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

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 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

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

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.

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

TWO ELECTRICAL STIMULATION EXPERIMENTS IN THE CAUDATE NUCLEUS

Neuromodulation of Auditory Phantoms▫ Loudness Level

(0-none; 5-conversation; 10-jet engine)

▫ Sound Quality(description)

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

Testable Hypothesis:Abnormal Corticostriatal Connectivity

Hinkley et al. (2015) Frontiers in Human Neuroscience

Resting-State fMRI: Chronic Tinnitus with Hearing Loss versus Normal Controls

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 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

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).

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.

Multimodal Brain Imaging3T fMRI

7T SpectroscopyMEGI

New Treatment Targets and Biomarkers

3T Resting-State fMRI Potential Targets

Hinkley et al. (2015) Frontiers in Human Neuroscience

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

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)

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.

Deep Brain Stimulation: Paul LarsonfMRI: Leighton Hinkley, Pratik Mukherjee, &

Srikantan NagarajanMR Spectroscopy: Yan LiMEGI: Danielle Mizuiri and Carly Demopoulos

Investigators and Collaborators

Contacts

Steven.Cheung@ucsf.edu (PI)Jennifer.Henderson-Sabes@ucsf.edu (DBS and Imaging)Danielle.Mizuiri@ucsf.edu (Imaging)Sarah.Wang@ucsf.edu (DBS)