Central Nervous System (CNS) Aspects of Motor Control II
In this lecture, I review how the basal ganglia, thalamus and cerebellum work with the motor cortex to influence and produce movement. I use historic cases of motor deficits and disease, including Parkinson's disease, to reflect on how knowledge has progressed. Included are discussions on how the MPTP model of Parkinson's disease was discovered, the standard "rate model" developed by Albin et al., and modern theories concerning firing rates and firing patterns than are employed by the thalamocortical system.
View the annotated PDF When Movement Breaks
2:00 - Development of MPTP Model
In the 1980's a number of young heroin addicts were admitted to hospitals in California. Initially, doctors were confused about their symptoms: extreme bradykinesia (slowness of movement), despite full cognitive abilities. Doctors eventually were able to connect these cases and identify a botched batch of heroin as central connection between them. Instead of synthesizing Desmethylprodine, or MPPP, an opioid, the amateur drug makers synthesized MPTP, which is a dopaminergic neurotoxin. The discovery that MPTP was highly selective to the dopamine transporter in the primate brain ushered in a new age of experimental investigation concerning disorders where dopamine cells are damaged, such as Parkinson's disease.
NOVA produced a documentary following this story, The Case of the Frozen Addict. Related to the story of dopamine, the movie, Awakenings, chronicles the discovery and first use of L-DOPA in humans, based on Oliver Sacks book.
Muramatsu, Yasuko, and Tsutomu Araki. "Glial cells as a target for the development of new therapies for treating Parkinson’s disease." Drug News Perspect 15.9 (2002): 586-590.
Przedborski, Serge, and Miquel Vila. "MPTP: a review of its mechanisms of neurotoxicity." Clinical Neuroscience Research1.6 (2001): 407-418.
5:30 - Parkinson's disease Pathology & the Rate Model
Parkinson's disease is a result of dopamine cell death in the substantia nigra pars compacta. Substantia nigra translates to, "black substance," reflecting its dark pigmentation due to L-DOPA being a precursor to the neuromelanin.
In the late 1980's several researchers were pioneering a new model of basal ganglia function based on the biochemical, experimental and clinical understanding at that time. Albin and DeLong, in tandem, introduced similar models that explained how changes in firing rates through specific basal ganglia structures could explain how movement is generated, and compromised in several movement disorders.
Albin, Roger L., Anne B. Young, and John B. Penney. "The functional anatomy of basal ganglia disorders." Trends in neurosciences 12.10 (1989): 366-375.
DeLong, Mahlon R. "Primate models of movement disorders of basal ganglia origin." Trends in neurosciences 13.7 (1990): 281-285.
7:40 - Rate Model Inconsistencies and the Thalamic Paradox
While the rate model was incredibly successful at explaining some disorders, it failed to explain ongoing observations. One of the issues was that lesions of the basal ganglia output was therapeutic to both hypo and hyper-kinetic movement disorders. For example, lesions or deep brain stimulation in the globus pallidus pars internus (GPi) is used to treat slow movement in Parkinson's disease and aberrant movement in dystonia and chorea.
Furthermore, experimental findings were showing considerable disagreement with predictions of the rate model. This includes the fact that decreases in thalamic firing, which should slow movement, make primates move better according to a modified Parkinson's disease rating scale.
Muralidharan, Abirami, et al. "Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease." Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation 10.1 (2017): 126-138.
Nelson, Alexandra B., and Anatol C. Kreitzer. "Reassessing models of basal ganglia function and dysfunction." Annual review of neuroscience 37 (2014): 117-135.
14:20 - Low Threshold Spiking (LTS) of T-type Calcium Channels
Recently, some focus has shifted towards understanding firing patterns rather than firing rates. This extends the pathway-centric understand of basal-ganglia-thalamocortical function by recognizing that the need for a temporal dimension that describes how neuronal firing changes in time. For instance, basal ganglia structures become "bursty" in Parkinson's disease.
At the level of the thalamus, a structure that has been long-deemed a "relay", there are mechanisms that may be engaged which can fundamentally alter the way in which information is brought together and sent out. This includes the expression of low threshold spiking (LTS), T-type calcium channels, which activate at very low membrane potentials. This leads to post-inhibitory rebound spiking when strong inhibition is present from the basal ganglia. In this way, inhibition can evoke strong firing in the postsynaptic neuron.
Bosch-Bouju, Clémentine, Brian I. Hyland, and Louise C. Parr-Brownlie. "Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions." Frontiers in computational neuroscience 7 (2013): 163.
Kim, Jeongjin, et al. "Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus." Neuron 95.5 (2017): 1181-1196.
Rubin, Jonathan E., et al. "Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects." European Journal of Neuroscience 36.2 (2012): 2213-2228.
16:50 - Thalamic Firing Modes
Several firing regimes have been suggested based on evidence in animal model systems that can include entrainment, disinhibition/gating, and rebound firing in the thalamus depending on the type of input thalamic cells receive.
Goldberg, Jesse H., Michael A. Farries, and Michale S. Fee. "Basal ganglia output to the thalamus: still a paradox." Trends in neurosciences 36.12 (2013): 695-705.
19:20 - Interim Conclusions, Updated view of Thalamic Function
An updated understanding of thalamic function deems it a central hub of neuronal activity where subcortical motor signaling is integrated and shaped. It has been proposed that first-order circuits serve to relay important information regarding movement preparation and initiation, whereas ongoing behavior is influenced by higher-order circuits which form anatomic and functional loops with other motor nuclei. This understanding, along with the introduction of several potential firing modes the thalamus might use, points out the complexities of thalamic physiology.
Sherman, S. Murray. "Thalamus plays a central role in ongoing cortical functioning." Nature neuroscience 19.4 (2016): 533.
21:40 - The Primary Motor Loop (+Cerebellum)
The cerebellum is a major glutamatergic input to the thalamus, in contrast to the largely GABAergic afferents from the basal ganglia. The major role for the cerebellum has been recognized as maintaining fluid motion, however, modern techniques have enabled studies that implicate it in far more complex motor behaviors (extended below).
Houk, J. C., et al. "Action selection and refinement in subcortical loops through basal ganglia and cerebellum." Philosophical Transactions of the Royal Society B: Biological Sciences 362.1485 (2007): 1573-1583.
Kuramoto, Eriko, et al. "Complementary distribution of glutamatergic cerebellar and GABAergic basal ganglia afferents to the rat motor thalamic nuclei." European Journal of Neuroscience 33.1 (2011): 95-109.
23:00 - Basal Ganglia Function
The basal ganglia are a group of subcortical nuclei involved in motor behavior. One way to begin understanding their function is to recognize that they are major recipients of dopaminergic signaling, which is the neurotransmitter underlying a lot of our learning processes. Therefore, it is unsurprising that a known role for the basal ganglia is in motor learning.
Another major function of the basal ganglia is "action selection". For millions of years vertebrates have been required to assess their environment and turn those assessments into actions that promote survival. Being evolutionarily conserved down to the lamprey, the basal ganglia are likely the structures involved in the process of selecting one-of-many actions. One of the major functions of each stage of the basal ganglia is to filter and refine a motor program. Many movement disorders are thought to reflect the inability if the basal ganglia to select, or accurately refine an action.
Putting these two concepts together results in the more recent suggestion, that we can understand the basal ganglia as regulating vigor. This stems from the observation that the basal ganglia are involved in scaling movement velocity rather than directing movement patterns themselves. The worsening of Parkinson’s disease symptoms, specifically, the decline in movement, may be most succinctly described as a loss of vigor.
Cui, Guohong, et al. "Concurrent activation of striatal direct and indirect pathways during action initiation." Nature494.7436 (2013): 238.
Friend, Danielle M., and Alexxai V. Kravitz. "Working together: basal ganglia pathways in action selection." Trends in neurosciences 37.6 (2014): 301-303.
Kravitz, Alexxai V., et al. "Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry." Nature 466.7306 (2010): 622.
Mink, Jonathan W. "The basal ganglia: focused selection and inhibition of competing motor programs." Progress in neurobiology 50.4 (1996): 381-425.
Turner, Robert S., and Michel Desmurget. "Basal ganglia contributions to motor control: a vigorous tutor." Current opinion in neurobiology 20.6 (2010): 704-716.
Yttri, Eric A., and Joshua T. Dudman. "Opponent and bidirectional control of movement velocity in the basal ganglia." Nature 533.7603 (2016): 402.
31:40 - Cerebellar Function
The cerebellum forms a sensorimotor feedforward motor loop with the thalamus and motor cortex. In doing so, the cerebellum is implicated not only in fluidity of movement, but also in predictive and timing functions. Recently, it has been shown that the cerebellum may be ideally situated to initiate movements based on external cues.
Understanding how the cerebellum projects through the thalamus is becoming increasingly important, as lesions to the cerebellar-recipient thalamus are therapeutic to tremor disorders. Identifying the link between Parkinson's disease, a basal ganglia disorder, and essential tremor, a disorder that complements Parkinson's disease in only some cases, remains elusive. Clues are emerging that subcortical communication between the basal ganglia and cerebellum might be critical to coordinating motor behaviors.
Bastian, A. J., and W. T. Thach. "Cerebellar outflow lesions: a comparison of movement deficits resulting from lesions at the levels of the cerebellum and thalamus." Annals of neurology38.6 (1995): 881-892.
Bostan, Andreea C., Richard P. Dum, and Peter L. Strick. "The basal ganglia communicate with the cerebellum." Proceedings of the national academy of sciences 107.18 (2010): 8452-8456.
Heiney, Shane A., et al. "Precise control of movement kinematics by optogenetic inhibition of Purkinje cell activity." Journal of Neuroscience 34.6 (2014): 2321-2330.
Lee, Ka Hung, et al. "Circuit mechanisms underlying motor memory formation in the cerebellum." Neuron 86.2 (2015): 529-540.
34:50 - Subcortical Structures Review
One interesting contrast between basal ganglia and cerebellar function is that these structures appear preferentially involved in internally versus externally guided movements, respectively. That is, cued behaviors may rely more on the cerebellum. This potentially explains why people with Parkinson's disease, a basal ganglia disorder, have trouble initiating movements, but have been observed locking their gate to an auditory metronome, catching a ball thrown to them unexpectedly, and stepping over a line spontaneously drawn before them.
Van Donkelaar, P., et al. "Neuronal activity in the primate motor thalamus during visually triggered and internally generated limb movements." Journal of Neurophysiology 82.2 (1999): 934-945.
38:30 - Hints about the Motor Cortex
The motor cortex is involved in fine motor behaviors, however, to the extent that it can also subserve movement initiation or action selection is contested. One consistent finding is that the motor cortex undergoes a degree of learning and consolidation driven by subcortical structures like the basal ganglia. In that way, the basal ganglia mirrors the function of the hippocampus, as both are involved in short-term learning but ultimately leverage the cortex for long-term storage; the only difference is that one memory is declarative, the other is motor.
Desmurget, Michel, and Robert S. Turner. "Motor sequences and the basal ganglia: kinematics, not habits." Journal of Neuroscience 30.22 (2010): 7685-7690.
42:35 - The Symphony of Movement
A metaphor for how movement is generated in the brain is not simple. If taken that a resulting movement is symphonic in quality, here is how I might put it: the basal ganglia controls what notes to play and with what veracity, the cerebellum coordinates timing and the underlying metronome that establishes a rhythm for the music, the thalamus is the symphony house where the acoustics are combined together and harmonized, and finally, the motor cortex conducts the piece from a-high, shaping and coercing all players when needed. Those are the four C's of movement.