Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson’s disease

Abstract

The onset of Parkinson’s disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[18F]fluoro-L-dopa (18 F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with 18F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.

Dopaminergic modulation of motor network compensatory mechanisms in Parkinson's disease

“…Nevertheless, we offer proof of PD‐related alterations in primarily contralateral activation across multiple cortical regions. Our findings suggest that, in later stages of the disease, laterality decrease is no longer associated solely with compensatory ipsilateral hyperactivation as in drug‐naïve PD (Blesa et al, ; Wu et al, ). Instead, we observed contralateral hypoactivation, which suggests the appearance of maladaptive processes, related to chronic medication usage and/or to the spread of pathology throughout the motor circuit.…”

“…The group‐level comparison corresponding to the effect of disease showed a negative parameter estimate from the most affected (left) hand to the RSMA, corresponding to reduced excitation (Figure , left panel). This finding makes sense given that the left hand was most affected by the disease and the cortical output of the basal ganglia is known to be reduced in PD (Blesa et al, ). The group‐level comparison corresponding to the effect of medication did not show any significant differences (even at Pp > 0.5).…”

“…Interhemispheric imbalances in nigrostriatal dopamine (DA) levels, inherent to both humans and animals, have been shown to correlate with lateralization of motor behavior (de la Fuente-Fernández, Kishore, Calne, Ruth, & Stoessl, 2000;Molochnikov & Cohen, 2014). It has been proposed that a time-dependent mechanism differentially regulates the DA system in both hemispheres and that this mechanism is initially able to compensate for alterations in the endogenous DA imbalance related to neurodegeneration (Blesa et al, 2011;Molochnikov & Cohen, 2014).…”

Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease

“…However, a unilateral model of dopamine depletion was chosen for several reasons. First, individuals with PD often present with asymmetric nigrostriatal dopamine depletion [6] and this unilateral model can represent earlier stages of PD. Second, unilateral 6-OHDA models in rats have consistently shown cranial sensorimotor deficits with regard to vocalization, [7] tongue use, [10,41] biting, [41] and oropharyngeal swallowing.…”

The contribution of each leg to bipedal balance control : it takes two

“…From this perspective, asymmetric balance control might paradoxically be a good phenomenon in certain stages of the disease, possibly preventing falls. Results of another recent study actually point in this direction: in primates asymmetry between brain hemispheres improved clinical signs (Blesa et al, 2011).…”