Is therapy a realistic option at the present time? Felipe Fregni LEASE DO NOT COPY. Spauding Neuromodulation Center Harvard Medical School

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1 Is therapy a realistic option at the present time? Felipe Fregni Spauding Neuromodulation Center Harvard Medical School

2 Arguments supporting therapeutic use of tdcs Questions to be answered: Is there a biological rationale supporting the therapeutic effect of tdcs? Is safety data convincing for clinical application? Is efficacy data convincing?

3 Some Scenarios: Should tdcs be used clinically? Biological Rationale Scenario 1 Scenario 2 Scenario 3 Scenario 4 Safety Efficacy Outcome YES Maybe No (unless risk/benefi t ratio is greater) Maybe

4 Additional challenges Development of a new drug: Established clinical trial phases: phase I, II, III and IV Medical Devices: Exploratory provide information about safety and improvement of device s design/parameters. Similar to phase I and II studies (but not as linear) Pivotal safety and effectiveness Similar to phase III studies (but usually smaller sizes)

5 - Stroke Rehabilitation (motor; language) - Chronic Neuropathic Pain - Epilepsy - Parkinson s Disease - Migraine Potential Clinical Applications

6 Clinical Application: stroke One of the first tested clinical applications of tdcs (after 2000) first small trial published in 2005 Motor recovery first tested application Language recovery followed

7 - tdcs has been shown to induce neuroplasticity in animal and human models - Recovery after stroke is associated with potential to induce neuroplasticity in damaged circuits - tdcs has been shown to enhance the effects of behavioral training; thus inducing guided plasticity FIRST ITEM: Biological Rationale

8 Safety Data Animal studies have shown safety for potential citotoxicity using current parameters of stimulation Human studies (in stroke, healthy and other clinical conditions) have not demonstrated detrimental effects SECOND ITEM:

9 Efficacy data There are no pivotal trials for stroke Efficacy data comes from combined data Systematic methods of combining data

10 Evidence-based review Similar methods of recent evidence-based review (Lefaucheur et al, 2014) Classification of studies: class I to IV; based on this, classify in levels: A: Definitive effective B: Probably effective C: Possibly effective

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12 THIRD ITEM: Efficacy

13 So Is therapy a realistic option at the present time? Biological Rationale Scenario 1 Scenario 2 Scenario 3 Scenario 4 Safety Efficacy Outcome YES Maybe No (unless risk/benefi t ratio is greater) Stroke Neuropathic Pain Maybe Other Neurological applications?

14 Additional Support There are a lack of alternative therapies with strong evidence Other therapies associated with adverse effects tdcs enhances the effects of therapy (does not act independently) = synergistic effect

15 Clinical Decision is multifactorial and dynamic further data may strengthen or weaken clinical application of TDCS Art of Medicine: Combining scientific and clinical data

16 However, we discussed the three checks Safety Efficacy Biological Rational However.How to assess evidence in these papers a study showing efficacy or safety may be biased!

17 What is evidence based medicine?

18 Evidence Based Medicine More than just reading papers 'The conscientious, explicit and judicious use of best evidence in making decisions about the care of individual patients'

19 Crisis in EBM? Pace of research has increased significantly Clinicians are becoming busier Enough time and training to assess information accurately?

20 What happens when EBM is ignored?

21 How to assess evidence? Reading literature critically But what to read?

22 Hierarchy of evidence

23 But study design is not enough Editor of BMJ: "only 1% os articles are free of methodological flaws" Problem persists in high impact journals

24 Looking at RCTs Strengths: Rigorous evaluation of a single variable Prospective design Potentially eradicates bias by comparing two otherwise groups Allows for meta-analyses

25 RCTs Weaknesses: Too few patients or two short Expensive - funded by companies or large grant agencies Surrogate endpoints Imperfect randomization and other sources of biases External validity

26 Cohort studies Important advantages: more ethical, increased external validity Disadvantages: increased risk of bias and confounding

27 Clinical truth Clinical trial Meta-analysis Guidelines Unknown Bias, confounding, conflict of interest Bias, confounding, conflict of interest Bias, confounding, conflict of interest

28 Given that data is not perfect, how to analyze critically tdcs results?.and how to design the next generation of tdcs studies?

29 Keep questioning and critically analyzing the literature. Be careful with biases as usually they are not detected easily. There is a great potential for neuromodulation techniques; however, we still need to learn a lot more

30 Thank you!