A beginner’s guide to using magnetic brain
stimulation to study neuroplasticity and its
relevance to neurorehabilitation
Michael C Ridding
NHMRC Senior Research Fellow
Robinson Institute
University of Adelaide
Australia
Talk outline
 Neuroplasticity
 TMS
to “measure” neuroplasticity
 TMS
approaches to induce neuroplasticity
 How
is TMS useful
 Problems
 The
future
Neuroplasticity
“Reorganisation of brain connectivity through
experience”

Occurs throughout life

A number of processes involved

Neuron growth (limited, long term process)

Synaptogenesis/synaptic pruning (short-medium
term)

Changes in efficacy of existing synapses (short
term) – largely through activity dependent
mechanisms LTP/LTD
Critical for learning, memory and recovery from injury
Investigating motor cortical (M1) plasticity with transcranial
magnetic stimulation (TMS)
TMS
Motor evoked
potential (MEP)
25ms
TMS
Muscle
Non-invasive brain stimulation (NBS)
Repetitive transcranial
magnetic stimulation (rTMS)
 Repetitive
trains of TMS
 Freq/inten/dur
Paired associative
stimulation (PAS)
 Paired
TMS + contralateral
peripheral nerve stimuli
dependent
effects
 Approx
200 pairs of stimuli
every 10-20 sec
 Applied
over periods of
30-40 sec to many
minutes (15)
 Effects
last 30-60 min
 TMS
- nerve stimuli ISI
determines effect (25 ms 
excitability, 10 ms 
excitability, form of STDP)
Transcranial direct current
stimulation (tDCS)
 DC
stimulation applied
through pads placed on
scalp
stimulation 
excitability
 Anodal
stimulation 
excitability
 Cathodal
 Applied
 Effects
≈10 minutes
last 30-60 min
 Effects
last 30-60 min
Repetitive transcranial magnetic stimulation (rTMS)

Low frequency (<1 Hz) stimulation -
cortical excitability

High frequency (>5 Hz) stimulation -

Newer techniques (TBS) apply short bursts of high frequency stimuli
increases cortical excitability
General characteristics of rTMS
protocols
Huang et al., 2005
Mechanisms of rTMS induced effects
consistent with activity dependent changes in synaptic efficacy - brought about
by long-term potentiation (LTP) and long-term depression (LTD)
Interesting because:
LTP/LTD are key mechanisms of many forms of learning and memory
including motor learning
•
Rapidly induced
•
Lasting but reversible
•
Pathway specific
•
NMDA receptor dependent
Available synaptic
population
Consistent features:
Excitatory rTMS
(synaptic
potentiation)
Synaptic
population
Inhibitory rTMS
(synaptic
weakening)
How is rTMS useful – therapeutic intervention?
Stroke
Depression
(Ridding & Rothwell 2007 Nat Rev Neurosci)
Excitatory rTMS to
hypoactive, lesioned
motor cortex
Inhibitory rTMS to
hyperactive, nonlesioned motor cortex
Excitatory rTMS to
hypoactive left
prefrontal cortex
Inhibitory rTMS to
hyperactive left
prefrontal cortex
How is rTMS useful – therapeutic intervention?
Inhibitory
Excitatory
Talelli et al., Clin Neurophysiol 2007
•
•
6 chronic stroke patients 12 -108 months post stroke
iTBS to stroke hemisphere improved SRT (vs sham)
• 54 patients with
ischaemic/haemorrhagic stroke
• 3-12 months post first ever stroke
• 4 groups (n=13-16)
•
A= contra 1Hz + ipsi iTBS
•
B= contra sham 1 Hz + ipsi iTBS
•
C= contra 1 Hz + sham ipsi iTBS
•
D = sham contra 1 Hz + sham ipsi iTBS
• 20 daily sessions (10 x 2
interventions)
• Wolf Motor Function Test /Fugl
Meyer/SRT/finger flexor MRC/tapping
But!
•
41 stroke patients randomised to receive iTBS/cTBS/sham
•
At least 1 year post stroke
•
TBS followed by therapy for 10 working days
•
Assessed at 4,30, 90 days post intervention
•
No difference between iTBS/cTBS/sham in any primary outcome
measures (9 hole peg test, Jebsen Taylor Test, grip/pinch strength)
How is rTMS useful – characterising neuroplasticity?
• Investigate mechanisms of human neuroplasticity
• Characterise neuroplasticity in conditions where changes
in it might underpin behavioural abnormalities
(neurodevelopmental influence)
• Use as a marker for early detection of neurodegeneration
(AD)?
• Characterise time-course of neuroplastic change to
optimise treatment/interventions
• Assess impact of interventions on neuroplasticity
Early life experience/environment
Preterm birth
•
Effects on cortical microstructure
•
Associated with poorly understood
ongoing cognitive and motor deficits
28 adolescents (age 13.8 ± 0.5 years) born preterm but without evidence
of overt brain injury

Term born >37 weeks GA, n=7

Late preterm 33-36 weeks GA, n=10

Early preterm <32 weeks GA, n=11
Investigated with cTBS (inhibitory “LTD-like” paradigm).
Preterm birth
•
•
•
Preterm birth associated with impaired
neuroplasticity into adolescence
May underpin abnormalities in cognition
and motor skills
Impact of early life environment likely to
be important
Problems and challenges for rTMS!
• Mechanisms responsible poorly understood (time-course
/reversibility)
• Effects on behaviour generally small and transient
• High variability
• “Transferability” (M1 to other regions)
• Study size
Variability in NBS induced effects
Sale et al., 2007 EBR
Goldsworthy et al., 2012 in press Clin
Neurophysiol
Hamada et al., 2012 Cerebral Cort

PAS25 protocol

cTBS

cTBS / iTBS

10 subjects 3 sessions
separated by at least 1 week

12 subjects - single session

52 subjects – two randomised
sessions
Known influences on M1 plasticity
Ridding & Ziemann 2010 J Physiol
Time of day effects
Sale et al., 2008 J Neurosci

25 subjects tested (8 am and 8 pm)

Greater PAS response in the evening

Component of this effect due to cortisol (circadian) modulation
Anatomical/physiological influences
Inter-individual variability in networks activated by TMS modify
neuroplastic response to NBS
Hamada et al., Cereb Cort 2012
cTBS
iTBS

Subjects in which stimulus likely to engage late I wave circuits more likely to be responders

Mechanisms not clear – however, provides evidence that some of the inter-subject variability
is due to differences in the cortical circuitry activated during the interventions

Might be useful for better targeting
The future
• Development of better stimulation paradigms
– Effects more closely resemble those seen in animal models
– Will provide more opportunities for therapeutic intervention
• Better targeting
• Alternative methods for “measuring” neuroplasticity (TMS-EEG)
• Greater understanding between neurophysiology and function
• Studies (both basic and clinical) need to be better designed and
powered
Development of more effective stimulation paradigms
Goldsworthy et al., Clin Neurophysiol 2012
Optimisation of induction paradigm characteristics (e.g. burst characteristics)
Development of more effective stimulation paradigms
Longer lasting effects
 More consistent
 Resistant to behavioural disruption
 Consistent with evidence from animal model

Goldsworthy et al., 2012 Eur J Neurosci
Conclusions

rTMS can induce bidirectional changes in excitability – modify network “accessibility”

However, currently effects are small, short lasting and easily disrupted

May offer therapeutic potential in combination with other therapies
To maximise behavioural/therapeutic effects we need to:

gain greater understanding of influences on neuroplasticity induction

targeted approach

develop more effective stimulation paradigms - both intrinsic characteristics of paradigm and
application (e.g. temporal patterns of application)

Conduct larger studies