In this study, we examined the subcortical shape abnormalities in patients with NPC who underwent RT or CCRT, compared with untreated NPC patients. Our main findings can be summarized as follows. First, compared with the pre-RT group, patients in the post-RT group showed significant regional atrophy in the medial posterior segment of the bilateral thalamus. Second, compared with the pre-RT group, patients in the post-CCRT group showed significant regional atrophy in the medial posterior segment of the bilateral thalamus, bilateral putamen, left pallidum, and left caudate, and significant regional inflation in the lateral anterior segment of the left pallidum. Finally, in treated NPC patients, the maximum dosage of RT for temporal lobes was negatively correlated with the morphological changes of the superior segment of the bilateral thalamus. Taken together, these findings suggest that RT and CT may interact in altering the morphology of subcortical structures in NPC.
Compared with the pre-RT group, patients in the post-RT group showed significant regional atrophy in the medial posterior segment of the bilateral thalamus. This finding is consistent with some previous fMRI studies, showing decreased fractional amplitude of low frequency fluctuation and ReHo values in the thalamus of NPC patients after RT(Ding et al., 2018; Y. M. Zhang et al., 2019). The observed regional atrophy in the bilateral thalamus might be the anatomical substrates of the functional alterations in NPC patients treated with RT. Compared with the pre-RT group, patients in the post-CCRT group showed significant atrophy in the medial posterior segment of bilateral thalamus. Of note, the thalamic area identified with significant regional atrophy in the post-CCRT group was much larger than that identified in the post-RT group, suggesting possible interactions between RT and CT. In addition, using the pooled data of the post-RT and post-CCRT groups, we also found a significant negative correlation between the morphological changes of the thalamus and the maximum dose of RT for temporal lobe, suggesting that the thalamic abnormalities could arise from the direct effects of RT or from abnormal afferent inputs from RT-lesioned temporal lobe via the reciprocal thalamo-cortical connections(Hwang, Bertolero, Liu, & D'Esposito, 2017).
Compared with the pre-RT group, patients in the post-CCRT group showed significant atrophy in the medial posterior segment of the bilateral putamen, left pallidum, and the left caudate. This finding is consistent with previous neuroimaging studies conducted to investigate the effect of CT on the brain structure. For example, Nelson et al. found higher mean diffusivity values in multiple subcortical nuclei (thalamus, putamen, globus pallidus, etc.) in long-term survivors of childhood brain tumor after CT(Nelson et al., 2014). Similarly, two cross-sectional morphologic MRI studies showed significant reduction in the volume of multiple subcortical nuclei in long-term survivors of childhood acute lymphoblastic leukemia after CT(Genschaft et al., 2013; van der Plas et al., 2017). Compared with the pre-RT group, the present study also found significant regional inflation in the lateral anterior segment of the left pallidum in the post-CCRT group. The finding of concurrent atrophy and inflation in the pallidum may indicate functional heterogeneity of different nuclei of the pallidum. However, the underlying mechanism of such alteration remains unclear and requires further investigation. Collectively, given that no significant shape abnormalities in putamen, pallidum and caudate were found in the post-RT group, we therefore speculate that the shape alterations of these subcortical structures may primarily occur as a result of CT.
The exact pathophysiological mechanism that leads to these significantly morphological alterations of subcortical structures remains unclear. It is possible that multiple mechanisms, including DNA damage, apoptosis, inflammatory response and oxidative stress, vessel abnormity, and destruction of the blood-brain barrier (BBB), are involved in the development of the brain injury after RT or CT(Lumniczky, Szatmari, & Safrany, 2017; X. Ren et al., 2019). In fact, in the studies of the mechanism of RT or CT, the inflammatory response mediated by reactive microglia has always been of particular interest. More specifically, cellular debris from RT- or CT- damaged neuron could activate microglia, which in turn could release pro-inflammatory cytokines and other neurotoxic factors that damage neurons(Block, Zecca, & Hong, 2007). Similarly, there is evidence that reactive astrocytes induced by reactive microglia are also neurotoxic(Liddelow et al., 2017). Besides, increased BBB permeability caused by CCRT also seems to be able to indirectly exacerbate existing levels of inflammatory response(Zlokovic, 2008). However, we cannot exclude the involvement of other mechanisms in causing the morphologic alterations in treated NPC patients.
Functionally, the thalamus, as a hub, plays a particularly critical role in controlling the transmission and integration of information flow in the cortical and subcortical networks, which is the basis for its support of related cognitive functions(Hwang et al., 2017; Nakajima & Halassa, 2017; Sherman, 2016). The thalamus and its connections to other brain regions (including the medial temporal lobe, cerebellum, prefrontal cortex, etc.) are instrumental in several neurocognitive domains, including memory, executive function, sleep and arousal, and information processing speed (Bolkan et al., 2017; Hwang et al., 2017; Kafkas, Mayes, & Montaldi, 2020; Nakajima & Halassa, 2017; Niendam et al., 2012; Prevosto & Sommer, 2013), which are thought to be most affected by RT or CT(Ahles & Saykin, 2007; Lumniczky et al., 2017). Similarly, the putamen, the pallidum and the caudate have been involved in learning, language and reward mechanism, which are closely related to cognitive function(Bick et al., 2019; Doi, Fan, Gold, & Ding, 2020; Hervais-Adelman, Egorova, & Golestani, 2018; Vinas-Guasch & Wu, 2017). The morphological alterations of these structures may be related to the neurocognitive changes after RT or CCRT for NPC patients. Alternatively, as the basal ganglia-thalamocortical circuits have been shown to be essential for motor control (Alexander, DeLong, & Strick, 1986), alterations in these subcortical structures may also underlie the motor deficits in treated NPC patients, such as dysphagia(McDowell, Corry, Ringash, & Rischin, 2020).