Altered Brain Structure in Chronic Visceral Pain: Specific Differences in Gray Matter Volume and Associations With Visceral Symptoms and Chronic Stress

Abstract

Structural brain alterations in chronic pain conditions remain incompletely understood, especially in chronic visceral pain. Patients with chronic-inflammatory or functional bowel disorders experience recurring abdominal pain in concert with other gastrointestinal symptoms, such as altered bowel habits, which are often exacerbated by stress. Despite growing interest in the gut-brain axis and its underlying neural mechanisms in health and disease, abnormal brain morphology and possible associations with visceral symptom severity and chronic stress remain unclear. We accomplished parallelized whole-brain voxel-based morphometry analyses in two patient cohorts with chronic visceral pain, i.e., ulcerative colitis in remission and irritable bowel syndrome, and healthy individuals. In addition to analyzing changes in gray matter volume (GMV) in each patient cohort vs. age-matched healthy controls using analysis of covariance (ANCOVA), multiple regression analyses were conducted to assess correlations between GMV and symptom severity and chronic stress, respectively. ANCOVA revealed reduced GMV in frontal cortex and anterior insula in ulcerative colitis compared to healthy controls, suggesting alterations in the central autonomic and salience networks, which could however not be confirmed in supplemental analyses which rigorously accounted for group differences in the distribution of sex. In irritable bowel syndrome, more widespread differences from healthy controls were observed, comprising both decreased and increased GMV within the sensorimotor, central executive and default mode networks. Associations between visceral symptoms and GMV within frontal regions were altered in both patient groups, supporting a role of the central executive network across visceral pain conditions. Correlations with chronic stress, on the other hand, were only found for irritable bowel syndrome, encompassing numerous brain regions and networks. Together, these findings complement and expand existing brain imaging evidence in chronic visceral pain, supporting partly distinct alterations in brain morphology in patients with chronic-inflammatory and functional bowel disorders despite considerable overlap in symptoms and comorbidities. First evidence pointing to correlations with chronic stress in irritable bowel syndrome inspires future translational studies to elucidate the mechanisms underlying the interconnections of stress, visceral pain and neural mechanisms of the gut-brain axis.

A review of neuroendocrine immune system abnormalities in IBS based on the brain–gut axis and research progress of acupuncture intervention

“…Increased neuronal activity has been reported in the medial prefrontal cortex, the insula, and the anterior cingulate gyrus, which are brain regions associated with visceral pain in patients with IBS (Grinsvall et al, 2021 ), and a larger area of excitation was observed in brain regions associated with nociceptive processing (e.g., the prefrontal cortex, the anterior cingulate gyrus, the thalamus, etc.,) (Seminowicz et al, 2010 ). Similarly, in a cohort study, the IBS group exhibited extensive structural changes in the brain compared with that in the controls, and these changes in the brain included a reduction or increase in gray matter volume in multiple regions of the sensorimotor, central executive, and default mode networks, and these changes were strongly associated with chronic visceral pain (Öhlmann et al, 2021 ). Another study found that spontaneous activity in the amygdala and the anterior insula was significantly increased in patients with IBS, while spontaneous activity in sensorimotor areas tended to reduce (Hong et al, 2013 ).…”

Neural circuits regulating visceral pain

“…The insular cortex is a highly polar center that integrates visceral autonomous activities and is known as the “visceral brain”. Imaging studies have shown that, compared with controls, patients with IBS exhibit decreased thickness and lower gray matter volume in the insula, which are associated with a longer disease duration and visceral hypersensitivity 175 , 176 . The insula is continuously activated during the resting state and during colorectal distension stimulation in patients or rodents with IBS 176 , 177 .…”

“…Imaging studies have shown that, compared with controls, patients with IBS exhibit decreased thickness and lower gray matter volume in the insula, which are associated with a longer disease duration and visceral hypersensitivity 175 , 176 . The insula is continuously activated during the resting state and during colorectal distension stimulation in patients or rodents with IBS 176 , 177 . In rats with chronic pancreatitis induced by trinitrobenzene sulfonic acid and NMD, increased c-Fos expression and potentiated excitatory synaptic transmission within the insular cortex were observed.…”

Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders

“…However, it is generally difficult to localize. Among heterogenous pathogenic hypotheses, the neurological dysfunction is significantly linked to visceral pain [ 78 , 79 , 80 , 81 , 82 ]. In fact, visceral pain and neuropathic pain are mostly characterized by hypersensitivity to stimulus, potentially due to hypersensitivity of primary sensory afferent neurons and dysregulation of neurotransmission [ 79 , 83 ].…”