Neural mechanisms underlying deafferentation pain: a hypothesis from a neuroimaging perspective

Deafferentation pain following nerve injury annoys patients, and its management is a challenge in clinical practice. Although the mechanisms underlying deafferentation pain remain poorly understood, progress in the development of multidimensional neuroimaging techniques is casting some light on these issues. Deafferentation pain likely results from reorganization of the nervous system after nerve injury via processes that interact with the substrates for pain perception (the pain matrix). Therapeutic effects of motor cortex stimulation on deafferentation pain suggest that the core mechanisms underlying deafferentation pain also interact with the motor system. Therefore, simultaneous neuroimaging and brain stimulation, an emerging neuroimaging technique, was developed to investigate complicated interactions among motor, somatosensory, and pain systems. In healthy participants, parts of the pain matrix (the anterior cingulate cortex, parietal operculum, and thalamus) show activity during both somatosensory stimulation and brain stimulation to the motor cortex. This finding indicates that motor, somatosensory, and pain systems communicate among each other via the neural network. A better understanding of the plastic mechanisms influencing such cross-talk among these systems will help develop therapeutic interventions using brain stimulation and neurofeedback.     

Magnetic resonance spectroscopy detects biochemical changes in the brain associated with chronic low back pain: a preliminary report

Magnetic resonance (MR) spectroscopy is a noninvasive technique that can be used to detect and measure the concentration of metabolites and neurotransmitters in the brain and other organs. We used in vivo (1)H MR spectroscopy in subjects with low back pain compared with control subjects to detect alterations in biochemistry in three brain regions associated with pain processing. A pattern recognition approach was used to determine whether it was possible to discriminate accurately subjects with low back pain from control subjects based on MR spectroscopy. MR spectra were obtained from the prefrontal cortex, anterior cingulate cortex, and thalamus of 32 subjects with low back pain and 33 control subjects without pain. Spectra were analyzed and compared between groups using a pattern recognition method (Statistical Classification Strategy). Using this approach, it was possible to discriminate between subjects with low back pain and control subjects with accuracies of 100%, 99%, and 97% using spectra obtained from the anterior cingulate cortex, thalamus, and prefrontal cortex, respectively. These results demonstrate that MR spectroscopy, in combination with an appropriate pattern recognition approach, is able to detect brain biochemical changes associated with chronic pain with a high degree of accuracy.     

Association between brain and low back pain

Most chronic low back pain includes elements of nociceptive pain, neuropathic pain, and nonorganic pain. We conducted screening for nonorganic pain with use of the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP), which is simple and can be used for multidimensional assessment. Research on pain areas using functional magnetic resonance imaging (fMRI) and positron emission tomography has shown that the dopamine system contributes to the pathology of chronic low back pain. Chronic low back pain patients show decreased activation of the anterior cingulate cortex, prefrontal cortex, and nucleus accumbens. Given that both the anterior cingulate cortex and prefrontal cortex belong to the descending inhibitory system, and that the nucleus accumbens, which is involved in the dopamine system, releases μ-opioids that act to relieve pain, decreased activation in these three brain regions may be related to decreased function of the descending inhibitory system. A pathological condition that can be explained at the molecular biological level clearly exists between chronic low back pain and psychosocial factors, and investigations of a pathological condition of chronic low back pain including brain function are needed.     

Dissociable roles of prefrontal and anterior cingulate cortices in deception

Recent neuroimaging studies have shown the importance of the prefrontal and anterior cingulate cortices in deception. However, little is known about the role of each of these regions during deception. Using positron emission tomography (PET), we measured brain activation while participants told truths or lies about two types of real-world events: experienced and unexperienced. The imaging data revealed that activity of the dorsolateral, ventrolateral and medial prefrontal cortices was commonly associated with both types of deception (pretending to know and pretending not to know), whereas activity of the anterior cingulate cortex (ACC) was only associated with pretending not to know. Regional cerebral blood flow (rCBF) increase in the ACC was positively correlated with that in the dorsolateral prefrontal cortex only during pretending not to know. These results suggest that the lateral and medial prefrontal cortices have general roles in deception, whereas the ACC contributes specifically to pretending not to know.     

Imaging pain modulation by subanesthetic S-(+)-ketamine

Little is known about the effects of low-dose S-(+)-ketamine on the cerebral processing of pain. We investigated the effects of subanesthetic IV S-(+)-ketamine doses on the perception of experimental painful heat stimuli. Healthy volunteers were evaluated with functional magnetic resonance imaging (fMRI) while receiving the painful stimuli in conjunction with placebo and increasing doses (0.05, 0.1, 0.15 mg x kg(-1) x h(-1)) of ketamine infusion. Vital variables were monitored and all subjects rated pain intensity and unpleasantness on a numerical rating scale. Alterations in consciousness were measured using a psycho-behavioral questionnaire. Pain unpleasantness declined as ketamine dosage was increased (55.1% decrease, placebo versus 0.15 mg x kg(-1) x h(-1) ketamine). Pain intensity ratings also decreased with increasing ketamine dosage but to a lesser extent (23.1% decrease). During placebo administration, a typical pain activation network (thalamus, insula, cingulate, and prefrontal cortex) was found, whereas decreased pain perception with ketamine was associated with a dose-dependent reduction of pain-induced cerebral activations. Analysis of the dose-dependent ketamine effects on pain processing showed a decreasing activation of the secondary somatosensory cortex (S2), insula and anterior cingulate cortex. This part of the anterior cingulate cortex (midcingulate cortex) has been linked with the affective pain component that underlines the potency of ketamine in modulating affective pain processing.     

Inner experience of pain: imagination of pain while viewing images showing painful events forms subjective pain representation in human brain

Pain is an unpleasant sensation, and at the same time, it is always subjective and affective. Ten healthy subjects viewed 3 counterbalanced blocks of images from the International Affective Picture System: images showing painful events and those evoking emotions of fear and rest. They were instructed to imagine pain in their own body while viewing each image showing a painful event (the imagination of pain). Using functional magnetic resonance imaging, we compared cerebral hemodynamic responses during the imagination of pain with those to emotions of fear and rest. The results show that the imagination of pain is associated with increased activity in several brain regions involved in the pain-related neural network, notably the anterior cingulate cortex (ACC), right anterior insula, cerebellum, posterior parietal cortex, and secondary somatosensory cortex region, whereas increased activity in the ACC and amygdala is associated with the viewing of images evoking fear. Our results indicate that the imagination of pain even without physical injury engages the cortical representations of the pain-related neural network more specifically than emotions of fear and rest; it also engages the common representation (i.e., in ACC) between the imagination of pain and the emotion of fear.     

Neuronale Netzwerke und Schmerzverarbeitung Ergebnisse bildgebender Verfahren

Imaging techniques with high spatial and temporal resolution (PET,fMRI, MEG) provide detailed information about the brains' processing of pain. Structures detected by these techniques are not understood as pain centers but as nodal points of a dynamic network which is influenced by physiological and psychological input. Imaging techniques can be used for the investigation of different pain components. The neuronal network that encodes sensory-discriminative information consists of the primary and secondary somatosensory cortex which receive input from lateral thalamic nuclei. Information for the affective pain component reach the anterior cingulate cortex, insula and prefrontal cortex via medial thalamic nuclei. Until now only little is known about cortical structures mediating the cognitive pain component. In chronic pain the cortical and subcortical processing of nociceptive input is presumably modified. Reorganization in the primary somatosensory cortex is presented as an example of neuronal plasticity induced by chronic pain.     

Functional magnetic resonance imaging studies of pain: an investigation of signal decay during and across sessions

BACKGROUND: Several investigations into brain activation caused by pain have suggested that the multiple painful stimulations used in typical block designs may cause attenuation over time of the signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been investigated. The signal decay across a task of four repeating pain stimulations and between two serial pain tasks separated by a 4-min interval was examined to determine whether signal attenuation may significantly confound pain investigations. METHODS: The characteristics of the brain activation of six subjects were determined using whole brain blood oxygenation level-dependent functional magnetic resonance imaging on a 1.5-T scanner. Tasks included both tingling and pain induced by transcutaneous electrical stimulation of the median nerve. The average group maps were analyzed by general linear modeling with corrected cluster P values of less than 0.05. The time courses of individual voxels were further investigated by analysis of variance with P values of less than 0.05. RESULTS: Significant differences between pain and tingling were found in the ipsilateral cerebellum, contralateral thalamus, secondary somatosensory cortex, primary somatosensory cortex, and anterior cingulate cortex. Highly significant signal decay was found to exist across each single pain task, but the signal was found to be restored after a 4-min rest period. CONCLUSIONS: This work shows that serial pain tasks can be used for functional magnetic resonance imaging studies using electrical nerve stimulation as a stimulus, as long as sufficient time is allowed between the two tasks.     

Clinical hypnosis modulates functional magnetic resonance imaging signal intensities and pain perception in a thermal stimulation paradigm

OBJECTIVE: This study was designed to describe regional changes in blood oxygenation level dependent signals in functional magnetic resonance images (fMRI) elicited by thermal pain in hypnotized subjects. These signals approximately identify the neural correlates of the applied stimulation to identify neuroanatomic structures involved in the putative effects of clinical hypnosis on pain perception. METHODS: After determination of the heat pain threshold of 12 healthy volunteers, fMRI scans were performed at 1.5 Tesla by using echoplanar imaging technique during repeated painful heat stimuli. Activation of brain regions in response to thermal pain during hypnosis (using a fixation and command technique of hypnosis) was compared with responses without hypnosis. RESULTS: With hypnosis, less activation in the primary sensory cortex, the middle cingulate gyrus, precuneus, and the visual cortex was found. An increased activation was seen in the anterior basal ganglia and the left anterior cingulate cortex. There was no difference in activation within the right anterior cingulate gyrus in our fMRI studies. No activation was seen within the brainstem and thalamus under either condition. CONCLUSION: Our observations indicate that clinical hypnosis may prevent nociceptive inputs from reaching the higher cortical structures responsible for pain perception. Whether the effects of hypnosis can be explained by increased activation of the left anterior cingulate cortex and the basal ganglia as part of a possible inhibitory pathway on pain perception remains speculative given the limitations of our study design.     

Assessment of pain due to lumbar spine diseases using MR spectroscopy: a preliminary report

Background data

There is a considerable difference in pain perception among individuals. In patients with chronic pain, recent studies using fMRI, PET and SPECT have shown that functional changes mainly occurred in the anterior cingulate cortex (ACC), prefrontal cortex (PFC) and thalamus. Brain magnetic resonance spectroscopy (MRS) can evaluate brain chemistry by measuring metabolites such as N-acetyl aspartate (NAA). The purpose of this study was to analyze whether brain MRS could assess pain due to lumbar spine diseases.

Methods

NAA levels were determined relative to the concentration of creatine/phosphocreatine complex (Cr) and choline (Cho), which is commonly used as an internal standard. The NAA/Cr and NAA/Cho ratios in the ACC, PFC and thalamus were compared between six patients with unilateral pain (left side) and six control patients without pain.

Results

In the right thalamus (contralateral side to symptom), the NAA/Cr in the patients with pain was statistically significantly lower compared with the control patients (p < 0.05). Also, in the right thalamus, the NAA/Cho in pain patients was significantly lower compared with controls (p < 0.01). When considering just the right thalamus, there were statistically significant correlations between the numerical rating scale for pain (NRS) and NAA values.

Conclusions

Lumbar pain can be assessed indirectly by analyzing the decrease in NAA concentration in the thalamus.     

Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil

BACKGROUND: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers. METHODS: Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach. RESULTS: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray. CONCLUSIONS: Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.     

Interactions of pain intensity and cognitive load: the brain stays on task

Pain naturally draws one's attention. However, humans are capable of engaging in cognitive tasks while in pain, although it is not known how the brain represents these processes concurrently. There is some evidence for a cortical interaction between pain- and cognitive-related brain activity, but the outcome of this interaction may depend on the relative load imposed by the pain versus the task. Therefore, we used 3 levels of cognitive load (multisource interference task) and 2 levels of pain intensity (median nerve stimulation) to examine how functional magnetic resonance imaging activity in regions identified as pain-related or cognitive-related responds to different combinations of pain intensity and cognitive load. Overall, most pain-related or cognitive-related brain areas showed robust responses with little modulation. However, during the more intense pain, activity in primary sensorimotor cortex, secondary somatosensory cortex/posterior insula, anterior insula, paracentral lobule, caudal anterior cingulate cortex, cerebellum, and supplementary motor area was modestly attenuated by the easy task and in some cases the difficult task. Conversely, cognitive-related activity was not modulated by pain, except when cognitive load was minimal during the control task. These findings support the notion that brain networks supporting pain perception and cognition can be simultaneously active.     

Thalamus and pain

The thalamus is a key relay station for the transmission of nociceptive information to the cerebral cortex. We review the input–output connection, functional imaging, direct neuronal recording, stimulation, and lesioning studies on the involvement of thalamus in acute and chronic pain functions. Based on its specific reciprocal connection with the cerebral cortex, strong nociceptive responsiveness, and the severe chronic pain when it is damaged, the thalamus may hold the key to pain consciousness and the key to understanding spontaneous and evoked pain in chronic pain conditions. A work plan is proposed for future study.     

The cross-modal interaction between pain-related and saccade-related cerebral activation: a preliminary study by event-related functional magnetic resonance imaging

Pain-related cerebral activation in functional magnetic resonance imaging shows less consistent signals that decay earlier than in conventional task-related activation. This may result from pain's top-down inhibition mediated by cognitive or hemodynamic interaction that could affect activation by other modalities. Using event-related functional magnetic resonance imaging, we examined whether pain affects cerebral activation by a saccade task through such cross-modal interaction. Six right-handed volunteers underwent whole-brain echo-planar imaging on a 3.0 T magnetic resonance imaging scanner while they received thermal pain stimulus at 50 degrees C on the right forearm (P; n = 6), performed a visually guided saccade task (V; n = 6), and went through a simultaneous pain-plus-saccade paradigm (PV; n = 5). Averaged functional activation maps were synthesized and signal time courses were analyzed at activation clusters. P activated the bilateral secondary somatosensory cortex (S2). V activated the posterior, supplementary, frontal eye fields, and visual areas. PV enhanced the S2 activation and activated additional pain-related areas, including the bilateral premotor area, right insula, anterior, and posterior cingulate cortices. In contrast, V-related activation was attenuated in PV. We propose that pain caused cross-modal suppression on the oculomotor activity and that an oculomotor task enhanced pain-related activation by triggering attention toward pain. IMPLICATIONS: Pain-related cerebral activation is enhanced by attention toward pain. It may involve top-down suppression over the unrelated neural networks of saccade.     

A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder

OBJECT: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial. METHODS: Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus. CONCLUSIONS: Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.     

Dissociable neural systems resolve conflict from emotional versus nonemotional distracters

The human brain protects the processing of task-relevant stimuli from interference ("conflict") by task-irrelevant stimuli via attentional biasing mechanisms. The lateral prefrontal cortex has been implicated in resolving conflict between competing stimuli by selectively enhancing task-relevant stimulus representations in sensory cortices. Conversely, recent data suggest that conflict from emotional distracters may be resolved by an alternative route, wherein the rostral anterior cingulate cortex inhibits amygdalar responsiveness to task-irrelevant emotional stimuli. Here we tested the proposal of 2 dissociable, distracter-specific conflict resolution mechanisms, by acquiring functional magnetic resonance imaging data during resolution of conflict from either nonemotional or emotional distracters. The results revealed 2 distinct circuits: a lateral prefrontal "cognitive control" system that resolved nonemotional conflict and was associated with enhanced processing of task-relevant stimuli in sensory cortices, and a rostral anterior cingulate "emotional control" system that resolved emotional conflict and was associated with decreased amygdalar responses to emotional distracters. By contrast, activations related to both emotional and nonemotional conflict monitoring were observed in a common region of the dorsal anterior cingulate. These data suggest that the neuroanatomical networks recruited to overcome conflict vary systematically with the nature of the conflict, but that they may share a common conflict-detection mechanism.     

Brain targets for pain control.

A variety of brain sites have been targeted for surgical treatment of intractable pain. Both ablative and chronic stimulation procedures have been reported to attenuate such pain. These targets include the thalamus and its projections, the periventricular gray, the cingulate cortex and the motor cortex. An overview of these procedures and their efficacy is provided.     

Functional Magnetic Resonance Imaging Studies of Pain: An Investigation of Signal Decay during and across Sessions

Background: Several investigations into brain activation caused by pain have suggested that the multiple painful stimulations used in typical block designs may cause attenuation over time of the signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been investigated. The signal decay across a task of four repeating pain stimulations and between two serial pain tasks separated by a 4-min interval was examined to determine whether signal attenuation may significantly confound pain investigations.

Methods: The characteristics of the brain activation of six subjects were determined using whole brain blood oxygenation level-dependent functional magnetic resonance imaging on a 1.5-T scanner. Tasks included both tingling and pain induced by transcutaneous electrical stimulation of the median nerve. The average group maps were analyzed by general linear modeling with corrected cluster P values of less than 0.05. The time courses of individual voxels were further investigated by analysis of variance with P values of less than 0.05.

Results: Significant differences between pain and tingling were found in the ipsilateral cerebellum, contralateral thalamus, secondary somatosensory cortex, primary somatosensory cortex, and anterior cingulate cortex. Highly significant signal decay was found to exist across each single pain task, but the signal was found to be restored after a 4-min rest period.     

Dissociating the roles of the rostral anterior cingulate and the lateral prefrontal cortices in performing two tasks simultaneously or successively

A fundamental question about the nature of cognitive control is whether performing two tasks successively or simultaneously activates distinct brain regions. To investigate this question, we designed a functional magnetic resonance imaging (fMRI) study that compared task-switching and dual-task performance. The results showed that performing two tasks successively or simultaneously activated a common prefronto-parietal neural network relative to performing each task separately. More importantly, we found that the anterior cingulate and the lateral prefrontal cortices were differently activated in dual-task and task-switching situations. When performing two tasks simultaneously, as compared to performing them in succession, activation was found in the rostral anterior cingulate cortex. In contrast, switching between two tasks, relative to performing them simultaneously, activated the left lateral prefrontal cortex and the bilateral intra-parietal sulcus region. We interpret these results as indicating that the rostral anterior cingulate cortex serves to resolve conflicts between stimulus-response associations when performing two tasks simultaneously, while the lateral prefrontal cortex dynamically selects the neural pathways needed to perform a given task during task switching.     

A study of pyramidal cell structure in the cingulate cortex of the macaque monkey with comparative notes on inferotemporal and primary visual cortex

Recent studies have revealed a marked degree of variation in the pyramidal cell phenotype in visual, somatosensory, motor and prefrontal cortical areas in the brain of different primates, which are believed to subserve specialized cortical function. In the present study we carried out comparisons of dendritic structure of layer III pyramidal cells in the anterior and posterior cingulate cortex and compared their structure with those sampled from inferotemporal cortex (IT) and the primary visual area (V1) in macaque monkeys. Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors was determined, and somal areas measured. We found that pyramidal cells in anterior cingulate cortex were more branched and more spinous than those in posterior cingulate cortex, and cells in both anterior and posterior cingulate were considerably larger, more branched, and more spinous than those in area V1. These data show that pyramidal cell structure differs between posterior dysgranular and anterior granular cingulate cortex, and that pyramidal neurons in cingulate cortex have different structure to those in many other cortical areas. These results provide further evidence for a parallel between structural and functional specialization in cortex.