**2. Prevalence of sensory abnormalities in central pain?**

Patients with central pain (CP) inevitably show stimulus-evoked sensory abnormalities which include negative symptoms such as hypoesthesia and hypoalgesia, as well as positive symptoms such as hyperalgesia Hyperalgesia is increased pain evoked by a stimulus which can be painful, such as deep pressure over a muscle which has been injured or bruised. Another positive symptom is allodynia which is pain evoked by a stimulus which is not normally painful, such as pain evoked by light touch following a sunburn.

When studied by quantitative sensory testing (QST, Table 1), patients with central poststroke pain (CPSP) exhibit hypoesthesia for cold in 85-91% of patients, for warmth in 85- 100%. Decreased sensation for pain (hypoalgesia) is found for cold pain in roughly 45% of patients, and for heat pain in 7-91% (Boivie et al., 1989;Leijon et al., 1989;Andersen et al., 1995;Vestergaard et al., 1995;Greenspan et al., 2004). As shown in Table 1, CPSP patients show decreased tactile sensibility in 27-52% of cases. These results demonstrate that decreased sensation or negative sensory signs vary widely across the CPSP patient population. Overall, these patients do not show sensory deficits for all types of thermal and

Deconstructing Central Pain with Psychophysical and Neuroimaging Studies 453

between cold & heat pain threshold

sensitive thresholds.

difference between cold & heat pain threshold

93% abnormal

Table 1. Summary of QST and descriptors of CPSP. The fourth column included both clinical findings (n=16) (Vestergaard et al., 1995) and quantitative sensory testing (n=11) (Andersen et al., 1995). Similarly, the third column included both clinical (Leijon et al., 1989) and sensory testing results (both N=27) (Boivie et al., 1989). Another very large series could not included because quantitative sensory testing results were not described as population

painful stimuli, but they do show decreased sensitivity to at least some submodality of

Another important observation is that some patients with injuries or disease of the central nervous system (CNS) may experience thermal hypoesthesia or hypoalgesia as a result of a CNS lesion without developing central pain. This has been demonstrated for patients with lesions of the spinal cord (Ducreux et al., 2006;Finnerup et al., 2003), and brain (Andersen et

In the case of cortical lesions, the results of a recent study demonstrate warm and cold hypoesthesia based on QST thresholds in all subjects with lesions of parietal or insular cortex or both (Veldhuijzen et al., 2009). The largest degree of thermal hypoesthesia by threshold measures was found in the subject with the largest lesion, which involved extensive parietal and insular lobar lesions (see also (Greenspan et al., 1999). Suprathreshold measures demonstrated that sensory loss for painful and nonpainful hot and cold modalities

Subjects with relatively small lesions restricted to the posterior insula and retroinsula showed central pain and cold allodynia, based on thresholds and clinical assessment. Cold allodynia based on thresholds but not on clinical assessment were observed in patients with parietal lesions sparing the insula. Similarly, a study of two patients with lesions of the insula and adjacent cortical lobes confirmed normal heat pain thresholds but increased ratings of heat pain compared to controls (Starr et al., 2009). These results suggest that non-painful cold and heat sensations are jointly mediated by parietal and insular cortical structures, while thermal pain sensation is more robust, requiring larger cortical lesions of these same structures to produce hypoalgesia. In addition, these studies dramatically demonstrate that neither the presence nor the extent of abnormal thermal sensation nor cold allodynia following a CNS

The variability of negative and positive symptoms and signs in patients with central pain raises the possibility that the level of spontaneous pain is correlated with the extent of sensory loss in patients with central pain. Such a relationship has been reported among patients with central pain resulting from spinal cord injury (SCI) (Ducreux et al., 2006). Specifically, two differences were observed between syringomyelia patients with or without allodynia. Those with allodynia tended to have 1) lesser thermosensory deficits and 2) more

lesion predicts the presence or the characteristics of central pain syndromes.

9%, 1/11.

91%, 10/11.

0/11

**Heat pain – method** 

Hypoalgesia 7%, 1/13

statistics, (Bowsher, 1997).

thermal or noxious stimuli.

al., 1995;Garcia-Larrea et al., 2010).

was maximal for the largest parietal lesions.

**As above**

(2 indeterminate)

Allodynia 0/13 (2 borderline) No abnormally

Normal 93%, 12/13 7% normal difference


location

50%, 5/10 48%, 13/27. 54%, 6/11.

hyperalgesia

15%, 2/13 0/27 9%, 1/11.

Hypoesthesia 50%, 5/10 52%, 14/27 27%, 3/11.

**Peltier Medoc Peltier Somedic, warm** 

31%, 4/13 7% normal difference

15%, 2/13 - -

Allodynia 23%, 3/13 No abnormally sensitive

Hypoesthesia 85%, 11/13 Diff in cool-warm

54% 7/13. 16/27, 59% -

1989;Leijon et al., 1989)

Aching 30%, Pricking 30%, lacerating 26%.

**V Frey for threshold; Pin prick for hyperalgesia**

**minus cool threshold** 

Diff in cool-warm thresholds 17/27; larger change in cool 2/27

between cold & heat pain threshold

thresholds, but 5/22 (23%) reported discomfort to metal at room temperature

thresholds, 17/27; larger change in warm

threshold 8/27

difference between cold & heat pain threshold

93% abnormal

59%, 16/27 38%, 6/16

Clinic (Vestergaard et al., 1995) QST (Andersen et

al., 1995).

(freezing 3/16)

3.3 median (0-7)

**V Frey hair, V Frey.** 

1/11-hyperalgesia to rotating von Frey hair

18%, 2/11-unaffected side

45%, 5/11 (4/11 bilateral)

**Peltier Somedic** 

91%, 10/11.

lower

0/11

11/11

86%, 23/27.

(Ohara et al., 2004) (Boivie et al.,

**Pain rating** 7.1 mean, 2.0 SD 2.5-7.9 mean by stroke

53% overall;

77% overall 33%, sharp/stab; 23%, pressure heavy; tight/ squeezing 7% each

38%, burning & cold; 15%, hot and cold;

**Von Frey for threshold; brushes for allodynia** 

3 with equal bilateral

hypoesthesia

(2 indeterminate)

**As above**

**As above**

**Burning cold/cold pain** 

**Touch – method** 

Normal threshold

**Cool – method** 

Normal threshold

**Cold pain – method** 

Normal threshold

**Warm – method** 

Normal threshold

85%, 11/13,

Hypoalgesia 46%, 6/13

Allodynia/ hyperalgesia

**Mechanical pain** 


Table 1. Summary of QST and descriptors of CPSP. The fourth column included both clinical findings (n=16) (Vestergaard et al., 1995) and quantitative sensory testing (n=11) (Andersen et al., 1995). Similarly, the third column included both clinical (Leijon et al., 1989) and sensory testing results (both N=27) (Boivie et al., 1989). Another very large series could not included because quantitative sensory testing results were not described as population statistics, (Bowsher, 1997).

painful stimuli, but they do show decreased sensitivity to at least some submodality of thermal or noxious stimuli.

Another important observation is that some patients with injuries or disease of the central nervous system (CNS) may experience thermal hypoesthesia or hypoalgesia as a result of a CNS lesion without developing central pain. This has been demonstrated for patients with lesions of the spinal cord (Ducreux et al., 2006;Finnerup et al., 2003), and brain (Andersen et al., 1995;Garcia-Larrea et al., 2010).

In the case of cortical lesions, the results of a recent study demonstrate warm and cold hypoesthesia based on QST thresholds in all subjects with lesions of parietal or insular cortex or both (Veldhuijzen et al., 2009). The largest degree of thermal hypoesthesia by threshold measures was found in the subject with the largest lesion, which involved extensive parietal and insular lobar lesions (see also (Greenspan et al., 1999). Suprathreshold measures demonstrated that sensory loss for painful and nonpainful hot and cold modalities was maximal for the largest parietal lesions.

Subjects with relatively small lesions restricted to the posterior insula and retroinsula showed central pain and cold allodynia, based on thresholds and clinical assessment. Cold allodynia based on thresholds but not on clinical assessment were observed in patients with parietal lesions sparing the insula. Similarly, a study of two patients with lesions of the insula and adjacent cortical lobes confirmed normal heat pain thresholds but increased ratings of heat pain compared to controls (Starr et al., 2009). These results suggest that non-painful cold and heat sensations are jointly mediated by parietal and insular cortical structures, while thermal pain sensation is more robust, requiring larger cortical lesions of these same structures to produce hypoalgesia. In addition, these studies dramatically demonstrate that neither the presence nor the extent of abnormal thermal sensation nor cold allodynia following a CNS lesion predicts the presence or the characteristics of central pain syndromes.

The variability of negative and positive symptoms and signs in patients with central pain raises the possibility that the level of spontaneous pain is correlated with the extent of sensory loss in patients with central pain. Such a relationship has been reported among patients with central pain resulting from spinal cord injury (SCI) (Ducreux et al., 2006). Specifically, two differences were observed between syringomyelia patients with or without allodynia. Those with allodynia tended to have 1) lesser thermosensory deficits and 2) more

Deconstructing Central Pain with Psychophysical and Neuroimaging Studies 455

No relation between the size or location of a lesion and the presence or intensity of central pain has been found, although CP requires an impairment of thermosensory pathways or nociceptive pathways or both (see Table 1) (Boivie et al., 1989;Leijon et al., 1989;Andersen et al., 1995;Vestergaard et al., 1995;Greenspan et al., 2004;Lewis-Jones et al., 1990). In addition, studies of patients with central pain secondary to SCI show that the spinothalamic tract is not differentially affected in pain-free patients as opposed to patients with ongoing central pain (Ducreux et al., 2006;Finnerup et al., 2003). Therefore, lesions involving the spinothalamic pathway and its cortical connections, while necessary, are not sufficient to

In a large series of patients (n=270) investigated for somatosensory abnormalities following stroke, five subjects were identified that presented with central pain and pure thermoalgesic sensory loss contralateral to the cortical stroke. All of these patients had involvement of the posterior insula and inner parietal operculum. Lemniscal sensory modalities and somatosensory evoked potentials to non-noxious inputs were preserved, while thermal and pain sensations were profoundly altered, and laser-evoked potentials were abnormal in all

The nature of neural abnormalities in central pain is poorly understood. It has been proposed that thalamic bursting (low-threshold spike or LTS pattern) occurs at a higher rate among neurons in the region of the Ventral caudal (Vc) nucleus in patients with central pain as opposed to those with movement disorders (Jeanmonod et al., 1996;Lenz et al., 1989;Lenz et al., 1994). Another report found no difference in the thalamic burst rate between patients with chronic pain as opposed to those with movement disorder (Radhakrishnan et al., 1999). In the latter report, most of the neuronal recordings were made outside Vc in patients with peripheral neuropathic pain rather than central pain. Thus, this latter report does not speak directly to the mechanism of central pain. Electrical stimulation in the area of Vc evoked pain more commonly in central pain patients with allodynia, versus those without allodynia (Lenz et al., 1998;Davis et al., 1996). Overall, these studies suggest that reorganization of the

In a study of MR spectroscopy, concentrations of markers for neurons (N-acetyl aspartate, NA) and glial cells (myo-inositol, Ins) in the thalamus were significantly different between patients with versus without central pain after SCI (Pattany et al., 2002;Stanwell et al., 2010). NA concentrations and NA/Ins ratios were lower in patients with pain versus those without, while Ins concentrations were higher for pain patients. In addition, NA concentrations were inversely correlated with VAS pain intensity, and Ins was directly correlated with pain intensity in the pain group. These results suggest that in SCI patients, dysfunction or loss of thalamic neurons is greater among SCI patients with central pain than

A recent study of SCI patients used a sophisticated wavelet-based analysis of the entire MRS signal to identify differences between SCI patients and intact controls, and between SCI patients with versus without central pain (DiPiero et al., 1991;Hsieh et al., 1995;Iadarola et al., 1995). Signals from the thalamus best discriminated between SCI patients and intact controls, yet signals from regions of the anterior cingulate and prefrontal cortex, but not the thalamus, highly discriminated between SCI patients with versus without central pain. While such an approach cannot identify the specific molecular differences, it does reveal which brain regions

Neuroimaging studies of CP patients have most often reported thalamic hypoactivity, but some have observed thalamic hyperactivity. PET (positron emission tomography) studies

exhibit neurochemical differences that relate specifically to neuropathic central pain.

**3.1 Ongoing pain** 

explain the development of central pain.

region of Vc contributes to the symptoms of central pain.

(Garcia-Larrea et al., 2010).

among those without.

asymmetrical thermosensory deficits than those without allodynia. The intensity of the spontaneous burning pain was correlated with the degree of thermal sensory loss. Additionally, thermal deficits were less severe in patients with cold allodynia compared to those with tactile allodynia. Therefore, the pattern of thermal sensory loss may differentially influence different features of central pain.

Another study of SCI secondary to syringomyelia compared diffusion tensor imaging (DTI) and electrophysiological potentials between patients with and without neuropathic pain and healthy controls (Hatem et al., 2010). Among those SCI patients with neuropathic pain, higher average daily pain intensity correlated with the extent of structural damage to the spinal cord tracts. Additionally, the number of intact nerve axons within the whole spinal cord was inversely correlated with deep spontaneous pain and dysaesthesias. Patients with both spontaneous and evoked pain had less structural spinal cord damage by morphological and electrophysiological criteria compared to patients with only spontaneous pain. Therefore, in patients with SCI there was strong evidence that the extent of structural lesions is strongly correlated with the expression of spontaneous and evoked pain, or hypersensitivity (Hatem et al., 2010).

Based on the sample of 30 central pain patients (mostly CPSP) evaluated with QST at our research center, we found no relationship between the extent of thermosensory loss (based on cool or warm thresholds), and the level of ongoing pain. Therefore, thermal hypoesthesia may manifest differently in patients with different etiologies of central pain.
