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Applause sign

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This article is about the diagnostic test. For applause signs in TV show production, see Studio audience.

The applause sign is a behavioural indicator, relevant to neurodegenerative conditions, characterised by a patient’s inability to execute the same number of hand claps as demonstrated by an examiner.[1]

Background

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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]

Indicative uses and mechanisms

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Frontal lobe dysfunction

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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[8] results.

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]

Basal ganglia dysfunction

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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).

The basal ganglia and its relevant substructures

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] Hence, when the STN is dysfunctional, unwanted movements such as additional claps go unprevented,[18] and we see appearance of the applause sign.

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

Combined mechanism (Frontalstriatal disconnection syndrome)

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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).

List of conditions associated with frequent appearance

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Evidence of clinical effectiveness

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As a test of neurodegenerative disorder

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The applause sign has been able to identify patients with neurodegenerative conditions from healthy controls at 100% success rate.[1][3][5]

When identifying PSP

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Separating PSP patients and healthy controls using the sign had a mean success rate of 64.7% across 4 known studies, effectiveness as high as 85% in one.[5][21][22][24]

Appearance of the sign, when used in conjunction with 4 classical parkinsonian disease findings, enables highly accurate PSP diagnosis.[25]

When identifying FTD

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One study reported the sign as present in 80% of patients with the disinhibited subtype of the behavioral variant of FTD (bvFTD).[24]

As a test of executive function

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TCT scores show correlation with Stroop test scores[24] and performance on the Initiation/Preservation task of the Dementia rating scale results,[26] which are both common measures of executive function.

As part of a combined test of cognitive impairment

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A Rapid Cognitive Screen Test (RCS-T) combined with a triple test of the applause and two other signs appears effective in identifying specific cognitive impairment.[27]

Criticisms

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Lacking specificity

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The applause sign is detectable in any condition impacting the frontal lobe,[3] so it often fails to discriminate between neurodegenerative conditions, including PSP from parkinsonian disorders, and CBD from MSA.[21] The applause sign is also present in 72% of patients with any form of cognitive impairment, regardless of whether this is mild cognitive impairment (MCI) or dementia.[28]

Additionally, it may also reflect only certain condition subtypes, rather than all forms: in one study, prevalence of applause sign was 63% in atypical parkinsonism and only 29% in typical PD.[20] Another reported the occurrence of the sign in cortical dementias patients as 10%, but a much higher 39% in cortico-subcortical dementia patients.[23]

The applause sign also fails to discriminate between individuals who clap more and individuals who clap less[24] than 3 times, sometimes called a non-applause sign. Both of these demonstrate an applause sign, but which of these response categories they fall into changes the dysfunctional motor initiative responsible for failure.[24]

The applause sign's non-specificity may make it more appropriate as part of wider diagnostic framework, or as an observational clue, similar to glabellar, masseter, and palmomental signs in parkinsonian disorders.[2]

Contradictory evidence from Alzheimer's research

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One study finds no correlation between results of a test of motor behaviour (Luria motor sequence) and the applause sign.[4] If the applause sign demonstrates motor disruption as theorised,[5] then this presents significant opposition to that claim.

This criticism has been downplayed on the basis that applause sign exclusively reflects motor perseveration and therefore association to performance in motor planning and execution tests is unlikely.[4]

Lack of published research

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22 distinct studies exist[2] on the applause sign and its effectiveness. Within this, only 129 PSP patients have been examined across 6 studies, including one sample of only 5.[2] Relation to CBD is based on 2 studies sampling 2 and 9 participants.[2] Small sample sizes hugely reduce generalisability of findings. Further studies about the diagnostic properties of the applause sign must come forward to clarify its practical value and specific role as a sign of frontostriatal disconnection.[2]

References

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  1. ^ a b c Dubois, B.; Defontaines, B.; Deweer, B.; Malapani, C.; Pillon, B. (1995). "Cognitive and behavioral changes in patients with focal lesions of the basal ganglia". Advances in Neurology. 65: 29–41. ISSN 0091-3952. PMID 7872147.
  2. ^ a b c d e f g h i j Moura, João (2021-01-20). "A Round of Applause: A Review of the Applause Sign". Sinapse. 21 (4). doi:10.46531/sinapse/ar/210054/2021 (inactive 2024-11-15). ISSN 1645-281X. S2CID 246397507.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  3. ^ a b c d e f g h Luzzi, S.; Fabi, K.; Pesallaccia, M.; Silvestrini, M.; Provinciali, L. (2011-08-01). "Applause sign: is it really specific for Parkinsonian disorders? Evidence from cortical dementias". Journal of Neurology, Neurosurgery & Psychiatry. 82 (8): 830–833. doi:10.1136/jnnp.2010.224394. ISSN 0022-3050. PMID 21245475. S2CID 27191862.
  4. ^ a b c d e Luzzi, Simona; Fabi, Katia; Pesallaccia, Martina; Silvestrini, Mauro; Provinciali, Leandro (2012-07-20). "Applause sign in Alzheimer's disease: relationships to cognitive profile and severity of illness". Journal of Neurology. 260 (1): 172–175. doi:10.1007/s00415-012-6608-1. ISSN 0340-5354. PMID 23010943. S2CID 8971544.
  5. ^ a b c d e f g h i Schönecker, Sonja; Hell, Franz; Bötzel, Kai; Wlasich, Elisabeth; Ackl, Nibal; Süßmair, Christine; Otto, Markus; Anderl-Straub, Sarah; Ludolph, Albert; Kassubek, Jan; Huppertz, Hans-Jürgen; Diehl-Schmid, Janine; Riedl, Lina; Roßmeier, Carola; Fassbender, Klaus (2018-12-01). "The applause sign in frontotemporal lobar degeneration and related conditions". Journal of Neurology. 266 (2): 330–338. doi:10.1007/s00415-018-9134-y. ISSN 0340-5354. PMID 30506397. S2CID 54434291.
  6. ^ a b Anneser, Johanna M.H.; Krzovska, Marija; Borasio, Gian Domenico; Danek, Adrian (October 2015). "Occurrence of the "applause sign" in patients with amyotrophic lateral sclerosis". Clinical Neurology and Neurosurgery. 137: 8–10. doi:10.1016/j.clineuro.2015.06.005. ISSN 0303-8467. PMID 26117556. S2CID 27063600.
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  11. ^ Rubia, Katya; Smith, Anna B; Brammer, Michael J; Taylor, Eric (September 2003). "Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection". NeuroImage. 20 (1): 351–358. doi:10.1016/s1053-8119(03)00275-1. ISSN 1053-8119. PMID 14527595. S2CID 25940084.
  12. ^ Aron, Adam; Schlagheckent, Friedericka; Fletcher, Paul; Bullmore, Ed; Eimert, Martin; Sahakian, Barbara; Robbins, Trevor (June 2001). "Modulation of premotor cortex caused by subliminal priming in a reaction time experiment". NeuroImage. 13 (6): 1123. doi:10.1016/s1053-8119(01)92448-6. ISSN 1053-8119. S2CID 54312524.
  13. ^ Brown, Jason W.; Chobor, Karen L. (1989-01-01). "Frontal lobes and the problem of perseveration". Journal of Neurolinguistics. 4 (1): 65–85. doi:10.1016/0911-6044(89)90005-5. ISSN 0911-6044. S2CID 53187027.
  14. ^ Braak, H.; Braak, E. (September 1991). "Neuropathological stageing of Alzheimer-related changes". Acta Neuropathologica. 82 (4): 239–259. doi:10.1007/bf00308809. ISSN 0001-6322. PMID 1759558. S2CID 668690.
  15. ^ Braak, H.; Braak, E. (April 1996). "Evolution of the neuropathology of Alzheimer's disease". Acta Neurologica Scandinavica. 94 (S165): 3–12. doi:10.1111/j.1600-0404.1996.tb05866.x. ISSN 0001-6314. PMID 8740983. S2CID 23604326.
  16. ^ Ray Li, Chiang-Shan; Yan, Peisi; Sinha, Rajita; Lee, Tien-Wen (July 2008). "Subcortical processes of motor response inhibition during a stop signal task". NeuroImage. 41 (4): 1352–1363. doi:10.1016/j.neuroimage.2008.04.023. ISSN 1053-8119. PMC 2474693. PMID 18485743.
  17. ^ Basinger, Hayden; Joseph, Joe (2023), "Neuroanatomy, Subthalamic Nucleus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644428, retrieved 2023-03-28
  18. ^ Caligiore, Daniele; Mannella, Francesco; Arbib, Michael A.; Baldassarre, Gianluca (2017-03-30). "Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome". PLOS Computational Biology. 13 (3): e1005395. Bibcode:2017PLSCB..13E5395C. doi:10.1371/journal.pcbi.1005395. ISSN 1553-734X. PMC 5373520. PMID 28358814.
  19. ^ Adams, Christopher; Suescun, Jessika; Haque, Anam; Block, Kelly; Chandra, Shivika; Ellmore, Timothy M.; Schiess, Mya C. (2023-01-27). "Updated Parkinson's disease motor subtypes classification and correlation to cerebrospinal homovanillic acid and 5-hydroxyindoleacetic acid levels". Clinical Parkinsonism & Related Disorders. 8: 100187. doi:10.1016/j.prdoa.2023.100187. ISSN 2590-1125. PMC 9922918. PMID 36793590.
  20. ^ a b c d e Abdo, W. F.; Norden, A. G. W.; Laat, K. F.; Leeuw, F-E.; Borm, G. F.; Verbeek, M. M.; Kremer, P. H. P.; Bloem, B. R. (October 2007). "Diagnostic accuracy of the clapping test in Parkinsonian disorders". Journal of Neurology. 254 (10): 1366–1369. doi:10.1007/s00415-007-0551-6. ISSN 0340-5354. PMID 17934886. S2CID 24380493.
  21. ^ a b c d e Wu, Laura J.C.; Sitburana, Oraporn; Davidson, Anthony; Jankovic, Joseph (2008-12-15). "Applause sign in parkinsonian disorders and Huntington's disease". Movement Disorders. 23 (16): 2307–2311. doi:10.1002/mds.22090. ISSN 0885-3185. PMID 18972544. S2CID 25748671.
  22. ^ a b c Somme, Johanne; Gómez-Esteban, Juan Carlos; Tijero, Beatriz; Berganzo, Koldo; Lezcano, Elena; Zarranz, Juan Jose (August 2013). "The applause sign and neuropsychological profile in progressive supranuclear palsy and Parkinson's disease". Clinical Neurology and Neurosurgery. 115 (8): 1230–1233. doi:10.1016/j.clineuro.2012.11.013. ISSN 0303-8467. PMID 23253819. S2CID 23110215.
  23. ^ a b c Isella, Valeria; Rucci, Francesco; Traficante, Debora; Mapelli, Cristina; Ferri, Francesca; Appollonio, Ildebrando M. (2012-12-02). "The applause sign in cortical and cortical-subcortical dementia". Journal of Neurology. 260 (4): 1099–1103. doi:10.1007/s00415-012-6767-0. ISSN 0340-5354. PMID 23212756. S2CID 36293600.
  24. ^ a b c d e f Luzzi, S.; Fabi, K.; Pesallaccia, M.; Cafazzo, V.; Silvestrini, M.; Provinciali, L. (2014-01-31). "To clap or not to clap? Applause sign in apathetic and disinhibited/stereotypical behavioural variants of FTD". Journal of Neurology, Neurosurgery & Psychiatry. 85 (7): 823–824. doi:10.1136/jnnp-2013-307116. ISSN 0022-3050. PMID 24487382. S2CID 45620669.
  25. ^ Carota, Dr Antonio (2014-03-29). "Applaud please".
  26. ^ Tomic, Svetlana; Vladetic, Mirjana; Solic, Kresimir; Misevic, Sanja; Soldo, Silva Butkovic (2013-12-01). "The applause sign in Parkinson's disease patients is related to dysexecutive syndrome". Journal of Clinical Neuroscience. 20 (12): 1734–1736. doi:10.1016/j.jocn.2013.02.024. ISSN 0967-5868. PMID 23972562. S2CID 40495084.
  27. ^ Isik, Ahmet T.; Soysal, Pinar; Kaya, Derya; Usarel, Cansu (March 2018). "Triple test, a diagnostic observation, can detect cognitive impairment in older adults". Psychogeriatrics. 18 (2): 98–105. doi:10.1111/psyg.12289. ISSN 1479-8301. PMID 29409161. S2CID 3749734.
  28. ^ Bonello, M.; Larner, A. J. (2016). "Applause sign: screening utility for dementia and cognitive impairment". Postgraduate Medicine. 128 (2): 250–253. doi:10.1080/00325481.2016.1118353. ISSN 1941-9260. PMID 26560747. S2CID 205452306.
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