Study finds new way to understand why debilitating conditions occur in cancer patients



Severe and persistent disability often compromises the vital benefits of cancer treatment. Pain and fatigue -; as well as sensory, motor and cognitive disorders -; are the main among the constellation of side effects that occur with platinum-based agents widely used in chemotherapy treatments around the world.

A new study by Georgia Tech researchers in the lab of Timothy C. Cope has found a new way to understand why these debilitating conditions occur in cancer patients and why scientists should focus on all the possible neural processes that cause them. sensory or motor problems to a patient’s brain -; including the central nervous system -; and not just the “peripheral degeneration of sensory neurons” that occurs far from the center of the body.

The new findings “Mechanisms of Neural Circuitry of Sensorimotor Disability in Cancer Treatment” are published in the Proceedings of the National Academy of Sciences (PNAS) and could impact the development of effective treatments that are not yet available to restore a patient’s normal abilities to receive and process sensory information in post-cancer treatment, in particular.

Stephen N. (Nick) Housley, postdoctoral researcher at the School of Biological Sciences, Integrated Cancer Research Center, and Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech, is the lead author of the study. Co-authors include Paul Nardelli, researcher and Travis Rotterman, postdoctoral fellow (both from the School of Biological Sciences), as well as Timothy Cope, who is a professor with joint appointments at the School of Biological Sciences at Georgia Tech and the Coulter Biomedical Engineering Department at Emory University and Georgia Tech.

Neurological consequences

Chemotherapy undoubtedly negatively influences the peripheral nervous system, which is often considered the main culprit of neurological disorders during cancer treatment. “

Stephen N. (Nick) Housley, lead author of the study

However, he says, for the nervous system to function normally, the peripheral nervous system and the central nervous system must cooperate.

“It happens through synaptic communication between neurons. Through an elegant series of studies, we show that these communication hubs in the central nervous system are also vulnerable to the adverse effects of cancer treatment,” Housley shares , adding that the results force “recognition of the many places in the nervous system that we must treat if we are ever to repair the neurological consequences of cancer treatment – because correcting just any one may not be enough to improve human function and quality of life. “

“These disabilities remain clinically unmitigated and empirically unexplained as the research focuses on the peripheral degeneration of sensory neurons,” the research team in the study explains, “while minimizing the possible involvement of neural processes in the nervous system. The current results demonstrate functional defects in fundamental information processing properties localized in the central nervous system, “concluding that” long-lasting sensorimotor disabilities and possibly other disabilities induced by cancer treatment result from independent, worsened neural defects in the peripheral and central nervous systems “.

Sensorimotor and “cOIN” disability

The research team notes that cancer survivors “rank sensorimotor disability among the most distressing long-term consequences of chemotherapy. Impaired walking, balance, and skillful movement are generally attributed to damage. chemotoxic agents of peripheral sensory neurons without taking into account the deterministic role played by neural circuits which translate sensory information into motion “, adding that this oversight” prevents sufficient mechanistic understanding and contributes to the lack of effective treatment to reverse the disability induced by chemotherapy ”.

According to Cope, the team resolved this omission “by using a combination of electrophysiology, behavior and modeling to study the function of a spinal sensorimotor circuit in vivo” in a rodent model of “induced chronic neuropathy. by oxaliplatin (chemotherapy): cOIN. “

Key sequential events have been investigated in the encoding of ‘propriosensory’ information (think kinaesthesia: the body’s ability to sense its location, movements, and actions) and its translation into circuits in synaptic potentials produced in the body. motor neurons.

In “cOIN” rats, the team noted that several classes of propriosensory neurons expressed defective discharge that reduced the precise sensory representation of muscle mechanical responses to stretching, adding that the accuracy “deteriorated further in translation. propriosensory signals into synaptic potentials due to mechanical defects residing inside the spinal cord.

Joint expression, independent defects

“These sequential, peripheral, and central defects combined to drive the sensorimotor circuit into a functional collapse which resulted in the prediction of significant errors in propriosensory guided movement behaviors demonstrated here in our rat model and reported for sufferers. of COIN, “Cope and Housley report. “We conclude that the sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.”

“These findings have a broad impact on the scientific field and on the clinical management of the neurological consequences of cancer treatment,” Housley said. “As a clinician and scientist, I can imagine the urgent need to jointly develop quantitative clinical tests capable of identifying parts of a patient’s nervous system that are affected by their cancer treatment.”

Housley also says that having the ability to monitor neural function at various sites during treatment “provides a biomarker on which we can optimize treatment – for example maximizing antineoplastic effects while minimizing adverse effects,” adding that, as we move on to next-generation cancer treatments, “clinical tests that can objectively monitor specific aspects of the nervous system will be exceptionally important in testing for the presence of an off-target effect.”

Source:

Journal reference:

Housley, SN, et al. (2021) Neural Circuit Mechanisms of Sensorimotor Disability in Cancer Treatment. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2100428118.


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