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Spinal cord injuries (SCI) are debilitating injuries affecting a large portion of Canadian society. Motor deficits, a hallmark feature of spinal lesions, can be improved in less severe cases through neuroplasticity in the central nervous system. However, commonly used psychoactive drugs, such as alcohol and cannabis, have been shown to impair cortical neuroplasticity, which may impair recovery in individuals with SCIs. The objective of this proposal is to assess the acute effects of both alcohol and THC usage on neuroplasticity in SCI patients as well as their chronic effects on the time-course of SCI motor recovery. It is expected that both drugs will reduce the motor evoked potential amplitude increase following induction of neuroplasticity, and that chronic use will delay the time-course of motor recovery. This would imply that cannabis and alcohol impair cortical neuroplasticity, which results in a reduced ability to rehabilitate the nervous system.
Literature Overview
Spinal cord injuries (SCI) affect approximately 86,000 Canadians and up to 755 million individuals worldwide 1. A majority of these injuries result from car accidents, falls, and sports injuries which lead to mechanical contusion or compression spinal cord lesions 2. Consequently, they have the potential to be extremely debilitating, with symptoms ranging from numbness and motor difficulties to total sensory loss and paralysis 3. A large proportion of patients have incomplete SCIs, allowing for symptom improvement 8.
Whereas the peripheral nervous system (PNS) exhibits a relatively robust neuroplasticity-mediated regrowth in response to damage, central nervous system (CNS) neurons are unable to regenerate axons, thus restricting functional recovery following SCI 2,4. However, neuroplastic changes, observed through functional reorganization of brain regions as well as synaptic and dendritic modifications of neuronal populations, are prevalent in the CNS 5,6. In fact, innate neuroplastic processes begin to shape motor function and reorganize cortical areas immediately following injury. For instance, a rat model of a partial cervical lesion displayed increased cortical forelimb representation and decreased hindlimb representation 8. In humans, transcranial magnetic stimulation (TMS) and functional imaging have demonstrated remapping of limb representations in the motor cortex following SCI, in addition to corticospinal tract restructuring 9,10,11,12. This suggests that intrinsic structural plasticity within the CNS may provide a mechanism through which limited recovery in individuals with SCIs can occur.
A previous study found that, in a cohort of incomplete SCI patients displaying tetraplegia, 40% were able to walk upon hospital discharge 7. This recovery is partially attributable to rehabilitation-induced motor cortex remodeling. Rehabilitation and functional recovery in both SCI patients and animal models have been associated with plasticity of cortical and spinal circuitry (e.g. M1 reorganization, spinal tract sprouting) 13,14,15. The ability to improve motor recovery following SCI by inducing motor plasticity (using TMS, for example) further supports the hypothesis that neuronal plasticity is a vital mechanism through which SCI recovery occurs 16,17.
However, several widely available psychoactive substances, such as alcohol and cannabis, may impair recovery in clinical SCI populations. Alcohol and cannabis are common recreational (and medicinal, in the case of cannabis) drugs in Canada, with almost 80% of Canadians consuming alcohol each year and 42.5% of Canadians currently or previously using cannabis 18,19. Acute alcohol use impairs neuroplasticity in the human motor cortex and dorsolateral prefrontal cortex, while exogenous cannabinoids (e.g. THC and cannabidiol, the major psychoactive components of cannabis) disrupt long-term depression (LTD) and long-term potentiation (LTP) in the CNS of animals as well as humans 20,21,22,23,24. This is especially pressing given the high prevalence of alcohol abuse and potential future of cannabis as a chronic pain treatment in these patients 25,26. Thus, alcohol and cannabis use during rehabilitation could possibly impair neuroplasticity-mediated functional recovery following SCI. It is currently unclear whether alcohol or cannabis use affects focal induction of plasticity in SCI patients and whether this impacts motor recovery in these individuals.
Objective
The aim of this proposal is to first assess the acute effects of both alcohol and THC usage on SCI patient neuroplasticity, and second, assess the chronic effects of these drugs on the time-course of SCI motor recovery as well as limb representation in the motor cortex.
Methods
Experiment 1: Incomplete cervical SCI patients and healthy age/sex/education-matched controls will be administered either low-dose ethanol (0.3 g/kg of 96% ethanol 5 mM blood alcohol) in orange juice and a placebo nasal spray, a placebo drink (orange juice with bitter syrup to imitate ethanol content) and a Sativex® nasal spray (25 mg/mL each of THC and cannabidiol), or both placebos (6 groups total) (adapted from Lucke et al. 21 and Koch et al. 24). A paired associative stimulation (PAS) protocol of the motor cortex (as described by Bunday & Perez 16; i.e. stimulating nerves in the least-impaired wrist while simultaneously stimulating the motor cortex via TMS) will be performed 30 minutes after drug consumption. Motor evoked potentials (MEPs) will be measured immediately prior to drug administration (baseline 1), prior to PAS (baseline 2), and both 2 minutes and 30 minutes following PAS. The strength of TMS will be adjusted at baseline 2 to account for confounding effects of alcohol or cannabinoids on MEP amplitude.
Experiment 2: Incomplete SCI patients with quadriparesis and healthy age/sex/education-matched controls will be followed shortly post-injury, who will be administered either low-dose ethanol in orange juice and a placebo nasal spray, a placebo drink (orange juice with bitter syrup) and a Sativex® nasal spray, or both placebos (6 groups total) once daily over the course of 3 months. Improvement in motor impairment was assessed with the American Spinal Injury Association (ASIA) Standard Neurological Classification of SCI 27 every two weeks. Additionally, every two weeks, participants will be placed in an fMRI and asked to complete 15-second blocks of a least-impaired wrist extension task (adapted from 14), with a focus on the volume of blood oxygen-level dependent (BOLD) response in the primary and premotor cortices (measuring SCI BOLD response volume relative to the controls).
Expected Results
Experiment 1: Based on previous literature illustrating that both alcohol and exogenous cannabinoids have been shown to impair neuroplasticity, it is expected that the magnitude of MEP amplitude increase following the PAS protocol will be reduced or abolished compared to the placebo group. This effect may be seen in both the SCI and non-SCI (healthy) groups. Because cannabinoids seem to impair LTD as well as LTP, it may be that the effect of alcohol on PAS-induced MEP increases will be greater than that of cannabis (reduce MEPs more than cannabis). Conversely, cannabinoids alter the expression of NMDA receptor subunits, which are critically involved in modulating neuroplasticity 24, and thus THC may have a larger effect than alcohol (which mainly inhibits GABA receptors) 22.
Experiment 2: Since both acute cannabinoid and alcohol exposure have been shown to impair neuroplasticity, a process which is critical in the functional recovery of patients with SCI, chronic administration of these drugs will be expected to delay the time-course of motor recovery as assessed by the ASIA scale. However, due to tolerance of the physiological effects of both cannabis and alcohol which develops over prolonged use 28,29, it is likely that the effect of these drugs will attenuate over time. Additionally, it is expected that increased movement-associated cortical volume (as measured via fMRI) will be delayed in drug-administered SCI participants compared to the placebo SCI group. It is not anticipated that one will observe any changes in the motor score or motor cortex BOLD volume in any of the control groups.
Implications and Conclusions
Experiment 1: If the hypotheses are confirmed, it further verifies previous findings that the CNS is capable of neuroplasticity (based on comparisons between the placebo SCI and control groups with MEP changes seen in the drug groups). One can also conclude that acute administration of either alcohol or exogenous cannabinoids impairs short-term neuroplasticity in the human motor cortex. While alcohol has previously been shown to reduce neuroplasticity in a PAS paradigm 21, this experiment demonstrates the result in a clinical population and would be a novel finding regarding the negative relationship between cannabinoids and human motor cortex plasticity. A common side-effect of alcohol or cannabis exposure is the impairment of spatial and working memory (processes which require neuroplasticity) 30,31,32. Thus, the findings presented also support a plausible mechanism through which these drugs may inhibit memory formation.
Experiment 2: The expected results of the second experiment establish that alcohol or cannabinoid use impairs motor recovery following SCI. However, it is yet to be determined whether these effects are clinically relevant in the long-term (i.e. 6 months to a year) and if they stop or simply slow down the recovery process. From the results illustrating a decrease in representational volume growth in the motor cortex, we can gather that not only do these drugs inhibit neuroplasticity acutely, but that chronic administration can sustain this dysfunctional plasticity as well. The results also provide a causal, rather than a correlative, link between neuroplasticity and recovery following SCI.
Therefore, these two experiments demonstrate that alcohol and cannabis reduce neuroplasticity, decreasing the ability of the CNS to rehabilitate following SCI. Consequently, researchers and clinicians will have to re-evaluate the possible use of cannabinoids as a form of analgesic relief for patients suffering from SCI-induced chronic pain (or pain due to any nervous system condition for that matter, e.g. stroke), as it may slow the recovery rate. Alcohol abuse is also prevalent in this clinical population (possibly as a form of self-medication), and therefore substance use disorder in these patients should be prioritized to improve motor recovery following SCI (along with other health/emotional issues stemming from alcohol abuse).
References
- Noonan, V. K., Fingas, M., Farry, A., Baxter, D., Singh, A., Fehlings, M. G., & Dvorak, M. F. (2012). Incidence and prevalence of spinal cord injury in Canada: a national perspective. Neuroepidemiology, 38(4), 219-226.
- Ding, Y., Kastin, A. J., & Pan, W. (2005). Neural plasticity after spinal cord injury. Current pharmaceutical design, 11(11), 1441-1450.
- Waters, R. L., Adkins, R. H., & Yakura, J. S. (1991). Definition of complete spinal cord injury. Paraplegia, 29(9), 573-581.
- Geuna, S., Fornaro, M., Raimondo, S., & Giacobini-Robecchi, M. G. (2010). Plasticity and regeneration in the peripheral nervous system. Italian Journal of Anatomy and Embryology, 115(1/2), 91-94.
- Heuninckx, S., Wenderoth, N., & Swinnen, S. P. (2008). Systems neuroplasticity in the aging brain: recruiting additional neural resources for successful motor performance in elderly persons. Journal of neuroscience, 28(1), 91-99.
- Hess, G., & Donoghue, J. P. (1994). Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. Journal of neurophysiology, 71(6), 2543-2547.
- Burns, S. P., Golding, D. G., Rolle Jr, W. A., Graziani, V., & Ditunno Jr, J. F. (1997). Recovery of ambulation in motor-incomplete tetraplegia. Archives of physical medicine and rehabilitation, 78(11), 1169-1172.
- Hollis, E. R., Ishiko, N., Yu, T., Lu, C. C., Haimovich, A., Tolentino, K. & Jo, E. (2016). Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nature Neuroscience, 19(5), 697-705.
- Moore, C. I., Stern, C. E., Dunbar, C., Kostyk, S. K., Gehi, A., & Corkin, S. (2000). Referred phantom sensations and cortical reorganization after spinal cord injury in humans. Proceedings of the National Academy of Sciences, 97(26), 14703-14708.
- Streletz, L. J., Belevich, J. K., Jones, S. M., Bhushan, A., Shah, S. H., & Herbison, G. J. (1995). Transcranial magnetic stimulation: cortical motor maps in acute spinal cord injury. Brain topography, 7(3), 245-250.
11. Perani, D., Brunelli, G. A., Tettamanti, M., Scifo, P., Tecchio, F., Rossini, P. M., & Fazio, F. (2001). Remodelling of sensorimotor maps in paraplegia: a functional magnetic resonance imaging study after a surgical nerve transfer. Neuroscience letters, 303(1), 62-66.
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