bio382.md

BIO382

GNU General Public License v3.0 licensed. Source available on github.com/zifeo/EPFL.

Spring 2015: Neuroscience for Engineers

[TOC]

Somatosensory system, reinnervation

• somatosensory system : SNS
  • nerve cells : sensory receptors (thermo, mechano, chemi, noci/douleur)
    • slow, static : stimuli intensity, length
    • fast, dynamic : stimuli variation
  • spinal cord : moelle épinière dans canal rachidien (colonne vertébrale), signals pathway
    • circuit descendant : information motrices vers les muscles
    • circuit ascendant : information sensorielle
    • centre coordination : reflexes
  • brain
• medulla : bulbe rachidien, moelle allongé, partie inférieur du tronc cérébrale en avant du cervelet
• cerebellum : cervelet, attention, language, fear, coordination
• somatosensory processing : from skin to primary somatosensory cortex (S1), limb (extrémités) prosthetics
• touch & proprioception : dorsal column medial lemniscal system
• somatosensory pathways
  • skin
    • 2 point discrimination : 2PD, tactile perception
  • peripheral nerve : tactile signals from index finger travel in median nerve
    • dorsal root ganglions : formed by median nerves at different levels of spinal cord
  • spinal cord : tacile signals enter dorsal horn
  • brain stem : fibers cross here and travel as medial lemniscal tract to thalamus
    • arm signals : end in cuneate nucleus (lateral cuneate tract)
    • leg signals : end in medial gracile nucleus (gracile tract)
    • face signals : joined medial lemniscal
  • thalamus : contains arm, leg, face and somatotopic order in ventral posterior nucleus
  • primary somatosensory cortex : S1, index finder represented at specific position
    • somatotopic coding : somatotopy characterized by predefined sequence of where in S1 different body parts are encoded, preserved across differnet species (cats)
    • cortical magnification : sensitivity corresponds with size of somatosensory cortex, homunculus
    • regions : 4 distinct with distinct functions
  • posterior parietal cortex
  • secondary somatosensory cortex
• dorsal column medial lemniscal system : converys tactile, proprioceptive signals from skin to cortex, pathway with 4 neurons
  • fast conducting peripheral (myelinated) nerve fibers enters dorsal root
  • ascends spinal cord in dorsal column (ipsilateral)
  • crosses in brainstem (contralateral)
  • thalamus
  • S1
• brodmann regions : based on histological and cytoarchitectonic differences, 47 in total, anatomico-functional organization
  • relative prominence of cortical layers above and below layer 4
  • cell size
  • packing characteristics
• receptive fields
  • tactile : across 4 brodmann areas
    • area 3b : small
    • area 1 : larger
    • area 2 : even larger
    • proprioceptive (relative position) input : area 2, area 3a
      • arm, hand position : posture neuron, static coding
      • arm movements : movement neuron, dynamic coding
      • movement across several joints : some neurons in area 2
      • interaction between tactile and proprioceptive signals : some neuron in area 5
    • touch : areas 3b, 1
    • proprioception : areas 3a, 2
    • tracile, proprioceptive, visual integration : area 2
  • visual
• organization principle
  • hierarchical : progressive increase in complexity, areas 3a,b,1,2 to 5,7
  • parallel : stipes corresponding adjacent regions, hand, face, foot
• motor cortex : functional organization ressembles to somatosensory
• somatosensory reinnervation : peripheral nerves now targeted to chest skin
  • intercostal brachial nerve : connected with residual median nerve
  • supraclavicular nerve : connected with residual nerve
  • reconnection speed
    • 3 month : first sign, tingling sensation in missing hand, reffered sensation
    • 5 month : any stimulus to previously insesate skin perceived in phantom hand, refferend chest to hand sensations
    • after 6 months : weak sensation of being touched on single finger, referred chest to hand sensation
  • phantom limbs
• motor and somatosensory reinnervation : peripheral motor and somatosensory nerves now targetted to chest muscules (motor fibers) and chest skin (somatosensory fibers)
  • reconnection speed
    • 3 month : first signs of re-innervation, muscle twitches
    • 5 month : strong muscule contraction when patient close her hand or bend elbow
    • after 6 month : EMG testing with motorized elbow, wrist rotator, hand
• midline : body mid line between left and right

Bioelectronics

• cochlear implant : 1960s
• retinal implant : late 1960s
• deep brain simulation : 1980s
• neuron
  • spatial propagation of action potential
• electrical stimulation
• conduction velocity : depending on fiber types
  • large diameter axons : faster, squid d=1mm needed for fast reponse
  • decreasing membrane capacitance $C_m$ : increases transmission velocity
  • myelin : nature solution, fatty sheath (fourreau) wrapped around neurons
• synaptic transmission : neuron-to-neuron communication
• detection
  • implanted electrodes : loss from ischemia (blood), neuron loss maintained at long time points
• brains made of
  • neurons : generate, conduct electrical impulses (action potentials)
  • oligodendrocytes : provide myelination (insulating)
  • astrocytes : maintain homeostatic concentrations of chemicals around neurons, remove excess of neurotransmisster, maintenance of bloodbrain barrier, respond to injury
  • microglia : resident immune cell, analagous to macrophage (rest of body)
  • ependymal cell : maintains blood-brain barrier
• neural interface devices
  • superficial arrays : a-b
  • penetrating shafts : c-e
  • planar electrodes in case of eye : f-g
  • peripheral nerves
    • cuff : h
    • sieve : i
    • intrafascicular electrodes : j
  • book electrodes in spinal cord : k
• generic bioelectronic interface system : external device (wired, wireless), pulse generator/neural signal amplifier, electrodes
• peripheral nervous system electrodes
  • surface : lowest selectivity and invasivity
  • circumneural
    • peripheral nervous system : PNS anatomy
    • cuff : bipolar, tripolar with platinum foil bands, flat version (4 outer contacts, 4 inner contacts) improve selectivity
    • helical : arround vagus nerve (nerf X, régulation végétative)
  • intraneural
    • life : record 1mm non-insulated (kevlar, titanium, gold, platinum, silicone)
    • time
  • regenerative : highest selectivity and invasivity
• central nervous system electrodes
  • surface : lowest selectivity and invasivity
  • retinal
  • cochlear
  • ECoG : electro cortico graphy, enforce good connectivity with small thickness
  • shaft/needle : utah array (penetrating cortical probes)
    • michigan probe
• flexible electronics : physiological tensile strains reach 20%, need stretchable substrates, also include microfluidic channel for drug delivery

Robotics and synergies

• traditional therapy
  • physical therapist assists patient during execution of motor task
  • promotes relearning of motor tasks and recovery capabilities
  • limits : few hours per week, patient forced to go to hosptial, functional assessment is qualitative
• robot : mechanical or virtual artificial agent guided by computer program
• assisted-as-needed approach
• robot-based neurorehabilitation : as effective as traditional intensive care
  • desired properties : robot should remain invisible, human-friendly, safe, small, lightwright, quiet, compliant, therapist keep the patient confidence
  • gain : more intense and involving, minimal supervision, exercises can be diversified with level of difficulty, sensory feedback, objective parameters
  • advantages : long periods of time, consistent, precise, measure, track progress, could be mass-produced for home
  • telerehabilitation : connected and supervised through internet
  • end-effector interface : synergies, mimic behavior of natural effector (hand)
• types
  • class I systems : more sophisticated mechanical and control structure, high cost
  • class II systems : simple mechanical structure, no backdrivability (only the motor can move it), active compensation of inertia/friction required, low cost
• MEMOS : class II, movements between $P1$ and $P2$, controller checks whether voluntary movement, if no starts to complete passively the move, $s(t)=k_pF_p(t)+V_Rt\delta(F_{MIN},T_D)$
  • force estimation : $F_p$
  • stiffness : $k_p$
  • clinical validation : robot well accepted
  • force control : understand motor control recovery achieved
  • assessment parameters
  • comparison : provide benefit but main advantage related to training intensity
• stroke : AVC
  • ischemic : blood vessel blocked
  • hemoragic
  • acute phase : following 14 days
  • subacute phase : 14 days to 6 months
  • chronique phase : after
  • cortical and peripheral changes
• exoskeletons : mimic natural moves, not better than traditional therapy
  • lower limb
  • upper limb
  • hand
• future
  • neuromuscular electrical stimulation
  • virtual reality
  • tDCS
  • unexpected protocol
• tailored robotic therapy : generally, therapist selects exercice, difficulty, duration, not many attempt to make it quantitative (e.g. kinematics performances, EMG activity, psychophysiological measurements based)
• personalized robot-based neurorehabilitation : statistical model of learning, selection of protocol
• abnormalities caused by different muscular activation patterns : could result alterated behavioural and kinematics outcomes, motor performance alone cannot offer a representation of the patient state
• robot choice of trajectories/speed impact brain organization : still poor choices, during passive moves robot should follow natural one to avoid unnatural sensory feedback- non invasive study
  • cortical signals during moves : EEG microstates
    • meta-stables states characterized by period of coherent synchronized activation of neural network (duration of 8-120ms)
    • alteration asociated with mood disorders
    • visualization of global brain activity during moves
    • building blocks of information processing in resting state
    • experimental protocol : HM trajectories differ from LT and MJ and speed profile in LT differs from one in MJ and HM
    • conclusion
      • EEG microstate does not seem to be influced by choice of trajectory, speed and acceleration in healthy individuals
      • choice of trajectory and speed should be carefully considered in design of passive robot-mediated rehabilitative training
  • muscle activity : muscle synergies (found in cat, monkeys, humans)
    • human musculoskeletal system : very complex, high number of muscles and DoFs, neurological coupling among, multi-articular muscles, redundancy, laws of mechanics, coactivation
    • spinal force fields
    • motor synergies encoder : MSE, possibily identified
      • molecular markers to track neurons involved in MSE have been found
      • received input from CNS (central nervous system) and periphery sensory pathway
      • controls voluntary movements, reflexes, activated from nociceptive pathways
      • seems to represent one strategies adopted by CNS to reduce complexity of motor control
    • neuroscience definition : coordination of muscules recruited by CNS to simplifiy control
    • neurorehabilitation : stereotyped muscle activation patterns due to loss of independent control
    • electromyography : analysis of muscle activity, hgihly variable and difficult to interpret
      • factorization analysis : relation between synergies and muscule activation
      • computational aspects : task variability, muscule selection, preprocessing (low pass, normalization, space, time), decomposition algo, synergies number
      • state-of-the-art
        • locomotion : five basic muscle activation patterns account for muscle activity during human locomotion
        • posture
        • reaching : modulation of phasic and tonic muscle synergies with reaching direction and speed
        • grapshing : muscle synergies as a predictive framework for EMG patterns of new hand postures
        • development : babies
    • spinal cord injuries effects : reorganization of motor modules in limbs, modification of activations number in some conditions
    • stroke effects : timing activation preserved, alteration of shoulder activation
      • chronic : possible to observe preseveration, merging or fractionation
      • subacute : possible to observe preservation
    • motor impairment causes : dysfunctional recruitment, merging, disruption
      • neuromotor recovery : achieved with recovery of correct recruitement, reorganization or new ones (compensatory and adaptive) - application : quantitative indicators of impairment and efficacy of treatments, feedback based exercices, assistive approach for restoring muscle synergy and recruitment

Brain machine interaction (BMI)

• robot arm control
• neural activity : biochemical processes gives rises to electrical signals
  • direct mesurements : EEG, MEG, ECoG, LFP, SUA, MUA
  • indirect measurements : hemodynamic activity (refleced in changes in blood flow), fMRI, NIRS, PET
  • single unit recordings : surgically implanted in the cortex
  • multiunit recordings
  • extracellular recordings
• BMI modalities
• decoding algo : linear modelas
• electrocorticogram : ECoG, electrode do not peenetrate cortex, only over cortical surface
  • local field potential
• BMI design : which best feature reflect wanted phenomenon, how to build single-trial classifier, real-time
• modalities
  • evoked : event-related potentials, phase-locked activity
    • P300 : evoked potential, await infrequent stimulus
    • VEP : visual evoked potential
    • SSVEP : steady-state-visual evoked potentials
  • spontaneous : user can voluntarily produce the required signal, non phase-locked activity
    • SCP : slow cortical potentials
    • ERD/ERS : oscilliations $\mu$ and $\beta$
    • cortical neuronal action potentials
• synchronization
• motor imagery
• mental tasks
  • left/right-hand movement : repetitive, fingers, hand or arm
  • subtractions : successive subtractions by fixed number
  • cude rotation : visualize 3D cube in rotation around one of its axis
  • language : concatenates related words
  • reflex
• spatial filtering : high-pass, emphasizes components with highly focal distributions
• feature extraction : dimensionality increases if we work with frequency domain, identity discriminant and stable pattern, gaussian classifier
• interaction principles : asynchronous approach, cognitive interface, blending of intelligences
• application
  • motor substitution : assistive mobility, telepresence robot, end-user evalution, lower limb motor recovery

Audition

• frequency coding
  • pitch/color : perceptual quality of frequency
  • loudness/brightness : perceptual quality of amplitude
• outer and middle ear
  • outer : filter
  • middle : sound amplifier, protection, transmission from air to liquid (inner ear)
    • oval window : 18x smaller than tympanic membrane
    • 2 muscules : smallest of human body can contract to avoid sound transmission, paralysis leads to hyperacousis
    • delay : 200 ms, cannot be protected by fast loud sound waves
• inner ear : cochlea
  • organ of corti : transduces sound into neural signals, differ in cells count and speed of response from retina
  • sound transmission : travelling wave in cochlea
  • anatomical fourier transformator
  • tonotopy : frequency tuning of auditory nerves
    • characteristic frequency CF : for each nerve, low sound amplitudes 10-20 dB
    • 10500 outer hair cells
    • complex signals : tone supression can occur, louder, response of entire auditory nerve more than adding up all fivers responses to its characteristic frequency
    • rate saturation : occurs when neuron tuned to different frequency range for different sound amplitudes
      • boardening of tuning curve for louder tones
      • cannot rely on signle auditory nerve fiber to discriminate sound frequency
      • 150spike/s could code any frequency between 300 to 2500Hz
      • isointensity curves : discharge rate in spike/s
• hair cells of inner ear to primary auditory cortex pathway
• primary auditory cortex
  • Heschl gyrus : brodmann regions 41/42
• auditory nerve : 14000 per ear
• auditory brain stem (tronc cérébrale)
• inferior colliculus
• sound localization : retinal position differ in sensory location not sound
  • interaural time differences : ITDs, time arrival differences
    • medial superior olive : MSO, compute location of sound where auditory system right and left input converge
  • interaural level differences : ILDs, sound intensity differences
    • lateral superior olive : LSO
  • ambiguous sound localization : sources at 60° and 120° give same ITDs/ILDs, human function disctinction required (not auditory brain related)
    • cone of confusion : considering elevation every ITDs/ILDs can arise from any circle of cone, infinity of these cones
• questions
  • what happens to ITDs when the head doubles its size ?
  • how does this influence the perception of sound location based on ITDs ?
  • can coding in the medial superior olive adapt to these changes ? how ?
  • describe this for a left sound source at 60°

Visual prosthetics

• blindness : visual acuity of less than 20/400, or visual field loss to less than 10° in better eye with best possible correction
  • 32 millions people : 70% had preventable/treable cause (cataract, trachoma, etc.), other unidentified or untreatable
  • bangkok definition : after treatment, has VA of les than 6/18 in best eye or VF less than 10°
  • legal definition : VA 20/200 with best eye and corrections, less than 20° VF
• low vision : 20/70 but equal or better than 20/400 with visual field loss to less than 20 degrees in the better eye with best possible correction
• visual acuity : measure of capability in discriminating separated lines (spatial resolution), expressed as number of cycles per degree
  • normal : 20/20, 6/6 meters contours approximately 1.75mm apart, 1 cycle per 2 arc min, 30 cycles per degree
  • well-corrected healty young : 20/10
  • visual angle
  • MAR : 1 minute arc over 6 meter
• visual field : total area in which objects can be seen in the side (peripheral) vision while you focus your eyes on central point
  • normal : 60-100° vertical, 50-70° horizontal
• cones vs rodes
• visual prostheses
  • retinal prostheses
    • argus II
    • vision encoding
    • phospheres : appeared white or yellow and round or oval
    • shapes : 0.5 to 2 inches in diameter at arm's length, 2-3°
    • brightness as function of amplitude
    • design
      • AMD patients : implementation only if worth the risk, provide substantial improvements in visual acuity
      • retinitis pigmentosa : benefit only little unles enlargement of VF
      • pixel densisty : determines maximal amout of information, maximal spatial resolution
        • distance : between electrodes and target cells, large distances between cells and closely spaced electrodes result in cross-talk, need for high charge density and power stimulation (electrodes erosion, heating)
      • retinal coverage : 1.5mm -> 5°, 3mm -> 10°, 6mm -> 15°
  • optic nerve prostheses : lower stimulation thresholds, processing, treat large amount, high signal compression allows probe miniaturisation
    • optic nerve : introcular (~1mm), intraorbital (~30mm), intracanalicular (~6-10mm), intracranial (~10mm)
    • MIVIP : spiral cuff electrode around optic nerve, connected to stimulator implanted in small depression in the skull, external worn camera
  • cortical prostheses : not yet fully developped, surface electrodes require high currents (10mA unsafe), complex processing, theorectically may treat all
    • Dobelle artificial vision system : AVS, $100k, only allowed in portugal, max 4 a day
  • epiretinal prostheses : large prostheses to stimulate, processing, usable only if retinal ganglion cells and remaining visual path preserved, good results
  • subretinal prostheses : usable only if entire visual pathway preseved, senstivity to encapsulation, shorter life-time, mimics photoreceptors functions, lower stimulating thresholds
  • MEA-based protheses : epi-retinal or sub-retinal, simple fabrication, require additional components (VPU, stimulator, camera)
  • MPDA-based prostheses : sub-retinal implants, require on-chip electroncs, shorter life-time,could be powered by incident light
• neuromorphic encoding
• muscule activation : MP
  • command interface
    • recorded generated signals : EMG, voice, switches, respiration
    • use least number of input channel : reduce amount of noise (SNR)
    • transition rate important
    • performance reliability
    • interface must be cheap, simple, invisible
  • control unit
    • command processor : system state, activation pattern selection
    • control processor : converts signals from command processor into actual function (muscle stimulation)
  • stimulus delivery system
    • surface electrodes : skin point where nerve and muscle join, noninvasive, not all muscle can be activated, large power and voltage (80V) to drive across skin impedance
    • percutaneous electrodes : inserted throug skin with needle near motor point of muscle, barbed to ensure anchoring, low power, skin irritation or infection
    • implanted electrodes : epimysial sutured near muscule motor point, intramuscular inserted needle, nerve cuff encircle nerve, highly selective, less power, invasive
  • foot stimulators : correction of foot drop, switch on sole of shoe (closed when lifted)
  • hand stimulators : cervical injury at 4-5th level, flexion by using spring between thumb, middle, index fingers
  • limitations : denervation (tissue heating), muscle spasticity (action potentials spontaneously active, override any possible MP action), limited feedback available

Memory and modulation by stress

• key problem : where does memory take place in brain
• methods : amneias, lesions, animal models, neuroimaging, psychopharmacology, optogenetics, pharmacogenetics
• H.M. : patient with removed brain lobes due to epilepsia, similar IQ, no deficits in perception, abstract thinking, reasoning ability, but amnesic effects
• memory
  • separated from perception and intelligence
  • short-term memory and working memory : distinct from long-term memory
  • H.M. lobes important for encoding new memories
  • memory outside conscious and unconscious recollection depend on different memory system
  • different mechanismes for different types of learning
  • H.M. has specific problem with memory consolidation
  • hippocampus : play central role in memory formation
• mirror-drawing test : image flipped left to right
• pavlovian or classical conditioning : learning whereby a neutral stimulus (tone) comes to elicit a response because of its repeated pairing with some event (food delivery)
  • conditioned stimulus : CS, neutral stimulus that after association with an unconditioned stimulus triggers a conditioned response
  • unconditioned stimulus : UCS, stimulus that unconditionally triggers a response
  • eye-blink condition : pair formerly neutral stimulus to defensive eye-blinking response
• learning types
  • implicit memories : procedural or non declarative, do not require conscious awareness
  • explicit memories : declaractive, conscious memories expressed through language
• non-associative learning : aplysia, based on siphon-withdrawal reflex and gill-withdrawal reflex
  • habituation : observed when moderate stimulus delivered repeatedly to siphon, every 90s resulted in rapidly declined response
  • sensitization : observed when strong stimulus administered to tail, enhances gill-withdrawl response to siphon stimulation
• types explicit or declaractive memory
  • semantic memory : semantic knowledge independent of persons, localities, time (mars is a planet), "I know"
  • episodic memory : semantically, spatially, temporally distinct events related to own life (last weed, I went hiking to the Alps), "I remember"
    • autobiographic memory : in the center
• memory consolidation : neurobiological process to store information in long-term memory
• medial temporal lobe areas : MTL
• hippocampal circuit
  • high density of MR and GR (receptors of glucocorticoids) : exert differential effects in neurl excitability
    • MR expression : hippocampus, septum, amygdala
    • GR expression : widely distributed
    • glucocorticoids (cortisol/corticosterone) : 10x higher affinity for MR than GR
• long-term potentiation and depression : LTP, LDP
  • plasticity mecanism
• impact of intrinsic stress on relational learning
• Yerkes-Dodson law
• computational model based on reinforcement learning
  • learning rate : $\alpha$
  • exploitation factor : $\beta$
  • reward discount factor : $\gamma$
• chronic stress

Cochlear implants

• word comprehension before : deafness on right side, bilateral hearing loss
• word comprehension after 3 month : CI implants on the right
• word comprehension after 1 year
• cochlear implants : effective procdure in majority of cases (200 cases per year), 10% complication or failure
• bilateral cochlear implantion : binaural hearing possible, improved sound localisation and comprehension, but doubling surgical risk and cost
• nanoci : multi-electrode array recordings of spiral ganglion neural cells, 2d guidance of auditory neurons
  • implants
  • process
    • invivo
  • take home
    • proof of principle : guided growth of auditory nerve fivers towards the cochlear implant electrode array sufrace in vivo obtained, gapless interface
    • reduction of energy-consumption possible in vitro by factor 5 when distance between nerve and electrode is eliminated
    • no information yet on improvement of auditory resolution

Animal models of memory

• molecular memory : memory time span bigger than molecules (expect DNA) lifetime so how
• epigentic mechanisms : on or above the gene, regulating compaction of cromatin and learning/memory by orchestrating gene expression changes
• strenghen memory
• memory book
  • closure of book in Alzheimer's disease : how stress might contribute to cognitive impairments
    • histone acetylation : cognitive processes
      • increases : facilitates synaptic plasticity, learning and memory
      • descreases : constrains synaptic plasticity, learning and memory
        • repulsive force between $-COCH_3$ and partially negatively charged DNA facilitate gene transcription
    • histone acetyl transferases : HAT favor learning and memory
    • histone deacetylases : HDAC2 blocks learning and memory, binds to neurplasticity genes
    • reversing HDAC2 levels by AAV-mediated HDAC2-shRNA expression : via virus mediated gene transfer, restore histone acetylation and gene expression
    • epigenetic blockade on cognitive function : potentially reversible
    • stress circuitry : hypothalamus, pituitary, adrenal glands (HPA axis), involved in stress response and secretion (glucocorticoids, minealocorticoids)
      • stress and cognition : inverted U-shape curve
      • repetitive fear conditioning and chronic restraint stress : object memory deficits, HDAC2 increase in hippocampus
    • amygdala-specific activation : mimics effects of chronic stress, can be done via optogenetic manipulation
  • re-opening in posttraumatic stress disorder : how memory aids on chromatin for changing traumatic memories
    • traumatic memories : PTSD, anxiety disorder that can develop after exprosure to terrifying event or ordeal in which grave physical harm occurred or threatened
    • psychotherpeutic treatment : exposure-based therapy by simulating safe environnement shortly after event
      • relean traumatic context as safe
      • dissociate association traumatic context as fear
    • fear circuitry of recent memories : 1 day old
    • fear circuitry of remote memories : 30 day old, unknown
    • memory organization
    • exposure-based for remote memories : resistant
      • reduced learning capacities upon remote memory recall : not salient enough to induce hippocampal histone acetylation, fails as HDAC remains linked to chromatin
        • HDAC2-mediated chromatin plasticity important to update remote memories
        • PTSD patients show less hippocampal activity
        • overcoming with HDAC inhibitors (HDACi) : remote memories become amenable to persistent attenuation, reinstate chromatin plasticity, reinstate structural and functional neuronal plasticity
        • other mechanism
          • lfg2 : critical for extinction of recent memories
          • adcy6 : regulating neurite growth
          • cFos : regulating remote memory storage
          • Npas4 : critical for extinction of recent cued fear memories
          • arc : regulating remote memory storage
        • neuroplasticity
          • structural plasticity : HDACi reinstate structural neuronal plasticity
      • new approach at chromatin level to treat PTSD : histone acetylation as a molecular mnemonic to learn to forget
    • other drug-based treatments
      • D-cycloserine : cognitive enhancer, NMDAr agonist
      • glucocorticocoids : impairment of fear memory retrieval
      • propranolol : beta-adrenergic blocker (sedative effect), impairment of arousal associated with fear memory retrieval

Vision

• why vision is hard
• retina
  • rod
• vision in brain : mainly in partial, infertemporal and occipital cortexes
• achromatopsia : world seen as devoid of color
• luminance : illuminance * reflectance
• vision
  • involve knowledge processing
  • not template matching
• neglect : right-hemisphere lesion patient tend to bisect horizontal line more to the right, intattentional blindness
• rivalry : show distinct image to both eyes vs 4s shift

Diffusion spectrum, tensor imaging

• diffusion MRI : towards global brain connectivity analysis
• molecular diffusion : brownian motion, pdf of relative number of melecules as a function of their displacement in a given time (gaussian)
  • homogeneous media : isotropic guassian with $\sigma^2=2D\delta$ for $D$ diffusion coeifficient (depends on temperature, viscosity)
  • complex media
    • impermeable spheres : smaller variance
    • semi-permeable spheres : in between variance, close to biological reality
    • neuronal tissues (fibrillar) : anisotropic diffusion, more restricted in direction perpendicular to axonal orientation
    • fiber crossing : not gaussian
• imaging diffusion by MRI
  • ideally 6D : position and displacement, too complex
  • simplified representations
    • isosurfaces
    • orientation distribution function : ODF
  • NMR : based on nuclear magnetic resonance
    • constant magnetic field $B_0$ : spins of protons align with the field
    • Larmor frequency $\omega=\gamma B$ : as precessing around $B_0$ axis when exicted by an RF signal
    • stopping RF signal : spins return to equilibrium and emits RF that can be read by antenna
    • changing magnetic field locally : enable to detect signals from each individual locations in a volume
    • single direction
  • DSI : diffusion spectrum imaging : with images (usually 515) and fourier transform reconstruct whole diffusion pdf at every point of brain (simplified as ODF)
    • diffusion weighted imaging : DWI, 1 direction, 1 gradient strength
    • mean diffusion coefficient : 3 orthogonal directions, average, very used in strokes
    • diffusion tensor imaging : DTI, assume gaussian ansiotropic, 6 degrees of freedom (6 differents gradients direction enough)
      • diffusion tensor : covariance matrix 3x3
    • fibre tracking : infer from diffusion field axonal trajectories connectivity, computation of trajectories following principal directions of diffusion in the tensor field
    • whole brain simulation : trajectories intiated all over brain WM, estimate whole brain activity
    • tract selection, virtual dissection : fibre selection using ROIs
• application : study of language networks
• application : whole brain connectivity analysis

Functional magnetic resonsance and connectivity

• MRI : 1-10mm^3 resolution, endogenous contrast mechansim
  • vs EEG : deep inside brain
  • vs PET/SPECT : no radioactive tracers injected
• MRI vs functional MRI
• BOLD response
  • hemodynamic response
• fMRI : series of MRI images over time, test for small fluctuations in signal intensity related to neural activity
• example : face-selective brain region
  • stimuli to modeled bold response : convolve stimulus time course with HRF
  • linear regression : LSE
  • GLM fitting
• resting-state fMRI : 2% body weight, consume 20% energy, tasks difference explan less than 5%
  • systematic pattern of de-activation : when task related data
  • functional connectivity during rest between left/right motor cortex : temporal correlation
  • blind (mixing) of spatial brain sources
  • spatial ICA
  • functional connectome : parcellation into brain regions based on atlas, pairwise correlations between regionally-averaged timecourses of all brain regions
    • profile
    • fingerprint
  • facts
    • small-word : high clustering (function segregation), high efficiency (functional integration)
    • cost-efficient : high efficiency for low connection cost
    • hubby : fat-tailed degree distributions, hierarchical but still resilient to attacks and errors
    • modular : more dense connections to nodes in module than nodes in other modules
  • functional connectivity
• combining EEG and FMRI

Memory prosthetics

• cardiac pacemaker : thin leads carry electrical signals to heart and record activity, pulse generator contains battery
• deep brain stimulation : DBS
  • Parkinson disease : neurodegenrative disease of central nervous system affecting motor system, 60K new patient/year
    • symptomes : resting tremor (shaking), bradykinesia (slow movement), rigidity (stiffness)
    • dopamine : important neurotransmitter for movement control
    • cause : death of dopamine generating neurons in substantia nigra
    • neuroanatomical structures for motor control : substantia nigra, sratum, subthalamic nucleus, motor cortex
    • brain stimulation : when not responding to drug treatment
      • side effect : cortical dopmaniergic hyperactivity given rise to hallucinations, psychosis, schizophrenia
  • obessive compulsive disorder : OCD, 2% general population
    • symptom : obsessions, compulsions, patients realize senslessness, > 8h/day
    • treatments : pharmacological, behavioral treatments
    • DBS : anterior bundle of internal capsule, 130Hz functional ablation, interruption of motor pathways that induce OCD behavior
  • major depression
    • symptom : persistently depressed mood, concentration, sleep problems, high risk of suicide, 16% US
    • treatments : pharmacological and behavioral treatments
    • DBS : under investigation, negative mood has been associated with activation of medial prefrontal cortex
  • other diseases : strike, pain, alzheimer, psychiatry for 500 mio patients worldwide
    • most of them impair regions outside moro and sensory cortices
    • need to develop other neuroprosthetic : industry decreased research because cost too high, rarely drug approvals, too long development, animal models not good
• cortical stimulation
  • vascular stroke : 15mio per year with 5mio deficits
  • epidural stimulation : stroke rehabilitation
    • electrodes : placed over activated regions when patients repeated wrist extension-flexion
    • to be confirmed : increase neural plasticity, enhance motor performance compared to control patient
  • alzheimer disease : AD, neurodegenerative, progessive loss of structure and function of neurons, most common type dementia, 10% above 60 suffers, 40% above 85 suffers
    • pathology : amyloid plaques and neurofibillary tangles, first noticed in enorhinal cortex, memory loss, pathological brain changes often begin 10 to 20 years before symptoms
  • memory prostheses desing : know human memory, know neuroscience of memory, know neurotechnologies, know how diease affects, know alternative medical treatment strategies
  • entorhinal cortex stimulation : increase memory performance, applied during encoding
  • hippocampus stimulation : does not increase memory, impair memory
• electrical stimulation
  • intra-operative electrical stimulation : determination of tumor or functional cortex
  • sensory cortex
  • motor cortex
  • subdural stimulation : prolonged electrocortical recordings and repeated extra-operative stimulations (less stress and more time for patient and for surgeon)
    • electrodes : 3mm with 1cm inter distance, MRI compatible
    • seizures : can be recored
      • classification
      • generalized epilepsy
      • absences seizures : almost always induced by hyperventilation, 15% by photic stimulation
      • partial (localized) seizure : most complex partial seizures originate from medial temporal lobe (hippocampus)
      • responsive cortical stimulation
  • language cortex : Broca's and Wernicke's area