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Role of Gastric Electrical Stimulation in the Treatment of Gastroparesis
Review
Peer-Review Record

Status of Brain Imaging in Gastroparesis

Gastrointest. Disord. 2020, 2(2), 58-70; https://doi.org/10.3390/gidisord2020006
Reviewer 1: Anonymous
Reviewer 2: Mark Fox
Gastrointest. Disord. 2020, 2(2), 58-70; https://doi.org/10.3390/gidisord2020006
Received: 6 March 2020 / Revised: 3 April 2020 / Accepted: 7 April 2020 / Published: 9 April 2020
(This article belongs to the Special Issue Gastroparesis)

Round 1

Reviewer 1 Report

The structure of manuscript has the commonly required criteria. The topic of presented work is very actual. The pathophysiology of nausea and vomiting in gastroparesis is complicated and multifaceted involving the collaboration of both the peripheral and central nervous systems. Most treatment strategies and studies performed in gastroparesis have focused largely on the peripheral effects of this disease, while our understanding of the central nervous system mechanisms of nausea and in this entity is still evolving.

Gastroparesis is a chronic heterogeneous motor disorder with variable clinical manifestations including episodic nausea, vomiting, retching, post-prandial fullness, early satiety, and/or upper abdominal pain in the absence of mechanical obstruction. The sensation of nausea is an unpleasant subjective sensation that is difficult to define, and can occur alone or in conjunction with vomiting. 

The pathophysiology of nauzea and vomiting is complex and involves the transmission of sympathetic and parasympathetic visceral afferent pathways to the nucleus tractus solitarius in the medulla which activates the emetic circuitry.

Functional MRI (fMRI) and Positron Emission Tomography (PET) are two basic classes of brain imaging techniques that allow for measurement of brain activity. They can allow mapping of local metabolic or physiological consequences of altered brain activity.

Some studies have used  fMRI to show that extensive brain networks are involved in nausea evoked by visual stimulation. The different brain regions can be activated by visually- evoked nausea with worsening nausea associated with an increasing phasic brain response involving an extensive network of different brain regions. The prior to nausea regions of the brain that were activated were the amygdala, ventral putamen, and locus coeruleus – areas know to process stress, fear, and emotion. Then, during transitioning to higher-intensity nausea, it was noted that recruitment of more brain regions occurred including the insular, anterior cingulate, prefrontal, and orbitofrontal cortices, as well as activation of subcortical regions (ventral tegmental area, nucleus accumbens, putamen). During periods of intense nausea, a linkage between the anterior insula and midcingulate areas was sustained. Altogether a large network of brain neurons in supratententorial regions including limbic, cognitive, somatosensory, and interoceptive areas were noted to be important neural circuits in the production of the emetic response.

In humans with refractory gastroparesis, gastric electrical stimulator GES increased thalamic activity as detected by PET central nervous imaging. Enhanced vagal activity was also appreciated through significantly decreased sympathovagal balance through power spectral analysis of heart rate variability. These findings suggest that GES may provide symptomatic improvement by enhancing relaxation of the gastric fundus by improving vagal autonomic function as well as by activating central control mechanisms of nausea and vomiting through thalamic pathways. This suggests that central mechanisms for nausea and vomiting are mediated and activated via thalamic pathways in the central nervous system in severe gastroparetic patients after GES therapy and that indeed, the major symptomatic benefit of GES therapy for severe gastroparesis is by being an anti-emetic, albeit a very powerful anti-emetic. This explains symptom relief in GES, an anti-emetic prescription for gastroparetics when there is no improvement with other standard medical therapies.

            In the current study, authors assess the current status of brain imaging and summarize the theories about our present understanding on the central mechanisms involved in nausea and vomiting in patients with gastroparesis.

            The research work follows several aims and interesting parametric studies. The results are documented in figures that present the review of the obtained data.  

            The citations are well-chosen and relevant and their format respects usual standards. 

            Summarizing, I recommend that the manuscript can be published.   

Author Response

We are very much thankful to Reviewer 1 for his/her detailed and valuable review.  Reviewer 1 has provided us with thoughts and comments about our manuscript, with recommendation that the manuscript be published.  Reviewer 1 did not ask for any revisions, and therefore, no point-by-point response is required. Thank you again.  

Reviewer 2 Report

The diagnoses of gastroparesis involves central brain as well as peripheral disease mechanisms.  Gonzalez and McCallum provide a timely and well constructed review of the central nervous system mechanisms that underly nausea in this entity. New data from a case-control study of 10 patients with the clinical diagnosis of gastroparesis performed by the authors is discussed in detail.

Comments and Queries

Major

The diagnoses of gastroparesis and functional dyspepsia are closely inter-twined. It is clear that central brain as well as peripheral disease mechanisms are involved in both conditions.  Gastric distension is a key stimulus in both; however, conceptually, gastroparesis is more closely related to abnormal gastric emptying and FD to heightened visceral sensitivity and abnormal central regulation; however, this distinction is difficult to establish in clinical practice. Nevertheless, this issue is important because it has implications for individual therapy targeted at the key underlying cause of symptoms. The overlap with functional GI disorders and gastroparesis should be addressed. Is there evidence from brain imaging that the causes of symptoms and disease are shared… or separate.

 

Minor

The pros and cons of MRI and PET–CT are neatly outlined. A key reason in certain studies to prefer PET to functional MRI is because the relatively long acquisition time increases test sensitivity and is less subject to variation over time (important if the optimal time for acquisition of brain imaging after ingestion of a meal is uncertain)

The role of GES in the management of nausea is a focus of the review. The fact that, although defined by its presence, delayed gastric emptying is only weakly associated with nausea and that GES, even when effective, does not improve gastric emptying should be noted. A very recent, key RCT that highlights this discrepancy could be cited: Ducrotte Gastroenterology. 2020 Feb;158(3):506-514.e2. doi: 10.1053/j.gastro.2019.10.018.

The role of antidepressants in the management of nausea is not discussed. This effect is central and some limited brain imaging data exist in patients with symptoms of gastroparesis / functional dyspepsia. Additionally it is of interest that this medication appears to have less effect in patients with objective delay in gastric emptying than in those with normal emptying is of interest: Talley Gastroenterology. 2015 Aug;149(2):340-9.e2. doi: 10.1053/j.gastro.2015.04.020

 

 

 

Author Response

Dear Gastrointestinal Disorders,

Attached please find our manuscript entitled “Status of Brain Imaging in Gastroparesis” that has been revised based on the critique received from the reviewers.  In addition, below, please find a point-by-point response to the comments and queries of the reviewers.  We would like to thank the reviewers for their input which we feel has improved this manuscript.  We hope it is now able to be accepted for publication, but if further questions remain, we will be glad to address them. 

Sincerely,
Drs. McCallum and Gonzalez

 

Reviewer 2
The diagnoses of gastroparesis involves central brain as well as peripheral disease mechanisms.  Gonzalez and McCallum provide a timely and well constructed review of the central nervous system mechanisms that underly nausea in this entity. New data from a case-control study of 10 patients with the clinical diagnosis of gastroparesis performed by the authors is discussed in detail.

Comments and Queries
Major
Point 1: The diagnoses of gastroparesis and functional dyspepsia are closely inter-twined. It is clear that central brain as well as peripheral disease mechanisms are involved in both conditions.  Gastric distension is a key stimulus in both; however, conceptually, gastroparesis is more closely related to abnormal gastric emptying and FD to heightened visceral sensitivity and abnormal central regulation; however, this distinction is difficult to establish in clinical practice. Nevertheless, this issue is important because it has implications for individual therapy targeted at the key underlying cause of symptoms. The overlap with functional GI disorders and gastroparesis should be addressed. Is there evidence from brain imaging that the causes of symptoms and disease are shared… or separate.
Response 1:  We agree it is important to understand the differences in altered CNS responses to gastric stimuli between FD and gastroparesis in order to better understand these two entities and in order to develop more effective treatment strategies in the future.  Appropriate modification to the revised manuscript can be found on pages 7 and 8. 

Minor
Point 2: The pros and cons of MRI and PET–CT are neatly outlined. A key reason in certain studies to prefer PET to functional MRI is because the relatively long acquisition time increases test sensitivity and is less subject to variation over time (important if the optimal time for acquisition of brain imaging after ingestion of a meal is uncertain)
Response 2. We would like to thank the reviewer for pointing out this advantage of PET over functional MRI.  This has been added to the revised manuscript on page 4. 

Point 3: The role of GES in the management of nausea is a focus of the review. The fact that, although defined by its presence, delayed gastric emptying is only weakly associated with nausea and that GES, even when effective, does not improve gastric emptying should be noted. A very recent, key RCT that highlights this discrepancy could be cited: Ducrotte Gastroenterology. 2020 Feb;158(3):506-514.e2. doi: 10.1053/j.gastro.2019.10.018.
Response 3: Please note the revision of the manuscript on page 7 to address this comment.

Point 4: The role of antidepressants in the management of nausea is not discussed. This effect is central and some limited brain imaging data exist in patients with symptoms of gastroparesis / functional dyspepsia. Additionally it is of interest that this medication appears to have less effect in patients with objective delay in gastric emptying than in those with normal emptying is of interest: Talley Gastroenterology. 2015 Aug;149(2):340-9.e2. doi: 10.1053/j.gastro.2015.04.020
Response 4: Please note the revision of the manuscript on page 8-9 to address this comment.

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