A beginner’s guide to using magnetic brain relevance to neurorehabilitation

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A beginner’s guide to using magnetic brain stimulation to study neuroplasticity and its relevance to neurorehabilitation Michael C Ridding NHMRC Senior…

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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 Paired associative Transcranial direct current magnetic stimulation (rTMS) stimulation (PAS) stimulation (tDCS)  Repetitive trains of TMS  Paired TMS + contralateral  DC stimulation applied peripheral nerve stimuli through pads placed on  Freq/inten/dur dependent scalp effects  Approx 200 pairs of stimuli every 10-20 sec  Anodal stimulation   Applied over periods of excitability 30-40 sec to many  TMS - nerve stimuli ISI minutes (15) determines effect (25 ms   Cathodal stimulation  excitability, 10 ms  excitability  Effects last 30-60 min excitability, form of STDP)  Applied ≈10 minutes  Effects 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 - increases cortical excitability  Newer techniques (TBS) apply short bursts of high frequency stimuli 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 Consistent features: ã Rapidly induced Available synaptic ã Lasting but reversible population Excitatory rTMS ã Pathway specific (synaptic potentiation) ã NMDA receptor dependent Synaptic Inhibitory rTMS population (synaptic weakening) How is rTMS useful – therapeutic intervention? Stroke Depression (Ridding & Rothwell 2007 Nat Rev Neurosci) Excitatory rTMS to Inhibitory rTMS to Excitatory rTMS to Inhibitory rTMS to hypoactive, lesioned hyperactive, non- hypoactive left hyperactive left motor cortex lesioned motor cortex prefrontal cortex prefrontal cortex How is rTMS useful – therapeutic intervention? Excitatory Inhibitory Talelli et al., Clin Neurophysiol 2007 ã 6 chronic stroke patients 12 -108 months post stroke ã iTBS to stroke hemisphere improved SRT (vs sham) ã 54 patients with ischaemic/haemorrhagic stroke ã 3-12 months post first ever stroke ã 4 groups (n=13-16) ã A= contra 1Hz + ipsi iTBS ã B= contra sham 1 Hz + ipsi iTBS ã C= contra 1 Hz + sham ipsi iTBS ã D = sham contra 1 Hz + sham ipsi iTBS ã 20 daily sessions (10 x 2 interventions) ã Wolf Motor Function Test /Fugl Meyer/SRT/finger flexor MRC/tapping But! ã 41 stroke patients randomised to receive iTBS/cTBS/sham ã At least 1 year post stroke ã TBS followed by therapy for 10 working days ã Assessed at 4,30, 90 days post intervention ã 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? ã Investigate mechanisms of human neuroplasticity ã Characterise neuroplasticity in conditions where changes in it might underpin behavioural abnormalities (neurodevelopmental influence) ã Use as a marker for early detection of neurodegeneration (AD)? ã Characterise time-course of neuroplastic change to optimise treatment/interventions ã Assess impact of interventions on neuroplasticity Early life experience/environment Preterm birth ã Effects on cortical microstructure ã 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 ã Preterm birth associated with impaired neuroplasticity into adolescence ã May underpin abnormalities in cognition and motor skills ã Impact of early life environment likely to be important Problems and challenges for rTMS! ã Mechanisms responsible poorly understood (time-course /reversibility) ã Effects on behaviour generally small and transient ã High variability ã “Transferability” (M1 to other regions) ã Study size Variability in NBS induced effects Sale et al., 2007 EBR Goldsworthy et al., 2012 in press Clin Hamada et al., 2012 Cerebral Cort Neurophysiol  PAS25 protocol  cTBS  cTBS / iTBS  10 subjects 3 sessions  12 subjects - single session  52 subjects – two randomised separated by at least 1 week 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 ã Development of better stimulation paradigms – Effects more closely resemble those seen in animal models – Will provide more opportunities for therapeutic intervention ã Better targeting ã Alternative methods for “measuring” neuroplasticity (TMS-EEG) ã Greater understanding between neurophysiology and function ã 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 Goldsworthy et al., 2012 Eur J Neurosci  More consistent  Resistant to behavioural disruption  Consistent with evidence from animal model 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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