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      Alterations in brain neurocircuitry following treatment with the chemotherapeutic agent paclitaxel in rats

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          Highlights

          • Imaging the reorganization of pain neural circuitry within 8 days of chemotherapy.

          • Using rat model of neuropathy with multimodal MRI.

          • Showing loss of anticorrelation between prefrontal cortex and PAG.

          • Identifying the interaction between periaqueductal gray and brainstem raphe.

          Abstract

          Human and animal studies suggest that both traumatic nerve injury and toxic challenge with chemotherapeutic agents involves the reorganization of neural circuits in the brain. However, there have been no prospective studies, human or animal, using magnetic resonance imaging (MRI) to identify changes in brain neural circuitry that accompany the development of chemotherapy-induced neuropathic pain (i.e. within days following cessation of chemotherapy treatment and without the confound cancer). To this end, different MRI protocols were used to ascertain whether a reorganization of brain neural circuits is observed in otherwise normal rats exposed to the taxane chemotherapeutic agent paclitaxel.

          We conducted an imaging study to evaluate the impact of a well-established paclitaxel dosing regimen, validated to induce allodynia in control rats within eight days of treatment, on brain neural circuitry. Rats received either paclitaxel (2 mg/kg/day i.p; cumulative dose of 8 mg/kg) or its vehicle four times on alternate days (i.e. day 0, 2, 4, 6). Following the cessation of treatments (i.e. on day 8), all rats were tested for responsiveness to cold followed by diffusion weighted magnetic resonance imaging and assessment of resting state functional connectivity. Imaging data were analyzed using a 3D MRI rat with 173 segmented and annotated brain areas.

          Paclitaxel-treated rats were more sensitive to a cold stimulus compared to controls. Diffusion weighted imaging identified brain areas involved in the emotional and motivational response to chronic pain that were impacted by paclitaxel treatment. Affected brain regions included the prefrontal cortex, amygdala, hippocampus, hypothalamus and the striatum/nucleus accumbens. This putative reorganization of gray matter microarchitecture formed a continuum of brain areas stretching from the basal medial/lateral forebrain to the midbrain. Resting state functional connectivity showed reorganization between the periaqueductal gray, a key node in nociceptive neural circuitry, and connections to the brainstem.

          Our results, employing different imaging modalities to assess the central nervous system effects of chemotherapy, fit the theory that chronic pain is regulated by emotion and motivation and influences activity in the periaqueductal gray and brainstem to modulate pain perception.

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          Most cited references47

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Descending pain modulation and chronification of pain.

            Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain 'chronification'. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition. Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual. Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain 'chronification'. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.
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              Candidate mechanisms for chemotherapy-induced cognitive changes.

              The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function.
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                Author and article information

                Contributors
                Journal
                Neurobiol Pain
                Neurobiol Pain
                Neurobiology of Pain
                Elsevier
                2452-073X
                27 May 2019
                Aug-Dec 2019
                27 May 2019
                : 6
                : 100034
                Affiliations
                [a ]Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
                [b ]Depts Psychology and Pharmaceutical Sciences, Northeastern University, United States
                [c ]Dept of Psychology and Brain Sciences, Indiana University, Bloomington, IN, United States
                Author notes
                [* ]Corresponding author: Department of Psychology, Northeastern University, 125 NI Hall, 360 Huntington Ave, Boston, Massachusetts 02115-5000, United States. c.ferris@ 123456northeastern.edu
                Article
                S2452-073X(19)30009-1 100034
                10.1016/j.ynpai.2019.100034
                6565758
                ec0d16ae-54e9-42f9-b558-f9be0be96a18
                © 2019 Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 April 2019
                : 9 May 2019
                : 26 May 2019
                Categories
                Original Research Article

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