Differential effects of deep brain stimulation and levodopa on brain activity in Parkinson's disease

Abstract

Levodopa is the first-line treatment for Parkinson's disease, although the precise mechanisms mediating its efficacy remain elusive. We aimed to elucidate treatment effects of levodopa on brain activity during the execution of fine movements and to compare them with deep brain stimulation of the subthalamic nuclei. We studied 32 patients with Parkinson's disease using functional MRI during the execution of finger-tapping task, alternating epochs of movement and rest. The task was performed after withdrawal and administration of a single levodopa dose. A subgroup of patients (n = 18) repeated the experiment after electrode implantation with stimulator on and off. Investigating levodopa treatment, we found a significant interaction between both factors of treatment state (off, on) and experimental task (finger tapping, rest) in bilateral putamen, but not in other motor regions. Specifically, during the off state of levodopa medication, activity in the putamen at rest was higher than during tapping. This represents an aberrant activity pattern probably indicating the derangement of basal ganglia network activity due to the lack of dopaminergic input. Levodopa medication reverted this pattern, so that putaminal activity during finger tapping was higher than during rest, as previously described in healthy controls. Within-group comparison with deep brain stimulation underlines the specificity of our findings with levodopa treatment. Indeed, a significant interaction was observed between treatment approach (levodopa, deep brain stimulation) and treatment state (off, on) in bilateral putamen. Our functional MRI study compared for the first time the differential effects of levodopa treatment and deep brain stimulation on brain motor activity. We showed modulatory effects of levodopa on brain activity of the putamen during finger movement execution, which were not observed with deep brain stimulation.

Keywords: Parkinson’s disease; deep brain stimulation; dopaminergic treatment; functional magnetic resonance imaging; levodopa.

Graphical Abstract

Figure 1

Brain activity increase with LDOPA treatment in the LDOPA cohort of 32 patients with Parkinson’s disease. Using an experiment of consecutive blocks of finger tapping (TAP) and rest (REST), contrast images of TAP–REST were created for each participant. With a pairwise comparison of these contrast images (between the ON and OFF sessions with and without LDOPA treatment, respectively), a significant increase in the TAP–REST contrast was obtained after LDOPA treatment in the left and right putamen (P < 0.05 FWE corrected at the voxel level, see Table 1 for details).

Figure 2

Differential pattern of brain activity change with LDOPA treatment during finger tapping and rest within the LDOPA cohort of 32 patients with Parkinson’s disease. Using an experimental design with consecutive blocks of finger tapping and rest in both treatment states with (ON) and without (OFF) LDOPA medication, we observed a differential pattern of brain activity change in the putamen. During phases of finger tapping (TAP), an increased brain activity was obtained with LDOPA medication (left column, A, colour coded in red). In contrast, during resting periods (REST), putamen activity was decreased with LDOPA (middle column, B, colour coded in blue). A significant interaction between both factors of experimental condition (TAP/REST) and LDOPA treatment (OFF/ON) was observed in the left and right putamen (right column, A–B). All results were obtained with P < 0.05 with FWE correction at the voxel level (see Table 1 for details).

Figure 3

Contrast estimates of a factorial model containing both experimental conditions of finger tapping and rest in both treatment states without and with LDOPA medication for the LDOPA cohort of 32 patients with Parkinson’s disease. Contrast estimates of the putamen showed a differential pattern of brain activity change after LDOPA treatment (ON versus OFF) during finger tapping (TAP) and rest (REST). In particular, during REST periods, we found a significant activity decrease (see A and C on the left, see also B in Fig. 2). In contrast to the differential pattern of brain activity in the left and right putamen, we did not observe any brain activity differences between the OFF and ON states in the left or right motor cortex M1, neither in the TAP nor in the REST condition (see B and D on the right).

Figure 4

Differential pattern of brain activity change with finger tapping during LDOPA treatment and deep brain stimulation (DBS) in the LDOPA-DBS cohort of 18 patients with Parkinson’s disease. Using the subcohort of patients who underwent DBS, the pairwise ON–OFF comparison revealed a brain activity increase with LDOPA treatment with finger tapping in the left and the right putamen (top row, A, colour coded in red, P < 0.05 FWE corrected at the voxel level, see also Fig. 1 for the full cohort). In contrast, we did not observe any significant brain activity change when comparing the ON and OFF states of DBS even when using the more liberal CDT approach (top row, B, see also Table 2 and Supplementary Table 2). The interaction model using a flexible factorial design with both factors LDOPA/DBS and OFF/ON revealed a significant result in the left and right putamen showing a significant difference between the ON–OFF differences of LDOPA and DBS (top row, A and B). The pairwise comparison between both ON states of LDOPA treatment and DBS revealed a significant brain activity decrease with finger tapping when changing the treatment from LDOPA to DBS (bottom row, C). Comparing both OFF states between LDOPA and DBS (the so-called microlesion effect), we did not find any significant brain activity differences in the left and right putamen but in the vicinity of the anterior thalamus and the internal globus pallidus (bottom row, D). Note that the interaction C–D is exactly the same as A–B shown in the top row.

Figure 5

Contrast estimates of a factorial model containing both experimental conditions of finger tapping and rest in both treatment states without and with DBS within the subgroup of 18 patients with Parkinson’s disease. In contrast to a differential pattern of brain activity change with LDOPA treatment (see Fig. 3), we did not find any significant brain activity differences with DBS (ON versus OFF), neither for finger tapping (TAP) nor for the rest (REST) condition. Independent of the ON or OFF state of DBS, we found a reversed pattern of brain activity in the putamen (see A and C on the left) and in the primary motor cortex M1 (see B and D on the right).