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 ForebrainBasal Forebrain
Anterior commissure
Anterior commissure
Substantia inominata
(nucleus basalis of Meynert)
Substantia inominata
(nucleus basalis of Meynert)
Amygdaloid complex
Amygdaloid complex
Septal nucleiSeptal nuclei
Uncinate fasciculusUncinate fasciculus
Ventral pallidumVentral pallidum
Diagonal band of Broca
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
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
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