A beginner s guide to using magnetic brain stimulation to study neuroplasticity and its relevance to neurorehabilitation

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1 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

2 Talk outline Neuroplasticity TMS to measure neuroplasticity TMS approaches to induce neuroplasticity How is TMS useful Problems The future

3 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

4 Investigating motor cortical (M1) plasticity with transcranial magnetic stimulation (TMS) TMS Motor evoked potential (MEP) Muscle TMS 25ms

5 Non-invasive brain stimulation (NBS) Repetitive transcranial magnetic stimulation (rtms) Paired associative stimulation (PAS) Transcranial direct current stimulation (tdcs) Repetitive trains of TMS Freq/inten/dur dependent effects Applied over periods of sec to many minutes (15) Effects last min Paired TMS + contralateral peripheral nerve stimuli Approx 200 pairs of stimuli every sec TMS - nerve stimuli ISI determines effect (25 ms excitability, 10 ms excitability, form of STDP) Effects last min DC stimulation applied through pads placed on scalp Anodal stimulation excitability Cathodal stimulation excitability Applied 10 minutes Effects last min

6 Repetitive transcranial magnetic stimulation (rtms) Low frequency (<1 Hz) stimulation - cortical excitability High frequency (>5 Hz) stimulation - increases cortical excitability Newer techniques (TBS) apply short bursts of high frequency stimuli General characteristics of rtms protocols Huang et al., 2005

7 Available synaptic population 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 Consistent features: Rapidly induced Lasting but reversible Pathway specific NMDA receptor dependent Synaptic population Excitatory rtms (synaptic potentiation) Inhibitory rtms (synaptic weakening)

8 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

9 How is rtms useful therapeutic intervention? Excitatory Inhibitory Talelli et al., Clin Neurophysiol chronic stroke patients months post stroke itbs to stroke hemisphere improved SRT (vs sham)

10 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

11 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)

12 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

13 Preterm birth Early life experience/environment 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 weeks GA, n=10 Early preterm <32 weeks GA, n=11 Investigated with ctbs (inhibitory LTD-like paradigm).

14 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

15 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

16 Variability in NBS induced effects Sale et al., 2007 EBR Goldsworthy et al., 2012 in press Clin Neurophysiol Hamada et al., 2012 Cerebral Cort PAS 25 protocol 10 subjects 3 sessions separated by at least 1 week ctbs 12 subjects - single session ctbs / itbs 52 subjects two randomised sessions

17 Known influences on M1 plasticity Ridding & Ziemann 2010 J Physiol

18 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

19 Anatomical/physiological influences Inter-individual variability in networks activated by TMS modify neuroplastic response to NBS ctbs itbs Hamada et al., Cereb Cort 2012 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

20 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

21 Development of more effective stimulation paradigms Goldsworthy et al., Clin Neurophysiol 2012 Optimisation of induction paradigm characteristics (e.g. burst characteristics)

22 Development of more effective stimulation paradigms Goldsworthy et al., 2012 Eur J Neurosci Longer lasting effects More consistent Resistant to behavioural disruption Consistent with evidence from animal model

23 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

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