Neuromodulation – what the future brings…

Alon Y. Mogilner, MD, PhDAssociate Professor of NeurosurgeryDirector, Center for Neuromodulation

NYU Langone Medical Center

Disclosures

• Medtronic neurological:– Consultant, fellowship/grant support

• St. Jude Medical:– Grant support, consultant

• Boston Scientific– Grant Support

Neuromodulation – the past…

Neuromodulation: Emerging Indications

• DBS: Currently FDA-approved for:– Movement Disorders (PD, ET, Dystonia)– Psychiatric Conditions (OCD)

• In clinical trials for:– Treatment-refractory depression– Chronic pain

• Other conditions:– Tourette’s syndrome– Brain injury states– Obesity– Cognitive/Memory Enhancement

Psychiatric Indications

• OCD:• Approved under an FDA HDE (humanitarian device

exemption)• Few cases reported in the literature• Target: anterior limb of the internal capsule (ALIC)

OCD demographics

• OCD affects approx 2-3% of the population• An estimated 4m people affected in the US• An estimated 20% of OCD patients suffer from

intractable or treatment resistant symptoms (Husted DS, 2004).

OCD Pathophysiology

• The “ventral cognitive” component of the cortico-striato-thalamo-cortical (CSTC) circuit appears central to the pathophysiology of OCD

• This circuit projects from the anterior and lateral orbitofrontal cortex (OFC) through the putamen and regulates context-related operations and response inhibition (Dougherty DD, 2010)

OCD Pathophysiology, cont’d

• The cortico-thalamic pathway (C-T), which is excitatory, lies within this circuit and runs from OFC to the thalamus to ALIC.

• It is balanced by an inhibitory pathway that runs from the OFC through the ventral striatum to the thalamus (C-S-T)

• OCD symptoms are believed to arise when the CST pathway does not appropriately inhibit the CT pathway (e.g., decreased CST or increased CT activity). (Shah DB, 2008)

OCD Pathophysiology: CSTC Circuit

Bear et al, J Clin Neurosci 2010

Anterior Capsulotomy

• Targets ALIC and underlying striatum• Disconnects PFC and DM thalamus• 3 year study n=35 reported 25 with

marked improvement, 10 with modimprovement, 5 with no change. Responders demonstrated reducedhypermetabolism in ACC, OFC, caudate(Liu, J Clin Neurosci 2008)

First DBS OCD publication: Lancet 1999

Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder

Bart Nuttin, Paul Cosyns, Hilde Demeulemeester, Jan Gybels, Björn Meyerson

Chronic electrical stimulation instead of bilateral capsulotomy was done in four selected patients with long-standing treatment-resistant obsessive-compulsive disorder. In three of them beneficial effects were observed.

ALIC Stimulation

• ALIC connects the PFC and thalamus

• Stimulation may disrupt over-active C-T pathway

• Active electrodes often involve nuc accumbens

• Typical settings

DBS lead location: ALIC

3 YR Data on DBS for OCD

• N=10 across 2 centers. Age 21-58 (6m/4f), presurgical YBOCS 32-38; 8/10 w/ depression. Not controlled/blinded

• One asymptomatic hemorrhage, one seizure and one infection. One later died from BRCA.

• DBS discontinued in 2 due to lack of efficacy (12 and 24m)• Mean YBOCS 22.3 at 36m• 4 of 8 defined as responders at 36m (> 35% reduction in

YBOCS), 6 out of 8 achieved > 25% reduction• 6 subjects able to return to work (vs 0 pre-op)• No domains of cognitive decline on f/u neuropsych

Greenberg, Neuropsychopharm 2006

3-Yr DBS outcomes, contd

Assessing Candidacy for OCD DBS

• Severe OCD meeting DSM criteria (e.g., YBOCS > 27)• At least 10 wks of a maximally tolerated dose of > 3

SSRIs and augmentation x 1m with at least 2 of the following: lithium, buspirone, clonazepam or neuroleptic

• At least 20h of behavioral therapy• Adequate compliance and dose levels• A treating psychiatrist able to follow peri- and post-

operatively

Dougherty et al, Am J Psych 2002

Obsessive picking post-DBS

Tourette’s Syndrome• Presence of motor and vocal tics, typically

beginning before age 18 and not secondary to another neurological condition

• Often comorbid ADHD and OCD (40-70%). Debated if OCD in TS is different than isolated OCD

• Prevalence between 1 – 30 out of 1000; 3x more common in males

• Frequent family history though genetics unclear• Typically wanes by end of adolescence but approx

25% still have continuation of tics in adulthood.

Tourette’s Syndrome• Presence of motor and vocal tics, typically

beginning before age 18 and not secondary to another neurological condition

• Often comorbid ADHD and OCD (40-70%). Debated if OCD in TS is different than isolated OCD

• Prevalence between 1 – 30 out of 1000; 3x more common in males

• Frequent family history though genetics unclear• Typically wanes by end of adolescence but approx

25% still have continuation of tics in adulthood.

DBS and Tourette’s

Optimal target not yet determined:Anterior limb of internal

capsuleCentromedian nucleus of

thalamusGlobus Pallidus interna

Approximately 100 cases thus far with promising but mixed results

Thalamic stim for TSAuthor Target N Effect Follow-

up

Vandewalle 1999;2003;2010

Medialthalamus

3 72-90% reduction 8-72m

Macunias 2007 Med thal 5 40% less motor; 20% more vocal tics

3m

Bajwa 2007 Med thal 1 66% reduction + improved OCD

24m

Ackermans 2011 Med thal 6 37% improvement 12m

Servello 2008 Ant/med thal 18 24-79% improvement 3-18m

Porta 2009 Med thal 15 YGTSS 76 to 36 24m

Adapted from Ackermans, World NS 2012

Most GPi and IC/NA data limited to single case reports except Martinez-Fernandez 2011 (3 pts,Gpi, 37% improvement at 18m and Servello 2009 (4 pts, IC/NA, 49-82% improvement at 26m)

A learning experience…

DBS for Depression: Clinical Trials

• Brodmann’s area 24/25 – BROADEN study (St. Jude Medical)– 18 sites– Approximately 200 patients– Randomized, double blinded trial

• VC/VS - RECLAIM study (Medtronic)– Randomized, double-blinded trial

Other indications

• Cognitive/Memory Enhancement:– Forniceal/hypothalamic stimulation

• Brain Injury States:– Medial thalamic stimulation

Peripheral Stimulation for headache and craniofacial pain

• Goadsby (1997): Stimulation of greater occipital nerve (GON) in cats resulted in increased metabolic activity of the trigeminal nucleus caudalis and cervical dorsal horn3

• Weiner (1999): Peripheral neurostimulation for occipital neuralgia4

• Goadsby (2004): ONS for migraine headache5

3. Goadsby PJ, Knight YE, Hoskin KL. Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Pain 1997; 73(1):23-8.4. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2(3):217-21.5. Matharu MS, Bartsch T, Ward N, Frackowiak RSJ, Weiner RL, Goadsby PJ. Central neuromodulation in chronic migraine patients with suboccipital stimulators: A PET study. Brain 2004;127:220-30.

Peripheral Stimulation: headache and facial pain

• Most Common technique:– Occipital Nerve Stimulation

• Occipital stimulation• “BOTH” stimulation

• Other techniques:– Trigeminal branch stimulation

• Supraorbital• Supratrochlear• Auriculotemporal

Procedure

Results: Analysis of Indications

Diagnosis Number of

PatientsNumber of Successful Trials

Number of Permanent Systems still used at Last Follow-up

7.7: Headache attributed to Chiari Malformation type I

28 18 15

1.1 or 1.2: Migraine Headache with or without Aura

24 21 19

5.2.2: Chronic post-traumatic headache attributed to mild head injury

11 10 8

13.8: Occipital Neuralgia 8 7 7

5.7.2: Post-Craniotomy Headache 7 7 6

3.1.2: Chronic Cluster Headache 5 4 4

6.1.1: Headache attributed to ischemic stroke

5 3 1

13.7: Other terminal branch neuralgias 5 4 1

11.2.1: Cervicogenic Headache 4 3 3

4.7: Hemicrania Continua 1 1 1

7.4.4:Headache attributed to hypothalamic or pituitary hyper- or hyposecretion

1 1 0

Neurostimulation for Migraine: Clinical Trials

• 3 to date, Boston Scientific, Medtronic, St. Jude• Most recent: St. Jude study

– Significant group differences for reduction in number of headache days, MIDAS, Zung PAD, VAS, quality of life and satisfaction at 12 weeks were observed (p< 0.05).

– In the Active and Control groups respectively, number of headache days (defined as a > 4 hours duration at moderate intensity) decreased by 7.3 and 4.3, total MIDAS scores improved by 64.6 and 20.4, MIDAS headache days improved by 22.5 and 3.4, PAD scores improved by 13.3 and 5.5, VAS scores decreased by 13.6 and 6.9, 37.1% and 17.3% of patients achieved a 30% reduction in VAS.

– In addition, 66.7% of patients in the Active group reported improved quality of life whereas only 17.2% of patients in the control group reported the same. For satisfaction, 51.4% of patients in the Active group reported being satisfied whereas only 19.2% in the Control group reported being satisfied.

– HOWEVER, primary endpoint (>50% pain reduction) not reached

Hardware improvements

• “Closed-loop stimulation”– System senses abnormal activity and changes

output accordingly

• “Current steering”– Multiple contacts with current fractionalization

may allow finer tuning of stimulation with fewer side effects

The future?

“The future ain’t what it used be…

Summary

• We are entering a “brave new world” of neuromodulation

• Future advances will entail:– Better understanding of pathophysiology– Improvements in technology– Clear evidence-based medicine documenting

clinical benefit…

Thank you

Email: alon.mogilner@nyumc.org

michael.pourfar@nyumc.org