Squintani G, Donato F, Turri M, Deotto L, Teatini F, Moretto G, Erro R. Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray. J Neurol Sci. 2016;370:263-268. doi: 10.1016/j.jns.2016.09.054.
BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS.
METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls.
RESULTS: A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth.
DISCUSSION:Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.
During the MS trials it was impossible for them to find an effect on the Ashworth scale of spasticity and this is one of the reasons why sativex is not available in the USA, because the FDA want to see an effect on the Ashworth, but here we are seeing an effect with just 38 people 19 on drug and 19 not on drug.
Here they look at electrophysiology (movement of nerve impulses) in the brain and the spinal cord.
Cortical (cortex outside of the brain) output depends on the balance between different inhibitory and facilitatory circuits. Transcranial magnetic stimulation (TMS) is a widely used technique to examine motor cortical physiology in humans.
Depending on the stimulus parameters, TMS can be used to test different inhibitory and facilitatory circuits in the motor cortex (M1).
With a subthreshold (below threshold) conditioning stimulus (CS) followed by a suprathreshold (above threshold) test stimulus (S1) at interstimulus interval (ISI) of 1–6 ms, the motor (movement) evoked potential (nerve signal) (MEP) generated by the S1 is inhibited and this is known as short interval intracortical inhibition (SICI).
On the other hand, the MEP generated by S1 is facilitated at ISI of 8–30 ms and this is termed intracortical facilitation (ICF).
If the S1 is followed by a second pulse (S2) at threshold intensity, another type of facilitation, known as short interval intracortical facilitation (SICF) or indirect (I) wave facilitation, can be elicited
Following electrical stimulation of M1 two waves are noted. The first wave was the direct (D) wave due to direct activation of the axon of corticospinal neurons and the subsequent I waves were due to trans-synaptic activation of these output neurons. I waves appeared at regular clocklike intervals of 1.5 ms. Since the three peaks of SICF also occur at about 1.5 ms intervals, it has been suggested that SICF is due to interaction of I waves generated by the two stimuli (S1 and S2)
SICF originates in the cortical level because there was no facilitation if electrical stimulation was used to elicit S2 and it is associated with increased amplitudes (height) of the I waves generated by the S1. SICF-1 is likely to be due to I2 waves from S1 interacting with I1 waves from S2; SICF-2 is likely to be due to I3 waves from S1 interacting with I1 waves from S2; and SICF-3 is likely to be related to I4 waves from S1 interacting with I1 waves from S2. Additionally, anterior–posterior (AP) directed current in the M1 preferentially induces I3 waves whereas the usual posterior–anterior (PA) directed currents induce I1 waves. SICF-1 elicited by S1 and S2 in the AP direction is likely to be due to I3 waves from S1 interacting with I2 waves from S2 .
LICI results in attenuation of the MEP when a suprathreshold CS is paired with a suprathreshold TS at long ISIs (50-200 ms)
Don’t worry I dont understand it either:-)
The H-reflex test is performed using an electric stimulator and an EMG
set to record the muscle response. An M-wave, an early response, occurs 3-6 ms after the onset of stimulation travels down the motor/movement nerve. There is a response that moves up the sensory nerves into the spinal cord and then travels down the motor nerve to the muscle. The H-wave occurs 28-35 ms after the stimulus, in mice because they are small the H wave arrives 7 ms (a thousandth of a second)
H-reflex is analogous to the mechanically induced spinal stretch reflex
(for example, knee jerk reflex
). “The primary difference between the H-reflex and the spinal stretch reflex is that the H-reflex bypasses the muscle spindle, and, therefore, is a valuable tool in assessing modulation of monosynaptic (single synapse) reflex activity in the spinal cord.
H-reflex amplitudes measured by EMG, increases in spasticity because the inhibitory circuits are reduced and amplifying the nerve signal as it travels through the damaged spinal cord.
Hypertonia is a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by injury to motor pathways in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle tone, and reflexes.
There was too much excitation in the spinal cord which will mean that muscles are contracted.
Cannabis inhibited this
The Dizziness is because the people in the study were “stoned/high”
So in short more evidence for cannabis controlling spasticity. But we need ways to control this without the dizziness
CoI This what we are trying to do.