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The cortical silent period is a period of motor inhibition following transcranial magnetic stimulation over the primary motor cortex. Transcranial magnetic stimulation over the motor cortex is useful for investigating the corticospinal pathway. In such experiments electromyography electrodes are placed on the target muscle and record the responses to a single transcranial magnetic stimulation pulse. Two responses are elicited, the first is an excitatory motor evoked potential which is immediately followed by a period of silence. Following the silence activity levels resume to those recorded pre-stimulus. This period of silence is referred to as the cortical silent period, typically lasting between 100-300ms. However, it can last up to 1000ms.

=History = The first studies to identify and investigate the cortical silent period were conducted on animals, specifically monkeys and cats. Adrian & Moruzzi first identified the existence of a silent period whilst investigating pyramidal tract responses to electrical stimulation. During these experiments, the authors delivered single-pulse electrical stimulation directly to the exposed surface of the cortex (medulla) in anaesthetised cats. One of their main findings was that this single pulse stimulation resulted in an excitatory response followed by a period of complete inactivity of the pyramidal tract.

Merton (1951) was the first to identify a silent period in a human subject however this was not caused by stimulation of the cortex. Participants' arms were held in a fixed splint, with the thumb projecting forward, two stimulating electrodes were placed on the wrist and elbow (connected to the peripheral nerve) and an indifferent electrode was placed on the upper arm. A shock was elicited whilst participants made a voluntary contraction, this shock gives rise to a large muscle action potential which is manifested as an involuntary "twitch" (lasting 100msec). The "twitch" is followed by a silent period (lasting 50msec). They argued that the silent period occurs due to changes in the afferent inflow from the muscle and is likely a reflection of the pause in the sensory discharge of the muscle spindles during the twitch. Thus, a silent period does not occur without a twitch and the two are positively correlated (the duration of the silent period increases as the duration of the twitch increases).

The ability to stimulate the human brain was historically limited due to a lack of humane, non-invasive and safe methods and many studies had tried and failed to electrically stimulate the intact human cortex. The first authors to identify the silent period in humans used a brief high-voltage electrical shock (transcranial electric stimulation) over the arm area of the motor cortex. They identified that this stimulation produced a muscle twitch in the voluntarily activated contralateral limb muscles as well as a period of suppressed electromyography activity.

Despite Merton and Marsden (1951) arguing that electrical stimulation was a safe method, many individuals felt that it was painful. Thus the development of transcranial magnetic stimulation in 1985 allowed for a safer, painless, and comfortable method to investigate the silent period, and subsequent studies employed this method

Origin
The cortical silent period has become largely established due to its reproducibility as a direct effect of transcranial magnetic stimulation and its reliability as a measure of neural inhibition. However, its origins are still unclear and largely up for debate.

Spinal Origin
There are a number of mechanisms which are believed to contribute to the spinal origin of the cortical silent period. Firstly, stimulation of the motor cortex results in activation of the spinal motor neurons which produces spinal inhibition through the activation of inhibitory Renshaw cells (the Renshaw inhibition is dependent on the level of pre-stimulus motor neuron activity). In the early part of the silent period, the Renshaw cells inhibit the motor neurons of the contracting muscle, however motor neuron excitability returns before the end of the silent period. The second mechanism is that efferent pathways from the motor cortex activate the spinal interneurons which produce inhibitory postsynaptic potentials in the spinal motor neurons (for a period of <100ms). Lastly, it is argued that the "twitch" produced by the stimulation interrupts the activity of muscle spindles and activates Golgi tendon organs which results in less activation and more inhibition. It has become largely accepted that the mechanisms for spinal origins only last around 50-100ms which suggests that spinal inhibitory mechanisms are responsible for the first part of the cortical silent period

Cortical Origin
It is suggested that most of the duration of the cortical silent period is of cortical origin. An early study used magnetic stimulation to produce a muscle response "twitch" which was then followed by the silent period. During the silent period they elicited a second stimulus (electric) which was timed to produce a second response. Despite being presented during the silent period the second stimulus produced a muscle response which was larger than the original. This suggests that the spinal motor neurons are active and that the inhibition is occurring within the brain.

One cortical mechanism of the cortical silent period is to optimize movement planning. It is believed that intracortical inhibition in the primary motor cortex is reduced during the initiation of voluntary movements, however, movement prevention is linked to rapid inhibition within the primary motor cortex. Thus, the motor-evoked potential triggered by magnetic stimulation creates high excitability of the motor cortex. The "twitch" resulting from the motor-evoked potential is an interference and an unwanted contraction that the cortex tends to avoid. The silent period allows for a balance between wanted and unwanted contractions and guarantees precision of movements and the ability to regain movement control. Another function of the cortical silent period is to compensate for the high excitability of the motor cortex (caused by motor-evoked potential) by inhibiting the motor cortex. This works to avoid further excitation of the motor neurons. There is a correlation between the motor-evoked potential amplitude, the excitability of the motor cortex and the length of the cortical silent period. For example, if the motor-evoked potential is lower, the excitability is reduced and the cortical silent period is shorter (as there is less need to stabilise the cortico-spinal neurons post-excitation).

Neurotransmitters
Gamma-aminobutyric acid (GABA) is known as an inhibitory neurotransmitter within the brain and is known to have inhibitory effects of over one second when GABAB receptors are activated within the thalamus. Thus the cortical silent period represents GABAB receptor-mediated inhibition of cortical excitability. The role of GABA in the cortical silent period is often researched for pharmacological and therapeutic use. Baclofen is a GABA agonist and has been found to elongate the cortical silent period in conditions such as dystonia (individuals with dystonia usually have shortened cortical silent periods). However, the effects of baclofen on the cortical silent period have been disputed which could indicate a need for further research on the effect of GABA on intracortical inhibition.

Dopamine has also been found to elongate the duration of the cortical silent period. The dopaminergic drug (L-dopa) which is used in the treatment of Parkinson's disease has been found to increase the cortical silent period in Parkinson's patients and a smaller but similar change can also be seen in normal subjects. This indicates that mechanisms at the basal ganglia also impact cortical inhibition.

Parkinson's Disease
Parkinson's disease is a neurological disease which affects motor control and produces symptoms such as tremors, bradykinesia and slow movement. Parkinson's disease is known to reduce the cortical silent period duration and this is likely due to the inability to control voluntary movement. Individuals with Parkinson's disease have intact primary motor cortex, and lesions occur at the level of the basal ganglia.

Huntington's
Alternatively Huntington's disease leads to a lengthened silent period. The motor symptoms of Huntington's are rigidity and abnormal posturing, thus the lengthened silent period could be a result of the increased inhibition of GABAergic neurons within the basal ganglia.

Motor Neuron Disease
The cortical silent period duration is reduced in patients with motor neuron disease when compared to controls. This altered duration is due to the cortical hyperexcitability in early motor neuron disease that is caused by the dysfunction of cortical inhibitory interneurons.

Basal Ganglia
The basal ganglia main output target is the primary motor cortex, with signals from the cortex arriving in the thalamus which then returns processed information to motor areas. This process is referred to as the cortico-basal ganglia-thalamo-cortical loop (CBGTC). There are two pathways within the loop (direct and indirect) which have opposite effects. The direct pathway activates the motor cortex and the indirect pathway inhibits the motor cortex, however, neither is thought to be activated by transcranial magnetic stimulation. It is argued that the hyper-direct pathway is significant for motor control, plays an important role in the development of mature inhibition and is associated with reactive inhibition. It is believed to be the activated pathway when voluntary movement is prepared. Thus, the hyper-direct pathway generates inhibition in the thalamus following the strong, sudden activation in the motor cortex during magnetic stimulation. This suggests that the hyper-direct pathway contributes to the later part of the cortical silent period.