Brain processes in chronic back pain
Using painful electric stimulation of the skin at the back or at the finger of CBP patients during a MEG recording, Flor et al. (1997) showed significant brain activation differences between CBP patients and healthy controls. Stimulation at the affected back but not at the finger led to a significantly higher magnetic field in the early time window (<100 ms) for CBP compared to controls. The signal strength in this time window and the duration of pain were positively correlated, suggesting increased cortical responsivity with increasing chronicity. The source of this early activity originated from SI and the localization of the fingers did not differ between patients and controls. However, the localization of the back was more inferior and medial in the patients. This indicates a shift and expansion toward the cortical representation of the leg (see Figure 6.2) suggesting that chronic pain leads to an expansion of the cortical representation zone related to nociceptive input, and that the amount of cortical reorganization increases with pain duration. This is similar to the expansions of cortical representations that have been documented to occur with other types of behaviourally relevant stimulation, but different from the changes that occur with deafferentation where the changes correlate with pain intensity rather than chronicity.
Flor et al (2004) used painful and non-painful electric stimulation to the finger in CBP patients, patients with headache and controls. Only the CBP patients displayed significantly lower pain thresholds and tolerance as well as a reduced habituation, i.e. sensitization. Although the stimulation intensity for the three groups was different (i.e. lower in the CBP group), the CBP patients showed equally high levels of evoked brain responses as assessed by multichannel EEG recordings suggesting also central sensitization. A later study by Diers et al. (2007) expanded these results to intramuscular recordings and observed both higher pain ratings (perceptual sensitization) over the course of the stimulation in the CBP patients and also enhanced central nervous system processing as evidenced by an enhanced N80 component (see Figure 6.3).
Enhanced perceptual sensitization to tonic rather than phasic stimulation was found in CBP patients by Kleinbohl et al. (1999). They used extended heat pain and a behavioral response as indicator of sensitization.
Giesecke et al. (2004) compared chronic low back pain patients, patients with fibromyalgia and healthy controls. During the fMRI measurements they administered two kinds of painful stimulation to the thumbnails of the participants: (1) stimuli of equal pressure and (2) equal subjective pain intensity. The pressure required to produce moderate pain was significantly higher for both patient groups than for the control participants, indicating hyperalgesia. Equal amounts of pressure applied to the thumb revealed activation in five common brain regions for the two patients groups: contralateral SI, bilateral SII, the inferior parietal lobule and the cerebellum. In healthy controls this stimulation resulted only in activation of the contralateral SII. These results can be interpreted as an increased central pain processing in CBP even when the painful stimulus is at a site distant to the region involved in clinical pain. When subjects received a stimulus that resulted
Fig. 6.2 (Also see Colour Plate 4) Localization of the representation of the digits and the back in primary somatosensory cortex in back pain patients and healthy controls. Stimulation was on the left side of the body, the representations are on the hemisphere contralateral to the stimulation side. Please note the shift of the back representation of the back pain patients into a more medial position (i.e. towards the leg representation). The shift amounted to about 2-3 cm. Reprinted from Neuroscience Letters, 224(1), H. Flor, C. Braun, T. Elbert, and N. Birbaumer, Extensive reorganization of primary somatosensory cortex in chronic back pain patients, pp. 5-8,
Copyright (1997), with permission from Elsevier.
in the same amount of pain, all three groups showed activation in the central components of the pain matrix (SI, SII, insula, ACC, inferior parietal lobe), with the magnitude of activation being greater for the two patient groups.
Baliki et al. (2006) examined variations in habitual pain rather than applying acute pain stimuli in patients with CBP. During the fMRI measurements patients were asked to continuously rate their habitual pain level on a scale from 0-10. An increase of spontaneous pain in CBP patients activated regions also seen in acute pain (i.e. the anterior and posterior insula, SII, the midcingulate cortex, SI and the cerebellum). However, sustained high pain additionally engaged brain areas involved in emotion, cognition, and motivation such as the medial prefrontal cortex, rostral anterior cingulate cortex, posterior thalami, ventral striatum, and extended amygdala. Insular activity was also present and correlated with pain duration leading the authors to conclude that it may reflect the chronicity of CBP. In contrast, activation of the medial prefrontal cortex correlated with pain intensity ratings.
In a later study Baliki et al. (2008) investigated two groups of chronic pain patients: a group with CBP and a group with osteoarthritis (OA) of the knee. Both groups were placed in the fMRI scanner and rated the intensity of their pain with a finger-span logging device. The CBP patients rated their current pain and its fluctuations and the OA patients rated their pain in response to pressure applied to their knee. During the pain rating task CBP patients reported fluctuations of their spontaneous pain intensity in the absence of any overt experimental stimulus. Activation related
Fig. 6.3 Central processing and behavioral correlates of acute muscle pain in chronic low back pain patients. Part (a) of the figure shows the pain-related somatosensory evoked potential wave forms for intramuscular stimulation of the left lower arm. The solid line represents the activation in the CBP patients and the dotted line the healthy controls. The analysis revealed significantly higher amplitude of the N80 for the pain patients. Part (b) of the figure displays the differences in perceived intensity of the stimulation of the left lower arm at the beginning and at the end of the stimulation period. Both groups sensitized during the course of the experiment, with the CBP displaying higher sensitization than the healthy controls. Means and standard errors are displayed. Reprinted from Journal of Clinical Neurophysiology, 24(1), M. Diers, C. Koeppe, E. Diesch, et al. Central processing of acute muscle pain in chronic low back pain patients: An EEG mapping study. Copyright (2007), with permission from Wolters Kluwer Health.
to these spontaneous fluctuations seemed to be mainly related to emotion/reward mediating areas (i.e. the medial prefrontal cortex and the nucleus accumbens). Activations due to pressure pain in the OA group were found in SII, the insula, the supplementary motor area, the ACC, the medial frontal gyrus, the thalamus, the right putamen and the left amygdala. This activation pattern was similar to that found in healthy participants in response to acute pain (i.e. activation of the pain matrix). In a pre-post design the authors also investigated the activation of brain regions before and after a 2-week treatment with a lidocaine patch applied to the painful body part. On a behavioral level, CBP patients experienced a robust decrease in pain intensity in response to the two week treatment. Before treatment, CBP patients showed increased brain activity mainly in the frontal cortex (including the medial prefrontal cortex, the rostral anterior cingulate cortex, bilateral superior frontal gyrus, and the nucleus accumbens). Increased brain activity was also found in the inferior temporal gyrus, and the left posterior parietal cortex. After treatment the authors reported only one significant cluster of activation that showed increased activity for spontaneous pain, the left motor area (MT). The medial prefrontal cortex was the brain area the correlated best with the treatment effect. The authors conclude that the spontaneous pain occurring in CBP is primarily of an emotional nature and assume that lidocaine treatment decreases mainly emotional pain aspects.
Using PET and noxious heat stimulation Derbyshire et al. (2002) examined 16 CBP patients and 16 matched controls. They were interested in the correlation of pain scores and brain activation patterns. Significant bilateral activation was present in the cerebellum, the midbrain (including the PAG region), the thalamus, the lentiform nucleus, the insula and the midcingulate cortex for both healthy controls and CBP patients. They reported no significant differences between the two groups and concluded that there is no abnormal nociceptive processing in patients with low back pain. Although the authors reported a significant difference in anxiety between the patients and the controls, with the patients being more anxious than the controls, they did not include this difference in their analysis. They also reported a trend towards a difference in depression scores between the two groups, again with the patients being more depressed than the controls and discuss the possible implications of depression on their results.
Thunberg et al. (2005) also used PET in healthy volunteers and injected hypertonic saline into the right m. erector spinae at the level of L3 in an attempt to mimic the pain of low back pain patients. The authors distinguished between two phases: an early acute phase (4min after the start of the infusion), and a late tonic phase (21min after the start of the infusion). They assumed that the latter should be a more realistic model of the chronic muscle pain found in patients. The cerebral response differed in the acute and tonic phase and longer lasting tonic muscle pain resulted in decreases in three clusters (left insula, right insula and right cingulate cortex). Increases in rCBF were only found bilaterally in the occipital cortex. The authors interpret the decrease in subjective levels between the early phase and the late phase as a habituation effect and thus also attribute the changes in brain activity to this habituation. When the late phase was compared with a baseline condition, regions that are implicated in the processing of all three components of pain (sensory-discriminative, motivational-affective, and cognitive-evaluative) were active. These included an increase of activation in the contralateral medial PFC as well as a decrease of activation in the insula, the ACC and the dorsolateral prefrontal cortex of the ipsilateral hemisphere. The authors conclude that this dysfunction of the network may contribute to the development of chronic pain.
Almost all studies on brain imaging revealed that certain brain regions show a deactivation during task performance. This fact has led to the proposal of a ‘default mode network’ (DMN) of brain function (Raichle et al. 2001). Baliki et al. (2008) suggested that long-term pain alters the functional connectivity of the cortical regions of the DMN, which suggests that chronic pain has a widespread impact on overall brain function and not only on the pain matrix. They studied CBP patients and healthy controls during a simple visual attention task while the blood-oxygen-level- dependent (BOLD) response was measured. Task performance was similar in both groups, but the CBP patients showed a reduced deactivation in the medial prefrontal cortex, amygdalae and PCC. The disruption of the DMN was interpreted as cause of many of the cognitive and behavioral impairments that accompany chronic pain (i.e. depression, anxiety, sleep disturbances, or decision-making abnormalities).
