Basal Ganglia Neuromodulation for No personal financial or - PDF document

9/4/2013 Disclosure Basal Ganglia Neuromodulation for • No personal financial or institutional interest in any Tinnitus Suppression of the drugs, materials, or devices discussed in this presentation. Audiology Amplification Update XI Steven W. Cheung University of California, San Francisco 1 November 2013 Tinnitus – Auditory Phantoms Agenda Auditory Percept Without an External Source Pathophysiology  Background  Aberrant Activity Originating from the Auditory System  New Onset Tinnitus Clinical Course  Hyperactivity; Synchronized Oscillations; Reorganized Cortical Maps  Basal Ganglia Overview  Brain Networks Acting in Concert  Target Selection for Deep Brain Stimulation (DBS) Tinnitus ‐ Related Distress  DBS of the Striatum: Two Experiments  Auditory Phantom Qualia Uncorrelated with Tinnitus Severity  Tinnitus Conceptual Model  Loudness Level; Sound Character  Phase I Clinical Trial  Modulators  Limbic System: Reinforcement, Mood, Behavior  Others: Eye, Facial, Cervical Movements; Sounds 1

9/4/2013 Tinnitus Functional Index (0 – 100 score) Therapeutic Modalities ≤ 10 (not a problem), 10-20 (small problem), 30-40 (moderate problem), 40-60 (big problem), and 60-90 (very big problem) Reduce Contrast Reclassify Phantom Percept Mask Phantom Percept Reduce Saliency Suppress Hyperactivity Mitigate Emotional Distress Examples Examples o Hearing Aids o Tinnitus Retraining o Maskers o Cognitive-behavioral therapy o Cochlear Implants o Neuromonics o Cortical Stimulation o Fractal tones o Vagal N Stimulation o Antidepressants Auditory-Striatal-Limbic Connectivity Disrupt Information Conveyance Examples o Transcranial Magnetic Stimulation o Direct Electrical Stimulation o Basal Ganglia Neuromodulation Investigational Therapies ‘Natural History’ of New Auditory Phantoms Initial Complaints ( ≤ 3 months) ▫ Unfamiliar ▫ Relatively loud ▫ Commands attention ▫ Intrusive and annoying Typical Course (6 – 12 months; 80%) ▫ Familiar ▫ Much softer ▫ Easy to ignore ▫ Not particularly noticeable Atypical Course ( ≥ 1 year; 20%) ▫ Familiar ▫ Remains relatively loud ▫ Still commands attention ▫ Drives associated emotional and behavioral reactions 2

9/4/2013 General Role of the Basal Ganglia Medial Surface of the Basal Ganglia 1. Head of Caudate Nucleus 2. Body of Caudate Nucleus A multisensory integration system that: 3. Caudatolenticular Gray Bridge 4. Putamen • Detects interpretations of sensory patterns 5. Tail of Caudate Nucleus • Releases responses 6. External segment of Globus Pallidus 7. Internal segment of Globus Pallidus 8. Amygdaloid Body 9. Nucleus Accumbens 3

9/4/2013 Corticobasal Loops and Interconnectivity Functional Loops of the Basal Ganglia Limbic to Sensorimotor Connections Sensorimotor ▫ Sensorimotor (Auditory) and Premotor Cortices ▫ Tectum (Colliculi) DLS – Dorsolateral Striatum Associative ▫ Dorsolateral Prefrontal Cortex ▫ Lateral Orbitofrontal Cortex IL - Infralimbic ▫ Higher Order Auditory Cortex Limbic ▫ Limbic and Paralimbic Cortices ▫ Hippocampus ▫ Amygdala Diffuse Basal Ganglia Lesion 63 year old otolaryngologist with 40 year history of mostly constant, high ‐ pitched tinnitus. Tinnitus was mostly louder in the left ear, with episodic increases in loudness. Audiogram showed right moderate and left moderate ‐ to ‐ severe sensorineural hearing losses. Left hemispheric stroke involving ‘the more dorsal part of Basal Ganglia Target Selection the corona radiata. In addition there is involvement of the neostriatum, including the body of the caudate and the caudodorsal aspect of the putamen. As such it most likely involves thalamocortical radiations and corticothalamic projection in addition to corticocortical fibers running in the superior longitudinal fasciculus.’ o Tinnitus Suppressed Completely o Hearing Remained Unchanged Lowry et al (2004) Otol Neurotol 4

9/4/2013 Focal Basal Ganglia Lesion Deep Brain Stimulation System 56 year old woman underwent deep brain stimulation (DBS) for implantation of the left subthalamic nucleus for medically refractory Parkinson’s disease. Baseline ‘hissing’ tinnitus Anchor Secures was reported to be reduced on the first postoperative day. Long ‐ term data showed Probe to the skull enduring outcomes. Connector Establishes Probe Delivers stimulation link to the Controller to deep brain nuclei Controller Determines parameters for brain stimulation and houses the Programmer Communicates power source with the Controller to customize o Tinnitus Suppressed Substantially therapy o Hearing Remained Unchanged Larson and Cheung (2012) J Neurosurgery Caudate Nucleus (Area LC) – DBS Target T WO E LECTRICAL S TIMULATION E XPERIMENTS IN THE C AUDATE N UCLEUS • The caudate is routinely traversed during deep brain stimulation surgery for movement disorders. Neuromodulation of Auditory Phantoms ▫ Opportunity to perform acute caudate stimulation experiments without altering the surgical procedure. ▫ Loudness Level ▫ Study population with known nigrostriatal dysfunction. ▫ Sound Quality • IRB approval obtained. 5

9/4/2013 Loudness Level Modulation Caudate Nucleus Confirmed by Stealth Trajectory and Microelectrode Recordings Sound Quality Modulation Summary of Deep Brain Stimulation in Area LC Tinnitus Loudness & Sound Qualia Modulation Subject Stimulation Stimulation Tinnitus Tinnitus Tinnitus Area LC (age/gender) parameters in threshold to baseline baseline loudness at Neuromodulation effect & side of frequency & effect in volts quality loudness stimulation stimulation pulse width (range) (0 ‐ 10 scale) threshold A (63/m) Microlesion 5 Left 0 Left Suppress Tonal Right/Left effect 1 Right 1 Right existing phantom B (51/m) 185 Hz 5V 5 Left 0 Left Suppress Noise ‐ like Right 90 µsec (0 ‐ 8) 5 Right 0 Right existing phantom C (57/m) 180 Hz 10V 5 Left 1 Left Suppress Cricket ‐ like Right 90 µsec (0 ‐ 10) 5 Right 1 Right existing phantom D(67/m) 150 Hz 4V 4 Left 2 Left Suppress Musical Right 60 µsec (0 ‐ 8) 4 Right 2 Right existing phantom E (66/m) 185 Hz 3V 3 Left 2 Left Suppress Tonal Right 90 µsec (0 ‐ 8) 7 Right 2 Right existing phantom F (61/m) 180 Hz 4V 0 Left 2 Left Trigger None Right 60 µsec (0 ‐ 10) 0 Right 0 Right click sequences G (50/f) 10 Hz 2V 0 Left 6 Left Trigger None Right 60 µsec (0 ‐ 10) 0 Right 0 Right jet takeoff sounds H (67/f) 10 Hz 4V 0 Left 1 Left Trigger None Left 60 µsec (0 ‐ 10) 0 Right 1 Right creaking sounds Cheung and Larson (2010) Neuroscience Larson and Cheung (2012) Neurosurgery 6

9/4/2013 Tinnitus Conceptual Framework Striatal Neuromodulation Effects on Tinnitus Key Features • Baseline loudness of auditory phantoms was modulated, to higher and lower perceptual levels.  Instruction on details of phantom percepts are represented in the central auditory system. ▫ Mostly Bilateral • New auditory phantoms may be triggered in a  Permission to gate candidate phantom percepts for conscious awareness is controlled by the controllable manner. dorsal striatum. ▫ Mostly Contralateral  Action to attend, reject or accept phantom • No changes to hearing with acute stimulation. percepts, and form perceptual habits is decided by the ventral striatum. • No seizures up to 10V stimulation.  Determination of tinnitus distress severity is mediated through the limbic and paralimbic system ‐ nucleus accumbens ‐ ventral striatum loop. Phase I Clinical Trial Study Flowchart o NIH/NIDCD Funded (8 – 10 Subjects) o Key Inclusion Criterion: TFI > 50 o Enrollment Starts Winter 2013 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). o Enrollment Starts Winter 2013 7

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