TY - JOUR
T1 - Dopaminergic therapy and prefrontal activation during walking in individuals with Parkinson’s disease
T2 - does the levodopa overdose hypothesis extend to gait?
AU - Dagan, Moria
AU - Herman, Talia
AU - Bernad-Elazari, Hagar
AU - Gazit, Eran
AU - Maidan, Inbal
AU - Giladi, Nir
AU - Mirelman, Anat
AU - Manor, Brad
AU - Hausdorff, Jeffrey M.
N1 - Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/2
Y1 - 2021/2
N2 - The “levodopa-overdose hypothesis” posits that dopaminergic replacement therapy (1) increases performance on tasks that depend on the nigrostriatal-pathway (e.g., motor-control circuits), yet (2) decreases performance on tasks that depend upon the mesocorticolimbic-pathway (e.g., prefrontal cortex, PFC). Previous work in Parkinson’s disease (PD) investigated this model while focusing on cognitive function. Here, we evaluated whether this model applies to gait in patients with PD and freezing of gait (FOG). Forty participants were examined in both the OFF anti-Parkinsonian medication state (hypo-dopaminergic) and ON state (hyper-dopaminergic) while walking with and without the concurrent performance of a serial subtraction task. Wireless functional near-infrared spectroscopy measured PFC activation during walking. Consistent with the “overdose-hypothesis”, performance on the subtraction task decreased (p = 0.027) after dopamine intake. Moreover, the effect of walking condition on PFC activation depended on the dopaminergic state (i.e., interaction effect p = 0.001). Gait significantly improved after levodopa administration (p < 0.001). Nonetheless, PFC activation was higher (p = 0.013) in this state than in the OFF state during usual-walking. This increase in PFC activation in the ON state suggests that dopamine treatment interfered with PFC functioning. Otherwise, PFC activation, putatively a reflection of cognitive compensation, should have decreased. Moreover, in contrast to the OFF state, in the ON state, PFC activation failed to increase (p = 0.313) during dual-tasking, perhaps due to a “ceiling effect”. These findings extend the “levodopa-overdose hypothesis” and suggest that it also applies to gait in PD patients. While dopaminergic therapy improves certain aspects of motor performance, optimal treatment should consider the "double-edged sword" of levodopa.
AB - The “levodopa-overdose hypothesis” posits that dopaminergic replacement therapy (1) increases performance on tasks that depend on the nigrostriatal-pathway (e.g., motor-control circuits), yet (2) decreases performance on tasks that depend upon the mesocorticolimbic-pathway (e.g., prefrontal cortex, PFC). Previous work in Parkinson’s disease (PD) investigated this model while focusing on cognitive function. Here, we evaluated whether this model applies to gait in patients with PD and freezing of gait (FOG). Forty participants were examined in both the OFF anti-Parkinsonian medication state (hypo-dopaminergic) and ON state (hyper-dopaminergic) while walking with and without the concurrent performance of a serial subtraction task. Wireless functional near-infrared spectroscopy measured PFC activation during walking. Consistent with the “overdose-hypothesis”, performance on the subtraction task decreased (p = 0.027) after dopamine intake. Moreover, the effect of walking condition on PFC activation depended on the dopaminergic state (i.e., interaction effect p = 0.001). Gait significantly improved after levodopa administration (p < 0.001). Nonetheless, PFC activation was higher (p = 0.013) in this state than in the OFF state during usual-walking. This increase in PFC activation in the ON state suggests that dopamine treatment interfered with PFC functioning. Otherwise, PFC activation, putatively a reflection of cognitive compensation, should have decreased. Moreover, in contrast to the OFF state, in the ON state, PFC activation failed to increase (p = 0.313) during dual-tasking, perhaps due to a “ceiling effect”. These findings extend the “levodopa-overdose hypothesis” and suggest that it also applies to gait in PD patients. While dopaminergic therapy improves certain aspects of motor performance, optimal treatment should consider the "double-edged sword" of levodopa.
KW - Freezing of gait
KW - Functional near-infrared spectroscopy
KW - Imaging
KW - Levodopa-overdose hypothesis
KW - Parkinson’s disease
KW - Prefrontal cortex
KW - fNIRS
UR - http://www.scopus.com/inward/record.url?scp=85090466015&partnerID=8YFLogxK
U2 - 10.1007/s00415-020-10089-x
DO - 10.1007/s00415-020-10089-x
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C2 - 32902733
AN - SCOPUS:85090466015
SN - 0340-5354
VL - 268
SP - 658
EP - 668
JO - Journal of Neurology
JF - Journal of Neurology
IS - 2
ER -