Advances in Tinnitus
Imaging and Treatment
The Brain at War 2015
Steven W. Cheung
Staff Physician, Surgical Service, SFVAMC
University of California, San Francisco
15 October 2015
Disclosure
• No personal financial or institutional interest in any of
the drugs, materials, or devices discussed in this
presentation.
Cheung and Larson (2010) Neuroscience
Agenda
Background - Tinnitus Definition and Observations
 Rationale for a Basal Ganglia-Centric Approach
 Visualizing Tinnitus by fMRI
 Modulating Tinnitus by Deep Brain Stimulation
 Identifying New Treatment Targets
 Extending Work to Tinnitus in TBI

Tinnitus Overview

Common Condition with Varying Levels of Distress

10%-15% Prevalence in Adults

3% Interferes with Work, Sleep, Concentration, and Social
Interactions

0.5% Tinnitus Severely Disrupts “Normal” Life
 Chronic Auditory Pain

13 Million in US and Europe Seek Care

Veterans Compensable Disability
 $0.5 B 2008
 $1.0 B 2011
 $2.0 B 2020
Tinnitus – Auditory Phantoms
Auditory Percept Without an External Source
Pathophysiology
 Aberrant Activity Originating from the Auditory System


Hyperactivity; Synchronized Oscillations; Reorganized Cortical Maps
Brain Networks Acting in Concert
Tinnitus-Related Distress
 Modulators


Limbic: Mood (anxiety, depression); Reinforced Behavior (OCD); Stress
Sensorimotor: Auditory (hyperacusis); Somatic; Motor (eye, cervical)
Basal Ganglia Target Selection
General Role of the Basal Ganglia
A multisensory integration system that:
• Detects interpretations of motor and sensory
patterns
• Releases responses
Basal Ganglia Medial Surface
Area
LC
CH
1.
2.
3.
4.
5.
6.
7.
NA
8.
9.
Head of Caudate Nucleus
Body of Caudate Nucleus
Caudatolenticular Gray Bridge
Putamen
Tail of Caudate Nucleus
External segment of Globus
Pallidus
Internal segment of Globus
Pallidus
Amygdaloid Body
Nucleus Accumbens
Diffuse Basal Ganglia Lesion
Case Report
•
•
•
•
63 M with chronic tinnitus, louder in
the poorer ear.
Left CVA involving body of caudate
and adjacent subcortical structures.
Tinnitus suppressed completely.
Asymmetric hearing loss remained
unchanged.
Lowry et al (2004) Otol Neurotol
Focal Basal Ganglia Lesion
Case Report
•
•
•
•
56 F with chronic tinnitus and
Parkinson’s disease.
Left focal caudate infarction following
deep brain stimulation (DBS) lead
placement.
Tinnitus suppressed substantially.
Symmetric hearing loss remained
unchanged.
Larson and Cheung (2012) Neurosurgery
Deep Brain Stimulation System
Anchor Secures
Probe to the skull
Probe Delivers stimulation
to deep brain nuclei
Programmer Communicates
with the Controller to customize
therapy
Connector Establishes
link to the Controller
Controller Determines
parameters for brain
stimulation and houses the
power source
TWO ELECTRICAL STIMULATION EXPERIMENTS IN THE CAUDATE NUCLEUS
Neuromodulation of Auditory Phantoms
▫ Loudness Level
(0-none; 5-conversation; 10-jet engine)
▫ Sound Quality
(description)
Summary of Deep Brain Stimulation in Area LC
Tinnitus Loudness & Sound Qualia Modulation
Subject
(age/gender)
& side of
stimulation
Stimulation
parameters in
frequency &
pulse width
A (63/m)
Right/Left
Stimulation
threshold to
effect in volts
(range)
Tinnitus
baseline
quality
Tinnitus
baseline
loudness
(0-10 scale)
Tinnitus
loudness at
stimulation
threshold
Area LC
Neuromodulation effect
Microlesion
effect
Tonal
5 Left
1 Right
0 Left
1 Right
Suppress
existing phantom
B (51/m)
Right
185 Hz
90 µsec
5V
(0 - 8)
Noise-like
5 Left
5 Right
0 Left
0 Right
Suppress
existing phantom
C (57/m)
Right
180 Hz
90 µsec
10V
(0 - 10)
Cricket-like
5 Left
5 Right
1 Left
1 Right
Suppress
existing phantom
D(67/m)
Right
150 Hz
60 µsec
4V
(0 - 8)
Musical
4 Left
4 Right
2 Left
2 Right
Suppress
existing phantom
E (66/m)
Right
185 Hz
90 µsec
3V
(0 - 8)
Tonal
3 Left
7 Right
2 Left
2 Right
Suppress
existing phantom
F (61/m)
Right
180 Hz
60 µsec
4V
(0 - 10)
None
0 Left
0 Right
2 Left
0 Right
Trigger
click sequences
G (50/f)
Right
10 Hz
60 µsec
2V
(0 - 10)
None
0 Left
0 Right
6 Left
0 Right
Trigger
jet takeoff sounds
H (67/f)
Left
10 Hz
60 µsec
4V
(0 - 10)
None
0 Left
0 Right
1 Left
1 Right
Trigger
creaking sounds
Cheung and Larson (2010) Neuroscience
Larson and Cheung (2012) Neurosurgery
Testable Hypothesis:
Abnormal Corticostriatal Connectivity
Resting-State fMRI: Chronic Tinnitus with
Hearing Loss versus Normal Controls
Hinkley et al. (2015) Frontiers in Human Neuroscience
Increased Corticostriatal Connectivity is
Specific to Area LC
Hinkley et al. (2015) Frontiers in Human Neuroscience
From Observation to Intervention:
Phase I Clinical Trial
Tinnitus Treatment Overview
Reduce Contrast
Mask Phantom Percept
Suppress Hyperactivity
Reclassify Phantom Percept
Reduce Saliency
Mitigate Emotional Distress
Examples
o
o
o
Examples
Hearing Aids
Maskers
Neuromonics
o
o
o
Auditory-Limbic Connectivity
Network Dynamics Modulation
Examples
Transcranial Magnetic Stimulation
o Direct Electrical Stimulation
o
Tinnitus Retraining
Cognitive-behavioral therapy
Fractal tones
Phase I Clinical Trial
o NIH/NIDCD U01 (8 – 10 Subjects; 3 Implanted)
o Key Inclusion Criterion: TFI > 50
o Enrollment Start Date: April 2014
o Specific Aims
 To estimate the treatment effect size of DBS in area
LC on tinnitus severity (TFI score).
 To assess preliminary safety and tolerability of DBS
in area LC (neuropsychological assays).
Study Flowchart
Three Subjects: Early Observations
• Unilateral caudate nucleus stimulation has
strongest effects on the ipsilateral ear.
• Tinnitus Loudness: softer or louder.
• Tinnitus Sound Quality: FM and AM changes.
• Tinnitus Spatial Location: from a particular ear
to a quadrant of the acoustic scene.
• No seizures or serious adverse events.
New Treatment Targets and Biomarkers
Multimodal Brain Imaging
3T fMRI
7T Spectroscopy
MEGI
3T Resting-State fMRI Potential Targets
Hinkley et al. (2015) Frontiers in Human Neuroscience
7T Spectroscopy Potential Biomarkers
GABA-edited MRS at 7T (#3203)
GABA+ = GABA + MM
For the in vivo dataset, the macro-molecules (MM) resonating at 3.0
ppm couple to spins at 1.7 ppm and are co-edited in the editing cycles.
The placement of editing pulses at 2.0 and 1.4 ppm removed the effect
of GABA overestimation due to MMs (GABA+).
Li et al. (2015) unpublished data
MEGI Potential Biomarkers
• Increased connectivity with tinnitus :
▫ Bilateral middle frontal gyrus
 Consistent with previous findings (Chen, et al 2015)
▫ Left inferior parietal lobule
▫ Left postcentral gyrus
3 regions with increased connectivity
in participants with tinnitus (p<0.05)
• Associations between THI score and decreased
connectivity was seen in the superior parietal lobule
Demopoulos et al. (2015) unpublished data
Next Step: Tinnitus in Mild TBI
• Tinnitus and associated auditory impairments
following blast exposure mTBI is common (60%).
• Paucity of studies to address peripheral and
central consequences.
• Leverage “TRACK TBI: A Precision Medicine
Approach” subjects and infrastructure to execute
next study.
Investigators and Collaborators
Deep Brain Stimulation: Paul Larson
fMRI: Leighton Hinkley, Pratik Mukherjee, &
Srikantan Nagarajan
MR Spectroscopy: Yan Li
MEGI: Danielle Mizuiri and Carly Demopoulos
Contacts
Steven.Cheung@ucsf.edu (PI)
Jennifer.Henderson-Sabes@ucsf.edu (DBS and Imaging)
Danielle.Mizuiri@ucsf.edu (Imaging)
Sarah.Wang@ucsf.edu (DBS)