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Cerebral blood flow changes associated with experimental pain stimulation in patients with major depression
Journal of Affective Disorders 107 (2008) 161 – 168 www.elsevier.com/locate/jad
Research report
Cerebral blood flow changes associated with experimental pain stimulation in patients with major depression Ariel Graff-Guerrero a,b , Francisco Pellicer c , Yazmín Mendoza-Espinosa d , Patricia Martínez-Medina e , Juan Romero-Romo b , Camilo de la Fuente-Sandoval f,⁎ a
Centre for Addiction and Mental Health, PET Centre, Toronto, Canada Centro de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Mexico Laboratorio de Neurofisiología Integrativa, Subdirección de Neurociencias, Instituto Nacional de Psiquiatría, México D.F., Mexico d Asociación Psicoanalítica Mexicana, Mexico e Centro Michoacano de Salud Mental, Morelia, Michoacán, Mexico f Laboratorio de Psiquiatría Experimental, Instituto Nacional de Neurología y Neurocirugía, México D.F. CP 14269, Mexico b
c
Received 11 April 2007; received in revised form 23 August 2007; accepted 28 August 2007 Available online 29 September 2007
Abstract Background: The clinical relationship between pain and depression has been extensively reported. The purpose of this study was to compare the cerebral blood flow (CBF) of patients with major depressive disorder (MDD) during stimulation with experimental pain tolerance or sham stimulation, before and after 2 weeks of at least partially effective antidepressant treatment (ADT), in order to determine the cerebral regions associated with pain processing in the two clinical states. Methods: Twenty-four antidepressant-free outpatients diagnosed with MDD (DSM-IV), without any pain complaints and a basal score ≥ 20 points on the Hamilton Rating Scale for Depression were included. Cerebral SPECTs were performed before and after ADT. Patients were stimulated with pain pressure tolerance (PT) or sham stimulation during the radiotracer cerebral uptake time. Results: The comparison between PT and sham stimulation before ADT showed an increase of CBF of PT stimulated patients in right temporal gyrus, left amygdale, right anterior cingulated cortex, bilateral medial frontal gyrus, bilateral insula, lingual gyrus, right precentral gyrus and left postcentral gyrus. Equal comparison after ADT showed an increase of CBF of PT stimulated patients only in left middle frontal gyrus. Limitations: The sample includes exclusively outpatients with mild–moderate depression. Conclusion: CBF before ADT increases in brain areas related with the affective and cognitive components of pain; in contrast, after ADT increases only in cognitive pain related areas. These results offer new avenues to investigate the cerebral substrate of the common relationship between pain and depression. © 2007 Elsevier B.V. All rights reserved. Keywords: Pain tolerance; Depression; Neuroimaging; SPECT; Frontal cortex; Anterior cingulate cortex; Limbic; SPM2; 99m-Tc-ECD
1. Introduction ⁎ Corresponding author. Tel.: +52 55 56 063822. E-mail address: [email protected] (C. de la Fuente-Sandoval). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.08.021
The clinical relationship between pain and depression has been extensively studied. The psychiatric comorbidity
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more frequently related to chronic pain is major depressive disorder (MDD) (Fishbain et al., 1997). Seventeen percent of patients with MDD have a pain complaint (Von Korff and Simon, 1996; Graff-Guerrero, 2001) and the patients with MDD over-dimension the emotional component of pain (Crook et al., 1989). Moreover, MDD constitutes a state of increased vulnerability to clinical pain symptoms and modifies the way one deals with them (Haythornthwaite et al., 1991). Emphasis has been placed on the close resemblance between chronic pain syndrome and MDD. Both conditions entail many common neurobiological mechanisms (Blumer et al., 1982; Von Knorring et al., 1986; Almay et al., 1987; Almay et al., 1988; Eberhard et al., 1989); and are processed in a common cerebral distributed system including limbic structures and the prefrontal cortex (Coghill et al., 1994; Drevets, 2000). Therefore the study of pain in patients with MDD may be valuable in the investigation of the pathophysiology of pain and depression. The influence of depression on pain perception is complex because patients with depression have an increased vulnerability to pain; however, the experimental measure of pain has shown that in depressed patients there is an increased pain threshold when compared to normal subjects (Von Knorring and Espvall, 1974; Von Knorring et al., 1978; Davis et al., 1979; Adler and Gattaz, 1993; Lautenbacher and Krieg, 1994; Lautenbacher et al., 1994; Lautenbacher et al., 1999; Bar et al., 2003; Dickens et al., 2003), returning this experimental measure to normal in individuals who have recovered from depression (Von Knorring and Espvall, 1974; Bar et al., 2005). The aim of the present study was to compare the cerebral blood flow (CBF) of patients with MDD during stimulation with experimental pain tolerance or sham stimulation, before and after antidepressant treatment
(ADT). This is in order to determine the cerebral regions associated with pain processing during and after a major depression episode. 2. Methods 2.1. Clinical sample Twenty-four outpatients with a clinical diagnosis of unipolar depression (according to DSM-IV criteria for MDD) were included; they were antidepressant drugfree for at least 4 weeks; eight of the patients in their first depressive episode, ten in the second episode and six in the third episode. All patients had a Hamilton Rating Scale for Depression (HRSD, 21-item version) (Hamilton, 1960) mean score equal or greater than 20 points and at least 30% reduction in the total score of the HRSD after 2 weeks of ADT. The descriptive characteristics of the sample are shown in Table 1. The twenty-four patients included for this study were obtained from a total sample of thirty-five patients. The patients were included form February 2002 to November 2006. Eleven patients quit the study or did not meet the 30% reduction criteria in the HRSD after 2 weeks of ADT. Psychiatrists not related to the objectives of this study made the diagnosis in independent clinical (open) interviews. It was confirmed in another clinical interview by a psychiatrist involved in the study, following the DSM-IV criteria. Patients with comorbidity in axis I diagnosis according to the clinical evaluation or with any medical pain complaints were excluded. Subjects with psychotic symptoms, medical or neurological diseases, substance abuse and those with any current psychopharmacologic treatment or taking any analgesic drug were also excluded.
Table 1 Characteristics of the patients included in the study
Number of patients Age in years (mean ± SD) Sex (men:women) Number of previous depressive episodes (mean ± SD) Duration of actual episode, in months (mean ± SD) Total score of Hamilton Rating Scale for Depression: Basal Final Number of patients per treatment (dose mean ± SD): Fluoxetine Paroxetine Reboxetine
PT stimulation group
Sham stimulation Group
Total
PT vs. Sham
12 29.7 ± 7.2 3:9 2.0 ± 0.7 11.9 ± 5.6
12 32.6 ± 6.4 3:9 1.8 ± 0.8 10.2 ± 5.5
24 31.2 ± 6.8 6:18 1.9 ± 0.7 11.0 ± 5.57
NS NS NS NS NS
26.6 ± 3.5 13.9 ± 4.3 ⁎⁎
26.2 ± 3.7 13.5 ± 3.9 ⁎⁎
26.4 ± 3.5 13.7 ± 4.0 ⁎⁎
NS NS
5 (28 ± 8.3) 5 (24 ± 8.9) 2 (6 ± 2.8)
5 (30 ± 10) 5 (24 ± 8.9) 2 (4 ± 0)
10 (26.3 ± 12.0) 10 (24 ± 8.4) 4 (5 ± 2)
NS NS NS
SD, standard deviation. PT, Pain tolerance. NS, no significant difference between PT vs. Sham groups. ⁎⁎ Paired T test Basal vs. Final, p b 0.005.
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Routine chemical laboratory studies, abuse drug screening, electroencephalogram, and cerebral magnetic resonance imaging or computer tomography scan were performed, and those patients with abnormalities were excluded. All female patients had negative pregnancy test results at inclusion and before each SPECT scan. The Academic and Ethic Committees of the National Psychiatric Institute approved the study and every patient signed an informed consent posterior to an explanation of the research objectives. Twelve patients were assigned to each group: pain tolerance (PT) stimulation and sham stimulation. The group assignment was open to facilitate the best age-, sex- and treatment-match between groups, and it was performed by an investigator blind to any other clinical data. The patients' characteristics and ADT are shown in Table 1. Two cerebral single photon emission computer tomography (SPECT) scans were performed to all the patients. The first was acquired previous to ADT on the same day of the basal HRSD evaluation. The second SPECT image was acquired after 2 weeks of ADT; a final HRSD was also performed on the last day. 2.2. Pain pressure tolerance The pressure tolerance (PT) was determined on the right distal phalanx of the fifth finger, in a midpoint between the distal articulation and the beginning of the nail, by an electronic pressure algometer with a modified Randall–Selitto test (Basile Analgesy-Meter). The device exerted a force that increased at a constant rate of 32 g per s over a sharp tip with 1.3 mm in diameter. The pain pressure threshold was established as the lowest force determined by the patient as painful. The PT was established as the time endured by the patient with the applied force that was determined as painful by the patient threshold. Pain threshold and PT were measured on the same day of both SPECT scans approximately 1 h before the radiotracer injection. The PTs obtained before the second SPECT scan were measured with the pain threshold as determined on the same day, and with the threshold determined before the first SPECT scan. The PT stimulation trials during the second SPECT scan were performed with the pain threshold as determined on the same day. PT measure and stimulations were performed on the right hand.
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Guerrero et al., 2004). Briefly, a catheter was placed in a vein of the left forearm of each subject 30 min before radiotracer injection. The patients remained 15 min before and 30 min after 99m-Tc-ECD administrations in a room attenuated of visual and auditory stimuli. The 99m-Tc-ECD dosage was 740–925 MBq (20–25 mCi). During the 30 min after radiotracer injection, the patients received PT stimulation or sham stimulation. The pain pressure threshold was determined 1 h prior to radiotracer injection. The duration for each PT trial was determined by the time endured by every patient, alternating with rest periods of 2 min between each stimulus trail. Sham stimulation trails had duration of 1 min alternating with rest periods of 2 min. The pressure applied during sham stimulation was the minimal pressure allowed with the PT device. Thirty minutes after the injection, after PT or sham trials, patients were placed in the SPECT camera with their heads positioned in the orbito-meatal axis to initiate data acquisition. The equipment, acquisition and reconstruction were described elsewhere (Graff-Guerrero et al., 2004). 2.4. Image analysis The images were transformed to Analyze format using MRIcro software (Rorden and Brett, 2000) (www.mricro. com) and the spatially normalization and analysis were performed using SPM2 software (SPM2, Wellcome Department of Cognitive Neurology, London; http:// www.fil.ion.ucl.ac.uk/spm) (Friston, 1995). The SPECT images were spatially normalized to the Montreal Neurological Institute (MNI) space using the SPECT template provided in SPM2. The interpolation was made by the trilinear method and the voxel size was fixed in 2 × 2 × 2 mm. The images were smoothed by a 14 × 14 ×14 mm (∼2 times FWHM). The analysis was performed having all the images in a multi-subjects design. Then, the comparisons between PT group and Sham group before and after ADT were performed with T contrasts. The significant threshold for a priori regions (frontal, temporal, parietal and limbic regions) was a p-corrected b 0.05 and clusters formed by more than 30 voxels. The statistically significant a priori regions were corrected for multiple comparisons using the false discovery rate (FDR) approach (Genovese et al., 2002). Results were graphically presented in the Talairach–Tournoux coordinate system (Talairach and Tournoux, 1988), and overlaid on the MNI template of average T1 MRI.
2.3. Cerebral SPECT and pain stimulation 2.5. Statistical analysis Cerebral blood flow imaging was done by SPECT, using 99m-Tc-dimer of ethyl-cisteinat (99m-Tc-ECD) as a radiotracer prepared as previously described (Graff-
The analysis was made using the Statistical Program for the Social Sciences (version 10.0; SPSS, Chicago, IL).
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Results are presented as means ± standard deviation (SD). To compare the demographic characteristics of the sample a T test for continuous variables and Chi2 Test for nonparametric analysis of categorical variables were used. To compare pain measurements between groups T test for independent groups was used, and between time (before and after ADT) paired T test was used. Significance was assumed at p b 0.05.
3. Results 3.1. Pressure tolerance image results The brain areas with higher CBF in the PT group vs. Sham group before and after ADT are described in Table 2 and illustrated in Fig. 1. The PT group and Sham group were composed of 12 subjects each; every
Table 2 Statistical parametric mapping results (SPM2) showing clusters of voxels having significant differences Coordinates (MNI)
Before ADT PT group N Sham group
After ADT PT group N Sham group Sham group Before ADT bAfter ADT
PT group Before ADT NAfter ADT
PT group After ADT N Before ADT
X
Y
Z
42 46 − 22 18 − 46 − 26 36 − 38 − 12 54 50 −4 − 44
−4 −60 −8 46 −52 18 −14 −12 −60 0 −10 −48 −34
− 36 12 − 30 28 26 32 2 6 2 24 42 30 46
− 32
38
2
22 8
−52 −34
− 22 16
Hemisphere
Region
Cluster size
Values T
p-corr
34 96 147 5147 1747 4802 148 1620 33 120 216 95 100
8.30 9.32 10.13 13.82 12.88 14.72 13.45 14.86 9.53 13.03 14.52 11.81 9.93
b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005
317
10.24
b0.005
81 61
4.90 4.96
b0.05 b0.05
Right Right Left Right Left Left Right Left Left Right Right Left Left
Inferior temporal gyrus Middle temporal gyrus Amygdale–hippocampus Anterior cingulate cortex and medial frontal gyrus Supramarginal gyrus Medial frontal gyrus Insula Insula Lingual gyrus Precentral gyrus Precentral gyrus Posterior cingulate Postcentral gyrus
Left
Middle frontal gyrus
− 46 − 26
Right Right
Cerebellum Pons
−8 42
− 30 36
Left Right
128 4930
9.75 13.87
b0.005 b0.005
− 46 54 46 − 26 36 − 38 56 50 −4 − 44
−52 −36 −62 18 −16 −12 0 −10 −48 −34
26 − 10 14 32 4 6 22 42 30 46
Left Right Right Left Right Left Right Right Left Left
Amygdale–hippocampus Anterior cingulate cortex Medial frontal gyrus Supramarginal gyrus Middle temporal gyrus Middle temporal gyrus Medial frontal gyrus Insula Insula Precentral gyrus Precentral gyrus Posterior cingulate Postcentral gyrus
1306 49 60 4391 142 1458 84 178 71 67
11.24 7.86 7.65 14.81 12.82 15.19 11.41 14.96 10.73 8.99
b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005
− 30 22 56
42 −18 −12
4 0 −2
Left Right Right
Middle frontal gyrus Thalamus Superior temporal gyrus
451 32 48
10.29 4.28 4.34
b0.005 b0.05 b0.05
Coordinates correspond to Montreal Neurological Institute (MNI) brain using Talairach–Tournoux system. T values correspond to the maximal voxel of each cluster. p-corr, p-corrected using false discovery rate (FDR) approach. Voxel size = 2 × 2 × 2 mm.
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Fig. 1. Statistical parametric maps displaying regions of higher cerebral blood flow before antidepressant treatment in the Pain Tolerance stimulated group (12 subjects) vs. Sham stimulated group (12 subjects). Significant areas (p-corrected FDR b 0.05, voxels per cluster N 30) are shown superimposed on a T1-average magnetic resonance brain surface render in three views. ADT, antidepressant treatment. For details of localization and cluster size see Table 2.
subject was scanned before and after ADT. There were no brain areas with higher CBF in the Sham group vs. PT group neither before nor after ADT. The comparisons between each group before and after ADT are presented in Table 2.
3.2. Pain parameter results The results and comparison are given in detail in Table 3. There was no difference between PT before ADT and PT after ADT when using the corresponding
Table 3 Pain threshold and pain tolerance (PT) of the patients included in the study
Pain pressure threshold, (mean ± SD): Before ADT (12 subjects) After ADT (12 subjects) Pain pressure tolerance, in seconds (mean ± SD): Before ADT (12 subjects) After ADT (12 subjects) Pain pressure tolerance, in seconds (mean ± SD) using basal pain pressure threshold: After ADT (12 subjects)
PT stimulation group (n = 12)
Sham stimulation group (n = 12)
Total
PT vs. Sham
11.29 ± 5.7 9.23 ± 4.06
10.08 ± 5.57 8.1 ± 4.07
10.68 ± 5.58 8.66 ± 4.02⁎
NS NS
24.58 ± 6.99 23.75 ± 3.72
23.66 ± 6.76 24.41 ± 2.53
24.12 ± 6.74 24.08 ± 3.13
NS NS
16.66 ± 6.79
17.50 ± 5.72
17.08 ± 6.12⁎⁎
NS
⁎Paired T test between before and after ADT, ⁎p b 0.05; ⁎⁎p b 0.01. SD, standard deviation. NS, no significant difference between PT and Sham groups.
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pain thresholds for each day. However, the comparison between PT before ADT and PT after ADT showed differences (p = 0.002) when measured using the pain threshold as obtained before ADT. Moreover, the comparison between pain threshold before and after ADT reached a statistical difference reduction (p = 0.04). 4. Discussion Our results illustrated the differences in the CBF changes associated with experimental pain tolerance before and after ADT. These results confirmed our implicit hypothesis stating that a difference should exist between the cerebral activation patterns of pain tolerance in patients with MDD according to the clinical state. Moreover, our psychophysical pain measures confirmed that experimental pain threshold and tolerance were increased during the depression state. Pain PT has been mainly related to the affectivemotivational and cognitive–evaluative components of pain (Graff-Guerrero et al., 2005). The brain regions activated before ADT comprised areas of the limbic system such as ACC; somatosensory areas such as insula; and cognitive-processing related areas such as frontal cortex. After ADT, the activated areas were only cognitive-processing areas. There are a few functional imaging studies in which the cerebral response to painful stimuli has been assessed in depressed patients. Among them, Derbyshire and Jones (1998) performed a study in which an increase in CBF was detected in the inferior parietal cortex during pain threshold evaluation in two chronic depressed patients. This finding was contrary to what was expected since the neural response of pain in depressed patients was hypothesized to be accentuated in similar limbic cerebral regions, for a common mechanism was to be shared in both conditions. However, Giesecke et al. (2005) found that the MDD was associated with activation in brain regions implicated in processing the affective dimension of pain in patients with fibromyalgia. Our results replicated the finding of Derbyshire and Jones (1998) in the parietal cortex before ADT (depressed state). Moreover, we found a strong pattern of activation involving limbic and cognitive pain related areas which agree with Giesecke et al.'s (2005) findings. The cerebral areas activated with pain tolerance before ADT were mainly limbic and prefrontal areas, which have been extensively related to the affective-motivational (Rainville et al., 1997) and cognitive components of pain processing (Derbyshire et al., 1997). This pattern of activation could be explained by the over affective interpretation that patients with MDD may have when subjected
to painful stimuli and could also help to explain the increase in clinical pain problems observed in depression (Von Korff and Simon, 1996; Giesecke et al., 2005). After ADT, only the middle frontal cortex was activated. This region has been associated with diverse functions, including pain intensity processing (Derbyshire et al., 1997; Graff-Guerrero et al., 2005), attentional organization during pain (Derbyshire et al., 1994), and supervisory processes and temporal behavior organization (Shallice and Burgess, 1991). The difference in the brain areas before and after ADT could reflect that the processing of the pain tolerance challenge after ADT may be related mainly to cognitive functions. While MDD has high prevalence of clinical pain complains, most of the experimental pain measurements are persistently increased (Von Knorring and Espvall, 1974; Von Knorring et al., 1978; Davis et al., 1979; Adler and Gattaz, 1993; Lautenbacher and Krieg, 1994; Lautenbacher et al., 1994; Lautenbacher et al., 1999; Bar et al., 2003; Dickens et al., 2003), with few reports describing a decrease (Merskey, 1965; Ward et al., 1982) especially those studying ischemic induced muscle pain (PineruaShuhaibar et al., 1999; Bar et al., 2005). However, a metaanalysis sustains that experimental pain threshold is higher in MDD (Dickens et al., 2003). Overall, the weight of evidence seems to support our finding of increased pain threshold and tolerance during the drug-free state. The variables such as change of experimental pain perception during the course of the disease and the effect of ADT have rarely been studied. Bar et al. (2003) reported a partial normalization of pain threshold and tolerance after recovery of depression, probably independent to the antidepressant effect. While this evidence agrees with our results after ADT, the effect of antidepressant in experimental pain perception needs further study. Lautenbacher and Krieg (1994) proposed a hypothesis to reconcile the increased vulnerability to pain complains in MDD with a simultaneous increase in experimental pain threshold. They hypothesize an impairment of the sensory system in patients with MDD which includes: hypoalgesia to phasic experimental pain due to diminished spinal and brainstem transmission, and hyperalgesia to endogenous painful sensations due to insufficient activation of inhibitory systems. This hypothesis has been successfully proved comparing experimental phasic pain (surface pain) and experimental deep somatic pain (ischemic pain) (Bar et al., 2003). However, the neurobiological mechanism of this paradox is still elusive. To the best of our knowledge, our study is the first to describe the CBF changes induced by experimental pain tolerance stimulation in depressed patients, before and after
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ADT. One important limitation of our longitudinal design is the possible test–retest effect (habituation) to pain induction and scanning procedures that could explain the differences in the brain activation patterns. However, the test–retest effect is unlikely to have an affect over the PT measures because a high reliability has been previously described (Persson et al., 2004; Jones et al., 2007). Our results cannot be generalized to all the patients with MDD, since only outpatients with mild depression, and without any pain complaint or comorbid disorders comprised the clinical sample. In addition other limitations should be considered prior to any generalization such as: the sample included multiple antidepressant drugs with short time of treatment (2 weeks); lack of placebo and healthy control groups; low response threshold (30% rather than 50% or more of HDRS decrease); small sample size (12 each group); and use of relative rather than absolute CBF. The difference in the pattern of cerebral pain activation in the two clinical (mood) states emphasizes the influence of emotion in the central processing of pain. It also illustrates the importance of bearing in mind the subjective emotional experience of pain in understanding the neurobiology and pathophysiology of depression and pain. Our results contribute to understand the common relationship between pain and depression. Role of funding source Funding for this study was provided by INPRF Internal Grant and AG-G, CdF-S, YM-E CONACyT scholarships. INPRF and CONACyT had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All other authors declare that they have no conflicts of interest.
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Rorden, C., Brett, M., 2000. Stereotaxic display of brain lesions. Behav. Neurol. 12, 191–200. Shallice, T., Burgess, P.W., 1991. Deficits in strategy application following frontal lobe damage in man. Brain 114 (Pt 2), 727–741. Talairach, J., Tournoux, P., 1988. Co-planar Stereotaxic Atlas of the Human Brain. Von Knorring, L., Almay, B.G., Johansson, F., Terenius, L., 1978. Pain perception and endorphin levels in cerebrospinal fluid. Pain 5, 359–365. Von Knorring, L., Espvall, M., 1974. Experimentally induced pain in patients with depressive disorders. Acta Psychiatr. Scand., Suppl. 255, 121–133. Von Knorring, L., Oreland, L., Haggendal, J., Magnusson, T., Almay, B., Johansson, F., 1986. Relationship between platelet MAO activity and concentrations of 5-HIAA and HVA in cerebrospinal fluid in chronic pain patients. J. Neural Transm. 66, 37–46. Von Korff, M., Simon, G., 1996. The relationship between pain and depression. Br. J. Psychiatr., Suppl. 101–108. Ward, N.G., Bloom, V.L., Dworkin, S., Fawcett, J., Narasimhachari, N., Friedel, R.O., 1982. Psychobiological markers in coexisting pain and depression: toward a unified theory. J. Clin. Psychiatry 43, 32–41.
Research report
Cerebral blood flow changes associated with experimental pain stimulation in patients with major depression Ariel Graff-Guerrero a,b , Francisco Pellicer c , Yazmín Mendoza-Espinosa d , Patricia Martínez-Medina e , Juan Romero-Romo b , Camilo de la Fuente-Sandoval f,⁎ a
Centre for Addiction and Mental Health, PET Centre, Toronto, Canada Centro de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Mexico Laboratorio de Neurofisiología Integrativa, Subdirección de Neurociencias, Instituto Nacional de Psiquiatría, México D.F., Mexico d Asociación Psicoanalítica Mexicana, Mexico e Centro Michoacano de Salud Mental, Morelia, Michoacán, Mexico f Laboratorio de Psiquiatría Experimental, Instituto Nacional de Neurología y Neurocirugía, México D.F. CP 14269, Mexico b
c
Received 11 April 2007; received in revised form 23 August 2007; accepted 28 August 2007 Available online 29 September 2007
Abstract Background: The clinical relationship between pain and depression has been extensively reported. The purpose of this study was to compare the cerebral blood flow (CBF) of patients with major depressive disorder (MDD) during stimulation with experimental pain tolerance or sham stimulation, before and after 2 weeks of at least partially effective antidepressant treatment (ADT), in order to determine the cerebral regions associated with pain processing in the two clinical states. Methods: Twenty-four antidepressant-free outpatients diagnosed with MDD (DSM-IV), without any pain complaints and a basal score ≥ 20 points on the Hamilton Rating Scale for Depression were included. Cerebral SPECTs were performed before and after ADT. Patients were stimulated with pain pressure tolerance (PT) or sham stimulation during the radiotracer cerebral uptake time. Results: The comparison between PT and sham stimulation before ADT showed an increase of CBF of PT stimulated patients in right temporal gyrus, left amygdale, right anterior cingulated cortex, bilateral medial frontal gyrus, bilateral insula, lingual gyrus, right precentral gyrus and left postcentral gyrus. Equal comparison after ADT showed an increase of CBF of PT stimulated patients only in left middle frontal gyrus. Limitations: The sample includes exclusively outpatients with mild–moderate depression. Conclusion: CBF before ADT increases in brain areas related with the affective and cognitive components of pain; in contrast, after ADT increases only in cognitive pain related areas. These results offer new avenues to investigate the cerebral substrate of the common relationship between pain and depression. © 2007 Elsevier B.V. All rights reserved. Keywords: Pain tolerance; Depression; Neuroimaging; SPECT; Frontal cortex; Anterior cingulate cortex; Limbic; SPM2; 99m-Tc-ECD
1. Introduction ⁎ Corresponding author. Tel.: +52 55 56 063822. E-mail address: [email protected] (C. de la Fuente-Sandoval). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.08.021
The clinical relationship between pain and depression has been extensively studied. The psychiatric comorbidity
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more frequently related to chronic pain is major depressive disorder (MDD) (Fishbain et al., 1997). Seventeen percent of patients with MDD have a pain complaint (Von Korff and Simon, 1996; Graff-Guerrero, 2001) and the patients with MDD over-dimension the emotional component of pain (Crook et al., 1989). Moreover, MDD constitutes a state of increased vulnerability to clinical pain symptoms and modifies the way one deals with them (Haythornthwaite et al., 1991). Emphasis has been placed on the close resemblance between chronic pain syndrome and MDD. Both conditions entail many common neurobiological mechanisms (Blumer et al., 1982; Von Knorring et al., 1986; Almay et al., 1987; Almay et al., 1988; Eberhard et al., 1989); and are processed in a common cerebral distributed system including limbic structures and the prefrontal cortex (Coghill et al., 1994; Drevets, 2000). Therefore the study of pain in patients with MDD may be valuable in the investigation of the pathophysiology of pain and depression. The influence of depression on pain perception is complex because patients with depression have an increased vulnerability to pain; however, the experimental measure of pain has shown that in depressed patients there is an increased pain threshold when compared to normal subjects (Von Knorring and Espvall, 1974; Von Knorring et al., 1978; Davis et al., 1979; Adler and Gattaz, 1993; Lautenbacher and Krieg, 1994; Lautenbacher et al., 1994; Lautenbacher et al., 1999; Bar et al., 2003; Dickens et al., 2003), returning this experimental measure to normal in individuals who have recovered from depression (Von Knorring and Espvall, 1974; Bar et al., 2005). The aim of the present study was to compare the cerebral blood flow (CBF) of patients with MDD during stimulation with experimental pain tolerance or sham stimulation, before and after antidepressant treatment
(ADT). This is in order to determine the cerebral regions associated with pain processing during and after a major depression episode. 2. Methods 2.1. Clinical sample Twenty-four outpatients with a clinical diagnosis of unipolar depression (according to DSM-IV criteria for MDD) were included; they were antidepressant drugfree for at least 4 weeks; eight of the patients in their first depressive episode, ten in the second episode and six in the third episode. All patients had a Hamilton Rating Scale for Depression (HRSD, 21-item version) (Hamilton, 1960) mean score equal or greater than 20 points and at least 30% reduction in the total score of the HRSD after 2 weeks of ADT. The descriptive characteristics of the sample are shown in Table 1. The twenty-four patients included for this study were obtained from a total sample of thirty-five patients. The patients were included form February 2002 to November 2006. Eleven patients quit the study or did not meet the 30% reduction criteria in the HRSD after 2 weeks of ADT. Psychiatrists not related to the objectives of this study made the diagnosis in independent clinical (open) interviews. It was confirmed in another clinical interview by a psychiatrist involved in the study, following the DSM-IV criteria. Patients with comorbidity in axis I diagnosis according to the clinical evaluation or with any medical pain complaints were excluded. Subjects with psychotic symptoms, medical or neurological diseases, substance abuse and those with any current psychopharmacologic treatment or taking any analgesic drug were also excluded.
Table 1 Characteristics of the patients included in the study
Number of patients Age in years (mean ± SD) Sex (men:women) Number of previous depressive episodes (mean ± SD) Duration of actual episode, in months (mean ± SD) Total score of Hamilton Rating Scale for Depression: Basal Final Number of patients per treatment (dose mean ± SD): Fluoxetine Paroxetine Reboxetine
PT stimulation group
Sham stimulation Group
Total
PT vs. Sham
12 29.7 ± 7.2 3:9 2.0 ± 0.7 11.9 ± 5.6
12 32.6 ± 6.4 3:9 1.8 ± 0.8 10.2 ± 5.5
24 31.2 ± 6.8 6:18 1.9 ± 0.7 11.0 ± 5.57
NS NS NS NS NS
26.6 ± 3.5 13.9 ± 4.3 ⁎⁎
26.2 ± 3.7 13.5 ± 3.9 ⁎⁎
26.4 ± 3.5 13.7 ± 4.0 ⁎⁎
NS NS
5 (28 ± 8.3) 5 (24 ± 8.9) 2 (6 ± 2.8)
5 (30 ± 10) 5 (24 ± 8.9) 2 (4 ± 0)
10 (26.3 ± 12.0) 10 (24 ± 8.4) 4 (5 ± 2)
NS NS NS
SD, standard deviation. PT, Pain tolerance. NS, no significant difference between PT vs. Sham groups. ⁎⁎ Paired T test Basal vs. Final, p b 0.005.
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Routine chemical laboratory studies, abuse drug screening, electroencephalogram, and cerebral magnetic resonance imaging or computer tomography scan were performed, and those patients with abnormalities were excluded. All female patients had negative pregnancy test results at inclusion and before each SPECT scan. The Academic and Ethic Committees of the National Psychiatric Institute approved the study and every patient signed an informed consent posterior to an explanation of the research objectives. Twelve patients were assigned to each group: pain tolerance (PT) stimulation and sham stimulation. The group assignment was open to facilitate the best age-, sex- and treatment-match between groups, and it was performed by an investigator blind to any other clinical data. The patients' characteristics and ADT are shown in Table 1. Two cerebral single photon emission computer tomography (SPECT) scans were performed to all the patients. The first was acquired previous to ADT on the same day of the basal HRSD evaluation. The second SPECT image was acquired after 2 weeks of ADT; a final HRSD was also performed on the last day. 2.2. Pain pressure tolerance The pressure tolerance (PT) was determined on the right distal phalanx of the fifth finger, in a midpoint between the distal articulation and the beginning of the nail, by an electronic pressure algometer with a modified Randall–Selitto test (Basile Analgesy-Meter). The device exerted a force that increased at a constant rate of 32 g per s over a sharp tip with 1.3 mm in diameter. The pain pressure threshold was established as the lowest force determined by the patient as painful. The PT was established as the time endured by the patient with the applied force that was determined as painful by the patient threshold. Pain threshold and PT were measured on the same day of both SPECT scans approximately 1 h before the radiotracer injection. The PTs obtained before the second SPECT scan were measured with the pain threshold as determined on the same day, and with the threshold determined before the first SPECT scan. The PT stimulation trials during the second SPECT scan were performed with the pain threshold as determined on the same day. PT measure and stimulations were performed on the right hand.
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Guerrero et al., 2004). Briefly, a catheter was placed in a vein of the left forearm of each subject 30 min before radiotracer injection. The patients remained 15 min before and 30 min after 99m-Tc-ECD administrations in a room attenuated of visual and auditory stimuli. The 99m-Tc-ECD dosage was 740–925 MBq (20–25 mCi). During the 30 min after radiotracer injection, the patients received PT stimulation or sham stimulation. The pain pressure threshold was determined 1 h prior to radiotracer injection. The duration for each PT trial was determined by the time endured by every patient, alternating with rest periods of 2 min between each stimulus trail. Sham stimulation trails had duration of 1 min alternating with rest periods of 2 min. The pressure applied during sham stimulation was the minimal pressure allowed with the PT device. Thirty minutes after the injection, after PT or sham trials, patients were placed in the SPECT camera with their heads positioned in the orbito-meatal axis to initiate data acquisition. The equipment, acquisition and reconstruction were described elsewhere (Graff-Guerrero et al., 2004). 2.4. Image analysis The images were transformed to Analyze format using MRIcro software (Rorden and Brett, 2000) (www.mricro. com) and the spatially normalization and analysis were performed using SPM2 software (SPM2, Wellcome Department of Cognitive Neurology, London; http:// www.fil.ion.ucl.ac.uk/spm) (Friston, 1995). The SPECT images were spatially normalized to the Montreal Neurological Institute (MNI) space using the SPECT template provided in SPM2. The interpolation was made by the trilinear method and the voxel size was fixed in 2 × 2 × 2 mm. The images were smoothed by a 14 × 14 ×14 mm (∼2 times FWHM). The analysis was performed having all the images in a multi-subjects design. Then, the comparisons between PT group and Sham group before and after ADT were performed with T contrasts. The significant threshold for a priori regions (frontal, temporal, parietal and limbic regions) was a p-corrected b 0.05 and clusters formed by more than 30 voxels. The statistically significant a priori regions were corrected for multiple comparisons using the false discovery rate (FDR) approach (Genovese et al., 2002). Results were graphically presented in the Talairach–Tournoux coordinate system (Talairach and Tournoux, 1988), and overlaid on the MNI template of average T1 MRI.
2.3. Cerebral SPECT and pain stimulation 2.5. Statistical analysis Cerebral blood flow imaging was done by SPECT, using 99m-Tc-dimer of ethyl-cisteinat (99m-Tc-ECD) as a radiotracer prepared as previously described (Graff-
The analysis was made using the Statistical Program for the Social Sciences (version 10.0; SPSS, Chicago, IL).
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Results are presented as means ± standard deviation (SD). To compare the demographic characteristics of the sample a T test for continuous variables and Chi2 Test for nonparametric analysis of categorical variables were used. To compare pain measurements between groups T test for independent groups was used, and between time (before and after ADT) paired T test was used. Significance was assumed at p b 0.05.
3. Results 3.1. Pressure tolerance image results The brain areas with higher CBF in the PT group vs. Sham group before and after ADT are described in Table 2 and illustrated in Fig. 1. The PT group and Sham group were composed of 12 subjects each; every
Table 2 Statistical parametric mapping results (SPM2) showing clusters of voxels having significant differences Coordinates (MNI)
Before ADT PT group N Sham group
After ADT PT group N Sham group Sham group Before ADT bAfter ADT
PT group Before ADT NAfter ADT
PT group After ADT N Before ADT
X
Y
Z
42 46 − 22 18 − 46 − 26 36 − 38 − 12 54 50 −4 − 44
−4 −60 −8 46 −52 18 −14 −12 −60 0 −10 −48 −34
− 36 12 − 30 28 26 32 2 6 2 24 42 30 46
− 32
38
2
22 8
−52 −34
− 22 16
Hemisphere
Region
Cluster size
Values T
p-corr
34 96 147 5147 1747 4802 148 1620 33 120 216 95 100
8.30 9.32 10.13 13.82 12.88 14.72 13.45 14.86 9.53 13.03 14.52 11.81 9.93
b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005
317
10.24
b0.005
81 61
4.90 4.96
b0.05 b0.05
Right Right Left Right Left Left Right Left Left Right Right Left Left
Inferior temporal gyrus Middle temporal gyrus Amygdale–hippocampus Anterior cingulate cortex and medial frontal gyrus Supramarginal gyrus Medial frontal gyrus Insula Insula Lingual gyrus Precentral gyrus Precentral gyrus Posterior cingulate Postcentral gyrus
Left
Middle frontal gyrus
− 46 − 26
Right Right
Cerebellum Pons
−8 42
− 30 36
Left Right
128 4930
9.75 13.87
b0.005 b0.005
− 46 54 46 − 26 36 − 38 56 50 −4 − 44
−52 −36 −62 18 −16 −12 0 −10 −48 −34
26 − 10 14 32 4 6 22 42 30 46
Left Right Right Left Right Left Right Right Left Left
Amygdale–hippocampus Anterior cingulate cortex Medial frontal gyrus Supramarginal gyrus Middle temporal gyrus Middle temporal gyrus Medial frontal gyrus Insula Insula Precentral gyrus Precentral gyrus Posterior cingulate Postcentral gyrus
1306 49 60 4391 142 1458 84 178 71 67
11.24 7.86 7.65 14.81 12.82 15.19 11.41 14.96 10.73 8.99
b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005 b0.005
− 30 22 56
42 −18 −12
4 0 −2
Left Right Right
Middle frontal gyrus Thalamus Superior temporal gyrus
451 32 48
10.29 4.28 4.34
b0.005 b0.05 b0.05
Coordinates correspond to Montreal Neurological Institute (MNI) brain using Talairach–Tournoux system. T values correspond to the maximal voxel of each cluster. p-corr, p-corrected using false discovery rate (FDR) approach. Voxel size = 2 × 2 × 2 mm.
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Fig. 1. Statistical parametric maps displaying regions of higher cerebral blood flow before antidepressant treatment in the Pain Tolerance stimulated group (12 subjects) vs. Sham stimulated group (12 subjects). Significant areas (p-corrected FDR b 0.05, voxels per cluster N 30) are shown superimposed on a T1-average magnetic resonance brain surface render in three views. ADT, antidepressant treatment. For details of localization and cluster size see Table 2.
subject was scanned before and after ADT. There were no brain areas with higher CBF in the Sham group vs. PT group neither before nor after ADT. The comparisons between each group before and after ADT are presented in Table 2.
3.2. Pain parameter results The results and comparison are given in detail in Table 3. There was no difference between PT before ADT and PT after ADT when using the corresponding
Table 3 Pain threshold and pain tolerance (PT) of the patients included in the study
Pain pressure threshold, (mean ± SD): Before ADT (12 subjects) After ADT (12 subjects) Pain pressure tolerance, in seconds (mean ± SD): Before ADT (12 subjects) After ADT (12 subjects) Pain pressure tolerance, in seconds (mean ± SD) using basal pain pressure threshold: After ADT (12 subjects)
PT stimulation group (n = 12)
Sham stimulation group (n = 12)
Total
PT vs. Sham
11.29 ± 5.7 9.23 ± 4.06
10.08 ± 5.57 8.1 ± 4.07
10.68 ± 5.58 8.66 ± 4.02⁎
NS NS
24.58 ± 6.99 23.75 ± 3.72
23.66 ± 6.76 24.41 ± 2.53
24.12 ± 6.74 24.08 ± 3.13
NS NS
16.66 ± 6.79
17.50 ± 5.72
17.08 ± 6.12⁎⁎
NS
⁎Paired T test between before and after ADT, ⁎p b 0.05; ⁎⁎p b 0.01. SD, standard deviation. NS, no significant difference between PT and Sham groups.
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pain thresholds for each day. However, the comparison between PT before ADT and PT after ADT showed differences (p = 0.002) when measured using the pain threshold as obtained before ADT. Moreover, the comparison between pain threshold before and after ADT reached a statistical difference reduction (p = 0.04). 4. Discussion Our results illustrated the differences in the CBF changes associated with experimental pain tolerance before and after ADT. These results confirmed our implicit hypothesis stating that a difference should exist between the cerebral activation patterns of pain tolerance in patients with MDD according to the clinical state. Moreover, our psychophysical pain measures confirmed that experimental pain threshold and tolerance were increased during the depression state. Pain PT has been mainly related to the affectivemotivational and cognitive–evaluative components of pain (Graff-Guerrero et al., 2005). The brain regions activated before ADT comprised areas of the limbic system such as ACC; somatosensory areas such as insula; and cognitive-processing related areas such as frontal cortex. After ADT, the activated areas were only cognitive-processing areas. There are a few functional imaging studies in which the cerebral response to painful stimuli has been assessed in depressed patients. Among them, Derbyshire and Jones (1998) performed a study in which an increase in CBF was detected in the inferior parietal cortex during pain threshold evaluation in two chronic depressed patients. This finding was contrary to what was expected since the neural response of pain in depressed patients was hypothesized to be accentuated in similar limbic cerebral regions, for a common mechanism was to be shared in both conditions. However, Giesecke et al. (2005) found that the MDD was associated with activation in brain regions implicated in processing the affective dimension of pain in patients with fibromyalgia. Our results replicated the finding of Derbyshire and Jones (1998) in the parietal cortex before ADT (depressed state). Moreover, we found a strong pattern of activation involving limbic and cognitive pain related areas which agree with Giesecke et al.'s (2005) findings. The cerebral areas activated with pain tolerance before ADT were mainly limbic and prefrontal areas, which have been extensively related to the affective-motivational (Rainville et al., 1997) and cognitive components of pain processing (Derbyshire et al., 1997). This pattern of activation could be explained by the over affective interpretation that patients with MDD may have when subjected
to painful stimuli and could also help to explain the increase in clinical pain problems observed in depression (Von Korff and Simon, 1996; Giesecke et al., 2005). After ADT, only the middle frontal cortex was activated. This region has been associated with diverse functions, including pain intensity processing (Derbyshire et al., 1997; Graff-Guerrero et al., 2005), attentional organization during pain (Derbyshire et al., 1994), and supervisory processes and temporal behavior organization (Shallice and Burgess, 1991). The difference in the brain areas before and after ADT could reflect that the processing of the pain tolerance challenge after ADT may be related mainly to cognitive functions. While MDD has high prevalence of clinical pain complains, most of the experimental pain measurements are persistently increased (Von Knorring and Espvall, 1974; Von Knorring et al., 1978; Davis et al., 1979; Adler and Gattaz, 1993; Lautenbacher and Krieg, 1994; Lautenbacher et al., 1994; Lautenbacher et al., 1999; Bar et al., 2003; Dickens et al., 2003), with few reports describing a decrease (Merskey, 1965; Ward et al., 1982) especially those studying ischemic induced muscle pain (PineruaShuhaibar et al., 1999; Bar et al., 2005). However, a metaanalysis sustains that experimental pain threshold is higher in MDD (Dickens et al., 2003). Overall, the weight of evidence seems to support our finding of increased pain threshold and tolerance during the drug-free state. The variables such as change of experimental pain perception during the course of the disease and the effect of ADT have rarely been studied. Bar et al. (2003) reported a partial normalization of pain threshold and tolerance after recovery of depression, probably independent to the antidepressant effect. While this evidence agrees with our results after ADT, the effect of antidepressant in experimental pain perception needs further study. Lautenbacher and Krieg (1994) proposed a hypothesis to reconcile the increased vulnerability to pain complains in MDD with a simultaneous increase in experimental pain threshold. They hypothesize an impairment of the sensory system in patients with MDD which includes: hypoalgesia to phasic experimental pain due to diminished spinal and brainstem transmission, and hyperalgesia to endogenous painful sensations due to insufficient activation of inhibitory systems. This hypothesis has been successfully proved comparing experimental phasic pain (surface pain) and experimental deep somatic pain (ischemic pain) (Bar et al., 2003). However, the neurobiological mechanism of this paradox is still elusive. To the best of our knowledge, our study is the first to describe the CBF changes induced by experimental pain tolerance stimulation in depressed patients, before and after
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ADT. One important limitation of our longitudinal design is the possible test–retest effect (habituation) to pain induction and scanning procedures that could explain the differences in the brain activation patterns. However, the test–retest effect is unlikely to have an affect over the PT measures because a high reliability has been previously described (Persson et al., 2004; Jones et al., 2007). Our results cannot be generalized to all the patients with MDD, since only outpatients with mild depression, and without any pain complaint or comorbid disorders comprised the clinical sample. In addition other limitations should be considered prior to any generalization such as: the sample included multiple antidepressant drugs with short time of treatment (2 weeks); lack of placebo and healthy control groups; low response threshold (30% rather than 50% or more of HDRS decrease); small sample size (12 each group); and use of relative rather than absolute CBF. The difference in the pattern of cerebral pain activation in the two clinical (mood) states emphasizes the influence of emotion in the central processing of pain. It also illustrates the importance of bearing in mind the subjective emotional experience of pain in understanding the neurobiology and pathophysiology of depression and pain. Our results contribute to understand the common relationship between pain and depression. Role of funding source Funding for this study was provided by INPRF Internal Grant and AG-G, CdF-S, YM-E CONACyT scholarships. INPRF and CONACyT had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All other authors declare that they have no conflicts of interest.
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