Research Articles, Systems/Circuits

A Virtual In Vivo Dissection and Analysis of Socioaffective Symptoms Related to Cerebellum-Midbrain Reward Circuitry in Humans

Linda J. Hoffman, Julia M. Foley, Josiah K. Leong, Holly Sullivan-Toole, Blake L. Elliott and Ingrid R. Olson
Journal of Neuroscience 9 October 2024, 44 (41) e1031242024; https://doi.org/10.1523/JNEUROSCI.1031-24.2024

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Visualization for a representative polysynaptic tractography originated in crus II of segment c1 of the cerebrocerebellum, overlaid on a T1-weighted image. The number 1 indicates where the node-wise segmentation originated, while 100 represents where the segmentation ended. The boundaries of each quarter are indicated by white lines on the sagittal view of the tract, and the color coding corresponding to each quarter is summarized in the color bar at the bottom of the figure. In cases of monosynaptic tractographies that were also split into quarters, this segmentation involves the equal quarterization of Q3 and Q4 visualized above, although they are not visualized in the current figure. That is, the monosynaptic quarters correspond to Q3–4 in the current illustration.

  • Figure 2.
    Figure 2.

    Tractography results showing connections between the cerebellar cortex in a representative subject, deep cerebellar nuclei, and VTA overlaid on the FA image. A, Right hemisphere ipsilaterally traveling polysynaptic tracts are shown for sagittal segments (a, b, and c1–c4) within each cerebellar lobule. B, Anatomical regions of interest (ROIs) include the three deep cerebellar nuclei (fastigial, interposed, and dentate) and the VTA. Tractography results of the monosynaptic tracts between the deep cerebellar nuclei and VTA, color-coded by the nuclei from which they were seeded.

  • Figure 3.
    Figure 3.

    Illustrations of the main effect and interaction effect statistics with controls are not illustrated in Figure 4. A, The statistical results of the main effects under study when controlling for average tract length. B, The statical results of the segment by lobule interactions when controlling for average tract length (B.1.) and waypoint volume (B.2.). Note that the flat maps on the left in B contain pattern-coded highlights of which lobule contained the greatest streamline density within each segment when taking into account different controls. Note that for the flat map in B.1., lobule VI and crus I are highlighted, as they both contained more connectivity than crus II, but did not differ from each other. Moreover, as in Figure 2C, no difference was found between crus I and II in segment c4, and so it remains both unhighlighted in the flap map and unrepresented in the violin plots.

  • Figure 4.
    Figure 4.

    A summary of statistical results investigating gross pairwise comparisons. These are reported for both the polysynaptic (A) and monosynaptic (B) reconstructions. Each result is illustrated twice: on the left are the results using raw streamlines, and on the right are the streamline results when controlling for waypoint volume in voxels. Note that all plots are violin plots wherein dots outside the inner boxplot represent outliers. The results for the lobule-by-segment interactions are illustrated by cerebellar flat maps in section (C). The flat map on the left is meant to orient the viewer to the location of the cerebellar lobules and segments under study, while the flat map on the right has highlighted the lobule for each segment where streamline density was the highest. Note that segment c1 is highlighted in crus I and II as both lobules contained more streamlines in this segment than lobule VI without being statistically different from each other. Also, segment c4 contains no remaining highlights since the streamline count in crus I and II did not significantly differ from each other in this segment (this segment did not extend into lobule VI). How main effects and interactions change when controlling for tract length and waypoint volume are depicted in Figure 3. Note that R–R = tract originating in the right cerebellar and terminating in the ipsilateral VTA, L–L = tract originating in the left cerebellum and terminating in the ipsilateral VTA, R–L = tract originating in the right cerebellum and terminating in the contralateral VTA, and L–R = tract originating in the left cerebellum and terminating in the contralateral VTA. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01, ***p < 0.001.

  • Figure 5.
    Figure 5.

    Topographical organization of cerebellum-VTA connectivity overlaid on FA image. A, Medial segments of each cerebellar lobule have the highest connectivity with the VTA. B, Representative tractography reconstructions for the segment of each cerebellar lobule with the highest connectivity to the VTA. Note that the laterality and directionality of the tracts are not meaningful but show instances of decussation in the polysynaptic reconstructions. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01, ***p < 0.001.

  • Figure 6.
    Figure 6.

    Summary of correlations between subscales on the ASR and FA averaged across all 100 nodes of the right-to-right traveling polysynaptic tracts of highest streamline density. Note that the p-values reflected here are not controlled for multiple comparisons. Correlations between ASR scores and FA in monosynaptic tracts are illustrated in Figure 7. Note that in the scatterplots, the lines represent trendlines illustrating the slope of the relation, and the shaded area around each trend line represents confidence bands. Confidence bands visualize sampling error around each slope. Significance flags: ⌀p > 0.05, †p = 0.05, *p < 0.05, **p < 0.01.

  • Figure 7.
    Figure 7.

    The results between monosynaptic tractography FA for each deep cerebellar nucleus traveling right-to-right and ASR measures. Note that FA is averaged across all 100 nodes for each tract, and the p-values are not corrected for multiple comparisons. Significance flags: ⌀p > 0.05, *p < 0.05, **p < 0.01.

Tables

  • Table 1.

    Thresholds for ROIs

    Cerebellar cortex
    Crus ICrus IILobule VI
    HemisphereVermisHemisphereVermisHemisphereVermis
    Left25125202520
    Right
    Deep cerebellar nuclei
    Fastigial nucleusInterposed nucleusDentate nucleus
    Left52545
    Right

    • These threshold values were fed into fslmaths using the -thr argument in order to yield the final ROI masks. Note that “left” and “right” indicate how the thresholds were applied across each cerebellar hemisphere. In every case, the thresholding was performed symmetrically.

  • Table 2.

    ROI and tractography parameters

    Polysynaptic anchor and tractography parameters
    Crus I
    HemisphereSegment
    abc1c2c3c4
    Anc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/vox
    Left7952,0698701,8911,4371,1452,3377043,3974842,346701
    Right5023,2778981,8321,5221,0812,4496723,5104692,349700
    Crus II
    Segment
    abc1c2c3c4
    HemisphereAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/vox
    Left4074,0421,5311,0741,7579361,6899742,2187421,725954
    Right3295,0001,2871,2781,8209041,6929721,9078631,686976
    Lobule VI
    Segment
    abc1c2c3
    HemisphereAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/vox
    Left1,2621,3031,4451,1382,1807552,5896351,2211,347
    Right 9641,7061,4331,1482,0727942,4516711,0931,505
    Monosynaptic anchor and tractography parameters
    Deep cerebellar nuclei
    Fastigial nucleusInterposed nucleusDentate nucleus
    HemisphereAnc. VolSeeds/voxAnc. VolSeeds/voxAnc. VolSeeds/vox
    Left944,8402032,2413221,413
    Right915,0001992,2863181,431

    • The anchor volume for each seed region is reported in voxels. Seeds per voxel were calculated by dividing the anchor volume in voxels by 1,645,000 in the case of the polysynaptic tractography and by 455,000 in the case of the monosynaptic tractography. Anc, anchor; Vol, volume; vox, voxel.

  • Table 3.

    Anatomical main effects for poly- and monosynaptic tracts

    Measure 1Measure 2n 1n 2WppBonferroniEff. Size (r)95% CIMagnitude
    LowerUpper
    Polysynaptic tractography main effects
     Direction
      R–RL–L92805512.37 × 10−61.42 × 10−5****0.540.370.70Large
    R–L334.10 × 10−142.46 × 10−130.850.820.87
    L–R32
      L–LR–L80802,3182.58 × 10−91.55 × 10−8****0.710.570.81Large
    L–R325279.31 × 10−105.59 × 10−90.870.850.87
      R–L502.82 × 10−51.69 × 10−4***0.700.480.85
    Lobule
      Crus ICrus II49565080.3220.966ns0.160.0070.44Small
    Lobule VI433910.2190.6570.210.010.52
      Crus II563610.669>0.9990.070.0050.41
    Segment
      ab77831,851.51.00 × 10−31.50 × 10−2*0.390.180.58Moderate
    c1755624.00 × 10−35.60 × 10−2†0.370.120.60
    c262217.58.70 × 10−51.00 × 10−3**0.560.330.75Large
    c348271.83 × 10−82.74 × 10−7****0.800.660.87
    c45685.68 × 10−128.52 × 10−110.860.810.87
      bc183752,4431.93 × 10−92.90 × 10−80.700.560.82
    c2621,7017.49 × 10−101.12 × 10−80.800.710.86
    c3481,1257.11 × 10−141.07 × 10−120.870.850.87
    c4561,4312.46 × 10−103.69 × 10−90.870.870.87
      c1c275621,669.53.27 × 10−94.90 × 10−80.770.660.84
    c3481,1281.42 × 10−142.13 × 10−130.870.870.87
    c4561,4851.67 × 10−102.50 × 10−9
      c2c362489901.14 × 10−131.71 × 10−12
    c4561,1251.14 × 10−91.71 × 10−8
      c3489462.27 × 10−133.40 × 10−12
    Monosynaptic tractography main effects
    Direction
      R–RL–L1011004,1065.50 × 10−83.30 × 10−7****0.540.390.68Large
    R–L1015,0802.20 × 10−171.32 × 10−160.840.810.86
    L–R934,3715.66 × 10−173.40 × 10−160.870.870.87
      L–LR–L1001014,6068.46 × 10−135.08 × 10−120.720.610.80
    L–R934,3715.66 × 10−173.40 × 10−160.870.870.87
      R–L1014,0754.56 × 10−132.74 × 10−120.750.650.83
    Deep cerebellar nuclei
      FNIN97995505.02 × 10−111.51 × 10−10****0.670.550.77Large
    DN942,9341.30 × 10−23.90 × 10−2*0.260.050.46Small
      IN993,9431.67 × 10−115.01 × 10−11****0.700.570.81Large

    • Nonparametric pairwise comparisons using Wilcoxon signed-rank test investigating streamline count differences based on tract direction, lobule, segment, and deep nucleus. All confidence intervals were bootstrapped with 10,000 iterations. Success rates for all tractographies are reported in Table 3-1. Changes in results when controlling for tract length and waypoint volume are depicted in Tables 3-2 and 3-3. Directions are coded as follows: R–R, right to right (unilateral tract); L–L, left to left (unilateral tract); R–L, right to left (decussating tract); L–R, left to right (decussating tract). Note that in direction codes, the letter to the left of the hyphen represents the cerebellar hemisphere in which the tractography was seeded, while the letter right of the hyphen represents the VTA where it was terminated. Segments are coded as follows: a = vermis, b = paravermis; c1–c4 = neocerebellum, with higher numbers indicating more lateral segments. FN, fastigial nucleus; IN, interposed nucleus; DN, dentate nucleus. Further, n 1, the number of subjects included in the analyses for Measure 1, n 2, the number of subjects included in the analyses for Measure 2, and W, Wilcoxon test statistic. These subjects include those for whom nonzero “successful” reconstructions were achieved. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  • Table 4.

    Polysynaptic anatomical interactions

    Measure 1Measure 2n 1n 2WppbonferroniEff. Size (r)CI 95%Magnitude
    LowerUpper
    Direction × Lobule
     Crus I
      R–RL–L97873,1311.97 × 10−91.18 × 10−8****0.650.510.77Large
    R–L903,9531.49 × 10−158.94 × 10−150.850.810.86
    L–R521,3265.30 × 10−103.18 × 10−90.870.870.87
      L–LR–L87902,818.55.04 × 10−83.02 × 10−70.610.450.73
    L–R521,3255.63 × 10−103.38 × 10−90.870.860.87
      R–L90521,235.58.25 × 10−84.95 × 10−70.750.610.85
     Crus II
      R–RL–L99903,1815.14 × 10−63.08 × 10−5****0.480.300.64Moderate
    R–L883,8562.90 × 10−151.74 × 10−140.840.800.86Large
    L–R601,8291.76 × 10−111.06 × 10−100.870.860.87
      L–LR–L90883,019.51.12 × 10−96.72 × 10−90.670.550.78
    L–R601,8281.85 × 10−111.11 × 10−100.870.860.87
      R–L881,4511.02 × 10−76.12 × 10−70.710.550.83
     Lobule VI
      R–RL–L95862,581.53.85 × 10−42.00 × 10−3**0.390.190.57Moderate
    R–L883,8731.64 × 10−159.84 × 10−15****0.850.820.86Large
    L–R459901.14 × 10−136.84 × 10−130.870.870.87
      L–LR–L86883,1245.65 × 10−123.39 × 10−110.770.670.83
    L–R459892.27 × 10−131.36 × 10−120.870.860.87
      R–L888101.63 × 10−59.78 × 10−50.620.400.78
    Direction × segment
     a
      R–RL–L100973,695.55.87 × 10−73.52 × 10−6****0.510.340.66Large
    R–L984,6522.70 × 10−161.62 × 10−150.830.790.86
    L–R783,0022.61 × 10−141.57 × 10−130.870.870.87
      L–LR–L97983,4782.66 × 10−51.60 × 10−4***0.430.250.59Moderate
    L–R783,0801.78 × 10−141.07 × 10−13****0.870.870.87Large
      R–L982,701.57.46 × 10−94.48 × 10−80.650.510.78
     b
      R–RL–L1011003,637.51.32 × 10−47.92 × 10−4***0.380.200.55Moderate
    R–L984,7631.22 × 10−167.32 × 10−16****0.840.800.86Large
    L–R853,6551.19 × 10−157.14 × 10−150.870.870.87
      L–LR–L100984,235.52.27 × 10−111.36 × 10−100.680.560.77
    L–R98853,6531.28 × 10−157.68 × 10−150.870.860.87
      R–L3,144.52.01 × 10−101.21 × 10−90.700.570.80
     c1
      R–RL–L99943,3458.96 × 10−65.38 × 10−5****0.460.280.63Moderate
    R–L964,6156.51 × 10−173.91 × 10−160.850.830.87Large
    L–R762,9263.68 × 10−142.21 × 10−130.870.870.87
      L–LR–L94963,3793.62 × 10−72.17 × 10−60.530.370.66
    L–R96762,9253.83 × 10−142.30 × 10−130.870.870.87
      R–L2,5948.19 × 10−114.91 × 10−100.750.640.84
     c2
      R–RL–L99913,348.53.69 × 10−82.21 × 10−7****0.580.420.72Large
    R–L924,2363.25 × 10−161.95 × 10−150.850.820.87
    L–R642,0793.79 × 10−122.27 × 10−110.870.860.87
      L–LR–L91922,978.56.69 × 10−64.01 × 10−50.480.300.63Moderate
    L–R642,0774.16 × 10−122.50 × 10−110.870.860.87Large
      R–L921,8233.00 × 10−91.80 × 10−80.750.620.85
     c3
      R–RL–L98873,072.52.30 × 10−71.38 × 10−6****0.560.380.71Large
    R–L914,0595.89 × 10−163.53 × 10−150.850.830.87
    L–R501,2241.22 × 10−97.32 × 10−90.870.860.87
      L–LR–L87912,6944.52 × 10−62.71 × 10−50.510.330.66
    L–R501,2221.78 × 10−141.07 × 10−130.870.850.87
      R–L911,100.51.24 × 10−67.44 × 10−60.690.510.83
     c4
      R–RL–L97882,5809.84 × 10−46.00 × 10−3**0.360.160.54moderate
    R–L3,794.51.76 × 10−151.06 × 10−14****0.850.820.87large
    L–R591,7054.92 × 10−112.95 × 10−100.860.840.87
      L–LR–L88882,5459.23 × 10−65.54 × 10−50.500.310.65moderate
    L–R591,7672.86 × 10−111.72 × 10−100.870.860.87large
      R–L1,336.53.21 × 10−71.93 × 10−60.690.530.81
    Lobule × segment
     a
      Crus ICrus II8090491.54.97 × 10−71.49 × 10−6****0.570.400.73Large
    Lobule VI9098811.59 × 10−134.77 × 10−130.830.760.87
      Crus II483.55.21 × 10−101.56 × 10−90.660.520.77
     b
      Crus ICrus II91942,9941.64 × 10−54.92 × 10−5****0.460.280.61Moderate
    Lobule VI892,7445.98 × 10−51.79 × 10−4***0.440.240.61
      Crus II941,7496.02 × 10−1>0.999ns0.060.0040.26Small
     c1
      Crus ICrus II94892,294.56.80 × 10−22.05 × 10−1ns0.200.020.39Small
    Lobule VI772,482.51.32 × 10−73.96 × 10−7****0.610.430.75Large
      Crus II891,964.54.00 × 10−31.30 × 10−2*0.330.110.54Moderate
     c2
      Crus ICrus II83879633.00 × 10−38.00 × 10−3**0.340.130.53Moderate
    Lobule VI642,0165.29 × 10−121.59 × 10−11****0.870.870.87Large
      Crus II871,9528.15 × 10−122.45 × 10−110.870.860.87
     c3
      Crus ICrus II77775303.09 × 10−59.27 × 10−5****0.500.310.67Moderate
    Lobule VI501,1761.68 × 10−95.04 × 10−90.870.870.87Large
      Crus II1,2757.77 × 10−102.33 × 10−90.870.870.87
     c4
      Crus ICrus II64697100.475-ns0.100.0060.36Small

    • Nonparametric pairwise comparisons using the Wilcoxon signed-rank test investigating interactions between direction and lobule; direction and segment; and lobule and segment. All confidence intervals are bootstrapped using 10,000 iterations to yield stable estimates around the effect size. Changes in results when controlling for tract length and waypoint volume are depicted in Extended Data Tables 4-1 and 4-2, respectively. The orange area in the bottom panel overlaid on the tractography results represents the VTA. Note that R–R = tract originating in the right cerebellar and terminating in the ipsilateral VTA, L–L = tract originating in the left cerebellum and terminating in the ipsilateral VTA, R–L = tract originating in the right cerebellum and terminating in the contralateral VTA, and L–R = tract originating in the left cerebellum and terminating in the contralateral VTA. Further, n = 1 is the number of subjects included in the analyses for Measure 1, n = 2 is the number of subjects included in the analyses for Measure 2, and W represents the Wilcoxon test statistic. These subjects include those for whom nonzero “successful” reconstructions were achieved. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  • Table 5.

    Polysynaptic associations with microstructure and psychiatric symptoms

    SegmentLobuleSectionRho (ρ)p-valuep-value FDR95% CI: lower, upper
    Fractional anisotropy correlations: ASR anxiety and depression
     a:vermisVIAvg.0.280.004**0.016**(0.09, 0.46)
    Q10.230.023*
    Q20.240.017*
    Q30.240.014*
    Q40.090.362ns
     b:paravermisCrus IAvg.0.230.020*0.032*(0.03, 0.42)
    Q10.120.235ns
    Q20.210.034*
    Q30.230.020*
    Q40.090.391ns
     c1:cerebrocerebellumAvg.0.180.074†0.074†(−0.02, 0.37)
    Q10.050.647ns
    Q20.060.545ns
    Q30.200.044*
    Q40.090.379ns
    Crus IIAvg.0.220.024*0.032*(0.03, 0.40)
    Q10.230.022*
    Q20.110.260ns
    Q30.220.026*
    Q40.060.523ns
    Fractional anisotropy correlations: ASR internalizing symptoms
     a:vermisVIAvg.0.280.004**0.013*(0.08, 0.47)
    Q10.260.010*
    Q20.260.009**
    Q30.230.020*
    Q40.060.541ns
     b:paravermisCrus IAvg.0.260.010*0.013*(0.05, 0.44)
    Q10.190.058†
    Q20.240.018*
    Q30.240.014*
    Q40.070.462ns
     c1:cerebrocerebellumAvg.0.210.040*0.040*(0.01, 0.39)
    Q10.110.279ns
    Q20.120.247ns
    Q30.200.041*
    Q40.070.470ns
    Crus IIAvg.0.260.010*0.013*(0.06, 0.43)
    Q10.270.007*
    Q20.200.046*
    Q30.240.014*
    Q40.060.561ns
    Fractional anisotropy correlations: ASR social withdrawal
     a:vermisVIAvg.0.150.142ns0.142ns(−0.04, 0.33)
    Q10.250.011*
    Q20.150.137ns
    Q30.070.484ns
    Q4−0.020.819ns
     b:paravermisCrus IAvg.0.190.064†0.085†(−0.02, 0.38)
    Q10.270.007**
    Q20.210.040*
    Q30.160.120ns
    Q40.010.908ns
     c1:cerebrocerebellumAvg.0.200.041*0.082†(0.01, 0.39)
    Q10.200.046*
    Q20.170.085†
    Q30.170.091†
    Q40.040.663ns
    Crus IIAvg.0.230.019*0.076†(0.04, 0.41)
    Q10.210.032*
    Q20.300.003**
    Q30.210.033*
    Q40.030.737ns
    Fractional anisotropy correlations: ASR somaticizing symptoms
     a:vermisVIAvg.0.280.004**0.014*(0.08, 0.48)
    Q10.290.003**
    Q20.33<0.001***
    Q30.230.023*
    Q40.020.878ns
     b:paravermisCrus IAvg.0.270.007**0.014*(0.07, 0.45)
    Q10.220.027*
    Q20.260.010**
    Q30.240.016*
    Q40.030.805ns
     c1:cerebrocerebellumAvg.0.190.060†0.060†(−0.02, 0.38)
    Q10.160.110ns
    Q2−0.080.199ns
    Q30.170.090†
    Q40.020.830ns
    Crus IIAvg.0.230.020*0.027*(0.05, 0.41)
    Q10.270.006**
    Q20.220.031*
    Q30.210.032*
    Q40.040.702ns
    Fractional anisotropy correlations: ASR attention problems
     a:vermisVIAvg.0.200.041*0.050 †(0.01, 0.39)
    Q10.100.317ns
    Q20.250.014*
    Q30.150.135ns
    Q40.030.784ns
     b:paravermisCrus IAvg.0.200.050†0.050†(−0.004, 0.37)
    Q10.120.247ns
    Q20.180.079†
    Q30.210.038*
    Q40.060.536ns
     c1:cerebrocerebellumAvg.0.200.050†0.050†(0.002, 0.38)
    Q10.160.108ns
    Q20.120.221ns
    Q30.180.081†
    Q40.060.567ns
    Crus IIAvg.0.230.020*0.050†(0.05, 0.40)
    Q10.290.003**
    Q20.200.042*
    Q30.200.044*
    Q40.060.540ns

    • Correlations with Achenbach Self-Report (ASR) subscales and fractional anisotropy (FA) values for the right-to-right traveling polysynaptic tracts with the highest densities. A double dissociation between spinocerebellum (i.e., vermis and paravermis sending projections through the fastigial and interposed nuclei, respectively) and cerebrocerebellum (i.e., lateral cortical regions sending projections through the dentate) on somaticizing symptoms and social withdrawal, respectively. The N for all correlations is 101, the degrees of freedom for all tests is 99, and all confidence intervals are bootstrapped using 10,000 iterations. False discovery rate (FDR) correction for multiple comparisons was performed for the number of tracts within the polysynaptic (4 tracts). We used the FDR method to control for multiple comparisons, as we anticipated the effects to be smaller than those in the anatomy analyses and did not want to be unduly strict. Moreover, we chose to look at self-report measures for which we had a priori hypotheses, further warranting a less stringent approach to significance testing. Bootstrapped confidence intervals to further check for robustness of effects. Extended data supporting the findings here are reported in Extended Data Tables 5-1 through 5-3. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01, ***p < 0.001.

  • Table 6.

    Monosynaptic relations between microstructure and psychiatric symptoms

    Deep cerebellar nucleusSectionRho (ρ)p-valuep-value FDR95% CI: lower, upper
    Fractional anisotropy correlations: ASR anxiety and depression
     FastigialAvg.0.240.017*0.051†(0.03, 0.42)
    Q10.160.107ns
    Q20.250.011*
    Q30.170.096†
    Q40.030.778ns
     InterposedAvg.0.200.044*0.066†(0.01, 0.38)
    Q10.200.044*
    Q20.220.030*
    Q30.130.204ns
    Q40.050.606ns
     DentateAvg.0.140.159ns0.159†(−0.07, 0.33)
    Q10.040.707ns
    Q20.120.231ns
    Q30.140.166ns
    Q40.090.348ns
    Fractional anisotropy correlations: ASR internalizing symptoms
     FastigialAvg.0.230.023*0.069†(0.02, 0.42)
    Q10.160.110ns
    Q20.260.010*
    Q30.140.155ns
    Q40.010.908ns
     InterposedAvg.0.200.048*0.072†(0.001, 0.38)
    Q10.200.045*
    Q20.220.026*
    Q30.130.200ns
    Q40.040.696ns
     DentateAvg.0.170.098†0.098†(−0.04, 0.35)
    Q10.120.240ns
    Q20.160.117ns
    Q30.150.147ns
    Q40.080.459ns
    Fractional anisotropy correlations: ASR social withdrawal
     FastigialAvg.0.070.481ns0.481ns(−0.12, 0.26)
    Q10.010.900ns
    Q20.110.256ns
    Q30.030.734ns
    Q4−0.050.605ns
     InterposedAvg.0.10; 0.3250.325ns0.481ns(−0.09, 0.29)
    Q10.08; 0.4390.439ns
    Q20.11; 0.2610.261ns
    Q30.08; 0.4360.436ns
    Q40.001;0.9960.996ns
     DentateAvg.0.17; 0.0900.090†0.270ns(−0.04, 0.36)
    Q10.24; 0.0180.018*
    Q20.15; 0.1250.125ns
    Q30.11; 0.2680.268ns
    Q40.05; 0.5970.597ns
    Fractional anisotropy correlations: ASR somaticizing symptoms
     FastigialAvg.0.24; 0.0140.014*0.042*(0.03, 0.45)
    Q10.260.008**
    Q20.260.008**
    Q30.100.344ns
    Q4−0.010.918ns
     InterposedAvg.0.200.046*0.069†(−0.01, 0.39)
    Q10.230.019*
    Q20.240.017*
    Q30.110.290ns
    Q4−0.010.945ns
     DentateAvg.0.150.139ns0.139ns(−0.06, 0.35)
    Q10.150.143ns
    Q20.150.125ns
    Q30.140.164ns
    Q4−0.010.940ns
    Fractional anisotropy correlations: ASR attention problems
     FastigialAvg.0.150.138ns0.181ns(−0.0, −0.33)
    Q10.100.310ns
    Q20.170.100ns
    Q30.090.376ns
    Q40.0040.968ns
     InterposedAvg.0.180.068†0.181ns(−0.01, 0.36)
    Q10.180.074†
    Q20.190.054†
    Q30.110.278ns
    Q40.010.946ns
     DentateAvg.0.130.181ns0.181ns(−0.07, 0.33)
    Q10.120.246ns
    Q20.090.358ns
    Q30.150.133ns
    Q40.050.652ns

    • Correlations with Achenbach Self-Report (ASR) subscales and fractional anisotropy (FA) values for the right-to-right traveling monosynaptic tracts with the highest densities. It is also reported which quarter is responsible for driving each effect. FDR corrections are performed only for associations between personality traits and tracts averaged across all 100 nodes resulting in a vector of 3 p-values per correction). In Extended Data Table 6-1, we check for robustness of results between both the poly- and monosynaptic tractography FA and ASR measures when accounting for genetic relatedness within the sample. The N for all correlations is 101, and the degrees of freedom for all tests is 99. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01.

  • Table 7.

    Poly- and monosynaptic relations between microstructure and personality traits

    TypeSegment/DCNLobuleSectionRho (ρ)p-valuep-value FDR95% CI
    LowerUpper
    A. Relations between personality factors and fractional anisotropy alone
     Big five-factor inventory neuroticism
      R–R Polysynaptica:vermisVIAvg.0.280.005**0.012*0.070.46
    Q10.130.212ns−0.080.32
    Q20.210.032*0.010.40
    Q30.250.010*0.050.44
    Q40.140.171ns−0.070.33
    b:paravermisCrus IAvg.0.270.006**0.012*0.080.45
    Q10.140.172ns−0.060.33
    Q20.290.004**0.090.46
    Q30.240.015*0.040.42
    Q40.130.189ns−0.080.33
    c1:cerebro-cerebellumAvg.0.220.026*0.026*0.020.40
    Q10.040.712ns−0.160.25
    Q20.140.169ns−0.050.32
    Q30.210.039*0.010.39
    Q40.130.196ns−0.080.33
    Crus IIAvg.0.250.012*0.016*0.050.43
    Q10.190.059†−0.0040.37
    Q20.150.142ns−0.050.34
    Q30.210.040*0.010.39
    Q40.110.256ns−0.090.31
      R–R MonosynapticFastigialAvg.0.250.014*0.036*0.050.42
    Q10.150.141ns−0.060.34
    Q20.250.010*0.050.44
    Q30.180.065†−0.020.37
    Q40.080.432ns−0.130.28
    InterposedAvg.0.220.024*0.036*0.030.40
    Q10.220.031*0.020.39
    Q20.240.016*0.050.41
    Q30.130.186ns−0.070.32
    Q40.120.242ns−0.100.32
    DentateAvg.0.180.074†0.074†−0.020.37
    Q10.050.615ns−0.150.24
    Q20.130.212ns−0.070.32
    Q30.150.129ns−0.040.34
    Q40.150.143ns−0.070.35
     Big five-factor inventory agreeableness
      R–R Polysynaptica:vermisVIAvg.0.240.017*0.068†0.050.41
    Q10.020.831ns−0.180.23
    Q20.160.118ns−0.040.35
    Q30.290.003**0.110.46
    Q40.170.084†−0.020.36
    b:paravermisCrus IAvg.0.170.100ns0.100ns−0.030.34
    Q1−0.100.341ns−0.300.11
    Q2−0.020.838ns−0.220.19
    Q30.240.015*0.060.41
    Q40.140.156ns−0.050.33
    c1:cerebro-cerebellumAvg.0.170.089†0.100ns−0.020.35
    Q1−0.160.120ns−0.350.04
    Q20.040.707ns−0.170.24
    Q30.250.013*0.060.42
    Q40.130.185ns−0.060.32
    Crus IIAvg.0.170.096†0.100ns−0.010.34
    Q10.010.951ns−0.220.22
    Q2−0.050.608ns−0.250.15
    Q30.200.041*0.020.38
    Q40.120.242ns−0.080.30
      R–R MonosynapticFastigialAvg.0.270.006**0.015*0.090.44
    Q10.200.042*0.010.38
    Q20.290.004**0.100.45
    Q30.170.099†−0.030.35
    Q40.130.190ns−0.070.32
    InterposedAvg.0.260.010**0.015*0.080.42
    Q10.220.025*0.030.40
    Q20.260.008**0.070.44
    Q30.150.134ns−0.040.33
    Q40.100.323ns−0.100.29
    DentateAvg.0.210.033*0.033*0.020.39
    Q10.040.728ns−0.170.24
    Q20.150.124ns−0.050.35
    Q30.240.018*0.050.41
    Q40.090.377ns−0.110.28
    B. Partial correlations with fractional anisotropy, personality factors, and gender
     Big five-factor inventory neuroticism
      R–R Polysynaptica:vermisVIAvg.0.240.017*0.041*0.030.43
    Q10.110.263ns−0.090.31
    Q20.180.071†−0.020.38
    Q30.220.031*0.0040.41
    Q40.110.262ns−0.100.32
    b:paravermisCrus IAvg.0.230.024*0.041*0.020.41
    Q10.120.223ns−0.080.33
    Q20.240.016*0.060.42
    Q30.190.053†−0.010.38
    Q40.120.226ns−0.090.32
    c1:cerebro-cerebellumAvg.0.170.087†0.087ns−0.030.37
    Q10.020.841ns−0.170.22
    Q20.080.435ns−0.110.27
    Q30.160.110ns−0.030.36
    Q40.120.239ns−0.090.32
    Crus IIAvg.0.220.031*0.041*0.030.40
    Q10.190.064†−0.010.38
    Q20.120.252ns−0.090.31
    Q30.170.095†−0.030.36
    Q40.100.325ns−0.110.30
      R–R MonosynapticFastigialAvg.0.210.037*0.094†0.010.40
    Q10.110.262ns−0.090.31
    Q20.210.032*0.020.41
    Q30.170.083†−0.030.37
    Q40.060.575ns−0.150.26
    InterposedAvg.0.190.063†0.094†0.0030.37
    Q10.160.108ns−0.020.35
    Q20.200.051†0.010.38
    Q30.120.229ns−0.080.32
    Q40.100.333ns−0.110.31
    DentateAvg.0.130.208ns0.208ns−0.070.32
    Q10.0020.986ns−0.190.20
    Q20.070.472ns−0.130.27
    Q30.110.269ns−0.080.31
    Q40.140.163ns−0.070.35
     Big five-factor inventory agreeableness
      R–R Polysynaptica:vermisVIAvg.0.200.042*0.168ns0.020.38
    Q10.010.931ns−0.190.21
    Q20.130.210ns−0.080.32
    Q30.240.008**0.090.43
    Q40.150.127ns−0.050.34
    b:paravermisCrus IAvg.0.120.226ns0.226ns−0.070.31
    Q1−0.110.266ns−0.320.10
    Q2−0.070.462ns−0.270.13
    Q30.200.042*0.020.38
    Q40.130.183ns−0.060.32
    c1:cerebro-cerebellumAvg.0.130.210ns0.226ns−0.060.31
    Q1−0.170.084†−0.360.02
    Q2−0.020.862ns−0.210.19
    Q30.210.032*0.020.39
    Q40.120.221ns−0.070.31
    Crus IIAvg.0.140.178ns0.226ns−0.050.32
    Q10.0010.999ns−0.220.23
    Q2−0.090.402ns−0.280.12
    Q30.170.085†−0.010.35
    Q40.110.299ns−0.100.30
      R–R MonosynapticFastigialAvg.0.250.014*0.036*0.060.41
    Q10.180.080†−0.010.35
    Q20.250.011*0.060.43
    Q30.160.123ns−0.030.33
    Q40.110.260ns−0.080.30
    InterposedAvg.0.230.024*0.036*0.050.39
    Q10.180.073†−0.0020.35
    Q20.230.022*0.040.41
    Q30.140.156ns−0.050.32
    Q40.080.416ns−0.120.28
    DentateAvg.0.170.088†0.088†−0.020.35
    Q1−0.010.948ns−0.210.19
    Q20.110.268ns−0.090.31
    Q30.210.040*0.020.38
    Q40.080.416ns−0.110.27

    • Average and segment-wise correlations with the NEO Five-Factor Inventory (NEO-FFI) subscales for neuroticism and agreeableness and fractional anisotropy (FA) values for the right-to-right traveling tracts with the highest densities. The N for all correlations is 101, and all confidence intervals are bootstrapped using 10,000 iterations. The degrees of freedom for the main correlations (not controlling for sex) is 99, and the degrees of freedom for partial correlations accounting for sex is 98. False discovery rate (FDR) correction for multiple comparisons was performed for the number of tracts within the polysynaptic (4 tracts) and monosynaptic (3 tracts) correlation domains for overall tract averages, separately. Corrections were not performed for the four quarters, as this was an exploratory analysis used to “drill down” into which portions of the tract were driving the effects where significant or trending associations were uncovered. Note that there was a significant difference between the sexes for each personality trait, so partial correlations are reported in the section. In Extended Data Table 7-1, we check for robustness of results between both the poly- and monosynaptic tractography FA and NEO-FFI measures when accounting for genetic relatedness alone and then together with sex. Significance flags: †p < 0.10, *p < 0.05, **p < 0.01.

  • Table 8.

    Quarter-wise brain self-report numeric “heatmap”

    AssessmentVariableAbbrev.Quarter
    Q1Q2Q3Q4
    R–R polysynaptic: four tracts
     ASRAnxiety/depressionAnx. Dep2240
    InternalizingInter2340
    Social withdrawalSoc. Withd4210
    SomaticizingSoma3330
    Attention problemsAttn1220
     NEO-FFINeuroticismN0240
    AgreeablenessA0040
    Neuroticism-Ctrl (Sex)N-Ctrl0110
    Agreeableness-Ctrl (Sex)A-Ctrl0030
     Total1214220
     Total-Ctrl (Sex)1213180
    R–R monosynaptic: three tracts
     ASRAnxiety/depressionAnx. Dep1210
    InternalizingInter1200
    Social WithdrawalSoc. Withd1000
    SomaticizingSoma2200
    Attention problemsAttn0000
     NEO-FFINeuroticismN1100
    AgreeablenessA2210
    Neuroticism-Ctrl (Sex)N-Ctrl0100
    Agreeableness-Ctrl (Sex)A-Ctrl0210
     Total8920
     Total-Ctrl (Sex)5920

    • A numeric “heatmap” of degree to which each quarter for the brain–behavior analyses is implicated as the driver of the brain self-report effects. For polysynaptic tract investigations, the total possible number of times a single quarter may be significant is four, since there were four polysynaptic tracts under study, while the total number of times a monosynaptic quarter may be significant is three, since only three monosynaptic tracts were under study. For example, a value of “4” in a cell for the polysynaptic tracts would indicate that that quarter was significant in all four polysynaptic tracts for a given brain self-report association. The row titled “Total” represents the total number of times a given quarter was the significant driver of the overall tract average brain self-report associations. The “Total-Ctrl (Sex)” row shows how these results change when controlling for sex in the NEO-FFI correlations. Extended Data Table 8-1 shows how these results change when accounting for genetic relatedness within the sample.

Extended Data

  • Table 3-1

    Success rate for each tractography by number of non-zero reconstructions. Download Table 3-1, DOCX file.

  • Table 3-2

    Main effects controlling for length. Nonparametric pairwise comparisons using Wilcoxon sign-rank test investigating streamline count differences based on tract direction, lobule, and segment for polysynaptic tractographies; and direction and deep nuclei macrostructural differences in monosynaptic tractographies. Download Table 3-2, DOCX file.

  • Table 3-3

    Main effects controlling for waypoint volume. Nonparametric pairwise comparisons using Wilcoxon sign-rank test investigating streamline count differences based on tract direction, lobule, and segment for polysynaptic tractographies. Download Table 3-3, DOCX file.

  • Table 4-1

    Interactions controlling for length. Nonparametric pairwise comparisons using Wilcoxon signed-rank test investigating interactions between direction and lobule; direction and segment; and lobule and segment. All confidence intervals are bootstrapped using 10,000 iterations to yield stable estimates around the effect size. Download Table 4-1, DOCX file.

  • Table 4-2

    Interactions controlling for waypoint volume. Nonparametric pairwise comparisons using Wilcoxon signed-rank test investigating interactions between direction and lobule; direction and segment; and lobule and segment. All confidence intervals are bootstrapped using 10,000 iterations to yield stable estimates around the effect size. Download Table 4-2, DOCX file.

  • Table 5-1

    Descriptive statistics for self-report measures under study. Download Table 5-1, DOCX file.

  • Table 6-1

    Download Table 6-1, DOCX file.

  • Table 7-1

    Download Table 7-1, DOCX file.

  • Table 8-1

    Download Table 8-1, DOCX file.

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A Virtual In Vivo Dissection and Analysis of Socioaffective Symptoms Related to Cerebellum-Midbrain Reward Circuitry in Humans
Linda J. Hoffman, Julia M. Foley, Josiah K. Leong, Holly Sullivan-Toole, Blake L. Elliott, Ingrid R. Olson
Journal of Neuroscience 9 October 2024, 44 (41) e1031242024; DOI: 10.1523/JNEUROSCI.1031-24.2024
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