Background & Aims

The periaqueductal grey (PAG) is an important mediator of defensive behavior including escape locomotion (1). Deep brain stimulation (DBS) of the PAG has been used for modulating pain in numerous studies and for many conditions (2-4) including pain after spinal cord injury (SCI) (5,6). We have previously shown that stimulation of the cuneiform nucleus (CnF) of the mesencephalic locomotor region (MLR) adjacent to the PAG induces activity-dependent Fos expression in the PAG (7) consistent with tracer studies which show strong interconnections between the two structures (8) We are currently investigating the efficacy of MLR DBS to facilitate walking following SCI using a translational large animal model of SCI (Yucatan micropig) and human directional DBS electrodes. Since chronic pain is a common occurrence after SCI (9) we also examined whether PAG neurons were activated in this animal model during stimulation of brainstem locomotor circuits to improve walking after SCI.

Methods

Directional, 8-channel DBS leads were implanted bilaterally into putative MLR sites of six female Yucatan micropigs using MRI-guided stereotactic targeting. Diffusion weighted MRIs were used to generate tractography utilizing a standardized seed region (CnF) and inclusion/exclusion criteria for the tracking algorithm in MRtrix3 (10) defined in a common template space (11). During manual treadmill experiments, activation thresholds were determined for each contact and those parameters which elicited reproducible locomotion were identified. Finite-element modeling was used to predict the neural activation for each subject and to quantitatively predict a common volume of tissue activated that explained MLR-DBS effects based on contact position/orientation and stimulation strength (12). Animals were given a midthoracic contusion SCI and followed over 12 weeks of recovery with MLR DBS testing. Animals were stimulated and processed for Fos expression to identify activated neurons (7).

Results

Our results show that sites effective for evoking locomotion activate pathways entering and/or exiting the CnF seed region with streamlines projecting towards the medullary medial reticular formation, a known relay projecting to spinal locomotor circuits. Effective stimulation sites also show activation profiles to the PAG outside of the activation zone. Increasing stimulation strength increases locomotor output and tract activation, including those projecting to the PAG. Directional control of stimulation post-operatively minimized the unintended off-target stimulation in this region (13). Stimulation of this circuit improved muscle activity, speed of locomotion, stepping frequency, interlimb coordination, weight bearing while reducing stepping variability after SCI. Fos expression within the PAG was increased during an MLR-evoked locomotor task.

Conclusions

Stimulation of the MLR improves locomotor recovery and shows promise for treating gait dysfunction after incomplete SCI. DBS of the CnF nucleus also activates the PAG at frequencies that are within the range reported previously for neuropathic pain (14-16). Further research is needed to determine whether pain modulation occurs in this animal model of injury.

Supported by DoD Grant W81XWH2110791 (SC200294).

References

1)Koutsikou, S., Apps, R., and Lumb, B. M. (2017). Top down control of spinal sensorimotor circuits essential for survival. J Physiol 595, 4151–4158. doi: 10.1113/JP273360
2)Coffey RJ. (2001). Deep brain stimulation for chronic pain: results of two multicenter trials and a structured review. Pain Medicine 2(3):183-92. doi:10.1046/j.1526-4637.2001.01029.x
3)Hamani C, Schwalb JM, Rezai AR, et al. (2006). Deep brain stimulation for chronic neuropathic pain: long-term outcome and the incidence of insertional effect. Pain 125(1-2):188-96. doi:10.1016/j.pain.2006.05.019
4)Frizon LA, Yamamoto EA, Nagel SJ, et al. (2019). Deep brain stimulation for pain in the modern era: a systematic review. Neurosurgery 86(2): 191-202. doi:10.1093/neuros/nyy552
5)Hentall ID, Luca CC, Widerstrom-Noga E, et al. (2016). The midbrain central gray best suppresses chronic pain with electrical stimulation at very low pulse rates in two human cases. Brain Res 1632:119-26. doi:10.1016/j.brainres.2015.12.021
6)Jermakowicz WJ, Hentall ID, Jagid JR, et al. (2017). Deep brain stimulation improves the symptoms and sensory signs of persistent central neuropathic pain from spinal cord injury: a case report. Front Hum Neurosci 11:177. doi:10.3389/fnhum.2017.00177
7)Opris I, Dai X, Johnson DMG, Sanchez FJ, Villamil LM, Xie S, Lee-Hauser CR, Chang SJ, Jordan LM, Noga BR. (2019). Activation of brainstem neurons during mesencephalic locomotor region-evoked locomotion in the cat. Front Syst Neurosci 13:69. doi: 10.3389/fnsys.2019.00069
8)Mantyh, P. W. (1983). Connections of midbrain periaqueductal gray in the monkey. II. Descending efferent projections. J Neurophysiol 49, 582–594. doi: 10.1152/jn.1983.49.3.582
9)Widerström-Noga E, Anderson KD, Perez S, Martinez-Arizala A, Cambridge JM. (2018). Subgroup perspectives on chronic pain and its management after spinal cord injury. J Pain 19:1480–90. https://doi.org/10.1016/j.jpain.2018.07.003
10)Tournier JD, Smith R, Raffelt D, et al. (2019). MRtrix3: A fast, flexible and open software framework for medical image processing and visualisation. Neuroimage 202:116137. doi: 10.1016/j.neuroimage.2019.116137
11)Chang SJ, Santamaria AJ, Sanchez FJ, et al. (2020). In vivo Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig. Front Neuroanat 14:599701. doi:10.3389/fnana.2020.599701
12)Zitella LM, Mohsenian K, Pahwa M, Gloeckner C, Johnson MD. (2013). Computational modeling of pedunculopontine nucleus deep brain stimulation. J Neural Engineering 10(4):045005. doi:10.1088/1741-2560/10/4/045005
13)Chang SJ, Santamaria AJ, Sanchez FJ, Villamil LM, Saraiva PP, Benavides F, Nunez-Gomez Y, Solano JP, Opris I, Guest JD, Noga BR. (2021). Deep brain stimulation of midbrain locomotor circuits in the freely moving pig. Brain Stimul 14(3):467-476. doi: 10.1016/j.brs.2021.02.017
14)Mandat V, Zdunek PR, Krolicki B, et al. (2023). Periaqueductal/periventricular gray deep brain stimulation for the treatment of neuropathic facial pain. Front Neurol 14:1239092. doi: 10.3389/fneur.2023.1239092
15)Green AL, Wang S, Owen SLF, Xie K, Bittar RG, Stein JF, Paterson DJ, Aziz TZ. (2006). Stimulating the human midbrain to reveal the link between pain and blood pressure. Pain 124(3):349-359. doi: 10.1016/j.pain.2006.05.005
16)Lubejko ST, Graham RD, Livrizzi G, Schaefer R, Banghart MR, Creed MC. (2022). The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia. Front Syst Neurosci 16:1044686. doi: 10.3389/fnsys.2022.1044686

Presenting Author

Brian R Noga

Poster Authors

Brian Noga

PhD

Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami

Lead Author

E-mail

Jeffrey Serville

MS Biomedical Engineering

Biomedical Engineering, University of Miami

Lead Author

E-mail

Francisco Sanchez

DVM

Miami Project to Cure Paralysis, University of Miami

Lead Author

E-mail

Luz Villamil

MD

Miami Project to Cure Paralysis, University of Miami

Lead Author

E-mail

Jorge Bohorquez

PhD

Biomedical Engineering, University of Miami

Lead Author

E-mail

Juan Solano

MD

Pediatrics, University of Miami

Lead Author

E-mail

Christopher Butson

PhD

University of Florida

Lead Author

E-mail

James Guest

MD

Miami Project to Cure Paralysis, University of Miami

Lead Author

E-mail

Topics

  • Treatment/Management: Interventional Therapies – Neuromodulation