Future Tools for Diagnosis and Monitoring of Mild TBI

1. Future Tools for Diagnosis and Monitoring of mild TBI Maheen M. Adamson, PhD Director of Clinical Neuroscience,War Related Illness and Injury Study Center (WRIISC) VA Palo Alto Health Care System Clinical Assistant Professor (Affiliated) of Psychiatry and Behavioral Sciences Stanford University School of Medicine, CA

2. Disclaimer The views expressed in this presentation are those of the authors and DO NOT reflect the official policy of the Department of Veterans Affairs or the United States Government

3. Outline • Task-related Functional MRI • Resting State Functional MRI • Functional Connectivity – why is it important? • Combining neuroimaging methods • Promising future avenues for mTBI research

4. Why Functional MRI Common things heard in hallways: • fMRI is not clinical • Analysis takes a long time and is very confusing • Statistical significance = red/blue blobs? • Any task will show activation – what difference does it make?

5. MRI vs. fMRI MRI studies brain anatomy Functional MRI (fMRI)studies brain function

6. The meaning of CONTRAST An example using PET - = Stimulation Control/baseline Difference fMRI measures Blood Oxygenation Level Dependent (BOLD) signal indirect measure of neural activity. Neural activity Blood oxygen fMRI signal

8. Developing fMRI literature on TBI • Task-induced changes that differentiate clinical and healthy samples during cognitive, motor and sensory tasks. • Working memory deficits after TBI: universal observation of increased involvement of the regions critical for WM, including prefrontal cortex (PFC) and anterior cingulate cortex (ACC) and occasionally parietal regions in TBI (Christodoulou et al., 2001; Hillary et al., 2010, 2011; McAllister et al., 1999, 2001; Medaglia et al., 2011; Newsome et al., 2007; Scheibel et al., 2007).

9. Working Memory in mTBI McAllister et al., 2001

10. Longitudinal fMRI in Severe TBI • Increased activation observed after 6-month evolution in TBI patients during the 3-back condition. • The most striking changes were seen in the bilateral prefrontal cortex, with left hemisphere predominance. • The second region that showed statistical significant changes was the bilateral parietal posterior region. • Both regions are involved in working memory processes. Statistical Parametric Maps with left as left. Sanchez-Carrion et al., 2008

11. Functional Brain changes with recovery of TBI • A recent study represents the first effort in systems neuroscience to examine how practice of a cognitive task influences BOLD signal change after neurological compromise (Medaglia et al., 2011). • The goal of this study was to induce plasticity in PFC via task practice using a well-established working memory task in individuals with TBI to test that right PFC recruitment represents a latent support system.

12. N = 1 back task N = 2 back task Right BA 46 (DLPFC) Regions of interest show reduced activation following practice, including the anterior cingulate and right prefrontal cortices. Neural recruitment in brain injury does not represent reorganization but a natural extension of latent mechanisms that engage transiently and are contingent upon cerebral challenge

13. What About Intrinsic Differences In Brain Activity Irrespective Of Task?

14. Conventional MRI and resting-state fMRI correlation analysis in a 21-year-old with verbal memory deficits following severe TBI • Conventional MRI (FLAIR) revealed bilateral superior frontal lesions but no abnormalities that would explain the patient’s verbal memory deficit (left to right: transverse slices at the level of hippocampus, thalamus, fornix, cingulum). • Volumetric MRI showed 18% loss of left hippocampus. • DTI revealed subtle abnormalities in the left and right cingulum bundles as well as left and right fornices. Relative anisotropy in the cingulum and fornix were lower than the mean of 10 control subjects matched in age, gender, and handedness. Relative anisotropy was not more than 2 SD below the mean in any of the regions - cannot be considered definitively abnormal. MacDonald et al., 2008

15. Resting State fMRI • Resting state fMRI correlation analysis clearly demonstrates disruption of the normal connectivity of the left hippocampal network • Analysis revealed that the BOLD fluctuations in the left hippocampus correlated poorly with those in several other structures implicated in memory including anterior thalamus and the ventral anterior cingulate cortex (vACC) • In contrast, the fluctuations in the right hippocampus were normally correlated with those in these structures. No such left-right asymmetry in the hippocampal-anterior thalamic and hippocampal-vACC correlations was seen in 10 age-matched controls. MacDonald et al., 2008

16. What Is This ‘RESTING STATE” Business? • Why do a Resting State FMRI? • INTRINSIC CONNECTIVITY NETWORK (ICN) is another way to refer to Resting State. • Functional connectivity (FC): is the correspondence over time (co-activation) between spatially distinct neurophysiological events without implying directionality • May be observed from the spontaneous activity of the resting brain.

17. What Does the Data Look Like? • Synchronous low frequency fluctuations (LFF) signals within blood oxygen level-dependent fMRI data can be useful for investigating the functional connections of brain cortices. • Brain cortices are characterized by LFF frequencies less than 0.1 Hz, distinct from respiratory and cardiac effects, with a frequency spectrum ranging from 0.1 to 0.5 Hz and 0.6 to 0.12 Hz, respectively.

18. Methods of Analysis • Seed Analysis • Connectivity between the seed of right hippocampus and a set of regions was disrupted in the early stage of Alzheimer’s Disease (AD), whereas the seed of left hippocampus showed increased connectivity with some other regions (Wang et al. 2006) • Independent Component Analysis (ICA) • In mild AD, FC is deficient between the PCC and left hippocampus or other regions within default (Greicius et al., 2004)

19. Most Common Networks • Default Mode Network • Significant resting-state coactivation of Posterior Cingulate Cortex (PCC), bilateral inferior parietal cortex, left inferolateral temporal cortex, & ventral anterior cingulate cortex. Abnormal changes in Alzheimer’s (Li et al., 2002) • Salience Network • Anterior cingulate cortex and fronto-insula, amygdala and striatum –disrupted in behavioral variant frontotemporal dementia.

20. How Many Networks?

21. Terms used • The synchrony of LFF implies that within neural networks, the nodes function together • Task “on” vs. Task “off” and brain at rest. • “Co-activation” of task “on” regions with task “off” regions: Those regions activated during task “on” period (e.g., visuo-spatial task) are deactivated when the task is “off” (e.g., fixation) –Goal Directed networks • Inward or self-reflected network – resting state or ICN

22. Task-on and Task-off • It is not that these networks are reciprocal so that at moments where goal-directed behavior is necessary, the “inward” or self-reflective default mode network remits, giving way to neural activity relevant to task. • Default mode activity plays a role in task and the magnitude of deactivation in default mode regions contribute to task performance (Cole et al., 2010; Hampson et al., 2010)

23. Changes in Resting Connectivity During Recovery in TBI Hillary et al., 2011

24. Change in Connectivity in TBI

25. FA/ICN Combined for mTBI Investigations • DTI/FA values (seed regions). • fMRI resting state, network analysis Mayer et al., 2011 What the future holds?

26. Real-world Performance http://www.huffingtonpost.com/2008/12/01/army-bases-brace-for-surg_n_147360.html

27. Brain Function During Real-world Performance

28. Thank you! Questions?