Neuroimaging of the Brain-Gut Axis: From Basic Understanding to Treatment of Functional GI Disorders  Emeran A. Mayer, Bruce D. Naliboff, A.D. Bud Craig  Gastroenterology  Volume 131, Issue 6, Pages 1925-1942 (December 2006) DOI: 10.1053/j.gastro.2006.10.026 Copyright © 2006 AGA Institute Terms and Conditions

Figure 1 Ascending projections of homeostatic afferents. (A) Organization of interoceptive pathways. Small diameter afferents that travel with sympathetic and with parasympathetic efferents provide input to lamina I and NTS, respectively. In mammals, the activity of both types of afferents is integrated in the PBN, which projects to insular cortex. In non-human and human primates, a direct projection from lamina I and from the NTS exist to ventromedial thalamic nuclei (VMpo and VMb, respectively). Neurons in these nuclei project in a topographical fashion to the mid/posterior insula. In humans, this cortical image of the homeostatic state of the organism is re-represented in the anterior insula on the same side of the brain. These re-representations provide the substrate for a subjective evaluation of interoceptive state. PBN, parabrachial nucleus. Reprinted with permission from Craig 2002.2 (B) Spino-thalamo-cortical system. Summary diagram illustrating the projections in primates of homeostatic afferent pathways from lamina I (spinal) and NTS (vagal) to thalamic nuclei, and the 2 cortical regions involved in the sensory (insula) and motivational (ACC) dimensions of homeostatic emotions. NTS, nucleus tractus solitarius. ACC, anterior cingulate cortex. Modified from Craig 2003.138 Gastroenterology 2006 131, 1925-1942DOI: (10.1053/j.gastro.2006.10.026) Copyright © 2006 AGA Institute Terms and Conditions

Figure 2 Hierarchical organization of homeostatic reflex systems involving the sympathetic nervous system. (A) Homeostatic afferents that report the physiological condition of all tissues in the body, including the GI tract, terminate in lamina I of the dorsal horn. The ascending projections of these neurons provide the basis for reflex arcs at the spinal, medullary and mesencephalic levels. Limbic, paralimbic, and prefrontal centers provide modulatory influences on the gain of these reflexes. Reprinted with permission from Craig 2002.2 (B) Cortical modulation of homeostatic afferent input to the central nervous system. PFC regions (dorsolateral PFC [dlPFC], orbitofrontal cortex [orbFC]) modulate activity in limbic and paralimbic regions (amygdala [amy], ACC subregions, and hypothalamus [Hypoth]), which in turn regulate activity of descending inhibitory and facilitatory descending pathways through the PAG and pontomedullary nuclei. Activity in these corticolimbic pontine networks mediates the effect of cognitions and emotions on the perception of homeostatic feelings, including visceral pain and discomfort. Gastroenterology 2006 131, 1925-1942DOI: (10.1053/j.gastro.2006.10.026) Copyright © 2006 AGA Institute Terms and Conditions

Figure 3 Schematic illustration of different, overlapping brain networks mediating the effects of cognitions and emotions on the perception of homeostatic feelings, including visceral pain and discomfort. Differential dysregulations of one or several of these networks could result in altered perception, even in the presence of normal visceral afferent input to the brain. Gastroenterology 2006 131, 1925-1942DOI: (10.1053/j.gastro.2006.10.026) Copyright © 2006 AGA Institute Terms and Conditions

Figure 4 Central arousal networks and visceral hypersensitivity. Normalization of discomfort visual analogue scale ratings (left upper graph), and discomfort threshold (right upper graph) in 24 IBS patients undergoing experimental rectal balloon distention every 3 months over a 12-month period. Brain images obtained in a subset of 12 individuals during the initial and the fourth experimental session showed decreases in central arousal circuits involving the mid-cingulate cortex (MCC), amygdala (not shown), and dorsal pons (including LCC region). Similar decreases were observed during an expectation condition and during the actual distention. Reprinted with permission from Naliboff et al.101 Gastroenterology 2006 131, 1925-1942DOI: (10.1053/j.gastro.2006.10.026) Copyright © 2006 AGA Institute Terms and Conditions

Figure 5 Role of corticolimbic inhibitory network in pain modulation. Medial frontal cortical (FC) mediation of the impact of right lateral FC on the PAG. The dotted line indicates that the relationship between right lateral PFC [RLPF] and the PAG is indirect. Unstandardized coefficients with associated standard errors in parentheses are reported. The coefficients in brackets indicate the direct effect of RLFC on PAG prior to the inclusion of the mediating medial FC. ** indicates P < .01. FC, frontal cortex. PAG, periaqueductal gray. RLFC, right lateral frontal cortex. Reprinted with permission from Mayer et al.109 Gastroenterology 2006 131, 1925-1942DOI: (10.1053/j.gastro.2006.10.026) Copyright © 2006 AGA Institute Terms and Conditions