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Brain Networks Underlying the Clinical Effects of Long-Term Subthalamic Stimulation for Parkinson’s Disease: A 4-Year Follow-up Study with rCBF SPECT

¹ Nuclear Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
² Nuclear Medicine Unit, Department of Diagnostic Imaging, Ospedale Misericordia e Dolce, Prato, Italy
³ Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

View larger version (16K): [in a new window]   FIGURE 1. Plots of individual clinical scores for motor UPDRS, H&Y, and S&E for preoperative (T0) and postoperative on-stimulation conditions at 5 mo (T1) and 42 mo (T2). Clinical scores were assessed in unmedicated patients. Reduction in motor UPDRS and H&Y scores and increase in S&E score indicate improvement in motor function, global stage disease, and performance of activities of daily living, respectively. Differences between mean scores for UPDRS, H&Y, and S&E at T0 and T1 and at T0 and T2 were significant. No significant differences were present between mean scores at T1 and T2.

View larger version (32K): [in a new window]   FIGURE 2. Brain areas showing significant rCBF increase from pre- to postoperative on-stimulation condition at 5-mo follow-up (main effect of condition). Results are displayed as SPM projections in 3 orthogonal views (P < 0.0001, uncorrected). Pre-SMA = rostral part of the supplementary motor area.

View larger version (94K): [in a new window]   FIGURE 3. (A) Brain areas show significant rCBF increase from postoperative on-stimulation condition at 5 mo to postoperative on-stimulation condition at 42-mo follow-up. Results are displayed as SPM projections in 3 orthogonal views (P < 0.0001, uncorrected). MI = primary motor cortex; pre-SMA = rostral part of supplementary motor area; SI: primary sensory cortex; Gpe = globus pallidus pars externa; SN = substantia nigra. (B) rCBF increases in pre-SMA and SN were superimposed on normalized T1-weighted MR images to increase clarity.

View larger version (68K): [in a new window]   FIGURE 4. (A) Brain regions in which rCBF increases significantly in association with improvement in motor function (motor UPDRS) from pre- to postoperative on-stimulation conditions at 5- and 42-mo follow-up (P < 0.0001, uncorrected). Pre-SMA = rostral part of the supplementary motor area. (B and C) rCBF increases superimposed on normalized T1-weighted MR images and on 3-dimensional brain. (D) Plot of individual rCBF values related to motor improvement for pre-SMA from pre- to postoperative conditions. (E) Relationship between rCBF values in pre-SMA and motor UPDRS scores during course of the study.

View larger version (47K): [in a new window]   FIGURE 5. Proposed functional model of basal ganglia in patients with parkinsonism (A) and hypothetic schematic diagram of mechanisms by which STN-DBS produces its clinical benefit in the long term (B). For clarity, the neuroanatomy and interconnections shown are incomplete. Excitatory connections are indicated by solid arrowheads and inhibitory connections are indicated by open arrowheads. Relative increases and decreases in tonic discharge rates associated with parkinsonism and DBS are denoted by wider and thinner lines and outlining of each box, respectively. Dashed line indicates the inhibitory effect of long-term DBS on overactive STN. Cortical and subcortical regions resulting in activation in our study are displayed on a glass brain. (A) Parkinsonism arises from loss of dopaminergic neurons in the pars compacta segments of the substantia nigra (SNc). Reduced inhibition via the direct pathway (striatum to the globus pallidus pars interna [Gpi] and the pars reticulata of the substantia nigra [SNr]) combined with increased excitation from the STN via the indirect pathway (striatum to the globus pallidus pars externa [Gpe]) leads to overactivity of GPi and SNr. This abnormal activity may determine motor impairment by suppressing thalamocortical and cerebellocortical facilitation and by altering brainstem locomotor areas. (B) Reduction of excessive excitatory activity of the STN would partially reverse this state by eliminating excessive inhibition of both components of the output of basal ganglia. This may lead to enhanced activation responses in motor/associative areas of frontal lobes, possibly involving elements within the basal ganglia–thalamocortical motor circuits during the first months of stimulation as well as within the cerebellothalamocortical motor loop, the nigral dopaminergic system, and the brainstem during subsequent years of therapy.