The level of interest and knowledge among scientists about human physiology and anatomy is appalling.
We know that higher primates (including humans) have a special corticospinal system for dealing with tasks that need high skills. Most animal models of ALS do not have this kind of corticospinal system. Another feature of this corticospinal system in higher primates is that the connection from upper motor neurons to lower motor neurons is done directly in some cases (for example the hands), while in most animals the interconnection is done with interneurons, which take in charge automatic and repetitive movements such as walking.
Yet publications are still written that discuss at length of interneurons' role in ALS. One such publication (a review) is interesting as it starts well, by stating the obvious, that as there were hundreds of unsuccessful clinical trials on ALS drugs, we must have missed something important.
Alas, the authors resort to an old hypothesis, one of the first about ALS etiology, which is the excitotoxicity hypothesis.
This old hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. As the authors recall many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not one was effective.
On the contrary, the authors never mentioned that the only clinical trials that were successful were about mutations in some rare cases (SOD1). A few other clinical trials did better than the average but they were far from providing a cure, they addressed cellular stress. It seems obvious now that for the majority of ALS patients, the cellular stress response is defective.
The authors correctly state that the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays the scientists use to study it.
The authors ask for more research:
Network activity: Assess the activity level of the affected networks, not just excitability.
Individual neurons: Investigate how ALS pathology affects the function of individual neurons, including lower motor neurons and interneurons.
Interneurons: Understand their role and how their activity changes in ALS.
Point 1. looks like we are still in the 1940' with the Nernst and Goldman equations.
Point 2. is about the function of individual neurons. That's weird, people are not made of individual neurons, neuron types are numerous and are not even the sole cell population, and there are many more non-neuronal cells than neurons in the CNS. All these cells type collaborate and compete in what we call "tissue".
Point 3. is weird, ALS strikes a special kind of muscle (skeletal muscles) and nerves (corticospinal). In most cases, the lower motor neurons that connect to these muscles are not themself connected to an interneuron.
What to conclude from this review? I assume the authors are in good faith, but by perpetrating obsolete ideas they slow any progress toward a cure for ALS