Neural engineering

Stimulating the nervous system

EE and BIOEN 460/560

Chet Moritz
Center for Neurotechnology
Electrical & Computer Engineering
Rehabilitation Medicine
Physiology & Biophysics
ctmoritz@uw.edu
 Interfacing with the Nervous System

Stimulation of the nervous system

Peripheral Nervous System (PNS)

• Muscles & Peripheral Nerves

Central Nervous System (CNS)

• Spinal Cord (con’t)
• Brain
Discussion: Spinal stimulation
• By what mechanisms could epidural stimulation
lead to improved volitional movement after SCI?

Epidural Stimulation

Incomplete
Spinal Injury
Discussion: Spinal stimulation
• Mechanisms of epidural
stimulation?

• Bring networks closer to

threshold so remaining
descending drive can activate

Epidural Stimulation

Incomplete Epidural
Spinal Injury Stimulation
 Epidural spinal stimulation +
Rehabilitation leads to recovery
• Leg function for people with AIS A-D SCI
Harkema…Edgerton Lancet 2011, Angeli… Harkema Brain 2014,
Rejc… Harkema, Sci Rep 2017, Gill… Zhao Nature Medicine 2018, Angeli…
Harkema NEJM 2018, Wagner… Courtine Nature 2018, Darrow… Samadina J
Neurotrauma 2019

Gill… Zhao Nat. Medicine

Wagner… Courtine Nature
2018
Angeli… Harkema 2018
NEJM 2018
https://www.nejm.org/doi/full/10.1056/NEJMoa1803588
 Restoration of walking with training +
epidural spinal stimulation

CA Angeli et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1803588

https://www.nejm.org/doi/full/10.1056/NEJMoa1803588
Stimulation + Rehabilitation leads to recovery
(*persisting beyond stimulation*)

• Leg function for people with AIS A-D SCI

Harkema…Edgerton Lancet 2011, Angeli… Harkema Brain 2014,
Rejc… Harkema, Sci Rep 2017,* Gill… Zhao Nature Medicine 2018,
Angeli… Harkema NEJM 2018, Wagner… Courtine Nature 2018*,
Darrow… Samadina J Neurotrauma 2019

• Hand function for people with AIS B-D SCI Angeli… Harkema
Lu… Edgerton Neurorehab Neu Repair 2016,*
Gad… Edgerton J Neurotrauma 2018,* NEJM 2018
Inanici…Moritz IEEE TNSRE 2018,*
Baseline Stimulation

Gill… Zhao Nat.

Medicine 2018
Wagner… Courtine
Inanici… Moritz IEEE TNSRE 2018* Nature 2018*
Do you really need to implant the
stimulator?
Epidural Stimulation

Gad et al., IEEE EMBC 2015

Gerasimenko et al., Annals of Phys Med Rehabilitation 2015
Gad et al., Edgerton Frontiers Neuroscience 2017
 Noninvasive Spinal Stimulation
improves hand function after injury

10 kHz 1 ms

30 Hz

10 kHz carrier frequency permits stimulation to be applied

through the skin of the neck over the spinal cord injury

Inanici, Samejima, Gad, Edgerton, Hofstetter, Moritz (2018) IEEE TNSRE

 Participant with AIS B:
Pinch force returns with
stimulation treatment
PT only
Baseline Stim+PT Follow-up
Lateral Pinch Force (N)

4.0
3.5
3.0
2.5
2.0
1.5
1.0
Left
0.5
Right
0.0
-0.5
-4 0 4 8 12 16 20 24 28 32 36 40 44
Weeks
Inanici et al,… Moritz – in progress
Immediate effect 12 years after injury
Transcutaneous spinal stimulation for
standing and walking
Participant resumed playing guitar 12 years after injury
Discussion: Lasting benefits of stimulation

• Both epidural and

transcutaneous spinal
stimulation lead to
benefits that outlast the
stimulation (Rejc et al Sci. Reports
2017; Inanici et al. IEEE TNSRE 2018)

• What are the likely

mechanisms of this
lasting recovery?
Discussion: Lasting benefits of stimulation

• What are the likely

mechanisms of this
lasting recovery?

• Engineered
Neuroplasticity:
– Synapses may become
stronger in circuits
bypassing the lesion (e.g.,
blue interneurons)
– Myelin may reform on
axons passing near the
lesion
5 min break?
 Interfacing with the Nervous System

Stimulation of the nervous system

Peripheral Nervous System (PNS)

• Muscles & Peripheral Nerves

Central Nervous System (CNS)

• Spinal Cord
• Brain
Wilder Penfield, Neural Cartographer

Penfiled & Boldrey, Brian 1937

 Direct cortical electrical stimulation
May produce “positive” or “negative” effects

Nature Reviews Neuroscience 13, 63-70 (January 2012)

 Cortical Stimulation for Sensory
Feedback
Intracortical microstimlation
for sensory feedback

ECoG stimulation for sensory feedback

Non-specific but
can create sensory illusions
Johnson et al. Ojemann, J Neural Eng 2013

Romo et al., Nature 1998

Tabot et al. Bensmaia PNAS 2013
 Closed-
loop BCI
with intra-
cortical
Stimulation
for Sensory
Feedback

O’Doherty et al., Nature 2011

 Intracortical brain stimulation for
sensation

Cortex cues on charge rather than frequency

David Bjånes
Bjånes & Moritz, Beh. Brain Res. 2018; Bjånes & Moritz, IEEE TNSRE 2019
 Optogenetic stimulation
– Requires genetic
manipulation
– Express genes that
code for light sensitive
ion channels
– Transfected neurons
become light sensitive
(excitatory or inhibitory)
– Fiber-optic wave guide
typically implanted in or
on the brain
Nature Methods 8, 24–25 (2011)
Guru et al., Int. J. Neurophsychopharmacol. 2015
 Discussion:
Non-invasive deep
brain stimulation?

• How might you stimulate a structure deep

within the brain without surgery?

• What technologies could be used for this?

Non-invasive deep
brain stimulation?

Grossman et al., Boyden Cell 2017

Discussion: Can non-invasive electrical brain
stimulation make you smarter?
• Some studies show enhanced motor and
cognitive function when electrical brain
stimulation is paired with practice.
• Based on this, there is a DIY movement
for transcranial direct current stimulation
(tDCS).
• Hype or Hypothesis: ‘Overclocking your
brain with tDCS will make you smarter?
Transcranial Electrical Stimulation (TES)
&
Transcranial Direct Current Stimulation
(tDCS)
• Standard TES is painful due to activation of skin sensory axons
and scalp muscles (Klomjai et al., Annals of Physical & Rehabilitation Med. 2015)

• tDCS uses low levels of constant/direct current

– Studies show enhanced retention of learned skills with tDCS
(Kadosh et al., Current Biology 2010)

– But enhancement due to tDCS interferes with other cognitive

functions (e.g., learning vs. automaticity)
(Iuculano & Kadosh J Neurosci 2013)
 Transcranial Magnetic Stimulation
(TMS)
• TMS excites superficial cortex and then
deeper neurons trans-synaptically
(Terao & Ugawa, J. Clin. Neurophysiol. 2002; Klomjai et al.,
Annals of Physical & Rehabilitation Med. 2015)

– E.g., magnetic field induces current flow and

action potentials in horizontal neurons which
then synapse on pyramidal neurons

• Activates ~ 1cm3 of brain surface tissue

• Repetitive TMS can be inhibitory

34
 Paired Associative Stimulation (PAS)

Spike timing dependent

plasticity

“Cells that fire together

wire together”

Stefan et al. Brain 2000, J Physiol 2002

Jayaram & Steiner Exp Brain Res 2008
Ferris et al., Neurorehabil. & Neural Repair, 2018
Transcranial ultrasound
– Sound waves travel
through bone and soft
tissues
– Low-intensity pulsed
ultrasound influences
neural activity without
thermal effects
– Exact mechanisms
unknown – may affect
mechanically sensitive
ion channel kinetics
– Also modulated, focused
ultrasound with rice-grain
resolution (Tyler et al., PloS
One 2008; Mehic et al., PLoS One Nature Neuroscience 17, 322–329 (2014)
2014)
Summary: Stimulating the Nervous System
Peripheral Nervous System (PNS)
• Peripheral nerves are activated before
muscles
• Peripheral nerves are activated from
largest to smallest diameter fibers

Central Nervous System (CNS)

• Axons are activated before cell bodies
using electrical stimulation
• Magnetic stimulation activates neurons
parallel to coil
• Cell body/initial segment and axon via
optogenetics
Towne et al., PLoS One 2013
 Day 4 Quiz
https://canvas.uw.edu/courses/1395894/quizzes/1323269
or email answers to jmishler@uw.edu if not yet enrolled

1. Select the best answer below in regard to

stimulating the brain
a. Electrical stimulation of cortex can evoke sensory
responses.
b. Transcranial Magnetic Stimulation (TMS) paired with
peripheral stimulation can induce neuroplasticity.
c. Multiple sources of high frequency stimulation can
combine to produce low frequency brain stimulation.
d. All of the above