A particular effect of sleep, but not pain or depression, on the blood-oxygen-level dependent response during working memory tasks in patients with chronic pain

Figures & data

Table 1 Demographics, level of pain, depression, and sleep quality and working memory performance in 15 chronic pain patients and matched healthy controls

Measure	CP (n=15)	HC (n=17)	P-value	Cohen’s d
Age, years	38.6±7.2 (22–49)	37.6±7.0 (23–48)	0.69	0.14
Education	4.5±2.4 (0–10)	5.1±2.5 (1–11)	0.51	0.24
NRS	6.0 (3–8)	0.0 (0–2)	0.00*	3.64a
BDI	12.0 (0–33)	1.0 (0–8)	0.00*	1.69a
PSQI	11.0 (2–16)	2.0 (0–6)	0.00*	2.39a
Letter number sequencing	8.0±2.1 (5–12)	9.4±2.4 (6–14)	0.11	0.61
Digit span forward	8.3±2.0 (6–12)	9.3±2.3 (6–14)	0.23	0.45
Digit span backward	5.4±1.3 (4–8)	6.0±1.9 (3–9)	0.32	0.37

Notes: Numbers are average scores ± standard deviation and (range) in CP patients with pain self-rating of ≥4/10 for ≥6 months and in HC. Numbers are mean ± standard deviation where both groups had a normal distribution. Only where one or more group was not normally distributed, the median is reported. Range is given in parenthesis. Statistical differences were estimated/calculated with a two-tailed two-sample t-test where equal variance was assumed if Levene’s test for equality of variances was significant with a P<0.05. For measures that were not normally distributed in both groups (NRS, BDI, and PSQI among HC), an independent Mann–Whitney U test was used.

* Significance on t-test for P≤0.001;

a large effect sizes. Education: Years of education after high school. Handedness recorded with Edinburgh Handedness Inventory.

Abbreviations: CP, chronic pain; HC, healthy controls; NRS, average pain last 24 hours, rated on a numerical rating scale before scanning; BDI, Beck Depression Inventory II score; PSQI, Pittsburgh Sleep Quality Index score.

Figure 1 Body map over pain location in CP group.

Notes: Colored areas correspond to the areas where patients reported pain on the human figure from the Brief Pain Inventory questionnaire. Color intensity corresponds with number of patients that report pain in the given area, the colored box indicates color intensity corresponding to one patient (lightest pink) to five patients (darkest pink).
Abbreviation: CP, chronic pain.

Table 2 Performance on the fMRI paradigms for chronic pain patients and healthy controls

Test	CP (n=15)	HC (n=17)	P-value	Cohen’s d
0-back
Score	60.0 (39.0–60.0)	60.0 (55–60)	0.60	0.63
RT	521 (404–1,146)	555 (437–856)	0.71	0.40
ICV	0.18 (0.05–0.73)	0.15 (0.09–0.26)	0.15	0.76a
EC	0.0 (0.0–7.0)	0.0 (0.0–2.0)	0.35	0.63
EO	0.0 (0.0–17.0)	0.0 (0.0–5.0)	0.58	0.54
2-back
Score	54.5±3.6 (47.0–59.0)	56.4±3.0 (51.0–60.0)	0.12^n	0.55
RT	598 (478–1,311)	630 (461–1,261)	0.85	0.08
ICV	0.26±0.12 (0.11–0.51)	0.27±0.09 (0.16–0.43)	0.88^n	0.06
EC	2.0 (0.0–5.0)	1.0 (0.0–4.0)	0.58	0.26
EO	3.5±2.5 (0.0–8.0)	2.1±1.5 (0.0–6.0)	0.08^n	0.65
PVSAT
Score	99.9±3.7 (94.0–105.0)	100.1±3.9 (91.0–105.0)	0.89^n	0.05
RT	848 (634–1,224)	876 (615–1,377)	0.63	0.23
ICV	0.30±0.08 (0.18–0.49)	0.27±0.07 (0.12–0.35)	0.20^n	0.47
EC	2.0 (0.0–5.0)	1.0 (0.0–5.0)	0.55	0.13
EO	2.0 (0.0–10.0)	2.0 (0.0–9.0)	0.85	0.00

Notes: Numbers are medians and ranges in CP patients with pain self-rating of ≥4/10 for ≥6 months and their matched HC. Numbers are mean ± standard deviation where both groups had a normal distribution. Only where one or more group was not normally distributed, the median is reported. Range is given in parentheses. There were no statistical significant group differences found with the two-tailed independent sample Student’s t-test (where both variables were normally distributed, marked withⁿ) or the Mann–Whitney U test (where one or more variables were not normally distributed) with significance level set to P<0.05;

a large effect sizes. Score: Subjects get 1 point when they correctly push or correctly refrain from pushing the response button.

Abbreviations: fMRI, functional magnetic resonance imaging; CP, chronic pain; HC, healthy controls; PVSAT, paced visual serial addition test; RT, reaction time in milliseconds; ICV, individual coefficient of variation for RT variability; EC, errors of commission, responding when nonresponse was correct; EO, errors of omission, nonresponse when response was correct.

Table 3 Correlations between working memory test, pain (NRS), depression (BDI), and sleep problems (PSQI) scores in chronic pain patients

Self-report and test scores	NRS	BDI	PSQI
NRS	1	–	–
BDI	−0.041	1	–
PSQI	−0.230	0.157	1
0-back score	−0.346	−0.235	0.124
2-back score	−0.277	0.012	0.240
PVSAT score	−0.021	−0.390	0.126

Notes: All numbers are Spearman’s r between factors in a bivariate correlation analysis in a group of 15 CP patients with pain self-rating of ≥4/10 for ≥6 months. There were no significant correlations using a two-tailed analysis and a statistical threshold of r P<0.05.

Abbreviations: CP, chronic pain; NRS, average pain last 24 hours, rated on a numerical rating scale before scanning; BDI, Beck Depression Inventory II score; PSQI, Pittsburgh Sleep Quality Index score; PVSAT, paced visual serial addition test.

Figure 2 Between-group differences in working memory activation.

Notes: Brown corresponds to HC > CP activation in the 2-back > 0-back condition, red to the PVSAT > 0-back condition, green to the 0-back > PVSAT condition, and magenta to the 2-back > PVSAT condition. All images are thresholded at Z>3.0, cluster level P<0.05. There was no activation above threshold for the HC < CP contrast in the 2-back > 0-back condition. Coordinates are given in MNI 152 coordinate space.
Abbreviations: HC, healthy controls; CP, chronic pain; PVSAT, paced visual serial addition test; MNI, Montreal Neurological Institute.

Figure 3 Brain regions with decreased activation at the whole brain level for contrast 0-back > 2-back with sleep problem score (PSQI), and scores for depression (BDI) and pain (NRS) as orthogonalized covariates in the CP group alone (blue), HC group alone (yellow), and the significant difference between them (HC > CP; green).

Notes: The areas where there is a significant difference in activation overlaps closely with the regions where HC have higher deactivation than CP. Thus the areas where the CP group seems to have higher activation than HC are in fact areas where HC has higher deactivation than CP. Coordinates are given in MNI 152 coordinate space.
Abbreviations: HC, healthy controls; CP, chronic pain; PSQI, Pittsburgh Sleep Quality Index score; BDI, Beck Depression Inventory II score; NRS, average pain last 24 hours, rated on a numerical rating scale before scanning; MNI, Montreal Neurological Institute.

Table 4 Clusters of significantly increased or decreased activity in the CP versus HC groups during working memory fMRI

Contrast	HC > CP		HC < CP
	Clusters	Total no of voxels	Clusters	Total no of voxels
2-back > 0-back	70	21,486	7	941
PVSAT > 0-back	39	13,755	20	5,138
PVSAT > 2-back	3	294	33	6,661

Notes: Numbers are numbers of clusters above threshold equivalent to q<0.05 false discovery rate between a group of 15 patients with pain self-rating of ≥4/10 for ≥6 months and 17 HC.

Abbreviations: CP, chronic pain; HC, healthy controls; fMRI, functional magnetic resonance imaging; PVSAT, paced visual serial addition test.

Table 5 Localization of maxima of increased and decreased BOLD signal in patients with CP versus HC for working memory tasks with sleep problems as main regressor and pain and depression scores orthogonalized

Cluster number	Cluster peak	Lateralization	Cluster voxel size	Cluster Z max	Coordinates (MNI) for cluster peak			Symmetry w/cluster number
					X (mm)	Y (mm)	Z (mm)
2-back > 0-back; HC > CP
1	Lateral occipital cortex, superior division	L and R	33,282	5.08	28	−68	37	5, 1*
2	Middle frontal gyrus	L	15,682	4.60	−52	30	22	3, 9
3	Middle frontal gyrus	R	14,706	5.04	40	34	14	2, 7
4	Superior frontal gyrus	R	10,028	4.97	25	10	55	–
5	Lateral occipital cortex, superior division	L	7,512	4.38	−46	−40	39	1
6	Paracingulate gyrus	L and R	5,522	4.59	8	19	35	5*
7	Frontal pole	L	4,793	4.19	−32	51	14	3
8	Inferior temporal gyrus, temporooccipital part	R	2,929	4.35	54	−46	−12	–
9	Inferior frontal gyrus, pars opercularis	R	2,536	4.34	54	14	9	2
10	Thalamus	L	1,735	4.13	−13	−13	−4	–
PVSAT > 0-back; HC > CP
11	Lateral occipital cortex, superior division	R	12,196	4.66	28	−67	36	14, 16
12	Middle frontal gyrus	R	6,304	4.76	30	11	58	13
13	Paracingulate gyrus	L and R	2,998	4.52	−9	2	60	12, 13*
14	Lateral occipital cortex, superior division	L	2,717	4.00	−16	−65	47	11
15	Precentral gyrus	L	2,039	4.25	−47	−2	37	–
16	Supramarginal gyrus, posterior division	L	2,031	4.20	−40	−46	39	11
17	Inferior frontal gyrus	R	1,767	4.29	38	33	15	–
0-back > PV SAT; HC > CP
18	Medial frontal lobe	L and R	9,313	−4.33	−4	62	19	18*
2-back > PV SAT; HC > CP
19	Frontal pole	L	3,454	4.03	−34	51	12	20
20	Frontal pole	R	2,114	4.02	37	50	3	19

Notes: Statistical threshold was set to Z≥3.0 and cluster P<0.05 in all analyses. Activation was judged as symmetrical if similar activation was found above threshold in the contralateral hemisphere. Symmetrical activation is marked with an

* if the bilateral activation is in the same cluster. The cluster peak coordinates are given in mm in an MNI 152 coordinate space. Lateralization: R, right side; L, left side. The Harvard-Oxford cortical and subcortical structural atlases were used in deciding which anatomical region each maximum belonged to.

Abbreviations: BOLD, blood-oxygen-level dependent; CP, chronic pain; HC, healthy controls; PVSAT, paced visual serial addition test; MNI, Montreal Neurological Institute.