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Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010.

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Translational Pain Research: From Mouse to Man.

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Chapter 13Central Pain as a Thalamocortical Dysrhythmia

A Thalamic Efference Disconnection?

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The intrinsic electrical properties of neurons are presently considered as a salient parameter in brain function (Llinas 1988; Getting 1989; Connors and Gutnick 1990; Turrigiano et al. 1994; Margolis and Detwiler 2007). This is in contrast to the classical purely reflexological view, where neurons are considered to be passive agents that are activated or inhibited synaptically. This intrinsic functional view has been addressed in recent years in relation to thalamic neuron function and to its recurrent interaction with the cortex. Such a view is based upon single-cell neuronal electrophysiology (c.f. Llinas 1988; Steriade and Llinas 1988), and thalamocortical anatomy (Jones 2007). The neurological consequences of such a perspective (Llinas et al. 1999) have been corroborated by magnetoencephalography (MEG), single-cell intraoperative recordings, and encouraging surgical outcomes (Jeanmonod et al. 1996, 2001b, 2003). Moreover, as in the case of tinnitus, where a sound stimulus can suppress the centrally generated sensation (Coles and Hallam 1987), central pain can be modulated by peripheral stimulus (Somers and Somers 1999; Inui et al. 2006). From a functional imaging perspective, electroencephalogram (EEG) (Jeanmonod et al. 1993) and MEG data have shown the presence of a distinct increase in low-frequency activation in central pain (Schulman et al. 2005). In all patients with central, but not peripheral, pain, there was a second site of low-frequency oscillations that was localized to the mesial/orbito frontal and anterior cingulated cortices, as well as the temporal (insular) cortex. Central pain patients with these MEG characteristics did not respond to spinal cord stimulation. By contrast, patients without the frontal low-frequency component responded well to such stimulation.

In addition to clinical studies, direct experimental evidence for the functional organization of the thalamo-cortico-thalamo loop has been obtained in in vitro studies of rodent thalamocortical slices (Llinas et al. 2002) that have been extended to in vivo animal studies concerning neuropathic pain (Gerke et al. 2003; Kim et al. 2003) and thalamic deafferentation (Wang and Thompson 2008). These latter results have established a direct relationship between abnormal thalamic rhythmicity and the occurrence of central pain.

The relevance of an “essential thalamic structure” (i.e., a central generator) for neuropathic pain was first suggested by Head (Head and Holmes 1911). The findings summarized here extend this original proposal by addressing brain activity obtained from MEG, EEG, and preoperative unit recordings from patients with chronic neuropathic pain. We also briefly touch upon the contribution of animal studies to understanding the cellular and molecular components of neuropathic pain generation in the context of increased T-type calcium channel activty.


Spontaneous brain activity was recorded from three patients with deafferentation pain syndrome (phantom arm, braichial plexus avulsion, laterial thalamic lesion) using magnetoencephalography (MEG). Recordings were made while participants were alert with their eyes closed (Schulman et al. 2005).

13.2.1. Power Spectral Findings

The power spectra in these three patients showed a distinct increase in high theta-range (7–9 Hz) power. The spectra were similar to those of other thalamocortical dysrhythmia (TCD) disorders (Llinas et al. 2001). Calculation of the mean spectral energy (MSE) in two bands (7–9 Hz and 9–11 Hz) allows comparison of these results with those of other patient and control groups (Figure 13.1).

FIGURE 13.1. Comparisons of mean spectra energy (power ratio 7–9 Hz: 9–11 Hz) in three groups of patients and control group.


Comparisons of mean spectra energy (power ratio 7–9 Hz: 9–11 Hz) in three groups of patients and control group. The patients with successful SCS were not significantly different from the control group. In contrast, those in which the SCS (more...)

13.2.2. Localization of Theta Activity

Independent component (IC) analysis revealed somatotopically meaningful theta-range activity in two of these patients. In the patient with a right thalamus vascular lesion (who suffered from thalamic pain syndrome and tinnitus), theta activity was localized to the right sensorimotor cortex and superior temporal gyrus. In the patient with a left brachial plexus avulsion, theta-range activation was localized to the right somatosensory cortex as shown in the dorsal view of the brain in Figure 13.2. Theta activity was also present in the left temporal and bilateral mesial orbitofrontal cortices (Figure 13.2). This is significant considering that this person suffered from anxiety and depression as well as chronic pain. The limbic source distribution is consistent with reported structural and functional aberrations that have been identified in these disorders independently (Saxena et al. 1998; Mayberg 2000), and in the context of chronic pain in particular (Grachev et al. 2002). The presence of limbic sources in the same IC as aberrant somatosensory activation underscores the point that the affective component of the pain experience is physiologically tightly coupled with the sensory complaints. (Localization was not possible for the phantom pain subject due to metal artifacts.)

FIGURE 13.2. (see color insert following page 166) Example of localization of theta activity in a patient with brachial plexus avulsion pain.


(see color insert following page 166) Example of localization of theta activity in a patient with brachial plexus avulsion pain. Activity is localized to the contralateral somatosensory cortex and bilaterally to the mesial orbitofrontal cortices. (Modified (more...)


In this group patients experience chronic pain following injury to an extremity or to their back. MEG recordings were made in eight of these patients who had electrodes implanted in the spinal cord (SC) for stimulation (SCS) to alleviate the pain. Of this group, five reported a reduction in pain of more than 50% while the other three did not report improvement. The MEG recordings were made while the patients’ eyes were closed (Schulman et al. 2005). (SC stimulation was turned off during the MEG recordings.)

13.3.1. MEG Power Spectra

Theta range activity was seen in the power spectra of the three patients who did not receive pain relief with SC stimulation. In contrast, the power spectra from the five patients who obtained relief from SCS were comparable to those of healthy controls. This is illustrated when the MSE ratios are compared (Figure 13.1). These findings suggest that in patients in whom SCS is successful, the pathology is likely to be either spinal or peripheral, and the effectiveness of SCS is derived from the locally induced activation of inhibitory interneurons as described in the Gate-Control theory (Melzack and Wall 1965). In contrast, in patients in whom SCS fails, these findings suggest that the pathology is thalamocortical, and the distant induction of dorsal column depolarization provided by SCS is insufficient to effectively modify thalamocortical physiology.

13.3.2. Localization of Theta Activity

Independent component localization revealed somatotopically meaningful theta-range activity in two of the patients in the SCS failure group with back pain. There was bilateral theta activation in areas near the classical homoncular sensory representation of the trunk (Penfield 1958). Comparable independent components were not present in patients with successful SCS or in healthy, pain-free controls.


MEG recordings were made in 11 patients with complex regional pain syndrome (CRPS) type I. This disorder is a chronic progressive disease characterized by severe pain, swelling, and changes in the skin in the region of pain. The absence of a nerve lesion distinguishes Type I from Type II CRPS.

13.4.1. Power Spectra

As in the other MEG recordings of spontaneous activity in patients with neuropathic pain, the power spectra of these patients were characterized by the presence of activity in the theta range. Activity in the delta range was also marked in seven people in this group.

13.4.2. Localization of Theta and Delta Activity

Independent component analysis revealed that every patient had components with activation in the theta frequency range localized over the somatosensory cortex. These localizations were somatotopically meaningful with respect to their pain localization. In addition, every patient had component in the delta (4–8 Hz) frequency range that was localized bilaterally to mesial orbitofrontal cortex and temporal pole (Dubois et al. 2008).


13.5.1. EEG and Field Potential Recordings

In agreement with the MEG findings summarized above, the power spectra of spontaneous cortical EEGs recorded from patients with chronic neuropathic pain were characterized by excess activity in the theta and beta frequency ranges compared to healthy controls (Stern et al. 2006; Boord et al. 2008). Activity was localized to several pain-associated areas including insula, anterior cingulate, prefrontal, and somatosensory cortices (Stern et al. 2006).

To examine the functional relationship between the EEG recordings and thalamus, field potential recordings were made from a region of the central lateral thalamic nucleus (Sarnthein and Jeanmonod 2008). Analysis of EEG and field potential power spectra revealed high temporal coherence in the theta band (6–9 Hz) in recordings from patients with neuropathic pain (Sarnthein and Jeanmonod 2008). Coherence between the activity of the tens of thousands of neurons seen by an EEG electrode and the estimated 5–10 thalamic neurons seen by the local field electrode is remarkable indeed. This finding supports the hypothesis that TCD is due to abnormal low-frequency activity in the thalamo-cortical loop, rather than in the thalamus or in the cortex alone.

13.5.2. Perioperative Unit Recordings

Low-frequency bursting, consistent with the MEG and EEG findings, has been recorded from single neurons in the thalamus of patients with neurogenic pain during preoperative recordings (Modesti and Waszak 1975; Lenz et al. 1989; Rinaldi et al. 1991; Jeanmonod et al. 1993, 1996).

Although these bursts were elicited by spinal column stimulation in the earliest recording (Modesti and Waszak 1975), they have since been found to occur spontaneously. Single-cell recordings have been made from ventral posterior nucleus in thalamic regions related to the deafferented body area with neurogenic pain following spinal cord injury (Lenz et al. 1989), from the intralaminar nucleus in patients with deafferentation pain (Rinaldi et al. 1991), and from medial thalamus in a large group of patients with peripheral and central neurogenic pain related to injury or to cancer (Jeanmonod et al. 1993, 1996). Both spontaneous sporadic activity and spike bursts have been recorded. The rhythmically bursting units all discharged at 3–5 Hz while randomly bursting units and those characterized by sporadic spontaneous activity tended to be in this frequency range as well (Jeanmonod et al. 1993, 1996, 2001a). The firing pattern within each burst was also consistent. The first spike within the burst has the largest amplitude, and there is a positive correlation between the length of the first interspike interval and the number of spikes within the burst with a mean spike frequency of 206 Hz (Jeanmonod et al. 2001b).


An understanding of the cellular and molecular basis for TCD and its role in neuropathic pain has been pioneered by studies in animals. That thalamic neurons switch from tonic firing to bursting was first reported in the 1980s (Llinas and Jahnsen 1982; Carbone and Lux 1984; Jahnsen and Llinas 1984b) in animal studies. This bursting was elicited when the cells were hyperpolarized and were called low-threshold spikes (LTS). This bursting is supported by the activation of low-voltage activated (T-type, Cav3.1) calcium channels. That these LTS bursts may be the origin of neuropathic pain was hypothesized in 1992 in a rodent study (Roberts et al. 1992). Spontaneous oscillatory burst firing was recorded from thalamic neurons in rodents with allodynia following a spinal cord lesion (Gerke et al. 2003). The abnormal burst responses were absent in control animals. In addition to the thalamic dysrhythmia, rats with spinal cord lesions also demonstrated exaggerated vocal responses to normally innocuous mechanical skin stimulation. That this thalamic dysrhythmia may be due to deafferentation is supported by the finding of a delayed, marked increase in cortical theta rhythm and behavioral aberrations following experimentally induced lesions of the rostral pole of the thalamic reticular nucleus of rats (Marini et al. 2002). Finally, mice that lack the T-type calcium channel show a reduced behavioral response to pain and increased threshold for paw withdrawal to mechanical stimulation (Na et al. 2008).


13.7.1. Thalamocortical Generation of Theta Activation

In states of thalamocortical dysrhythmia, an ongoing theta-range thalamic activity serves as the trigger for cortical dysfunction. In the case of neurogenic pain, this self-sustaining generation of low-frequency oscillations results in a long-term pathological equilibrium in the cortical pain matrix. The generation of low-frequency activity by the thalamocortical circuit was first proposed in 1999 (Llinas et al. 1999) and has been developed since then based on findings in animal and intraoperative human recordings as summarized above. Changes in this circuit in neuropathic pain may be summarized in terms of three interconnected loops: the thalamo-thalamic, the specific (sensory) thalamo-cortico-specific thalamic, and the non-specific thalamo-cortico-thalamic.

Deafferentation of the specific and non-specific thalamic nuclei leads to hyperpolarization of these cells (Steriade et al. 1987). When they are hyperpolarized, thalamic neurons change from high-threshold tonic firing to low-threshold, theta-range oscillatory bursts (Llinas and Jahnsen 1982; Jahnsen and Llinas 1984a, b; Steriade et al. 1990) supported by T-type calcium currents. This shift to periodic bursting activity leads to a decrease in the excitatory input to the reticular thalamus (RT) and their subsequent hyperpolarization and low-frequency bursting (Steriade et al. 1993). Feedback of RT to the thalamic nuclei further supports the low-frequency bursts.

Specific thalamo-cortico-specific thalamic loop: Specific thalamic neurons send low-frequency input to the apical dendrites of layer IV and V pyramidal neurons. This reduced thalamic input leads to reduced firing rates at cortical level. Layer VI neurons feed back to the specific thalamus and RT. Layer V pyramidal neurons feed back to both specific and non-specific thalamus. In addition to pyramidal cells, specific thalamus also innervates cortical inhibitory interneurons leading to disinhibition in adjacent columns (see “edge effect,” below).

Non-specific thalamo-cortico-thalamic loop: Bursting of non-specific thalamus innervates the apical dendrites of layer V pyramidal cells that feed back to both specific and non-specific thalamus, reinforcing the low-frequency thalamo-cortical-thalamo circuit.

13.7.2. Thalamocortical Generation of Gamma Range Activity, the “Edge Effect

It is hypothesized that under normal conditions, a given region of cortex activated in the gamma range inhibits other gamma activity from occurring in its periphery. On the cortical level, during normal high-frequency cortical activity, Layer III-IV cortical interneurons release GABA onto neighboring cells, in a process termed lateral inhibition (Beierlein et al. 2000).

We have hypothesized that in thalamocortical dysrhythmia, where projections from thalamus entrain a core of low-frequency cortical activity, lateral inhibition is abolished due to the lower rate of firing. This phenomenon was first described in the retina by Hartline (Hartline 1967), who found that when a given region of limulus retina is activated, a reduction of lateral inhibition creates a physiological border between activated and silent zones.

Evidence from voltage-sensitive dye experiments of deafferented cortex supports the idea that disconnection-induced hyperpolarization of thalamocortical modules leads to the deinactivation of T-type Ca++ channels and low-threshold spike activity, accompanied by adjacent increases in high-frequency firing (Leznik et al. 2002).

The low-frequency activity due to asymmetric lateral inhibition forces adjacent cortical areas into high-frequency (gamma) oscillations. This “edge effect” (Llinas et al. 2005) has also been shown in tinnitus patients (Weisz et al. 2005; De Ridder et al. 2007), in central pain patients (Sarnthein and Jeanmonod 2008), and in an animal model (Ghazal et al. 2007). This abnormal gamma band in turn has been proposed as generating the positive symptoms of pain and allodynia (Schulman et al. 2005).

This hypothesis also finds support in a recent study of migraineurs (Coppola et al. 2007). They found that gamma band oscillations (GBO) evoked by visual stimuli differed in patients and controls in two respects: (1) There was an increased GBO response to the first two stimulus bands, but (2) there was a deficit in habituation to later stimuli in the patient group. They hypothesized that this was consistent with thalamic disconnection combined with a decreased cortical lateral inhibition. That is, an edge effect.


13.8.1. Thalamic Lesions

Thalamic lesions have proven to be an effective treatment in patients with chronic pain who were resistant to therapy. That the rhythmic EEG and MEG activity and underlying thalamic bursting recorded perioperatively is an essential element in the generation and perception of neuropathic pain is supported by such results. Indeed, the bursting unit activity summarized above is co-localized with the most efficient therapeutic lesions. Targeted centrolateral nucleus lesions lead to 50%-100% pain relief in a majority of patients (Jeanmonod et al. 2001a, 2001b) with no somatosensory deficits in over 90% of the cases (Jeanmonod et al. 2001a). These lesions are thought to disrupt the synchronous, low-frequency activity in the thalamo-cortico-thalamo loop of which the posterior centrolateral nucleus is a part. These lesions have proven to be more beneficial to patients with intermittent pain or allodynia than to those with continuous pain.

13.8.2. Stimulation

The use of deep brain stimulation (DBS) as a treatment in several disorders was recently reviewed (Kringelbach et al. 2007b). DBS has proven to be a successful treatment in some types of pain (Kumar et al. 1997; Nandi et al. 2003; Bittar et al. 2005a, 2005b; Rasche et al. 2006; Yamamoto et al. 2006; Kringelbach et al. 2007a) and other instances of TCD, particularly in Parkinson’s disease (Benabid et al. 2003). The effectiveness of this therapy is consistent with the mechanisms postulated above: High-frequency stimulation could raise the resting potential of RT or intralaminar neurons above the level of T-type Ca++ channel deinactivation, and thalamic cells switch from bursting to tonic firing. The effectiveness of motor cortex stimulation in treating some cases of neuropathic pain (Carroll et al. 2000; Katayama et al. 2001a, 2001b) may be understood as resulting from top-down thalamic depolarization. It should be noted that the qualified success of this approach speaks to the challenge of modifying the thalamocortical loop using a depolarizer effectively situated outside the system. Recent advances using transcranial magnetic stimulation may similarly derive their effectiveness from a temporary rise in thalamocortical resting potential.

Consistent with this view and with the correlation between low-frequency activity and subjective pain experience is the fact that clinical improvement has been correlated with a reduction of low-frequency cortical activity. For example, reduction of neuropathic pain sensation following transcranial magnetic stimulation is concomitant with a reduction of low-frequency activity; pre-existing TCD electrical abnormalities have been attenuated after spinal cord stimulation leading to pain relief (Schulman et al. 2005); and the alleviation of phantom limb pain with DBS is correlated with a reduction of theta- and beta-band activity (Ray et al. 2009). These results are similar to those found in tinnitus cases (Richter et al. 2006; De Ridder et al. 2007). Moreover, such sound masking resulting in the disappearance of the tinnitus is accompanied by the marked reduction, or total abolition, of the low-frequency signature at the auditory cortex (Tyler 2000; Llinas et al. 2005).

13.8.3. Unsuccessful Treatments

In addition to these successes, some of the therapeutic failures for chronic pain also lend support to the theory that deafferentation pain can be related to a centrally generated hyperpolarization. For example, the finding that sensory blockade is known to increase pain in some patients (Bonica 1991), coupled with the low success rate for surgical tractotomy (Tasker 1996), is consistent with a paradigm in which the additional sensory blockade deafferents the thalamus even further and adds to the disfacilitation that causes low-threshold spike bursts. Conversely, some patients with plexus avulsions report pain reduction with input to the affected limb. This presumably activates the thalamus, temporarily counteracting the deafferentation effects. These findings are supported by a model in which increased input to the thalamus restores a more depolarized CNS mode.


A fundamental issue to be considered here is that of sensory binding and its functional correlates. This chapter presents a set of electrophysiological findings that indicate that pain, in this case central pain, is correlated with two distinct electrical components: one that defines the localization on the body of the pain experience and, as such, is sui generis for each patient; and one that is similar and omnipresent in all patients. While the former signature is indeed a description of location, the latter relates to the emotional sensation of pain, as it is common to all patients and is reduced by procedures that obliterate the emotional component of the sensation, that is, the hurt. It is very clear that the unpleasant sensation/emotion of being hurt happens without actual localization, as for instance with moral pain or as it happens with emotions such as fear. Having fear in one’s hand would be of no survival value, but localizing pain is invaluable for survival. As such then a careful analysis of issues as temporal coherence between low frequencies in localized pain versus noncoherent activity between simultaneous but unrelated stimuli may go a long way in clarifying the electrophysiological mechanism for temporal binding.


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Copyright © 2010 by Taylor and Francis Group, LLC.
Bookshelf ID: NBK57255PMID: 21882456


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