Name: In vivo Positron Emission Tomography to Reveal Activity Patterns Induced by Deep Brain Stimulation in Rats (Video) | JoVE Journal
Uploaded: 2022-03-23T12:45:00.000+00:00
Duration: 9 min 36 s
Description: Learn in vivo FDG-PET imaging to evaluate metabolic neuromodulation from deep brain stimulation in rats. This protocol reveals brain activity patterns and helps refine stimulation parameters for neurological research.

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We thank Prof. Christine Winter, Julia Klein, Alexandra de Francisco and Yolanda Sierra for their invaluable support in the optimization of the methodology here described.&#160;MLS was supported by the&#160;Ministerio de Ciencia e Innovaci&#243;n, Instituto de Salud Carlos III (project number PI17/01766&#160;and grant number BA21/0030)&#160;co- financed by European Regional Development Fund (ERDF), &#34;A way to make Europe&#34;; CIBERSAM (project number CB07/09/0031); Delegaci&#243;n del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); Fundaci&#243;n Mapfre; and Fundaci&#243;n Alicia Koplowitz.&#160;MCV was supported by Fundaci&#243;n Tatiana P&#233;rez de Guzm&#225;n el Bueno as scholarship holder of this institution, and EU Joint Programme - Neurodegenerative Disease Research (JPND). DRM was supported by Consejer&#237;a de Educaci&#243;n e Investigaci&#243;n, Comunidad de Madrid, co-funded by European Social Fund &#34;Investing in your future&#34; (grant number PEJD-2018-PRE/BMD-7899). NLR was supported by Instituto de Investigaci&#243;n Sanitaria Gregorio Mara&#241;&#243;n, &#34;Programa Intramural de Impulso a la I+D+I 2019&#34;. MD work was supported by Ministerio de Ciencia e Innovaci&#243;n&#160;(MCIN) and Instituto de Salud Carlos III (ISCIII) (PT20/00044).&#160;The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovaci&#243;n (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

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The authors declare that there are no conflicts of interest in connection with this article.

Given the advances in the understanding of brain function and the neural networks involved in the pathophysiology of neuropsychiatric disorders, more and more research is recognizing the potential of DBS in a wide range of neurologically-based pathologies2. However, the mechanism of action of this therapy remains unclear. Several theories have attempted to explain the effects obtained in specific pathological and stimulation circumstances, but the heterogeneity of the proposed studies makes it ver...

The term neurostimulation encompasses a number of different techniques aimed at stimulating the nervous system with a therapeutic objective1. Among them, deep brain stimulation (DBS) stands out as one of the most widespread neurostimulation strategies in clinical practice. DBS consists of the stimulation of deep brain nuclei with electrical pulses delivered by a neurostimulator, implanted directly into the patient&#39;s body, through electrodes placed into the brain target to be modulated by stereotactic surgery. The number of articles evaluating the feasibility of DBS application in different neurological and psychiatric disorders is continuously growing2, although only some of them have been approved by the Food and Drug Association&#160;(FDA) (i.e., essential tremor, Parkinson&#39;s disease, dystonia, obsessive-compulsive disorder, and medically refractory epilepsy)3. Furthermore, a large number of brain targets and stimulation protocols are under research for DBS treatment of many more pathologies than officially approved, but none of them are considered definitive. These inconsistencies in DBS research and clinical procedures may in part be due to a lack of full understanding of its mechanism of action4. Therefore, huge efforts are being made to decipher the in vivo effects of DBS on brain dynamics, as every advance, however small, will help refine DBS protocols for greater therapeutic success.
In this context, molecular imaging techniques open a direct window to observe in vivo neuromodulatory effects of DBS. These approaches provide the opportunity not only to determine the impact of DBS while it is being applied but also to unravel the nature of its consequences, prevent undesired side effects and clinical improvement, and even adapt stimulation parameters to the patient&#39;s needs5. Among these methods, positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) is of particular interest because it provides specific and real-time information on the activation state of different brain regions6. Specifically, FDG-PET imaging provides an indirect evaluation of neural activation based on the physiological principle of metabolic coupling between neurons and glial cells6. In this sense, several clinical studies have reported DBS-modulated brain activity patterns using FDG-PET (see3 for review). Nevertheless, clinical studies easily incur several drawbacks when focusing on patients, such as heterogeneity or recruitment difficulties, which strongly limit their research potential6. This context leads researchers to use animal models of human conditions to evaluate biomedical approaches before their clinical translation or, if already applied in clinical practice, to explain the physiological origin of therapeutic benefits or side effects. Thus, despite the large distances between human pathology and the modeled condition in laboratory animals, these preclinical approaches are essential for a safe and effective transition into clinical practice.
This manuscript describes an experimental DBS protocol for murine models, combined with a longitudinal FDG-PET study, in order to assess the acute consequences of DBS on brain metabolism. The outcomes obtained with this protocol may help to unravel the intricate modulatory patterns induced on brain activity by DBS. Therefore, a suitable experimental strategy to examine in vivo the consequences of stimulation is provided, allowing clinicians to anticipate therapeutic effects under specific circumstances and then adapt stimulation parameters to the patient&#39;s needs.

<table><tbody><tr><td>7-Tesla Biospec 70/20 scanner</td><td>Bruker, Germany</td><td>SN0021</td><td>MRI scanner for small animal imaging</td></tr><tr><td>Betadine</td><td>Meda Pharma S.L., Spain</td><td>644625.6</td><td>Iodine solution (iodopovidone)</td></tr><tr><td>Beurer IL 11</td><td>Beurer</td><td>SN87318</td><td>Infra-red light</td></tr><tr><td>Bipolar cable 50 cm w/50 cm mesh covering up to 100 cm</td><td>Plastics One, USA</td><td>305-305 (CM)</td><td></td></tr><tr><td>Bipolar cable TT2&amp;nbsp; 50 cm up to 100 cm</td><td>Plastics One, USA</td><td>305-340/2</td><td>Bipolar cable TT2&amp;nbsp; 50 cm up to 100 cm</td></tr><tr><td>Buprex</td><td>Schering-Plough, S.A</td><td>961425</td><td>Buprenorphine (analgesic)</td></tr><tr><td>Ceftriaxona Reig Jofr&amp;eacute; 1g IM</td><td>Laboratorio Reig Jofr&amp;eacute; S.A., Spain</td><td>624239.1</td><td>Ceftriaxone (antibiotic)</td></tr><tr><td>Commutator</td><td>Plastics One, USA</td><td>SL2+2C</td><td>4 Channel Commutator for DBS</td></tr><tr><td>Concentric bipolar platinum-iridium electrodes</td><td>Plastics One, USA</td><td>MS303/8-AIU/Spc</td><td>Electrodes for DBS</td></tr><tr><td>Driller</td><td>Bosh</td><td>T58704</td><td>Driller</td></tr><tr><td>FDG</td><td>Curium Pharma Spain S.A., Spain</td><td>-----</td><td>2-[18F]fluoro-2-deoxy-D-glucose (PET radiotracer)</td></tr><tr><td>Heating pad</td><td>DAGA, Spain</td><td>23115</td><td>Heating pad</td></tr><tr><td>Ketolar</td><td>Pfizer S.L., Spain</td><td>776211.9</td><td>Ketamine (anesthetic drug)</td></tr><tr><td>Lipolasic 2 mg/g</td><td>Bausch &amp;amp; Lomb S.A, Spain</td><td>65277</td><td>Ophthalmic lubricating gel</td></tr><tr><td>MatLab R2021a</td><td>The MathWorks, Inc</td><td></td><td>Support software for SPM12</td></tr><tr><td>MRIcro</td><td>McCausland Center for Brain Imaging,&amp;nbsp; University of South Carolina, USA</td><td>v2.1.58-0</td><td>Software for imaging preprocessing and analysis</td></tr><tr><td>Multimodality Workstation (MMWKS)</td><td>BiiG, Spain</td><td></td><td>Software for imaging processing and analysis</td></tr><tr><td>Omicrom VISION VET</td><td>RGB Medical Devices, Spain</td><td>731100 ReV B</td><td>Cardiorrespiratory monitor for small imaging</td></tr><tr><td>Prevex Cotton buds</td><td>Prevex, Finland</td><td>-----</td><td>Cotton buds</td></tr><tr><td>Sevorane</td><td>AbbVie Spain, S.L.U, Spain</td><td>673186.4</td><td>Sevoflurane (inhalatory anesthesia)</td></tr><tr><td>Small screws</td><td>Max Witte GmbH</td><td>1,2 x 2 DIN 84 A2</td><td>Small screws</td></tr><tr><td>Standard U-Frame Stereotaxic Instrument for Rat, 18&amp;deg; Ear Bar</td><td>Harvard Apparatus, USA</td><td>75-1801</td><td>Two-arms Stereotactic frame for rat</td></tr><tr><td>Statistical Parametric Mapping (SPM12)</td><td>The Wellcome Center for Human Neuroimaging, UCL Queen Square Institute of Neurology, UK</td><td>SPM12</td><td>Software for voxel-wise imaging analysis</td></tr><tr><td>STG1004</td><td>Multi Channel Systems GmbH, Germany</td><td>STG1004</td><td>Isolated stimulator</td></tr><tr><td>SuperArgus PET/CT scanner</td><td>Sedecal, Spain</td><td>S0026403</td><td>NanoPET/CT scanner for small animal imaging</td></tr><tr><td>Suture thread with needle, 1/&amp;ordm;</td><td>Lorca Mar&amp;iacute;n S.A., Spain</td><td>55325</td><td>Braided natural silk non-absorbable suture 1/0, with triangle needle</td></tr><tr><td>Technovit 4004 (powder and liquid)</td><td>Kulzer Technique, Germany</td><td>64708471; 64708474</td><td>Acrylic dental cement for craniotomy tap</td></tr><tr><td>Wistar rats (&lt;em&gt;Rattus norvergicus&lt;/em&gt;)</td><td>Charles River, Spain</td><td>animal facility</td><td>Animal model used</td></tr><tr><td>Xylagesic</td><td>Laboratorios Karizoo, A.A, Spain</td><td>572599-4</td><td>Xylazine (anesthetic drug)</td></tr><tr><td></td><td>Normon S.A., Spain</td><td>602910</td><td>Mepivacaine in gel for topical use</td></tr></tbody></table>

in vivo positron emission tomography to reveal activity patterns induced by deep brain stimulation in rats

In vivo Positron Emission Tomography to Reveal Activity Patterns Induced by Deep Brain Stimulation in Rats

Deep brain stimulation (DBS) is an invasive neurosurgical technique based on the application of electrical pulses to brain structures involved in the patient&#39;s pathophysiology. Despite the long history of DBS, its mechanism of action and appropriate protocols remain unclear, highlighting the need for research aiming to solve these enigmas. In this sense, evaluating the in vivo effects of DBS using functional imaging techniques represents a powerful strategy to determine the impact of stimulation on brain dynamics. Here, an experimental protocol for preclinical models (Wistar rats), combined with a longitudinal study [18F]-fluorodeoxyclucose positron emission tomography (FDG-PET), to assess the acute consequences of DBS on brain metabolism is described. First, animals underwent stereotactic surgery for bilateral implantation of electrodes into the prefrontal cortex. A post-surgical computerized tomography (CT) scan of each animal was acquired to verify electrode placement. After one week of recovery, a first static FDG-PET of each operated animal without stimulation (D1) was acquired, and two days later (D2), a second FDG-PET was acquired while animals were stimulated. For that, the electrodes were connected to an isolated stimulator after administering FDG to the animals. Thus, animals were stimulated during the FDG uptake period (45 min), recording the acute effects of DBS on brain metabolism. Given the exploratory nature of this study, FDG-PET images were analyzed by a voxel-wise approach based on a paired T-test between D1 and D2 studies. Overall, the combination of DBS and imaging studies allows describing the neuromodulation consequences on neural networks, ultimately helping to unravel the conundrums surrounding DBS.

The animals were sacrificed using CO2 at the end of the study or when the animal’s welfare was compromised. An example of a complete PET/CT study from an operated animal is shown in Figure 3. Thus, the electrode inserted into the rat brain can be clearly observed in the CT image shown in Figure 3A. This imaging modality provides good anatomical information and facilitates the registration of FDG-PET images, given that functional modalities tend to be ...

We describe a preclinical experimental method to evaluate metabolic neuromodulation induced by acute deep brain stimulation with in vivo FDG-PET. This manuscript includes all experimental steps, from stereotaxic surgery to the application of the stimulation treatment and the acquisition, processing, and analysis of PET images.

Deep brain stimulation (DBS) is an invasive neurosurgical technique based on the application of electrical pulses to brain structures involved in the ...

in-vivo-positron-emission-tomography-to-reveal-activity-patterns

Research

JoVE Journal

Neuroscience

Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain.  This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Source: Casquero-Veiga, M. et al. In vivo Positron Emission Tomography to Reveal Activity Patterns Induced by Deep Brain Stimulation in Rats. J. Vis. Exp. (2022).This video demonstrates the metabolic effects of deep brain stimulation (DBS) using FDG-PET imaging in a rat model. It outlines the steps involved in FDG administration, DBS application, and PET/CT imaging to map brain regions with increased or suppressed metabolic activity.

Assessing Metabolic Neuromodulation Induced by Acute Deep Brain Stimulation in Rats Using In Vivo FDG-PET

Source: Batra, V., et al. A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration. J. Vis. Exp. (2016).This video demonstrates a rat model of drug addiction in which the animal self-administers intravenous methamphetamine by pressing a lever, leading to compulsive drug-seeking behavior driven by dopamine release in the nucleus accumbens. To counteract this, the rat undergoes deep brain stimulation (DBS) via an implanted bipolar...

Deep Brain Stimulation as a Treatment for Drug Addiction in a Rat Model

Source: Selvakumar, T., et al., Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus. J. Vis. Exp. (2015)This video demonstrates the procedure for implanting electrodes into the rat brain to apply deep brain stimulation (DBS), which modulates neuronal activity and enhances communication with the hippocampus, supporting neuronal survival and neurogenesis.

Effects of Deep Brain Stimulation on Hippocampal Neuronal Activity in a Rat Model

This video demonstrates the detailed procedure for preparing an anesthetized rat for electrophysiological recordings of brain activity from multiple sites. The scalp is dissected to access the skull, and holes are drilled at precise locations to install and secure electrodes. Tungsten microwire electrodes are then inserted into the targeted location to record the data.

In Vivo Electrophysiological Recordings of Brain Activities from Multiple Sites in Rats

This protocol describes a standard method for simultaneous functional magnetic resonance imaging and deep brain stimulation in the rodent. The combined use of these experimental tools allows for the exploration of global downstream activity in response to electrical stimulation at virtually any brain target.

Deep Brain Stimulation with Simultaneous fMRI in Rodents

The mechanism underlying the therapeutic effects of Deep Brain Stimulation (DBS) surgery needs investigation. The methods presented in this manuscript describe an experimental approach to examine the cellular events triggered by DBS by analyzing the gene expression profile of candidate genes that can facilitate neurogenesis post DBS surgery.

Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus

A method for implanting electrodes into the subthalamic nucleus (STN) of rats is described. Better localization of the STN was achieved by using a microrecording system. Furthermore, a stimulation set-up is presented that is characterized by long-lasting connections between the head of the animal and the stimulator.

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

We applied repetitive transcranial magnetic stimulation (rTMS) to the unilateral hemisphere of rat brain, by placing a 25-mm figure-8 coil 1 cm lateral to the vertex on the biauricular line and angulating the coil by 45°. An in-house water cooling system was used for rTMS for more than 20 min.

Repetitive Transcranial Magnetic Stimulation to the Unilateral Hemisphere of Rat Brain

In this study, the methodology is presented on how to perform multi-site in vivo electrophysiological recordings from the hyperdirect pathway under urethane anesthesia.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

Learn in vivo FDG-PET imaging to evaluate metabolic neuromodulation from deep brain stimulation in rats. This protocol reveals brain activity patterns and helps refine stimulation parameters for neurological research.

In vivo Positron Emission Tomography to Reveal Activity Patterns Induced by Deep Brain Stimulation in Rats

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