J Orthop Sci DOI 10.1007/s00776-014-0534-2
ORIGINAL ARTICLE
Significant differences of brain blood flow in patients with chronic low back pain and acute low back pain detected by brain SPECT Yukio Nakamura • Kenya Nojiri • Hiroyuki Yoshihara • Takeshi Takahata • Kumiko Honda-Takahashi • Saori Kubo • Kazuyuki Sakatsume • Hiroyuki Kato Toshihiko Maruta • Tetsumi Honda
•
Received: 24 July 2013 / Accepted: 8 January 2014 Ó The Japanese Orthopaedic Association 2014
Abstract Background The aim of this study was to examine and compare the areas of brain blood flow in patients with chronic low back pain (CLBP) without structural abnormality and acute low back pain (ALBP) with lumber disc herniation (LDH). Functional neuroimaging studies provide evidence of abnormalities in the regional cerebral blood flow during low back pain. Recent studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain. However, there has been no Y. Nakamura Department of Orthopaedic Surgery, Showa Inan General Hospital, Komagane 399-4117, Japan e-mail: [email protected] Y. Nakamura H. Kato Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan K. Nojiri T. Takahata Department of Orthopaedic Surgery, Isehara Kyodo Hospital, Isehara 259-1132, Japan H. Yoshihara Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY 10003, USA K. Honda-Takahashi T. Honda (&) Department of Rehabilitation Medicine, Showa Inan General Hospital, Komagane 399-4117, Japan e-mail: [email protected] S. Kubo K. Sakatsume Faculty of Education and Integrated Arts and Sciences, Waseda University, Tokyo 169-8050, Japan T. Maruta Department of Psychiatry, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
report yet statistically or by neuro-images on the compared brain single photon-emission computed tomography (SPECT) findings between CLBP and ALBP patients. Methods The subjects comprised 14 patients, 7 CLBP and 7 ALBP patients. The CLBP group included the patients who had no or minor structural abnormality in the lumbar spine on magnetic resonance imaging (MRI) and met the criteria for a classification of ‘‘pain disorder’’ (chronic) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. The ALBP group included the patients who had symptoms within 3 months of onset and LDH revealed by MRI. All patients were assessed using brain SPECT. We then performed a two-tailed view analysis using the easy Z score imaging system, determined the mean Z scores, and performed vBSEE software (Fujifilm RI Pharma, Tokyo, Japan) for both CLBP and ALBP patients. Results The CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe and increased blood flow in the bilateral posterior lobe of the cerebellum. Conclusions SPECT images and statistical analyses revealed the brain blood flow alterations in the patients with ALBP and CLBP. These results may suggest that the dysfunction of the prefrontal cortex could lead to the appearance of unconscious pain behavior controlled by the cerebellum in the patients with CLBP.
Introduction Low back pain (LBP) is a highly prevalent condition and debilitating problem worldwide, generally caused by common diseases, such as lumber disc herniation (LDH) and lumber spinal canal stenosis (LSCS). It has been
123
Y. Nakamura et al.
previously reported that the painful condition is resolved naturally in approximately 80–90 % of the patients with LBP within 12 weeks. On the other hand, the remaining 10–20 % of patients are likely troubled with chronic LBP (CLBP), despite not having any apparent structural abnormalities detected by radiograph or magnetic resonance imaging (MRI). Also, back pain is the most common cause of activity limitation in the US [1, 2]. Maruta et al., have previously reported that depression could be one of the causes of back pain for the last few decades. The authors proposed that psychological stresses in socioeconomic class, such as smaller families, at an earlier age, could affect LBP [3]. In recent years, novel knowledge about the mechanism of CLBP in the brain has accumulated with the development of functional neuroimaging studies, such as single photon-emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) [4]. These functional neuroimaging studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain [5]. However, the underlying mechanism by which LBP occurs is still largely unknown. Table 1 The diagnostic psychiatric criteria of the United States DSM-IV-TR Diagnostic criteria for pain disorder is as follows: A. Pain in one or more anatomical sites is the predominant focus of the clinical presentation and is of sufficient severity to warrant clinical attention B. The pain causes clinically significant distress or impairment in social, occupational, or other important areas of functioning C. Psychological factors are judged to have an important role in the onset, severity, exacerbation, or maintenance of the pain D. The symptom or deficit is not intentionally produced or feigned (as in factitious disorder or malingering) E. The pain is not better accounted for by a mood, anxiety, or psychotic disorder and does not meet criteria for dyspareunia Chronic: duration of 6 months or longer
The present study highlights the statistical relationship between brain blood flow distributions in patients with CLBP and acute low back pain (ALBP) using SPECT.
Materials and methods The present study was approved by our institutions and was conducted in compliance with the accepted ethical standards. The subjects were 14 consecutive patients who visited our institutions during the period from January 2007 to April 2008, complaining of LBP. All 14 patients were right-handed, had no histories of cerebrovascular disease or psychiatric illness, and were free from any medication within 24 h of this study. We used a 0–10 cm visual analog scale (VAS) to measure the intensity of pain at their first visit. When they met the following inclusion and exclusion criteria for CLBP and ALBP, informed consent was obtained for this study. CLBP was defined as LBP lasting longer than 6 months, with a VAS score which is more than or equal to 3, and met the criteria for a ‘‘pain disorder’’ (chronic) of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TRÒ) (Table 1) [6]. No psychotic abnormalities of CLBP patients were confirmed by clinical psychologists or a psychiatrist. When structural abnormality in the lumbar spine on MRI was found in any patients with CLBP, we classified the patients as in the CLBP group if the symptoms had been more serious than MRI findings. Since the patients with CLBP complained of not only LBP, but also various types of leg pain, which had not been followed by typical spine-oriented dermatomes, they were classified as a non-specific LBP (NSLBP) group according to Robinson and Apkarian [7]. The ALBP group included patients who had it within 3 months of onset and displayed LDH as revealed by MRI. The subjects included 7 patients with ALBP (ALBP group) and 7 patients with CLBP (CLBP group). Six of 7
Table 2 Various parameters of age, gender, LDH (lumber disc herniation), the period between first visit and SPECT examination, VAS (visual analogue scale) for LBP (low back pain), VAS for leg pain, and paralysis in the ALBP group Patient
Age
Gender
LDH
The period between first visit and SPECT examination
VAS for LBP
VAS for leg pain
Treatment
Paralysis
Case 1
66
M
L4/5
2 weeks
8
2
Op (LOVE)
–
Case 2
45
M
L4/5
2 weeks
6
0
Op (LOVE)
–
Case 3
53
M
L4/5
1 month
4
0
Op (LOVE)
–
Case 4
31
M
L5/S
1 and a half months
7
3
Op (LOVE)
–
Case 5
44
M
L4/5
2 weeks
6
1
Op (LOVE)
–
Case 6 Case 7
67 42
M F
L3/4 L4/5
2 and a half months 1 and a half months
6 6
1 2
Op (LOVE) Conservative
– –
ALBP
123
Brain blood flow by SPECT with back pain Table 3 Various parameters of age, gender, the period between first visit and SPECT examination, VAS for LBP, and paralysis in the CLBP group Patient
Age
Gender
The period between first visit and SPECT examination
VAS for LBP
Treatment
Paralysis
Case 1
24
Case 2 Case 3
26 63
M
8 years
6.9
Conservative
–
F F
11 years 6 years
6.4 7
Conservative Conservative
– –
Case 4 Case 5
76
M
4 years and 10 months
4.4
Conservative
–
47
M
2 years and 4 months
9.7
Conservative
–
Case 6
60
F
2 years
6.4
Conservative
–
Case 7
55
F
15 years
3.3
Conservative
–
CLBP
There was no statistical difference among the increased blood flow of the bilateral parietal lobe in CLBP group
CLBP 1
CLBP 2
CLBP 3
CLBP 4
CLBP 6
CLBP 7
ALBP 1
ALBP 2
ALBP 4
ALBP 5
ALBP 6
ALBP 7
CLBP 5
ALBP 3
Fig. 1 Each patient data of superior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the lowest left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the 4 CLBP cases (1, 2, 3, 5) showed increased blood flow in the bilateral parietal lobe
patients in ALBP group had a surgery for LDH and the remaining 1 had conservative treatment, such as NSAIDs, whose pain was much improved thereafter. Straight leg
raising test was positive in all of the patients in the ALBP group, while 5 of 7 patients complained of leg pain. The mean VAS score of LBP in the ALBP and CLBP group, and that of leg pain in the ALBP group, was evaluated at their first visit (Tables 2, 3). There are several neuroimaging approaches for understanding the mechanism of CLBP in the brain. Matsuda et al., have previously performed the brain SPECT (Millennium VGÒ, General Electric Inc., CT, USA) with 99m Tc-ethyl cysteinate dimmer (99mTc-ECD) to construct the database of functional brain alterations in various neuropsychiatric diseases [8]. In this study, with the cooperation of Fujifilm RI Pharma, we also used the brain SPECT with 99m Tc-ECD and performed a two-tailed view analysis using the easy Z score imaging system (eZIS, Fujifilm RI Pharma, Tokyo, Japan) on all of our patients. Z score is a dimensionless quantity obtained by subtracting the population mean from an individual raw score and then dividing the difference by the population standard deviation (SD). The e-ZIS two-tailed view analysis assessed the extent and the degree of regional blood flow for subjects as a Z score value and showed them as a graduation hue in the brain surface of Talairach Deamon. The score \2 SD was ignored. The numbers of voxels for significant increased or decreased rCBF in 12 segments defined as lobe level 2 by Talairach Deamon was calculated using vBSEE software (Fujifilm RI Pharma, Tokyo, Japan). In this study, an extent value was computed by subtracting the numbers of voxels for significantly decreased rCBF from significantly increased rCBF in each segment. In this case, the extent value was large if the region of increased rCBF became wider and was a negative value when the region of decreased rCBF was wider than the region of increase. After all 14 cases of SPECT images were visually evaluated, the brain blood flow in each lobe was statistically analyzed. The rank-difference correlation
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Y. Nakamura et al. Fig. 2 Combined data of brain blood flow and each patient data of the calculated voxel numbers in each segment in the CLBP group and the ALBP group. Segmentation in Talairach Level 2 was used to assess the brain blood flow. Anterior view (a) and inferior view (b) of the brain SPECT in patients with CLBP show significantly reduced blood flow (blue color) in the bilateral prefrontal cortex of the frontal lobe and significantly increased blood flow (red color) in the bilateral posterior lobe of the cerebellum. Anterior view (c) and inferior view (d) of the brain SPECT in patients with ALBP were also shown. The increased brain blood flow is shown as red (%) and the decreased brain blood flow is shown as blue (%) (e, f) in each group, compared to the database (Ref. [4])
Prefrontal cortex of Frontal lobe
(b)
(a)
Celleberum (posterior portion)
(d)
(c)
CLBP 2 ALBP 3 ALBP 2 ALBP 6 CLBP 6 ALBP 4 ALBP 5 ALBP 1 ALBP 7 CLBP 4 CLBP 7 CLBP 3 CLBP 1 CLBP 5
1.75 1.09 -1.42 -2.67 -3.28 -4.29 -4.82 -4.86 -5.56 -12.43 -17.27 -20.21 -26.39 -32.44
(e)
CLBP 6 CLBP 2 CLBP 7 CLBP 3 CLBP 1 ALBP 1 CLBP 4 ALBP 6 ALBP 4 ALBP 2 ALBP 5 ALBP 7 CLBP 5 ALBP 3
14.56 14.30 13.67 13.22 8.44 5.71 5.35 4.34 4.20 3.42 2.40 2.14 0.62 0.51
(f)
official approval of the Mann–Whitney U test was first performed for both ALBP and CLBP groups with extent values arranged by descending order in each segment (P \ 0.05 was considered as significant) [9]. Power analysis was then performed calculating the power value and effect size in the statistically significant brain segments [10].
and increased blood flow in the bilateral posterior lobe of the cerebellum in the CLBP group were seen (P = 0.013) (Fig. 2e, f). The power value was 0.22 both in the prefrontal cortex of frontal lobe and in the posterior portion of the cerebellum. The effect size was 0.51 in the prefrontal cortex of the frontal lobe and 0.88 in the posterior portion of the cerebellum.
Results
Discussion
In this study, we enrolled 7 patients with CLBP (3 men, 4 women, mean age 50.1 years) and 7 patients with ALBP (6 men, 1 woman, mean age 49.7 years). The mean VAS score of LBP at their first visit was 6.3 (range 3.3–9.7) in the CLBP group and 6.1 (range 4.0–8.0) in the ALBP group. The mean VAS of leg(s) was 1.3 (0–3.0) in the ALBP group. There was no statistically significant difference with respect to the age and VAS score between the ALBP and CLBP groups (Tables 2, 3). We then performed SPECT images on all of the patients. While the increased blood flow of the bilateral parietal lobe in the CLBP group (patient 1, 2, 3, and 7) was observed (Fig. 1), there was no statistical difference among them (Table 3). We also performed the Mann–Whitney U test on all of the patients. Significantly reduced blood flow in the bilateral frontal lobe of the prefrontal cortex (P = 0.049)
In this quantitative comparison of brain blood flow using brain SPECT between ALBP and CLBP groups, significantly reduced blood flow in the bilateral frontal lobe of the prefrontal cortex and increased blood flow in the bilateral posterior lobe of the cerebellum in the CLBP group were observed. Since the number of cases was relatively small in this study, the power value was both 0.22 in the bilateral frontal lobe of the prefrontal cortex and in the bilateral posterior lobe of the cerebellum. However, the effect size was 0.51 in the prefrontal cortex of the frontal lobe and 0.88 in the posterior portion of the cerebellum, both of which were substantially great in value (Figs. 3, 4). Pain is caused not only by nociception accompanying structural alterations by plain radiograph or MRI, but also by a complex of the nerve conduction pathway and the central nervous system [9]. In this study, the criteria for the patients were as follows: (1) ALBP group caused by LDH,
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Brain blood flow by SPECT with back pain
CLBP1
CLBP2
CLBP3
CLBP1
CLBP2
CLBP3
CLBP4
CLBP6
CLBP7
CLBP5
CLBP5 CLBP4
CLBP6
CLBP7
ALBP1
ALBP1
ALBP2
ALBP2
ALBP4
ALBP4 ALBP3 ALBP5
ALBP3 ALBP5
ALBP6
ALBP7
Fig. 3 Each patient data of inferior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the most lower left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the CLBP group showed significantly increased blood flow in the bilateral posterior lobe of the cerebellum
who had obvious structural alterations and cured with ordinary orthopedic treatment, and (2) CLBP group classified as pain disorder with the psychiatric classification or NSLBP [7], whose pain had continued more than 6 months despite ordinary medical treatment and with indigent structural abnormalities. We first investigated the brain blood flow in each group. As expected, the blood flow was decreased in the prefrontal cortex of the frontal lobe, and was increased in the posterior lobe of the cerebellum in the CLBP group. Also, the increased blood flow in the somatosensory cortex of the parietal lobe was observed, although there was no statistical difference among the data in the CLBP group. By comparing the brain MRI in patients with CLBP and in normal subjects, Apkarian et al. [5] previously have reported on the mechanism of pain perception and found that the frontal cortex was significantly atrophied in the CLBP group. Recently, the progression of functional neuroimaging systems have made it possible to visualize intracerebral changes in patients with CLBP. It is common that
ALBP6
ALBP7
Fig. 4 Each patient data of anterior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the lowest left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe
functional brain images, such as fMRI or PET, examine the brain reaction at the time of nociceptive stimuli to the patients. However, Baliki et al. [11] have reported that the pain perception and related cortical activation patterns were similar between CBP patients and controls in response to acute noxious thermal stimuli. Therefore, we performed brain SPECT focusing on the cortical activities without noxious stimuli. Brain SPECT is an easy-to-use technique and suffers minimum stressors to the patients that involve only the administration of a radioisotope through the venous circulation and visualizes the accumulation of radioisotope by tomographic imaging [8]. Using brain SPECT (one-tailed view), we have already reported that the decreased blood flow of prefrontal cortex regions in 15 patients with chronic pain was observed [12]. Loeser proposes ‘‘the multifaceted model of pain’’ that involves 4 domains of pain phenomena: (1) the detection of tissue damage (nociception), (2) the recognition of nociceptive stimulation by the central nervous system (pain), (3) the negative affective response to pain (suffering), and (4) what a person does or does not do or say that leads the observer to infer that the patient is suffering from a noxious stimulus (pain behavior) [13].
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The prefrontal cortex is well known to control higher levels of mental activity, such as executive function, emotional control, and initiation of behavior, and it dysfunctions when facing the overwhelming stress [14]. The cerebellum is believed to control perception, the integration of motor function, balance, muscular tone, and voluntary muscle movement. Recently, in addition to these roles in motor function, the cerebellum has been investigated as participating in cognition and emotion. Kawato and Wolpert [15] propose the internal model of cerebellum, that mimics the voluntary sensorimotor system and determines the motor commands required to perform specific tasks instead of that from the frontal cortex. Levin [16] speculated on the contribution of the internal model of the cerebellum to the unconscious and automatic human behavior. From the view point of developmental psychology, pain behavior is not a reflexive movement to nociception, but is a behavior learned as a help behavior while in infancy from their mothers’ reactions when facing dangerous situations [17]. Moulton et al. [18] have reviewed that the cerebellum is an important integrator of pain modulation, although the mechanism of cerebellum functions on the pain modulation is largely unknown. In this study, we showed that increased blood flow in the bilateral posterior lobe of the cerebellum was observed in the CLBP group, suggesting that the cerebellum might play a role in the pathophysiology of CLBP. Together with these findings, we speculatively propose that CBP patients facing overwhelming stress are in a condition as follows: since their executive functions of the prefrontal lobe are unable to cope with psychosocial sensors [3], it would be consequently apparent that the unconscious help behavior be triggered in the cerebellum as pain behavior. In this study, though not statistically significant, the blood perfusion in the somatosensory cortex of parietal lobe also increased in 4 of 7 CLBP patients. Chronic stress has been reported to induce central sensitization [19]. Also, the limitations of this study were that the number of enrolled patients was relatively small. Taken together, the following future studies are needed: (1) to clarify the relation between pathological central hypersensitization states, such as fibromyalgia or allodynia and CLBP, (2) to have more detailed analyses for specific areas of brain blood flow in that between ALBP and CLBP groups with a larger population, and (3) to apply cognitive-behavioral therapy for clinical improvement and a detailed examination of brain blood flow alterations in patients with CLBP. Acknowledgments We thank Mr. Kaneko Hiroyasu, Mr. Akihiro Nanri, and Mr. Shuji Fujita of FUJIFILM RI Pharma Co. Ltd. Tokyo, Japan for their technical advice and support. We thank Professor Katsuhiko Takeda at the International University of Health and Welfare for his valuable advice and suggestions. We also thank the Survey Research Center for their statistical analyses regarding power and effect size in
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this study. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Andersson GB. Epidemiological features of chronic low back pain. Lancet. 1999;354:581–5. 2. Deyo RA, Weinstein JN. Low back pain. N Engl J Med. 2001;344:363–70. 3. Maruta T, Swanson DW, Swenson WM. Pain as a psychiatric symptom: comparison between low back pain and depression. Psychosomatics. 1976;17:123–7. 4. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:463–84. 5. Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24:10410–5. 6. American Psychiatric Association. Quick reference to the diagnostic criteria from DSM-IV-TRÒ 2000. Washington, DC; 1994. p. 358. 7. Robinson JP, Apkarian VA. Low back pain. In: Mayer EA, Bushnell MC, editors. Functional pain syndrome. Seattle: IASP Press; 2009. p. 23–53. 8. Matsuda H, Mizumua S, Soma T, Takemura N. Conversion of brain SPECT images between different collimators and reconstruction process for analysis using statistical parametric mapping. Nucl Med Commun. 2004;25:67–74. 9. Mann HB, Whitney DR. On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat. 1947;18:50–60. 10. Mizumoto A, Takeuchi O. Basics and considerations for reporting effect sizes in research papers. Eigo Kyoiku Kenkyu. 2008;31:57–66 (in Japanese). 11. Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron. 2010;66:149–60. 12. Honda T, Maruta T, Takahashi K. Brain perfusion abnormality in patients with chronic pain. Keio J Med. 2007;56:48–52. 13. Loeser JD, Eagan KJ. History and organization of the University of Washington multidisciplinary pain center. In: Loeser JD, Eagan KJ, editors. Managing the chronic pain patient. New York: Raven Press; 1989. p. 3–20. 14. Shansky RM, Lipps J. Stress-induced cognitive dysfunction. Hormone–neurotransmitter interactions in the prefrontal cortex. Front Hum Neurosci. 2013;7:123. 15. Kawato M, Wolpert D. Internal models for motor control. Novartis Found Symp. 1998;218:291–304. 16. Levin FM. Introduction to the cerebellum: Ito Maso’s controllerregulator model of the brain and some implications for psychodynamic psychiatry and psychoanalysis. Emotion and the psychodynamics of the cerebellum, Chapter 7. London: Karnac; 2009. p. 145–57. 17. Maruta T. Jinkakuno Hattatsu to Itami, Chapter 3. Itamino Shinrigaku. Chukoshinsyo; 1989. p. 37–53 (in Japanese). 18. Moulton EA, Schmahmann JD, Borsook D. The cerebellum and pain. Passive integrator or active participator? Brain Res Rev. 2010;65:14–27. 19. Senba E, Imbe H, Okamoto K. Descending facilitation in chronic stress and chronic pain state. Nihon Shinkei Seishin Yakugaku Zasshi. 2008;28:29–35 (in Japanese).
ORIGINAL ARTICLE
Significant differences of brain blood flow in patients with chronic low back pain and acute low back pain detected by brain SPECT Yukio Nakamura • Kenya Nojiri • Hiroyuki Yoshihara • Takeshi Takahata • Kumiko Honda-Takahashi • Saori Kubo • Kazuyuki Sakatsume • Hiroyuki Kato Toshihiko Maruta • Tetsumi Honda
•
Received: 24 July 2013 / Accepted: 8 January 2014 Ó The Japanese Orthopaedic Association 2014
Abstract Background The aim of this study was to examine and compare the areas of brain blood flow in patients with chronic low back pain (CLBP) without structural abnormality and acute low back pain (ALBP) with lumber disc herniation (LDH). Functional neuroimaging studies provide evidence of abnormalities in the regional cerebral blood flow during low back pain. Recent studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain. However, there has been no Y. Nakamura Department of Orthopaedic Surgery, Showa Inan General Hospital, Komagane 399-4117, Japan e-mail: [email protected] Y. Nakamura H. Kato Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan K. Nojiri T. Takahata Department of Orthopaedic Surgery, Isehara Kyodo Hospital, Isehara 259-1132, Japan H. Yoshihara Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY 10003, USA K. Honda-Takahashi T. Honda (&) Department of Rehabilitation Medicine, Showa Inan General Hospital, Komagane 399-4117, Japan e-mail: [email protected] S. Kubo K. Sakatsume Faculty of Education and Integrated Arts and Sciences, Waseda University, Tokyo 169-8050, Japan T. Maruta Department of Psychiatry, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
report yet statistically or by neuro-images on the compared brain single photon-emission computed tomography (SPECT) findings between CLBP and ALBP patients. Methods The subjects comprised 14 patients, 7 CLBP and 7 ALBP patients. The CLBP group included the patients who had no or minor structural abnormality in the lumbar spine on magnetic resonance imaging (MRI) and met the criteria for a classification of ‘‘pain disorder’’ (chronic) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. The ALBP group included the patients who had symptoms within 3 months of onset and LDH revealed by MRI. All patients were assessed using brain SPECT. We then performed a two-tailed view analysis using the easy Z score imaging system, determined the mean Z scores, and performed vBSEE software (Fujifilm RI Pharma, Tokyo, Japan) for both CLBP and ALBP patients. Results The CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe and increased blood flow in the bilateral posterior lobe of the cerebellum. Conclusions SPECT images and statistical analyses revealed the brain blood flow alterations in the patients with ALBP and CLBP. These results may suggest that the dysfunction of the prefrontal cortex could lead to the appearance of unconscious pain behavior controlled by the cerebellum in the patients with CLBP.
Introduction Low back pain (LBP) is a highly prevalent condition and debilitating problem worldwide, generally caused by common diseases, such as lumber disc herniation (LDH) and lumber spinal canal stenosis (LSCS). It has been
123
Y. Nakamura et al.
previously reported that the painful condition is resolved naturally in approximately 80–90 % of the patients with LBP within 12 weeks. On the other hand, the remaining 10–20 % of patients are likely troubled with chronic LBP (CLBP), despite not having any apparent structural abnormalities detected by radiograph or magnetic resonance imaging (MRI). Also, back pain is the most common cause of activity limitation in the US [1, 2]. Maruta et al., have previously reported that depression could be one of the causes of back pain for the last few decades. The authors proposed that psychological stresses in socioeconomic class, such as smaller families, at an earlier age, could affect LBP [3]. In recent years, novel knowledge about the mechanism of CLBP in the brain has accumulated with the development of functional neuroimaging studies, such as single photon-emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) [4]. These functional neuroimaging studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain [5]. However, the underlying mechanism by which LBP occurs is still largely unknown. Table 1 The diagnostic psychiatric criteria of the United States DSM-IV-TR Diagnostic criteria for pain disorder is as follows: A. Pain in one or more anatomical sites is the predominant focus of the clinical presentation and is of sufficient severity to warrant clinical attention B. The pain causes clinically significant distress or impairment in social, occupational, or other important areas of functioning C. Psychological factors are judged to have an important role in the onset, severity, exacerbation, or maintenance of the pain D. The symptom or deficit is not intentionally produced or feigned (as in factitious disorder or malingering) E. The pain is not better accounted for by a mood, anxiety, or psychotic disorder and does not meet criteria for dyspareunia Chronic: duration of 6 months or longer
The present study highlights the statistical relationship between brain blood flow distributions in patients with CLBP and acute low back pain (ALBP) using SPECT.
Materials and methods The present study was approved by our institutions and was conducted in compliance with the accepted ethical standards. The subjects were 14 consecutive patients who visited our institutions during the period from January 2007 to April 2008, complaining of LBP. All 14 patients were right-handed, had no histories of cerebrovascular disease or psychiatric illness, and were free from any medication within 24 h of this study. We used a 0–10 cm visual analog scale (VAS) to measure the intensity of pain at their first visit. When they met the following inclusion and exclusion criteria for CLBP and ALBP, informed consent was obtained for this study. CLBP was defined as LBP lasting longer than 6 months, with a VAS score which is more than or equal to 3, and met the criteria for a ‘‘pain disorder’’ (chronic) of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TRÒ) (Table 1) [6]. No psychotic abnormalities of CLBP patients were confirmed by clinical psychologists or a psychiatrist. When structural abnormality in the lumbar spine on MRI was found in any patients with CLBP, we classified the patients as in the CLBP group if the symptoms had been more serious than MRI findings. Since the patients with CLBP complained of not only LBP, but also various types of leg pain, which had not been followed by typical spine-oriented dermatomes, they were classified as a non-specific LBP (NSLBP) group according to Robinson and Apkarian [7]. The ALBP group included patients who had it within 3 months of onset and displayed LDH as revealed by MRI. The subjects included 7 patients with ALBP (ALBP group) and 7 patients with CLBP (CLBP group). Six of 7
Table 2 Various parameters of age, gender, LDH (lumber disc herniation), the period between first visit and SPECT examination, VAS (visual analogue scale) for LBP (low back pain), VAS for leg pain, and paralysis in the ALBP group Patient
Age
Gender
LDH
The period between first visit and SPECT examination
VAS for LBP
VAS for leg pain
Treatment
Paralysis
Case 1
66
M
L4/5
2 weeks
8
2
Op (LOVE)
–
Case 2
45
M
L4/5
2 weeks
6
0
Op (LOVE)
–
Case 3
53
M
L4/5
1 month
4
0
Op (LOVE)
–
Case 4
31
M
L5/S
1 and a half months
7
3
Op (LOVE)
–
Case 5
44
M
L4/5
2 weeks
6
1
Op (LOVE)
–
Case 6 Case 7
67 42
M F
L3/4 L4/5
2 and a half months 1 and a half months
6 6
1 2
Op (LOVE) Conservative
– –
ALBP
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Brain blood flow by SPECT with back pain Table 3 Various parameters of age, gender, the period between first visit and SPECT examination, VAS for LBP, and paralysis in the CLBP group Patient
Age
Gender
The period between first visit and SPECT examination
VAS for LBP
Treatment
Paralysis
Case 1
24
Case 2 Case 3
26 63
M
8 years
6.9
Conservative
–
F F
11 years 6 years
6.4 7
Conservative Conservative
– –
Case 4 Case 5
76
M
4 years and 10 months
4.4
Conservative
–
47
M
2 years and 4 months
9.7
Conservative
–
Case 6
60
F
2 years
6.4
Conservative
–
Case 7
55
F
15 years
3.3
Conservative
–
CLBP
There was no statistical difference among the increased blood flow of the bilateral parietal lobe in CLBP group
CLBP 1
CLBP 2
CLBP 3
CLBP 4
CLBP 6
CLBP 7
ALBP 1
ALBP 2
ALBP 4
ALBP 5
ALBP 6
ALBP 7
CLBP 5
ALBP 3
Fig. 1 Each patient data of superior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the lowest left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the 4 CLBP cases (1, 2, 3, 5) showed increased blood flow in the bilateral parietal lobe
patients in ALBP group had a surgery for LDH and the remaining 1 had conservative treatment, such as NSAIDs, whose pain was much improved thereafter. Straight leg
raising test was positive in all of the patients in the ALBP group, while 5 of 7 patients complained of leg pain. The mean VAS score of LBP in the ALBP and CLBP group, and that of leg pain in the ALBP group, was evaluated at their first visit (Tables 2, 3). There are several neuroimaging approaches for understanding the mechanism of CLBP in the brain. Matsuda et al., have previously performed the brain SPECT (Millennium VGÒ, General Electric Inc., CT, USA) with 99m Tc-ethyl cysteinate dimmer (99mTc-ECD) to construct the database of functional brain alterations in various neuropsychiatric diseases [8]. In this study, with the cooperation of Fujifilm RI Pharma, we also used the brain SPECT with 99m Tc-ECD and performed a two-tailed view analysis using the easy Z score imaging system (eZIS, Fujifilm RI Pharma, Tokyo, Japan) on all of our patients. Z score is a dimensionless quantity obtained by subtracting the population mean from an individual raw score and then dividing the difference by the population standard deviation (SD). The e-ZIS two-tailed view analysis assessed the extent and the degree of regional blood flow for subjects as a Z score value and showed them as a graduation hue in the brain surface of Talairach Deamon. The score \2 SD was ignored. The numbers of voxels for significant increased or decreased rCBF in 12 segments defined as lobe level 2 by Talairach Deamon was calculated using vBSEE software (Fujifilm RI Pharma, Tokyo, Japan). In this study, an extent value was computed by subtracting the numbers of voxels for significantly decreased rCBF from significantly increased rCBF in each segment. In this case, the extent value was large if the region of increased rCBF became wider and was a negative value when the region of decreased rCBF was wider than the region of increase. After all 14 cases of SPECT images were visually evaluated, the brain blood flow in each lobe was statistically analyzed. The rank-difference correlation
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Y. Nakamura et al. Fig. 2 Combined data of brain blood flow and each patient data of the calculated voxel numbers in each segment in the CLBP group and the ALBP group. Segmentation in Talairach Level 2 was used to assess the brain blood flow. Anterior view (a) and inferior view (b) of the brain SPECT in patients with CLBP show significantly reduced blood flow (blue color) in the bilateral prefrontal cortex of the frontal lobe and significantly increased blood flow (red color) in the bilateral posterior lobe of the cerebellum. Anterior view (c) and inferior view (d) of the brain SPECT in patients with ALBP were also shown. The increased brain blood flow is shown as red (%) and the decreased brain blood flow is shown as blue (%) (e, f) in each group, compared to the database (Ref. [4])
Prefrontal cortex of Frontal lobe
(b)
(a)
Celleberum (posterior portion)
(d)
(c)
CLBP 2 ALBP 3 ALBP 2 ALBP 6 CLBP 6 ALBP 4 ALBP 5 ALBP 1 ALBP 7 CLBP 4 CLBP 7 CLBP 3 CLBP 1 CLBP 5
1.75 1.09 -1.42 -2.67 -3.28 -4.29 -4.82 -4.86 -5.56 -12.43 -17.27 -20.21 -26.39 -32.44
(e)
CLBP 6 CLBP 2 CLBP 7 CLBP 3 CLBP 1 ALBP 1 CLBP 4 ALBP 6 ALBP 4 ALBP 2 ALBP 5 ALBP 7 CLBP 5 ALBP 3
14.56 14.30 13.67 13.22 8.44 5.71 5.35 4.34 4.20 3.42 2.40 2.14 0.62 0.51
(f)
official approval of the Mann–Whitney U test was first performed for both ALBP and CLBP groups with extent values arranged by descending order in each segment (P \ 0.05 was considered as significant) [9]. Power analysis was then performed calculating the power value and effect size in the statistically significant brain segments [10].
and increased blood flow in the bilateral posterior lobe of the cerebellum in the CLBP group were seen (P = 0.013) (Fig. 2e, f). The power value was 0.22 both in the prefrontal cortex of frontal lobe and in the posterior portion of the cerebellum. The effect size was 0.51 in the prefrontal cortex of the frontal lobe and 0.88 in the posterior portion of the cerebellum.
Results
Discussion
In this study, we enrolled 7 patients with CLBP (3 men, 4 women, mean age 50.1 years) and 7 patients with ALBP (6 men, 1 woman, mean age 49.7 years). The mean VAS score of LBP at their first visit was 6.3 (range 3.3–9.7) in the CLBP group and 6.1 (range 4.0–8.0) in the ALBP group. The mean VAS of leg(s) was 1.3 (0–3.0) in the ALBP group. There was no statistically significant difference with respect to the age and VAS score between the ALBP and CLBP groups (Tables 2, 3). We then performed SPECT images on all of the patients. While the increased blood flow of the bilateral parietal lobe in the CLBP group (patient 1, 2, 3, and 7) was observed (Fig. 1), there was no statistical difference among them (Table 3). We also performed the Mann–Whitney U test on all of the patients. Significantly reduced blood flow in the bilateral frontal lobe of the prefrontal cortex (P = 0.049)
In this quantitative comparison of brain blood flow using brain SPECT between ALBP and CLBP groups, significantly reduced blood flow in the bilateral frontal lobe of the prefrontal cortex and increased blood flow in the bilateral posterior lobe of the cerebellum in the CLBP group were observed. Since the number of cases was relatively small in this study, the power value was both 0.22 in the bilateral frontal lobe of the prefrontal cortex and in the bilateral posterior lobe of the cerebellum. However, the effect size was 0.51 in the prefrontal cortex of the frontal lobe and 0.88 in the posterior portion of the cerebellum, both of which were substantially great in value (Figs. 3, 4). Pain is caused not only by nociception accompanying structural alterations by plain radiograph or MRI, but also by a complex of the nerve conduction pathway and the central nervous system [9]. In this study, the criteria for the patients were as follows: (1) ALBP group caused by LDH,
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Brain blood flow by SPECT with back pain
CLBP1
CLBP2
CLBP3
CLBP1
CLBP2
CLBP3
CLBP4
CLBP6
CLBP7
CLBP5
CLBP5 CLBP4
CLBP6
CLBP7
ALBP1
ALBP1
ALBP2
ALBP2
ALBP4
ALBP4 ALBP3 ALBP5
ALBP3 ALBP5
ALBP6
ALBP7
Fig. 3 Each patient data of inferior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the most lower left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the CLBP group showed significantly increased blood flow in the bilateral posterior lobe of the cerebellum
who had obvious structural alterations and cured with ordinary orthopedic treatment, and (2) CLBP group classified as pain disorder with the psychiatric classification or NSLBP [7], whose pain had continued more than 6 months despite ordinary medical treatment and with indigent structural abnormalities. We first investigated the brain blood flow in each group. As expected, the blood flow was decreased in the prefrontal cortex of the frontal lobe, and was increased in the posterior lobe of the cerebellum in the CLBP group. Also, the increased blood flow in the somatosensory cortex of the parietal lobe was observed, although there was no statistical difference among the data in the CLBP group. By comparing the brain MRI in patients with CLBP and in normal subjects, Apkarian et al. [5] previously have reported on the mechanism of pain perception and found that the frontal cortex was significantly atrophied in the CLBP group. Recently, the progression of functional neuroimaging systems have made it possible to visualize intracerebral changes in patients with CLBP. It is common that
ALBP6
ALBP7
Fig. 4 Each patient data of anterior views of brain blood flow in the CLBP group and the ALBP group. A representative case CLBP5 is shown on the most upper left. Other CLBP1, 2, 3, 4, 6, and 7 cases are also shown on the upper right sides. A representative case ALBP3 is shown on the lowest left. Other ALBP1, 2, 4, 5, 6, and 7 cases are also shown on the lower right sides. Note that the CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe
functional brain images, such as fMRI or PET, examine the brain reaction at the time of nociceptive stimuli to the patients. However, Baliki et al. [11] have reported that the pain perception and related cortical activation patterns were similar between CBP patients and controls in response to acute noxious thermal stimuli. Therefore, we performed brain SPECT focusing on the cortical activities without noxious stimuli. Brain SPECT is an easy-to-use technique and suffers minimum stressors to the patients that involve only the administration of a radioisotope through the venous circulation and visualizes the accumulation of radioisotope by tomographic imaging [8]. Using brain SPECT (one-tailed view), we have already reported that the decreased blood flow of prefrontal cortex regions in 15 patients with chronic pain was observed [12]. Loeser proposes ‘‘the multifaceted model of pain’’ that involves 4 domains of pain phenomena: (1) the detection of tissue damage (nociception), (2) the recognition of nociceptive stimulation by the central nervous system (pain), (3) the negative affective response to pain (suffering), and (4) what a person does or does not do or say that leads the observer to infer that the patient is suffering from a noxious stimulus (pain behavior) [13].
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Y. Nakamura et al.
The prefrontal cortex is well known to control higher levels of mental activity, such as executive function, emotional control, and initiation of behavior, and it dysfunctions when facing the overwhelming stress [14]. The cerebellum is believed to control perception, the integration of motor function, balance, muscular tone, and voluntary muscle movement. Recently, in addition to these roles in motor function, the cerebellum has been investigated as participating in cognition and emotion. Kawato and Wolpert [15] propose the internal model of cerebellum, that mimics the voluntary sensorimotor system and determines the motor commands required to perform specific tasks instead of that from the frontal cortex. Levin [16] speculated on the contribution of the internal model of the cerebellum to the unconscious and automatic human behavior. From the view point of developmental psychology, pain behavior is not a reflexive movement to nociception, but is a behavior learned as a help behavior while in infancy from their mothers’ reactions when facing dangerous situations [17]. Moulton et al. [18] have reviewed that the cerebellum is an important integrator of pain modulation, although the mechanism of cerebellum functions on the pain modulation is largely unknown. In this study, we showed that increased blood flow in the bilateral posterior lobe of the cerebellum was observed in the CLBP group, suggesting that the cerebellum might play a role in the pathophysiology of CLBP. Together with these findings, we speculatively propose that CBP patients facing overwhelming stress are in a condition as follows: since their executive functions of the prefrontal lobe are unable to cope with psychosocial sensors [3], it would be consequently apparent that the unconscious help behavior be triggered in the cerebellum as pain behavior. In this study, though not statistically significant, the blood perfusion in the somatosensory cortex of parietal lobe also increased in 4 of 7 CLBP patients. Chronic stress has been reported to induce central sensitization [19]. Also, the limitations of this study were that the number of enrolled patients was relatively small. Taken together, the following future studies are needed: (1) to clarify the relation between pathological central hypersensitization states, such as fibromyalgia or allodynia and CLBP, (2) to have more detailed analyses for specific areas of brain blood flow in that between ALBP and CLBP groups with a larger population, and (3) to apply cognitive-behavioral therapy for clinical improvement and a detailed examination of brain blood flow alterations in patients with CLBP. Acknowledgments We thank Mr. Kaneko Hiroyasu, Mr. Akihiro Nanri, and Mr. Shuji Fujita of FUJIFILM RI Pharma Co. Ltd. Tokyo, Japan for their technical advice and support. We thank Professor Katsuhiko Takeda at the International University of Health and Welfare for his valuable advice and suggestions. We also thank the Survey Research Center for their statistical analyses regarding power and effect size in
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this study. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. Conflict of interest of interest.
The authors declare that they have no conflict
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