Ultra-high field functional magnetic resonance imaging reveals subregional hypothalamic and brainstem activation patterns in response to noxious heat stimuli in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a rare, debilitating chronic pain condition that develops after limb trauma and is characterised by persistent pain, hypersensitivity, autonomic and motor dysfunction, and emotional changes. Current treatments are ineffective, highlighting the need to better understand central mechanisms underlying CRPS, particularly autonomic circuitry responses to painful stimuli. Using ultra-high field 7-Tesla MRI for the first time in CRPS, we investigated noxious-evoked brain activity at a subregional level in people with CRPS (n = 25) compared to controls (n = 25). Noxious heat stimulation of CRPS-affected limbs revealedalterations in pain-related and autonomic control regions, using an uncorrected, exploratory statistical threshold. CRPS-affected limb stimulation showed increased activation within discrete ipsilateral hypothalamic nuclei, including the paraventricular and lateral nuclei. CRPS-affected upper and lower limb stimulation demonstrated somatotopic activation differences in the contralateral ventrolateral periaqueductal gray (vlPAG). In exploratory analyses, cardiac responses to noxious heat stimuli applied to the CRPS-affected limb were correlated with activation in the hypothalamus and PAG. Activity changes in the primary somatosensory cortex, thalamus, and amygdala were observed following CRPS-affected limb stimulation. These findings indicate that CRPS is associated with altered noxious-evoked activity in discrete subcortical and brainstem regions critical for autonomic regulation, pain modulation, and emotional processing. This study provides the first evidence of subregional hypothalamic activation in CRPS in response to noxious stimulation. Somatotopic changes in the vlPAG may suggest imbalances in descending pain modulation. Whether these alterations evolve with disease progression and represent therapeutic targets should be determined by future studies. PERSPECTIVE: This ultra-high field MRI study reveals, for the first time, distinct subregional hypothalamic and brainstem activation patterns in response to noxious stimuli in Complex Regional Pain Syndrome. This indicates altered autonomic circuits may contribute to ongoing pain in CRPS, identifying them as therapeutic targets for this debilitating chronic pain condition.