stimulation, we are joined by Dr Marom Bikson (City University of New York), Dr Til Ole Bergman (University of Mainz), Dr Ines Violante (University of Surrey), Dr Romy Lorenz (University of Cambridge), Dr Alik Widge (University of Minnesota), Dr Flavio Frohlich (University of North Carolina), and Dr Hamed Ekhtiari (Laureate Institute for Brain Research) for two hours of lectures, discussions, and practical challenges, including:

• Closed-loop stimulation

• Brain-state dependent brain stimulation

• A framework for optimizing tES with closed-loop real-time fMRI

• Searching through the large brain stimulation parameter space

• What NIBS can learn from closed-loop invasive brain stimulation

• Closed-loop transcranial alternating current stimulation: Towards personalized treatments

• Online closed-loop real-time tES-fMRI: Potentials and challenges

The knowledge gained in this webinar will provide all attendees with the required knowledge to design, set up, and carry out their own optimized NIBS study, and is suitable for both new users of non-invasive brain stimulation techniques, and those with an existing knowledge of how to use these techniques

Dr. Marom Bikson speaks at Advances in Transcranial Direct Current Stimulation in Psychiatric Disorders on April 17, 2021 on “Best Practices and Latest Developments in tDCS”

Slides PDF

Zeinab Esmaeilpour, a PhD student in the lab of Dr. Marom Bikson will present her defense of her research proposal on Friday, April 2, 2021 at 3pm. A copy of her abstract is below. If you would like to attend, please contact Zeinab at zesmaei000@citymail.cuny.edu for the Zoom meeting ID.

Abstract

Understanding the cellular mechanism of direct current (DC) and kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation in both invasive and noninvasive methods. More specifically there is large mismatch between enthusiasm to for clinical applications of the methods and understanding of DC and kHz mechanism of action. In the case of kilohertz stimulation, there is a well-established and validated low pass filtering characteristics of neuronal membrane. This feature attenuates sensitivity of nervous system to any waveforms with high frequency components. On the contrary, kilohertz stimulation has revolutionized spinal cord stimulation and even generated promising results in transcranial stimulation.

Effects DC stimulation have been studied in neuronal depolarization/hyperpolarization, synaptic plasticity and neuronal network modulation. Recent evidence suggests that DC stimulation can induce polarity dependent water exchange across blood brain barrier (BBB) in cell culture experiments through a mechanism called electroosmosis. Modulating water exchange rate across BBB is of broad interest in neurological disease such as dementia, Alzheimer’s, and stroke where brain clearance system is disrupted. Investigating effect of electrical stimulation on water exchange across BBB can potentially lead to therapeutic pathways.

This dissertation provides the first direct in vitro evidence on acute effects kilohertz electrical stimulation in central nervous system using both unmodulated and Amplitude-modulated waveforms. While supported by membrane characteristic of neurons, we uncovered that using low kilohertz stimulation diminishes the sensitivity of hippocampal neurons to electrical stimulation. Moreover, using Amplitude-Modulated waveform can generate a different pattern of modulation and even higher sensitivity to stimulation. However, required electric field in this case is significantly higher than low frequency stimulation methods such as tACS. We plan to study effect of direct current stimulation on water exchange rate across blood brain barrier (BBB) as new avenue of mechanism for electrical stimulation. We will investigate whether tDCS can increase water exchange rate and blood flow in healthy population using and advanced MR imaging technique.

Below please find information in regards to BME PhD student Jason Ki’s dissertation defense, which is open to all and will take place on Tuesday, March 30th at 3:00pm via Zoom. Please email Jason at jki00@citymail.cuny.edu for the Zoom link. Jason’s abstract is also below.

When the Brain Plays a Game:

Neural responses to visual dynamics during naturalistic visual tasks.

Department of Biomedical Engineering

Jason Ki

Mentor: Lucas C Parra

ABSTRACT

Many day-to-day tasks involve processing of complex visual information in a continuous stream. While much of our knowledge on visual processing has been established from reductionist approaches in lab-controlled settings, very little is known about the processing of complex dynamic stimuli experienced in everyday scenarios. Traditional investigations employ event-related paradigms that involve presentation of simple stimuli at select locations in visual space or discrete moments in time. In contrast, visual stimuli in real-life are highly dynamic, spatially-heterogeneous, and semantically rich. Moreover, traditional experiments impose unnatural task constraints (e.g. inhibited saccades), thus, it is unclear whether theories developed under the reductionist approach apply in naturalistic settings. Given these limitations, alternative experimental paradigms and analysis methods are necessary. Here, we introduce a new approach for investigating visual processing, applying the system identification (SI) framework. We investigate the modulation of stimulus-evoked responses during a naturalistic task (i.e. kart race game) using non-invasive scalp recordings.

In recent years, multivariate modeling approaches have become increasingly popular for assessing neural response to naturalistic stimulus. Encoding models use stimulus patterns to predict brain responses and decoding models use patterns of brain responses to predict stimulus that drove these responses. In this dissertation, we employ a hybrid method that “encodes” the stimulus to predict “decoded” brain responses. With this approach, we measure the stimulus-response correlation (SRC, i.e. temporal correlation of neural response and dynamic stimulus) to assess the strength of stimulus-evoked activity to uniquely experienced naturalistic stimulus. To demonstrate this, we measured the SRC during a kart race videogame. We find that SRC increased with active play of the game, suggesting that stimulus-evoked activity is modulated by the visual task demands. Furthermore, we analyzed the selectivity of neural response across the visual space. While it is well-established that neural response is spatially selective to discrete stimulus, it is unclear whether this is true during naturalistic stimulus presentation. To assess this, we measured the correlation of neural response with optical flow magnitude at individual locations on the screen during the videogame. We find that the SRC is greater for locations in space that are task-relevant, enhancing during active play. Moreover, the spatial selectivity differs across scalp locations, which suggest that individual brain regions are spatially selective to different visual dynamics.

Overall, we leveraged the SI framework to investigate visual processing during a naturalistic stimulus presentation, extending visual research to ecologically valid paradigms. Our findings shed new insights about the stimulus-evoked neural response to visual dynamics during a uniquely experienced naturalistic visual task. We show that selectivity of neural response can be spatially-resolved at pixel-level from a low-SNR EEG. In the future, by further probing other spatial and temporal dimensions of the stimuli (beyond optical flow), we may gain new insights into how neural signals convey visual processing during dynamic natural visual experiences.

New publication in frontiers in Human Neuroscience

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)

Adam D. Farmer, Adam Strzelczyk, Alessandra Finisguerra, Alexander V. Gourine, Alireza Gharabaghi, Alkomiet Hasan, Andreas M. Burger, Andrés M. Jaramillo, Ann Mertens, Arshad Majid, Bart Verkuil, Bashar W. Badran, Carlos Ventura-Bort, Charly Gaul, Christian Beste, Christopher M. Warren, Daniel S. Quintana, Dorothea Hämmerer, Elena Freri, Eleni Frangos, Eleonora Tobaldini, Eugenijus Kaniusas, Felix Rosenow, Fioravante Capone, Fivos Panetsos, Gareth L. Ackland, Gaurav Kaithwas, Georgia H. O'Leary, Hannah Genheimer, Heidi I. L. Jacobs, Ilse Van Diest, Jean Schoenen, Jessica Redgrave, Jiliang Fang, Jim Deuchars, Jozsef C. Széles, Julian F. Thayer, Kaushik More, Kristl Vonck, Laura Steenbergen, Lauro C. Vianna, Lisa M. McTeague, Mareike Ludwig, Maria G. Veldhuizen, Marijke De Couck, Marina Casazza, Marius Keute, Marom Bikson, Marta Andreatta, Martina D'Agostini, Mathias Weymar, Matthew Betts, Matthias Prigge, Michael Kaess, Michael Roden, Michelle Thai, Nathaniel M. Schuster, Nicola Montano, Niels Hansen, Nils B. Kroemer, Peijing Rong, Rico Fischer, Robert H. Howland, Roberta Sclocco, Roberta Sellaro, Ronald G. Garcia, Sebastian Bauer, Sofiya Gancheva, Stavros Stavrakis, Stefan Kampusch, Susan A. Deuchars, Sven Wehner, Sylvain Laborde, Taras Usichenko, Thomas Polak, Tino Zaehle, Uirassu Borges, Vanessa Teckentrup, Vera K. Jandackova, Vitaly Napadow, & Julian Koenig

Frontiers in Human Neuroscience | (2021) 14:568051 | https://doi.org10.3389/fnhum.2020.568051

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Abstract: Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

A subject in Marom Bikson’s research group using the taVNS device with telemedicine support.

While COVID’s often deadly outcome has resulted in the worst pandemic in a century, studies are unveiling a post-COVID phase for survivors during which neuropsychiatric symptoms, such as fatigue, anxiety and depression, can occur. How to treat this debilitating phase, called NeuroCOVID, is the challenge City College of New York biomedical engineer Marom Bikson and his team are tackling.

The first stage of COVID is characterized by fever, heart or lung problems. NeuroCOVID is second stage, characterized by one or a combination of symptoms like vertigo, loss of smell, headaches, fatigue and irritability, as well as anxiety and depression, said Bikson, professor in the Grove School of Engineering. These second stage symptoms can persist, leaving patients with ongoing mental health complications. 

Bikson is leading a multi-center trial utilizing a revolutionary noninvasive technology developed in his neural engineering lab. It involves stimulating the vagus nerve in an attempt to both directly activate brain healing mechanisms and also reduce inflammation in participants with reported neuroCOVID symptoms. Using this two-prong approach, which aims to reverse neuropathic changes in brain function while also reducing inflammation (which is known to cause a host of problems in the body) it is hoped that some or all of the patients’ neuroCOVID symptoms will subside.

In addition to state-of-the-art technology to activate the nervous system, the clinical trial incorporates advanced home-based real-time monitoring of patient vitals, and a clinician-patient portal for real-time assessment of progress and remote-control of the technology. “This is truly personalized medicine, with the ability for physicians to adjust therapy in real-time and monitor patient progress at-home with rigor usually reserved for advanced medical centers. The trial is one example of hundreds of medical treatments developed at CCNY being tested or in use,” said Bikson.

The device used in the trial includes a small clip placed on the ear. A hand-held stimulator provides barely perceptible electrical stimulation to the ear to stimulate the auricula branch of the vagus nerve. The technique is generally called transcutaneous Auricular Nerve Stimulation or tAVNS. The Bikson group worked with clinicians at the Medical University of South Carolina (MUSC) to optimize tAVNS so it can be used reliably and easily in patients’ homes. The partners also designed a trial allowing entirely home-based treatment for NeuroCOVID.

Bikson directs one of the most productive medical device design labs in the country with support from the National Institutes of Health and numerous corporate partners. It develops medical devices to treat neurological and psychiatric disorders, including devices that apply minute levels of energy to activate the brain and nervous system. 

The devices for the NeuroCOVID trial are built by Soterix Medical, a medical device company co-founded by Bikson as a spin-off from CCNY research.  

About the City College of New York
Since 1847, The City College of New York has provided a high-quality and affordable education to generations of New Yorkers in a wide variety of disciplines. CCNY embraces its position at the forefront of social change. It is ranked #1 by the Harvard-based Opportunity Insights out of 369 selective public colleges in the United States on the overall mobility index. This measure reflects both access and outcomes, representing the likelihood that a student at CCNY can move up two or more income quintiles. In addition, the Center for World University Rankings places CCNY in the top 1.8% of universities worldwide in terms of academic excellence. Labor analytics firm Emsi puts at $1.9 billion CCNY’s annual economic impact on the regional economy (5 boroughs and 5 adjacent counties) and quantifies the “for dollar” return on investment to students, taxpayers and society. At City College, more than 16,000 students pursue undergraduate and graduate degrees in eight schools and divisions, driven by significant funded research, creativity and scholarship. CCNY is as diverse, dynamic and visionary as New York City itself. View CCNY Media Kit.

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.