Instantaneous antidepressant effect of lateral habenula deep brain stimulation in rats studied with functional MRI
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eLife assessment
The authors present an important contribution to the field of deep brain stimulation (DBS) for depression by providing further evidence for the validity of the lateral habenula as a DBS target. The evidence provided is compelling and particularly strong in its use of fMRI to delineate target subregions best corresponding both to clinical and downstream fMRI response. This study provides information relevant to both surgical targeting and the mechanism of action for this DBS target.
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Abstract
The available treatments for depression have substantial limitations, including low response rates and substantial lag time before a response is achieved. We applied deep brain stimulation (DBS) to the lateral habenula (LHb) of two rat models of depression (Wistar Kyoto rats and lipopolysaccharide-treated rats) and observed an immediate (within seconds to minutes) alleviation of depressive-like symptoms with a high-response rate. Simultaneous functional MRI (fMRI) conducted on the same sets of depressive rats used in behavioral tests revealed DBS-induced activation of multiple regions in afferent and efferent circuitry of the LHb. The activation levels of brain regions connected to the medial LHb (M-LHb) were correlated with the extent of behavioral improvements. Rats with more medial stimulation sites in the LHb exhibited greater antidepressant effects than those with more lateral stimulation sites. These results indicated that the antidromic activation of the limbic system and orthodromic activation of the monoaminergic systems connected to the M-LHb played a critical role in the rapid antidepressant effects of LHb-DBS. This study indicates that M-LHb-DBS might act as a valuable, rapid-acting antidepressant therapeutic strategy for treatment-resistant depression and demonstrates the potential of using fMRI activation of specific brain regions as biomarkers to predict and evaluate antidepressant efficacy.
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Author Response
Reviewer #1 (Public Review):
Li et al investigated the behavioral response and fMRI activations associated with deep brain stimulation (DBS) of the lateral habenula (LHb) in 2 distinct rodent models of depression. They found that a) LHb DBS reduces depressive and anxiety behaviors using multiple behavioral tests: sucrose preference, forced swim, and open field. These results held across multiple models of depression and multiple tests, and generally restored results of these behavioral tests to parity with controls. Furthermore, fMRI activations of brain regions with known connectivity to LHb strongly correlated with behavioral responses to LHb DBS, particularly in limbic regions. These behavioral responses clearly depended on electrode location, with more medial placements within the LHb producing a more robust …
Author Response
Reviewer #1 (Public Review):
Li et al investigated the behavioral response and fMRI activations associated with deep brain stimulation (DBS) of the lateral habenula (LHb) in 2 distinct rodent models of depression. They found that a) LHb DBS reduces depressive and anxiety behaviors using multiple behavioral tests: sucrose preference, forced swim, and open field. These results held across multiple models of depression and multiple tests, and generally restored results of these behavioral tests to parity with controls. Furthermore, fMRI activations of brain regions with known connectivity to LHb strongly correlated with behavioral responses to LHb DBS, particularly in limbic regions. These behavioral responses clearly depended on electrode location, with more medial placements within the LHb producing a more robust behavioral effect.
The conclusions of this paper are generally well supported by the data, with the primary weaknesses of the study being 1) limited novelty due to LHb already being a well-established target for DBS in depression, and 2) the questionable validity of rodent models of depression in general. The authors deal with the first point (novelty) by extending their study to electrode localization and fMRI correlates with the behavioral response, leading to insight into surgical targeting as well as mechanism of effect, respectively. They also partially mitigate fundamental problems with rodent models of depression by using 2 different models and showing consistent responses to LHb DBS across both. The methods used in this study were sound, with high-quality techniques used for electrode implantation, confirmation of electrode placement, fMRI acquisition, anesthesia and physiological monitoring, as well as an appropriate statistical analytic approach.
We thank the reviewer deeply for the positive assessment on our work.
Reviewer #2 (Public Review):
This important paper is a real tour de force and combines functional MRI, behaviour, and brain stimulation to characterise the effect of stimulation of the lateral habenula in a rodent model for depression. The results are stunning and the data presented seems compelling.
My only comment is I would like more discussion on the relevance of these results for the treatment of depression in humans, both in terms of the rodent model and in terms of the results shown in this study.
We thank the reviewer deeply for the positive assessment on our work. We have added discussion on the relevance of our finding for the treatment of depression in humans on Page 17 of the revised manuscript as follows:
“The WKY and LPS-treated depressive rat models share similar characteristics, including abnormalities in various neurotransmitter and endocrine systems and emotional changes resulting from inflammatory stimuli. These models are widely used in pharmacological and nonpharmacological depression treatment studies(Caldarone et al., 2015; Aleksandrova et al., 2019; Lasselin et al., 2020). Previous research indicates that classic antidepressants used in humans, such as selective serotonin reuptake inhibitors, also cause an antidepressant reaction in WKY rats. Ketamine, a rapid-acting antidepressant in clinical practice, has been shown to be effective in both WKY and LPS-treated rats(Aleksandrova et al., 2019; J. Zhao et al., 2020). In WKY rats, DBS of the NAc increased exploratory activity and exerted anxiolytic effects, and NAc-DBS was found to be effective for TRD treatment in humans(Dandekar et al., 2018; Aleksandrova et al., 2019). These results suggest that the depression rat models can provide valuable information about the efficacy of various pharmacological and nonpharmacological therapies. In a recent case report, researchers observed acute stimulation effects in addition to long-term clinical improvements in depression, anxiety, and sleep in a patient with TRD upon administering LHb-DBS (Wang et al., 2020). This finding supports the clinical relevance of our observations. However, no animal model of depression can completely replicate human symptoms, and further research is necessary to validate our findings in human patients. Additionally, the long-term efficacy and side effects of LHb-DBS require further investigation. Nevertheless, we believe that our findings propose a promising addition to the rapid-acting therapeutic options for the most refractory depression patients.”
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eLife assessment
The authors present an important contribution to the field of deep brain stimulation (DBS) for depression by providing further evidence for the validity of the lateral habenula as a DBS target. The evidence provided is compelling and particularly strong in its use of fMRI to delineate target subregions best corresponding both to clinical and downstream fMRI response. This study provides information relevant to both surgical targeting and the mechanism of action for this DBS target.
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Reviewer #1 (Public Review):
Li et al investigated the behavioral response and fMRI activations associated with deep brain stimulation (DBS) of the lateral habenula (LHb) in 2 distinct rodent models of depression. They found that a) LHb DBS reduces depressive and anxiety behaviors using multiple behavioral tests: sucrose preference, forced swim, and open field. These results held across multiple models of depression and multiple tests, and generally restored results of these behavioral tests to parity with controls. Furthermore, fMRI activations of brain regions with known connectivity to LHb strongly correlated with behavioral responses to LHb DBS, particularly in limbic regions. These behavioral responses clearly depended on electrode location, with more medial placements within the LHb producing a more robust behavioral effect.
The …
Reviewer #1 (Public Review):
Li et al investigated the behavioral response and fMRI activations associated with deep brain stimulation (DBS) of the lateral habenula (LHb) in 2 distinct rodent models of depression. They found that a) LHb DBS reduces depressive and anxiety behaviors using multiple behavioral tests: sucrose preference, forced swim, and open field. These results held across multiple models of depression and multiple tests, and generally restored results of these behavioral tests to parity with controls. Furthermore, fMRI activations of brain regions with known connectivity to LHb strongly correlated with behavioral responses to LHb DBS, particularly in limbic regions. These behavioral responses clearly depended on electrode location, with more medial placements within the LHb producing a more robust behavioral effect.
The conclusions of this paper are generally well supported by the data, with the primary weaknesses of the study being 1) limited novelty due to LHb already being a well-established target for DBS in depression, and 2) the questionable validity of rodent models of depression in general. The authors deal with the first point (novelty) by extending their study to electrode localization and fMRI correlates with the behavioral response, leading to insight into surgical targeting as well as mechanism of effect, respectively. They also partially mitigate fundamental problems with rodent models of depression by using 2 different models and showing consistent responses to LHb DBS across both. The methods used in this study were sound, with high-quality techniques used for electrode implantation, confirmation of electrode placement, fMRI acquisition, anesthesia and physiological monitoring, as well as an appropriate statistical analytic approach.
-
Reviewer #2 (Public Review):
This important paper is a real tour de force and combines functional MRI, behaviour, and brain stimulation to characterise the effect of stimulation of the lateral habenula in a rodent model for depression. The results are stunning and the data presented seems compelling.
My only comment is I would like more discussion on the relevance of these results for the treatment of depression in humans, both in terms of the rodent model and in terms of the results shown in this study.
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