Effects of distraction on pain perception: magneto- and electro-encephalographic studies

After a painful CO2 laser stimulation to the skin, the magnetoencephalography (MEG) response (164 ms in average peak latency) was not affected by distraction, but the sequential electroencephalography (EEG) responses (240-340 ms), probably generated by a summation of activities in multiple areas, were markedly affected. We suspect that the MEG response, whose dipole is estimated in the bilateral second somatosensory cortex (SII) and insula, reflects the primary activities of pain in humans.     

Mechanisms of intracerebral pain and itch perception in humans

Electrophysiological studies involving techniques such as magnetoencephalography (MEG) and hemodynamic studies involving techniques such as functional magnetic resonance imaging (fMRI) have recently been intensively used to elucidate the mechanisms underlying pain and itch perception in humans. The MEG results obtained after A-delta fiber (first pain) and C fiber (second pain) stimulation were similar, except for longer latency in the case of C fibers. Initially, the primary somatosensory cortex (SI) contralateral to the stimulation is activated, and the secondary somatosensory cortex (SII), insula, amygdala, and anterior cingulate cortex (ACC) in both hemispheres are then activated sequentially. The fMRI findings obtained after the stimulation of C fibers and those obtained after the stimulation of A-delta fibers both showed activation of the bilateral thalamus, bilateral SII, right (ipsilateral) middle insula, and bilateral Brodmann's area (BA) 24/32, with most of the activity being detected in the posterior region of the ACC. However, the magnitude of activity in the anterior insula on both sides and in BA 32/8/6, including the ACC and pre-supplementary motor area (pre-SMA), after the stimulation of C nociceptors was significantly stronger than that after the stimulation of A-delta nociceptors. We have recently developed a new stimulation electrode that causes an itching sensation via electrical stimulation applied to skin. The conduction velocity (CV) of the signals caused by this stimulation is approximately 1 m/sec in a range of CV of C fibers. The findings obtained after itch stimulation were similar to those obtained after pain stimulation, but the precuneus may be an itch-selective brain region. This unique finding was confirmed by both MEG and fMRI studies.     

Primary somatosensory cortex is actively involved in pain processing in human

We recorded somatosensory evoked magnetic fields (SEFs) by a whole head magnetometer to elucidate cortical receptive areas involved in pain processing, focusing on the primary somatosensory cortex (SI), following painful CO(2) laser stimulation of the dorsum of the left hand in 12 healthy human subjects. In seven subjects, three spatially segregated cortical areas (contralateral SI and bilateral second (SII) somatosensory cortices) were simultaneously activated at around 210 ms after the stimulus, suggesting parallel processing of pain information in SI and SII. Equivalent current dipole (ECD) in SI pointed anteriorly in three subjects whereas posteriorly in the remaining four. We also recorded SEFs following electric stimulation of the left median nerve at wrist in three subjects. ECD of CO(2) laser stimulation was located medial-superior to that of electric stimulation in all three subjects. In addition, by direct recording of somatosensory evoked potentials (SEPs) from peri-Rolandic cortex by subdural electrodes in an epilepsy patient, we identified a response to the laser stimulation over the contralateral SI with the peak latency of 220 ms. Its distribution was similar to, but slightly wider than, that of P25 of electric SEPs. Taken together, it is postulated that the pain impulse is received in the crown of the postcentral gyrus in human.     

Effects of distraction on pain-related somatosensory evoked magnetic fields and potentials following painful electrical stimulation

We aimed to compare the effects of distraction on pain-related somatosensory evoked magnetic fields (pain SEF) following painful electrical stimulation with simultaneous recordings of evoked potentials (pain SEP). Painful electrical stimuli were applied to the right index finger of eleven healthy subjects. A table with 25 random two-digit numbers was shown to the subjects, who were asked to add 5 numbers of each line in their mind (calculation task) or to memorize the numbers (memorization task) during the recording. In the SEF recording, 3 short-latency components within 50 ms of the stimulation were generated in the primary sensory cortex (SI) of the hemisphere contralateral to the stimulated finger. Middle-latency components between 100 and 250 ms after the stimuli were recorded from the secondary somatosensory cortex (SII) in the bilateral hemispheres or the cingulate cortex. No SEF components were significantly affected by either task. In the SEP recording, the middle-latency components (N140 and P230) were identified as being maximal around the vertex. Amplitudes of the N140 and P230 were not affected by each task, but the peak-to-peak amplitude (N140-P230) was significantly decreased by both the calculation and memorization tasks, particularly by the former. Subjective pain rating was decreased in both the calculation and memorization tasks, particularly in the former. We concluded that distraction tasks reduced activities in the limbic system, in which the middle-latency EEG component probably generated, while neither the short-latency SEF components generated in SI nor the primary pain-related SEF components generated in SII-insula are affected.     

Reactions of neurons in the primary and secondary somatosensory zones of the cortex to stimulation of the ventral posterior nucleus of the thalamus]

Neuronal responses in the first and second somatosensory cortex (SI and SII) to stimulation of the ventroposterior nucleus of the thalamus (VP) were studied in experiments on cats immobilized with d-tubocurarine. 12.0% responding neurons in SI and 9.5% in SII were activated antidromically by VP stimulation. In the majority of antidromic responses the latencies did not exceed 1.0 ms. The minimal latency of orthodromic spikes was 1.5 ms in SI and 1.7 ms in SII. In SI the number of neurons whose orthodromic spike latencies did not exceed 3.0 ms was larger than neurons activated with latencies of 3.1-4.5 ms. In SII an inverse quantitative relationship between those two neuronal groups was observed. In SII a significantly larger number of neurons was excited with latencies of EPSPs ranged between 1.1-9.0 ms in SI and between 1.4-6.6 ms in SII and the latencies of IPSPs between 1.5-6.8 ms in SI and 2.2-9.4 ms in SII. The importance of different pathways for excitatory and inhibitory VP influences to neurons of SI and SII is discussed.     

Spatiotemporal dynamics of bimanual integration in human somatosensory cortex and their relevance to bimanual object manipulation

Little is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration.     

Analysis of pain-related somatosensory evoked magnetic fields using the MUSIC (multiple signal classification) algorithm for magnetoencephalography.

We evaluated the effectiveness of the Multiple Signal Classification (MUSIC) algorithm by analysing pain-related somatosensory-evoked magnetic fields (SEFs) by 148-channel whole-head-type magnetoencephalography. MUSIC peaks of middle latency components were located around the primary somatosensory cortex (SI), contralateral to the stimulated finger. Long latency components were located around the bilateral secondary somatosensory cortices (SII) and cingulate gyri. Peaks at the SII and cingulate gyri were more prominent on very painful and moderately painful stimulation than on weak stimulation. The results were in very good agreement with results from single dipole estimation. These findings suggest that the MUSIC algorithm could be a useful tool for analysis of pain-related SEFs.     

Functional characterization of human second somatosensory cortex by magnetoencephalography

Magnetoencephalographic (MEG) recordings allow noninvasive monitoring of simultaneously active brain areas with reasonable spatial and excellent temporal resolution. Whole-scalp neuromagnetic recordings show activation of contralateral primary (SI) and bilateral second (SII) somatosensory cortices to unilateral median nerve stimulation. Recent MEG studies on healthy and diseased human subjects have shown some functional characteristics of SII cortex. Besides tactile input, the SII cortex also responds to nociceptive afferents. The SII activation is differentially modulated by isometric muscle contraction of various body parts. Lesions in the SII cortex may disturb the self-perception of body scheme. Moreover, the SI and SII cortices may be sequentially activated within one hemisphere, but the SII cortex may also receive direct peripheral input on the ipsilateral side.     

The profile of the recovery cycle in human primary and secondary somatosensory cortex: a magnetoencephalography study.

OBJECTIVE: To estimate the lifetime of sensory memory in human primary (SI) and secondary (SII) somatosensory cortex with a view to furthering our understanding of the roles played by these cortices in the processing of tactile information. METHODS: Somatosensory evoked fields (SEFs) were recorded following trains of 5 electrical pulses applied to the right median nerve at the wrist using a whole-head 80 channel magnetoencephalography (MEG) system. Recordings were acquired for trains of pulses with differing interstimulus intervals (ISIs) occurring at 100, 200, 300, 400 and 500 ms. The profile of SEF intensities for the different ISIs provided an estimate of the recovery cycle of evoked neuronal activity, and the time constant of the exponential curve fitted to the recovery cycle was calculated to obtain a putative measure of the lifetime of somatic sensory memory in SI and SII. RESULTS: The estimated time constants were 0.11+/-0.06 s (mean+/-SD) in SI and 0.82+/-0.34 s in SII. The mean time constant in SII was significantly longer than that in SI (Student's paired t test: P=0.021; analysis of variance: F(1,3)=19.7, P=0.021). CONCLUSIONS: These data indicate that the lifetime of somatic sensory memory is of longer duration in higher order cortical areas than in primary sensory cortex in the somatosensory information processing system.     

Pain processing within the primary somatosensory cortex in humans

To investigate the processing of noxious stimuli within the primary somatosensory cortex (SI), we recorded magnetoencephalography following noxious epidermal electrical stimulation (ES) and innocuous transcutaneous electrical stimulation (TS) applied to the dorsum of the left hand. TS activated two sources sequentially within SI: one in the posterior bank of the central sulcus and another in the crown of the postcentral gyrus, corresponding to Brodmann's areas 3b and 1, respectively. Activities from area 3b consisted of 20- and 30-ms responses. Activities from area 1 consisted of three components peaking at 26, 36 and 49 ms. ES activated one source within SI whose location and orientation were similar to those of the TS-activated area 1 source. Activities from this source consisted of three components peaking at 88, 98 and 109 ms, later by 60 ms than the corresponding TS responses. ES and TS subsequently activated a similar region in the upper bank of the sylvian fissure, corresponding to the secondary somatosensory cortex (SII). The onset latency of the SII activity following ES (109 ms) was later by 29 ms than that of the first SI response (80 ms). Likewise, the onset latency of SII activity following TS (52 ms) was later by 35 ms than that of area 1 of SI (17 ms). Therefore, our results showed that the processing of noxious and innocuous stimuli is similar with respect to the source locations and activation timings within SI and SII except that there were no detectable activations within area 3b following noxious stimulation.     

Pain-related magnetic fields evoked by intra-epidermal electrical stimulation in humans.

OBJECTIVES: We recently developed a new method for the preferential stimulation of Adelta fibers in humans. The aim of the present study was to examine whether this method can serve as an appropriate stimulus in a magnetoencephalographic study. METHODS: We recorded somatosensory-evoked magnetic fields (SEFs) following intra-epidermal electrical stimulation applied to the hand and elbow. Superficial parts of the skin were electrically stimulated through a needle electrode whose tip was inserted in the epidermis. RESULTS: In all 13 subjects, the equivalent current dipole was estimated in the secondary somatosensory cortices (SII). In 5 out of 13 subjects, simultaneous activation of the primary somatosensory cortex (SI) in the hemisphere contralateral to the stimulation was identified. The mean peak latencies of magnetic fields corresponding to contralateral SI, SII and ipsilateral SII activation following hand stimulation were 162, 158 and 171 ms, respectively. The respective latency following elbow stimulation was 137, 139 and 157 ms, respectively. Estimated peripheral conduction velocity was 15.6m/s. CONCLUSIONS: All the results were consistent with previous findings in pain SEF studies. We concluded that our novel intra-epidermal electrical stimulation is useful for pain SEF studies since it does not need special equipment and is easy to control.     

Brain generators of laser-evoked potentials: from dipoles to functional significance

In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a "lumped" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.     

Cortical nociceptive responses and behavioral correlates in the monkey

Experiments were performed to characterize cerebral cortical activity and pain behavior elicited by electrical stimulation of the tooth pulp in unanesthetized monkeys. Four monkeys were trained on two different operant paradigms: two on a simple escape task and two on an appetitive tolerance-escape task. All monkeys were implanted with bipolar stimulating electrodes in the right maxillary canine tooth and subdural recording electrodes over the left primary (SI) and/or secondary (SII) somatosensory cortices. Subdural tooth pulp-evoked potentials (TPEPs) recorded over the SII consisted of components P1 (27.5 ms), N1 (40.3 ms), P2 (84.0 ms), N2 (163.5 ms), P3 (295.3 ms), and N3 (468.0 ms). The long latency component (P3-N3) was found exclusively over the SII and was elicited by high intensity stimulation. The appearance of component P3-N3 required the recruitment of A delta nerve fibers into the maxillary nerve compound action potential and was correlated with high frequencies of escape. Administration of morphine sulfate (4 mg/kg, i.m.) caused a contemporaneous reduction in escape frequency and in the amplitude of P3-N3 recorded over the SII. The relationships between TPEP amplitude, escape behavior and A delta nerve fiber activity strongly suggest that the SII is involved with nociception and pain behavior.     

Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study

Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the β-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz β band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing.     

Neurophysiology and functional neuroanatomy of pain perception.

The traditional view that the cerebral cortex is not involved in pain processing has been abandoned during the past decades based on anatomic and physiologic investigations in animals, and lesion, functional neuroimaging, and neurophysiologic studies in humans. These studies have revealed an extensive central network associated with nociception that consistently includes the thalamus, the primary (SI) and secondary (SII) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC). Anatomic and electrophysiologic data show that these cortical regions receive direct nociceptive thalamic input. From the results of human studies there is growing evidence that these different cortical structures contribute to different dimensions of pain experience. The SI cortex appears to be mainly involved in sensory-discriminative aspects of pain. The SII cortex seems to have an important role in recognition, learning, and memory of painful events. The insula has been proposed to be involved in autonomic reactions to noxious stimuli and in affective aspects of pain-related learning and memory. The ACC is closely related to pain unpleasantness and may subserve the integration of general affect, cognition, and response selection. The authors review the evidence on which the proposed relationship between cortical areas, pain-related neural activations, and components of pain perception is based.     

Characteristics of the human contra- versus ipsilateral SII cortex.

OBJECTIVES: In order to study the interaction between left- and right-sided stimuli on the activation of cortical somatosensory areas, we recorded somatosensory evoked magnetic fields (SEFs) from 8 healthy subjects with a 122 channel whole-scalp SQUID gradiometer. METHODS: Right and left median nerves were stimulated either alternately within the same run, with interstimulus intervals (ISIs) of 1.5 and 3 s, or separately in different runs with a 3 s ISI. In all conditions 4 cortical source areas were activated: the contralateral primary somatosensory cortex (SI), the contra- and ipsilateral secondary somatosensory cortices (SII) and the contralateral posterior parietal cortex (PPC). RESULTS: The earliest activity starting at 20 ms was generated solely in the SI cortex, whereas longer-latency activity was detected from all 4 source areas. The mean peak latencies for SII responses were 86-96 ms for contralateral and 94-97 ms for ipsilateral stimuli. However, the activation of right and left SII areas started at 61+/-3 and 62+/-3 ms to contralateral stimuli and at 66+/-2 and 63+/-2 ms to ipsilateral stimuli, suggesting a simultaneous commencing of activation of the SII areas. PPC sources were activated between 70 and 110 ms in different subjects. The 1.5 s ISI alternating stimuli elicited smaller SII responses than the 3 s ISI non-alternating stimuli, suggesting that a considerable part of the neural population in SII responds both to contra- and ipsilateral stimuli. The earliest SI responses did not differ between the two conditions. There were no significant differences in source locations of SII responses to ipsi- and contralateral stimuli in either hemisphere. Subaverages of the responses in sets of 30 responses revealed that amplitudes of the SII responses gradually attenuated during repetitive stimulation, whereas the amplitudes of the SI responses were not changed. CONCLUSIONS: The present results implicate that ipsi- and contralateral SII receive simultaneous input, and that a large part of SII neurons responds both to contra- and ipsilateral stimulation. The present data also highlight the different behavior of SI and SII cortices to repetitive stimuli.     

Effects of spinal cord stimulation on the cortical somatosensory evoked potentials in failed back surgery syndrome patients

ObjectiveTo evaluate the functional activation of the somatosensory cortical regions in neuropathic pain patients during therapeutic spinal cord stimulation (SCS).MethodsIn nine failed back surgery syndrome patients, the left tibial and the left sural nerves were stimulated in two sessions with intensities at motor and pain thresholds, respectively. The cortical somatosensory evoked potentials were analyzed using source dipole analysis based on 111 EEG signals.ResultsThe short-latency components of the source located in the right primary somatosensory cortex (SI: 43, 54 and 65 ms) after tibial nerve stimulation, the mid-latency SI component (87 ms) after sural nerve stimulation, and the mid-latency components in the right (≈161 ms) and left (≈168 ms) secondary somatosensory cortices (SII) were smaller in the presence of SCS than in absence of SCS. The long-latency source component arising from the mid-cingulate cortex (≈313 ms) was smaller for tibial and larger for sural nerve stimuli during SCS periods compared to periods without SCS.ConclusionsSCS attenuates the somatosensory processing in the SI and SII. In the mid-cingulate cortex, the effect of SCS depends on the type of stimulation and nerve fibers involved.SignificanceResults suggest that the effects of SCS on cortical somatosensory processing may contribute to a reduction of allodynia during SCS.     

Neuromagnetic gamma-band activity in the primary and secondary somatosensory areas

To evaluate the gamma-band activity related to somatosensory processing, we recorded neuromagnetic signals from seven healthy subjects. The source power changes evoked by electrical stimulation of the median nerve were estimated with synthetic aperture magnetometry (SAM). Source power in the low gamma band (40 Hz) decreased in the contralateral primary somatosensory cortex (SI) for a few hundred milliseconds (i.e. middle and long latency) and then increased inversely. Source power in the high gamma band (70-90 Hz) increased simultaneously both in the contralateral SI and contra/ipsilateral secondary somatosensory cortex (SII) in 80-180 ms. These results suggest that low and high gamma oscillations work under independent mechanisms during somatosensory processing. In particular, high gamma oscillations may play an essential role in making a functional connection between SI and SII.     

Effects of an acute D2-dopaminergic blockade on the somatosensory cortical responses in healthy humans: evidence from evoked magnetic fields

We tested the possible role of dopaminergic activity in the processing of somatosensory afferent information in healthy humans. Somatosensory evoked magnetic fields (SEFs) were recorded in seven subjects in response to left median nerve stimulation. SEFs were obtained in all subjects after oral administration of 2 mg haloperidol, an antagonist to dopaminergic D2 receptors, and placebo, which were given in a randomized, double-blind cross-over design. SEFs were analyzed using a multiple equivalent current dipole (ECD) model, with one dipole at the right primary somatosensory cortex (SI) and at both left and right secondary somatosensory cortices (SII). The earliest responses from SI, peaking at about 20 ms (N20m) and 35 ms (P35m), were not affected by haloperidol. A later deflection peaking at about 75 ms (P60m), however, was slightly reduced (p < 0.05). Responses arising from SII were not significantly changed. The results suggest that dopaminergic activity may be involved in modulating somatosensory processing after the initial stages of cortical activation.     

Abnormal brain structure implicated in patients with functional dyspepsia

Recent studies suggest dysfunctional brain-gut interactions are involved in the pathophysiology of functional dyspepsia (FD). However, limited studies have investigated brain structural abnormalities in FD patients. This study aimed to identify potential differences in both cortical thickness and subcortical volume in FD patients compared to healthy controls (HCs) and to explore relationships of structural abnormalities with clinical symptoms. Sixty-nine patients and forty-nine HCs underwent 3T structural magnetic resonance imaging scans. Cortical thickness and subcortical volume were compared between the groups across the cortical and subcortical regions, respectively. Regression analysis was then performed to examine relationships between the structure alternations and clinical symptoms in FD patients. Our results showed that FD patients had decreased cortical thickness compared to HCs in the distributed brain regions including the dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), medial prefrontal cortex (mPFC), anterior/posterior cingulate cortex (ACC/PCC), insula, superior parietal cortex (SPC), supramarginal gyrus and lingual gyrus. Significantly negative correlations were observed between the Nepean Dyspepsia Index (NDI) and cortical thickness in the mPFC, second somatosensory cortex (SII), ACC and parahippocampus (paraHIPP). And significantly negative correlations were found between disease duration and the cortical thickness in the vlPFC, first somatosensory cortex (SI) and insula in FD patients. These findings suggest that FD patients have structural abnormalities in brain regions involved in sensory perception, sensorimotor integration, pain modulation, affective and cognitive controls. The relationships between the brain structural changes and clinical symptoms indicate that the alternations may be a consequence of living with FD.