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The Mechanism(s) of Deep Brain Stimulation
Deep brain stimulation (DBS) is the application of high-frequency electrical stimulation to deep brain structures as a treatments of neurological and psychiatric disorders such as Parkinson’s disease (PD), dystonia and depression. High-frequency stimulation are sent through implanted electrodes, provided by a medical device called a neurostimulator to specific targets in the subcortical structures of the brain (brain nuclei).

DBS to internal globus pallidus (GPi), subthalamic nucleus (STN) and thalamus are used to treat symptoms of movement disorder such as Parkinson’s disease, dystonia, seizures, tremors and differ in their action of mechanism. DBS normalizes or alters the pathophysiological states of movement disorders in Parkinson’s disease as well as other movement disorders. PD is a neurodegenerative disorder caused by the progressive depletion of nigrostriatal dopaminergic neurons of the substantia nigra pars compacta. Depletion of the dopaminergic neurons induces motor dysfunction such as akinesia, tremors, rigidity. The exact mechanism of action of DBS is unknown due to different hypothesis existing, one being the inhibition hypothesis and another excitation hypothesis. Rather than a single mechanism, there are several non-exclusive mechanism found that vary in importance and are dependent on the condition being treated and specific targets being stimulated,  provide different mechanisms ..

Brain structures involved
In the brain, dopamine acts as neurotransmitter, that send signals through several distinct dopamine pathways, where in various parts of the brain are involved in the role of reward-motivated behaviour, hormone control and motor control. For each dopamine pathway in the brain, release are modulated by two mechanisms; phasic and tonic transmission. Phasic dopamine release, is the release of neurotransmitters in the nervous system driven by action potentials in cells containing dopamine. Tonic dopamine transmission is the release of small amounts of dopamine released without being preceded by presynaptic action potentials and regulation varies in factors including activity of other neurons and neurotransmitter re uptake. Direct pathway of movement is the neuronal path through the basal ganglia enabling the initiation and execution of voluntary movement and diseases involved results in hypokinesia - a disease leading to a lack of motion. Whereas indirect pathway of movement aids the prevention of unwanted muscle contractions from voluntary movements and interruptions or dysfunctions in pathway results in dyskinesias – a disease that leads to the production of additional involuntary muscle activity.

Inhibition Hypothesis of DBS
Firing rate model is when dopamine depletion can reduce and make changes to both tonic excitatory and inhibitory inputs to the GPi and external globus pallidus (GPe) – regulator of voluntary movement. Dopamine provides tonic excitatory inputs to striatal. Dopamine provides tonic excitatory inputs to striatal direct pathways towards the GPi and tonic inhibitory inputs to striatal indirect pathways neurons projected towards the exterior parts of the (GPe). Dopamine depletion causes changes for both excitatory and inhibitory inputs by increasing firing rates of the GPi and substantia nigra pars reticulata (SNr). Increased mean firing rates in the nuclei output of the basal ganglia induces decreased activity within the motor control system of the thalamic and the provision of cortical neurons - allowing activity in voluntary movement that can result in akinesia. Firing rates changes within the basal ganglia were found in MPTP-induced parkinsonian monkeys, where increased firing rates occurred in the GPi and STN whilst decreased firing rates in the GPe. Hyperkinetic disorders that exhibit involuntary movement such as dystonia and hemiballism have been found to have decreased firing rates in the GPe and GPi and the development of involuntary movement’s disorder are due to the reduction in inhibitory inputs to the thalamus from the GPi pathway. The periodic and/or synchronised firings of the basal ganglia disables individual neurons from processing and relaying motor-related information causing the failure of appropriate movements. Similar, the firing pattern model is the depletion of dopamine that enhances connectivity between the GPe and STN whilst promoting oscillatory activity in the basal ganglia. Recorded bursts of abnormal firing patterns in the GPe, GPi and STN of parkinsonian monkeys and parkinsonian patients show the excitation of these neurons through their axon afferents.

Initial hypothesis
Observations of the similar effects of high-frequency stimulation and lesion therapy created the original idea that of the mechanism of DBS shared the same effects of lesion therapy to the same brain regions. Pallidotomy for the treatment of PD - where a tiny electrical probe is placed in the GPi (one of the basal nuclei of the brain) using heat to destroy that area of brain cells. High-frequency stimulation shared therapeutic effects similar to ablative surgery so initial hypothesis thought DBS acted as a reversible lesion by inhibiting neurons near stimulating electrode sites. DBS was instead found to have reversible and adjustable functions that are not similar to lesion therapy when treating movement disorders. Such as DBS to the ventral intermediate nucleus of the thalamus has been found to reduce resting tremors. DBS target to the STN and GPi have been used as treatment of PD and dyskinseia - a side effect of L -DOPA treatment, whilst DBS of the GPi for dystonia have found to improve symptoms The various clinical benefits of DBS do not provide the exact mechanism underlying its action mechanism.

The similar effects of DBS to those of lesion therapy created the initial hypothesis known as the inhibition hypothesis - DBS inhibits local neuronal elements. This was changed to DBS of the STN and GPi inhibited the firings of neighboring neurons of these regions and was explained as the firing rate and firing pattern model. The excitation hypothesis broadly states DBS excites local neuronal elements just as how a single stimulation does where DBS of STN and GPi excites their efferent - nerve fibres - and effects the GPi and thalamus.

Inhibition hypothesis
Similar to the initial hypothesis, the inhibition hypothesis derives from the effects of high frequency stimulation on neighbouring neurons of the STN and GPi occurs. In PD patient’s high frequency stimulation of 100-300 Hz to site of STN suppressed neuronal activity by producing inhibition in 42% of the 60 cells tested after initial stimulation whilst during stimulation inhibition was seen in 13 of 15 neurons, with a inhibitory period of 15-20ms after each stimulation. In 44% of high frequency stimulation producing inhibitions, early inhibitions were followed by excitation and inhibitory period that could be explained as hyperpolarization. Microstimulation to PD patients GPi have shown inhibitory effects on neuron activity near stimulation sites (where electrodes are placed) where 22/23 cells were inhibited with a duration of 10-25ms. Microstimulation (5Hz of 0.15 pulses) within the GPi excites striatal axon terminals and/or external pallidal neuron that causes the release of GABA as well as inhibits GPi neurons.

Excitation hypothesis
DBS excites local neuronal elements through spikes (firing patterns) when GPi is stimulated in GPi neurons. Reduced oscillatory bursts in thalamic neurons of parkinsonian monkeys and dystonia patients were found in GPi- DBS. In crab-eating macaques it was found high frequency stimulation produced reduced activity during stimulation in 77% of thalamic neurons. Of the 77%, 16% of the responsive cells increased in discharge during stimulation and, stimulation produced high levels of muscle contraction (rigidity). During stimulation thalamic neurons had a reduction in burst frequency and duration, therefore high-frequency stimulation within GPi interrupts abnormal patterns of thalamic discharge seen in parkinsonian symptoms. Subthreshold DBS, a stimulation too small to produce an action potential in excitable cells, suppresses essential firings in the cell bodies, whilst suprathreshold, produces action potentials in excitable cells and thus excites efferent axons and induces spikes to the target neclues.