Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood
- Centre for Brain and Cognitive Development, Birkbeck, University of London, United Kingdom
- Department of Medical Physics and Biomedical Engineering, University College London, United Kingdom
- Department of Women and Children’s Health, King's College London, United Kingdom
- Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Gambia
- Department of Psychology, University of Cambridge, United Kingdom
- School of Biological and Experimental Psychology, Queen Mary University of London, United Kingdom
- Department of Women and Children’s Health, University of Liverpool, United Kingdom
- Nutrition Innovation Centre for Food and Health, School of Biomedical Sciences, Ulster University, Ireland
- Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, United States
Figures
Figure 1
Experimental design.
(A) Measures taken in the BRIGHT project used in this work. The measuring tape represents anthropometric measures, the brain represents fNIRS FC and the test represents the cognitive flexibility assessment. (B) Schematic representation of the spatial layout of the fNIRS array. Sources are marked with red stars, detectors are marked with blue circles, channels are marked with grey lines and numbered with black circles. The channels/optodes used as a reference for the tragus are highlighted in green.
Figure 2
Linear mixed models results showing FC that displayed a statistically significant change with age.
(A) Significant results of the linear mixed model, blue indicates connections that decreased with age, red indicates connections that increased with age. (B) Mean and standard error of the mean (SE) of the functional connections that changed with age (HbO2). Error bars are 1 SE. (C) Violin plot showing the mean ± SD (red circles and lines) and the individual variability (coloured dots) of the FC that showed a change with time (HbO2).
Figure 3
Associations between FC, early growth and later cognitive flexibility.
(A) Significant positive associations are in green, significant negative associations are in orange, and non-significant associations are in blue. * indicates regressions that survived FDR correction for multiple comparisons. (B) Schematic representations of the early FC connections shown to predict cognitive flexibility in preschoolers. Significant positive associations are in green, significant negative associations are in orange (these results did not survive corrections for multiple comparisons).
Appendix 1—figure 1
Schematic representation of the fNIRS array and the functional connections tested.
(A) Each dot represents a channel, colours on the left plot correspond to colours on the right on the baby’s head. Six sections. (B) The 21 connections tested in the linear mixed models. Interhemispheric homotopic connections are in orange (connecting the same regions between hemispheres, that is front left with front right), intrahemispheric connections within section are in green (correlations of channels belonging to the same region), fronto-posterior are in blue (connecting front and middle, middle and back, and front and back regions of the same hemisphere), and crossing interhemispheric connections (interhemispheric non-homotopic, connecting the front and middle, middle and back, and front and back regions of the two hemispheres) are in yellow.
Appendix 1—figure 2
Linear mixed models result showing FC that displayed a statistically significant change with age (fNIRS pre-processing without global signal regression).
(A) Results of the linear mixed model, blue indicates connections that decreased with age, red indicates connections that increase with age. (B) Mean and SE of the functional connections that changed with age. Error bars are 1 SE.
Appendix 1—figure 3
Some examples of scatterplots showing the association between ΔWLZ and FC at 24 months.
The black lines represent the line of best fit and the 95% confidence intervals.
Appendix 1—figure 4
fNIRS preprocessing steps.
The column ‘infants included in the analyses’ in Table 3 refers to those participants whose data survived these preprocessing steps.
Appendix 1—figure 5
The effect of different thresholds for GVTD for motion detection and minimum valid data after pre-processing on data inclusion.
(A) Percentage of data included (left) and seconds of data included (right) per participant. Each line represents an infant, the black line represents the mean value. These graphs are reported from the 12 months sample as example. (B) Number of infants included in the LMM by varying STD threshold for GVTD and minimum length of valid data at different ages.
Appendix 1—figure 6
Strength of correlation between FC in the first and last portion of data.
This graph is reported from the age 12 month sample as example.
Tables
Table 1
FC that significantly changed with age.
Results are displayed in terms of estimated betas, standard errors and p values that survived Bonferroni correction. Regressions that survived Bonferroni correction for multiple comparisons are in bold.
| FC | F | p | Baseline(5 months)Betas (SE), p | 5–8 change Betas (SE), p | 5–12 change Betas (SE), p | 5–18 change Betas (SE), p | 5–24 change Betas (SE), p |
|---|---|---|---|---|---|---|---|
| HbO2 | |||||||
| Frontal interhemispheric | 11.03 | <0.001 | 0.28 (0.03),<0.001 | –0.09 (0.06), 0.12 | –0.20 (0.05),<0.001 | –0.25 (0.05),<0.001 | –0.33 (0.05),<0.001 |
| Left fronto-middle | 5.8 | <0.001 | –0.28 (0.04),<0.001 | 0.06 (0.06), 0.293 | 0.09 (0.05), 0.102 | 0.19 (0.05), <0.001 | 0.23 (0.05), <0.001 |
| Right fronto-middle | 4.86 | <0.001 | –0.70 (0.29), 0.018 | 0.01 (0.05), 0.982 | 0.05 (0.05), 0.288 | 0.13 (0.05), 0.007 | 0.19 (0.05), <0.001 |
| Right frontal-posterior | 5.52 | <0.001 | –0.20 (0.03),<0.001 | 0.16 (0.06), 0.005 | 0.14 (0.05), 0.006 | 0.20 (0.05), <0.001 | 0.22 (0.05), <0.001 |
| HHb | |||||||
| Frontal interhemispheric | 6.59 | <0.001 | 0.32 (0.03),<0.001 | –0.09 (0.06), 0.107 | –0.22 (0.05),<0.001 | –0.23 (0.05),<0.001 | –0.22 (0.05),<0.001 |
| Cross left fronto-right middle | 5.17 | <0.001 | –0.32 (0.04),<0.001 | 0.06 (0.06), 0.328 | 0.07 (0.05), 0.188 | 0.19 (0.05), <0.001 | 0.22 (0.05), <0.001 |
| Right fronto-middle | 5.55 | <0.001 | –0.78 (0.32), 0.036 | 0.01 (0.06), 0.86 | 0.05 (0.05), 0.301 | 0.16 (0.05), 0.002 | 0.21 (0.05), <0.001 |
| Right frontal-posterior | 5.38 | <0.001 | –0.24 (0.04),<0.001 | 0.10 (0.06) 0.073 | 0.08 (0.05) 0.133 | 0.23 (0.05), <0.001 | 0.02 (0.05), <0.001 |
Table 2
Results of the regression analyses of the effect of ΔWLZ on FC at 24 months.
Significant positive associations are in green, significant negative associations are in orange, and non-significant (NS) associations are in blue; * indicates regressions that are still significant after correcting for HCAZ at 7/14 days and ** indicates regressions that are still significant after correcting for neonatal HCAZ and WLZ. Regressions that survived FDR correction for multiple comparisons are in bold.
| Frontal interhemispheric FC at 24 months | |||||||
|---|---|---|---|---|---|---|---|
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | NS | F(1,68)=8.69, P=0.004*, R2=0.102 | F(1,67)=7.65, P=0.007*, R2=0.104 | F(1,69)=10.4, P=0.002**, R2=0.121 | F(1,68)=10.98, P=0.001**, R2=0.142 | F(1,59)=5.40, P=0.024*, R2=0.085 | |
| 1 month | F(1,77)=5.59, P=0.021**, R2=0.069 | NS | F(1,78)=4.74, P=0.032**, R2=0.058 | F(1,75)=4.45, P=0.038**, R2=0.057 | NS | ||
| 5 months | NS | NS | NS | NS | |||
| 8 months | NS | NS | NS | ||||
| 12 months | NS | NS | |||||
| 18 months | NS | ||||||
| 24 months | |||||||
| Left fronto-middle FC at 24 months | |||||||
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | NS | NS | F(1,67)=4.07, P=0.048**, R2=0.058 | NS | NS | F(1,59)=4.24, P=0.044**, R2=0.068 | |
| 1 month | NS | NS | NS | NS | NS | ||
| 5 months | NS | NS | NS | NS | |||
| 8 months | NS | NS | NS | ||||
| 12 months | NS | NS | |||||
| 18 months | NS | ||||||
| 24 months | |||||||
| Right fronto-middle FC at 24 months | |||||||
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | NS | NS | F(1,67)=4.74, P=0.033, R2=0.067 | NS | F(1,68)=5.29, P=0.024**, R2=0.073 | NS | |
| 1 month | F(1,77)=4.26, P=0.042**, R2=0.053 | F(1,75)=6.66, P=0.012**, R2=0.083 | NS | F(1,75)=5.33, P=0.024**, R2=0.067 | NS | ||
| 5 months | NS | NS | NS | NS | |||
| 8 months | NS | NS | NS | ||||
| 12 months | NS | NS | |||||
| 18 months | NS | ||||||
| 24 months | |||||||
| Right frontal-posterior FC at 24 months | |||||||
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | F(1,66)=8.26, P=0.006**, R2=0.113 | NS | NS | NS | NS | NS | |
| 1 month | F(1,69)=4.86, P=0.031*, R2=0.067 | F(1,68)=6.98, P=0.01**, R2=0.094 | F(1,71)=8.86, P=0.004**, R2=0.112 | F(1,67)=7.72, P=0.007**, R2=0.105 | F(1,57)=7.03, P=0.01**, R2=0.112 | ||
| 5 months | NS | NS | NS | NS | |||
| 8 months | NS | NS | NS | ||||
| 12 months | NS | NS | |||||
| 18 months | NS | ||||||
| 24 months | |||||||
Table 3
Demographic information per each age.
| Age | Age in days (mean ± SD) | Sex (M, F) | WLZ (mean ± SD) | HCZ (mean ± SD) |
|---|---|---|---|---|
| 5 months | 158.92±9.91 | 45,42 | –0.24±0.95 | –0.72±0.92 |
| 8 months | 249.34±17.97 | 28,25 | –0.24±1.01 | –0.81±0.90 |
| 12 months | 372.92±14.75 | 42,40 | –0.58±1.05 | –0.95±0.95 |
| 18 months | 560.37±24.38 | 48,49 | –0.85±0.91 | –0.82±0.93 |
| 24 months | 746.61±23.25 | 49,47 | –0.44±0.99 | –0.80±0.97 |
Appendix 1—table 1
FC that significantly changed with age (fNIRS pre-processing without global signal regression).
Results are displayed in terms of estimated betas, standard errors, and p values.
| FC | F | p | Baseline(5 months)Betas (SE), p | 5–8 change Betas (SE), p | 5–12 change Betas (SE), p | 5–18 change Betas (SE), p | 5–24 change Betas (SE), p |
|---|---|---|---|---|---|---|---|
| HbO2 | |||||||
| Left fronto-middle | 10.4 | <0.001 | –0.55 (0.29),<0.063 | 0.05 (0.05), 0.239 | 0.07 (0.04), 0.125 | 0.16 (0.04),<0.001 | 0.26 (0.04),<0.001 |
| Right fronto-middle | 4.82 | <0.001 | –0.24 (0.28), 0.398 | 0.03 (0.05), 0.535 | 0.05 (0.04), 0.246 | 0.08 (0.04), 0.051 | 0.18 (0.04),<0.001 |
| HHb | |||||||
| Frontal interhemispheric | 3.5 | 0.002 | 0.18 (0.33) 0.591 | –0.07 (0.06), 0.260 | –0.07 (0.05), 0.214 | –0.17 (0.05), 0.002 | –0.17 (0.05), 0.002 |
Appendix 1—table 2
Results of the regression analyses of the effect of FC on cognitive flexibility in younger and older preschoolers.
Significant positive associations are in green, significant negative associations are in orange, and non-significant (NS) associations are in blue.
| Cognitive flexibility in younger preschoolers | Cognitive flexibility in older preschoolers | ||
|---|---|---|---|
| Frontal interhemispheric FC | 5 months | F(1,38)=4.21, p=0.047, R2=0.102 | NS |
| 8 months | NS | NS | |
| 12 months | NS | NS | |
| 18 months | NS | F(1,45)=4.82, p=0.030, R2=0.115 | |
| 24 months | NS | NS | |
| Left fronto-middle FC | 5 months | NS | NS |
| 8 months | NS | NS | |
| 12 months | F(1,33)=7.86, p=0.009, R2=0.197 | NS | |
| 18 months | NS | F(1,45)=5.72, p=0.021, R2=0.115 | |
| 24 months | NS | NS | |
| Right fronto-middle FC | 5 months | NS | NS |
| 8 months | NS | NS | |
| 12 months | F(1,38)=4.82, p=0.034, R2=0.115 | NS | |
| 18 months | NS | NS | |
| 24 months | NS | NS | |
| Right frontal-posterior FC | 5 months | NS | NS |
| 8 months | F(1,32)=5.6, p=0.024, R2=0.153 | NS | |
| 12 months | NS | NS | |
| 18 mo | NS | NS | |
| 24 mo | NS | F(1,49)=4.85, P=0.032, R2=0.092 |
Appendix 1—table 3
Results of the correlational analyses between changes in growth (ΔWLZ) and cognitive flexibility in younger and older preschoolers.
| Cognitive flexibility in younger preschoolers | |||||||
|---|---|---|---|---|---|---|---|
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | r(54)=−0.169, p=0.214 | r(51)=−0.167, p=0.232 | r(51)=−0.249, p=0.072 | r(53)=−0.198, p=0.147 | r(51)=−0.151, p=0.280 | r(41)=−0.241, p=0.102 | |
| 1 mo | r(64)=0.031, p=0.805 | r(63)=0.001, p=0.993 | r(66)=0.013, p=0.916 | r(62)=0.084, p=0.511 | r(48)=−0.021, p=0.885 | ||
| 5 mo | r(64)=−0.075, p=0.548 | r(66)=−0.032, p=0.798 | r(63)=0.008, p=0.947 | r(50)=−0.091, p=0.520 | |||
| 8 mo | r(66)=−0.044, p=0.719 | r(62)=0.067, p=0.600 | r(50)=−0.041, p=0.775 | ||||
| 12 mo | r(64)=0.097, p=0.439 | r(51)=−0.012, p=0.932 | |||||
| 18 mo | r(49)=−0.107, p=0.454 | ||||||
| 24 mo | |||||||
| Cognitive flexibility in older preschoolers | |||||||
| ΔWLZ | birth | 1 month | 5 months | 8 months | 12 months | 18 months | 24 months |
| birth | r(55)=0.036, p=0.789 | r(58)=−0.122, p=0.353 | r(56)=−0.138, p=0.303 | r(56)=−0.153, p=0.252 | r(55)=−0.149, p=0.268 | r(53)=−0.137, p=0.319 | |
| 1 month | r(64)=−0.138, p=0.268 | r(61)=−0.113, p=0.379 | r(62)=−0.113, p=0.294 | r(59)=−0.013, p=0.919 | r(59)=−0.069, p=0.597 | ||
| 5 months | r(72)=−0.002, p=0.984 | r(73)=−0.025, p=0.829 | r(68)=0,064, p=0.601 | r(70)=0.046, p=0.704 | |||
| 8 months | r(72)=0.026, p=0.827 | r(68)=0.098, p=0.421 | r(69)=0.034, p=0.777 | ||||
| 12 months | r(68)=0.091, p=0.456 | r(70)=−0.057, p=0.634 | |||||
| 18 months | r(65)=−0.103, p=0.406 | ||||||
| 24 months | |||||||
Appendix 1—table 4
Results of the correlational analyses between changes in functional connectivity between 5 and 24 months and cognitive flexibility in younger and older preschoolers.
| Cognitive flexibility | ||
|---|---|---|
| ΔFC between 5 and 24 months | Younger preschoolers | Older preschoolers |
| Frontal interhemispheric connectivity | r(12)=−0.368, p=0.196 | r(20)=−0.188, p=0.401 |
| Left fronto-middle FC | r(10)=0.253, p=0.428 | r(17)=0.270, p=0.264 |
| Right fronto-middle FC | r(12)=0.248, p=0.392 | r(20)=0.192, p=0.392 |
| Right frontal-posterior FC | r(12)=0.188, p=0.520 | r(20)=0.164, p=0.465 |
Appendix 1—table 5
Characteristics of included and excluded participants and seconds of data included in the analyses at each age.
WD = withdrawn, D = deceased, MV = missed visit, DD = developmental delay, NIRS not undertaken = the participant was assessed but did not want or could not perform the NIRS assessments, FC not undertaken = the participant was assessed with other NIRS task, but not FC, Fussed out = the participant wore the headband and the FC acquisition had started but the participant showed signs of fussiness soon after the start of the acquisition, MP = missing pictures of the headband placement, EM = missing event markers, TI = technical issues during the NIRS testing session. The proportion of children included in the analysis was computed based on the infants with FC data.
| Age | N-% | Not tested | NIRS not undertaken | FC not undertaken | Infants with FC data | Fussed out | Experimental errors | Headband Placement | Too many channels excluded | Not enough data after pre-processing | Infants included in the analyses | Seconds of data included in the analyses (mean ± SD) | Inclusion rate (from the 204 infants recruited) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| WD | D | MV | DD | MP | EM | TI | ||||||||||||
| 5 months | N | 2 | 1 | 2 | 3 | 10 | 7 | 179 | 16 | 11 | 3 | 3 | 7 | 5 | 47 | 87 | 382.68±92.78 | 42% |
| % | 0.98 | 0.49 | 0.98 | 1.47 | 4.90 | 3.43 | 87.74 | 8.93 | 5.39 | 1.67 | 1.67 | 5.58 | 2.79 | 26.25 | 48.6 | |||
| 8 months | N | 7 | 1 | 5 | 3 | 18 | 14 | 156 | 7 | 6 | 0 | 1 | 23 | 6 | 60 | 53 | 372.93±80.66 | 25% |
| % | 3.43 | 0.49 | 2.45 | 1.47 | 8.82 | 6.86 | 76.47 | 4.48 | 3.84 | 0 | 0.64 | 14.7 | 3.84 | 38.46 | 33.97 | |||
| 12 months | N | 9 | 1 | 4 | 3 | 17 | 13 | 157 | 4 | 1 | 0 | 2 | 10 | 2 | 56 | 82 | 372.93±80.66 | 40% |
| % | 4.41 | 0.49 | 1.96 | 1.47 | 8.33 | 6.37 | 76.96 | 2.54 | 0.63 | 0 | 1.27 | 6.36 | 1.27 | 35.66 | 52.22 | |||
| 18 months | N | 8 | 1 | 15 | 3 | 12 | 5 | 160 | 4 | 0 | 0 | 1 | 16 | 4 | 38 | 97 | 388.85±81.63 | 47% |
| % | 3.92 | 0.49 | 7.35 | 1.47 | 5.88 | 2.45 | 78.43 | 2.5 | 0 | 0 | 0.62 | 10 | 2.5 | 23.75 | 60.62 | |||
| 24 months | N | 13 | 1 | 29 | 1 | 3 | 4 | 153 | 0 | 2 | 0 | 0 | 6 | 4 | 45 | 96 | 399.56±79.86 | 47% |
| % | 6.37 | 0.49 | 14.2 | 0.49 | 1.47 | 1.96 | 75 | 0 | 1.30 | 0 | 0 | 3.92 | 2.61 | 29.41 | 62.74 | |||
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Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood
eLife 13:RP94194.
https://doi.org/10.7554/eLife.94194.4
