Functional remapping in networks of the Parkinsonian brain: A preclinical neuroimaging perspective with clinical correlates

Abstract

Parkinson's disease (PD) is increasingly understood as a neurodegenerative condition whose pathology extends beyond the direct and indirect basal ganglia pathways. Clinically, patients are all too painfully aware of dysfunction not only of motor circuits but also of somatosensory, autonomic, cognitive, and emotional systems. Functional neuroimaging studies have begun to document a functional reorganization in the PD brain across a wide number of networks. In particular, the cerebellar-thalamocortical, as well as the fronto-striatal circuit, have been shown to undergo functional reorganization. In this narrative review, citing preclinical as well as clinical neuroimaging studies, our objective is to highlight trends and discuss the relevance of cerebral adaptive changes. It remains clear that not all changes contribute to the normalization of functions. Parsing differences between functional "compensation," "silencing," or "maladaptation" in neural circuits is important. A necessary next step in neurorehabilitation is the question of whether compensatory cerebral changes can be enhanced. In this regard, physical exercise remains of interest, given that in patients, exercise may allow some degree of symptom improvement and possibly slow the course of the disease. Future interventions may wish to integrate neuroimaging findings as potential targets to support neuroplastic changes.

Keywords: Parkinson’s disease; exercise; functional brain mapping; neurorehabilitation; plasticity.

Figure 1

Regions of statistically significant differences of functional brain activation in rats with bilateral 6-hydroxydopamine striatal lesions compared to sham-lesioned rats. Statistically significant lesion effects on regional cerebral blood flow (rCBF) during acute treadmill walking (Lesion/Walk, n = 9 vs Sham/Walk, n = 10) or at rest (Lesion/Rest, n = 10 vs Sham/Rest, n = 9) in rats are shown. The comparison highlights lesion effects (Lesion vs Sham). A selection of representative coronal slices (anterior–posterior coordinates relative to bregma) is shown. Colored overlays show statistically significant positive (red) and negative (blue) differences in rCBF. Abbreviations are those from the Paxinos and Watson rat atlas [5]: 5 (trigeminal n., motor, sensory), aca (anterior commissures), BL (basolateral amygdalar n.), Ce (central amygdalar n.), Cg (cingulate cortex), CM (central medial thalamic n.), CPu (CPu: anterior, ant-CPu; dorsal, d-CPu; ventral, v-CPu), d-HPC (dorsal hippocampus), DP (dorsal peduncular cortex), DS (dorsal subiculum), Ect (ectorhinal cortex), Ent (entorhinal cortex), GPe (external globus pallidus), GPi (internal globus pallidus/entopeduncular n.), I (insular cortex), IC (inferior colliculus), IL (infralimbic cortex), IP (interpeduncular n.), La (lateral amygdalar n.), LO (lateral orbital cortex), LP (lateral posterior thalamic n.), LS (lateral septum), M1, M2 (primary, secondary motor cortex), Me (medial amygdalar n.), MS (medial septum), mRT (mesencephalic reticular formation), Nv (navicular n.), PaS (parasubiculum), PH (posterior hypothalamus), Pir (piriform cortex), Pn (pons), PrL (prelimbic cortex), PtA (parietal association cortex), RPC (red n.), RS (retrosplenial cortex), S1DZ, S1FL, S1J, S1Tr, S1ULp, (primary somatosensory cortex: dysgranular, forelimb, jaw, trunk, upper lip), S2 (secondary somatosensory cortex), SC (superior colliculus), SN (substantia nigra), STN (subthalamic n.), TT (tenia tecta), vermis (2nd, 3rd cerebellar simple lobule), V1, V2 (primary, secondary visual cortex), v-HPC (ventral hippocampus), VL (ventral lateral thalamic n.), VM (ventromedial thalamic n.), VMH (ventromedial hypothalamus), VPL/VPM (ventral posterolateral, ventral posteromedial thalamic nuclei), VP (ventral pallidum), VS (ventral subiculum), ZI (zona inserta). Figure adapted from Wang et al. [6] under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with permission from the authors.

Figure 2

Basal ganglia-thalamic-cortical and cerebellar-thalamic-cortical circuits during externally or internally cued tasks. PreMC, lat. premotor cortex; PMC primary motor cortex; SMA, supplementary motor area; SMC, somato-sensory cortex; Vla ventrolateral anterior thalamic n.; Vlp (Vim) ventrolateral posterior thalamic n. (ventralis intermedius). A difference between externally or internally guided tasks is often related to the difference between internal and external timekeeping systems. Thickness of the line denotes dominance of the pathway. Adapted from Lewis et al. [8] with permission from Elsevier.

Figure 3

Regions of statistically significant differences of functional brain activation during treadmill walking in previously exercised (n = 10) and nonexercised (n = 10) normal rats. A selection of representative coronal slices (anterior–posterior coordinates relative to bregma) is shown. Colored overlays show statistically significant positive (red) and negative (blue) differences in cerebral blood flow (voxel level, p < 0.05, clusters < 100 contiguous voxels). Line drawings have been adapted from the Paxinos and Watson (2005) rat atlas with permission from Elsevier: Exercise training results in (i) decreased activation in M1, M2, CPu, and midline cerebellum and (ii) increased activation in globus pallidus, thalamus (VL, CM), and subthalamic n. Abbreviations: 2Cb, 3Cb (2nd and 3rd cerebellar lobules), Au (auditory cortex), CA3 (hippocampus CA3 region), Ce (central nucleus of the amygdala), Cg1 (cingulate cortex area 1), cp (cerebral peduncle), CPu (CPu), DEn (dorsal endopirform nucleus), DG (dorsal geniculate of the hippocampus), DLEnt (dorsolateral entorhinal cortex), DMTg (dorsomedial tegmental area), DPGi (dorsal paragigantocellular nucleus), GPE (external globus pallidus), GPI (internal globus pallidus), Hb (Habenula), IRT (intermediate reticular nucleus), IntA (interposed cerebellar nucleus), Lat (lateral or dentate cerebellar nucleus), M1, M2 (primary, secondary motor cortex), MD (medial thalamic nucleus), MeD (medial or fastigial cerebellar nucleus), PeFLH (perifornical part of the lateral hypothalamus), PF (parafascicular thalamus), PnC (pontine reticular nucleus, caudal), RN (red nucleus), RS (retrosplenial cortex), S1HL (primary somatosensory cortex, hindlimb), S2 (secondary somatosensory cortex), SC (superior colliculus), Sim A (simple lobule of the cerebellum), VL (ventrolateral thalamus), ZI (zona incerta). Figure adapted from Holschneider et al. [95] with permission from Elsevier.

Figure 4

Connectivity degree changes in the normal mouse in subregions of the caudoputamen (CPu) in response to 6 weeks of horizontal treadmill exercise. Imaging was performed during walking on a motor-driven wheel. (a) The connectivity degree of CPu domains in the control (nonexercise) group is color-coded. Here, “degree” represents a measurement of the number of functional connections linking the node to other nodes in the cortico-basal ganglia-thalamic network. (b) Connectivity degree of CPu domains in the exercise group. (c) Connectivity degree changes in the exercise group compared to controls. Here, a negative number implies a higher connectivity number in the nonexercised mice across the cortico-basal ganglia-thalamic network. CPr/CPi/CPc, rostral/intermediate/caudal caudoputamen. Domain maps were drawn based on the mouse structural connectome [120]. Reproduced without change from Wang et al. [121] under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with permission from the authors.

Figure 5

Exercise increases cortical functional connectivity of the primary motor cortex (M1) in the 6-OHDA lesion PD model. Rats received 6-OHDA lesions of the bilateral dorsolateral CPu, with controls being nonlesioned animals. Daily wheel running exercise was administered over 6 weeks, beginning 2 weeks postlesion. Thereafter, animals received intravenous injections of the cerebral perfusion tracer [¹⁴C]-iodoantipyrine during slow walking on a motorized horizontal treadmill. Following euthanasia, brains were cryosectioned and processed by autoradiography. Selection in each animal of 806 regions of interest (ROIs) along the cortical mantle across 34 coronal slices was used to generate cortical flatmaps. Color-coded maps of group averages in the flattened cerebral cortical surface are shown for the following groups (a) Sham/no exercise, (b) Lesion/No-Exercise, and (c) Lesion/Exercise. The rows denote coronal sections from anterior to posterior, with ROIs represented by cells and numbered starting from the midline. Right (R) and left (L) hemispheric ROIs are shown on the left and right sides of the figure, respectively. A functional seed is placed in the left anterior primary motor cortical area (M1) at bregma AP + 3.6 mm (black cell on the right side of each map). Each ROI is represented by a cell with its Pearson’s correlation coefficient with the M1 seed color-coded. Significant positive and negative correlations are denoted by red and blue colors, respectively. The critical value of correlation coefficient (R) for statistical significance (p < 0.05) is denoted by a dot (•) placed on the R-value color scale bar on the right. Abbreviations [141]: A, amygdala; Au, auditory; Fr3, frontal cortex area 3; I, insular; LEnt, lateral entorhinal; M1, primary motor; M2, secondary motor; O, olfactory; P, parietal; Pir, piriform; RS, retrosplenial; S1BF, primary somatosensory for the barrel fields; S1FL, forelimbs; S1HL, hindlimbs; S1J, jaw; S1ULp, upper lip region; S2, secondary somatosensory; TeA, temporal association; V1, primary visual; V2, secondary visual. Unlabeled regions represent transitional areas between two regions. Figure adapted from Peng et al. [140] under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with permission from the authors.

Figure 6

Exercise improves cognitive flexibility in a Parkinsonian rat model. Rats received 6-hydroxydopamine lesions of the bilateral dorsomedial CPu. Animals were exercised for 12 weeks, followed by tyrosine hydroxylase staining of the brain. Lesion/exercise rats compared to Lesion/Non-Exercise rats showed a modest improvement in processing-related responses in a 3-choice serial reaction time (3-CSRT) task and significant improvement during rule reversal of this task (3-CSRT-R). Cognitive flexibility is assessed by improved (a) response accuracy (nose-poke) and (b) inhibitory aptitude (premature responses). Avrg ±SEM, ^# p < 0.05 lesion/exercise (n = 22) vs lesion/sedentary (n = 12); ⁺ p < 0.05 lesion/sedentary (n = 12) vs sham/sedentary (n = 12), Fisher’s LSD multiple comparisons test. Figure adapted from Wang et al. [149] with permission from Elsevier.

Figure 7

Neuroplastic response: Functional compensation, silencing, or maladaptation in the Parkinsonian brain.