Reproducibility is necessary but insufficient for addressing brain science issues.

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1 1

2 Reproducibility is necessary but insufficient for addressing brain science issues. GLM promises nothing but the higher amplitude of the experimental trials on the average compared with the control trials. 2

3 Outline 1. Two methods of processing fmri data: GLM and ICC. 2. Analysis of two experimental datasets: Verbal working memory task, and resting-state with eyes-closed and -open. 3. Suprathreshold voxels in the GLM and ICC maps: The dorsal striatum and fusiform gyrus. 4. Functional MRI in the future. 3

4 1. General Linear Models (GLM) SPM, FSL, AFNI Within-Subject GLM, Between-Subject GLM 2. Intraclass Correlation Coefficients (ICC) (ICC(C,M) in McGraw & Wong, 1996) Within-Subject ICC, Between-Subject ICC 4

5 GLM yy ii : pre-processed BOLD time series in a given voxel for the ith subject. yy ii = Xββ ii + ee ii X: is the design matrix. ββ ii : the vector of regression parameters. Var(ββ ii ) = σσ ii 22 (XX XX) 11. σσ ii 22 : the residual variance associated with ee ii. 5

6 Within-Subject tt GGGGGG tt GGGGGG = NN ii ωω ii ββ ii and NN ii ωω ii = 1 ωω ii = 11 VVVVVV(ββ ii ) NN ii 11 VVVVVV(ββ ii ) 11 = ωωii + o(1) Var(tt GGGGGG ) = NN ii 11 VVVVVV(ββ ii ) 11 tt + GGGGGG = tt GGGGGG Var(tt GGGGGG ) 6

7 Between-Subject GLM?? 7

8 Between-Subject Reproducibility Between-Center Reproducibility Within-Subject Reproducibility 8

9 Notations (in each voxel): 1 n 1 n Replicate 1 Replicate M n: The length of the time course. M: Experimental replicates, subjects, centers etc. 9

10 ICC Σ: the variance covariance matrix (VCM) of yy jj for j = 1,, M in a single voxel ICC = MM MM ( σσ jj 22 MM jj=11 ) /σσ XX 22, σσ jj 22 : the jth element in the diagonal of Σ. σσ XX 22 : the sum of all elements in Σ. 10

11 < IIIIII 1 The conventional F-test may not work well especially for neuroimaging applications. McGraw & Wong (1996) Psychological Methods 11

12 Let the sample S have its population counterpart Σ and finite forth moments. As the number of scan volumes n within each replicate, it is known that nn(vechs vechσ) is asymptotically distributed according to the M(M+1)/2 dimensional Gaussian distribution with mean 0 and the following VCM. nn vechss vechσσ N 0, 2K M (ΣΣ ΣΣ)K M vechσσ = K M (vecσσ) 12

13 The sample IIIIII is a scalar-valued function of S, which is continuous with derivatives of the first and second order in a neighborhood of S ΣΣ. Their asymptotic distributions can be expressed as follows: nn ICC ICC N(00, 22ηη KK MM (ΣΣ ΣΣ)KK MM ηη) ηη = ICC/ vech Σ, and G M (vechσσ) = vecσσ 13

14 Between-Subject ICC tt IIIIII = IIIIII VVVVVV(IIIIII ) 14

15 Within-Subject ICC IIIIII + = NN ωω ii IIIIII ii ii and NN ii ωω ii = 1 ωω ii = 11 VVVVVV(IIIIII ii ) NN ii 11 VVVVVV(IIIIII ii ) 11 = ωωii + o(1) Var(IIIIII + ) = NN ii 11 VVVVVV(IIIIII ii ) 11 tt IIIIII + = IIIIII + Var(IIIIII + ) 15

16 Verbal Working Memory Task (A Modified Sternberg Verbal Working Memory Task) 27.5sec Run 1 L L H L H L H L H L H L H L H 8 Cycles (16 blocks) Run 2 16

17 Low Load Trial: 750ms 5550ms 2000ms # # Q # # # + q 50ms High Load Trial: S W T C D L + c Encoding Maintenance Retrieval Response 4750ms 5550ms 2000ms 700ms 17

18 Subjects: 15 healthy controls (7 males; age ± 8.382) 15 schizophrenic patients (7 males; age ± 8.379). Reaction Time: Controls: ± ms Patients: ± ms Accuracy: Controls: 0.95 ± Patients: ±

19 The two runs had different stimulus sets, and the order of the execution of the two runs was counterbalanced across subjects. Subjects were administered the task within a Siemens Trio 3T MRI scanner with 32 channels. EPI scans were performed with parameters TR/TE = 2500 ms/24 ms, flip angle = 90, 43 slices, 3.5 mm thick with no gap interleaved with 191 volumes per run. 19

20 fmri Experiment: No. of subjects: 30 (15 Males; Age 22.50±3.462 ). Task: 4-min Eyes-closed followed by 4-min Eyes-open. Siemens Skyra scanner and a standard 20-channel coil. fmri parameters: T2* (EPI): TR/TE 2000ms/30.0 ms; flip angle 84 deg; 35 slices; thickness 3.4mm; FOV 192mm. T1 (anatomical images): TR/TE ms/3.30ms; flip angle=7 deg; 192 slices; FOV 256 mm. 20

21 Caudate + Putamen Dorsal Striatum Lim et al., (2014) Frontiers in Neuroscience. doi: /fnins

22 SNc: substantia nigra pars compacta; SNr: substantia nigra pars reticulata; Gpi: globus pallidus (internal portion). 22

23 Karl Zilles OHBM,

24 15 Controls Verbal Working Memory Task 24

25 15 Controls Verbal Working Memory Task 25

26 15 Patients Verbal Working Memory Task 26

27 15 Patients Verbal Working Memory Task 27

28 30 Controls Resting (4min eyes-closed and 4min eyes-open) 28

29 30 Controls Resting (4min eyes-closed and 4min eyes-open) 29

30 Gomez et al. (Jan 2017). Microstructural proliferation in human cortex is coupled with the development of face processing. Science 355, p FG3 22 children (Age 5-12) 25 adults (Age 22-28) Shorter T1 relaxation time in FG2, but not in FG3 in adults. FG2 Fusiform gyrus; Occipital temporal sulcus; Collateral sulcus; Middle fusiform sulcus 30

31 Overlap of the fusiform gyrus between LONI and Jübrain templates LONI: fusiform gyrus Overlap/(LONI U Jübrain) Overlap/LONI Overlap/ Jübrain Label of Jübrain Label of Jübrain Label of Jübrain 'Area FG3' 0.17 'Area FG3' 0.18 'Area FG3' 0.74 'Area FG4' 0.14 'Area FG4' 0.16 'Area FG1' 0.60 'Area hoc4v [V4(v)]' 0.08 'Area hoc4v [V4(v)]' 0.10 'Area FG4' 0.48 'Area FG1' 0.07 'Area FG2' 0.07 'Area FG2' 0.37 'Area FG2' 0.06 'Area FG1' 0.07 'Area hoc4v [V4(v)]' 0.32 'Entorhinal Cortex' 0.02 'Entorhinal Cortex' 0.02 'Entorhinal Cortex' 0.14 'Area hoc3v [V3v]' 0.01 'Area hoc3v [V3v]' 0.01 'Area hoc3v [V3v]' 0.03 'Lobule VI (Hem)' 0.00 'Lobule VI (Hem)' 0.01 'Subiculum' 0.02 'Lobule V (Hem)' 0.00 'Lobule V (Hem)' 0.00 'Lobule V (Hem)' 0.01 'Area hoc4la' 0.00 'Area hoc4la' 0.00 'Lobule VI (Hem)' 0.01 By Dr. Po-Chih Kuo (Bruce) 2016/10/25 31

32 15 Controls Verbal Working Memory Task 32

33 15 Controls Verbal Working Memory Task 33

34 15 Patients Verbal Working Memory Task 34

35 15 Patients Verbal Working Memory Task 35

36 30 Controls Resting (4min eyes-closed and 4min eyes-open) 36

37 30 Controls Resting (4min eyes-closed and 4min eyes-open) 37

38 Eklund et al., 2015: Empirically investigating the statistical validity of SPM, FSL and AFNI for single subject fmri analysis. Eklund et al., 2016: Cluster failure: Why fmri inferences for spatial extent have inflated false-positive rates. Slotnick, 2017: Resting-state fmri data reflects default network activity rather than null data: A defense of commonly employed methods to correct for multiple comparisons. Kessler et al., 2016: Which findings from the functional neuroimaging literature can we trust? Nichols et al., 2017: A defense of using resting state fmri as null data for estimating false positive rates. 38

39 Functional MRI in the future: 1. Fast (TR = 0.5sec) and high resolution (1x1x1mm) imaging sequences accompanied by real experimental applications. 2. Auditory experiments in clinical and cognitive neuroscience. 3. Beyond GLM, there is rich information in BOLD signal; some information could be scientific sound. 4. For fmri studies, the JüBrain template is more accurate than other templates. 39

40 Functional MRI in the future: 5. It is essential to integrate molecular biology into a fmri center. 6. Functional differentiation between brain areas can be more substantial during the transition between two mental states (e.g., between eyes-closed and -open). It is also interesting to design real-life tasks which can be executed under various mental states. 40

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42 程爾觀 Alexander Savostyanov Matsuo Kayako Alexander Zhigalov (ISS, AS) (SBRAS, Russia) (DMU, Tochigi, Japan) (UH, Helsinki, Finland) 李俊德 孫玉峰 章珅鎝 簡士承 (MBA, NCCU) Cloudeep Innovation, Inc. (ISS, AS) (MPI, Leipzig, Germany) 42