Clinical trial NCT03972202: The Role of Cerebellum in Speech
Official title: The Role of Cerebellum in Speech
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Cerebellar Ataxia
Dysarthria
Healthy
Keywords: dysarthria
ataxia
cerebellum
cerebellar
adult
speaking
language
TMS
MRI
speech
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: University of California, Berkeley
name: National Institute on Deafness and Other Communication Disorders (NIDCD)
name: University of Wisconsin, Madison
First posted: 2019-06-03
Enrollment: 660
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This study will investigate the how the cerebellum is involved in speech motor learning over time and short-term corrections in patients with cerebellar ataxia and healthy controls. This will be accomplished through three approaches: behavioral studies, magnetic resonance imaging (MRI), and transcranial magnetic stimulation (TMS). During behavioral studies, participants will be asked to speak into a microphone while their voice is played back over earphones, and to do other speaking tasks. MRI will be acquired to perform a detailed analysis on brain function and anatomy related to speech and the cerebellum. In healthy controls, TMS will also be performed to temporarily disrupt the cerebellum before, during, or after the participant performs speaking tasks. Patients with cerebellar ataxia and healthy volunteers will be asked to complete behavioral studies and/or MRI; healthy volunteers may be asked to additionally participate in TMS.

Detailed description: This study will investigate the role of the cerebellum in speech, building upon prior work in understanding cerebellar function in reaching and walking. Neuroimaging and lesion studies have provided strong evidence that the cerebellum is an integral part of the speech production network, though its precise role in the control of speech remains unclear. Furthermore, damage to the cerebellum (either degenerative or focal) can lead to ataxic dysarthria, a motor speech disorder characterized, in part, by impaired articulation and severe temporal deficits. This project seeks to bridge the gap between theoretical models of cerebellar function and the speech symptoms associated with ataxic dysarthria. Two mechanisms underlie speech motor control - feedback and feedforward control. In feedback control, speakers use sensory feedback (e.g., of their own voice) to control their speech. In feedforward control, speakers use knowledge gained from their past speech productions, rather than on-line feedback, to control their speech. This study entails a systematic plan to elucidate the role of the cerebellum in feedforward and feedback control of speech. A central hypothesis is that the cerebellum is especially critical in the feedforward control of speech, but has little involvement in feedback control. To explore this hypothesis, we will obtain converging evidence from three innovative methodologies: 1) Neuropsychological studies of speech-motor responses to real-time altered auditory feedback in patients with cerebellar atrophy (CA) and matched healthy controls, 2) Parallel studies in healthy controls undergoing theta-burst transcranial magnetic stimulation to create "virtual lesions" of the cerebellum, and 3) Structural and functional studies in CA patients to examine the relationship between cerebellar lesion location, dysarthria symptoms, and feedforward and feedback control ability.

Speech provides an important opportunity to examine how well current theories of cerebellar function generalize to a novel effector (vocal tract) and sensory (auditory) domain. Its purpose for communication imposes exacting spectro-temporal constraints not seen in other motor domains. Furthermore, the distinctive balance of feedback and feedforward control in speech allows us to examine changes in both control types subsequent to cerebellar damage. Critically, this is the first work examining the link between theoretically motivated control deficits in CA patients and the speech symptoms associated with ataxic dysarthria, as well as their neural correlates.

Eligibility criteria: Inclusion criteria:

* Diagnosis of cerebellar ataxia (CA) resulting from degeneration of the cerebellum AND normal hearing abilities OR
* Healthy volunteers with no known history of physical or neurological abnormalities AND normal speech, hearing, and reading abilities
* For some studies, primary language of American English may be required

Exclusion criteria for healthy volunteers:

* Neurological impairment or psychiatric illness

Exclusion criteria for participants with cerebellar ataxia (CA):

* Neurological impairment or psychiatric illness apart from those arising from cerebellar damage

Exclusion criteria for participants with CA or for healthy volunteers participating in MRI (may still be eligible for other study procedures):

* Any contraindication to participating in an MRI study including the following: implanted metallic parts or implanted electronic devices, including pacemakers, defibrillators, stimulators, or implant medication pump, or nonremovable piercings; aneurysm clip or other metal in the head (except mouth); claustrophobia precluding MRI

Exclusion criteria for healthy volunteers participating in TMS (may still be eligible for other study procedures):

* Any contraindications to participating in a TMS study including the following: epilepsy, use of certain medications, heart disease, and pregnancy; scalp wounds or infections; any other contraindication discovered during screening procedures
* Any contraindication to participating in an MRI study including the following: implanted metallic parts or implanted electronic devices, including pacemakers, defibrillators, or implant medication pump, or nonremovable piercings; claustrophobia precluding MRI

Exclusion criteria for all potential participants:

* Pregnant or trying to become pregnant (may still be eligible for behavioral studies only)
* History of alcohol abuse, illicit drug use or drug abuse or significant mental illness
* Hypertensive or hypotensive condition
* Any condition that would prevent the subject from giving voluntary informed consent
* Enrolled or plans to enroll in an interventional trial during this study
* Ongoing seizures that are not well controlled despite medication
* Use of hearing aid or other device to improve hearing

Primary outcomes:
measure: Speech-motor response percent compensation
timeFrame: Baseline
measure: Dysarthria symptoms
timeFrame: Baseline
measure: Voxel-based morphometry (VBM)
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: University of California, Berkeley
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Madison
country: United States
facility: University of Wisconsin--Madison
state: Wisconsin
Study officials:
affiliation: University of California, San Francisco
name: John F. Houde, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Srikantan S. Nagarajan, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Berkeley
name: Richard Ivry, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Ben Parrell, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chang EF, Niziolek CA, Knight RT, Nagarajan SS, Houde JF. Human cortical sensorimotor network underlying feedback control of vocal pitch. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2653-8. doi: 10.1073/pnas.1216827110. Epub 2013 Jan 23.
citation: Hinkley LB, Marco EJ, Brown EG, Bukshpun P, Gold J, Hill S, Findlay AM, Jeremy RJ, Wakahiro ML, Barkovich AJ, Mukherjee P, Sherr EH, Nagarajan SS. The Contribution of the Corpus Callosum to Language Lateralization. J Neurosci. 2016 Apr 20;36(16):4522-33. doi: 10.1523/JNEUROSCI.3850-14.2016.
citation: Kort NS, Cuesta P, Houde JF, Nagarajan SS. Bihemispheric network dynamics coordinating vocal feedback control. Hum Brain Mapp. 2016 Apr;37(4):1474-85. doi: 10.1002/hbm.23114. Epub 2016 Feb 25.
citation: Ranasinghe KG, Gill JS, Kothare H, Beagle AJ, Mizuiri D, Honma SM, Gorno-Tempini ML, Miller BL, Vossel KA, Nagarajan SS, Houde JF. Abnormal vocal behavior predicts executive and memory deficits in Alzheimer's disease. Neurobiol Aging. 2017 Apr;52:71-80. doi: 10.1016/j.neurobiolaging.2016.12.020. Epub 2017 Jan 3.
citation: Moberget T, Gullesen EH, Andersson S, Ivry RB, Endestad T. Generalized role for the cerebellum in encoding internal models: evidence from semantic processing. J Neurosci. 2014 Feb 19;34(8):2871-8. doi: 10.1523/JNEUROSCI.2264-13.2014.
citation: Sokolov AA, Miall RC, Ivry RB. The Cerebellum: Adaptive Prediction for Movement and Cognition. Trends Cogn Sci. 2017 May;21(5):313-332. doi: 10.1016/j.tics.2017.02.005. Epub 2017 Apr 3.
citation: Koch G, Oliveri M, Torriero S, Salerno S, Lo Gerfo E, Caltagirone C. Repetitive TMS of cerebellum interferes with millisecond time processing. Exp Brain Res. 2007 May;179(2):291-9. doi: 10.1007/s00221-006-0791-1. Epub 2006 Dec 5.
citation: Jenkinson N, Miall RC. Disruption of saccadic adaptation with repetitive transcranial magnetic stimulation of the posterior cerebellum in humans. Cerebellum. 2010 Dec;9(4):548-55. doi: 10.1007/s12311-010-0193-6.
citation: Parrell B, Agnew Z, Nagarajan S, Houde J, Ivry RB. Impaired Feedforward Control and Enhanced Feedback Control of Speech in Patients with Cerebellar Degeneration. J Neurosci. 2017 Sep 20;37(38):9249-9258. doi: 10.1523/JNEUROSCI.3363-16.2017. Epub 2017 Aug 23.
citation: Parrell, B., Agnew, Z., Houde, J., Nagarajan, S., & Ivry, R. (2016) Individuals with cerebellar degeneration correct for within-category variation of vowels even in the absence of auditory feedback. Talk presented at Society for Neuroscience 2016, San Diego, CA, November 2016.
citation: Parrell, B. (2017). Evidence for reward learning in speech production. Poster presented at the 7th International Conference on Speech Motor Control, Groningen, the Netherlands, July 2017.
citation: Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.
citation: Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.
citation: Oberman L, Edwards D, Eldaief M, Pascual-Leone A. Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol. 2011 Feb;28(1):67-74. doi: 10.1097/WNP.0b013e318205135f.
citation: Tarapore PE, Picht T, Bulubas L, Shin Y, Kulchytska N, Meyer B, Berger MS, Nagarajan SS, Krieg SM. Safety and tolerability of navigated TMS for preoperative mapping in neurosurgical patients. Clin Neurophysiol. 2016 Mar;127(3):1895-900. doi: 10.1016/j.clinph.2015.11.042. Epub 2015 Dec 11.
citation: Tarapore PE, Picht T, Bulubas L, Shin Y, Kulchytska N, Meyer B, Nagarajan SS, Krieg SM. Safety and tolerability of navigated TMS in healthy volunteers. Clin Neurophysiol. 2016 Mar;127(3):1916-8. doi: 10.1016/j.clinph.2015.11.043. Epub 2015 Dec 11. No abstract available.
citation: Wassermann EM. Side effects of repetitive transcranial magnetic stimulation. Depress Anxiety. 2000;12(3):124-9. doi: 10.1002/1520-6394(2000)12:33.0.CO;2-E.
citation: Tarapore PE, Findlay AM, Honma SM, Mizuiri D, Houde JF, Berger MS, Nagarajan SS. Language mapping with navigated repetitive TMS: proof of technique and validation. Neuroimage. 2013 Nov 15;82:260-72. doi: 10.1016/j.neuroimage.2013.05.018. Epub 2013 May 20.
citation: Tarapore PE, Tate MC, Findlay AM, Honma SM, Mizuiri D, Berger MS, Nagarajan SS. Preoperative multimodal motor mapping: a comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation. J Neurosurg. 2012 Aug;117(2):354-62. doi: 10.3171/2012.5.JNS112124. Epub 2012 Jun 15.