Tangled messages: Tracing neural circuits to chemotherapy's
'constellation of side effects'
Neural pathways behind complex sensory and motor side effects of
chemotherapy

Date:
January 7, 2022
Source:
Georgia Institute of Technology
Summary:
Cancer patients undergoing chemotherapy can experience severe
side effects that persist long after treatments end. A new study
has found a novel pathway for understanding why these debilitating
conditions happen -- and why scientists should focus on 'all of the
possible neural processes that deliver sensory or motor problems
to a patient's brain' and not just those that occur away from the
center of the body.



FULL STORY ========================================================================== Severe and persistent disability often undermines the life-saving
benefits of cancer treatment. Pain and fatigue -- together with sensory,
motor, and cognitive disorders -- are chief among the constellation of
side effects that occur with the platinum-based agents used widely in chemotherapy treatments worldwide.


==========================================================================
A new study by Georgia Tech researchers in the lab of Timothy C. Cope
has found a novel pathway for understanding why these debilitating
conditions happen for cancer patients and why scientists should focus
on all of the possible neural processes that deliver 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 away from the center of the body.

The new findings "Neural circuit mechanisms of sensorimotor disability
in cancer treatment" are published in the Proceedings of the National
Academy of Sciences (PNAS) and could impact development of effective
treatments that are not yet available for restoring a patient's normal abilities to receive and process sensory input as part of post cancer treatment, in particular.

Stephen N. (Nick) Housley, a postdoctoral researcher in the School of Biological Sciences, the Integrated Cancer Research Center, and the
Parker H.

Petit Institute for Bioengineering and Bioscience at Georgia Tech,
is the study's lead author. Co-authors include Paul Nardelli, research scientist and Travis Rotterman, postdoctoral fellow (both of the School of Biological Sciences), along with Timothy Cope, who serves as a professor
with joint appointments in the School of Biological Sciences at Georgia
Tech and in the Coulter Department of Biomedical Engineering at Emory University and Georgia Tech.

Neurologic consequences "Chemotherapy undoubtedly negatively influences
the peripheral nervous system, which is often viewed as the main culprit
of neurologic disorders during cancer treatment," shares Housley. However,
he says, for the nervous system to operate normally, both the peripheral
and central nervous system must cooperate.



========================================================================== "This occurs through synaptic communication between neurons. Through an
elegant series of studies, we show that those hubs of communication in
the central nervous system are also vulnerable to cancer treatment's
adverse effects," Housley shares, adding that the findings force
"recognition of the numerous places throughout the nervous system that
we have to treat if we ever want to fix the neurological consequences
of cancer treatment -- because correcting any one may not be enough
to improve human function and quality of life." "These disabilities
remain clinically unmitigated and empirically unexplained as research concentrates on peripheral degeneration of sensory neurons," the
research team explains in the study, "while understating the possible involvement of neural processes within the central nervous system. The
present findings demonstrate functional defects in the fundamental
properties of information processing localized within the central nervous system," concluding that "long-lasting sensorimotor and possibly other disabilities induced by cancer treatment result from independent neural
defects compounded across both peripheral and central nervous systems." Sensorimotor disabilities and 'cOIN' The research team notes that cancer survivors "rank sensorimotor disability among the most distressing,
long-term consequences of chemotherapy. Disorders in gait, balance,
and skilled movements are commonly assigned to chemotoxic damage of
peripheral sensory neurons without consideration of the deterministic
role played by the neural circuits that translate sensory information
into movement," adding that this oversight "precludes sufficient,
mechanistic understanding and contributes to the absence of effective
treatment for reversing chemotherapy-induced disability." Cope says
the team resolved this omission "through the use of a combination of electrophysiology, behavior, and modeling to study the operation of
a spinal sensorimotor circuit in vivo" in a rodent model of "chronic, oxaliplatin (chemotherapy)-induced neuropathy: cOIN." Key sequential
events were studied in the encoding of "propriosensory" information
(think kinesthesia: the body's ability to sense its location, movements,
and actions) and its circuit translation into the synaptic potentials
produced in motoneurons.



==========================================================================
In the "cOIN" rats, the team noted multiple classes of propriosensory
neurons expressed defective firing that reduced accurate sensory
representation of muscle mechanical responses to stretch, adding that
accuracy "degraded further in the translation of propriosensory signals
into synaptic potentials as a result of defective mechanisms residing
inside the spinal cord." Joint expression, independent defects "These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential
in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people
with cOIN," Cope and Housley report. "We conclude that 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 broad impact on the
scientific field and on clinical management of neurologic consequences
of cancer treatment," Housley says. "As both a clinician and scientist,
I can envision the urgent need to jointly develop quantitative clinical
tests that have the capacity to identify which parts of a patient
nervous system are impacted by their cancer treatment." Housley also
says that having the capacity to monitor neural function across
various sites during the course of treatment "will provide a biomarker
on which we can optimize treatment -- e.g. maximize anti-neoplastic
effects while minimizing the adverse effects," adding that, as we move
into the next generation cancer treatments, "clinical tests that can objectively monitor specific aspects of the nervous system will be exceptionally important to test for the presence off-target effect."
special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> academy.newscientist.com/courses/science-of-sleep-and-dreams ========================================================================== Story Source: Materials provided by Georgia_Institute_of_Technology. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Stephen N. Housley, Paul Nardelli, Travis M. Rotterman, Timothy
C. Cope.

Neural circuit mechanisms of sensorimotor disability in cancer
treatment.

Proceedings of the National Academy of Sciences, 2021; 118 (51):
e2100428118 DOI: 10.1073/pnas.2100428118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220107173357.htm
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