We often fail to appreciate the small and precise functions of our motor system. How effortless and smooth our movements are when getting up from a chair! How quick and fine our movements are when driving a car!
These coordinated voluntary movements can be attributed to a region in the brain called the basal ganglia, which is a collection of functional nuclei. In order to prevent inappropriate bodily movements, or in other words, to enable movements only when desired, the basal ganglia has a constant inhibitory influence on the motor system. When a certain movement is desired, say, ‘getting up from a chair,’ this inhibition is reduced, thereby allowing the motor area to be activated, and the action to be carried out. This inhibitory function of our brain is analogous to a ‘red’ traffic light that controls inappropriate traffic entry. The function of the ‘traffic light’ is physiologically performed by dopamine, which is a substance produced by neurons in the substantia nigra, a region within the basal ganglia. When dopamine is released, the inhibition on the motor systems is removed for a small period (green light), and movements occur smoothly.
Sometimes, as individual ages, there is loss in the dopamine-producing neurons in the substantia nigra. This condition is known as Parkinson’s disease (PD), a progressive and degenerative movement disorder. Less dopamine means less inhibition of the motor system (longer green lights), and is thereby manifested by tremors and abnormal movements. PD is characterized by movement-related symptoms, namely, resting tremor, slowness in movements and stiffness in initiating a movement.
While there is no cure for the disorder itself, several symptoms associated with it can be alleviated by use of medications like L-dopa, which is converted into dopamine in the brain, or dopamine agonists, which mimic the effects of dopamine without being converted. If medication is unsuccessful, a surgical procedure known as deep brain stimulation (DBS) is approved to help alleviate PD symptoms. Deep brain stimulation uses a neurostimulator, a medical device, to deliver electrical stimulation to the region affected in PD, enabling controlled movements in PD patients. The subthalamic nucleus (STN), a region upstream to the PD-affected substantia nigra, is a common site for DBS procedure.
DBS is known to be effective in restoring motor function in PD patients, but the exact mechanism of its action is still largely unknown. A recent article in Neuron by Li et al. provided interesting insights into how DBS improves motor functions. They addressed the following question: when DBS is performed on the STN, does it affect the neurons in the same region, or does it, in fact, affect the neurons in the motor cortex, where the symptoms are manifested?
In this study multi-channel recording arrays were used to examine the neuronal activity (action potentials) in rat motor cortex. A drug called 6-OHDA was used to lesion the rats’ substantia nigra in order to produce a Parkinsonian-like condition. Then, a stimulating electrode was surgically implanted into the rats’ STN, where DBS was performed. While the STN was being stimulated by electrical impulses, activity of the neurons in the motor cortex was observed. Similar to medications, DBS did not correct the loss of dopaminergic neurons in the STN. But, DBS did have corrective effects in the motor cortex! What is even more intriguing is that the action potential spikes generated in the motor cortex were antidromic in nature, which means that instead of traveling from the soma to the axon, these action potentials went in the reverse direction, from axon to soma!
This research shows that DBS has its immediate action at the site of the STN, but modifies the firing potential of neurons projecting away from the cortex (cortico-efferent). It is this antidromic activation of the cortico-STN pathway that possibly contributes to the therapeutic mechanism of DBS. Previous optogenetic studies have shown that activation of neurons confined only to the STN are ineffective in alleviating PD symptoms, indicating the importance of the cortico-STN activation in DBS.
Although DBS is an already established therapy for PD, a close examination of its underlying functionality as performed by the above-mentioned team may give scope to reduce any side effects or risks associated with it.
~Li Q., Ke Y., Chan D.W., Qian Z.M., Yung K.L., Ko H., Arbuthnott G. & Yung W.H. (2012). Therapeutic Deep Brain Stimulation in Parkinsonian Rats Directly Influences Motor Cortex, Neuron, 76 (5) 1030-1041. DOI:10.1016/j.neuron.2012.09.032 Images adapted from www.extremetech.com and NIMH/Brain Stimulation Therapies.