Translating Pathological Brain Activity Primers in Parkinson's Disease Research

Abstract

Translational experimental approaches that help us better trace Parkinson's disease (PD) pathophysiological mechanisms leading to new therapeutic targets are urgently needed. In this article, we review recent experimental and clinical studies addressing abnormal neuronal activity and pathological network oscillations, as well as their underlying mechanisms and modulation. Our aim is to enhance our knowledge about the progression of Parkinson's disease pathology and the timing of its symptom's manifestation. Here, we present mechanistic insights relevant for the generation of aberrant oscillatory activity within the cortico-basal ganglia circuits. We summarize recent achievements extrapolated from available PD animal models, discuss their advantages and limitations, debate on their differential applicability, and suggest approaches for transferring knowledge on disease pathology into future research and clinical applications.

Fig. 1.

The cortico-basal ganglia network and motor pathways in Parkinson’s disease (PD) in human and mouse. Two-dimensional (2D) representation of the cortical and subcortical areas involved in motor control/performance in the human (left column) and mouse (right column) brain. For each brain, a depiction of the direct (blue arrows), indirect (red arrows), and hyperdirect (green arrows) pathway is given. The backdrop image for the human brain is reproduced from the BigBrain atlas, a near-cellular (20 μm) resolution 3D digitized model of a human brain [156]. The backdrop of the mouse model is a high-resolution magnetic resonance imaging (MRI) (15 μm) anatomic reference atlas of the C57BL/6J mouse [157] acquired at 16.4 T. Thick arrows represent increased activity, whereas thin arrows represent decreased activity, by PD. S1, primary somatosensory cortex; M1, primary motor cortex; PM, premotor cortex; SMA, supplementary motor area; preSMA, pre-supplementary motor area; GPe, globus pallidus pars externa; GPi, globus pallidus pars interna; STN, subthalamis nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata.

Fig. 2.

Oscillatory activity in a single patient with Parkinson’s disease (PD). (A) Raw signals at rest were recorded from a single patient with PD shortly after deep brain stimulation surgery. Electroencephalography (EEG) data were recorded from the electrode C3; concurrent local field potentials (LFP) data were recorded from the externalized electrodes implanted in the subthalamic nucleus (STN). (B) Same STN signal filtered at specific frequencies. Top: Filtered around the individual beta peak frequency (~20 Hz + −2 Hz). Middle: Filtered around 70 Hz, corresponding to finely tuned gamma oscillations. Bottom: Broadband gamma oscillatory activity between 35 and 200 Hz. (C) Left: Time–frequency dynamics for EEG and LFP data during the same rest interval followed by movement (spiral drawing). Beta power in the STN decreases with the beginning of the movement. Middle: Power spectra of the EEG and LFP channels (rest: continuous lines, movement: dashed lines). Both EEG and LFP present a spectral peak at around 20 Hz, which is reduced during movement execution. Right: Coherence (top) and cross-frequency coupling (bottom) between the EEG and LFP channels as markers of interregional connectivity. Increased cross-frequency coupling between beta frequencies (23 and 27 Hz) and broadband gamma frequencies (50 to 200 Hz). LFP, local field potentials; FTG, finely tuned gamma oscillations; MI, modulation index.

Fig. 3.

Distribution of dopamine D1, D2, glutamate, and GABA-A receptors in the cortico-basal ganglia. From top to bottom: 3D representation of the cortico-basal system, including a segmentation of the motor cortex according to the Human Motor Area Template (HMAT) [158]. Subcortical structures were manually delineated based on the multicontrast PD25 atlas, a PD population-specific template atlas [159]. Average gene expression profiles for dopamine receptors 1 and 2, as well as glutamate and GABA-A receptors derived from mRNA expression profiles derived from 6 adult human brain tissue samples mapped to Montreal Neurological Institute (MNI) coordinates as reported in the Adult Human Brain Atlas (AHBA) [160]. Within the basal ganglia itself, the caudate, putamen, and globus pallidum have the highest gene expression (red scale) of dopamine 1 receptors, whereas expression of these receptors is more distributed and less accentuated in the motor areas. The distribution pattern of dopamine 2 receptors includes higher expression in the SN, STN, and thalamus with down-regulated expression (blue colors) in the cortex. The gene expression for the glutamate receptor is similar to that of dopamine receptor 1 in the cortex but follows a different pattern in the subcortical nuclei, while the same holds true for GABA-A and dopamine receptor 2. Of note, AHBA has a broader coverage of the left hemisphere, and thus, no inferences about laterality can be reliably made for the gene expression based on these data.