- Email: [email protected]
The functional neuroanatomy of mental pain in depression
Psychiatry Research: Neuroimaging 181 (2010) 141–144
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s
The functional neuroanatomy of mental pain in depression Kees van Heeringen⁎, Dirk Van den Abbeele, Myriam Vervaet, Lieslot Soenen, Kurt Audenaert University Department of Psychiatry, Medical Psychology Unit for Suicide Research, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium
a r t i c l e
i n f o
Article history: Received 12 June 2007 Received in revised form 12 June 2009 Accepted 28 July 2009 Keywords: Depression Pain Imaging rCBF SPECT
a b s t r a c t This study aimed at determining the functional neuroanatomy of mental pain, a hitherto neglected symptom in the study of depression, which according to DSM-IV is stronglylinked with suicide. Mental pain (measured with the Orbach & Mikulincer Mental Pain Scale), suicidal ideation (measured using the Hamilton Rating Scale for Depression), hopelessness (measured using Beck's Hopelessness Scale), and regional cerebral blood flow as measured with single photon emission computed tomography were assessed in 39 depressed individuals. Levels of mental pain were significantly and positively associated with suicidal ideation and levels of hopelessness. When compared with patients with low levels of mental pain, those with high levels of mental pain showed relatively increased perfusion in the right dorsolateral prefrontal cortex, occipital cortex and inferior frontal gyrus and in the left inferior temporal gyrus, and relatively decreased perfusion at the medulla. The findings indicate that mental pain in depressed patients is associated with an increased risk of suicide and that high levels of mental pain are associated with changes in perfusion in brain areas that are involved in the regulation of emotions. Further study is warranted to understand whether this association reflects increased emotional processing or decreased cognitive control over mental pain in depressed individuals. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction An association between physical pain and depression is well documented, but depressed patients may also suffer from emotional pain. According to DSM-IV, depression can be excruciatingly painful, to such an extent that it may very well lead to suicide (American Psychiatric Association, 2004). Emotional pain has indeed been described in association with suicidal behaviour using terms such as 'psychache' (Shneidman, 1996), 'mental pain' (Orbach et al., 2003) or 'psychological pain' (Mee et al., 2006). In view of the fact that depressive episodes (and suicidal behaviour) are very commonly precipitated by interpersonal problems such as rejection, it is likely that the term ‘social pain’ (Eisenberger and Lieberman, 2004) describes a comparable emotional state. It has been suggested that an overlap between physical pain and social pain is an evolutionary development to aid social animals in responding to threats to inclusion (MacDonald and Leary, 2005). The induction of social pain in healthy volunteers is associated with increased activity in the anterior cingulate cortex and the right ventral prefrontal cortex, suggesting that social pain is analogous in its neurocognitive function to physical pain, alerting individuals when there is sustained injury to social connections, allowing restorative
measures to be taken (Eisenberger et al., 2003). In order for such measures to be taken, the neural circuitry involved in emotion regulation must function adequately, which may not be the case in depression. Neuroimaging studies in depressed patients have indeed shown deficiencies in brain areas that play a key role in emotion regulation and that include the dorsolateral prefrontal and anterior cingulate cortex (Beauregard et al., 2006; Leppänen, 2006). It is not yet clear why some depressed patients experience mental pain and others do not. In other words, it is not clear how the neural circuitry involved in emotion regulation functions differently in the case of mental pain. It can be expected that the study of the neural correlates of mental pain in depressed patients may help in understanding the nature of this psychopathological phenomenon, and thus contribute to the prevention of suffering and its potentially devastating consequences such as suicide. Based on a thorough review of the existing literature, it was recently suggested that future research might investigate a putative psychological pain system through neuroimaging technology (Mee et al., 2006). This study therefore aimed at examining whether such pain is associated with changes in activity in particular areas of the brain as revealed by functional neuroimaging. 2. Methods
⁎ Corresponding author. Unit for Suicide Research, Department of Psychiatry, University Hospital, De Pintelaan 185, 9000 Gent, Belgium. Tel.: +32 9 332 43 30; fax: +32 9 332 49 89. E-mail address: [email protected] (K. van Heeringen). 0925-4927/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2009.07.011
2.1. Subjects The study group consisted of 39 consecutively admitted inpatients at the Centre for Mood and Anxiety Disorders of the University
142
K. van Heeringen et al. / Psychiatry Research: Neuroimaging 181 (2010) 141–144
Department of Psychiatry, University Hospital Gent (Belgium). The study sample included 22 females and 17 males who were treated for a depressive episode according to DSM-IV-TR criteria.
Table 2 Brain areas (with Talairach coordinates) with relative hyperperfusion in patients with high versus patients with low levels of mental pain.
2.2. Measures Severity of depressive symptoms was assessed using the Beck Depression Inventory (BDI). Mental pain was assessed using the English version of the Orbach & Mikulincer Mental Pain Scale (OMMP) (Orbach et al., 2003), which was translated into Dutch and then back translated. The OMMP is self-ratied on a 5-point Likert scale with 44 items. Higher values on each item reflect stronger mental pain. The occurrence and severity of suicidal ideation and the level of hopelessness, both associated with an increased risk of suicide among depressed patients, were assessed using item 9 of the BDI and Beck's Hopelessness Scale (BHS), respectively. Regional cerebral blood flow was measured by means of single photon emission computed tomography (SPECT). All subjects were injected with 925 MBq 99mTc-ECD (Dupont Pharmaceuticals Ltd., Brussels, Belgium) under resting conditions. SPECT was performed on a Toshiba GCA-9300A triple headed camera with high resolution lead fan beam collimators and transmission CT sources. Fan beam projections were converted to 128 × 128 parallel data. A triple-energy window scatter correction was performed on the projection data. Non-uniform attenuation sets were calculated and the image datasets were automatically registered to an anatomical standardized stereotactic template using Brain Registration and Automated SPET semi-quantification (BRASS). Statistical analysis of images was performed using SPM5 (Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London), implanted in a Matlab 7 environment (MathWorks, Inc.). All images were preprocessed for spatial normalization into the Montreal Neurological Institute (MNI) template to remove intersubject anatomic variability, and then smoothed with a FWHM 16-mm Gaussian kernel to increase the signal-to-noise ratio and to account for subtle variations in anatomic structures. With relative masking, mean global calculation and proportional normalization, Tcontrasts were set up to define the regions of relative hyperperfusion and hypoperfusion (uncorrected P b 0.005, extent threshold 50). Conversion of coordinates from the MNI template to the Talairach system was carried out using Matthew Brett's mni2tal tool (see http: imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach) to enable approximate labelling of Brodmann areas.
Brain region (BA)
Side
Inferior frontal gyrus (44) Occipital cortex (19) Dorsolateral prefrontal cortex (9) Inferior temporal cortex (20)
Right 48, 8, 12
5.46
4.36
24 0.000
Right 13, −77, 31 Right 13, 39, 30
5.04 4.28
4.12 3.65
24 0.000 24 0.000
3.90
3.40
24 0.000
Left
Coordinates (x, y, z)
−47, −30, −18
T value Z value df
P value (uncorrected)
2.4. Ethical approval The local ethics committee approved the study. After complete description of the study to the subjects, written informed consent was obtained. 3. Results The mean age of the 39 individuals in this study was 40.8 years (S.D.=14.7, range=17–70). The mean BDI score at the day of the neuroimaging session was 28.8 (S.D.=13, range=9–54), while the mean OMMP score at that moment was 135 (S.D.=32.2, range=68– 192). Table 1 shows demographic and clinical data for the study groups. There was no correlation between total scores on the BDI and the OMMP, but the OMMP score correlated significantly with the score on the BDI ‘suicidality’ item (item 9; Spearman rho = 0.425; P b 0.05) and with the total score on the BHS (Spearman rho = 0.517; P b 0.001). Independent sample t-tests showed a significantly increased level of regional cerebral blood flow in the right occipital cortex, the left inferior temporal gyrus, the right dorsolateral prefrontal cortex and the right inferior frontal gyrus in the group of patients with high levels of mental pain compared with patients in the group with low levels (Table 2 and Fig. 1). A significantly decreased level of regional blood flow was found in the left medulla at pontine levels in the group of patients with high levels of mental pain compared with those with low levels (Talairach coordinates: x = 1, y = 16, z = 20; t = 4.46; Z score = 3.77; P value = 0.000). Correlational analyses show comparable findings in terms of involved prefrontal regions and levels of significance. Correction for age or severity of depression did not affect the results.
2.3. Statistical analysis 4. Discussion The study population was divided into three groups of 13 patients based on OMMP scores, thus constituting groups with low, medium and high levels of mental pain. To explore the functional characteristics of mental pain, the group with low levels of mental pain (mean OMMP score 89.8, range 68–121) was compared with the group with high levels (mean 170.2, range 153–192) regarding regional cerebral blood flow and clinical characteristics using a two-sample t-test.
This study is the first to report changes in brain functioning in association with mental pain in depressed patients. The results show that levels of mental pain do not correlate with severity of depression but are associated with an increased risk of suicide. The severity of mental pain in these depressed patients is associated with changes in cerebral blood flow in areas of the brain that are involved in the processing of emotions.
Table 1 Demographic and clinical characteristics of study group, according to level of mental pain.
Age (±S.D.) Gender (M/F) Beck Depression Inventory (±S.D.) Beck Hopelessness Scale (±S.D.) OMMP (±S.D.) *P b 0.05; **P b 0.001.
Low
Medium
High
High versus low
42.5 years (±15) 6/7 29.3 (±11.6) 8.77 (±4.6) 89.8 (±7.2)
35.15 years (±12.9) 5/8 32.5 (±11.9) 12.92 (±2.5) 136.1 (±9.5)
44.77 years (±15.3) 6/7 31.6 (±13.9) 13.31 (±3.6) 170.2 (±12)
t = − 0.37 χ2 = 1.92 t = − 1.62 t = − 2.73⁎ t = − 1.55⁎⁎
K. van Heeringen et al. / Psychiatry Research: Neuroimaging 181 (2010) 141–144
143
Fig. 1. Brain areas with relative hyperperfusion in depressed patients with high levels of mental pain compared with those with low levels of mental pain.
The interpretation of the demonstrated associations between cerebral blood flow and levels of mental pain can only be based upon speculation. However, in particular with regard to the involvement of the dorsolateral prefrontal cortex, the current findings, taken together with those from previous studies, may contribute to our understanding of the reasons why depressed individuals may become suicidal. Processing of emotional signals, in general, involves analysis of stimulus features (subserved by the occipitotemporal cortex), emotion recognition and emotional response (amygdala, insula, orbitofrontal cortex and ventral striatum) and emotion regulation (anterior cingulate cortex, and dorsomedial and dorsolateral prefrontal cortex) (Leppänen, 2006). The observation that depressed individuals become suicidal when they perceive their emotional state as painful and incapable of change (American Psychiatric Association, 2004) suggests a strong and persisting emotional input at the prefrontal level. While changes in dorsolateral activity in resting conditions in depressed individuals are heterogeneous (Fitzgerald et al., 2006), a comparative hyperactivity of the dorsolateral prefrontal cortex of depressed individuals is found in activation studies. Experimental studies in which depressed participants and healthy controls are exposed to pain (Bär et al., 2007) or perform cognitive tasks such as a working memory task (Fitzgerald et al., 2008; Walter et al., 2007), the Stroop task (Wagner et al., 2006) or the n-back test (Fitzgerald et al., 2008; Matsuo et al., 2007) indeed show greater dorsolateral activation in depressed subjects than in healthy controls. It is unclear whether the relative hyperactivity in this region in depressed individuals is related to prefrontal pathology leading to abnormal cognitive and affective control processes. In any case, the outcome appears to depend on the nature of the stimulus. Increased dorsolateral activity after exposure to pain stimuli is associated with increased pain thresholds in depression (and thus increased antinociception), while such hyperactivity during cognitive tasks is associated with similar (n-back; Fitzgerald et al., 2008; Matsuo et al., 2007) or worse (Tower of London; Fitzgerald et al., 2008) levels of performance. The findings from the current study indicate that dorsolateral hyperactivity is associated with increased levels of mental pain, but the interpretation of this association needs further study.
The current findings suggest an explanation for the heterogeneous nature of the changes in dorsolateral functioning in depressed individuals (Fitzgerald et al., 2006) by showing that the presence or absence of particular emotional phenomena or symptoms influences dorsolateral activity in depressed subjects. Further study is clearly needed to show whether changes in regional cerebral activity correlating with mental pain are associated with changes in cognitive mechanisms of control over such emotions, and to determine whether such changes in activity and functioning are amenable to treatment. Acknowledgement This study was supported by a research grant from Eli Lilly Benelux. References American Psychiatric Association, 2004. Diagnostic and Statistical Manual of Mental Disorders, fourth edition. APA, Washington, DC. Bär, K.J., Wagner, G., Koschke, M., Boettger, S., Boettger, M.K., Schlosser, R., Sauer, H., 2007. Increased prefrontal activation during pain perception in major depression. Biological Psychiatry 11, 1281–1287. Beauregard, M., Paquette, V., Lévesque, J., 2006. Dysfunction in the neural circuitry of emotional self-regulation in major depressive disorder. NeuroReport 17, 843–846. Eisenberger, N.I., Lieberman, M.D., 2004. Why rejection hurts: a common neural alarm system for physical and social pain. Trends in Cognitive Science 7, 294–300. Eisenberger, N.I., Lieberman, M.D., Williams, K.D., 2003. Does rejection hurt? An fMRI study of social exclusion. Science 302, 290–292. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research: Neuroimaging 148, 33–45. Fitzgerald, P.B., Srithiran, A., Benitez, J., Daskalakis, Z.Z., Oxley, T.J., Kulkarni, J., Egan, G.F., 2008. An fMRI study of prefrontal brain activation during multiple tasks in patients with major depression. Human Brain Mapping 29, 490–501. Leppänen, J.M., 2006. Emotional information processing in mood disorders: a review of behavioural and neuroimaging findings. Current Opinions in Psychiatry 19, 34–39. MacDonald, G., Leary, M.R., 2005. Why does social exclusion hurt? The relationship between social and physical pain. Psychological Bulletin 131, 202–223. Matsuo, K., Glahn, D.C., Peluso, M.A.M., Hatch, P., Monkul, E.S., Najt, P., Sanches, M., Zamarippa, F., Li, J., Lancaster, J.L., Fox, P.T., Gao, J.-H., Soares, J.C., 2007. Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Molecular Psychiatry 12, 158–166. Mee, S., Bunney, B.G., Reist, C., Potkin, S.G., Bunney, W.E., 2006. Psychological pain: a review of evidence. Journal of Psychiatric Research 40, 680–690.
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K. van Heeringen et al. / Psychiatry Research: Neuroimaging 181 (2010) 141–144
Orbach, I., Mikulincer, M., Sirota, P., Gilboa-Schechtman, E., 2003. Mental pain: a multidimensional operationalization and definition. Suicide and Life-Threatening Behavior 33, 219–230. Shneidman, E.S., 1996. The Suicidal Mind. Oxford University Press, Oxford. Wagner, G., Sinsel, E., Sobanski, T., Kohler, S., Marinou, V., Mentzel, H.J., Sauer, H., Schlosser, R.G.M., 2006. Cortical inefficiency in patients with unipolar depression:
an event-related MRI study with the Stroop task. Biological Psychiatry 29, 958–965. Walter, H., Wolf, R.C., Spitzer, M., Vasic, N., 2007. Increased left prefrontal activation in patients with unipolar depression: an event-related, parametric, performancecontrolled fMRI study. Journal of Affective Disorders 101, 175–185.
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s
The functional neuroanatomy of mental pain in depression Kees van Heeringen⁎, Dirk Van den Abbeele, Myriam Vervaet, Lieslot Soenen, Kurt Audenaert University Department of Psychiatry, Medical Psychology Unit for Suicide Research, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium
a r t i c l e
i n f o
Article history: Received 12 June 2007 Received in revised form 12 June 2009 Accepted 28 July 2009 Keywords: Depression Pain Imaging rCBF SPECT
a b s t r a c t This study aimed at determining the functional neuroanatomy of mental pain, a hitherto neglected symptom in the study of depression, which according to DSM-IV is stronglylinked with suicide. Mental pain (measured with the Orbach & Mikulincer Mental Pain Scale), suicidal ideation (measured using the Hamilton Rating Scale for Depression), hopelessness (measured using Beck's Hopelessness Scale), and regional cerebral blood flow as measured with single photon emission computed tomography were assessed in 39 depressed individuals. Levels of mental pain were significantly and positively associated with suicidal ideation and levels of hopelessness. When compared with patients with low levels of mental pain, those with high levels of mental pain showed relatively increased perfusion in the right dorsolateral prefrontal cortex, occipital cortex and inferior frontal gyrus and in the left inferior temporal gyrus, and relatively decreased perfusion at the medulla. The findings indicate that mental pain in depressed patients is associated with an increased risk of suicide and that high levels of mental pain are associated with changes in perfusion in brain areas that are involved in the regulation of emotions. Further study is warranted to understand whether this association reflects increased emotional processing or decreased cognitive control over mental pain in depressed individuals. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction An association between physical pain and depression is well documented, but depressed patients may also suffer from emotional pain. According to DSM-IV, depression can be excruciatingly painful, to such an extent that it may very well lead to suicide (American Psychiatric Association, 2004). Emotional pain has indeed been described in association with suicidal behaviour using terms such as 'psychache' (Shneidman, 1996), 'mental pain' (Orbach et al., 2003) or 'psychological pain' (Mee et al., 2006). In view of the fact that depressive episodes (and suicidal behaviour) are very commonly precipitated by interpersonal problems such as rejection, it is likely that the term ‘social pain’ (Eisenberger and Lieberman, 2004) describes a comparable emotional state. It has been suggested that an overlap between physical pain and social pain is an evolutionary development to aid social animals in responding to threats to inclusion (MacDonald and Leary, 2005). The induction of social pain in healthy volunteers is associated with increased activity in the anterior cingulate cortex and the right ventral prefrontal cortex, suggesting that social pain is analogous in its neurocognitive function to physical pain, alerting individuals when there is sustained injury to social connections, allowing restorative
measures to be taken (Eisenberger et al., 2003). In order for such measures to be taken, the neural circuitry involved in emotion regulation must function adequately, which may not be the case in depression. Neuroimaging studies in depressed patients have indeed shown deficiencies in brain areas that play a key role in emotion regulation and that include the dorsolateral prefrontal and anterior cingulate cortex (Beauregard et al., 2006; Leppänen, 2006). It is not yet clear why some depressed patients experience mental pain and others do not. In other words, it is not clear how the neural circuitry involved in emotion regulation functions differently in the case of mental pain. It can be expected that the study of the neural correlates of mental pain in depressed patients may help in understanding the nature of this psychopathological phenomenon, and thus contribute to the prevention of suffering and its potentially devastating consequences such as suicide. Based on a thorough review of the existing literature, it was recently suggested that future research might investigate a putative psychological pain system through neuroimaging technology (Mee et al., 2006). This study therefore aimed at examining whether such pain is associated with changes in activity in particular areas of the brain as revealed by functional neuroimaging. 2. Methods
⁎ Corresponding author. Unit for Suicide Research, Department of Psychiatry, University Hospital, De Pintelaan 185, 9000 Gent, Belgium. Tel.: +32 9 332 43 30; fax: +32 9 332 49 89. E-mail address: [email protected] (K. van Heeringen). 0925-4927/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2009.07.011
2.1. Subjects The study group consisted of 39 consecutively admitted inpatients at the Centre for Mood and Anxiety Disorders of the University
142
K. van Heeringen et al. / Psychiatry Research: Neuroimaging 181 (2010) 141–144
Department of Psychiatry, University Hospital Gent (Belgium). The study sample included 22 females and 17 males who were treated for a depressive episode according to DSM-IV-TR criteria.
Table 2 Brain areas (with Talairach coordinates) with relative hyperperfusion in patients with high versus patients with low levels of mental pain.
2.2. Measures Severity of depressive symptoms was assessed using the Beck Depression Inventory (BDI). Mental pain was assessed using the English version of the Orbach & Mikulincer Mental Pain Scale (OMMP) (Orbach et al., 2003), which was translated into Dutch and then back translated. The OMMP is self-ratied on a 5-point Likert scale with 44 items. Higher values on each item reflect stronger mental pain. The occurrence and severity of suicidal ideation and the level of hopelessness, both associated with an increased risk of suicide among depressed patients, were assessed using item 9 of the BDI and Beck's Hopelessness Scale (BHS), respectively. Regional cerebral blood flow was measured by means of single photon emission computed tomography (SPECT). All subjects were injected with 925 MBq 99mTc-ECD (Dupont Pharmaceuticals Ltd., Brussels, Belgium) under resting conditions. SPECT was performed on a Toshiba GCA-9300A triple headed camera with high resolution lead fan beam collimators and transmission CT sources. Fan beam projections were converted to 128 × 128 parallel data. A triple-energy window scatter correction was performed on the projection data. Non-uniform attenuation sets were calculated and the image datasets were automatically registered to an anatomical standardized stereotactic template using Brain Registration and Automated SPET semi-quantification (BRASS). Statistical analysis of images was performed using SPM5 (Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London), implanted in a Matlab 7 environment (MathWorks, Inc.). All images were preprocessed for spatial normalization into the Montreal Neurological Institute (MNI) template to remove intersubject anatomic variability, and then smoothed with a FWHM 16-mm Gaussian kernel to increase the signal-to-noise ratio and to account for subtle variations in anatomic structures. With relative masking, mean global calculation and proportional normalization, Tcontrasts were set up to define the regions of relative hyperperfusion and hypoperfusion (uncorrected P b 0.005, extent threshold 50). Conversion of coordinates from the MNI template to the Talairach system was carried out using Matthew Brett's mni2tal tool (see http: imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach) to enable approximate labelling of Brodmann areas.
Brain region (BA)
Side
Inferior frontal gyrus (44) Occipital cortex (19) Dorsolateral prefrontal cortex (9) Inferior temporal cortex (20)
Right 48, 8, 12
5.46
4.36
24 0.000
Right 13, −77, 31 Right 13, 39, 30
5.04 4.28
4.12 3.65
24 0.000 24 0.000
3.90
3.40
24 0.000
Left
Coordinates (x, y, z)
−47, −30, −18
T value Z value df
P value (uncorrected)
2.4. Ethical approval The local ethics committee approved the study. After complete description of the study to the subjects, written informed consent was obtained. 3. Results The mean age of the 39 individuals in this study was 40.8 years (S.D.=14.7, range=17–70). The mean BDI score at the day of the neuroimaging session was 28.8 (S.D.=13, range=9–54), while the mean OMMP score at that moment was 135 (S.D.=32.2, range=68– 192). Table 1 shows demographic and clinical data for the study groups. There was no correlation between total scores on the BDI and the OMMP, but the OMMP score correlated significantly with the score on the BDI ‘suicidality’ item (item 9; Spearman rho = 0.425; P b 0.05) and with the total score on the BHS (Spearman rho = 0.517; P b 0.001). Independent sample t-tests showed a significantly increased level of regional cerebral blood flow in the right occipital cortex, the left inferior temporal gyrus, the right dorsolateral prefrontal cortex and the right inferior frontal gyrus in the group of patients with high levels of mental pain compared with patients in the group with low levels (Table 2 and Fig. 1). A significantly decreased level of regional blood flow was found in the left medulla at pontine levels in the group of patients with high levels of mental pain compared with those with low levels (Talairach coordinates: x = 1, y = 16, z = 20; t = 4.46; Z score = 3.77; P value = 0.000). Correlational analyses show comparable findings in terms of involved prefrontal regions and levels of significance. Correction for age or severity of depression did not affect the results.
2.3. Statistical analysis 4. Discussion The study population was divided into three groups of 13 patients based on OMMP scores, thus constituting groups with low, medium and high levels of mental pain. To explore the functional characteristics of mental pain, the group with low levels of mental pain (mean OMMP score 89.8, range 68–121) was compared with the group with high levels (mean 170.2, range 153–192) regarding regional cerebral blood flow and clinical characteristics using a two-sample t-test.
This study is the first to report changes in brain functioning in association with mental pain in depressed patients. The results show that levels of mental pain do not correlate with severity of depression but are associated with an increased risk of suicide. The severity of mental pain in these depressed patients is associated with changes in cerebral blood flow in areas of the brain that are involved in the processing of emotions.
Table 1 Demographic and clinical characteristics of study group, according to level of mental pain.
Age (±S.D.) Gender (M/F) Beck Depression Inventory (±S.D.) Beck Hopelessness Scale (±S.D.) OMMP (±S.D.) *P b 0.05; **P b 0.001.
Low
Medium
High
High versus low
42.5 years (±15) 6/7 29.3 (±11.6) 8.77 (±4.6) 89.8 (±7.2)
35.15 years (±12.9) 5/8 32.5 (±11.9) 12.92 (±2.5) 136.1 (±9.5)
44.77 years (±15.3) 6/7 31.6 (±13.9) 13.31 (±3.6) 170.2 (±12)
t = − 0.37 χ2 = 1.92 t = − 1.62 t = − 2.73⁎ t = − 1.55⁎⁎
K. van Heeringen et al. / Psychiatry Research: Neuroimaging 181 (2010) 141–144
143
Fig. 1. Brain areas with relative hyperperfusion in depressed patients with high levels of mental pain compared with those with low levels of mental pain.
The interpretation of the demonstrated associations between cerebral blood flow and levels of mental pain can only be based upon speculation. However, in particular with regard to the involvement of the dorsolateral prefrontal cortex, the current findings, taken together with those from previous studies, may contribute to our understanding of the reasons why depressed individuals may become suicidal. Processing of emotional signals, in general, involves analysis of stimulus features (subserved by the occipitotemporal cortex), emotion recognition and emotional response (amygdala, insula, orbitofrontal cortex and ventral striatum) and emotion regulation (anterior cingulate cortex, and dorsomedial and dorsolateral prefrontal cortex) (Leppänen, 2006). The observation that depressed individuals become suicidal when they perceive their emotional state as painful and incapable of change (American Psychiatric Association, 2004) suggests a strong and persisting emotional input at the prefrontal level. While changes in dorsolateral activity in resting conditions in depressed individuals are heterogeneous (Fitzgerald et al., 2006), a comparative hyperactivity of the dorsolateral prefrontal cortex of depressed individuals is found in activation studies. Experimental studies in which depressed participants and healthy controls are exposed to pain (Bär et al., 2007) or perform cognitive tasks such as a working memory task (Fitzgerald et al., 2008; Walter et al., 2007), the Stroop task (Wagner et al., 2006) or the n-back test (Fitzgerald et al., 2008; Matsuo et al., 2007) indeed show greater dorsolateral activation in depressed subjects than in healthy controls. It is unclear whether the relative hyperactivity in this region in depressed individuals is related to prefrontal pathology leading to abnormal cognitive and affective control processes. In any case, the outcome appears to depend on the nature of the stimulus. Increased dorsolateral activity after exposure to pain stimuli is associated with increased pain thresholds in depression (and thus increased antinociception), while such hyperactivity during cognitive tasks is associated with similar (n-back; Fitzgerald et al., 2008; Matsuo et al., 2007) or worse (Tower of London; Fitzgerald et al., 2008) levels of performance. The findings from the current study indicate that dorsolateral hyperactivity is associated with increased levels of mental pain, but the interpretation of this association needs further study.
The current findings suggest an explanation for the heterogeneous nature of the changes in dorsolateral functioning in depressed individuals (Fitzgerald et al., 2006) by showing that the presence or absence of particular emotional phenomena or symptoms influences dorsolateral activity in depressed subjects. Further study is clearly needed to show whether changes in regional cerebral activity correlating with mental pain are associated with changes in cognitive mechanisms of control over such emotions, and to determine whether such changes in activity and functioning are amenable to treatment. Acknowledgement This study was supported by a research grant from Eli Lilly Benelux. References American Psychiatric Association, 2004. Diagnostic and Statistical Manual of Mental Disorders, fourth edition. APA, Washington, DC. Bär, K.J., Wagner, G., Koschke, M., Boettger, S., Boettger, M.K., Schlosser, R., Sauer, H., 2007. Increased prefrontal activation during pain perception in major depression. Biological Psychiatry 11, 1281–1287. Beauregard, M., Paquette, V., Lévesque, J., 2006. Dysfunction in the neural circuitry of emotional self-regulation in major depressive disorder. NeuroReport 17, 843–846. Eisenberger, N.I., Lieberman, M.D., 2004. Why rejection hurts: a common neural alarm system for physical and social pain. Trends in Cognitive Science 7, 294–300. Eisenberger, N.I., Lieberman, M.D., Williams, K.D., 2003. Does rejection hurt? An fMRI study of social exclusion. Science 302, 290–292. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research: Neuroimaging 148, 33–45. Fitzgerald, P.B., Srithiran, A., Benitez, J., Daskalakis, Z.Z., Oxley, T.J., Kulkarni, J., Egan, G.F., 2008. An fMRI study of prefrontal brain activation during multiple tasks in patients with major depression. Human Brain Mapping 29, 490–501. Leppänen, J.M., 2006. Emotional information processing in mood disorders: a review of behavioural and neuroimaging findings. Current Opinions in Psychiatry 19, 34–39. MacDonald, G., Leary, M.R., 2005. Why does social exclusion hurt? The relationship between social and physical pain. Psychological Bulletin 131, 202–223. Matsuo, K., Glahn, D.C., Peluso, M.A.M., Hatch, P., Monkul, E.S., Najt, P., Sanches, M., Zamarippa, F., Li, J., Lancaster, J.L., Fox, P.T., Gao, J.-H., Soares, J.C., 2007. Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Molecular Psychiatry 12, 158–166. Mee, S., Bunney, B.G., Reist, C., Potkin, S.G., Bunney, W.E., 2006. Psychological pain: a review of evidence. Journal of Psychiatric Research 40, 680–690.
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