Applause sign

The applause sign was first described by Dubois and colleagues in 1995, as "a simple test of motor control that helps to differentiate Progressive supranuclear palsy (PSP) from frontal or striatofrontal degenerative diseases",^[1] but has since appeared in various neurodegenerative conditions involving frontal lobe dysfunction.^[2]

The applause sign is identified by the three-clap test (TCT), where the patient is asked 'to clap three times as quickly as possible after demonstration'.^[3] The subject shows the applause sign when they fail to clap three times, usually continuing past 3.^[3] PSP patients are most common displayers of the sign,^[2] with occasional appearances in individuals with corticobasal degeneration, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease.^{[2][3][4][5][6]}

The applause sign can indicate frontal lobe dysfunction^[3] because deliberate movement functions are localised to the brain's frontal lobe, meaning all control of deliberate movement like clapping is the responsibility of frontal lobe structures.^[7] Hence, when the frontal lobe functions abnormally, an inability to execute movement according to intention results.^[8]

Ability to stop actions as and when intended is a process key to the applause sign, and to which voluntary movement control is integral. The inferior frontal gyrus is the specific part of the frontal lobe^[9] responsible for generating stop processes.^[10][11][12] Hence, when a patient experiences frontal lobe dysfunction, the inferior frontal gyrus is impacted, resulting in movement perseveration (an abnormal prolongation of current activity),^[13] and appearance of the applause sign.

Higher frequency of the applause sign in severe than mild and moderate Alzheimer's^[4] evidences this mechanism, with frontal lobe dysfunction only a feature of severe cases.^[14][15] FMRI studies in healthy participants also show increased activity in the frontal lobe during stop-signal tasks similar to the TCT.^[16]

The applause sign can also reflect dysfunction of the subthalamic nucleus (STN) and pallidum,^[5] two structures involved in function of the basal ganglia (a small group of brain structures involved in voluntary movement control networks).

Normal function of the STN prevents unwanted movement through its influence in the basal ganglia. It stimulates the pallidum to decrease activity in the thalamus, another structure implicated in movement control, which decreases movement.^[17] When the STN is dysfunctional, unwanted movements such as additional claps go unprevented,^[18] and the applause sign appears.

This mechanism is supported by correlation between TCT scores and high scores from a test of basal ganglia dysfunction (UPDRS part III).^[5][19]

One study^[2] proposes a combined mechanism, involving both the basal ganglia and the inferior frontal gyrus.

When basal ganglia pathways are dysfunctioning, the inferior frontal gyrus and other motor preparation areas stop receiving normal input from the basal ganglia about when to stop preparing and executing observed actions.^[20] This results in continuous activity in this imitation processing circuitry.^[20] Hence, we observe an inability to stop imitation of claps when desired during the TCT.

This mechanism may reflect increased prevalence of the sign in PSP patients,^[2] since PSP is associated with damage to both the frontal lobe and basal ganglia structures simultaneously. It may also explain why the sign appears regardless of if the individual's condition is predominantly frontal or predominantly subcortical (the level of the basal ganglia).

• Progressive supranuclear palsy^{[21][22][3][5]}
• Parkinson's disease^[20][21][22]
• Corticobasal degeneration^[21][20] and syndrome^[23][5]
• Alzheimer's disease^[23][4]
• Frontotemporal dementia^[3][24]
• Amyotrophic lateral sclerosis (ALS)^[5][6]