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Task-induced functional brain connectivity mediates the relationship between striatal D2/3 receptors and working memory

  1. Matthew M Nour  Is a corresponding author
  2. Tarik Dahoun
  3. Robert A McCutcheon
  4. Rick A Adams
  5. Matthew B Wall
  6. Oliver D Howes
  1. King’s College London, United Kingdom
  2. Hammersmith Hospital, United Kingdom
  3. Imperial College London, United Kingdom
  4. University College London, United Kingdom
  5. University of Oxford, United Kingdom
Research Article
Cite this article as: eLife 2019;8:e45045 doi: 10.7554/eLife.45045
4 figures, 1 table and 1 additional file


Task design and behavioural results.

(A) Letter n-back task design. The task consisted of 18 task blocks (20s each, interspersed with 10s rest blocks) that were pseudo-randomised to 0-, 1-, or 2-back conditions (6 blocks of each condition per task session). Participants indicated, as quickly as possible, whether the target was present or absent at the appearance of each letter, using two buttons of an MR-compatible button box. Each letter appeared on the screen for 2 s before the next letter was shown. This figure shows the last 4 trials of a 1-back task block, followed by a rest block. (B) Task behaviour. Penalised reaction time (pRT, using penalization ratio of 2.5) increases (indicating poorer performance) with increasing working memory load. Plotted as mean ± S.E.M.

Task-related neural activation and task-related cortical networks.

(A) Significant task-induced activations (red) and deactivations (blue) that correlate with increasing working memory load, showing increased activation within dorsolateral prefrontal cortex and parietal cortex, and decreased activation within ventromedial prefrontal cortex, posterior cingulate cortex and medial temporal lobe. Activation and deactivation maps thresholded at whole-brain cluster threshold (cluster-level family-wise error corrected P < 0.05), and displayed in coronal, sagittal and axial sections overlaid on a single-subject normalized T1 image in MNI space (see Table 1 for statistical results). (B) Lateral (top) and top-down (bottom) rendering illustrating nodes of the empirical task-positive (TPN, in red) and default mode (DMN, in blue) networks identified by the community detection algorithm.

Task-induced changes in DMN and TPN functional connectivity.

Increasing working memory load is accompanied by decreasing functional connectivity within the DMN (negative w1 values) and increasing functional connectivity within the TPN (positive w1 values). (A) Mean task-induced functional connectivity change of each network edge (node-node connection) in the whole sample. Each edge (cell of the matrix) represents the regression coefficient (w1 value) of connectivity change as a function of working memory load, averaged over the whole group. Arrows and black lines indicate the boundary separating nodes allocated to the empirical DMN vs TPN. (B) Mean task-induced functional connectivity change within the DMN, TPN and DMN-TPN across the whole group. Left: Group mean (± S.E.M) functional connectivity strength (Fisher z-transformed r-value) within the DMN, TPN and DMN-TPN as a function of working memory load. Right: Group mean (± S.E.M) task-induced functional connectivity change (w1) within the DMN, TPN and DMN-TPN. w1 was significantly different to zero in both the DMN (t50 = -2.33, P = 0.02, one-sample t-test) and TPN (t50 = 2.70, P = 0.01, one-sample t-test), but not the DMN-TPN (t50 = 0.65, P = 0.52, one-sample t-test). Repeated measures ANOVA indicated that w1 was not equal within the DMN, TPN and DMN-TPN edges (F2,100 = 11.16 P < 0.001), and post-hoc paired t-tests confirmed that the w1 of the DMN was significantly lower than both the TPN and DMN-TPN (t50 = -4.56, P < 0.001 and t50 = -3.01, P = 0.004, respectively), but that there was no significant difference between the w1 of the TPN and DMN-TPN (t50 = 1.62, P = 0.11).

The relationship between striatal D2/3R availability, task-induced change in DMN connectivity, and task performance.

(A) The significant positive correlation between striatal D2/3R availability and task-induced change in connectivity within the default mode network (DMN), where negative values on the y-axis indicate a reduction in connectivity. Lower caudate D2/3R availability is related to a task-induced reduction in DMN connectivity. (B) The relationship between task-induced functional connectivity change within the DMN and working memory robustness, -ΔpRT2.5 (a value of 0 indicates that performance is unaffected by increasing working memory load, while negative values indicate that performance decreases with increasing cognitive demands). Negative values on the x-axis indicate a task-induced reduction in DMN connectivity. Task-induced decreases in DMN connectivity were associated with greater working-memory related behavioural impairment. (C) Mediation analysis. Greater caudate D2/3R availability has a significant but indirect association with improved task performance, mediated via task-induced connectivity change within the DMN. Pearson’s correlation coefficients in (C) are reported in the sample of 48 participants (d.f. = 46) who had both PET and fMRI.



Table 1
Whole brain activation/deactivation results for parametric working memory load regressor.
PeakMNI coordinates (mm)
Activation clusters
Left middle/superior frontal gyrus<0.001−30−30456
Right middle/superior frontal gyrus<0.0012626457
Left middle frontal gyrus<0.001−39−39633
Left precuneus/superior parietal lobule<0.001-8-8−6951
Right precuneus/superior parietal lobule<0.00199−6354
Right superior parietal lobule<0.0013333−4844
Deactivation clusters
Left central operculum/posterior insula<0.00110.35−36−1618
Right central operculum/posterior insula<0.00110.2440−1622
Left central operculum/anterior insula<0.0019.30−36315
Left posterior cingulate<0.0017.79-4−4827
Right posterior cingulate0.0125.636−4821
Right posterior cingulate0.4554.2615−446
  1. Activation/deactivation peaks present in the significant clusters at whole-brain threshold of P < 0.05 (family wise error (FWE) – corrected), using a cluster defining threshold P < 0.001 (uncorrected) for both contrasts. Anatomical labelling corresponds to the peak MNI co-ordinate. MNI = Montreal neurological institute.

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