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Journal of Neurodevelopmental Disorders
Published in: Journal of Neurodevelopmental Disorders 1/2017

Open Access 01-12-2017 | Research

Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis

Authors: Michael S. Sidorov, Gina M. Deck, Marjan Dolatshahi, Ronald L. Thibert, Lynne M. Bird, Catherine J. Chu, Benjamin D. Philpot

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2017

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Abstract

Background

Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker.

Methods

We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population.

Results

Delta power was broadly increased and more dynamic in both the Angelman syndrome mouse model, relative to wild-type littermates, and in children with Angelman syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages.

Conclusions

Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman syndrome in both preclinical and clinical settings.
Appendix
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Literature
1.
Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013;48:271–9.CrossRefPubMed
2.
Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15:70–3.CrossRefPubMed
3.
Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997;15:74–7.CrossRefPubMed
4.
5.
Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, Geschwind DH, State MW, Martin CL, Ledbetter DH. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol Psychiatry. 2013;18:1090–5.CrossRefPubMed
6.
DiStefano C, Gulsrud A, Huberty S, Kasari C, Cook E, Reiter LT, Thibert R, Jeste SS. Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome. J Neurodev Disord. 2016;8:19.CrossRefPubMedPubMedCentral
7.
Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015;518:409–12.CrossRefPubMed
8.
Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton Jr JW, Lee HM, Chen X, et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2012;481:185–9.CrossRef
9.
Daily JL, Nash K, Jinwal U, Golde T, Rogers J, Peters MM, Burdine RD, Dickey C, Banko JL, Weeber EJ. Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome. PLoS One. 2011;6, e27221.CrossRefPubMedPubMedCentral
10.
Egawa K, Kitagawa K, Inoue K, Takayama M, Takayama C, Saitoh S, Kishino T, Kitagawa M, Fukuda A. Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome. Sci Transl Med. 2012;4:163ra157.CrossRefPubMed
11.
van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila FR, Jiang YH, Elgersma Y, Weeber EJ. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. Nat Neurosci. 2007;10:280–2.CrossRefPubMed
12.
Ciarlone SL, Grieco JC, D’Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiol Dis. 2016;96:38–46.CrossRefPubMed
13.
14.
Boyd SG, Harden A, Patton MA. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr. 1988;147:508–13.CrossRefPubMed
15.
Viani F, Romeo A, Viri M, Mastrangelo M, Lalatta F, Selicorni A, Gobbi G, Lanzi G, Bettio D, Briscioli V, et al. Seizure and EEG patterns in Angelman’s syndrome. J Child Neurol. 1995;10:467–71.CrossRefPubMed
16.
Casara GL, Vecchi M, Boniver C, Drigo P, Baccichetti C, Artifoni L, Franzoni E, Marchiani V. Electroclinical diagnosis of Angelman syndrome: a study of 7 cases. Brain Dev. 1995;17:64–8.CrossRefPubMed
17.
Laan LA, Renier WO, Arts WF, Buntinx IM, vd Burgt IJ, Stroink H, Beuten J, Zwinderman KH, van Dijk JG, Brouwer OF. Evolution of epilepsy and EEG findings in Angelman syndrome. Epilepsia. 1997;38:195–9.CrossRefPubMed
18.
Minassian BA, DeLorey TM, Olsen RW, Philippart M, Bronstein Y, Zhang Q, Guerrini R, Van Ness P, Livet MO, Delgado-Escueta AV. Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Ann Neurol. 1998;43:485–93.CrossRefPubMed
19.
Buoni S, Grosso S, Pucci L, Fois A. Diagnosis of Angelman syndrome: clinical and EEG criteria. Brain Dev. 1999;21:296–302.CrossRefPubMed
20.
Valente KD, Andrade JQ, Grossmann RM, Kok F, Fridman C, Koiffmann CP, Marques-Dias MJ. Angelman syndrome: difficulties in EEG pattern recognition and possible misinterpretations. Epilepsia. 2003;44:1051–63.CrossRefPubMed
21.
Vendrame M, Loddenkemper T, Zarowski M, Gregas M, Shuhaiber H, Sarco DP, Morales A, Nespeca M, Sharpe C, Haas K, et al. Analysis of EEG patterns and genotypes in patients with Angelman syndrome. Epilepsy Behav. 2012;23:261–5.CrossRefPubMed
22.
Korff CM, Kelley KR, Nordli Jr DR. Notched delta, phenotype, and Angelman syndrome. J Clin Neurophysiol. 2005;22:238–43.CrossRefPubMed
23.
Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998;21:799–811.CrossRefPubMed
24.
Wang PJ, Hou JW, Sue WC, Lee WT. Electroclinical characteristics of seizures-comparing Prader--Willi syndrome with Angelman syndrome. Brain Dev. 2005;27:101–7.CrossRefPubMed
25.
Kriegeskorte N, Simmons WK, Bellgowan PS, Baker CI. Circular analysis in systems neuroscience: the dangers of double dipping. Nat Neurosci. 2009;12:535–40.CrossRefPubMedPubMedCentral
26.
Chu CJ, Leahy J, Pathmanathan J, Kramer MA, Cash SS. The maturation of cortical sleep rhythms and networks over early development. Clin Neurophysiol. 2014;125:1360–70.CrossRefPubMed
27.
Bruni O, Ferri R, D’Agostino G, Miano S, Roccella M, Elia M. Sleep disturbances in Angelman syndrome: a questionnaire study. Brain Dev. 2004;26:233–40.CrossRefPubMed
28.
Silber MH, Ancoli-Israel S, Bonnet MH, Chokroverty S, Grigg-Damberger MM, Hirshkowitz M, Kapen S, Keenan SA, Kryger MH, Penzel T, et al. The visual scoring of sleep in adults. J Clin Sleep Med. 2007;3:121–31.PubMed
29.
Matlis S, Boric K, Chu CJ, Kramer MA. Robust disruptions in electroencephalogram cortical oscillations and large-scale functional networks in autism. BMC Neurol. 2015;15:97.CrossRefPubMedPubMedCentral
30.
Judson MC, Wallace ML, Sidorov MS, Burette AC, Gu B, van Woerden GM, King IF, Han JE, Zylka MJ, Elgersma Y, et al. GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enhances seizure susceptibility. Neuron. 2016;90:56–69.CrossRefPubMedPubMedCentral
31.
Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9–21.CrossRefPubMed
32.
33.
McCormick DA, Bal T. Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci. 1997;20:185–215.CrossRefPubMed
34.
35.
Huang HS, Burns AJ, Nonneman RJ, Baker LK, Riddick NV, Nikolova VD, Riday TT, Yashiro K, Philpot BD, Moy SS. Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav Brain Res. 2013;243:79–90.CrossRefPubMedPubMedCentral
36.
Shaaya EA, Grocott OR, Laing O, Thibert RL. Seizure treatment in Angelman syndrome: a case series from the Angelman Syndrome Clinic at Massachusetts General Hospital. Epilepsy Behav. 2016;60:138–41.CrossRefPubMed
37.
38.
Mandel-Brehm C, Salogiannis J, Dhamne SC, Rotenberg A, Greenberg ME. Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression. Proc Natl Acad Sci U S A. 2015;112:5129–34.CrossRefPubMedPubMedCentral
39.
Larson AM, Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. Angelman syndrome in adulthood. Am J Med Genet A. 2015;167A:331–44.CrossRefPubMed
40.
Morita A, Kamei S, Mizutani T. Relationship between slowing of the EEG and cognitive impairment in Parkinson disease. J Clin Neurophysiol. 2011;28:384–7.PubMed
41.
Benz N, Hatz F, Bousleiman H, Ehrensperger MM, Gschwandtner U, Hardmeier M, Ruegg S, Schindler C, Zimmermann R, Monsch AU, Fuhr P. Slowing of EEG background activity in Parkinson’s and Alzheimer’s disease with early cognitive dysfunction. Front Aging Neurosci. 2014;6:314.CrossRefPubMedPubMedCentral
42.
Trillingsgaard A, Ostergaard JR. Autism in Angelman syndrome—an exploration of comorbidity. Autism. 2004;8:163–74.CrossRefPubMed
43.
Bonati MT, Russo S, Finelli P, Valsecchi MR, Cogliati F, Cavalleri F, Roberts W, Elia M, Larizza L. Evaluation of autism traits in Angelman syndrome: a resource to unfold autism genes. Neurogenetics. 2007;8:169–78.CrossRefPubMed
44.
Peters SU, Horowitz L, Barbieri-Welge R, Taylor JL, Hundley RJ. Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class. J Child Psychol Psychiatry. 2012;53:152–9.CrossRefPubMed
45.
Righi G, Tierney AL, Tager-Flusberg H, Nelson CA. Functional connectivity in the first year of life in infants at risk for autism spectrum disorder: an EEG study. Plos One. 2014;9.
46.
Duffy FH, Als H. A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls—a large case control study. BMC Med. 2012;10:64.CrossRefPubMedPubMedCentral
47.
Peters JM, Taquet M, Vega C, Jeste SS, Fernandez IS, Tan J, Nelson CA, Sahin M, Warfield SK. Brain functional networks in syndromic and non-syndromic autism: a graph theoretical study of EEG connectivity. BMC Med. 2013;11.
48.
Gabard-Durnam L, Tierney AL, Vogel-Farley V, Tager-Flusberg H, Nelson CA. Alpha asymmetry in infants at risk for autism spectrum disorders. J Autism Dev Disord. 2015;45:473–80.CrossRefPubMedPubMedCentral
49.
Coben R, Clarke AR, Hudspeth W, Barry RJ. EEG power and coherence in autistic spectrum disorder. Clin Neurophysiol. 2008;119:1002–9.CrossRefPubMed
50.
Heunis TM, Deng CA, de Vries PJ. Recent advances in resting-state electroencephalography biomarkers for autism spectrum disorder—a review of methodological and clinical challenges. Pediatr Neurol. 2016;61:28–37.CrossRefPubMed
51.
Jeste SS, Frohlich J, Loo SK. Electrophysiological biomarkers of diagnosis and outcome in neurodevelopmental disorders. Curr Opin Neurol. 2015;28:110–6.CrossRefPubMed
52.
Al Ageeli E, Drunat S, Delanoe C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, et al. Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases. Eur J Med Genet. 2014;57:5–14.CrossRefPubMed
53.
Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, Schanen NC, Esmer C, Lamport D, Reiter LT. The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature. Autism Res. 2013;6:268–79.CrossRefPubMedPubMedCentral
54.
Frohlich J, Senturk D, Saravanapandian V, Golshani P, Reiter LT, Sankar R, Thibert RL, DiStefano C, Huberty S, Cook EH, Jeste SS. A quantitative electrophysiological biomarker of duplication 15q11.2-q13.1 syndrome. PLoS One. 2016;11, e0167179.CrossRefPubMedPubMedCentral
55.
Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–7.CrossRefPubMed
56.
Qin M, Kang J, Burlin TV, Jiang CH, Smith CB. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neurosci. 2005;25:5087–95.CrossRefPubMed
57.
Qin M, Schmidt KC, Zametkin AJ, Bishu S, Horowitz LM, Burlin TV, Xia ZY, Huang TJ, Quezado ZM, Smith CB. Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice. J Cereb Blood Flow Metab. 2013;33:499–507.CrossRefPubMedPubMedCentral
58.
Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012;74:49–56.CrossRefPubMed
59.
Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Transl Med. 2012;4:152ra128.CrossRefPubMed
60.
Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RK, Bear MF. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron. 2013;77:243–50.CrossRefPubMedPubMedCentral
61.
Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med. 2012;4:152ra127.CrossRefPubMed
62.
Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016;8:321ra325.CrossRef
63.
Jeste SS, Geschwind DH. Clinical trials for neurodevelopmental disorders: at a therapeutic frontier. Sci Transl Med. 2016;8.
Metadata
Title
Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis
Authors
Michael S. Sidorov
Gina M. Deck
Marjan Dolatshahi
Ronald L. Thibert
Lynne M. Bird
Catherine J. Chu
Benjamin D. Philpot
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neurodevelopmental Disorders / Issue 1/2017
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI
https://doi.org/10.1186/s11689-017-9195-8

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