new work with ‘the wandering nerve’ · 2018-10-23 · new work with ‘the wandering nerve’...

New Work with ‘the Wandering

Nerve’

Mark S. George, MDDistinguished Professor of Psychiatry, Radiology and Neurology

Layton McCurdy Endowed Chair

Director, Brain Stimulation Laboratory

Medical University of South Carolina

Staff Physician

Ralph H. Johnson VA Medical Center

Charleston, SC USA

Editor-in-Chief

Brain Stimulation: Basic, Translational and

Clinical Research in Neuromodulation

RANZP Meeting

Melbourne, Australia, August 2018

• Acknowledgments -

– Foundations - NARSAD, Stanley, Dana, Hope, Tiny Blue Dot

– NIMH, NINDS, NIDA, NIAAA, NASA, DARPA, DOD, VA

– Industry grants (last 20 yrs) – Brainsway, Cadwell, Cortex, Cyberonics, Dantec, Darpharma, Electrocore, Glaxo Smith Kline, Jazz, MagStim, MECTA, Medtronic, Neostim, Neosync, Neuronetics, Neotonus, St. Jude Medical.

• Disclosures -

– No equity in any device or pharma company

– Speakers fees from industry (none in past 3 years)

– Past Paid Consultant - GSK, Cyberonics, NeuroPace, Jazz

– Unpaid Consultant – Brainsway, Neuronetics, Neostim, Neosync

– Paid Consultant – Tal Medical

– Editor-in-Chief, Brain Stimulation, Elsevier

Rationale for FEAST

More focal forms

of ECT appear to

have similar

efficacy to less

focal forms.

However have

fewer

amnestic

Side effects.

Rational for FEASTTreatment efficacy

appears to correlate

with PreFrontal

alterations.

Amnestic side effects

appear to correlate

with

Fronto-Temporal

alterations.

Focal Electrically Administered

Seizure Therapy (FEAST)

Amnestic Outcome:

5.5±6.4 Mins to 4/5

N=17 age 53±16

Clinical Outcome:

-5/16 Remission

-8/16 Response

-Mainly a Feasibility and Methods Development Study

Experimented with:

-Current delivery.

-Electrode size.

-Electrode placement.

Participant/Treatment

Characteristics:

Sahlem et al, J ECT 2016

Average Time to Reorientation:

(Eyes open to 4/5 correct responses

4.4+/-3.0 mins

Columbia Autobiographical Memory Index-

Short Form: Consistency score:

97.5%+/-4.1%

0

2

4

6

8

10

12

14

16

18

20

Baseline

Tx3

Tx5

Tx6

Tx7

Tx9

Tx11

Tx13Cu

mula

vePa

entsin

EachCa

tago

ry

Figure2b

FEASTResponder

FEASTRemi er

Loo 2015 U

BP-R

UL

Loo 2008 U

BP-R

UL

Galle

tly 2

014 U

BP-R

UL

Sienae

rt 2

009

UBP-R

UL

FEAST 2

015

Sackei

m 2

009

UBP-R

UL

Spaans

2013

UBP-R

UL

Sackei

m 2

008 U

BP-R

UL

0

20

40

60

80

100

% R

em

iss

ion

Rates of Remission following FEAST or UBP-RUL

Limitations:

• Open Label Design

• Using Historical Data to Contextualize Results

• Potential for Selection Bias (We may have unintentionally selected less severe/higher functioning patients

• Potential for Expectation Bias (We may have unintentionally rated optimistically)

Acute Treatment

Phase

24 hours

following final

treatment

FEAST 6X ST treatments

3X/week until remission or

plateau in response.

1: Enrollment: SCID, ATHF, etc.

2: Baseline HRSD24, Baseline Cognitive Battery, etc.

3: Imaging

Baseline

End HRSD24, Cognitive Battery, etc.

End Imaging

UBP-RUL 6X ST treatments

3X/week until remission or

plateau in response.

Follow-up Data out to 6-Months

Current/Future Directions:

1: Trials with an UBP-RUL comparison arm

2: Studies further exploring

mechanism of action

3: Further refinement of

technique

Summary to date

**

**

Proposed Multisite comparison

• FEAST will have similar efficacy to RUL

UBP

• FEAST will have less cognitive side

effects than RUL

Main Brain Stimulation Techniques (partial listing -08/18)

• ECT - Electroconvulsive Therapy• rTMS - repeated Transcranial Magnetic Stimulation

– Depression, acute migraine

• DBS - Deep Brain Stimulation – PD, dystonia, OCD– RST - Responsive Stimulation Therapy - Neuropace– Epidural Cortical Stimulation

• VNS - Vagus Nerve Stimulation – Cervical VNS - Epilepsy, Depression– Gastric VNS – Obesity– Non-invasive Cervical – Cluster Headaches

• tDCS - transcranial Direct Current Stimulation• TENS - transcutaneous Electrical Nerve Stimulation

– Cranial Electrical Stimulation (CES) Alpha-stim

• EPI-fMRI - echoplanar fMRI – Low Field Magnetic Stimulation (LFMS)

• Transcranial pulsed ultrasound

US FDA

Approved

Not

FDA

Approved

Outline

• Quickly review Vagus Nerve Anatomy and

function

• Review invasive cervical VNS for epilepsy and

depression

• New clinical indications for VNS

– Gastric for obesity

– Non-invasive cervical for cluster headache

• Paired VNS with Behavior to induce Plasticity

– Invasive Cervical – Microtransponder – aphasia, tinnitus

– Transcranial Auricular VNS (taVNS) – infant feeding

Vagus Nerve: Cranial Nerve X

• Cranial Nerve X

• Vagus, “wandering” in Latin

• Afferent pathway to the brain

• Projects to areas believed to be responsible for seizures, mood, appetite, memory, anxiety and pain

Cranial Nerve Name

I - OlfactoryII - OpticIII - OculomotorIV - TrochlearV - TrigeminalVI - AbducensVII - FacialVIII - VestibulocochlearXI - GlossopharyngealX - VagusXI - Spinal AccessoryXII - Hypoglossal

Vagus Nerve

From Higgins and George, A Concise Overview of Brain Stimulation Therapies, 2008, APPI Press.

Figure 5.4 The vagus nerve contains approximately 100,000 afferent and efferent axons.

A closer view shows that most axons are unmyelinated (the dark circles are myelin).

Cervical Vagus Nerve with VNS Lead

Information from the

Vagus Nerve Goes Straight to

Important Brain Structures

From George MS, Sackeim HA, Rush AJ et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry, 47(4), 287-295 (2000).

Behavioral Research with VNS

• 1938 - Bailey and Bremer, VNS in cat elicited synchronous orbital cortex

activity.

• 1949 - MacLean and Pribram - VNS in monkeys, lateral frontal changes.

• 1951 - Dell and Olson - VNS evoked a slow wave response in the anterior

rhinal sulcus, as well as in the amygdala in awake cats with high cervical

spinal section.

• 1980 - MacLean - VNS in monkey - marked single unit effects on cingulate,

thalamus, basal limbic structures.

• 1985 - Zabara - dogs, VNS caused cortical EEG changes, stopped seizures.

• 1988- Kiffin Penry (Bowman-Gray), human, resistant epilepsy patient.

• 1998 - MUSC, UTSW, NYSPI, Baylor - resistant depression.

What is VNS Therapy?

• Mild pulses applied to the

left vagus nerve in the neck

send signals to the brain

• Automatic intermittent

stimulation

• Simple in-office dose

adjustment

• Assured treatment

adherence

Cyberonics, Inc. Physician’s Manual for the VNS Therapy™ Pulse Model 102 Generator and VNS Therapy™ Pulse Duo Model 102R Generator. Houston, Tex; 2003.

From Higgins and George, A Concise Overview of Brain Stimulation Therapies, 2008, APPI Press.

VNS for Epilepsy:

Current Status

• Initial efficacy and safety established in two

controlled studies (1996-8).

• FDA approved as effective long-term, adjunctive

treatment for partial seizures

• Side effects are well-tolerated and decrease with

time

• VNS does not replace antiepileptic medications or

resective surgery; however, complements

antiepileptic drug therapies

VNS Modulates Blood Flow in Key

Brain Structures in Humans via

Positron Emission Tomography

Henry et al, Neurology, 1998

Initial VNS Clinical Trial Data in

Treatment Resistant Depression

• Initial Open Pilot Study (D01)1,2,3

– Long-term open data 5

• Acute Randomized Control Trial (D02) 6

– Long-term followup 7,8

• European Open Pilot Trial (D03) 9

• Comparison Study with Treatment as Usual (D04) 4

1. Rush AJ, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000;47(4):276-86. 2. Sackeim HA, et al. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry Neuropsychol Behav Neurol 2001;14(1):53-62. 3. Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001;25(5):713-28. 4. George MS, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biological Psychiatry 2005;58(5):364-73. 5. Nahas Z, et al. Two-Year Outcome of Vagus Nerve Stimulation (VNS) Therapy for Major Depressive Episodes. Journal of ClinPsychiatry 2005;66:1097-104. 6. Rush AJ, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biological Psychiatry 2005;58(5):347-54. 7. Rush AJ, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biological Psychiatry 2005;58(5):355-63. 8. Sackeim HA, et al. Durability of Antidepressant Response to VNS. Int J Neuropsychopharmacol 2007: 1-10. 9. Schlaepfer TE, et al. VNS for depression: Efficacy and Safety in a European Study. Psychological Medicine 2008

Pivotal Acute Study: Results

(12 Weeks)

0

5

10

15

20

% R

esp

on

se

VNS

Sham-control

HAMD24

p=0.238

15

10

n=111 n=110

IDS-SR30

p=0.032

17

8

n=109 n=106

Evaluable observed.

Rush AJ, Marangell LB, Sackeim HA, George MS, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

Biological Psychiatry, 58(5), 347-354 (2005).

Statistical Significance Demonstrated for

Primary Comparison Study Analysis

Evaluable analysis.

George MS, Rush AJ, Marangell LB et al. A one-year comparison of vagus nerve stimulation with treatment as usual

for treatment-resistant depression.

Biological Psychiatry, 58(5), 364-373 (2005).

32.633.234.135.7

42.9

39.238.238.2

40.3

43.8

20

30

40

50

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

Mean

ID

S-S

R3

0S

co

re

p<0.001

Pivotal study (n=205)

Comparative study (n=124)

Tragedy of Greed

• Because of corporate greed and corner cutting, the pivotal

depression trial was underpowered, and they did not fund

another trial

• This resulted in the treatment being FDA approved, but not

funded by insurance

• Many patients remained implanted for years, and are now

having their batteries run out...

• Hopefully insurers now see how cost effective this is over

time

• With non-invasive methods, the science of VNS is

reappearing

Higher VNS Intensity – Better

Long-term Outcome

VNS antidepressant

effects build over time

From: A 5-Year Observational Study of Patients With

Treatment-Resistant Depression Treated With Vagus

Nerve Stimulation or Treatment as Usual:

Comparison of Response, Remission, and Suicidality

American Journal of Psychiatry, Aaronson, 2017

Outline


function


depression







VNS is Promising in Animal Models

of Obesity and Ischemia

Obese Pigs: 2mA, 30Hz,

500μs

Val-Laillet et al 2010

Ay et al 2008Post-Ischemia, Rats: 0.5mA, 20Hz,

500μs

Infarct Volume

Neurological Score

Other Forms of VNS

• End Organ VNS

VBLOC

• FDA approved for morbid

obesity, instead of gastric bypass

•

Non-invasive VNS?

Electrocore – marketed in Europe to stop asthma attacks/COPD

US FDA approved for cluster headaches

Outline


function


depression







VNS Paired Plasticity

• Kilgard data

• Microtransponder data

Figure 6

Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation 2015 8, 637-644DOI: (10.1016/j.brs.2015.01.408)

Copyright © 2015 Elsevier Inc. Terms and Conditions

http://www.elsevier.com/termsandconditions

Figure 9

Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation 2015 8, 637-644DOI: (10.1016/j.brs.2015.01.408)

Copyright © 2015 Elsevier Inc. Terms and Conditions

http://www.elsevier.com/termsandconditions

Multiple pilot and pivotal studies

underway with paired invasive

cervical VNS

• Motor Stroke rehabilitation

• Tinnitus

• Aphasia Recovery

MSG is on Data Safety Monitoring Board for several of these

Pharynx

Larynx

Throat

HBP

Cardiac

Appetite

Bashar W. Badran MUSC

Can we access the vagus

noninvasively through the ear?

Can we make VNS noninvasive?

• Auricular branch of the vagus nerve is marked by green color

• Auriculotemporal nerve - red color

• Lesser occipital nerve - blue color

• Greater auricular nerve - yellow color

Badran BW et al 2017 Brain Stimulation


Like all forms of neuromodulation, there is

an infinite parameter space to navigate

– Pulse Width (μs)

– Frequency (Hz)

– Dosing Amplitude (mA)

– Duty Cycle (On/Off time)

– Dose Titration

– Direct or Alternating Current


Surrogate Marker of Vagal Tone

Vagus nerve activates the parasympathetic

nervous system…

Therefore we can use heart rate as a

surrogate, objective marker of vagal tone


Feasibility -> Safety -> Autonomic Effect -> Winner

Hypothesis: taVNS is 1) feasible 2)safe and 3)parameters of

greater energy density will have greater effects on the autonomic

nervous system

Phone

Screening

Experimental Visit 1

- Either Active or Sham

- 9 Randomized Stimulation

Rounds

Experimental Visit 2

- Either Active or Sham

- 9 Stimulation Rounds

(same order as visit 1)

Visit Stimulation

Condition

Randomized

3 days

Setup

Physio.

EquipmentDetermine

P.T. for

each pulse

width

Stim.

Round A

Baseline Period

90s

Randomized Stimulation Period **

60s

Recovery Period

180s

Stim.

Round B

Stim.

Round C

Stim.

Round D

Stim.

Round E

Stim.

Round F

Stim.

Round G

Stim.

Round H

Stim.

Round I

330s

Pain VAS Pain VAS Pain VAS Pain VAS Pain VAS Pain VAS Pain VAS Pain VAS Pain VAS

330s 330s 330s 330s 330s 330s 330s 330s

EN

D

** Stimulation period consisted of 1 of 9 randomized and counterbalanced parameters

1- 100μs, 1Hz 4- 200μs, 1Hz 7- 500μs, 1Hz

2- 100μs, 10Hz 5- 200μs, 10Hz 8- 500μs, 10Hz

3- 100μs, 25Hz 6- 200μs, 25Hz 9- 500μs, 25Hz Badran BW et al 2017 (prep)

- 15 healthy adult volunteers (7 females) were enrolled

- 2-visit, counterbalanced, sham-controlled, crossover trial exploring the safety, feasibility, and autonomic response

Parametric Optimization Trial

Mean Perceptual Threshold (PT) and

Stimulation Current

Tragus (Active) Earlobe (Sham)

100us 200us 500us 100us 200us 500us

Mean 4.64 2.66 1.5 3.28 1.82 0.99

SD 1.28 0.80 0.46 0.91 0.63 0.354PT

(mA)

Stim.

Curren

t

x2

100us 200us 500us 100us 200us 500us

9.28 5.32 3 6.56 3.64 1.98(mA)

x2

500μs, 25Hz

500μs, 10Hz

500μs, 1Hz100μs, 1Hz

100μs, 10Hz

100μs, 25Hz 200μs, 25Hz

200μs, 10Hz

200μs, 1Hz

A

B

C

D

E

F

G

H

I

B.L S.T. R.E

a

c

t

i

v

e

s

h

a

m

Baseline

Active

Sham

Stimulation Recovery

Baseline Stimulation Recovery

Parameter: 500us,

25Hz

Smoothed Heart

Rate


Overall Effect of Condition on HR?

Change Scores Adjusted to

Baseline

- No real overall condition effect (p=.203)

- Overall Condition x Time effect (p=.028)

Must be parameter dependent…

Act

ive Stim

Per

iod

Sham

Stim

Per

iod

Act

ive Rec

Per

iod

Sha

m R

ec P

erio

d

-2

-1

0

1

2

3

4

5

6

Me

an

Ch

an

ge

In

HR

fro

m B

.L.

Parasympathetic

Sympathetic

Badran BW et al 2017 (prep)

Act

ive

Stim

Per

iod

Sha

m S

tim P

erio

d

Act

ive

Rec

Per

iod

Sham

Rec

Per

iod

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

7

8

Me

an

Ch

an

ge

In

HR

fro

m B

.L.

2 of 9 Parameters Have Effect of Condition on HR

500μs, 25Hz 500μs, 10Hz

Act

ive

Stim P

erio

d

Sham S

tim P

erio

d

Act

ive

Rec

Per

iod

Sham R

ec P

erio

d

-2

-1

0

1

2

3

4

5

6

7

8

9

10

Me

an

Ch

an

ge

In H

R fro

m B

.L.

Repeated Measures ANOVA

Condition Effect (P=0.057)

Repeated Measures ANOVA

Condition Effect (P=0.007)

Active Stim

Decreases HR

Active Stim

Decreases HR


Stim Period Recovery Period Stim Period Recovery Period

Ranking Parameters by Effect Size

ParameterCondition

Effect P-valuePartial Eta sq.

500us, 25Hz Yes p=0.057 0.228

500us, 10Hz Yes p=0.007 0.419

500us, 1Hz No p=0.772 0.006

200us, 25Hz No p=0.794 0.005

200us, 10Hz No p=0.557 0.025

200us, 1Hz No p=0.316 0.072

100us, 25Hz No p=0.327 0.068

100us, 10Hz No p=0.270 0.086

100us, 1Hz No p=0.426 0.046

Rank Parameter

1 500us, 10Hz

2 500us, 25Hz

3 100us, 10Hz

4 200us, 1Hz

5 100us, 25Hz

6 100us, 1Hz

7 200us, 10Hz

8 500us, 1Hz

9 200us, 25Hz

Optimal

Parameters

500μs, 10Hz

500μs, 25Hz


Next Step in Parameter Optimization

• Head to head trial between optimal 2

parameters completed and replicates (n=20)

• Determine whether the parasympathetic

modulation (Heart Rate, HRV) is due to direct

brain activation (afferent)

Can we use fMRI to measure direct brain effect?


Developing tVNS/fMRI Method to

Investigate Direct Brain Effect

• Can we scan using fMRI while

simultaneously stimulating using taVNS?

• Issues

– RF

– Back-propagating current

– Electrode heat

– MRI Artifact


How It’s DoneEquipment Room Control RoomMagnet Room

Stimulation Cable

Trigger Cable

RF

Filter


Study Design• 17 Healthy inviduals (8 female)

• 2 30min fMRI scanning visits (active/sham)

• 4 Scan Sequences

– Structural MPRAGE (visit 1 only)

– Concurrent taVNS/fMRI Scan 1/3




taVNS/fMRI Block Design

60s 60s 60s 60s 60s 30s 30s

Stim ON

OFF OFF OFF OFF

Stimulation Parameter

Left Ear

500us Pulse Width

25 Hz

2x Perceptual Threshold (mean: 3.4mA)


Stim ON Stim ON

Sham taVNS Effect

n=17, P<0.05Badran BW et al 2017

Sensory

Left

Active taVNS Effect

n=17, P<0.05 Badran BW et al 2017

Bilateral ACC

Prefrontal Cortex

Bilateral Insula

Sensory

Overall taVNS Effect (Active -

Sham)

n=17, paired t-test, P<0.005 uncorrected

Bilateral ACCPrefrontal

Thalamus

Badran BW et al 2017 (Brain Stimulation)

Developing a user friendly, portable, closed loop, double blind

transcranial auricular vagus nerve stimulation (taVNS) system for

use in pediatric and adult rehabilitation

• VNS paired with behavior promotes change, behavioral plasticity

• Used in tinnitus, post-stroke rehab (Microtransponder, invasive,

neck implant)

• taVNS may do the same, non-invasively, with less cost

• Builds on adult volunteer and fMRI work of pre-doc Bashar

Badran

• Pilot study underway in neonates with stroke, unable to learn to

feed.

Fig. 2

• Custom-made electrodes placed on the left tragus. Digitimer

• DS7AH (Fig. 1).

• Perceptual Threshold (PT) at rest prior to sessions 1 & 6 starting

with 0.1mA, frequency 25Hz, pulse width 500ms.

• We then decreased stimulation by 0.1mA below the PT and

delivered taVNS while the infant was actively sucking from the

bottle, to ensure coupling of motor activity and stimulation.

• We stopped stimulation when the infant stopped sucking, or at the

end of a 2-minute train of successful sucking (due to concerns

about skin damage from the stimulation).

• We conducted taVNS-paired feeding once a day, up to 30 minutes,

for 10-22 days.

Badran BW, Jenkins DD, et al., Transcutaneous auricular vagus nerve stimulation (taVNS) for improving oromotor function

in newborns, Brain Stimulation (2018), https://doi.org/10.1016/j.brs.2018.06.009

Methods

• Safe, well tolerated

• Mean decrease of 20 ± 9 bpm or 13 ± 5% drop in HR within 20

± 10 seconds after starting stimulation with feeding

• 5 infants had attempted p.o. feeds for 30-101 days prior to taVNS.

Daily feeding volumes at enrollment were 35-64% of total needed

feeds for the 7 days prior to treatment.

• In these infants who had feeding difficulty due to delayed initiation

of feeds from illness or prematurity, 4 of the 5 infants were able to

achieve full oral feedings and weight gain adequate for discharge.

• 3/5 infants avoided g-tube placement. 1 had g-tube placed during a

different surgery, just in case but not needed.

Badran BW, et al., Transcutaneous auricular vagus nerve stimulation (taVNS) for improving oromotor function

in newborns, Brain Stimulation (2018), https://doi.org/10.1016/j.brs.2018.06.009

Preliminary Results

Outline


function


depression







Should be another great

meeting.

See you there!!

Thanks for wandering and

wondering with me

Questions??

new work with ‘the wandering nerve’ · 2018-10-23 · new work with ‘the wandering nerve’...

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