Anti-TNFα therapy in IBD alters brain activity reflecting visceral sensory function and cognitive-affective biases

Abstract

Background: In inflammatory bowel disease (IBD), immune activation with increased circulating TNF-α is linked to the intensity of gastrointestinal symptoms and depression or anxiety. A central feature of depression is cognitive biases linked to negative attributions about self, the world and the future. We aimed to assess the effects of anti-TNFα therapy on the central processing of self-attribution biases and visceral afferent information in patients with Crohn's disease.

Methods: We examined 9 patients with Crohn's disease (age 26.1±10.6. yrs, 5 female, 5 ileocolonic, 2 colonic and 2 ileal disease) during chronic anti-TNFα therapy (5 adalimumab, 4 infliximab). Patients were studied twice in randomized order before and after anti-TNFα administration. On each occasion patients underwent functional magnetic resonance imaging (fMRI) of the brain during a test of implicit attribution biases regarding sickness/health and undertook a standardized nutrient challenge.

Results: Following anti-TNFα treatment, ratings of 'fullness' following nutrient challenge reduced compared to pre-treatment ratings (p<0.05). Reaction times revealed improved processing of self-related and positive health words, consistent with improved implicit sense of wellbeing that correlated with improvements in sensory function after treatment (r = 0.67, p<0.05). Treatment-associated improvements in implicit processing were mirrored by alterations of prefrontal, amygdala, posterior cingulate and visual regions. Between patients, the degree of functional amygdala change was additionally explained by individual differences in attention regulation and body awareness rankings.

Conclusion: In patients with Crohn's disease, anti-TNFα administration reduces visceral sensitivity and improves implicit cognitive-affective biases linked to alterations in limbic (amygdala) function.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Implicit Associations Task—Experimental stimuli.

A) Task blocks begin by identifying the classification condition. In this condition, participants must decide if the stimulus word is self-related or positively valenced (Me or Positive). The stimulus word is then displayed (B), which the participant then classifies (C). In this case the participant correctly chose that the stimulus word “fatigued” was not a “Me or Positive” word. Visual feedback of each choice is displayed under the yes or no button box (dashed lines), and feedback about the classification accuracy is displayed below the stimulus word, in this case with a green tick. D) In this example, the participant incorrectly chose that the stimulus word “healthy” was an other-related or negatively valenced word (You or Negative). Participants are reminded of which buttons of the 4 button response box they are holding indicate yes and no by the illustrations at the top left and right of each screen.

Fig 2. Influence of anti-TNFα on subjective symptoms and classification biases.

A) The maximal tolerated volume of nutrient challenge tended to be higher after treatment (p = 0.06)(left); while subjective fullness was significantly reduced following anti-inflammatory therapy (p = 0.02) (right). Panels B-E present reaction times (left bar-graphs) underlying classification biases (right bar-graphs). Faster responses were made to self versus other related words (B-C), and to positive versus negative words (D-E). Treatment also reduced reaction times (B-E), and treatment x classification interactions revealed greater treatment effects for self-related and positive processing (B-D but not E). The significant three way interaction revealed anti-TNFα preferentially improved positively valenced self classification bias (B) over and above improvements in negatively valenced self classification bias (C), self-related positive classification bias (D) or other-related positive classification bias (E; no significant change).

Fig 3. Neural responses underlying anti-inflammatory influences on classification biases.

A) The predominant behavioral effect of anti-TNFα on increasing positively valenced self-classification bias directly reflected altered neural function within the left amygdala, right prefrontal cortex and left posterior cingulate. B) These effects were also seen outside our regions of interest, bilaterally in the inferior temporal gyrus. C) Responses within the inferior temporal gyrus also reflected behavioral increases in self-related positive classification bias. D) Region of interest inclusively masked entire frontal lobes, cingulate cortex and amygdala. Bar charts of parameter estimates are colored dark grey before and light grey after anti-TNFα treatment.

Fig 4. Associations between viscerosensory, behavioral neural and psychometric measures.

Across participants, increased facilitation of positive self-classification biases were seen in participants with A) larger reductions in viscerosensory (fullness) ratings and B) higher levels of trait anxiety. Treatment associated alterations in left amygdala were largest in participants with C) reduced ability to regulate attention and D) reduced levels of awareness.