Functional connectivity: Diseases of connectivity

1. ISMRM Educational course – 10th of May 2014 Functional connectivity: Diseases of connectivity Gwenaëlle Douaud FMRIB, University of Oxford

2. Diseases of connectivity or disconnection? • Lesion/degeneration/synaptic malfunction  structural connectivity  functional connectivity (e.g., Cabral et al., 2012): • Abnormal functional connectivity in schizophrenia Alzheimer’s Parkinson’s chronic pain depression • Functional connectivity impairment  disconnection syndrome, where “damage to the connection results in deficit that is dinstinct both from damage to the target and source regions” (Kleinschmidt & Vuilleumier, 2013) Gerstmann syndrome: acalculia +finger agnosia +left-right disorientation +agraphia Rusconi et al., 2009 ISMRM Educational course – 10th of May 2014

3. Resting-state fMRI: advantages • Increased signal-to-noise ratio (Fox & Greicius, Review 2010): • - at best, task-related modulation explains 20% of BOLD variance • - spontaneous ongoing activity explains 50-80% of BOLD variance ISMRM Educational course – 10th of May 2014

4. Resting-state fMRI: advantages • Covers the entire repertoire of functional networks used by the brain in “action” • (Smith et al., 2009) RSN: 36 healthy subjects fMRI: ~7,300 maps, ~30,000 subjects ISMRM Educational course – 10th of May 2014

5. Resting-state fMRI: advantages • Allows for a broader sampling of patient populations  asleep, sedated, too impaired for task-based fMRI scanning, etc. Greicius et al., 2008 • Is not confounded by task performance, effort, practice effects, etc. ISMRM Educational course – 10th of May 2014

6. Resting-state fMRI: inconvenients • “Rest” is a task state in itself, with potential performance differences, rather than differences in the underlying, stable brain organisation (Buckner et al., 2008, 2013) • “Rest” is a task state in itself, with potential performance differences, rather than differences in the underlying, stable brain organisation (Buckner et al., 2008, 2013)  Might still reveal some meaningful differences, just need careful interpretation  Might still reveal some meaningful differences, just need careful interpretation • More susceptible to movement confounds: •  add motion parameters as covariate •  use ICA+FIX (automatic denoising using FSL tools: Salimi-Khorshidi et al., 2014, Griffanti et al., 2014) ISMRM Educational course – 10th of May 2014

7. Resting-state fMRI: inconvenients • Interpretation: • - no causality information (yet)  effective functional connectivity • - no easy interpretation what (a change in) + and – correlations mean Smith et al., 2013 ISMRM Educational course – 10th of May 2014

8. Resting-state fMRI in disease: reviews • Mild cognitive impairment/Alzheimer’s disease: • - Dennis & Thompson, 2014 • - Sheline & Raichle, 2013 • Movement disorders (esp. Parkinson’s disease): • - Poston & Eidelberg, 2012 • Psychiatric disorders (e.g., schizophrenia, ADHD, autism): • - Greicius, 2008 • - Posner et al., 2014 ISMRM Educational course – 10th of May 2014

9. Resting-state fMRI analysis: seed-based approach in Parkinson’s disease • Seed-based approach - a priori knowledge/hypothesis • Parkinson’s disease: Helmich et al., 2010 ISMRM Educational course – 10th of May 2014

10. Resting-state fMRI analysis: seed-based approach in Parkinson’s disease • Seed-based approach - a priori knowledge/hypothesis • Parkinson’s disease: Helmich et al., 2010 ISMRM Educational course – 10th of May 2014

11. Resting-state fMRI analysis: seed-based approach in Parkinson’s disease • Seed-based approach - a priori knowledge/hypothesis • Parkinson’s disease: Helmich et al., 2010  Functional compensation with anterior putamen “taking over” connections to IPC: increased connectivity between IPC and anterior putamen in Parkinson’s was larger for the least-affected side • Very careful study: • - negative control with DMN • - corrected for motion (higher in patients) • - checked for the effect of tremor: no tremor versus tremor spatial map, regressing out muscle activity (electromyography) • Very careful study: • - negative control with DMN • Very careful study: • - negative control with DMN • - corrected for motion (higher in patients) • - checked for the effect of tremor: no tremor versus tremor spatial map, regressing out muscle activity (electromyography) • - checked effect of medication • - checked for grey matter volume differences of seeds and whole-brain VBM • Very careful study: • - negative control with DMN • - corrected for motion (higher in patients) • - checked for the effect of tremor: no tremor versus tremor spatial map, regressing out muscle activity (electromyography) • - checked effect of medication ISMRM Educational course – 10th of May 2014

12. Resting-state fMRI analysis: ICA-based approach in Alzheimer’s disease • ICA-based approach – more exploratory (though can also be hypothesis-driven) • Alzheimer’s disease: Zamboni et al., 2013 Dual regression for group comparisons ISMRM Educational course – 10th of May 2014

13. Resting-state fMRI analysis: ICA-based approach in Alzheimer’s disease • ICA-based approach – more exploratory (though can also be hypothesis-driven) • Alzheimer’s disease: Zamboni et al., 2013 ISMRM Educational course – 10th of May 2014

14. Resting-state fMRI analysis: ICA-based approach in Alzheimer’s disease • ICA-based approach – more exploratory (though can also be hypothesis-driven) • Alzheimer’s disease: Zamboni et al., 2013 • Resting-state fMRI less confounds, task fMRI more interpretable: • “Increased frontal activity during a memory task overlaps with increased frontal connectivity during rest in AD patients, suggesting that residual cognitive ability can be assessed using resting fMRI.” • Very careful study: • - same number of healthy and AD participants for ICA • - negative control with auditory RSN • - corrected for GM volume • - checked for the effect of physiological fluctuations (respiratory + cardiac activity) ISMRM Educational course – 10th of May 2014

15. Resting-state fMRI analysis: Graph-based approach in schizophrenia • Graph theory – exploratory (though mostly no basal ganglia or cerebellum) • Schizophrenia: van den Heuvel et al., 2013 ISMRM Educational course – 10th of May 2014

16. Resting-state fMRI analysis: Graph-based approach in schizophrenia • Graph theory – exploratory (though mostly no basal ganglia or cerebellum) • Schizophrenia: van den Heuvel et al., 2013  “Reduced level of rich club interconnectivity in patients with schizophrenia (…), potentially resulting in decreased global communication capacity and altered functional brain dynamics” • Careful study: • - includes basal ganglia • - used Freesurfer parcellation for ROIs (as opposed to AAL) • - replication dataset  effects not specific to Rich Club • - but: “This study did not reveal a clear association between clinical metrics of patients and rich club organization” • Careful study: • - includes basal ganglia • - used Freesurfer parcellation for ROIs (as opposed to AAL) ISMRM Educational course – 10th of May 2014

17. Resting-state fMRI analysis: Multi-modal approach in motor neuron disease • Combining information – diffusion tensor and tractography • Amyotrophic lateral sclerosis: Douaud, Filippini et al., 2011 Increase FC in ALS ISMRM Educational course – 10th of May 2014

18. Resting-state fMRI analysis: Multi-modal approach in motor neuron disease • Combining information – diffusion tensor and tractography • Amyotrophic lateral sclerosis: Douaud, Filippini et al., 2011 • Careful registration (BBR + VBM) Disease duration ISMRM Educational course – 10th of May 2014

19. Resting-state fMRI analysis: Multi-modal approach in motor neuron disease • Combining information – diffusion tensor and tractography • Amyotrophic lateral sclerosis: Douaud, Filippini et al., 2011 • Higher functional connectivity not necessarily better • Reconciling lower structural connectivity (SC) with higher functional connectivity? corpus callosum GABAergic interneurons Innocenti, 2009 ISMRM Educational course – 10th of May 2014

20. Resting-state fMRI analysis: Multi-modal approach in motor neuron disease • Combining information – diffusion tensor and tractography • Amyotrophic lateral sclerosis: Douaud, Filippini et al., 2011 • Low SC + high FC in ALS • = loss of GABA interneurons + FC - GABA ISMRM Educational course – 10th of May 2014

21. Resting-state fMRI analysis: Multi-modal approach in neurodegenerative diseases • Combining information – grey matter volume/structural covariance • Array of neurodegenerative disorders: Seeley et al., 2009 ISMRM Educational course – 10th of May 2014

22. Resting-state fMRI analysis: Multi-modal approach in neurodegenerative diseases • Combining information – grey matter volume/structural covariance • Array of neurodegenerative disorders: Seeley et al., 2009 • Dissociable networks for each disease ISMRM Educational course – 10th of May 2014

23. Variability of results in fcMRI Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

24. Variability of results in fcMRI: some guidelines Parkinson’s: Seeds in the striatum DMN as negative control Alzheimer’s: RSN (ICA) involving frontal areas auditory RSN as negative control Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

25. Variability of results in fcMRI: some guidelines + careful registration Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

26. Variability of results in fcMRI: some guidelines + careful registration Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

27. Variability of results in fcMRI: movement • “Scrub” the data, add motion parameters, or use ICA+FIX Power et al., 2012 ISMRM Educational course – 10th of May 2014

28. Variability of results in fcMRI: movement • “Scrub” the data, add motion parameters, or use ICA+FIX Salimi-Khorshidi et al., 2014 Griffanti et al., 2014 ISMRM Educational course – 10th of May 2014

29. Variability of results in fcMRI: some guidelines • Global signal regression, # of ICs etc. Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

30. Variability of results in fcMRI: some guidelines Fox & Greicius, 2010 ISMRM Educational course – 10th of May 2014

31. Variability of results in fcMRI: stability of networks • Inter-subject variability is higher in higher-order regions (Mueller et al., 2013) ISMRM Educational course – 10th of May 2014

32. Interpretation of functional connectivity results • Some RSN are more stable than others • Higher not necessarily better • Always check for each contrast what happens in each cluster  Absolute values of correlations matter ISMRM Educational course – 10th of May 2014

33. Interpretation of functional connectivity results • Some RSN are more stable than others • Higher not necessarily better • Always check for each contrast what happens in each cluster  It’s the absolute values of correlations that matter • Bear in mind that change in correlations can be observed even in the absence of a change in coupling (Friston, 2011)  Changes in correlation between A and B could be caused by a change in correlation elsewhere  Changes in correlation could be caused by a change in SNR (e.g., heart rate variability differs between two populations)  Changes in correlation could be caused by a change in the amplitude of the fluctuations • Bear in mind that “resting” is to some extent also a task ISMRM Educational course – 10th of May 2014

34. Special thanks to: FMRIB, University of Oxford - Steve Smith • Eugene Duff • Christian Beckmann • Reza Salimi-Khorshidi • Martin Turner • Giovanna Zamboni • Nicola Filippini • Marina Charquero Ballester THANK YOU FOR YOUR ATTENTION ISMRM Educational course – 10th of May 2014