Brain Stimulation for Memory

1. Brain Stimulation for Memory Mijail “Misha” D. Serruya, M.D., Ph.D.

2. Outline • Definitions of memory and stimulation • Macrostimulation • Microstimulation • Optical • Challenges

3. Memory • Procedural • Semantic • Episodic • Binding of item and context • Spatial context & navigation • Temporal context • Mental time travel

4. Electrical rTMS Stimulation Macro Micro Platinum-iridium, steel Cortical MEA Depth microwires 100kΩ to 2MΩ 10 to 100μm contacts 50 to 100 μA Epidural/Subdural Depth/DBS/Grids Low impedance <1kΩ 1-5 mm diameter 0.5 to 15 mA Non-Invasive Implanted tDCS Biologic Optical Chemical tACS, tSOS Microfluidics

5. 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

6. 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

7. Basal Forebrain Septal nuclei Ventral pallidum Anterior commissure Amygdaloid complex Substantiainominata (nucleus basalis of Meynert) Uncinate fasciculus Diagonal band of Broca

8. fornix

9. SS Metabolic benefitvs cognitive benefit? Fornix DBS What is going on? ‘Blind’ open-loop 130 Hz? Stay tuned

10. Entorhinal Cortex DBS • 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? • 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

11. -SME +SME ball tree flag tree Cortical Surface Macrostim SME = Subsequent Memory Effect • Kahana, Lega, Burke, Jacobs and colleagues • Verbal instead of spatial memory • A signature of enhanced encoding Free Recall Task + time baseline power gamma power increased compared to baseline

12. Leverage the Signature Electrical Stimulation ball tree flag tree! time +

13. Leverage the Signature Closed-Loop Real-time Feedback ball tree flag tree! time +

14. 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

15. Basic Hippocampal Circuit Schaffer collaterals Subiculum Mossy fiber pathway Dentate gyrus Perforant path Entorhinal cortex Associational commisure • Long loop: • EC2DGGCCA3CA1subiculumEC5 • Short loops: • EC3CA1EC5 • CA3 project mainly to CA1 and to recurrent CA3 population

16. It works! • Enhanced learning when activated • Restored learning if MK801 infused chronically into hippocampus • No restoration if microstim random • Butlife is not binary DNMS: real-world?

17. Spike-Triggered Microstimulation I love Vegas… Can’t… Stop… Playing…

18. 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

19. Optical Stimulation • Integrated opto-electronic devices are in development • Nurmikko, Deisseroth and colleagues:

20. Prototype Brain Interface: Percutaneous Ventricular Shunt 3.0 mm Connector 400 µm Signal OUT skin Connector cap Bone Arachnoid Dura I III Cortex V 500 µm VI White Matter J. Donoghue 1/2001

21. Biologic Interfaces • Cullen, Chen, Wolfe, Smith and colleagues Even 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

22. Bioprosthetic Neural Modules

23. Biological Hysteresis • Brown & Sherrington, 1912 • March ball electrode back and forth across macaque precentralgyrus • Record EMG from supinatorlongus: • Identical stimulation parameters at identical ‘cortical point’ causes different effects if intervening stimulation elsewhere occurs!

24. Biological Hysteresis • The effect of stimulation is a function of preceding, endogenous oscillatory power Change in Oscillatory z(Power) with Electrical Macro-Stimulation 0 0.2 1 Pre-Stimulation Oscillatory z(Power)

25. Given all this implanted hardware… Scalp (EEG) Electrode Subdural Grid (ECoG) Intraosseous / Epidural Array Depth Electrode (ECoG) or DBS Multi-electrode Array (unit) Microwires

26. …how do we forge a Cognitive Assistive Device? Learn facts, faces, voices Couple 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

27. 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 / nicvmusc • How different than simply infusing Ach into basal forebrain? Intrathecaldonepezil? • 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!

28. FINIS • STAY TUNED