Brain Stimulation for Memory

Mijail “Misha” D. Serruya, M.D., Ph.D.

Outline

• Definitions of memory and stimulation• Macrostimulation• Microstimulation• Optical• Challenges

Memory

• Procedural

• Episodic– Binding of item and context– Spatial context & navigation– Temporal context– Mental time travel

• Semantic

Stimulation

Non-Invasive

rTMS

tDCS

tACS, tSOS

Implanted

Electrical

Epidural/SubduralDepth/DBS/GridsLow impedance <1kΩ1-5 mm diameter0.5 to 15 mA

Cortical MEADepth microwires100kΩ to 2MΩ10 to 100μm contacts50 to 100 μA

Platinum-iridium, steel MicroMacro

Optical ChemicalBiologic

Microfluidics

Stimulation to Elicit Memory

• A seizure as ‘natural’ stimulation– Perirhinal ‘familiarity’ separate from context

experienced as déjà vu preceding an MTL seizure• Penfield:

– Cortical macro-stimulation could induce vague sensations of familiarity or vivid re-living or recollection of a memory

• Example: Reported patient who would hear orchestral piece at same tempo as it was originally heard; stopped when stimulation stopped and would restart at beginning when stimulation repeated

Basal Forebrain DBS• Hamani, Laxton, Lozano and colleagues• Hypothalamic fornix DBS in single patient in attempt to treat

obesity– Serendipitously provoked reversible retrievable of distinct

autobiographical episodes– EEG source localized activation to MTL / HF

• In 1969 Heath reported septal auto-stimulation in humans• Patient B7: zap awake out of narcoleptic

stupor; sexual• Patient B10: zap out of psychotic rage

into tranquil bliss• +4 decades: pilot trial:

• 6 patients with mild or probable AD• Mean age 62 years old• Fornix DBS for one year

θ

Basal Forebrain

Anterior commissure

Substantia inominata

(nucleus basalis of Meynert)

Amygdaloid complex

Septal nuclei

Uncinate fasciculus

Ventral pallidum

Diagonal band of Broca

fornix

SS

Fornix DBS

Stay tuned

What is going on?

‘Blind’open-loop 130 Hz?

Metabolic benefit vs cognitive benefit?

Entorhinal Cortex DBS• Suthana, Fried and colleagues• MTL (EC & hipp) macro-stimulation in patients with

medically refractory epilepsy

• Patients learned destinations in a virtual environment

• In half trials, focal stimulation (below after-discharge threshold) applied• Patients reached landmarks that were learned while

accompanied by EC stim more quickly and efficiently than locations that were not accompanied by stimulation

• Hippocampal stimulation had no such effect

• What is going on?• Enhancing salience of

incoming sensory information into perf path?

• Opposite: silencing EC input to enhance CA auto-association?

• How account for multiple comparisons?

• How account for propensity to wander aimlessly for prolonged period in ‘yellow cab’ task (adding significant noise)?

• How would it work in real world?

• Zap yourself when you park your car to solidify memory of where you parked it?

+

ball

treetime

tree

flag

-SME

+SME

SME = Subsequent

Memory Effect

baseline power

gamma power increased compared to baseline

Free Recall Task

• Kahana, Lega, Burke, Jacobs and colleagues• Verbal instead of spatial memory• A signature of enhanced encoding

Cortical Surface Macrostim

+tree!

time

ball

flag

tree

Leverage the SignatureElectrical Stimulation

+

ball

tree!

time

tree

flag

Leverage the SignatureClosed-Loop Real-time Feedback

Targeted Closed-Loop Microstimulation• Hampson, Deadwyler, Berger and colleagues• Macrostimulation non-specifically activates larger volumes of gray matter and

white matter fibers of passage in a possibly diffuse, modulatorymanner• Microstimulation specifically targets smaller volumes of gray matter, including

hippocampal sub-fields, hence could transmit specific information • Difference between enhancing an already existing circuit versus imparting an

entirely new circuit

Perforant path

Schaffer collaterals Subiculum

Mossy fiber pathway

Dentate gyrus Entorhinal

cortexAssociational commisure

Basic Hippocampal Circuit

• Long loop: • EC2DGGCCA3CA1subiculumEC5

• Short loops:• EC3CA1EC5

• CA3 project mainly to CA1 and to recurrent CA3 population

• It works!• Enhanced learning when activated• Restored learning if MK801 infused chronically

into hippocampus• No restoration if microstim random• But life is not binary DNMS: real-world?

Spike-Triggered Microstimulation

I love Vegas…Can’t…Stop…

Playing…

Optical Stimulation• While electrical microstimulation is far more spatially specific than

electrical macrostimulation it cannot match the specificity of optical stimulation of neurons genetically modified with ChR2 family

• Contextual component of fear memories– Dentate gyrus discriminates between similar contexts– Sparse (2%) populations of DG granule cells activated in given context– Although same population of DG cells activated repeatedly in same

enviornment, different environments activate different DG subpopulations

Optical Stimulation• Integrated opto-electronic devices are in

development• Nurmikko, Deisseroth and colleagues:

500 µm

Bone

Connector

Dura

White Matter

400 µm

Cortex

I

III

V

VI

Arachnoid

Prototype Brain Interface: Percutaneous

Connectorcap

Signal OUT

J. Donoghue 1/2001

skin

VentricularShunt

3.0 mm

Biologic Interfaces• Cullen, Chen, Wolfe, Smith and colleaguesEven if microelectrodes could record spatially specific

neurons, and even if optical fibers could activate spatially specific neurons:– Bandwidth limits– Nature already maximized

• Hybrid solution?• Autologous construct

Bioprosthetic Neural Modules

Biological Hysteresis

• Brown & Sherrington, 1912• March ball electrode back

and forth across macaque precentral gyrus

• Record EMG from supinator longus:

• Identical stimulation parameters at identical ‘cortical point’ causes different effects if intervening stimulation elsewhere occurs!

Biological Hysteresis• The effect of stimulation is a function of

preceding, endogenous oscillatory powerCh

ange

in O

scill

ator

y z(

Pow

er) w

ith E

lect

rical

M

acro

-Stim

ulati

on

Pre-Stimulation Oscillatory z(Power)

0

0.2 1

Given all this implanted hardware…

Intraosseous / Epidural Array

Depth Electrode (ECoG) or DBS

Subdural Grid (ECoG)Scalp (EEG) Electrode

Multi-electrode Array (unit)

Microwires

…how do we forge a Cognitive Assistive Device?

Learn facts, faces, voicesCouple to camera/microphone AI

Reminders for medications, tasks

Doctor to adjust connectivity between brain regions

Record and ‘replay’ local and global brain states and temporospatial activation patterns

Challenges• We understand a lot less about human memory than, for example,

Parkinson’s disease / dystonia or epilepsy• Memory deficits from Alzheimer’s disease, traumatic brain injury and other

etiologies are rarely as ‘lesion-specific’ as the focal nigrostriatal degeneration in PD

• Open-loop: how physiologic? – Ignore fine timing: altering precise temporal delay between septal & DG input to CA3

can mean difference between LTP and LTD / nic v musc– How different than simply infusing Ach into basal forebrain? Intrathecal donepezil?

• Modulating an existing network or injecting information?• How should the loop be closed?

– The physician derives parameters?– The patient improvises in daily life?– The device auto-associates?

• Optics: gene therapy in humans?– Optics for ‘DBS’ mismatch…while optics for memory ideal!

• How take into account biological hysteresis?• This is an airplane we will build while we are flying it!

FINIS

• STAY TUNED