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Advances in Tinnitus Imaging and Treatment
The Brain at War 2015
Steven W. CheungStaff Physician, Surgical Service, SFVAMC
University of California, San Francisco15 October 2015
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Disclosure•No personal financial or institutional interest in any of
the drugs, materials, or devices discussed in this presentation.
Cheung and Larson (2010) Neuroscience
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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
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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
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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)
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Basal Ganglia Target Selection
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General Role of the Basal Ganglia
A multisensory integration system that:• Detects interpretations of motor and sensory
patterns• Releases responses
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Basal Ganglia Medial Surface1. Head of Caudate Nucleus2. Body of Caudate Nucleus3. Caudatolenticular Gray Bridge4. Putamen5. Tail of Caudate Nucleus 6. External segment of Globus
Pallidus 7. Internal segment of Globus
Pallidus8. Amygdaloid Body9. Nucleus Accumbens
AreaLC
CH
NA
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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
Diffuse Basal Ganglia Lesion
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Larson and Cheung (2012) Neurosurgery
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.
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Probe Delivers stimulation to deep brain nuclei
Anchor SecuresProbe to the skull
Connector Establisheslink to the Controller
Programmer Communicates with the Controller to customize therapy
Controller Determines parameters for brain stimulation and houses the power source
Deep Brain Stimulation System
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TWO ELECTRICAL STIMULATION EXPERIMENTS IN THE CAUDATE NUCLEUS
Neuromodulation of Auditory Phantoms▫ Loudness Level
(0-none; 5-conversation; 10-jet engine)
▫ Sound Quality(description)
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Subject (age/gender)
& side of stimulation
Stimulation parameters in frequency & pulse width
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
A (63/m)Right/Left
Microlesion effect Tonal 5 Left
1 Right0 Left1 Right
Suppressexisting phantom
B (51/m)Right
185 Hz90 µsec
5V(0 - 8) Noise-like 5 Left
5 Right 0 Left0 Right
Suppressexisting phantom
C (57/m)Right
180 Hz90 µsec
10V(0 - 10) Cricket-like 5 Left
5 Right 1 Left1 Right
Suppressexisting phantom
D(67/m)Right
150 Hz60 µsec
4V(0 - 8) Musical 4 Left
4 Right 2 Left2 Right
Suppressexisting phantom
E (66/m)Right
185 Hz90 µsec
3V(0 - 8) Tonal 3 Left
7 Right 2 Left2 Right
Suppressexisting phantom
F (61/m)Right
180 Hz60 µsec
4V(0 - 10) None 0 Left
0 Right2 Left0 Right
Triggerclick sequences
G (50/f)Right
10 Hz60 µsec
2V(0 - 10) None 0 Left
0 Right6 Left0 Right
Triggerjet takeoff sounds
H (67/f)Left
10 Hz60 µsec
4V(0 - 10) None 0 Left
0 Right1 Left1 Right
Triggercreaking sounds
Cheung and Larson (2010) NeuroscienceLarson and Cheung (2012) Neurosurgery
Summary of Deep Brain Stimulation in Area LCTinnitus Loudness & Sound Qualia Modulation
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Testable Hypothesis:Abnormal Corticostriatal Connectivity
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Hinkley et al. (2015) Frontiers in Human Neuroscience
Resting-State fMRI: Chronic Tinnitus with Hearing Loss versus Normal Controls
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Increased Corticostriatal Connectivity is Specific to Area LC
Hinkley et al. (2015) Frontiers in Human Neuroscience
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From Observation to Intervention:Phase I Clinical Trial
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Tinnitus Treatment Overview
Reduce Contrast Mask Phantom Percept Suppress Hyperactivity Examples
o Hearing Aidso Maskerso Neuromonics
Reclassify Phantom Percept Reduce Saliency Mitigate Emotional Distress Examples
o Tinnitus Retrainingo Cognitive-behavioral therapyo Fractal tones
Network Dynamics Modulation Examples
o Transcranial Magnetic Stimulationo Direct Electrical Stimulation
Aud
itory Lim
bic
Auditory-Limbic Connectivity
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Phase I Clinical Trial
o NIH/NIDCD U01 (8 – 10 Subjects; 3 Implanted)o Key Inclusion Criterion: TFI > 50o Enrollment Start Date: April 2014o 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).
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Study Flowchart
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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.
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Multimodal Brain Imaging3T fMRI
7T SpectroscopyMEGI
New Treatment Targets and Biomarkers
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3T Resting-State fMRI Potential Targets
Hinkley et al. (2015) Frontiers in Human Neuroscience
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7T Spectroscopy Potential Biomarkers
Li et al. (2015) unpublished data
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+).
GABA-edited MRS at 7T (#3203)
GABA+ = GABA + MM
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MEGI Potential Biomarkers
Demopoulos et al. (2015) unpublished data
• Increased connectivity with tinnitus :▫Bilateral middle frontal gyrus
Consistent with previous findings (Chen, et al 2015)
▫Left inferior parietal lobule▫Left postcentral gyrus
• Associations between THI score and decreased connectivity was seen in the superior parietal lobule
3 regions with increased connectivity in participants with tinnitus (p<0.05)
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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.
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Deep Brain Stimulation: Paul LarsonfMRI: Leighton Hinkley, Pratik Mukherjee, &
Srikantan NagarajanMR Spectroscopy: Yan LiMEGI: Danielle Mizuiri and Carly Demopoulos
Investigators and Collaborators
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Contacts
[email protected] (PI)[email protected] (DBS and Imaging)[email protected] (Imaging)[email protected] (DBS)