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methods

Dr Katherine Dyke

katherine.dyke@nottingham
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 Learning Objectives

By the end of this lecture you should be able to:

•Provide a basic description of how TMS works and the numerous ways in
which it can be used to measure and modulate the brain.

•Recognise some of the methodological issues involved in conducting

research with non-invasive brain stimulation approaches.

•Identify some practical solutions for creating well designed studies using
non-invasive brain stimulation approaches.

•Be able to compare and contrast different types of non-invasive brain

stimulation.
 Lecture Overview

Quick history and recap of membrane/ action potentials.

Part 1a: Transcranial Magnetic Stimulation to measure the brain.

Part 1b: Transcranial Magnetic Stimulation to modulate the brain.
Part 1c: Limitations and consideration for TMS studies.

Part 2a: Transcranial Electrical Stimulation: particularly direct current (tDCS)

Part 2b: Limitations and considerations for tDCS studies

Part 3: Transcranial focused ultrasound

Part 4: Diversity in non-invasive brain stimulation

Summary and Conclusions

 A very brief history of brain stimulation
Transcranial ultrasound
Merton & Merton
Luigi Galvani & Motor cortex &
Giovanni Aldini shocks

2013

17th Cent 1980s

131- 1985
141AD 19 th
Cent

Barker & colleagues

Fish & Electroconvulsive
headaches therapy (ECT)
Resting state of a neurone

Na+ K+ Cl- -

Sodium Potassiu Chloride Organic anions

m

Inside cell at rest:

K+ - • More k+
-
Cl Na K+
• Net negative charge
Na +
+
K+ Cl
- Membrane potential at
rest: -70mV
K+ Cl
Na Na
+
-
+
Outside cell at rest:
Na
+
Na
+
Na
+ • More NA+
• Net positively charge
Ion
channels
 Action Potentials

1: Sodium channels open allowing Na to rush into

the cell. Channels close.

Na+ K+

Na+

2: Potassium channels open allowing k to rush out Sodium-

potassium pump
of the cell.
K+

3: Sodium-potassium pump to restore

equilibrium. 3 sodium out for 2 potassium in.
K+ K+

Na+ Na+ Na+

 Synaptic Transmission (pt1)

Action Potential
1:Specific enzymes help to
assemble neurotransmitter
molecules from precursors.
Synthesising vv
Enzyme

v
v

v
v 2: Neurotransmitter molecules
Vesicle are packaged together and
stored in vesicles.
Presynaptic membrane
Neurotransmitter
Postsynaptic
receptor 3: Action potential causes Ca2+ to enter
neurone which signals to vesicles to fuse
with the presynaptic membrane. This
causes them to release neurotransmitters
into the synapse.
 Synaptic Transmission (pt2)

4: Released
Synthesising
Enzyme neurotransmitters bind
with receptors on the
vv postsynaptic membrane.

v
v
Neurotransmitter

v
v
precursor

Vesicle 5: Unbound
neurotransmitter in the
Neurotransmitter synapse can removed
through reuptake into the
presynaptic neurone or
Postsynaptic
receptor degradation via
enzymes.
Synaptic Transmission (pt3)
Synaptic Transmission (pt4)
 Part 1a: Transcranial Magnetic stimulation

TMS as a measurement
How does TMS work?
How do we know TMS does anything?
Measuring cortical excitability: Single pulse.
Measuring cortical excitability: Paired pulse.
Measures of afferent inhibition.
Assessing relationships between connected regions.
Summary of TMS as an investigative tool.
 Part 1a: TMS to assess activity

Bergmann, T. O., Karabanov, A., Hartwigsen, G., Thielscher, A., & Siebner, H. R. (2016). Combining non-invasive transcranial brain stimulation with neuroimaging and
electrophysiology: current approaches and future perspectives. Neuroimage, 140, 4-19.
How TMS works : electro-magnetic induction (1)

1: A brief but strong electrical

current is delivered from an
electrical capacitor to the TMS
coil. The TMS coil contains
windings of copper wire which
conduct the current..

2: This produces a fluctuating

magnetic field which in turn
causes…

3: A secondary induced
electrical current on cortical
surface.
 How TMS works : electro-magnetic induction (2)
Search: Tourette Syndrome research: Transcranial Magnetic
Stimulation (TMS)
Or:
https://www.youtube.com/watch?v=LGXbLlQBMJE&t=
9s
Look very closely for lightbulb demo – it does work, honest!
Where/ how to measure
Motor cortex: Motor Evoked
Potentials (MEPs)

Brocas Area: Speech slurring

Visual cortex: Phosphenes

Behavioural EEG fMRI/MRS

tasks
-Technically a -Technically
-Task must be little tricky. tricky
carefully -But can be -Potential
chosen. very temporal
-As should informative. issues.
threshold.
Motor evoked potentials (MEPs)
Motor threshold (MT)

MEPs can be measured from various

muscle representations. But intensity
needed for each region varies.

Motor threshold (MT) is the minimum

intensity needed to generate MEPs of a
particular size 50% of the time.

Used to individualize intensities.

Primarily influenced by anatomy, some

modulation by glutamatergic activity. Can
be modulated by changing membrane
permeability.
Input output | Recruitment | stimulus-response curve
 Input output curve | Recruitment curve | stimulus-response curve

Tourette’s Syndrome Migraine

Pre (highlighted)
Post levtiracetam

Children/ adolescents with Tourette’s

show reduced cortical excitability. Those Migraine sufferers had increased
with shallowest functions had greater cortical excitability which normalised
symptoms ( tics). following 2 months of drug treatment
(levetiracetam).
Cosentino, G., Fierro, B., Vigneri, S., Talamanca, S., Palermo, A., Puma, A., &
Pépés, S. E., Draper, A., Jackson, G. M., & Jackson, S. R. (2016). Developmental Brighina, F. (2011). Headache: The Journal of Head and Face Pain, 51(5),
cognitive neuroscience, 19, 78-86. 726-733.
 TMS mapping of the cortex
Example – reorganisation
following stroke

Changes in hand area maps – area

and MEP amplitude following stroke.
Delvaux et al, (2003). Clinical
Rossini et al, 2015. Neurophysiology, 114(7), 1217-1225.
 General principle of paired pulse stimulation

1: Conditioning Stimulus (CS). The intensity of this is

important. Usually subthreshold, typically no MEP.

2: Inter stimulus interval (ISI). Time between pulses is critical

to outcomes.

3: Test Stimulus (TS). Intensity here needs to be

suprathreshold, so high enough for muscle contractions (if
using MEPs as outcome).

4: Also need unconditioned pulses to compare against.

Short interval intracortical inhibition (SICI) pt1

ISI 1-5ms

Conditioning pulse Test pulse

(Subthreshold) (Supra threshold)

CP results in activation of a low-

threshold cortical inhibitory circuit
(involving GABAergic
interneurons specifically GABA-A
receptor activity).

TP results in smaller MEP,

because CS reduces inputs to
corticospinal neurones, resulting
in fewer action potentials.
 Short interval intra-cortical inhibition (SICI) pt2
Uses of SICI. Exploring changes in GABA in healthy adults and clinical groups.

Testing Understanding Clinical

Interventions: mechanisms: differences:
Lots of work suggests
altered SICI in clinical
groups including:

Tourette Syndrome
ADHD
OCD
TMS GABA (SICI) does Schizophrenia
E.g. SICI decreases not correlated with MRS
indicating GABA GABA. Some finding
Important as may have correlations with
change post exercise
(Singh et al, 2015, J of motor behaviour). seemingly contradictory symptoms.
findings between
methods. (Dyke et al, 2017, Neuroimage)
Long interval inter-cortical inhibition (LICI)

ISI 50-200 ms

Conditioning pulse Test pulse

(Supra threshold) (Supra threshold)

• General consensus is that LICI

is primarily medicated by GABA-
B receptors.
• Pharmacological studies and
studies of intently suggest SICI
and LICI have different
underlying mechanisms despite
both resulting in a reduction in
MEP.
Intra-cortical facilitation (ICF)

ISI 7-20ms

Conditioning pulse Test pulse

(Subthreshold) (Supra threshold)

Underlying mechanisms of ICF

are less clear than SICI. But CS
appears to engage mechanisms
which result in more action
potentials.

Larger MEPs occur in response to

test pulse. More complex than
being opposite of SICI but
GABA/Glutamateric.
 Short/ long afferent inhibition (SAI/ LAI)

• Electrical stimulus at nerve (e.g. median nerve) precedes TMS pulse at M1, resulting
in reduced MEPS.
• Often used as an index of sensori-motor inhibition.
• SAI mechanisms: GABA-Aergic and cholinergic involvement.
• LAI mechanisms: less well researched but likely to also involve GABA and choline.
• Abnormal in some conditions e.g. Tourette syndrome. Which suggests less efficient
sensory-motor inhibition.
Turco, C. V., El-Sayes, J., Savoie, M. J., Fassett, H. J., Locke, M. B., & Nelson, A. J. (2018). Short-and long-latency afferent inhibition; uses, mechanisms
and influencing factors. Brain stimulation, 11(1), 59-74
 Measuring Connectivity: dual site TMS

• Cortico-cortical connectivity can be assessed using two TMS coils placed

over areas of interest.
• Particularly useful in studying areas related to motor cortex (dPM-M1, and
M1-M1).
• This allows us to look at inhibitory and facilitatory connections between
regions.
Summary: TMS as an index of neural activity (1)

TMS works via electromagnetic induction, leading to indirect electrical

stimulation of cortex.

TMS is able to induce action potentials, which when applied to the motor
cortex can generate motor evoked potentials (MEPS).

Motor threshold: the lowest intensity needed to generate an MEP. Typical

approach to individualizing stimulation.

Input- output curves: index of cortical gain. Useful in understanding

excitability.

Paired pulse approaches SICI and LICI allow us to explore engagement of

inhibitory circuits which are moderated by GABAergic activity.
 Summary: TMS as an index of neural activity (2)

ICF is another paired pulse approach which is underpinned by different

mechanisms which facilitate cortical excitability.

TMS can be paired with afferent stimulation to study levels of afferent

inhibition.

Dual site TMS can be used to study the nature of pathways between
different regions.

Overall: TMS can be used as an approach to explore cortical excitability and connectivity.
This is most well define in motor systems but by pairing TMS with other imaging
approaches it can be used to explore other regions. These approaches have revealed
difference in a number of clinical conditions.
 Part 1b: Transcranial Magnetic stimulation

TMS to modulate the brain

Repetitive Transcranial Magnetic stimulation (rTMS)

Theta burst stimulation (TBS).
Experimental example.
Therapeutic examples – depression.
 Part 1b: TMS to modulate activity

Bergmann, T. O., Karabanov, A., Hartwigsen, G., Thielscher, A., & Siebner, H. R. (2016). Combining non-invasive transcranial brain stimulation with neuroimaging and
electrophysiology: current approaches and future perspectives. Neuroimage, 140, 4-19.
 Repetitive TMS (rTMS)

Variable response though…

Maeda et al, 2000, Experimental Brain Research.
5+hz
rTMS

1hz
rTMS Valero-Cabre et al, 2017, Neuroscience & biobehvioural reviews .

General consensus: 1Hz stimulation has an

inhibitory effect where as 5Hz+ (typically 10Hz)
increases motor cortical excitability.

Approx 600 pulses in a single session. Supra

threshold (110- 120%RMT).
 Theta burst stimulation (TBS)

iTBS cTBS

Suppa et al, 2016,

Brain Stimulation.

TBS involved bursts of pulses delivered at 50Hz. Subthreshold (80% AMT). General
trend towards increase/ decrease excitation but – lots of individual variability.

Substantial variability in iTBS protocols. In

this study 42% of the same showed the
expected increase in cortical excitability.
Lopez- Alonzo et al, 2014,Brain stimulation.
TMS as a therapy

Sept 2022 July 2023 (+79,000)

 rTMS and depression

FDA approved meaning available as treatment in USA. NICE

Guidelines approve rTMS use when other treatments have
failed.

Hundreds of studies of varying levels of quality.

But several large scale RCTs. Meta analyses &
systematic reviews suggests real effects over
sham.

Strongest evidence base for therapeutic use of NIBS but still

a lot of unknowns and non responders.

Lefaucheur, J. P., Aleman, A., Baeken, C., Benninger, D. H., Brunelin, J., Di Lazzaro, V., ... &
Jääskeläinen, S. K. (2020). Evidence-based guidelines on the therapeutic use of repetitive
transcranial magnetic stimulation (rTMS): an update (2014–2018). Clinical
neurophysiology, 131(2), 474-528.
 rTMS as a treatment for depression

Berlim, M. T., McGirr, A., Dos Santos, N. R., Tremblay, S., & Martins, R.
Theta burst stimulation (TBS) (2017). Efficacy of theta burst stimulation (TBS) for major depression: an
exploratory meta-analysis of randomized and sham-controlled trials. Journal
of psychiatric research, 90, 102-109.

Sonmez, A. I., Camsari, D. D., Nandakumar, A. L., Voort, J. L. V., Kung, S., Lewis, C.
Accelerated TMS P., & Croarkin, P. E. (2019). Accelerated TMS for depression: a systematic review and
meta-analysis. Psychiatry research, 273, 770-781.
 Considerations….(therapy and research)

rTMS, TBS and more recently QPS are patterned forms of TMS which can be
used in research and therapy (LTP/ LTD like changes).

Net increase/ decrease in cortical excitability is over simplistic, but often cited…

There is evidence that this treatment can work. Particularly in major depression.
But maybe only in 50%....

To improve treatment outcomes we need:

1- Research into factors which predict response, leading to more individualised
approaches.
2- Better understand the underlying mechanisms through which these
approaches work.
Part 1c: Methodological considerations for brain stim research & therapeutic use

Stimulatio
n site
Control/
Effective
Sham
targeting
sites

Sample Intra/inter
size and subject
stats variability

Brain
state: Outcome
Active/ Stimulatio measures
passive n
parameter
s
 TMS sensations and sounds
Stimulation
site
Control/
Sham
sites

TMS can create scalp/facial twitches and other annoying sensations. This can
interfere with task performance – here shown as increased reaction times in
areas with most twitch. Implications for choice of control sites! (Meteyard &
Holmes, 2018)
 Brain
Interactions between TMS and task
state: Stimulatio
Active/ n
passive parameter
s

Self-initiated predictable TMS = smaller In computer generated pulses MEPs tended to be larger when
MEPs indicating lower cortical excitability. the occurred ahead of when they were expected.

Key message: MEPs are higher when TMS pulse is less predictable.

Tran et al, 2021, Neuroimage

 Accurate and replicable coil placement : Neural navigation
Effective
targeting

Navigated TMS:
Less spatial
variation between
sessions, larger
and less varied
MEPs.
However, RMT
unchanged.

Julkunen, P., Säisänen, L., Danner, N., Niskanen, E., Hukkanen, T., Mervaala, E., & Könönen, M. (2009).
Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor
threshold and motor evoked potentials. Neuroimage, 44(3), 790-795.
 Improving & individualising targets
Stimulatio
n site

Klooster, D. C., Ferguson, M. A., Boon, P. A., & Baeken, C. (2022). Personalizing repetitive transcranial magnetic stimulation parameters for depression treatment using multimodal neuroimaging. Biological Psychiatry: Cognitive
Neuroscience and Neuroimaging, 7(6), 536-545.
 Learning Check

Padlet: Please write three things you have learnt so far!

Also please write any anonymous questions you

currently have.

https://uonpsych.padlet.org/katherinedyke/non-invasive-brain-stim-oct-2023-t5h6oepn6mg6i0m
Part 2: Transcranial direct current stimulation

tDCS to modulate the brain

-tDCS set up and background.

-Potential physiological basis of effects.
-Variability in response to tDCS.
-tDCS as a therapy: examples from depression.
-Practical considerations.
 Transcranial electrical stimulation

‘Reference’ ‘Active’
electrode. electrode.
Rubber band (for attaching
electrodes to the head).

Cables
connecting
electrodes tDCS machine.
to power -duration
source. -intensity

Transcranial direct current stim (tDCS), Transcranial alternating current stim (tACS)
Transcranial random noise stim (tRNS)
 Transcranial direct current stimulation: physiology (1)

Many papers report that tDCS effects are polarity specific .

Anodal> Cathodal>

Mechanisms proposed for this:

Anodal stimulation: subthreshold membrane depolarization leading
to an increase in excitability.
Cathodal stimulation: subthreshold hyperpolarization of neuronal
membrane and decrease in neuronal excitability.
Baseline

Cathodal Anodal

Bindman et al, 1964.

 Transcranial direct current stimulation: physiology (2)

1.5
* kS

prm
with /without tDCS

1.25 m cm
pom

1.0 * oc
anodal
MEP-Amplitude

stimulation
Electrode positions:
0.75
m-cS m = motor cortex; prm = premotor
cortex; pom = post-motor cortex; oc
= occipital; cS = contralateral
cathodal
0.5 stimulation
forehead; cm = kontralateral motor
cortex

Cortical excitability increase Anodal tDCS increased Glutamate levels and

following anodal and reduced GABA levels within the voxel.
decrease following cathodal Cathodal stimulation resulted in decreases in
stimulation. both GABA and Glu.
Nitsche, M. A., & Paulus, W. (2000). Excitability
changes induced in the human motor cortex by Stagg, C. J., Best, J. G., Stephenson, M. C., O'Shea, J., Wylezinska, M., Kincses,
weak transcranial direct current stimulation. The Z. T., ... & Johansen-Berg, H. (2009). Polarity-sensitive modulation of cortical
Journal of physiology, 527(Pt 3), 633. neurotransmitters by transcranial stimulation. Journal of Neuroscience, 29(16),
5202-5206.
tDCS as a therapy
 tDCS as a treatment for depression (Example 1)

N=91 N=91 N=30

76.6% 86.8% 83.3%

tDCS: cathodal 2,mA, 10 min, 22 sessions. Follow up using depression inventory: 1,2,3, 6,8,10
weeks
Used latent trajectory modeling to identify different response patterns but no clear evidence of tDCS being
beneficial found.
Goerigk, S. A., Padberg, F., Bühner, M., Sarubin, N., Kaster, T. S., Daskalakis, Z. J., ... & Brunoni, A. R. (2021). Distinct trajectories of response to prefrontal tDCS in
major depression: results from a 3-arm randomized controlled trial. Neuropsychopharmacology, 46(4), 774-782.
 tDCS as a treatment for depression (example 2)

26 RCTs with 1204 participants with

2mA & 30 mins & medication free improve outcome.
depression.

Active tDCS (typically cathodal DLPFC) was superior to sham (post/pre).

But remission rates were comparable between active and sham – so effects short lived.
Zhang, R., Lam, C. L., Peng, X., Zhang, D., Zhang, C., Huang, R., & Lee, T. M. (2021). Efficacy and acceptability of transcranial direct current stimulation for treating
depression: A meta-analysis of randomized controlled trials. Neuroscience & Biobehavioral Reviews, 126, 481-490.
 Variability in response to tDCS (1)

Lots of variation of responses to

stimulation. Anodal does not
always increase excitability,
cathodal does not always
decrease.

Wiethoff, S., Hamada, M., & Rothwell, J. C. (2014). Variability in response to transcranial direct current stimulation of the
motor cortex. Brain stimulation, 7(3), 468-475.
 Variability in response to tDCS (2)

Effects of 2mA anodal tDCS

applied to the motor cortex for 20
minutes.

Each individual tested 4 times.

Can we optimise the effect for

someone like participant 9?

Dyke, K., Kim, S., Jackson, G. M., & Jackson, S. R. (2016). Intra-subject consistency and reliability of response following 2
mA transcranial direct current stimulation. Brain stimulation, 9(6), 819-825.
 tDCS method considerations

Stimulatio
n site
Control/
Effective
Sham
targeting
sites

Sample Intra/inter
size and subject
stats variability

Brain
state: Outcome
Active/ Stimulatio measures
passive n
parameter
s
 Transcranial electrical stimulation: technical set up

Effective
targeting

Fischer, D. B., Fried, P. J., Ruffini, G., Ripolles, O., Salvador, R., Banus, J., ... & Fox, M. D. (2017). Multifocal tDCS targeting the resting state motor network
increases cortical excitability beyond traditional tDCS targeting unilateral motor cortex. NeuroImage.
Exploring potential biomarkers of tDCS effectives

Sham/active tDCS to left prefrontal cortex

Intra/inter
during N-Back. All also received CBT. 8
subject
variability sessions.

Modest difference between sham/active but

n.s

Relationship between baseline activation in

stimulated region during working memory
task & symptom improvement. More BOLD
during task = better response.

When considering baseline activation 86%

accuracy in predicting clinical response to
tDCS.

Nord, C. L., Halahakoon, D. C., Limbachya, T., Charpentier, C., Lally, N., Walsh, V., ... & Roiser, J. P.
(2019). Neural predictors of treatment response to brain stimulation and psychological therapy in
depression: a double-blind randomized controlled trial. Neuropsychopharmacology, 44(9), 1613-1622.
Part 3: Transcranial Focused Ultrasound

Transcranial focused ultrasound

Background and recent developments.

Online effects example.
Offline effects example.
 Transcranial focused ultrasound: intro

• Low intensity sonic pulses.

• Pass through skull to brain – has the
ability to reach subcortical regions.
• Pairing FUS with other approaches –
mostly MRI has shown ‘online’ effects
of pulses. More recently evidence that
longer stimulation can cause changed
which outlast stimulation period.
• Very new to human research – most
papers produced 2020 onward.
• Lots still to find out.

Blackmore, J., Shrivastava, S., Sallet, J., Butler, C. R., & Cleveland, R. O. (2019). Ultrasound neuromodulation: a review of results, mechanisms and
safety. Ultrasound in medicine & biology, 45(7), 1509-1536.
 Transcranial focused ultra sound (tFUS) : overveiw

Sarica, C., Nankoo, J. F., Fomenko, A., Grippe, T. C., Yamamoto, K., Samuel, N., ... & Chen, R.
(2022). Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of
effectiveness and safety. Brain Stimulation.
 Transcranial focused ultrasound (tFUS): animal models

fEPSP: field excitatory post

synaptic potentials (measure
of synaptic connectivity)

Niu, X., Yu, K., & He, B. (2022). Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus. Brain Stimulation, 15(2), 352-359.
Transcranial focused ultra sound (tFUS) & MEPs

Transcranial ultrasound reduces cortical excitability (lighter grey line) in

comparison to baseline. First demonstration of tFUS ability to modulate cortical
excitability (N=12).
Legon, W., Bansal, P., Tyshynsky, R., Ai, L., & Mueller, J. K. (2018). Transcranial focused ultrasound
neuromodulation of the human primary motor cortex. Scientific reports, 8(1), 1-14.
 Transcranial focused ultrasound (tFUS) & MEPs 2

Tb TUS at Motor cortex:

IO increase (T5 &T30)
Decreased SICI (T5&T30)
Increased ICF (T5)
Zeng, K., Darmani, G., Fomenko, A., Xia, X., Tran, S., Nankoo, J. F., ... & Chen, R. (2022). Induction of human motor cortex plasticity by theta burst
transcranial ultrasound stimulation. Annals of Neurology, 91(2), 238-252.
 Transcranial focused ultrasound (tFUS): Acoustic confounds 1
Control/
Sham

TUS over left M1, TUS over face area

with/without sound of right M1 with and
mask. Before M1 without sound mask.
TMS pulse. Before M1 TMs
pulse.

Sound sham, no TUS stimulation of

TUS. Before TMS white matter with &
M1 pulse. without sound mask.
Before TMS pulse.

Kop, B. R., Oghli, Y. S., Grippe, T. C., Nandi, T., Lefkes, J., Meijer, S. W., ... & Verhagen, L. (2023). Auditory confounds can drive online effects of transcranial ultrasonic
stimulation in humans. bioRxiv, 2023-02. (Note: Pre-print not reviewed)
Transcranial focused ultrasound (tFUS): Acoustic confounds 2

• TUS seems to reduce

MEPs when applied to M1
(replicated past work).
• But TUS stimulation to
opposite hem face area
also reduced MEPs.
• This looks similar to the
reduction in MEP you see
when you just play sound
ahead of TMS pulse.
• Similar reduction when
stimulation white matter.

• MEP reduction = sound

confound rather than
stimulation.
 Transcranial focused ultrasound (tFUS): Acoustic confounds implications

• The auditory component of TUS seems to be driving the MEP inhibition.

• Potentially as this acts as an auditory cue that TMS will be presented soon
(recall previous work by Tran et al (2021) in which more predictable stimuli =
smaller MEPs.
• Could be a specific feature of the motor cortex and not applicable across brain.
• Evidence that TUS can produce ‘offline’ effects which seem less likely to be
driven by this.
• Additionally, evidence from mice models suggest TUS effects still present in both
heading and deaf mice: Mohammadjavadi, M et al (2019). Brain
stimulation, 12(4), 901-910.
• Overall – something to consider in online TUS studies and to carefully control for.
 Transcranial focused ultrasound (tFUS): Targeting

Effective
targeting

• Sound passes at different rates

through different surfaces.
• Skull bone is not an even surface.
• Can result in dephasing of ultrasonic
beam – less focus.
• CT scan or specialized MRI
approaches for bone needed.
• Modelled using various software.
Images from Leung et al, 2019.
• Some degree of error in all models &
https://doi.org/10.1038/s41598-019-43 can be tricky to validate.
775-6

Skull can cause dephasing of

ultrasonic beam.
More dephasing = less focus. Also can
 Sample biases in NIBS (hair type/ texture)

• Hair is an insulator…. This is not good for approaches like tDCS in which you
need current to flow.
• Thick hair = high impedance = not good for brain stim!
• To combat this often apply saline/gel but wet hair beyond electrode site –
current travel across hair not scalp.
• Often means exclusion of people with dense hair from tDCS/tACS/tRNS studies.
Particularly problematic when considering potential therapeutic application.
 Sample bias in neuro (sex & race)

Engagement in neuro studies is Many studies have historically favoured a

heavily biased to specific male only sample.
demographics. Improvements recently as many funders
require strong justification for any
exclusion.
Ricard, J. A., Parker, T. C., Dhamala, E., Kwasa, J., Allsop, A., & Holmes, Will, T. R., Proaño, S. B., Thomas, A. M., Kunz, L. M., Thompson,
A. J. (2023). Confronting racially exclusionary practices in the acquisition K. C., Ginnari, L. A., ... & Meitzen, J. (2017). Problems and
and analyses of neuroimaging data. Nature Neuroscience, 26(1), 4-11. progress regarding sex bias and omission in neuroscience
research. eneuro, 4(6).
 Why does it matter?

• Samples are often WEIRD: white, educated, industrialized, rich and

democratic.
• Research into brain stimulation and imaging are also likely to be driven by
researchers who fit this category.
• This type of research isn't cheap so is often restricted to certain
countries/institutes.
• Exclusion from research at a participant level may foster distrust of these
approaches in excluded groups – problematic if aiming to develop
treatments.
• Lack of representation within research teams may lead to interesting and
important questions being overlooked/ minimized.
• Lots of progress recently in representation of women in NIBS research
https://biaswatchneuro.com/ but other areas which are still very unequal.
General experimental design considerations for NIBS (1)
 Comparison of NIBS approaches
TMS tDCS tFUS
Practical -coil angle, size, shape. -electrode size, number, orientation -transducers – often custom
considerations -stimulation intensity. and placement.. made.
-Stimulation duration. -brain scans & modelling may be
-pulse type (mono/bi phasic). necessary.
Targeting -Typically cortical surface only. Cortical only. Large spread of -Subcortical possible.
-Neural nav helps. current. -Computational modelling and
-efield modelling may help. scans very much desirable.

Safety -Established technique -Generally very safe although skin -Early stages.
-Very rare, but potential seizure risk. irritation possible. -cautiously optimistic within set
parameters.
Sham & blinding -Sensation. -Sensation. -Acoustic noise.
-Twitches. -Potential skin. appearance
-Acoustic noise. changes.
Variability/ reliability Some approaches more reliable than -Known to be variable both within -Currently unknown.
others e.g. paired pulse. Modulatory and between participants.
approaches – variable.
Mechanisms -Action potentials when supra threshold. -Membrane changes no action -Membrane changes (ion
-interneurons for paired pulse. potentials. channel opening), no action
potentials.
Compatibility with other Compatible but produces artefacts – technically Excellent compatibility with TMS. Ok with Pairing with TMS is excellent. MRI and
methods challenging. EEG and MRI modalities. other approaches possible.

Activity: find evidence or reference to support each point. Or see if you can fill in an empty grid from scratch.
Conclusions: NIBS in research and therapy

The effects of TMS, tDCS and more recently tFUS have been show
to modulate the brain both during (online) and in some instances
after (Offline) the stimulation period. There are numerous ways
each can be used within research contexts.

Repeated sessions of stimulation may lead to therapeutically

relevant effects through LTP/LTD type mechanisms. Main
evidence current in treatment of depression. However – a lot of
variability and unknowns.
 Conclusions: NIBS in research and therapy (2)

Outstanding issues: study design (blinding, sham, task selection,

stimulation site); parameter selection (intensity, duration, pulse pattern);
individual variability.

Potential solutions: replication, open science, pre registration, improved

targeting, multimodal approaches to understand variability and identify
biomarkers of response.

Exciting new developments: Huge growth in exploration of tFUS which

has the potential for accurate targeting & modulation of subcortical
structures. Improved ability to combine approaches including TMS-EEG.
 People doing exciting things with NIBS / featured in lecture

Vincent Walsh, UCL,UK Charlotte Stagg, Oxford, UK

-TMS, tDCS -Multimodal imaging approaches.
-Plasticity -Motor systems
-exercise & sleep -TMS/ tDCS/ tACS/ FUS

Debby Klooster, Ghent University, NL Camilla Nord, Cambridge, UK

-Multimodal imaging -Multimodal imaging
-NIBS approaches
-Computational approaches -tDCS

Hartwig, Siebner, drcmr, DK Michael Nitsche, Leibniz research

-Multimodal imaging centre, DE
-NIBS -tDCS
-Motor control & decision making -Genetics & brain

Link to network of UK based NIBS researchers

 Independent study activities

Activities:

Find examples of rTMS approaches being used experimentally. What sorts of things
can be explored using this approach?

Explore other multimodal approaches using non-invasive brain stimulation. Consider

how pairing techniques allows for a huge range of questions to be explored (e.g.
consider the literature of TMS-EEG).

Learn more about recent research using non-invasive brain stimulation on the
Brainbox Youtube channel: https://www.youtube.com/c/BrainboxLtd

Create your own table contrasting non-invasive brain stimulation approaches and
supporting with relevant reference.
Questions?

[email protected]