Effects of Repeated Deep Brain Stimulation on Depressive- and Anxiety-Like Behavior in Rats: Comparing Entopeduncular and Subthalamic Nuclei

doi:10.1016/j.brs.2012.09.012

Brain Stimulation

Volume 6, Issue 4, July 2013, Pages 506-514

https://doi.org/10.1016/j.brs.2012.09.012 Get rights and content

Abstract

Background

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity.

Objective

To compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats.

Methods

DBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels.

Results

Repeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS.

Conclusions

Together these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN.

Introduction

Deep brain stimulation of the subthalamic nucleus or internal globus pallidus has been routinely used for the treatment of movement disorders, including Parkinson's disease, dystonia and tremor [1], [2], [3], [4]. While the therapeutic effects of DBS in these conditions are clear, clinical trials have also indicated that DBS can be associated with adverse effects, such as depression, apathy, anxiety, impulsivity and increased risk of suicide [5], [6], [7], [8], [9]. The mechanism(s) underlying these effects remain(s) unclear, and there is as yet no definitive consensus as to which target, the STN or GPi, has a more benign side effect risk profile.

In clinical populations, it is difficult to directly assess which target has a more favorable effect profile [10], [11], [12]. The overwhelming majority of studies assessing psychiatric side effects have been performed in patients with Parkinson's disease (PD), a condition where underlying motor or psychiatric pathology may obscure comparisons between STN and GPi as DBS targets. Moreover, STN-DBS has been more widely applied than GPi-DBS for the treatment of PD and as a result a larger volume of psychiatric effects that have been reported after STN-DBS than after GPi-DBS. In studies designed to directly compare DBS targets, it is emerging that STN-DBS may be associated with more affective side effects than GPi-DBS [13], although this finding has not been consistently reported in all clinical trials [7], [14].

The objective of the present study was to compare psychiatric-type effects of DBS applied to the STN and entopeduncular nucleus (EPN, the rodent homolog of the GPi), in the absence of motor disturbances or neurological pathology. We used a learned helplessness protocol to model depressive-like behavior and an elevated plus maze task to assess anxiety-like behavior in otherwise healthy rats that had undergone daily DBS for three weeks. Since hippocampal brain-derived neurotrophic factor (BDNF) has been implicated in depressive syndromes [15], [16], [17], we also measured BDNF levels as well as gene expression of its receptor, trkB, in the hippocampus of repeatedly stimulated rats. Finally, it has been hypothesized that STN-DBS may have a greater effect than EPN-DBS on brain regions distal from the target site [18], which may in turn contribute to their different symptom profiles. To address this possibility we used expression the early gene zif268, a marker of neuronal activity, to compare the effects of acute STN- vs. EPN-DBS on several brain areas that have been generally implicated in affective processes and emotional reactivity.

Section snippets

Methods

All procedures were approved by the Animal Care Committee at the Centre for Addiction and Mental Health and complied with Canadian Council on Animal Care (CCAC) and NIH standards and guidelines.

Learned helplessness

As expected, animals that were previously exposed to inescapable footshock showed impaired performance in the avoidance task relative to non-stressed controls (Fig. 2). A three-way ANOVA on number of failures over the three days indicated significant main effects of Inescapable Stress (F_1,42 = 20.63, P < 0.001) and brain manipulation (sham surgery, STN DBS or EPN DBS; F_2,42 = 123.04, P < 0.001), and no significant interaction among these factors (P > 0.05) or between these factors and the Test

Discussion

The main finding of this study was that DBS applied repeatedly to the STN, but not to the EPN, impaired performance in the learned helplessness model of depression, and was associated with lower levels of gene expression of BDNF and its receptor trkB. DBS applied to either target had no effect on performance in the elevated plus maze (Fig. 3) and did not affect general locomotor activity (Fig. 4).

In the LH paradigm STN DBS but not EPN had a significant worsening effect on escape performance in

Acknowledgments

We thank Roger Raymond and Mustansir Diwan for excellent technical help.

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Citation Excerpt :
Furthermore, impairments of performance in the learned helplessness model of depression have been reported following repeated applications of STN-DBS. This impairment was suggested to be via a mechanism involving the decline of zif268 gene expression (also known as early growth response protein 1 (EGR-1), a transcriptional regulator acting as a tumour suppressor gene (Fagerberg et al., 2014) and involved in processes of neuronal plasticity (Knapska and Kaczmarek, 2004)) in the DRN (Creed et al., 2013), and thus reinforces the notion that STN-DBS-induced depressive-like effects involve 5-hydroxytryptamine (5-HT) mechanisms. Considering the involvement of polysynaptic pathways, STN-DBS may involve a complex combination of excitation and inhibition modulating local neural activity of BG and the cortico-basal-ganglia-thalamo-cortical network.
Parkinson's disease (PD) is a progressive degenerative disorder that leads to disabling motor symptoms and a wide variety of neuropsychiatric symptoms. Apathy is the most common psychiatric disorder in the early stages of untreated PD and can be defined as a hypodopaminergic syndrome, which also includes anxiety and depression. Apathy is also considered the core feature of the parkinsonian triad (apathy, anxiety and depression) of behavioural non-motor signs, including a motivational deficit. Moreover, apathy is recognised as a distinct chronic neuropsychiatric behavioural disorder based on specific diagnostic criteria. Given the prevalence of apathy in approximately 40% of the general Parkinson’s disease population, this appears to be a contributing factor to dementia in PD; also, apathy symptoms are factors that potentially contribute to morbidity, leading to a major impairment of health-related quality of life, thus stressing the importance of understanding the pathophysiology of this disease. Several studies have clearly established a prominent role for DA-mediated signals in PD apathy. However, synergistic interaction between dopaminergic impairment resulting from the neurodegenerative process and deep brain stimulation of the subthalamic nucleus may cause or exacerbate apathy. Furthermore, serotoninergic mechanism signalling is also likely to be of importance in this pathophysiology.

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: This work was supported in part by operating grants from the Canadian Institutes for Health Research (CIHR) and the Ontario Mental Health Foundation (OMHF). MC was the recipient of a CIHR Doctoral Research award.

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Deep Brain Stimulation (DBS)Original ArticleEffects of Repeated Deep Brain Stimulation on Depressive- and Anxiety-Like Behavior in Rats: Comparing Entopeduncular and Subthalamic Nuclei

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Learned helplessness

Discussion

Acknowledgments

Parkinsonism Relat Disord

Lancet Neurol

Parkinsonism Relat Disord

Eur Neuropsychopharmacol

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Pharmacol Biochem Behav

J Neurosci Methods

Neuroimage

Neuron

Neurophysiol Clin

Prog Neurobiol

Neuroscience

Neuropharmacology

J Chem Neuroanat

Behav Brain Res

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Brain Res Mol Brain Res

Biol Psychiatry

Trends Neurosci

Rapid response of parkinsonian tremor to stn-dbs changes: direct modulation of oscillatory basal ganglia activity?

Mov Disord

Chronic deep brain stimulation in patients with tardive dystonia without a history of major psychosis

Mov Disord

Deep brain stimulation for hyperkinetics disorders: dystonia, tardive dyskinesia, and tics

Curr Opin Neurol

Long-term electrical inhibition of deep brain targets in movement disorders

Mov Disord

Suicide after successful deep brain stimulation for movement disorders

Neurology

Neuropsychiatric symptoms three years after subthalamic dbs in pd patients: a case-control study

J Neurol

Cognition and mood in parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the compare trial

Ann Neurol

Do stable patients with a premorbid depression history have a worse outcome after deep brain stimulation for parkinson disease?

Neurosurgery

Deep Brain Stimulation (DBS)
Original Article
Effects of Repeated Deep Brain Stimulation on Depressive- and Anxiety-Like Behavior in Rats: Comparing Entopeduncular and Subthalamic Nuclei