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Decreased prefrontal brain activation during verbal fluency task in patients with somatoform pain disorder: An exploratory multi-channel near-infrared spectroscopy study
Accepted Manuscript Decreased prefrontal brain activation during verbal fluency task in patients with somatoform pain disorder: An exploratory multichannel near-infrared spectroscopy study
Xiajin Ren, Jinlong Lu, Xiaomin Liu, Chenyu Shen, Xiaoqian Zhang, Xiangyun Ma, Jingjing Sun, Gaoxiang Sun, Kun Feng, Bo Xu, Pozi Liu PII: DOI: Reference:
S0278-5846(16)30361-X doi: 10.1016/j.pnpbp.2017.05.006 PNP 9100
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
14 November 2016 2 May 2017 8 May 2017
Please cite this article as: Xiajin Ren, Jinlong Lu, Xiaomin Liu, Chenyu Shen, Xiaoqian Zhang, Xiangyun Ma, Jingjing Sun, Gaoxiang Sun, Kun Feng, Bo Xu, Pozi Liu , Decreased prefrontal brain activation during verbal fluency task in patients with somatoform pain disorder: An exploratory multi-channel near-infrared spectroscopy study. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/j.pnpbp.2017.05.006
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Decreased prefrontal brain activation during verbal
fluency
task
in
patients
with
somatoform pain disorder: An exploratory near-infrared
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study
spectroscopy
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multi-channel
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Xiajin Rena,b, Jinlong Luc, Xiaomin Liub, Chenyu Shenb, Xiaoqian Zhang a,b, Xiangyun Maa,b, Jingjing Suna,b，Gaoxiang Sunb, Kun Feng b, Bo Xub, Pozi Liub.* a. Medical Center, Tsinghua Unversity, Beijing, China b. Department of Psychiatry, Yuquan Hospital, Tsinghua University, Beijing, China 1
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c. Guangwai Community Health Service Center, Beijing, China
* Corresponding author at: Department of Psychiatry, No. 5 Shijingshan Road, Shijingshan District, Beijing100049, China. Tel.: +86 1088257755x6111; fax: +86 83658195. E-mail address: [email protected] (P. Liu)
ACCEPTED MANUSCRIPT Abstract Background: Pain is a common phenomenon. Patients with somatoform pain disorder (SPD) suffer from lasting chronic pain which may cause cognitive impairment. The dysfunction of prefrontal cortex (PFC) may be involved in pain-induced cognition impairment, which is the most important part in regulating of cognitive function. Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive and low-cost functional neuroimaging technique being used to detect the prefrontal cortex activation during cognitive tasks to demonstrate the relationship between PFC dysfunction and cognition impairment in SPD patients.
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Methods: 24 patients with SPD and 24 age-, gender- and education level- matched healthy controls were examined by NIRS of the relative concentration of oxygenated hemoglobin (oxy-Hb)
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in PFC during verbal fluency task(VFT). All data analysis procedures were accomplished under MATLAB, SPM and SPM-fNIRS which is a SPM12-based software for fNIRS analysis. Results: 1.The number of words generated during the VFT tasks in SPD patients were fewer
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than healthy controls. 2.The activated areas in SPD patients were smaller than healthy controls.
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3.The average activation strength of [oxy-Hb] in SPD patients were much lower than healthy controls. 4.The difference of activation areas between left and right lobe were particularly
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obvious in SPD patients. Conclusion: There are evidence suggested that the markedly dysfunction in PFC especially bilateral dorsolateral prefrontal cortex (DLPFC) areas may be involved in the cognitive deficiency
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in patients with SPD.
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1. Introduction Pain is a multidimensional and complex phenomenon, which affects the physiological as well as psychological state of people. As we all know, pain is not only a purely sensory modality but also a
perception
and
comprised
of
sensory-discriminative,
motivational-affective
and
[1]
cognitive-evaluative aspects . Therefore, the cognition which is described as an information processing is an important role of pain experience. Clinical and experimental studies have eluc idated the brain mechanisms
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underlying cognitive modulation of pain [2-4]. Somatoform pain disorder (SPD), defined as a speculative diagnostic category for chronic somatic
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pain symptoms which are not explained by a general medical condition (American Psychiatric [5]
Association, 2000) , with a high lifetime prevalence, constitutes a large health care and clinical issue[6, 7].
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Lots of evidences are available for cognitive impairment in clinical of patients with chronic pain. These impairments including attention, memory and executive function aspects represent a great
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obstacle to the suffering long-lasting pain population in daily life. Some psychometric tests were used to assess the impairment of cognitive parameters function. Karp et al. considered chronic [8] pain patients perform poorly on D-KEFS trails number-letter switching test . Lee et al. used digit-symbol substitution test(DSST) to reflect the impaired cognition in chronic widespread pain patients which showed lower scores in this test [13]
[11]
. While few studies showed cognitive
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impairment in SPD. Christoph el at. used free recall recognition tasks to reflect the cognitive function of 14 SPD patients and 14 healthy controls, and impairment of memory performance was [14] observed in SPD patients. Paul Pauli el at. also found memory biases in SPD patients. The pathological mechanism of how SPD induced cognitive impairment is not clear. There are several
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hypothesis which may help to explain this phenomenon. Some researchers believed that the lasting pain symptom attracted too much attention and made other information acquistion process suppressed. So, when two parallel processing (ongoing pain and cognitive task) requiring cognition and attention occurred, they had to compete the limited cognitive resources, leading to
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poor cognitive performance[15,16]. Some researchers suggested that ongoing pain harm the “top-to-down” attention mechanism, causing the cognition related information filtered, leading to the cognition impairment [1]. Hart et al. [17] considered chronic pain caused changes of neural plasticity in brain, which led to the reorganization and rearrangement of neural. This rewiring or reorganization of neural interfered with normal cognitive processing. PFC structure or function alteration may be involved in the possible mechanisms above . In recent years, due to the development of brain functional imaging technologies , the structure, local blood flow, tissue metabolism and neurotransmitter changes, etc. of human brain can be visually observed easily. Most researchers used imaging methods to observe whether there is dysfunction in brain regions of SPD patients during resting state or by using simple negative stimulus, such as needling fingers, showing negative images or reading sad literary works [18-22]. Stoeter et al. [21] discovered the increased activation of the known pain-processing areas (thalamus, basal ganglia, operculo-insular cortex) in somatoform pain disorder patients, while increased activation of some prefrontal, temporal and parietal regions during cognitive stress, but reduced activation during emotional stress. Vale W et al. (2009) used magnetic resonance imaging to scan
ACCEPTED MANUSCRIPT 14 right-handed women who meet the DSM-IV criteria of somatoform pain disorder and 25 healthy age-matched healthy controls. The results showed that significant gray-matter decreased in prefrontal, cingulate, and insular cortex involved in the modulation of subjective pain [22] experiences . A SPECT study for chronic pain also showed rCBF increased in the subcortical area, especially in the thalamus and cingulate gyri, while decreased in the bilateral frontal and occipital lobes compared with control group [20]. Yoshino el al.(2014) used resting-state functional magnetic resonance imaging study to find that 11 patients with somatoform pain disorder exhibited atypical precentral gyrus activation compared with the age-matched healthy controls in a sad emotional condition[18].
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As the most important part of regulation of cognitive function, prefrontal cortex (PFC) is also the 2nd tier of pain matrix which has been shown as the most common site activated during pain
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processing with other five brain regions [23]. PFC may have dysfunctions in patients with SPD[24]. Therefore, the relationship of PFC and pain-induced cognitive impairment is worth studying. Near-infrared spectroscopy (NIRS), a non-invasive real-time optical imaging method to detect the [25]
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hemoglobin oxygenation in brain tissue, was first reported by Jöbsis in 1977 ( Jobsis, 1977) . As a neuroimaging technique, NIRS has the advantages of portable, bedside, low consumption,
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relatively low requirements for environment and repetitive operation, etc. Compared with other detective measurements, such as Magnetic Resonance Imaging (MRI), functional Magnetic Resonance Imaging (fMRI) and Positron Emission Computed Tomography (PET), NIRS has a high time resolution, making it possible to reflect the activation of the brain in real time [26, 27]. NIRS has been used widely in psychiatry and neurology as a detect measurement, such as [28-33]
depression, bipolar disorder, alzheimer and so on . NIRS is based on the modified Beer-Lambert law [34], and the principles of NIRS can be summarized as two main points:1.While
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stimulating the brain to activated state, the concentration of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin(deoxy-Hb) will change; 2.Human tissues for near-infrared light have
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special characteristics as low absorption and high scattering [35]. Verbal fluency task (VFT), is a classical cognitive task asking participants to generate as many words as possible in limited time [36]. VFT is widely used in neuropsychological cogitive assessment to support diagnoses of alzheimer’s disease[37], attention deficit hyperactivity disorder
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(ADHD) [38] and parkinson’s disease[39, 40]. The test validity of verbal ability and executive control functions in VFT has been proven because VFT demands not only verbal retrieval and recall, but also important aspects of cognition as self-monitoring, inhibition of responses when time is up[41]. Children with ADHD showed lower score in VFT compared with matched healthy controls suggesting the association of executive control functions and poor VFT performance[42].VFT has been successfully combined with NIRS to detect PFC activation in healthy people and mental disorders patients [31, 43-45] due to the closed relationship between frontal brain area and performance in VFT [46, 47]. The memory bias and attention distracting in SPD patients have been [13, 14]
observed in past experiments . These mechanisms indicated that patients with SPD are more sensitive to passive and negative words or situations, which may affect the modulation of affection and cognition. Therefore, VFT was selected as the cognitive task by using neuter words to eliminate these two phenomena and the results would be fairer. As far as we know, there are few functional imaging studies focusing on the PFC activation in SPD patients carrying out cognitive tasks, which makes the cognitive study of SPD patients insufficient. And considering the important role of PFC in cognitive function and the necessary of
ACCEPTED MANUSCRIPT exploring the relationship between SPD and cognitive function, it is very essential to find how SPD affects cognitive function and PFC activation. So in this study we aimed to find the relationship between PFC and cognitive function of SPD patient and how SPD affects PFC by using NIRS and VFT.
2. Materials and Methods 2.1 Subjects There were twenty-four patients with somatoform pain disorders and age, gender, education level matched healthy controls.Patients were diagnosed according to the DSM-IV criteria, recruited
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from February 2012 to May 2015 in Psychiatry Department of Yuquan Hospital, Beijing, China. Control participants were recruited from non-clinical populations. All subjects were right-handed.
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All participants were undergone the neurological examination and psychiatric interview and
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excluded language dysfunction including aphasia. Subjects with psychiatric symptoms or other psychotic disorders, chronic substance abuse, severe medical illness, cognitive disorders or cerebral organic lesion including trauma, tumor and inflammation were excluded. The study was approved by the ethic committees of Yuquan Hospital and written informed consent was obtained from all participants.
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2.2 Procedure
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All subjects were asked to sit on a comfortable chair and required to stare at the 50 cm-away-screen with eyes open, avoiding artifact, and perform the cognitive tasks in accordance with the screen prompt. Furthermore in the whole process subjects should try their best to avoid movements of head, chin, body, hands, feet and other parts of body.
2.3 VFT tasks
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We used the semantic category version of the verbal fluency task (VFT) as the cognitive task. The VFT were composed by 3 periods, 30s of baseline, 30s of tasks, and 30s of rest after tasks,
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which had a total of four groups of neutral words as vegetables, domestic appliance, animals with four legs and fruits. The four groups of neutral word were selected because of showing no statistical differences in healthy people in the preliminary work of our lab. The VFT lasted for 360s without breaking off. Participants needed to describe as many as possible the names of
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related species in the task time without repetition, and keep quiet and thoughtless in rest time. Relative concentration of hemoglobin (Hb) was measured during the VFT. (Figure 1)
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Figure 1 (a). FOIRE-3000 NIRS system. (b). Channel layout of NIRS cap. The red probes are emissions while blue for detectors (c). VFT task design.
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2.4 NIRS measurements
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A 45-channel near-infrared spectroscopy (FOIRE-3000, Shimadzu Corporation, Japan) was used to measure the three relative concentrations (oxy-Hb, deoxy-Hb, and total-Hb). Fourteen pairs of emission and detector probes were placed on the forehand of each participant with the distance of 3.0 cm. Each probe with the next one consisted a channel (Figure 1(b)). The prefrontal
2.5 NIRS Data
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cortex were covered by these channels. The lowest probes were positioned along the Fp1-Fp2 line according to the International 10-20 system of electroencephalogram electrode placement [48]. The oxy-Hb and deoxy-Hb parameter are both very vital information to conclusion. While
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according to the tomography principles of NIRS, total-Hb is summation of oxy-Hb and deoxy-Hb. Evidences showed that oxy-Hb is a much reliable parameter compared to deoxy-Hb and total-Hb[49-52]. The deoxy-Hb may be a handicap to show the actual cortical activation because that its has a worse signal-to-noise ratio than oxy-Hb reflect the PFC activation in both groups.
[53, 54]
. Therefore, oxy-Hb data was used to
2.6 Data Analysis
All data analysis procedures were accomplished under MATLAB (Mathworks, Natick, MA) , SPM[55] and SPM-fNIRS[56] which is a SPM12-based software for fNIRS analysis. During the experiment, the 3D coordinates of four anchor points and 45 NIRS channels were recorded by the 3D fastrak system of FOIRE-3000. The anchor points were used to transfer the 45 channels location into MNI space of normalized standard human brain with SPM which were located at midpoint of the eyebrow, left and mastoid process, center top of the head (CZ of the 10-20 system). In order to reduce motion artifact during the recording, a method based on moving standard deviation and spline interpolation[57] with a 1000ms moving window length. The threshold factor was set to 3 and smooth factor to 5.
ACCEPTED MANUSCRIPT General linear model (GLM) [55] was performed to the fNIRS signals between task and rest for both patients and health controls, and differences between patients and health controls during task period. t-value from the GLM results of each condition were interpolated and smoothed on the normalized human brain. After that, family-wise error (FWE) correction was performed for each condition and the significant areas were chosen where FWE-corrected p<0.05. Table 1 Demographic data and VFT performance of normal controls and SPD patients
Group
Normal Controls
SPD
N=24
N=24
Age（years）
11f/13m 33.2±10.5
12f/12m 36.5±11.4
Education level (years) Vegetables(VFT)
14±3.5 10.2±3.9
12.9±3.0 7.3±3.3
Family machines(VFT) Four-foot animals(VFT)
10.4±2.9 10.2±3.1
6.4±2.2 7.3±2.9
Fruits(VFT)
10.8±3.2
8.0±3.0
Average(VFT)
10.5±2.3
7.2±2.2
b two sample t-test(df=46)
3. Results
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Difference p-value a
0.7726 0.3024b
1.15 2.72
0.2569 0.0093b
5.34 3.53
<0.0001b 0.0018b
4.66
0.0035b
4.50
<0.0001
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-1.04
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a Chi-square test
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Gender（f/m）
t-value
3.1 Demographic data and VFT performance
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Demographic and clinical data were presented in Table 1. There are no significant group
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differences in age, gender and education level between normal controls and SPD patients. As expected, a significant difference was concluded between the two groups in number of words generated during the verbal fluency task. The number of words generated during the VFT task by the 2 groups is presented in Table 1. The differences between SPD patients and control group were
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identified in all four categories and on average. And control group showed much better performance than the patient group in all categories and on average (Table 1).
3.2. NIRS data
A significant increase in the [oxy-Hb] change occurred during the task period at thirty-nine channels(1,3,4,5,6,7,10,11,13,14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36, 37,38,39,40,41,42,44,45）in the healthy controls and at 17 channels in the SPD patients(6,13,14,18,19,20,24,25,26,27,32,33,37,38,39,44,45). (Figure 2) The average activation degree of [oxy-Hb] in all 17 activated channels in SPD patients were much lower than in all 39 channels in healthy controls.(Figure 3. (a)(b)). Considerable differences of activation degree of [oxy-Hb] were found in 12 channels (39,26,13,19,38； 20,33,40,34,21,27,14 ) during VFT between two groups. The differences of activation areas between left and right lobe were particularly obvious in SPD patients. There were 13 activated channels in left lobe while only 4 in right lobe. 2(b)
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Figure 2 Results of GLM analysis for oxy-Hb signals, all results were corrected with FEW(p<0.05) and the lighted up areas were significantly different areas . (a). The t-value distribution of significantly different areas between rest and VFT tasks for normal control group. (b). The t-value distribution of
Control
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SPD
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significantly different areas between rest and VFT tasks for patient group.
Figure 3 p-value significance map of t-tests for [oxy-Hb] increase in SPD patients compared with healthy controls during VFT. p-value significance map of cortical distribution of 45 channels in the PFC with lower [oxy-Hb] increase than healthy subjects during VFT. p-values in grey channels are higher than 0.05, whereas p-values in colored channels are lower than 0.05.
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*** **
***
*
*
0.004
**
The energy of ∆ concentration(M)
**
***
**
***
**
**
0.005
0.003
0.002 0.001
* p<0.05 ** p<0.01 *** p<0.001
0 13
14
19
20
21 Control
26
27
33
34
38
39
40
Patient
Figure 4. Average related concentration energy of oxy-Hb for channels where significant response was
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observed for both control group and patient group during VFT tasks period with a time window from 0s to 30s. The error bar indicate the standard deviation. The oxy -Hb activation of control group was
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significant stronger than that of patients on these channels.
4. Discussion
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In the present study, cognition performance was observed in PSD patients and control group by taking VFT as cognitive tasks, detecting the activation in PFC by using NIRS to explore the
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relationship between impaired cognition and alteration of PFC in SPD patients. In comparison to healthy control group, the patients of SPD showed poor performance of VFT and decreased activation in PFC, especially in DLPFC. As is known, this is the first time using NIRS technology during VFT to detect the function of PFC in PSD patients.
4.1 VFT
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In comparison to healthy control group, the patients generated less numbers of words in each category and on average which showed poor performance in VFT (Table 1). These results may suggested the impairment of executive dysfunction in SPD patients. The similar result was found
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in fibromyalgia patients that they showed poor performance in VFT and the number of words was significantly less than the normal control[58]. The pathological mechanisms behind the association between PSD and poor cognitive performance are still not clear. Some studies suggested that the change of brain structure and
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function induced by pain may lead to poor performance in VFT [15-17]. Previous studies of fNIRS combined with VFT on mental disorders showed that there was no significant differences between the patients with depressive disorder, bipolar disorder and [28, 30-32]
schizophrenia in the VFT task . This phenomenon may due to the different languages of subjects. However, the previous study of our lab found that, there were no significant differences between patients with depression and healthy controls in the same four categories words of VFT in mandarin[48]. This phenomenon may suggest that the pathological mechanism of SPD is different from other mental disorders such as depression. SPD patients may had a more pronounced decline in cognitive function because of the ongoing pain. Executive function is one of the most important aspects of cognitive function, which means the ability to integrate all the cognitive processing, reflecting the individual's cognitive level to a certain extent[59]. The impairment of executive function can lead to the destruction of patients' [60]
daily life, including learning ability, independent ability and the connection of social . Some scholars believed that cognitive impairment may aggravate or maintain the chronic pain [61] symptoms , therefore the cognitive impairment and pain symptoms of SPD patients can b caused
ACCEPTED MANUSCRIPT and effected. 4.2.1 PFC The reflection of cortical activation by the increased [oxy-Hb] in NIRS has been shown in [53, 62, 63] [32] PET and MRI studies . Tomohiro Suto et al (2004) indicated that the increased [oxyHb] while taking the VFT can reflect the cerebral activation owing to cognitive activation by NIRS. The present study showed that the activation of PFC during the VFT was evidently lower in most NIRS channels in SPD patients compared to the healthy group (Figure 2). Similar results were confirmed in PET, Single-Photon Emission Computed Tomography (SPECT) , fMRI experiments [18-22] . Karibe H et al[20](2010) examined 10 SPD patients measured by single photon
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emission computed tomography study and showed significant decreased regional cerebral blood flow（rCBF）) in the PFC .
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The imaging studies of SPD above showed not only the abnormal of PFC function, but also the other related area of pain neuromatrix in brain, as insular and cingulate gyrus. Accordingly, PFC dysfunction in SPD patients may be related to pain modulation dysfunction caused by
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ongoing pain. Ongoing pain stimulated the relevant pain neuromatrix regions, continuously leading to the sustained activation of these areas, which resulted in PFC dysfunction.
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Some studies suggested that PFC dysfunction was caused by the loss of connectivity with other cortical and limbic systems [64, 65]. It has also been found that the artificial persistent pain [66] symptoms in rat can lead to the alterations of PFC, including the change of specific cell types and neural lesion[67]. Previous studies showed that when individuals were exposed to noxious stimuli, the pain
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neuromatrix areas including PFC, were activated to generate pain; but when the PFC function was abnormal, all stimuli including noxious and non noxious stimuli would activate the pain [23] neuromatrix areas leading to the persistent pain symptom . Thus, the relationship between the ongoing pain symptoms and PFC dysfunction in SPD patients may provide clues for the
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pathogenesis of SPD. Furthermore, PFC is the most important part in regulating of cognitive function, especially the executive function. PFC is involved in pain referring to cognitive processing such as treatment process, assessment of pain, anxiety and placebo effect. PFC involves cognitive processes of pain
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symptoms, such as efficacy, pain assessment, anxiety and placebo effects [68]. Accordingly, the poor performance in VFT in SPD patients may be associated with PFC dysfunction. The researchers found that the artificial persistent pain symptoms in rat can lead to the anatomical structure changes of PFC, and these changes may cause cognitive impairment, especially the flexibility in cognition. Ji et al [69]associated the pain and cognitive damage by using behavioral sciences, electrophysiology and pharmacology in the rat gambling task and confirmed that pain can cause cognitive impairment, while the pain induced cognitive impairment due to the PFC dysfunction driven by amygdala. In this study, PFC decreased activation was observed in patients with SPD, suggesting that PFC may be dysfunctional in pain regulation and also involved in poor cognitive performance in SPD patients . 4.2.2 DLPFC The results showed that the bilateral dorsolateral prefrontal cortex (DLPFC) in SPD patients showed less activation compared to healthy controls（ch7、ch12）(Figure 3).The same finding was confirmed by a SPECT study which showed decreased rCBF in bilateral DLPFC
[70]
. The imaging
ACCEPTED MANUSCRIPT study of pain and transcranial magnetic stimulation study of brain showed that DLPFC played an [71]
important role in the regulation of pain, as the negative regulation and inhibitory effect pain . Therefore, the dysfunction of DLPFC may lead to the decreased inhibition function of pain causing the persistent pain symptoms in SPD patients. Moreover, a MRI study of patients with chronic back pain found that the cortical thickness of the left DLPFC was significantly lower in patients compared with healthy controls, but the thickness of the cortex increased after effective treatment
[72]
. It suggested that DLPFC dysfunction in SPD
patients may be reversible. However, the bilateral DLPFC dysfunction was observed in this study when taking cognitive task. The difference between two studies may be related to the detection
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technique (MRI and fNIRS) and detection state (resting state and task status). The DLPFC dysfunctions are general among mental disorders as schizophrenia [73] , depression[74]
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and substance abuse[69] . Imaging studies suggested that DLPFC played a crucial role in executive functions, such as working memory, cognitive flexibility, planning, inhibition and abstract reasoning[75, 76]. DLPFC was involved in the maintenance of target information to the priority in [22]
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bottom-up and top-down attention to avoid interference with the target irrelevant information . Therefore, the dysfuntion of DLPFC causing the filtering of irrelevant information reduced,
[77]
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sub-cortical regions)
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leading to the poor performance in cognitive tasks. Accordingly, DLPFC dysfunction may be involved in the persistent pain symptoms and poor performance in cognitive tasks in SPD patiens. Previous study of mild cognitive impairment of patients showed the connection reduction of DLPFC and other brain regions (inferior parietal lobule (IPL), superior/medial frontal gyrus and . The results indicated that DLPFC dysfunction induced cognitive
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impairment due to decreased functional connectivity with other brain regions. 4.2.3 Abnormal PFC Lateralization In this study, bilateral PFC was activated during VFT in healthy controls while SPD patients showed significant activation in left PFC , close to the Broca’s area (Figure 2). As is known to all,
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the brain regional asymmetry in structure and function has been proved. Language processing is typically leftward asymmetry and activate the dominant hemisphere, including the Broca’s area[78]. Broca’s area is a region in the frontal lobe of the dominant hemisphere (usually the left) of the human brain with functions linked to speech production.
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However, previous studies have confirmed that VFT is not just a language task, but a cognitive task reflecting executive function[78]. NIRS studies of healthy people showed no significance activation difference in bilateral PFC during VFT [79]. Therefore, the abnormal activation asymmetry of PFC in SPD patients may be associated with the decrease in executive function, thus showing a poor performance of VFT. Also, the left hemispheric asymmetries of cognitive processing in SPD patients may be related to neural circuits, but the underneath mechanisms is still unclear. Abnormal lateralization is common in mental disorders, as schizophrenia, depression and delusions. A study of schizophrenia patients found that right-handed patients showed remarkably left lateralization activation of PFC during VFT [80]. A study of depression patients suggested that patients with depression had over activation in right hemisphere [81]. The abnormal lateralization activation of PFC in patients with mental disorders may hint that the neural activity of brain can [82]
be affected by the psychopathological mechanism . It is noteworthy that some researchers found only left DLPFC thickness decreased in SPD [83] patients . It is suggested that the functional decline of left DLPFC is closely related to the
ACCEPTED MANUSCRIPT pathogenesis of SPD. While in this study, SPD patients showed more activated in left PFC than right PFC( the degree and range of activation in PFC was still lower than the healthy controls), which may due to the decreased cognitive function in SPD patients, but normal function of language.
4.3 Limitations Some limitations should be considered in our studies. The limited number of SPD patients, may increase random errors compared with large scale investigations. The medication conditions of patients may also affect the results of the experiment. Also, we didn’t exclude the SPD with or without depression or anxiety.
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4.4 Future studies
It has been proven that the high comorbidity rate of SPD patients with depression disorder
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and anxiety. Future studies should extend knowledge about the co-morbid may affect the cognitive deficient of SPD patients and the PFC dysfunction may be a etiological factor of mental illness.
5.Conclusion
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In conclusion, the multi-channel NIRS study in SPD patients provides novel evidence that SPD patients have dysfunctions in PFC, especially in DLPFC, which indicates the role of PFC in
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cognitive processing and pain matrix, and highlights the relationship between cognitive impairment and pain symptom.
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Author Contributions
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Acknowledgment
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Conceived and designed the experiments: Xiajin Ren, Jinlu Lu, Pozi Liu. Performed the experiments: Chenyu Shen, Xiaomin Liu. Analyzed the data: Jingjing Sun. Contributed reagents/materials/analysis tools: Xiaoqian Zhang, Gaoxiang Sun, Kun Feng. XQZ KF GXS. Wrote the paper: Xiajin Ren. Operated the equipment: Xiangyun Ma. Collected the data: Bo Xu.
This work was supported by the National Natural Science Foundation of China (No. 81061120532). Very grateful to the patients and the control group for their valuable participants'
[1]
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collection. Thanks to Shimadzu Corporation for the technical support provided.
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ACCEPTED MANUSCRIPT Highlights
Patients with somatoform pain disorder (SPD) suffer from lasting chronic pain which may cause cognitive impairment.
The dysfunction of prefrontal cortex and dorsolateral prefrontal cortex were involved in pain-induced cognition impairment. The asymmetries of dorsolateral prefrontal cortex may also cause cognition impairment in
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SPD patients.
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Xiajin Ren, Jinlong Lu, Xiaomin Liu, Chenyu Shen, Xiaoqian Zhang, Xiangyun Ma, Jingjing Sun, Gaoxiang Sun, Kun Feng, Bo Xu, Pozi Liu PII: DOI: Reference:
S0278-5846(16)30361-X doi: 10.1016/j.pnpbp.2017.05.006 PNP 9100
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
14 November 2016 2 May 2017 8 May 2017
Please cite this article as: Xiajin Ren, Jinlong Lu, Xiaomin Liu, Chenyu Shen, Xiaoqian Zhang, Xiangyun Ma, Jingjing Sun, Gaoxiang Sun, Kun Feng, Bo Xu, Pozi Liu , Decreased prefrontal brain activation during verbal fluency task in patients with somatoform pain disorder: An exploratory multi-channel near-infrared spectroscopy study. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/j.pnpbp.2017.05.006
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Decreased prefrontal brain activation during verbal
fluency
task
in
patients
with
somatoform pain disorder: An exploratory near-infrared
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study
spectroscopy
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multi-channel
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Xiajin Rena,b, Jinlong Luc, Xiaomin Liub, Chenyu Shenb, Xiaoqian Zhang a,b, Xiangyun Maa,b, Jingjing Suna,b，Gaoxiang Sunb, Kun Feng b, Bo Xub, Pozi Liub.* a. Medical Center, Tsinghua Unversity, Beijing, China b. Department of Psychiatry, Yuquan Hospital, Tsinghua University, Beijing, China 1
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c. Guangwai Community Health Service Center, Beijing, China
* Corresponding author at: Department of Psychiatry, No. 5 Shijingshan Road, Shijingshan District, Beijing100049, China. Tel.: +86 1088257755x6111; fax: +86 83658195. E-mail address: [email protected] (P. Liu)
ACCEPTED MANUSCRIPT Abstract Background: Pain is a common phenomenon. Patients with somatoform pain disorder (SPD) suffer from lasting chronic pain which may cause cognitive impairment. The dysfunction of prefrontal cortex (PFC) may be involved in pain-induced cognition impairment, which is the most important part in regulating of cognitive function. Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive and low-cost functional neuroimaging technique being used to detect the prefrontal cortex activation during cognitive tasks to demonstrate the relationship between PFC dysfunction and cognition impairment in SPD patients.
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Methods: 24 patients with SPD and 24 age-, gender- and education level- matched healthy controls were examined by NIRS of the relative concentration of oxygenated hemoglobin (oxy-Hb)
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in PFC during verbal fluency task(VFT). All data analysis procedures were accomplished under MATLAB, SPM and SPM-fNIRS which is a SPM12-based software for fNIRS analysis. Results: 1.The number of words generated during the VFT tasks in SPD patients were fewer
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than healthy controls. 2.The activated areas in SPD patients were smaller than healthy controls.
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3.The average activation strength of [oxy-Hb] in SPD patients were much lower than healthy controls. 4.The difference of activation areas between left and right lobe were particularly
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obvious in SPD patients. Conclusion: There are evidence suggested that the markedly dysfunction in PFC especially bilateral dorsolateral prefrontal cortex (DLPFC) areas may be involved in the cognitive deficiency
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in patients with SPD.
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1. Introduction Pain is a multidimensional and complex phenomenon, which affects the physiological as well as psychological state of people. As we all know, pain is not only a purely sensory modality but also a
perception
and
comprised
of
sensory-discriminative,
motivational-affective
and
[1]
cognitive-evaluative aspects . Therefore, the cognition which is described as an information processing is an important role of pain experience. Clinical and experimental studies have eluc idated the brain mechanisms
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underlying cognitive modulation of pain [2-4]. Somatoform pain disorder (SPD), defined as a speculative diagnostic category for chronic somatic
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pain symptoms which are not explained by a general medical condition (American Psychiatric [5]
Association, 2000) , with a high lifetime prevalence, constitutes a large health care and clinical issue[6, 7].
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Lots of evidences are available for cognitive impairment in clinical of patients with chronic pain. These impairments including attention, memory and executive function aspects represent a great
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obstacle to the suffering long-lasting pain population in daily life. Some psychometric tests were used to assess the impairment of cognitive parameters function. Karp et al. considered chronic [8] pain patients perform poorly on D-KEFS trails number-letter switching test . Lee et al. used digit-symbol substitution test(DSST) to reflect the impaired cognition in chronic widespread pain patients which showed lower scores in this test [13]
[11]
. While few studies showed cognitive
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impairment in SPD. Christoph el at. used free recall recognition tasks to reflect the cognitive function of 14 SPD patients and 14 healthy controls, and impairment of memory performance was [14] observed in SPD patients. Paul Pauli el at. also found memory biases in SPD patients. The pathological mechanism of how SPD induced cognitive impairment is not clear. There are several
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hypothesis which may help to explain this phenomenon. Some researchers believed that the lasting pain symptom attracted too much attention and made other information acquistion process suppressed. So, when two parallel processing (ongoing pain and cognitive task) requiring cognition and attention occurred, they had to compete the limited cognitive resources, leading to
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poor cognitive performance[15,16]. Some researchers suggested that ongoing pain harm the “top-to-down” attention mechanism, causing the cognition related information filtered, leading to the cognition impairment [1]. Hart et al. [17] considered chronic pain caused changes of neural plasticity in brain, which led to the reorganization and rearrangement of neural. This rewiring or reorganization of neural interfered with normal cognitive processing. PFC structure or function alteration may be involved in the possible mechanisms above . In recent years, due to the development of brain functional imaging technologies , the structure, local blood flow, tissue metabolism and neurotransmitter changes, etc. of human brain can be visually observed easily. Most researchers used imaging methods to observe whether there is dysfunction in brain regions of SPD patients during resting state or by using simple negative stimulus, such as needling fingers, showing negative images or reading sad literary works [18-22]. Stoeter et al. [21] discovered the increased activation of the known pain-processing areas (thalamus, basal ganglia, operculo-insular cortex) in somatoform pain disorder patients, while increased activation of some prefrontal, temporal and parietal regions during cognitive stress, but reduced activation during emotional stress. Vale W et al. (2009) used magnetic resonance imaging to scan
ACCEPTED MANUSCRIPT 14 right-handed women who meet the DSM-IV criteria of somatoform pain disorder and 25 healthy age-matched healthy controls. The results showed that significant gray-matter decreased in prefrontal, cingulate, and insular cortex involved in the modulation of subjective pain [22] experiences . A SPECT study for chronic pain also showed rCBF increased in the subcortical area, especially in the thalamus and cingulate gyri, while decreased in the bilateral frontal and occipital lobes compared with control group [20]. Yoshino el al.(2014) used resting-state functional magnetic resonance imaging study to find that 11 patients with somatoform pain disorder exhibited atypical precentral gyrus activation compared with the age-matched healthy controls in a sad emotional condition[18].
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As the most important part of regulation of cognitive function, prefrontal cortex (PFC) is also the 2nd tier of pain matrix which has been shown as the most common site activated during pain
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processing with other five brain regions [23]. PFC may have dysfunctions in patients with SPD[24]. Therefore, the relationship of PFC and pain-induced cognitive impairment is worth studying. Near-infrared spectroscopy (NIRS), a non-invasive real-time optical imaging method to detect the [25]
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hemoglobin oxygenation in brain tissue, was first reported by Jöbsis in 1977 ( Jobsis, 1977) . As a neuroimaging technique, NIRS has the advantages of portable, bedside, low consumption,
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relatively low requirements for environment and repetitive operation, etc. Compared with other detective measurements, such as Magnetic Resonance Imaging (MRI), functional Magnetic Resonance Imaging (fMRI) and Positron Emission Computed Tomography (PET), NIRS has a high time resolution, making it possible to reflect the activation of the brain in real time [26, 27]. NIRS has been used widely in psychiatry and neurology as a detect measurement, such as [28-33]
depression, bipolar disorder, alzheimer and so on . NIRS is based on the modified Beer-Lambert law [34], and the principles of NIRS can be summarized as two main points:1.While
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stimulating the brain to activated state, the concentration of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin(deoxy-Hb) will change; 2.Human tissues for near-infrared light have
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special characteristics as low absorption and high scattering [35]. Verbal fluency task (VFT), is a classical cognitive task asking participants to generate as many words as possible in limited time [36]. VFT is widely used in neuropsychological cogitive assessment to support diagnoses of alzheimer’s disease[37], attention deficit hyperactivity disorder
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(ADHD) [38] and parkinson’s disease[39, 40]. The test validity of verbal ability and executive control functions in VFT has been proven because VFT demands not only verbal retrieval and recall, but also important aspects of cognition as self-monitoring, inhibition of responses when time is up[41]. Children with ADHD showed lower score in VFT compared with matched healthy controls suggesting the association of executive control functions and poor VFT performance[42].VFT has been successfully combined with NIRS to detect PFC activation in healthy people and mental disorders patients [31, 43-45] due to the closed relationship between frontal brain area and performance in VFT [46, 47]. The memory bias and attention distracting in SPD patients have been [13, 14]
observed in past experiments . These mechanisms indicated that patients with SPD are more sensitive to passive and negative words or situations, which may affect the modulation of affection and cognition. Therefore, VFT was selected as the cognitive task by using neuter words to eliminate these two phenomena and the results would be fairer. As far as we know, there are few functional imaging studies focusing on the PFC activation in SPD patients carrying out cognitive tasks, which makes the cognitive study of SPD patients insufficient. And considering the important role of PFC in cognitive function and the necessary of
ACCEPTED MANUSCRIPT exploring the relationship between SPD and cognitive function, it is very essential to find how SPD affects cognitive function and PFC activation. So in this study we aimed to find the relationship between PFC and cognitive function of SPD patient and how SPD affects PFC by using NIRS and VFT.
2. Materials and Methods 2.1 Subjects There were twenty-four patients with somatoform pain disorders and age, gender, education level matched healthy controls.Patients were diagnosed according to the DSM-IV criteria, recruited
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from February 2012 to May 2015 in Psychiatry Department of Yuquan Hospital, Beijing, China. Control participants were recruited from non-clinical populations. All subjects were right-handed.
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All participants were undergone the neurological examination and psychiatric interview and
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excluded language dysfunction including aphasia. Subjects with psychiatric symptoms or other psychotic disorders, chronic substance abuse, severe medical illness, cognitive disorders or cerebral organic lesion including trauma, tumor and inflammation were excluded. The study was approved by the ethic committees of Yuquan Hospital and written informed consent was obtained from all participants.
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2.2 Procedure
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All subjects were asked to sit on a comfortable chair and required to stare at the 50 cm-away-screen with eyes open, avoiding artifact, and perform the cognitive tasks in accordance with the screen prompt. Furthermore in the whole process subjects should try their best to avoid movements of head, chin, body, hands, feet and other parts of body.
2.3 VFT tasks
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We used the semantic category version of the verbal fluency task (VFT) as the cognitive task. The VFT were composed by 3 periods, 30s of baseline, 30s of tasks, and 30s of rest after tasks,
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which had a total of four groups of neutral words as vegetables, domestic appliance, animals with four legs and fruits. The four groups of neutral word were selected because of showing no statistical differences in healthy people in the preliminary work of our lab. The VFT lasted for 360s without breaking off. Participants needed to describe as many as possible the names of
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related species in the task time without repetition, and keep quiet and thoughtless in rest time. Relative concentration of hemoglobin (Hb) was measured during the VFT. (Figure 1)
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Figure 1 (a). FOIRE-3000 NIRS system. (b). Channel layout of NIRS cap. The red probes are emissions while blue for detectors (c). VFT task design.
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2.4 NIRS measurements
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A 45-channel near-infrared spectroscopy (FOIRE-3000, Shimadzu Corporation, Japan) was used to measure the three relative concentrations (oxy-Hb, deoxy-Hb, and total-Hb). Fourteen pairs of emission and detector probes were placed on the forehand of each participant with the distance of 3.0 cm. Each probe with the next one consisted a channel (Figure 1(b)). The prefrontal
2.5 NIRS Data
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cortex were covered by these channels. The lowest probes were positioned along the Fp1-Fp2 line according to the International 10-20 system of electroencephalogram electrode placement [48]. The oxy-Hb and deoxy-Hb parameter are both very vital information to conclusion. While
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according to the tomography principles of NIRS, total-Hb is summation of oxy-Hb and deoxy-Hb. Evidences showed that oxy-Hb is a much reliable parameter compared to deoxy-Hb and total-Hb[49-52]. The deoxy-Hb may be a handicap to show the actual cortical activation because that its has a worse signal-to-noise ratio than oxy-Hb reflect the PFC activation in both groups.
[53, 54]
. Therefore, oxy-Hb data was used to
2.6 Data Analysis
All data analysis procedures were accomplished under MATLAB (Mathworks, Natick, MA) , SPM[55] and SPM-fNIRS[56] which is a SPM12-based software for fNIRS analysis. During the experiment, the 3D coordinates of four anchor points and 45 NIRS channels were recorded by the 3D fastrak system of FOIRE-3000. The anchor points were used to transfer the 45 channels location into MNI space of normalized standard human brain with SPM which were located at midpoint of the eyebrow, left and mastoid process, center top of the head (CZ of the 10-20 system). In order to reduce motion artifact during the recording, a method based on moving standard deviation and spline interpolation[57] with a 1000ms moving window length. The threshold factor was set to 3 and smooth factor to 5.
ACCEPTED MANUSCRIPT General linear model (GLM) [55] was performed to the fNIRS signals between task and rest for both patients and health controls, and differences between patients and health controls during task period. t-value from the GLM results of each condition were interpolated and smoothed on the normalized human brain. After that, family-wise error (FWE) correction was performed for each condition and the significant areas were chosen where FWE-corrected p<0.05. Table 1 Demographic data and VFT performance of normal controls and SPD patients
Group
Normal Controls
SPD
N=24
N=24
Age（years）
11f/13m 33.2±10.5
12f/12m 36.5±11.4
Education level (years) Vegetables(VFT)
14±3.5 10.2±3.9
12.9±3.0 7.3±3.3
Family machines(VFT) Four-foot animals(VFT)
10.4±2.9 10.2±3.1
6.4±2.2 7.3±2.9
Fruits(VFT)
10.8±3.2
8.0±3.0
Average(VFT)
10.5±2.3
7.2±2.2
b two sample t-test(df=46)
3. Results
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Difference p-value a
0.7726 0.3024b
1.15 2.72
0.2569 0.0093b
5.34 3.53
<0.0001b 0.0018b
4.66
0.0035b
4.50
<0.0001
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-1.04
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a Chi-square test
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Gender（f/m）
t-value
3.1 Demographic data and VFT performance
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Demographic and clinical data were presented in Table 1. There are no significant group
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differences in age, gender and education level between normal controls and SPD patients. As expected, a significant difference was concluded between the two groups in number of words generated during the verbal fluency task. The number of words generated during the VFT task by the 2 groups is presented in Table 1. The differences between SPD patients and control group were
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identified in all four categories and on average. And control group showed much better performance than the patient group in all categories and on average (Table 1).
3.2. NIRS data
A significant increase in the [oxy-Hb] change occurred during the task period at thirty-nine channels(1,3,4,5,6,7,10,11,13,14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36, 37,38,39,40,41,42,44,45）in the healthy controls and at 17 channels in the SPD patients(6,13,14,18,19,20,24,25,26,27,32,33,37,38,39,44,45). (Figure 2) The average activation degree of [oxy-Hb] in all 17 activated channels in SPD patients were much lower than in all 39 channels in healthy controls.(Figure 3. (a)(b)). Considerable differences of activation degree of [oxy-Hb] were found in 12 channels (39,26,13,19,38； 20,33,40,34,21,27,14 ) during VFT between two groups. The differences of activation areas between left and right lobe were particularly obvious in SPD patients. There were 13 activated channels in left lobe while only 4 in right lobe. 2(b)
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ACCEPTED MANUSCRIPT
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Figure 2 Results of GLM analysis for oxy-Hb signals, all results were corrected with FEW(p<0.05) and the lighted up areas were significantly different areas . (a). The t-value distribution of significantly different areas between rest and VFT tasks for normal control group. (b). The t-value distribution of
Control
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SPD
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significantly different areas between rest and VFT tasks for patient group.
Figure 3 p-value significance map of t-tests for [oxy-Hb] increase in SPD patients compared with healthy controls during VFT. p-value significance map of cortical distribution of 45 channels in the PFC with lower [oxy-Hb] increase than healthy subjects during VFT. p-values in grey channels are higher than 0.05, whereas p-values in colored channels are lower than 0.05.
ACCEPTED MANUSCRIPT 0.006
*** **
***
*
*
0.004
**
The energy of ∆ concentration(M)
**
***
**
***
**
**
0.005
0.003
0.002 0.001
* p<0.05 ** p<0.01 *** p<0.001
0 13
14
19
20
21 Control
26
27
33
34
38
39
40
Patient
Figure 4. Average related concentration energy of oxy-Hb for channels where significant response was
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observed for both control group and patient group during VFT tasks period with a time window from 0s to 30s. The error bar indicate the standard deviation. The oxy -Hb activation of control group was
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significant stronger than that of patients on these channels.
4. Discussion
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In the present study, cognition performance was observed in PSD patients and control group by taking VFT as cognitive tasks, detecting the activation in PFC by using NIRS to explore the
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relationship between impaired cognition and alteration of PFC in SPD patients. In comparison to healthy control group, the patients of SPD showed poor performance of VFT and decreased activation in PFC, especially in DLPFC. As is known, this is the first time using NIRS technology during VFT to detect the function of PFC in PSD patients.
4.1 VFT
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In comparison to healthy control group, the patients generated less numbers of words in each category and on average which showed poor performance in VFT (Table 1). These results may suggested the impairment of executive dysfunction in SPD patients. The similar result was found
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in fibromyalgia patients that they showed poor performance in VFT and the number of words was significantly less than the normal control[58]. The pathological mechanisms behind the association between PSD and poor cognitive performance are still not clear. Some studies suggested that the change of brain structure and
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function induced by pain may lead to poor performance in VFT [15-17]. Previous studies of fNIRS combined with VFT on mental disorders showed that there was no significant differences between the patients with depressive disorder, bipolar disorder and [28, 30-32]
schizophrenia in the VFT task . This phenomenon may due to the different languages of subjects. However, the previous study of our lab found that, there were no significant differences between patients with depression and healthy controls in the same four categories words of VFT in mandarin[48]. This phenomenon may suggest that the pathological mechanism of SPD is different from other mental disorders such as depression. SPD patients may had a more pronounced decline in cognitive function because of the ongoing pain. Executive function is one of the most important aspects of cognitive function, which means the ability to integrate all the cognitive processing, reflecting the individual's cognitive level to a certain extent[59]. The impairment of executive function can lead to the destruction of patients' [60]
daily life, including learning ability, independent ability and the connection of social . Some scholars believed that cognitive impairment may aggravate or maintain the chronic pain [61] symptoms , therefore the cognitive impairment and pain symptoms of SPD patients can b caused
ACCEPTED MANUSCRIPT and effected. 4.2.1 PFC The reflection of cortical activation by the increased [oxy-Hb] in NIRS has been shown in [53, 62, 63] [32] PET and MRI studies . Tomohiro Suto et al (2004) indicated that the increased [oxyHb] while taking the VFT can reflect the cerebral activation owing to cognitive activation by NIRS. The present study showed that the activation of PFC during the VFT was evidently lower in most NIRS channels in SPD patients compared to the healthy group (Figure 2). Similar results were confirmed in PET, Single-Photon Emission Computed Tomography (SPECT) , fMRI experiments [18-22] . Karibe H et al[20](2010) examined 10 SPD patients measured by single photon
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emission computed tomography study and showed significant decreased regional cerebral blood flow（rCBF）) in the PFC .
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The imaging studies of SPD above showed not only the abnormal of PFC function, but also the other related area of pain neuromatrix in brain, as insular and cingulate gyrus. Accordingly, PFC dysfunction in SPD patients may be related to pain modulation dysfunction caused by
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ongoing pain. Ongoing pain stimulated the relevant pain neuromatrix regions, continuously leading to the sustained activation of these areas, which resulted in PFC dysfunction.
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Some studies suggested that PFC dysfunction was caused by the loss of connectivity with other cortical and limbic systems [64, 65]. It has also been found that the artificial persistent pain [66] symptoms in rat can lead to the alterations of PFC, including the change of specific cell types and neural lesion[67]. Previous studies showed that when individuals were exposed to noxious stimuli, the pain
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neuromatrix areas including PFC, were activated to generate pain; but when the PFC function was abnormal, all stimuli including noxious and non noxious stimuli would activate the pain [23] neuromatrix areas leading to the persistent pain symptom . Thus, the relationship between the ongoing pain symptoms and PFC dysfunction in SPD patients may provide clues for the
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pathogenesis of SPD. Furthermore, PFC is the most important part in regulating of cognitive function, especially the executive function. PFC is involved in pain referring to cognitive processing such as treatment process, assessment of pain, anxiety and placebo effect. PFC involves cognitive processes of pain
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symptoms, such as efficacy, pain assessment, anxiety and placebo effects [68]. Accordingly, the poor performance in VFT in SPD patients may be associated with PFC dysfunction. The researchers found that the artificial persistent pain symptoms in rat can lead to the anatomical structure changes of PFC, and these changes may cause cognitive impairment, especially the flexibility in cognition. Ji et al [69]associated the pain and cognitive damage by using behavioral sciences, electrophysiology and pharmacology in the rat gambling task and confirmed that pain can cause cognitive impairment, while the pain induced cognitive impairment due to the PFC dysfunction driven by amygdala. In this study, PFC decreased activation was observed in patients with SPD, suggesting that PFC may be dysfunctional in pain regulation and also involved in poor cognitive performance in SPD patients . 4.2.2 DLPFC The results showed that the bilateral dorsolateral prefrontal cortex (DLPFC) in SPD patients showed less activation compared to healthy controls（ch7、ch12）(Figure 3).The same finding was confirmed by a SPECT study which showed decreased rCBF in bilateral DLPFC
[70]
. The imaging
ACCEPTED MANUSCRIPT study of pain and transcranial magnetic stimulation study of brain showed that DLPFC played an [71]
important role in the regulation of pain, as the negative regulation and inhibitory effect pain . Therefore, the dysfunction of DLPFC may lead to the decreased inhibition function of pain causing the persistent pain symptoms in SPD patients. Moreover, a MRI study of patients with chronic back pain found that the cortical thickness of the left DLPFC was significantly lower in patients compared with healthy controls, but the thickness of the cortex increased after effective treatment
[72]
. It suggested that DLPFC dysfunction in SPD
patients may be reversible. However, the bilateral DLPFC dysfunction was observed in this study when taking cognitive task. The difference between two studies may be related to the detection
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technique (MRI and fNIRS) and detection state (resting state and task status). The DLPFC dysfunctions are general among mental disorders as schizophrenia [73] , depression[74]
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and substance abuse[69] . Imaging studies suggested that DLPFC played a crucial role in executive functions, such as working memory, cognitive flexibility, planning, inhibition and abstract reasoning[75, 76]. DLPFC was involved in the maintenance of target information to the priority in [22]
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bottom-up and top-down attention to avoid interference with the target irrelevant information . Therefore, the dysfuntion of DLPFC causing the filtering of irrelevant information reduced,
[77]
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sub-cortical regions)
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leading to the poor performance in cognitive tasks. Accordingly, DLPFC dysfunction may be involved in the persistent pain symptoms and poor performance in cognitive tasks in SPD patiens. Previous study of mild cognitive impairment of patients showed the connection reduction of DLPFC and other brain regions (inferior parietal lobule (IPL), superior/medial frontal gyrus and . The results indicated that DLPFC dysfunction induced cognitive
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impairment due to decreased functional connectivity with other brain regions. 4.2.3 Abnormal PFC Lateralization In this study, bilateral PFC was activated during VFT in healthy controls while SPD patients showed significant activation in left PFC , close to the Broca’s area (Figure 2). As is known to all,
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the brain regional asymmetry in structure and function has been proved. Language processing is typically leftward asymmetry and activate the dominant hemisphere, including the Broca’s area[78]. Broca’s area is a region in the frontal lobe of the dominant hemisphere (usually the left) of the human brain with functions linked to speech production.
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However, previous studies have confirmed that VFT is not just a language task, but a cognitive task reflecting executive function[78]. NIRS studies of healthy people showed no significance activation difference in bilateral PFC during VFT [79]. Therefore, the abnormal activation asymmetry of PFC in SPD patients may be associated with the decrease in executive function, thus showing a poor performance of VFT. Also, the left hemispheric asymmetries of cognitive processing in SPD patients may be related to neural circuits, but the underneath mechanisms is still unclear. Abnormal lateralization is common in mental disorders, as schizophrenia, depression and delusions. A study of schizophrenia patients found that right-handed patients showed remarkably left lateralization activation of PFC during VFT [80]. A study of depression patients suggested that patients with depression had over activation in right hemisphere [81]. The abnormal lateralization activation of PFC in patients with mental disorders may hint that the neural activity of brain can [82]
be affected by the psychopathological mechanism . It is noteworthy that some researchers found only left DLPFC thickness decreased in SPD [83] patients . It is suggested that the functional decline of left DLPFC is closely related to the
ACCEPTED MANUSCRIPT pathogenesis of SPD. While in this study, SPD patients showed more activated in left PFC than right PFC( the degree and range of activation in PFC was still lower than the healthy controls), which may due to the decreased cognitive function in SPD patients, but normal function of language.
4.3 Limitations Some limitations should be considered in our studies. The limited number of SPD patients, may increase random errors compared with large scale investigations. The medication conditions of patients may also affect the results of the experiment. Also, we didn’t exclude the SPD with or without depression or anxiety.
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4.4 Future studies
It has been proven that the high comorbidity rate of SPD patients with depression disorder
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and anxiety. Future studies should extend knowledge about the co-morbid may affect the cognitive deficient of SPD patients and the PFC dysfunction may be a etiological factor of mental illness.
5.Conclusion
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In conclusion, the multi-channel NIRS study in SPD patients provides novel evidence that SPD patients have dysfunctions in PFC, especially in DLPFC, which indicates the role of PFC in
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cognitive processing and pain matrix, and highlights the relationship between cognitive impairment and pain symptom.
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Author Contributions
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Acknowledgment
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Conceived and designed the experiments: Xiajin Ren, Jinlu Lu, Pozi Liu. Performed the experiments: Chenyu Shen, Xiaomin Liu. Analyzed the data: Jingjing Sun. Contributed reagents/materials/analysis tools: Xiaoqian Zhang, Gaoxiang Sun, Kun Feng. XQZ KF GXS. Wrote the paper: Xiajin Ren. Operated the equipment: Xiangyun Ma. Collected the data: Bo Xu.
This work was supported by the National Natural Science Foundation of China (No. 81061120532). Very grateful to the patients and the control group for their valuable participants'
[1]
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collection. Thanks to Shimadzu Corporation for the technical support provided.
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ACCEPTED MANUSCRIPT Highlights
Patients with somatoform pain disorder (SPD) suffer from lasting chronic pain which may cause cognitive impairment.
The dysfunction of prefrontal cortex and dorsolateral prefrontal cortex were involved in pain-induced cognition impairment. The asymmetries of dorsolateral prefrontal cortex may also cause cognition impairment in
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SPD patients.
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