On the occasion of the National Day of Persons with Spinal Cord Injury, we interviewed Professor Giuliano Taccola, Professor of Pharmacology at SISSA in Trieste. In his “artisan laboratory of ideas,” he investigates the earliest mechanisms of spinal cord injury. From in vitro research to preclinical applications and developments in neuromodulation, a pathway emerges that opens new therapeutic perspectives while also highlighting the fundamental importance of basic research
He calls it an “artisan laboratory of ideas,” yet it is here, within this facility of the International School for Advanced Studies (SISSA) in Trieste, hosted at Gervasutta Hospital in Udine, that Professor Giuliano Taccola, together with PhD students in neurobiology, conducts basic research that is helping the scientific community better understand what happens during a spinal cord injury. His goal is to bring these ideas to a preclinical validation stage, and for this reason he collaborates with laboratories in the United States, where he can access equipment not available in Italy. Just a few weeks ago, one of his studies attracted the attention of both Italian and international media.
What was the focus of this research?
We investigated spinal shock, a “neglected” topic in the field of spinal cord injuries that has not received adequate attention from the scientific community, as evidenced by the fact that the last authoritative review dates back to 2004. Despite growing interest in secondary damage—which amplifies and worsens the initial traumatic injury—our understanding of the process remains limited. What we do know is that secondary damage is sustained by a cascade of events and mediators, but the first activation step occurs due to depolarization.
What does this involve?
It is a change in the membrane potential of spinal cord cells that occurs immediately after the physical impact. It is more an immediate than an acute effect, taking place at the very moment the spinal injury occurs, as the central nervous system is subjected to strong pressures and dynamic forces. Beyond this, very little was known about what happens in the first milliseconds following a spinal cord injury, partly due to experimental limitations.
What limitations?
First of all, the need to use anesthetized animal models in preclinical studies, which reduces the excitability of spinal cells and makes it difficult to observe these processes in real time. Moreover, for ethical reasons, experiments cannot be conducted without anesthesia. This is one of those cases in which in vitro preparations—biological preparations—are particularly useful. In this way, basic research techniques can fill an experimental gap, allowing exploration of aspects that would otherwise remain inaccessible.
So, what was the first step?
We first developed a preparation of the isolated central nervous system from rodents. Thanks to previous work and accumulated experience, we were able to maintain the system in good functional condition within a recording chamber for several hours after explantation. The second step was to develop, with the help of a mechatronics expert, a prototype micro-impactor capable of generating the pressures typical of spinal trauma, with controlled parameters such as velocity, acceleration, and tissue displacement. By combining these two resources, we were able to record what happens to spinal motor neurons at the exact moment the injury occurs.
What did you discover?
We confirmed that the very first compression generates a depolarizing response, a phenomenon already known in the literature but largely underestimated. What was previously referred to as the “injury potential” appears within a few hundred milliseconds after spinal cord compression. This potential propagates in all directions—rostrally and caudally, ventrally at the site of injury, and dorsolaterally. It is a true depolarizing wave, representing the initial response, followed by the release of mediators and pathological processes that amplify and extend the original damage, leading to secondary injury.
Were you able to determine whether this depolarizing wave can be contained or mitigated?
We attempted to do so in vitro using various pharmacological compounds, some previously explored in the literature for similar purposes. Among these, we observed that a selective blocker of a class of mechanoreceptors can reduce the injury potential. However, several questions remain open, also shared in clinical practice. For example, spinal shock—the transient phase occurring in the first hours to days after injury—is characterized by the absence of spinal reflexes, and reduced muscle tone. It is a highly complex clinical condition.
Are there other unanswered questions?
Certainly. In our experiments, stronger impacts to the cord produced depolarizing waves of greater amplitude and duration. One key question is whether the severity or duration of spinal shock has prognostic significance. If we were able to limit the initial depolarizing event—which leads to spinal shock and neuronal death through the mechanisms discussed—we might improve functional recovery. Another aspect concerns our experimental approach: in our models, the event lasts several tens of minutes, whereas biological preparations have inherently shorter time frames than clinical conditions. Finally, there are still uncertainties regarding mechanoreceptors themselves—mechanical sensors that open when the membrane is deformed, allowing ionic flux and causing depolarization. Since these structures are present from birth and located around the spinal cord, they may represent the earliest mediators of damage. The activation of mechanoreceptors may also help explain why significant neurological deficits can appear even when the spinal cord is not visibly damaged, and the dura remains intact. In fact, cord displacements at certain speeds and intensities, even without any structural injury, can trigger strong depolarizing responses that then start and spread secondary damage processes. The key question is how long these mechanisms remain active and how we might contain them before they trigger downstream effects.
Another of your well-known studies concerns a “noisy” stimulation protocol. What is it?
It is defined as “noisy” due to its intrinsic variability and differs from traditional stimulation, which follows stereotyped protocols where each pulse is identical, with variations only in frequency or amplitude. The idea was to more closely replicate the signals that peripheral receptors send to the nervous system during locomotion—signals inherently variable. The goal was to “trick” neural networks by providing stimuli similar to natural input, thereby reinforcing and modulating the locomotor pattern, which largely originates in the spinal cord.
Has it proven effective?
Yes. Its effectiveness, being closer to the natural locomotor pattern, has been demonstrated both in vitro and in preclinical animal models with spinal cord injury. This work led to a patent and the development of an electrostimulator through a spin-off based in California, although I have no commercial interest in it. Research in this direction, however, is ongoing.
What remains to be done?
I am trying to understand what level of variability is actually needed. Introducing highly variable signals, such as EMG traces recorded during locomotion, is extremely complex with current technology. It may not be necessary to use such a highly “noisy” signal. The effectiveness we observed likely derives from the wide range of variability in these signals—their complex frequency spectrum and amplitude variations. Within this variability, there may be a sufficient level to improve stimulation outcomes.
The goal is to increase spinal network excitability so that coordinated activity can emerge even after injury, correct?
Exactly. This opens an important area of investigation: the role of descending pathways and cortical input. Increasing spinal network excitability still requires descending input to recruit the network and enable voluntary movement. However, this approach is not limited to incomplete injuries. While incomplete lesions may benefit the most, discomplete lesions—representing the majority, may also benefit.
What are discomplete lesions?
A discomplete lesion is a clinically complete spinal cord injury in which overt motor function is absent, but neurophysiological evidence demonstrates residual, subclinical supraspinal drive to sensorimotor networks below the lesion. These descending influences remain undetectable through standard clinical examination but indicate partial anatomical or functional continuity across the lesion. Approximately 60–80% of individuals who appear to have a functionally complete lesion actually retain some degree of spinal integrity. These persons may regain voluntary motor control through neuromodulation, and some maintain these gains even after stimulation is discontinued, suggesting lasting changes in neural circuits. To date, the main limitation is the absence of standardized tools to identify discomplete lesions; consequently, assessment remains largely dependent on the evaluator’s clinical analytical skills.
What are the timelines for clinical translation?
It is difficult to answer precisely. In the past, there was a tendency to estimate timelines of five to ten years, but doing so requires solid evidence. From my experience, it can take about ten years for an in vitro concept to become a device such as a stimulator. However, this does not mean it is superior to existing technologies—it must be rigorously tested in specialized centers.
What are the current limitations?
There are no completed clinical trials on neuromodulation yet, although pilot studies show promising results in selected volunteers. Subject selection is crucial, otherwise it is not possible to conduct large-scale trials.
Another limitation is the lack of a clear understanding of the underlying mechanisms. While plausible hypotheses exist, there is no consensus. Early success has somewhat diverted attention from fundamental investigation, but this enthusiasm should instead drive deeper mechanistic research.
What is the relationship between basic, preclinical, and clinical research?
Basic research progresses through increasing levels of complexity toward clinical application. All phases are equally important but carried out by professionals with different expertise—clinicians and basic scientists. In spinal cord injury research, strong awareness among persons with spinal cord injury and families has driven urgency for solutions, which is understandable.
Has this overshadowed basic research?
Partly. The system has shifted toward clinical research, also affecting funding priorities. The focus is now on solutions for chronic and severe injuries using clinically relevant models.
What is the risk?
The risk is neglecting topics such as spinal shock, secondary damage, developmental injuries, and spontaneous recovery, among others which, although rare, may reveal mechanistic insights that can be extrapolated and applied to more prevalent chronic spinal cord injuries.
Is it difficult to pursue this research?
Yes. While I benefit from working in a flexible environment in Italy, this limits access to major funding and increases pressure to engage in clinical work beyond one’s expertise. Clinical research should remain in the hands of experienced clinicians with appropriate medical training.
