1. Poststroke Thalamic PainPoststroke thalamic pain (PS-TP), or broadly central poststroke pain (CPSP), is centralized, neuropathic, often characterized with hyperalgesia and allodynia, and is a complaint in 2.7 to 25% of stroke survivors [1,2,3,4,5]. The prevalence of PS-TP was highly variable because of the different study durations as well as the clinical characteristics of the stroke population included in the clinical studies, e.g., stroke etiology, distribution of stroke lesions, and clinical management [1,2,3,4]. PS-TP may develop immediately after a stroke; however, apparent PS-TP often comes later in the postacute phase or the recovery phase following the stroke, e.g., months to years [1,3,4,6], and thalamic stroke may be recalled again later because of the development of PS-TP, which has also been called the Dejerine–Roussy syndrome [1,6,7]. Thalamic pain syndrome commonly follows an ischemic stroke or hemorrhagic stroke in the thalamic and lateral medullary areas [3,8,9]. PS-TP occurs after thalamic stroke with sensory deficits, and it often comes up to 40% in the acute phase following the stroke, e.g., within a month of the stroke [10,11,12]. Over 40% of patients with PS-TP have symptoms between one and 12 months after the stroke, and sometimes PS-TP develops between one and six years poststroke [10,12].Up to 74% of stroke survivors with PS-TP showed gradually increased pain rather than rapid worsening following the stroke, in no relation with the general demographic data and the existence of sensory deficits. Younger age was shown as a risk factor of PS-TP .Right-sided stroke lesions were more commonly associated with the development of PS-TP than left-sided ones. The affected right hemisphere of the brain is better reactive for pain medication .
1.1. The Pathogenesis of PS-TPThe underlying mechanisms of PS-TP are poorly understood, contributing to challenges in its management. The thalamus, as a relay station for all sensory tracts in the brain, works to decode sensory information and process it, which goes to the somatosensory cortex where it is interpreted [14,15,16] (see Figure 1). Actually, several parts of thalamus, especially the ventrocaudal regions of the thalamus such as the ventral posterior nuclei or the ventral lateral nuclei, the lateral posterior nuclei, as well as the thalamic sensory tracts, e.g., the simultaneously affected spinothalamic tract and the anterior pulvinar nucleus, have been known as the high-risk areas of the development of PS-TP [14,17]. The damage to the thalamus or thalamic sensory tracts due to stroke can cause thalamic pain syndrome [14,17,18]. The damage-related changes of the processing and interpretation of peripheral sensory information, e.g., tactile, temperature, pressure, including the loss of them, as well as their malfunction in the afferent pathway from the thalamus to the cortex in central poststroke pain, e.g., tactile or temperature stimuli to the thalamus, can be interpreted as painful (allodynia) or amplifying of painful stimuli, which make it worse (hyperalgesia) [18,19,20,21]. On the other hand, the central sensitization of pain follows due to persistent overactivity [18,20,21].The pathogenesis of PS-TP has been considered and discussed by several possible theories, such as central imbalance, central disinhibition, central sensitization, other thalamic changes, and inflammatory responses on the affected neural pathway due to stroke [14,17,18,22].If the spinothalamic tract is damaged due to stroke, and the dorsal–medial lemniscus pathway functions normally, the central imbalance between the abnormal nociception and thermal sensation can occur. This central imbalance can also come from third neurons of the spinothalamic pathway, the anatomical projection from the thalamus to the insular cortex, or the anterior cingulate region [14,18].Due to the stroke affecting the lateral thalamus, this causes central disinhibition by the deafferentation of the GABAergic neurons of the ventral posterolateral nucleus, which causes the intrinsic inhibition of the ventral posterolateral nucleus, and the overactivation of cortical areas, developing pain. The delayed appearance of PS-TP may be explained by this. The disinhibition of temperature-sensing fibers (primarily those that sense cold) might be the cause of cold allodynia. Hyperactivities of central afferent neurons, called “central sensitization”, can lead pain spontaneously or already on suboptimal stimuli [14,18].The hypersensitivity of the remaining nerves in the spinothalamic tract, as well as the microglial activation after the stroke, can be associated with the development of PS-TP [18,23]. The activation of NLRP3 inflammasome (NOD-like receptor pyrin domain 3; NOD: nucleotide-binding and oligomerization domain) due to inflammatory responses following stroke can cause the decrease of descending fibers from the cortex to the thalamus, which may then induce the reduction of GABAergic release, resulting in the increased excitability of the ventral basal neurons in the thalamus . On the other side, NLRP3 inflammasome at the thalamus lesion strengthens the inflammatory response of microglia at the same time. Persisting inflammatory processes can induce GABAergic changes in the thalamus reticular neurons to inhibit the functions of ventral basal interneurons. These can develope PS-TP . Several factors, e.g., stress and skin temperature, also aggravate PS-TP .
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