Final Exam Material

Control and Communication in
the Nervous System
Chapter 1
The Brain and Behavior
Yazan M. Dweiri, Ph.D.
The Nervous System
1
The Brain
• 1400g (~2% body weight)
• Cerebral hemispheres
• Convolutions = folding= gyri (gyrus)

• Separated from each other by sulci
(sulcus)
• White matter – fiber tracts

• Grey matter – cell bodies and dendrites
(lack myelin)
• 1400g (~2% body weight)

• Cerebral hemispheres
• Convolutions = folding= gyri (gyrus)

• Separated from each other by sulci
(sulcus)
• White matter – fiber tracts

• Grey matter – cell bodies and dendrites
(lack myelin)
2
Cerebral hemispheres
3
Structure Major Function
Frontal Lobe
Motor cortex Plans and executes voluntary movements
Basal ganglia Smoothes movements
Broca’s area Controls speech
Prefrontal cortex Planning, impulse control
Parietal lobes
Somatosensory cortex Projection area for body senses
Association cortex Location of body and objects in space
Temporal lobes
Auditory cortex Auditory information
Wernicke’s area Language area – meaning
Inferior temporal cortex Visual identification of objects
Occipital lobes
Primary visual cortex Projection area for visual information
Visual association cortex Processes components of visual information
Mental Processes Are Represented in the Brain by Their

Elementary Processing Operations
4
Support and nourishment for the brain
Peripheral Nervous System

• Somatic
• Autonomic
• Sympathetic
• Parasympathetic
6
Somatic System
• Nerves to/from
spinal cord Brain
– control muscle
movements
– somatosensory inputs Sensory
• Both Voluntary Neuron
and reflex
movements Motor
• Skeletal Reflexes Skin receptors Neuron
– simplest is spinal Interneuron
reflex arc
Muscle
Autonomic System
• Two divisions:
– Sympathetic
– Parasympatheitic
• Control involuntary functions
– heartbeat
– blood pressure
– respiration
– perspiration
– digestion
• Can be influenced by thought and emotion
7
Sympathetic
• “Fight or flight” response CENTRAL NERVOUS SYSTEM SYMPATHETIC
Brain
• Release adrenaline and Dilates pupil

Stimulates salivation
noradrenaline Salivary
glands
Relaxes bronchi
• Increases heart rate and Spinal
Lungs
cord
blood pressure
• Increases blood flow to
Accelerates heartbeat
Heart
skeletal muscles Inhibits activity Stomach
• Inhibits digestive Pancreas
functions Stimulates glucose Liver
Secretion of adrenaline, Adrenal

nonadrenaline gland
Kidney
Relaxes bladder
Sympathetic Stimulates ejaculation

ganglia in male
Parasympathetic
• “Rest and digest”
CENTRAL NERVOUS SYSTEM PARASYMPATHETIC
Brain
system Contracts pupil

Stimulates salivation
• Calms body to Spinal
Constricts bronchi
conserve and cord
maintain energy Slows heartbeat
• Lowers heartbeat, Stimulates activity
breathing rate, &

blood pressure Stimulates gallbladder
Gallbladder
Contracts bladder
Stimulates erection
of sex organs
8
• The nervous system consists of two types of
cells:
1. Neurons
2. Glial cells (support cells, 10-50X more than
neurons)
The basic functional unit in the microcontrollers and computers

is the transistor
9
02-02
The basic functional unit in the NS is the neuron
10
Structures of a Neuron
How neurons communicate
• Neurons communicate by means of an

electrical signal called the Action Potential.
• Action Potentials are based on movements
of ions between the outside and inside of
the cell.
• When an Action Potential occurs a molecular
message is sent to neighboring neurons.
11
Neural Communication
 Synapse [SIN-aps]
 junction between the axon tip of the sending neuron and
the dendrite or cell body of the receiving neuron
 tiny gap at this junction is called the synaptic gap or cleft
 Neurotransmitters
 chemical messengers that traverse the synaptic gaps
between neurons
 when released by the sending neuron, neurotransmitters
travel across the synapse and bind to receptor sites on the
receiving neuron, thereby influencing whether it will
generate a neural impulse
Synapses
P.
40
12
Neurotransmitter Function
P.
42
02-09
W. W. Norton
13
02-10
W. W. Norton
14
02-11ab
W. W. Norton
02-13
W. W. Norton
15
02-14
Netter, F.H., The CIBA Collection of Medical Illustrations. Vol I: Nervous System, Part 1: Anatomy and Physiology.
Summit, NJ: CIBA Pharmaceutical Company, 1983. Adapted with permission of Novartis, formerly CIBA.
02-16ab
2.16A Adapted from Kandel, E.R. Schwartz, J.H., and Jessell, T.M. 2.16B Adapted from Kuffler, S., and Nicholls, J., From Neuron to
(Eds.), Principles of Neural Science, 3rd edition. Norwalk, Brain. Sunderland, MA: Sinauer Associates, 1976.
Connecticut: Appleton & Lange, 1991. Copyright © 1991 by Appleton
& Lange.
16
17
p.42
From Haeusser, M. (2000). The Hodgkin-Huxley theory of the action potential. Nat. Rev. Neurosci. 3:1165.
02-27
W. W. Norton
18
The knee-jerk reflex is controlled by a simple circuit of sensory and
motor neurons.
Types of glial cells
Oligodendrocyte and Schwann cells form the myelin sheath in the CNS
And PNS respectively
21
02-08
Astrocytes form the blood-brain barrier (BBB)
22
• The blood-brain barrier is a membrane that controls the
passage of substances from the blood into the CNS.
• It is a physical barrier between the local Blood vessels and

most parts of the central nervous system itself, and stops
many substances from travelling across it.
• The BBB is permeable to alcohol, and some heavy metals can

cross the blood-brain barrier as well.
Oligodendrocyte, Schwan cells and Astrocytes are categorized as

Macroglia
23
Macroglia:
Microglia is the brain’s phagocytes

the Nervous System
Chapter 6
Membrane Potential and the Passive
Electrical Properties of the Neuron
24
Information is carried within neurons and from neurons to their target cells
by electrical and chemical signals.
Transient electrical signals—receptor potentials, synaptic potentials, and

action potentials—are all produced by temporary changes in the electric
current into and out of the cell.
Two types of ion channels—resting and gated—
Resting channels are primarily important in maintaining the resting

membrane potential.
Gated channels are closed when the membrane is at rest and require a
specific gating changes to open. i.e. Neurotransmitter, change in membrane
potential, heat, light photons, ets.
The Resting Membrane Potential Results from the

Separation of Charge Across the Cell Membrane
25
Terminology
• The electric current is carried by ions, both positive
(cations) and negative (anions).
• The direction of current is conventionally defined as
the direction of net movement of positive charge.
• A reduction or reversal of charge separation, leading
to a less negative membrane potential, is called
Depolarization.
• An increase in charge separation leading to a more
negative membrane potential, is called
hyperpolarization.
Recording the Membrane Potential
26
The Resting Membrane Potential Is Determined by Ion Channels
The equilibrium potential for any ion X can be calculated

from an equation from basic thermodynamic principles :
Or: z is the valence of the ion
27
Open Channels in Resting Nerve Cells Are
Permeable to Several Ion Species
At Rest
At the peak of AP
Ion current vs net current
28
The Electrochemical Gradients of Sodium, Potassium, and
Calcium Are Established by Active Transport of the Ions
The Functional Properties of the Neuron Can Be Represented as an Electrical

Equivalent Circuit
iK = ϒK × Vm
Ion flux = (electrical driving force + chemical driving force) × membrane conductance.
29
Example: Use the information provided in the table to answer the following questions.
Cytoplasmic Equilibrium Relative

Ion species
concentration (mM) Potential (mV) permeability at rest
A+1 400 -65 20
B+1 50 45 5
C-1 100 0 1
What is the extracellular concentration for ion A+1
If the conductance for ion C-1 at rest is 1 µS, calculate the C-1 leakage current at Vm = -20 mV
What is the direction of the net electrochemical driving force for ions A+1 and B+1 at Vm =0 mV?
If the B+1 channels are completely blocked, calculate the resting membrane potential.
(RT/F is 25 mV)
At what membrane potential will the net electrochemical driving force be equal to twice the
chemical driving force for ion B+1?
30
AP is generated by the flow of Sodium
Sodium Channels are time dependent
34
Sodium Channels are time dependent
Membrane Conductance During an AP
35
The refractory period depends on Na conductance
The main ionic currents in an AP are Na and K currents
36
37
38
Types of voltage-gated ion channels
• Voltage gated 𝑁𝑎+ and 𝐾 + channels

• Voltage gated 𝐶𝑎+2 channels (Dep.)
• Voltage gated 𝐶𝑙 − channels (Neurons and
muscle cells) (Rep.)
• HCN (Hyperpolarization-activated channels)
(Dep. After Hyperpolarization), 𝑁𝑎+ and 𝐾 +
Variety of 𝐾 + channels
1. Slowly-activating 𝐾 + channels
2. Calcium- activated 𝐾 + channels
3. A-type 𝐾 + channels (Activated by large Dep.)
4. M-type 𝐾 + channels (Activated by small
Dep.)
39
Gating process can be influenced by
cytoplasmic factors
• Calcium concentration
• Second-messenger pathways
Excitability Properties Vary Between

Types of Neurons
• Peripheral myelinated axons: Repolarization at

the nodes of Ranvier is by fast inactivation of
Na+ channels combined with a large outward
K+ leakage current.
• Central myelinated axons have significant

numbers of voltage-gated K+ channels at their
nodes important for repolarization.
40
Excitability Properties Vary Between
Types of Neurons
Both central and peripheral myelinated axons K+

channels under the myelin sheath to suppress
any action potential that may be generated by
axon membrane under the myelin sheath.
41
Excitability properties vary between
regions of the neuron
𝐶𝑎 +2, 𝑁𝑎+, 𝐾 + , 𝐻𝐶𝑁
Voltage-gated 𝑁𝑎+ 𝑎𝑛𝑑 𝑘 +channels
Voltage-gated 𝑘 +channels
High density voltage gated 𝑁𝑎+channels

Voltage-gated
Low threshold M-type, A-Type 𝐾 + channels, 𝐶𝑎+2channels
𝐶𝑎+2
42
Model neuron section by section and
connect sections together
The neuron can be divided into unit lengths, each of which is a circuit
Resistance across the
Membrane = rm
Capacitance across the
Membrane = cm

Resistance across the
Membrane = rm
Capacitance across the
Membrane = cm
43
Resistance inside the cell through the cytoplasm

along the axis of the cylinder = ra

Resistance outside the cell through the extracellular space is << ra . It

is often modeled as a short circuit
44
45
Example:
A current pulse of amplitude 1nA is injected in an axon with a specific membrane
resistance Rm=10kΩ.cm2, specific axoplasmic resistance Ri= 100Ω.cm, specific
membrane capacitance Cm=1µF/cm2, Input impedance of 79.58MΩ and
diameter 4µm. The resting membrane potential is -68mV.
1- If the threshold level for the voltage-gated Na+ channels is -20mV, what is the
minimum pulse width of this injected current to cause an action potential?
2- If the injection site is 0.8 mm away from the axonal hillock where the threshold
level is -50mV, what is the minimum pulse width of the injected current to trigger
an action potential?

the Nervous System
Chapter 8
Overview of Synaptic Transmission
46
Synaptic transmission
• Signaling between neurons
• Synapses Are Either Electrical or Chemical
Electrical synapses
47
Synaptic transmission at chemical
synapses
48
Postsynaptic Receptors Gate Ion Channels
Either Directly or Indirectly
49
Example:
A current pulse of amplitude 1nA is injected in an axon with a specific membrane
resistance Rm=10kΩ.cm2, specific axoplasmic resistance Ri= 100Ω.cm, specific
membrane capacitance Cm=1µF/cm2, Input impedance of 79.58MΩ and
diameter 4µm. The resting membrane potential is ‐68mV.
1‐ If the threshold level for the voltage‐gated Na+ channels is ‐20mV, what is the
minimum pulse width of this injected current to cause an action potential?
2‐ If the injection site is 0.8 mm away from the axonal hillock where the threshold
level is ‐50mV, what is the minimum pulse width of the injected current to trigger
an action potential?

the Nervous System
Chapter 8
Overview of Synaptic Transmission
4
• Synapses Are Either Electrical or Chemical
10
5
Electrical synapses
11
12
6
Synaptic transmission at chemical
synapses
13
14
7
Postsynaptic Receptors Gate Ion Channels
Either Directly or Indirectly
15

the Nervous System
Chapter 9
Signaling at the Nerve‐Muscle
Synapse
16
8
The Neuromuscular Junction
17
The Neuromuscular Junction
18
9
The depolarization resulting from the opening of ACh receptor‐
channels at the end‐plate opens voltage‐gated Na+ channels
19
ACh receptor‐channel is permeable to

both Na and K ions
20
10
The end‐plate potential is produced by the simultaneous flow of
Na+ and K+ through the same receptor channels.
21
22
11
23
12
the Nervous System
Chapter 10
Synaptic Integration in the Central
Nervous System
1
3
2
classes of glutamate receptors
NMDA Receptors
3
A synaptic potential arising in a
dendrite can generate an action
potential at the axon initial segment.
integrate a variety of synaptic

inputs through temporal and
spatial summation of synaptic
potentials
4
9
10
5
11
12
6
Control and Communication in the Nervous System
Neural Interface Applications
Place of the PNS in the structural organization of the nervous system
CNS
PNS
Sensory division Motor division
Sympathetic
division Autonomic Somatic
nervous nervous
Parasympathetic system system
division
Human Anatomy and Physiology, 7e Copyright © 2007 Pearson Education, Inc.,

by Elaine Marieb & Katja Hoehn publishing as Benjamin Cummings.
1
• Peripheral nervous system carries
highly-processed neural commands
and feedback signals to communicate
with different physiological structures
across the body.
• Interfacing with the PNS provide an

access to these signals for Human-
Machine Interface (HMI) applications.
Basic Structural Components of the PNS
• Sensory receptors – pick up stimuli from inside or outside the body

• Motor endings – axon terminals of motor neurons innervate effectors
(muscle fibers and glands)
• Nerves and ganglia
– Nerves – bundles of peripheral axons
– Ganglia – clusters of peripheral neuronal cell bodies
2
A dermatome is an area of skin that is mainly supplied by afferent nerve fibers from a
single dorsal root of spinal nerve which forms a part of a spinal nerve
6
7
8
Structure of a nerve
Axon
Blood vessels Perineurium Myelin sheath
Endoneurium
Perineurium
Epineurium
Fascicle
Fascicle
Blood
vessels
Endoneurium Nerve fibers

(a)
(b)

9
Spinal Nerves and Nerve Plexuses
• Characteristics:
– Somatic sensation (conscious) and somatic motor control (voluntary
control) of skeletal muscles.
– Includes cranial nerves: I, II, IV-VI, VIII, XI and XII.
– Spinal nerves: 31
• Cervical: 8 (above C1, and below C1-C7)
• Thoracic: 12 (below T1-T12)
• Lumbar: 5 (below T1-T5)
• Sacral: 5 ( below S1-S5)
• Coccygeal: 1 exit coccyx
– Mixed nerves
• Sensory
• Motor
– Dorsal and ventral rami (nerve branches)  plexuses (network of nerves)
Distribution of spinal nerves
Cervical plexus
Cervical
nerves
Brachial plexus C1– C8
Cervical
enlargement
Intercostal Thoracic
nerves nerves
T1– T12
Lumbar
enlargement
Lumbar plexus Lumbar

nerves
L1– L5
Sacral plexus
Sacral
nerves
S1– S5
Cauda equina
Coccygeal
nerve
C0

12
Cervical Plexus
25
• The hypoglossal nerve is the twelfth cranial

nerve XII, and innervates muscles of the tongue.
• The phrenic nerve is a nerve that originates in

the neck (C3-C5) and passes down between the
lung and heart to reach the diaphragm. It is
important for breathing, as it passes motor
information to the diaphragm and receives
sensory information from it. There are two
phrenic nerves, a left and a right one.
13
Major Nerves of the
Axillary Upper Extremity
Musculocutaneus
27
• The axillary nerve supplies three muscles in

the arm: deltoid (a muscle of the shoulder),
teres minor (one of the rotator cuff muscles)
and the long head of the triceps brachii.
• Musculocutaneous nerve innervates the
coracobrachialis, biceps brachii, and the greater
part of the brachialis.
14
Median Nerve
30
15
Median Nerve
• Supplies no muscles of the arm

• Supplies anterior forearm (except flexor carpi
ulnaris)
• The median nerve is the only nerve
that passes through the carpal tunnel.
• Damage can cause
– Hand of benediction
– Ape Hand Patient trying to
– Carpal Tunnel Syndrome make a fist
31
Ulnar Nerve
• Supplies flexor carpi ulnaris
• “Funny Bone”
• Damage can cause claw hand; cannot adduct
or abduct fingers
32
16
Radial Nerve
• Supplies muscles on the posterior arm and
forearm
– Triceps brachii
– Extensor carpi radialis
– Extensor digitorum communis
• Damage can cause wrist drop
• Also called “waiter’s hand”
33
Carpel Tunnel Syndrome
Ape Hand
34
17
LUMBAR PLEXUS
3. LUMBAR PLEXUS
• FEMORAL NERVE is the main nerve to
the anterior thigh.
35
Lumbo-Sacral Plexus
• Lumbar:
– Femoral nerve
• Sacral:
– Sciatic nerve
36
18
The Lumbar Plexus
37
Figure 14.15
• The femoral nerve is a nerve in the thigh

that supplies skin on the upper thigh and
inner leg, and the muscles that extend the
knee.
• The sciatic nerve provides the connection
to the nervous system for nearly the whole
of the skin of the leg, the muscles of the
back of the thigh, and those of the leg and
foot. It branches into the tibial branch,
common fibular, and sural nerves
19
• common fibular nerve controls the tibialis anterior muscle
• It provides sensation and motor function to frontal parts of the
lower leg. When damaged or compressed, it can cause foot drop.
• Tibial Nerve controls the gastrocnemius

muscle.
The sural nerve is a sensory nerve in the calf region (sura) of the leg.
20
The reflex arc
• Characteristics: Structurally (number of neurons
involved)
– Monosynaptic arc: one synapse
– Polysynaptic arc: one or more association neurons.
• Somatic Reflexes (skeletal muscle effectors)
– Stretch reflexes: Postural and locomotion reflexes.
• Muscle spindle stimuli/Golgi organ in tendons
(stretching) initiates reflex.
– Reciprocal inhibition: antagonistic efferent
muscles are relaxed (damped).
– Patellar reflex (activity 1).
The stretch reflex
Interneuron
Cell body of
1 Afferent impulses sensory neuron
from stretch
receptor to Motor neuron
spinal cord serving quadriceps
2 Efferent Motor neuron

–
impulses to serving antagonist
alpha (a) motor muscle group
neurons cause (hamstrings)
Initial contraction Spinal cord
stimulus: of the stretched (L2–L4)
muscle muscle that
stretch resists/reverses
the stretch Muscle
Patella spindle
Quadriceps
Muscle (extensors)
spindle
Patellar
ligament Hamstrings
3 Efferent impulses
to antagonist (flexors)
muscles are
damped Key:
(reciprocal + Excitatory synapse
inhibition) – Inhibitory synapse
(a)
(b)

27
The Golgi tendon reflex
Golgi
tendon
Quadriceps organ
(extensor)
Hamstrings
(flexor)
Spinal cord
Interneurons
+
+ Afferent fiber
from Golgi
tendon organ
– Efferent fiber
+
to muscle
associated
with stretched
tendon
Key: Efferent fiber
+ Excitatory synapse to antagonistic
– Inhibitory synapse muscle

Anatomy of the muscle spindle and Golgi tendon organ
 Efferent motor fiber to spindle
Secondary
sensory
endings a Efferent
(type II fiber) motor fiber
to extrafusal
Primary muscle
sensory fibers
endings
(type Ia fiber) Extrafusal
muscle
Muscle spindle fiber
Intrafusal
muscle
Connective fibers
tissue capsule
Sensory
Capsule fiber
Tendon
Golgi tendon
organ

28
Operation of the muscle spindle
Muscle
spindle
Intrafusal
muscle fiber
Primary
sensory (la)
nerve fiber
Extrafusal
muscle fiber
Time Time Time Time
(a) Unstretched (b) Stretched muscle; (c) a Motor neuron (d) a -  Neuron
muscle; AP frequency stimulation only; no coactivation;
AP frequency increased APs, unable to signal AP frequency
constant length changes constant
AP: Action Potential

Somatic Reflexes
• Crossed extensor reflex: Withdrawal reflex,
followed by extension of the opposite limb.
• Activity 2?
29
The crossed-extensor reflex
+ Interneurons
+
–
+ +
–
Efferent
Afferent Efferent fibers
fiber fibers
Extensor
Flexor
inhibited
inhibited
Flexor Arm movements
Extensor
stimulated stimulated
Key:
+ Excitatory synapse Right arm Left arm (site of
– Inhibitory synapse (site of stimulus) reciprocal activation)

• Autonomic Reflexes
– Pupillary reflexes
– Salivary reflex
• Reaction time of a reflex
– Relative to the myelination of an axon and its
length relative to the interneuron or association
center.
– Visual stimulus 150-300 ms.
30
Visceral reflexes
Dorsal
Sensory root Central
receptor in ganglion nervous
viscera
Stimulus system
Visceral
Visceral reflex arc
(sensory)
(Autonomic reflex)
fiber
Postganglionic
axon
Response Visceral
effector Integration center
Ganglionic (may be preganglionic
neuron neuron)
Autonomic Preganglionic axon

ganglion

Esophagus
Heart
Appendix
Kidney
31
1
2
3
4
5
6
7
8
Interfacing with the PNS
Motivation Generate control signals for robotic prosthesis
1.7 million Americans with limb loss

• <40,000 with severe upper arm amputations
• Mostly machinery and farming accidents
• Recent influx of soldiers
1
Problem: reliably detecting the movement intent
Approach Interfacing with the peripheral nervous system
2
Introduction individual fascicles control individual muscles
Studies on nerve stimulation show that stimulating individual fascicles or fascicular

groups can produce selective muscle activation. [Leventhal DK et. al. ‘03, Tyler DJ et. al. ‘02,
Tarler MD et. al. ‘04 ]
Recording neural activity of these neural sources represents listening to how and
when the body is naturally controlling these muscles.
Neural Interface Methods
Kuiken et al 2009
Ceballos et al 2002
3
Branner et al 2001
Kuiken et al 2009
Ceballos et al 2002
Branner et al 2001
Kuiken et al 2009
Ceballos et al 2002
Tyler et al 1997
4
Branner et al 2001
Kuiken et al 2009
Ceballos et al 2002
LStn cat (82)
Median monkey (91)
Sciatic and s. Per. cat (96)
Sural human (94)
Tyler et al 1997
Median pig (11)
Hyp. Cat (94)
T.A. and s. Per. Cat (94)
Pancreatic Nerve
Branner et al 2001
Kuiken et al 2009
Ceballos et al 2002
Tyler et al 1997
Tyler et al 2002, Yoo et al 2005
5
The cocktail party effect
Peripheral Nerve Recording
The cocktail party effect
6
7
8
Cutting Edge Researches to Revolutionize Prosthetics:
1- Utah Slanted Electrode

Arrays are used for Recording
Sensory and Motor Information
from Peripheral Nerves.
Must penetrate the various

membranes that surround the
nerve
Gregory A. et al. 2011
2- Targeted muscle
Reinnervation, AKA Bionic
Arm project was developed
by Todd Kuiken, a
biomechanical engineer at
Northwestern University
developed Bionic Arm in
2002.
It utilize muscles to amplify

neural command signal from
the nerve in what called
biological amplifier.
9
2- Targeted muscle
Reinnervation, AKA Bionic
Arm project was developed
by Todd Kuiken, a
biomechanical engineer at
Northwestern University
developed Bionic Arm in
2002.
However, Robust and Reliable

device based on this
technology has not yet been
implemented
10
• Selective recording vs whole nerve recording
Governed by electrode size and material, whole nerve recording exhibits contact
impedance (𝑍 ) of < 1 kohm. low thermal noise is generated at the source.
Figure 2: A) ENG recording model B) Whole nerve vs selective (FINE) recording
11
Neuromodulation and
Neuroprosthetics
Neuromodulation
Its defined as sing electrical stimulation to improve control of an existing part
of the nervous system.
Examples include spinal cord stimulation systems used for chronic pain
management that block pain signals to the brain and gastric stimulation
systems, which are used to block the signals of hunger.
Some examples of neuromodulation techniques

including:
• Deep brain stimulation (DBS)

• Transcranial magnetic stimulation (TMS)
• Vagal nerve stimulation
1
Deep brain stimulation (DBS)
This involves the placement of an electrode inside the brain with a wire running down the neck
connected to a battery pack or pulse generator under the skin in the chest or abdomen.
Currently used to treat Parkinson's disease, epilepsy, stroke and severe obsessive compulsive disorders.
Research is underway into its use to treat obesity, Tourette's syndrome, anorexia, addictions.
• In Parkinson's disease, loss of dopamine-producing cells leads to excessive and

abnormally patterned activity in both the globus pallidus (Gpi) and the sub-
thalamic nuclei .
• "Pacing" of these nuclei with a constant, steady-frequency electrical pulse

corrects this excessive and abnormal activity.
• DBS does not act directly on dopamine producing cells and does not affect
brain dopamine levels. Instead, it compensates for one of the major secondary
effects of dopamine loss, the excessive and abnormally patterned electrical
discharge in the GPi or the STN (sub-thalamic nuclei).
• The exact mechanism by which the constant frequency stimulation pulse

affects nearby brain cells has not been determined.
2
Parkinson’s Disease
• FDA Approved in 2002
• Usual targets are the subthalamic nucleus or the
Globus Pallidus Interna
• Ideal candidates are Levodopa (Sinemet)
responsive and have classic Parkinson’s disease
Machado A et al. CCJM Vol 79, No. 2, Feb. 2012
Parkinson’s Disease: What DBS Does Help
• Increases “On” time

• Decreases Bradykinesia
and Rigidity
• Reduces Medication Dose
• Improves dyskinesia
• Effectively treats tremor
4
Parkinson’s Disease Outcomes
• 6 Randomized controlled trials support
DBS for Parkinson’s Disease
• DBS Statistically improves motor function
and Quality of Life
• Average increase of 4.6 hours per day of
“On” time
Essential Tremor
• FDA approved in 1997
• Familial or Essential tremor responds well
• Improves tremor that is medication refractory
• Target is the ventral intermediate (Vim) Nucleus
of the thalamus
Costa J et al. Journal of Neurophysiology Published 1

September 2008 Vol. 100 no. 3, 1610-1621
Movementdisorders.florida.edu
5
Essential Tremor Outcomes
• Randomized controlled trials demonstrated
improved Activities of Daily Living and Improved
tremor
• 80% improvement in tremor 70% improvement
in handwriting
Zhang K et al. J Neurosurg. 2010 Jun;112(6):1271-6. doi: 10.3171/2009.10.JNS09371.
Dystonia
• FDA Humanitarian Device exemption 2003
• Patients with medically resistant symptoms
• More commonly used for primary dystonias
(DYT-1, DYT-6) and torticollis
• Target is globus pallidus (Rarely subthalamic
nucleus)
Machado A et al. CCJM Vol 79, No. 2, Feb. 2012
6
Dystonia: What DBS Does Help/Outcomes
• 3 randomized controlled trials demonstrated

Improved Activities of daily living/quality of life
• Effects of stimulation are not immediate
• May improve pain in Cervical dystonia
• Younger patients may have better outcomes
Parkinson’s Disease: What DBS Doesn’t Help
• Gait or balance
• Cognitive problems
• Depression (unless
situational)
Studyblue.com
7
DBS Preoperative Evaluation
• Evaluation in the Neurology Movement
Disorders Clinic
• Neuropsychological testing
• Physical Therapy Evaluation
• Discussion in Movement Disorders Conference
• Neurosurgery Clinic Visit
DBS Placement
• Usually done awake IV pain medications,
local anesthesia and intermittent sedation
• Placement of small recording
microelectrodes
Above photo Courtesy of Leland

Albright
8
Neurophysiology and Intraop Testing
Final lead position is determined from

information obtained during microelectrode
recording and test stimulation.
Z Williams, J Neimat, G. Cosgrove, E. Eskandar. Timing and direction selectivity of subthalamic and
pallidal neurons in patients with Parkinson disease
Exp Brain Res (2005) 162: 407–416
3D Printed Stereotactic Frames

• Allow fast, accurate placement of DBS Leads
for Awake Cases
• Improve Patient Comfort
9
Risks of DBS Surgery
• Brain hemorrhage: ~3%, most are
asymptomatic but some can cause weakness
or deficits
• Infection: ~5%. Usually treated with removal
of the battery and antibiotics.
• Slurring of speech in Tremor patients
(dysarthria)
• Cognitive difficulties (risk increases with age)
• Balance Problems
Options for Asleep MRI Guided DBS

• Currently Emphasizing
Parkinson’s disease patients
• Generally reserved for
patients unable or unwilling
to tolerate awake surgery
11
Transcranial Magnetic Stimulation
When a strong, rapid current is passed through a stimulating coil (top), a rapidly changing
magnetic field is produced, which induces current into the brain (bottom).
Bolognini N , and Ro T J. Neurosci. 2010;30:9647-9650
History of TMS and obligatory funny pictures

Merton &Morton (1980). Successful Transcranial
Electrical Stimulation
Magnusson &
d’Arsonval (1896/1911) Stevens, 1911
Thompson, 1910
13
NeuroStar TMS Therapy System
Treatment Coil
Touchscreen
Head Support Unit
Mobile Console
Treatment Chair
NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
Effect of TMS on the Brain

Acute Effects
– Induces electric current
– Depolarizes neurons in superficial cortex
– Leads to local and trans-synaptic changes in brain activity
•Alteration of monoamine concentrations

(salivary cortisol)
•Induction of neurotrophin genes (e.g. BDNF)
•Stimulation of DLPFC alters functional activity of
deeper regions (anterior cingulate cortex, ACC)
15
TMS Produced Significant Improvements in
Depressive Symptoms
MADRS Total Score HAMD-24 Total Score

(Baseline to Endpoint Change)1 (Baseline to Endpoint Change)2
Baseline Week 2 Week 4 Week 6 Baseline Week 2 Week 4 Week 6
0 0
Change From Baseline
Change From Baseline

-2 -2
-4 -4
-6 ** -6
** ** **
P=.0018
P=.0063 P=.007 ** **
P=.0006
-8 -8 P=.0006 P=.0041
NeuroStar TMS Sham (n=76)

Therapy (n=88)
** P<.01.
LOCF analysis of evaluable study population.
1. Lisanby SH et al. Neuropsychopharmacology. 2009;34(2):522-534; 2. Data on file.
Neuronetics, Inc: Malvern, PA; 2008.
Analysis of Effect Size:

TMS vs. Antidepressant Medications
NeuroStar TMS Antidepressant

Therapy1 Medication2
Standardized Effect Size
Standardized Effect Size
(HAMD-17)
(HAMD-17)
[95% CI
0.21–0.83]
[95% CI
0.26–0.36]
N=164 N=12,564
1. Data on file. Neuronetics, Inc: Malvern, PA; 2008.

2. Turner EH et al. N Engl J Med. 2008;358(3):252-260.
17
TMS Therapy in Clinical Practice
• Non-invasive
• No anesthesia or sedation
• Outpatient procedure easily performed
in psychiatrists’ offices
• Approximately 40-minute daily
procedure
• 4-6 week treatment course
• Contraindication considerations
• Non-removable metallic objects in or
near the head
• Conductive, ferromagnetic, or other
magnetic sensitive metals that are
implanted or are
non-removable within 30 cm of
treatment coil
Other Brain-Behavior Techniques

• Lesion Studies
– Dependence of serendipity of nature or experimental models in animals
– Single or few case studies
– might be more than a single lesion
– lesion may be larger than the brain area under study
– Cognitive abilities may be globally impaired
– Lesion can only be accurately defined post mortem
– The damaged region cannot be reinstated to obtain control measures that
bracket the lesion-induced effect
– Comparisons must be made to healthy controls; internal double
dissociations are not possible
– Given brain plasticity, connections might be modified following lesions
18
• Cortical Stimulation
– Invasive
– Limited to the study of patients with brain
pathologies requiring neurosurgical
interventions
– Stressful situation in the OR and medications
might condition subject’s performance
– Time constraints limit the experimental
paradigms
– Retesting is not possible
• Neuroimaging (Brain Mapping)
– Non-invasive identification of the

brain injury correlated with a given
behavior
– Association of brain activity with
behavior - cannot rule out
epiphenomenon
– Cannot demonstrate the necessity of
given region to function
– Neuroimaging techniques are usually
only good either temporally or
spatially, not both (e.g. Pet & fMRI
lack temporal resolution, EEG lacks
spatial resolution)
19
Advantages of TMS: Virtual Patients
causal link between brain activity and behaviour
Braille Alexia
Real lesion TMS lesion
Cohen et al., 1997.

Occipital TMS disrupts
Hamilton et al., 2000. Reported braille reading in early
case of blind woman who lost blind, but not control
ability to read braille following subjects
bilateral occipital lesions
Blue = sighted; Red = E blind
Advantages of TMS: Chronometry
“Chronometry”:
timing the
contribution of focal
brain activity to
behavior
Role of “visual” cortex in

tactile information
processing in early blind
subjects
Hamilton and Pascual-

Leone, 1998
20
Functional connectivity- relate behaviour to the
interaction between elements of a neural network
TMS to FEF - correlation between TMS and CBF at

i) stimulation site
ii) distal regions consistent with known anatomical
connectivity of monkey FEF
Paus et al. TMS/PET
Summary: What can TMS add to Cognitive

Neuroscience ?
• “Virtual Patients”: causal link between brain activity

and behavior
• “Chronometry”: timing the contribution of focal
brain activity to behavior
• “Functional connectivity”: relate behavior to the
interaction between elements of a neural network
• Map and modulate neural plasticity
21
Safety
Seizure induction - Caused by spread of excitation. Single-pulse TMS has produced seizures in
patients, but not in normal subjects. rTMS has caused seizures in patients and in normal
volunteers. Visual and/or EMG monitoring for afterdischarges as well as spreading excitation
may reduce risk.
Hearing loss - TMS produces loud click (90-130 dB) in the most sensitive frequency range (2–7
kHz). rTMS = more sustained noise. Reduced considerably with earplugs.
Heating of the brain - Theoretical power dissipation from TMS is few milliwatts at 1 Hz, while
the brain's metabolic power is 13 W
Engineering safety - TMS equipment operates at lethal voltages of up to 4 kV. The maximum
energy in the capacitor is about 500 J, equal to dropping 100 kg from 50 cm on your feet. So
don’t put your tea on it.
Safety
Scalp burns from EEG electrodes - Mild scalp burns in subjects with
scalp electrodes can be easily avoided using, e.g., small low-
conductivity Ag/AgCl-pellet electrodes.
Effect on cognition - Slight trend toward better verbal memory,

improved delayed recall and better motor reaction time
Local neck pain and headaches - Related to stimulation of local muscles

and nerves, site and intensity dependant. Particularly uncomfortable
over fronto-temporal regions.
Effect on Mood in normals - Subtle changes in mood are site and

frequency dependant. High frequency rTMS of left frontal cortex
worsens mood. High frequency rTMS of right frontal cortex may
improve mood.
22
Safety
Follow published safety guidelines for rTMS
Maximum safe duration of single rTMS train at 110% MT
Frequency (Hz) Max. duration (s)

1 1800+
+ minimum inter-train interval
5 10 e.g. at 20Hz @1.0-1.1 T leave
>5s inter train
10 5
20 1.6
25 .84
Caution: Guidelines not perfect
Safety -Contraindications
•Metallic hardware near coil
–Pacemakers
–implantable medical pumps
–ventriculo-peritoneal shunts
(case studies with implanted brain stimulators and abdominal devices have not shown
complications)
•History of seizures or history of epilepsy in first degree relative
•Medicines which reduce seizure threshold
•Subjects who are pregnant
(case studies have not shown complications)
•History of serious head trauma
•History of substance abuse
•Stroke
•Status after Brain Surgery
•Other medical/neurologic conditions either associated with epilepsy or in whom a seizure
would be particularly hazardous (e.g. increased intracranial pressure)
23
Practical
T
considerations
Coil shape
The geometry of the

coil determines the
focality of the
magnetic field and of
the induced current -
hence also of the
targeted brain area.
Practical Considerations - stimulation depth

70x60 5mm
55x45 15mm
40x30 20mm
0 25mm
Cannot stimulate medial or sub-cortical areas
24
Control Conditions
Real
Different hemisphere
Different
effect or no
effect
Sham
Different site
Or interleave TMS with no TMS trials
Vagus Nerve Stimulation
Used to treat refractory epilepsy, produces a 40%

reduction in fits in 40% of patients
Vagus nerve is both motor and sensory
Mechanism not clearly understood - fMRI

indicates activation of thalamus & insular
cortex
27
Brain-machine interfaces (BMIs)
devices that detect intent—typically intended movement—from
brain activity, and translate it into an output action, such as
control of a cursor on a screen or a robotic arm.
1) acquiring a neural signal that can be consciously controlled;
2) analyzing that signal to identify an intended motor output; and
3) executing the intended action
NeuroSensing and Diagnostics are tools to improve monitoring

of activity in the nervous system, brain state activity or improve diagnosis
of a condition. A peripheral nerve sensing test system that detects
sensory impairments due to carpal tunnel syndrome is an example of a
neurosensing system in practice. Another example is EMG
(electromyography) devices utilized to communicate with a computer
system.
BCI connects the brain to a computer

Neuroprosthetics connect the nervous system to a
device
Matt Nagle's neuroprosthetic lets him

move a cursor using thought alone.
28
Retinal Implants
Blind people have described smiles on friendly faces, the food on their plates, and
household objects from telephones to dustbins, after surgeons fitted them with electronic
chips to partially restore their vision.
Results from the first eight patients to enrole in a clinical trial of the retinal implants show
that five found the chips improved their eyesight enough to be useful in everyday life.
Concepts
• Implant uses electric pulses to send signals to brain
to produce image
• Only restores vision for RP and AMD
• How implant receives information
• Restored vision quality
29
Targeted Conditions
• Retinitis Pigmentosa (RP)
– Inherited
– Photoreceptors dying from the periphery
– As early as 20 years old
• Age-related Macular Degeneration (AMD)
– Photoreceptors dying from the center out
– Age 65+
– Most common
• No cure for either forms of blindness
Epiretinal Implant
• Implant in front of the retina
• Requires a camera
• Work is done by Visual
Processing Unit
• Implant receives information
from the camera with light
• Implant sends electric impulses
to the optic nerve through
electrodes
• Implant power
30
Argus II
• Developed by Second Sight
• 20/1,000 vision
• Approved in March 2011
• In 2013, 70 people have the implant
• visual field of about 3.5 inches by 6.5 inches
• Uses 60 electrodes
• $150,000 US dollars
• The only implant commercially available
31
Stanford Retinal Implant
• Epiretinal Implant
• Clinical trial in France
• Grayscale
• 20/200 vision
• Threshold of legally being
legally blind
• Goal is to get the quality to
20/100
• 1 x 1 mm
• Powered with infrared light
32
Conclusion
• The implant only works with RP and AMD
• Does not completely restore sight
• Only a few people have the implant
• The implant is very expensive
• Implant is progressing to the point where the user
can recognize faces
NeuroPharmaceuticals is an emerging field of therapy, applied through the

use of devices combined with pharmaceuticals, particularly for cognition and
emotional treatments. Examples include pumps for baclofen to treat spasticity or
morphine for chronic pain.
Intrathecal pump delivers medication to spinal fluid. There is no feedback loop.
33
Control and Communication in the
Nervous System
Brain Plasticity
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Rehabilitation &
Neuro-Robotics
Stroke Disability
 Leading cause of severe long-term disability
 Arthritis is the leading cause of overall disability, but generally
less severe disability
 AHA 2005
 40% moderate functional impairment
 15-30% severe disability
 Framingham study (2003):
Ischemic stroke survivors ≥ 65 yrs @ 6 months
 68% functionally independent (32% not independent)
 50% had some hemiparesis
 30% unable to walk w/out some help
 26% dependent in ADLs
 19% had aphasia
 35% had depressive Sx
 26% were in SNFs

AHA/ASA – 2005 Practice Guidelines
• Strongly recommend that rehabilitation therapy start as early

as possible, once medical stability is reached.
• Supports early mobilization of acute stroke pts to prevent

complication like DVTs, skin breakdown, contractures,
constipation, PNA, etc.
• Recommend that the patient receive as much therapy as

“needed” to adapt, recover, and/or reestablish the pre-morbid
or optimal level of functional independence.
– No specific guidelines on intensity, duration, or location of
therapies
AHA/ASA – 2005 Practice Guidelines
• Better outcomes when pt receive coordinated, multidisciplinary
evaluation and intervention (both inpatient & outpatient rehab)
• More likely to live at home, more ADL independence, less mortality,
higher QOL at 5 yrs
– Indredaviks et al, Stroke 1997.
– Cifu et al, Archives PM&R 1999.
– Langhorne et al, Stroke 2001.
– Evans et al, Lancet 2001.
– Cochrane Database Syst Rev. 2007(4):CD000197.
Shoulder Pain
• AHA/ASA Guidelines
– Recommendation for prevention
• E-stim to improve shoulder lateral rotation
• Shoulder strapping (sling)
• Staff education (transfers, lifting, side lying, etc)
• Avoiding use of overhead pulleys
– Recommendations for treatment
• Intra-articular steroid injections
• Shoulder strapping
• ROM exercise program, esp ER/abduction
• Modalities: ice, heat, soft tissue massage
• FES
• Strengthening
Spasticity & Contracture Prevention
• Proper bed positioning

• ICU: early PROM with PT/OT, RNs
• Ward: early mobilization
• Daily stretching
• Frequent monitoring of joint ROM
• Resting hand splints
• Posterior foot splints
• Adequate pain control to
promote mobility
Serial Casting
• Indications: when PROM,

positioning, splinting have
failed to correct a contracture
• Goals: increase PROM or
prevent PROM loss, reduce
hypertonicity, improve long-
term function
• Only evidence: improved
PROM (Passive range of motion)
Dynamic and Static Progressive Orthoses
• Static progressive
orthoses
– Joint angle held constant for a
prescribed time
– Incremental like serial casting
– Patient can change joint angle
– Typically worn 30 minutes 2/3 time,
can be up to 6-12hrs daily
– Easier removal than serial casts
– Can be removed for therapies
• Dynamic orthoses
– Torque generated by a coil, gas,
or flat spring
– Coil spring, gas spring, clockwork
or flat spring
– Occasional adjustment w/ ∆ROM
Botulinum Toxin
• Botulinum toxin A (or B) for spasticity

– Neurotoxins from Clostridium botulinum
– Potent pre-synaptic blockade of acetylcholine
at neuromuscular junction
– Intramuscular injection
± EMG guidance
or muscle stimulation
Other Complication Rates
• Pulmonary Embolism: 13-16% of acute stroke deaths

– ~3% PE incidence after stroke
– 50% of pts with PEs after stroke die
– Leading cause of death in 2-4th wk post Cerebrovascular accident
• Malnutrition upon rehab admission
– 49% malnourished: all stroke pts
– 65% malnouished: stroke pts with dysphagia
• Bladder Incontinence: 50-70% in 1st month, 15% after 6
months (~general population)
Neuro-Robotics
Cutting Edge Technology
Exoskeleton Devices Brain Computer Interfaces
EEG Intracortical
Prosthetics EMG/FES NASA

Dean Kamen, Todd Kuiken
+/- mirrors
Cutting Edge Technology
• Pennsylvania local news
https://www.youtube.com/watch?v=8xH7HSs2dik
• NHK World (Japan’s public broadcasting network)

https://www.youtube.com/watch?v=2Ysb-
Oko3Bg&ebc=ANyPxKpw1JnXV44_5lLShrAUOFkCvttgc6ji7qbZrd8nB06c695691jpEWtRrjWkAi7pLP
G4-Nok
• Both can be used as active and passive devices

• Most exoskeleton devices are passive devices like
orthotics
2013-2014 HAL Exoskeleton Study
• 8 chronic motor incomplete SCI patients (ASIA A/B w/ ZPP & C/D)
– 1-19 years post-injury (mean ± SD: 97.2 ± 88.44 months)
• Must have trace motor function at KE, KF, HF, ± HE to trigger the
exoskeleton EMG surface electrodes
• Completed acute & subacute rehab at German L&I center
– Months of inpatient rehab similar to the U.S. in past decades
• Exoskeleton training with BWSTT: 5 days/week x12 weeks for 90
minute sessions (device donning/doffing & therapy)
The Spine Journal 14 (2014) 2847–2853
2013-2014 HAL Exoskeleton Study
• Functional outcome measures: treadmill walking distance/speed/time, 10-meter

walk test, time-up and go, 6-minute walk test, walking index for SCI II (WISCI ii)
• Physiologic measures: modified Ashworth scale, lower extremity motor score,
lower extremity circumference also measured and improved
• Mean WISCI II score improvement not statistically significant
• 1 pt improved from 6 (FWW, brace, w/ assist) to 9 (FWW, brace, w/out assist)
• 1 pt improved from 9 to 12 (2 crutches, brace, w/out assist)
Walking Index for Spinal Cord Injury II
Variable Availability
Dysphagia
Biofeedback
Virtual Reality
TMS
Widely Available Devices
Body Weight Wheelchairs
Supported Treadmill
Orthotics
FES
Many, Many More Devices
Traditional Devices
Walkers Canes
Crutches Splints
Limits of Conventional NeuroRehab
• Requires hours of therapy time
– Increasing therapy labor costs
• UK: ~10% of national stroke budget
• Aging population (ex: Japan) relative to trained therapists
– Rural access to specialists
• Frequent safety risks for patients & therapists
• Lacks repetition found to optimize neuroplasticity
– Body Weight Supported Treadmill training vs conventional
– Up to 1000 gait cycles in 30 min vs <50 cycles
• Low Compliance: home > hospital
– Less engaging/entertaining (VR), 1:1 hands-on supervision
• Difficult to obtain standard study objective measures
Benefits of Conventional NeuroRehab
• Teaches compensatory strategies

– Hemi technique for walking, dressing, eating, and other ADLs
• Much more adaptable and personalized
• Whole body > segmental approach
• Compensate for abnormal movement patterns
• Accounts for emotional & clinical status quickly
– Provide motivation for patients in real time
• Accounts for cognitive and sensory deficits
– Complex tasks such as stairs, toileting, gait on uneven terrain, etc.
– Performance of actual tasks instead of simulated tasks
• Use of cheaper and more available assistive devices
– Disability produces large financial burden, limited funds
Paradigm Shift
• Economic and marketing forces
– Widespread use leads to cheaper devices
• Nintendo Wii & Xbox Kinect
– Commercialization of devices
– Patients and families drawn to new technology
– Marketing advantage for rehab facilities
– ? ultimate rationale: escalating labor costs
• Debate on its inevitability
• Benefits of robotics
• Simulated tasks when actual tasks are dangerous
• More entertaining therapy (increase compliance)
• Increased repetition to promote neuroplasticity
• Replace missing or damaged body parts
• Psychological benefits
Paradigm Shift
• Will clinical insights keep pace with technological innovation?

– Protocols for using technology safely and effectively
• When, Who, Where, Dosage, Insurance coverage?
– Keeping up with patient demands, expectations
– ? evidence based medicine, ? enough large RCT studies
Rehab Robotics Studies
• Primarily studied in stroke population

– Less studies in SCI and amputation
• Upper extremity > gait devices
– Generally smaller and less expensive devices
• Most studies are small, single-center, non-randomized
• Often suboptimal control interventions
– Difficult to account for natural recovery
– Limited physiological ability to improve
• Underlying disease, residual deficit, plateau effect
• Gains often comparable to conventional therapy
– When comparing to dose-matched treatments
• Cochrane Review 2012 (19 studies, n=666)
• Mehrholz: Electromechanical and robot-assisted arm training for
improving generic ADL, arm function, and arm muscle strength
after stroke
“Electromechanical and robot-assisted arm training did improve generic

activities of daily living in people after stroke and may have improved arm
function, but did not improve muscle strength of the partial paralyzed
(paretic) arm. Because adverse events were rare, based on the data of 19
trials, these devices could be applied as a rehabilitation tool, but we still do
not know when, and how often they should be used.”
• 2008 Cochrane Mehrholz Review (11 studies, n=328)

– Safe, well accepted and improved function, but little evidence for ADLs.
BWSTT Studies
• Cochrane Review 2005/2009 (15 studies, n= 622)

• Moseley: Treadmill training and body-weight support
for walking after stroke
“Overall no statistically significant effect of treadmill training with or

without body weight support was detected. Although individual
studies suggested that treadmill training with body weight support
may be more effective than treadmill training alone and that treadmill
training plus task-oriented exercise may be more effective than sham
exercises, further trials are required to confirm these findings.”
BWSTT Studies
• RCT in acute CVA: equal (Nilsson et al, Clinical Rehab 2001)

– Severe CVA pts: BWSTT better tolerated than traditional
therapy treadmill (Danielsson et al, Archives PMR 2000)
• AHA/ASA 2005 Guidelines
• Recommends BWSTT as an adjunct to conventional therapy in pts
w/ mild-to-moderate dysfunction resulting in impaired gait.
• Recommends BWSTT for pts who are not walking 3m post-
CVA (Royal College of Physicians 2004)
FES
• AHA/ASA 2005 Guidelines

– Recommends FES for pts with:
• Impaired muscle contraction (esp ankle, knee, wrist)
• Shoulder subluxation
– Insufficient evidence to recommend for or against using
multi-channel FES for severe hemiplegic pts with gait
impairments
– Recommends FES for gait training in stroke
Marketing Advantage
• Many, many robotic product highlighted on
rehab center websites.
• Moss Rehab (Philadelphia, Dr. Esquenazi)

• University of Pittsburg (Dr. Boninger)
• Pushing Boundaries
• Swedish
– BWSTT, vision board, video game consoles, FES UE/LE/bike,
balance biofeedback, overhead ceiling lift, dysphagia biofeedback
– Similar to other NW ARUs +/-
– Use of robotics for research at UW/VA/Swedish → goals clinically
• Used clinically on East Coast
– Likely available at large rehab centers
Robotics Summary
• Many pros/cons to conventional and robotic therapy

– Ultimately a blending of the two approaches
– Optimize neurological recovery while addressing
compensatory strategies
• Ongoing need for clinical studies
• Financial barriers for widespread use
– Innovation > insurance coverage
• Marketing advantage for large rehab centers
Control and Communication in the
Nervous System
The Visual System
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2
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3
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4
9
10
5
11
12
6
13
14
7
15
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8
17
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19
Seizures and Epilepsy
Chapter 50
Electroencephalogram
Frequency bands Amplitude
• Delta frequency band • Measured in microvolt (μV)
• Under 4 Hz • Measuring total vertical distance
of wave
• Theta frequency band • Range
• From 4 to under 8 Hz • Low, under 20 μV
• Moderate or medium, 20-50 μV
• Alpha frequency band • High, over 50 μV
• From 8 to 13 Hz
• Beta frequency band

• Over 13 Hz
EEG Montage Example

Example of EEG
Wave = any change in difference of electrical

potential between two recording electrodes
“wave”
Activity = Sequence of waves
activity
Monophasic wave
(Single deflection: up or down)
monophasic wave
Diphasic wave
Sharp transient
Regular or rhythmic repetitive waves
Regular or rhythmic repetitive waves

Irregular or arrhythmic activity
Irregular or arrhythmic
repetitive waves
Sinusoidal wave form

Frequency is number of times a repetitive
wave recurring in one second.
1 sec
Delta frequency band
1 sec
Theta frequency band
1 sec
Alpha frequency band

Beta frequency band
Amplitude measurement
Lateralized distribution
Focal or localized distribution

Alpha rhythm blocked by eye opening
Alpha rhythm blocked by eye

closure
eye opening
eye closing
Beta rhythm
Beta frequency band
Definitions
• Seizure: the clinical manifestation of an abnormal,

excessive excitation and synchronization of a
population of cortical neurons
• Epilepsy: recurrent seizures (two or more) which are

not provoked by systemic or acute neurologic insults
A seizure is the manifestation of an abnormal, hypersynchronous discharge of a population of cortical

neurons. This discharge may produce subjective symptoms or objective signs, in which case it is a
clinical seizure, or it may be apparent only on an electroencephalogram (EEG), in which case it is an
electrographic (or subclinical) seizure.
Epidemiology of
Seizures and Epilepsy
• Seizures
• Incidence: 80/100,000 per year
• Lifetime incidence: 9%
(1/3 febrile convulsions)
• Epilepsy
• Incidence: 45/100,000 per year
• Point prevalence: 0.5-1%
• Cumulative lifetime incidence: 3%
The incidence of new-onset seizures in the general population is approximately 80 per 100,000 per year;
approximately 60% of these patients will have epilepsy, a tendency toward recurrent unprovoked
seizures.
At least two unprovoked seizures are required for the diagnosis of epilepsy. In the past, physicians were
reluctant to make this diagnosis even after repeated seizures, because of the adverse consequences
including social stigmatization and limitations on driving and employment. Despite advances in public
understanding of the condition, these issues remain active. The euphemism seizure disorder has been
frequently employed to avoid the term epilepsy, and may also be used to refer to situations
characterized by recurrent seizures where each is provoked by an identifiable stimulus; for example,
febrile convulsions. The current definition of epilepsy is the tendency to have repeated seizures (at least
two) as a consequence of a brain disorder, that is, unprovoked by an acute systemic or brain insult.
This definition stresses that the problem is one of brain function, and that the patient has the potential for
more seizures. This definition excludes seizures due to exogenous factors, such as ethanol or sedative
drug withdrawal, or to metabolic disorders, such as nonketotic hyperglycemia.
Estimates of the annual incidence of epilepsy in the general population range from 30 to 57 per 100,000.
These rates vary with age, being high in infants and young children, then decreasing throughout
adulthood until approximately age 60, when they again begin to increase. The overall prevalence of
epilepsy is approximately 6 per 1000.
ILAE Classification of
Seizures
Seizures
Partial Generalized
ILAE – International League Against Epilepsy
Seizures can be classified based on their clinical and electrographic features. The diagnosis of a
patient’s epilepsy syndrome is based on their clinical history and their seizure type(s).
Seizures
Seizures
Partial Generalized
Simple Partial Absence
Myoclonic
Complex Partial
Secondarily
Atonic
Generalized
Tonic
Tonic-Clonic
Seizures can be classified based on their clinical and electrographic features. The diagnosis of a
patient’s epilepsy syndrome is based on their clinical history and their seizure type(s).
Seizures
Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily Generalized
Partial seizures have onset in part of the brain; synonymous terms that are frequently used include
localization-related or focal seizures. Partial seizures are divided into two main types, depending on
whether or not consciousness is fully preserved. During simple partial seizures, consciousness is
preserved; the person is alert, can respond to questions or commands, and can remember what
occurred during the seizure. During complex partial seizures, consciousness is altered or lost; the ability
to pay attention or respond to questions or commands is thus impaired or lost. Often, there is no
memory of what happened during all or part of the complex partial seizure. The distinction between
simple and complex partial seizures is critical, because activities such as driving and operating
dangerous machinery must be restricted in patients with uncontrolled complex partial seizures;
restrictions for people with only simple partial seizures depend on the specific seizure manifestations
(and, for driving, on regulations in a particular state). Partial onset seizures may progress to secondarily
generalized seizures. Secondarily generalized seizures ultimately involve motor activity on both sides of
the body and can be difficult to distinguish from primary generalized seizures.
Complex Partial Seizures
Seizures
 Impaired consciousness
 Clinical manifestations vary with
site of origin and degree of Partial Generalized
spread
• Presence and nature of aura Complex
Partial
• Automatisms
• Other motor activity
 Duration typically < 2 minutes
Complex partial seizures are seizures which are associated with impairment of consciousness. A
common misunderstanding is that this requires seizure spread to both sides of the brain. The majority of
complex partial seizures originate in the temporal lobe and can affect consciousness while still
remaining focal. During complex partial seizures the patient tends to stare off. This is accompanied by
impaired responsiveness, cognitive function, and recall, although some degree of responsiveness may
be preserved (e.g., orienting toward a stimulus). Automatic movements (automatisms) are common and
involve the mouth (e.g., lip smacking, chewing, swallowing), upper extremities (e.g., fumbling, picking),
vocalization/verbalization (e.g., grunts, repeating a phrase), or complex acts (e.g., shuffling cards).
More dramatic automatisms occasionally occur (e.g., screaming, running, disrobing, pelvic thrusting).
Complex partial seizures usually last from 15 seconds to 3 minutes. After the seizure, postictal
confusion is common, usually lasting less than 15 minutes, although other symptoms, such as fatigue,
may persist for hours.
Secondarily Generalized
Seizures
 Begins focally, with or without
focal neurological symptoms Seizures
 Variable symmetry, intensity,

and duration of tonic
(stiffening) and clonic Partial Generalized
(jerking) phases
 Typical duration 1-3 minutes Secondarily
 Postictal confusion, Generalized

somnolence, with or without
transient focal deficit
Partial seizures can progress to generalized seizures with tonic-clonic activity. Once a partial seizure
secondarily generalizes it is generally impossible to differentiate from a primarily generalized seizure.
The history, electroencephalogram (EEG), neurologic exam (especially postictally), and neuroimaging
tests (CT or MRI) often help distinguish these seizure types. In secondarily generalized seizures,
patients may recall an aura prior to the convulsive activity or witnesses may observe a simple partial or
complex partial seizure prior to generalization. In addition, following a secondarily generalized seizure,
the patient may have focal weakness (Todd’s paralysis) on the side contralateral to seizure onset.
EEG: Partial Seizure
Right Frontal
seizure
The EEG in partial seizures is variable. During simple partial seizures, scalp-recorded EEG may be
normal, or show quite localized or lateralized abnormal rhythmic activity. During complex partial
seizures, rhythmic activity, which is often bilateral, is seen. During secondarily generalized seizures,
rhythmic activity is usually high amplitude, bilateral and diffuse, although it is usually obscured by artifact
from the abundant muscle activity characterizing these seizures.
Continuation of
the same seizure

with change in
amplitude and
frequency
Continuation of
the same seizure
with spread to the

other hemisphere
Continuation of
the same seizure
with spread to the

other hemisphere
Seizures
Seizures
Partial Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
Generalized seizures affect both cerebral hemispheres from the beginning of the seizure. They produce
loss of consciousness, either briefly or for a longer period of time, and are sub-categorized into several
major types: absence, myoclonic, atonic, tonic, and tonic-clonic.
Typical Absence Seizures
 Brief staring spells (“petit mal”) with
impairment of awareness Seizures
 3-20 seconds
 Sudden onset and sudden resolution
 Often provoked by hyperventilation Partial Generalized
 Onset typically between 4 and 14
years of age
 Often resolve by 18 years of age
Absence
 Normal development and intelligence
 EEG: Generalized 3 Hz spike-wave
discharges
Absence (petit mal) seizures are brief episodes, usually lasting 3-20 seconds, of staring with impairment
of awareness and responsiveness. There is no warning before the seizure, and immediately afterward
the person is alert and attentive. This lack of a postictal period is a key feature that allows one to
distinguish between absence and partial complex seizures. If duration is >10 seconds, there are often
accompanying motor phenomena (e.g., eye blinks, brief automatic mouth or hand movements, changes
in muscle tone). These spells usually begin between ages 4 and 14 years, and usually resolve by age
18. Absence seizures are often provoked by hyperventilation, an effective means of reproducing
seizures in the office or during the EEG. The EEG signature of absence epilepsy is the generalized 3 Hz
spike-wave discharge. Children with typical absence seizures usually have normal development and
intelligence.
EEG: Typical Absence Seizure
Myoclonic Seizures
Epileptic Myoclonus Seizures
 Brief, shock-like jerk of a muscle

or group of muscles
Partial Generalized
 Differentiate from benign,
nonepileptic myoclonus (e.g., while
falling asleep)
Myoclonic
 EEG: Generalized 4-6 Hz
polyspike-wave discharges
Myoclonic seizures involve a brief, shock-like jerk of a muscle or group of muscles. Benign myoclonus
occurs in healthy people (e.g., while falling asleep). This is not a myoclonic seizure. Pathologic
myoclonus can result from epileptic and nonepileptic causes. Epileptic myoclonus usually causes
bilateral, synchronous jerks most often affecting the neck, shoulders, upper arms, body, and upper legs.
Consciousness does not usually seem to be impaired, although this is difficult to verify given the brief
duration of <1 second; if several occur in rhythmic succession, this may be termed a clonic seizure, and
may be associated with altered awareness. EEG during a myoclonic seizure typically shows a
polyspike-and-slow-wave discharge. Myoclonic seizures occur in a variety of epilepsy syndromes.
Rarely they may be seen as part of a progressive, degenerative condition (i.e., progressive myoclonic
epilepsy).
Myoclonic Seizures
Tonic and Atonic Seizures
Tonic seizures
Seizures
Symmetric, tonic muscle contraction of
extremities with tonic flexion of waist and neck
Duration - 2-20 seconds. Partial Generalized
EEG – Sudden attenuation with generalized, low-

voltage fast activity (most common) or generalized
polyspike-wave. Tonic
Atonic seizures Atonic

Sudden loss of postural tone
When severe often results in falls
When milder produces head nods or jaw drops.
Consciousness usually impaired
Duration - usually seconds, rarely more than 1 minute
EEG – sudden diffuse attenuation or generalized
polyspike-wave
Atonic and tonic seizures, like atypical absence, are most common in people with other neurologic
abnormalities in addition to epilepsy.
In contrast to partial motor seizures, tonic seizures are generalized, involving bilateral musculature in a
symmetric or nearly symmetric manner. Tonic seizures are characterized by flexion at the waist and
neck, abduction and flexion or extension of the upper extremities, and flexion or extension of the lower
extremities. They typically occur during sleep and last 2-20 seconds. EEG usually shows generalized,
low-voltage, fast polyspikes.
Atonic seizures consist of a sudden loss of postural tone, often resulting in falls, or, when milder, head
nods or jaw drops. Consciousness is usually impaired and significant injury may occur. Duration is
usually several seconds, rarely more than 1 minute. EEG often shows an electrodecremental response.
Epileptic drop attacks may occur not just with atonic seizures, but also with myoclonic or tonic seizures if
the legs are involved.
Tonic and Atonic Seizures
Generalized Tonic-Clonic Seizures
 Associated with loss of

consciousness and post-ictal
confusion/lethargy Seizures
 Duration 30-120 seconds
 Tonic phase
Partial Generalized
 Stiffening and fall
 Often associated with ictal cry
 Clonic Phase Tonic-
Clonic
 Rhythmic extremity jerking
 EEG – generalized polyspikes
Primary generalized tonic-clonic (also called grand mal or convulsive seizures) seizures cause loss of
consciousness associated with an initial tonic phase of stiffening, a fall, and often a cry evoked by air
forced through contracted vocal cords. Legs are usually extended, and arms may be extended, flexed,
or each in succession. The subsequent clonic phase consists of jerking of the extremities which
gradually slows before stopping. Tonic-clonic seizures usually last 30-120 seconds. There may be
drooling or foaming resulting from lack of swallowing and excessive salivation; biting of the tongue,
cheek, or lip, causing bleeding; and bladder or bowel incontinence. Postictal lethargy and confusion
often last minutes to hours, and may be followed by transient agitation. The EEG shows generalized
polyspikes, but these are usually obscured by muscle artifact. Postictally, there is background
suppression and then diffuse slowing.
Epilepsy Syndromes
Epilepsy Syndrome
Grouping of patients that share similar:
• Seizure type(s)
• Age of onset
• Natural history/Prognosis
• EEG patterns
• Genetics
• Response to treatment
Epilepsy is an umbrella term, under which many types of diseases and syndromes are included. Some
authors distinguish between epilepsies and epileptic syndromes, depending on whether seizures are the
only neurologic disorder (an epilepsy) or are one of a group of symptoms (an epileptic syndrome).
Some of the epilepsies (e.g., juvenile myoclonic epilepsy) have well-defined genetics, clinical courses,
and responses to medication. Others (e.g., temporal lobe epilepsy) have natural histories which are
highly variable, and which reflect differences in pathology as well as in host response to that pathologic
process and to the treatments administered.
Epilepsy Syndromes
Epilepsy
Partial Generalized
Idiopathic Symptomatic Idiopathic Symptomatic
The current classification of the epilepsies and epileptic syndromes attempts to separate these disorders
according to their putative brain origins, that is, whether they arise in a circumscribed portion of the brain
(partial), or appear to begin diffusely in the cortex and its deeper connections (generalized). The
syndrome is idiopathic when the disorder is not associated with other neurologic or neuropsychologic
abnormalities; symptomatic indicates that such an abnormality is present and the cause is known.
Cryptogenic refers to syndromes that are presumed to be symptomatic but the cause in a specific
patient is unknown. Many idiopathic epilepsies occur in children and adolescents, and often remit in
adolescence or adulthood. There is evidence that most or all of these syndromes have a genetic basis,
and that when this basis becomes known, they will move from the idiopathic to the symptomatic
category.
INTERNATIONAL CLASSIFICATION OF EPILEPSIES AND EPILEPTIC SYNDROMES
1. Localization-Related (Local, Focal, Partial) Epilepsies and Syndromes
1.1 Idiopathic (with age-related onset)
Benign childhood epilepsy with centrotemporal spikes (‘rolandic epilepsy’); Childhood epilepsy with
occipital paroxysms
1.2 Symptomatic
Chronic progressive epilepsia partialis continua of childhood (e.g., ‘Rasmussen’s encephalitis’);
Frontal lobe epilepsies; Occipital lobe epilepsies; Parietal lobe epilepsies; Temporal lobe epilepsies
1.3 Cryptogenic
2. Generalized Epilepsies and Syndromes
2.1 Idiopathic (with age-related onset)
Benign neonatal familial convulsions; Benign neonatal convulsions; Benign myoclonic epilepsy in
childhood; Childhood absence epilepsy (pyknolepsy); Juvenile absence epilepsy; Juvenile myoclonic
epilepsy
2.2 Cryptogenic or Symptomatic
West syndrome; Lennox-Gastaut syndrome
3. Epilepsies and Syndromes Undetermined Whether Focal or Generalized
4. Special Syndromes
Etiology of Seizures and Epilepsy
 Infancy and childhood
• Prenatal or birth injury
• Inborn error of metabolism
• Congenital malformation
 Childhood and adolescence

• Idiopathic/genetic syndrome
• CNS infection
• Trauma
Etiology of Seizures and Epilepsy
 Adolescence and young adult
• Head trauma
• Drug intoxication and withdrawal*
 Older adult
• Stroke
• Brain tumor
• Acute metabolic disturbances*
• Neurodegenerative
*causes of acute symptomatic seizures, not epilepsy

Questions Raised by a First Seizure
 Seizure or not?
 Provoked? (ie metabolic precipitant?)
 Seizure type? (focal vs. generalized)
 Evidence of interictal CNS dysfunction?
 Syndrome type?
 Which studies should be obtained?
 Should treatment be started?
 Which drug should be used?
The initial evaluation after a single seizure should: 1) determine whether a seizure actually occurred, or
whether the patient experienced some other transient event; 2) search for evidence of partial onset; 3)
search for evidence of underlying central nervous system dysfunction;
4) search for evidence of systemic or metabolic disorders that could have precipitated the seizure; 5)
attempt to classify the patient’s seizure and condition; 6) determine what diagnostic studies are
appropriate; and 7) determine whether drug therapy should be instituted, and if so, with what agent.
Seizure Precipitants
 Metabolic and Electrolyte Imbalance
 Stimulant/other proconvulsant intoxication
 Sedative or ethanol withdrawal
 Sleep deprivation
 Antiepileptic medication reduction or inadequate
AED treatment
 Hormonal variations
 Stress
 Fever or systemic infection
 Concussion and/or closed head injury
Metabolic abnormalities and
seizures
Type Comment
Osmotic shifts, disrupted ionic balance, in anoxia w/
Hyponatremia
shutdown of Na-K pump
Hypo- or Rare to cause seizure. Sometimes through
hyperkalemia hypomagnesemia
Hypo- or Usually other seizures first, such as tetany or
hypercalcemia altered consciousness
Hypoglycemia BS <50, disrupted Na/K pump
May exacerbate epilepsy but rarely is de novo

Hyperthyroidism
cause
BS = blood sugar.
Seizure Precipitants
Stimulation/Other Pro-convulsant Intoxication
 IV drug use
 Cocaine
 Ephedrine
 Other herbal remedies
 Medication reduction
EEG Abnormalities
 Background abnormalities: significant asymmetries

and/or degree of slowing inappropriate for clinical
state or age
 Interictal abnormalities associated with seizures and
epilepsy
• Spikes
• Sharp waves
• Spike-wave complexes
 May be focal, lateralized, generalized
The EEG is most useful for classifying the seizure type and, in many cases, the epilepsy syndrome. A
normal EEG does not exclude the diagnosis of epilepsy. The EEG is only a very brief time sample of the
patient’s brain electrical activity and will miss intermittent or transient abnormalities. In evaluating a
patient suspected to have had a seizure, an EEG showing interictal (between seizures) epileptiform
activity provides corroborating evidence, but is not proof, unless the patient has a seizure during the
EEG (in which case the epileptiform activity is ictal rather than interictal).
Epileptiform activity includes spikes, sharp waves, electrographic seizures, and some other stereotyped
phenomena which are strongly associated with seizures. Spikes and sharp waves are interictal
epileptiform events. Background abnormalities indicate localized or diffuse cerebral dysfunction, and
may reflect a transient postictal disturbance or the underlying process responsible for the seizure.
EEG Abnormalities
Interictal
left temporal
sharp wave
consistent with
a diagnosis of
partial epilepsy
of left temporal
origin
EEG Abnormalities
Interictal generalized
polyspike-wave
complex consistent
with a diaganosis of
idiopathic
generalized epilepsy
Medical Treatment of
First Seizure
Whether to treat first seizure is
controversial
 16-62% will recur within 5 years
 Relapse rate might be reduced by antiepileptic drug treatment
 Abnormal imaging, abnormal neurological exam, abnormal
EEG or family history increase relapse risk
 Quality of life issues are important
Non-Drug Treatment/
Lifestyle Modifications
 Adequate sleep
 Avoidance of alcohol, stimulants, etc.
 Avoidance of known precipitants
 Stress reduction — specific techniques
Although AEDs are the mainstay of treatment, alternative treatment modalities have varying degrees of
clinical and experimental support. Lifestyle modifications, particularly avoidance of alcohol and sleep
deprivation, can be very important in certain syndromes and individuals. Relaxation, biofeedback, and
other behavioral techniques can help a subset of patients, especially those with a reliable aura
preceding complex partial or secondarily generalized seizures. Dietary supplements are of unproven
value, except for pyridoxine (vitamin B6), which is crucial for treating rare pyridoxine dependency of
neonates and infants and for seizures due to antituberculous therapy with isoniazid. Herbal remedies
are currently also under investigation.
Ketogenic Diet
 Main experience with children, especially with

multiple seizure types
 Likely anti-seizure effect of ketosis (beta
hydroxybutyrate), but other mechanisms also may be
responsible for beneficial effects
 Low carbohydrate, adequate protein, high fat
 50% with a >50% seizure reduction
 30% with >90% reduction
 Side effects include kidney stones, weight loss,
acidosis, dyslipidemia
The ketogenic diet has been used for more than 80 years in children with severe seizure disorders. It is
based on the observation that ketosis and acidosis have anti-seizure effects, although recently glucose
stabilization, caloric restriction, and direct anticonvulsant effects of polyunsaturated fatty acids have
been reported in animal models. Because of risks of severe metabolic abnormalities during and after
the initial fasting period, this diet is initiated in the hospital. Recently, the requirement for a fasting
period has been shown to be not valid; most centers will individualize nowadays. Strict protein, calorie,
and especially carbohydrate restriction in the setting of a high fat diet is needed for ketosis, and can be
difficult to maintain. In 10% of patients with intractable epilepsy, staying on this diet for months or years
can result in a sustained seizure freedom, and allow for withdrawal of AEDs. Side effects include weight
loss, acidosis, kidney stones (5%), growth slowing, and dyslipidemia.
.
Alternative Diets
 Modified Atkins diet
• 10 g/day carbohydrates to start, fats encouraged
• No protein, calorie, fluid restriction
• 3 reports to date from Johns Hopkins, 1 from South
Korea
– 47% all children with >50% seizure reduction
– Studies underway for adults
 Low-glycemic index treatment

• 40-60 g/day low-glycemic carbohydrates
• Portions generally controlled
• Single report from Massachusetts General
The recent emergence of less restrictive ketogenic diets, such as the modified Atkins diet from Johns
Hopkins and the low-glycemic index treatment from Massachusetts General, have added to options for
children as well as adults with intactable epilepsy. Both these diets have similar response rates
(although in small series) to the traditional ketogenic diet with fewer side effects. Further clinical trials
are underway
Patient Selection for
Surgery
 Epilepsy syndrome not responsive to medical
management
• Unacceptable seizure control despite maximum
tolerated doses of 2-3 appropriate drugs as monotherapy
 Epilepsy syndrome amenable to surgical

treatment
Most cases of epilepsy are well controlled with AEDs, 20– 30% of cases, however, are not. Surgical
therapy is worth considering in patients in whom seizures and/or medication side effects significantly
impair quality of life. Surgical treatment is indicated in such patients if seizures arise from an area that
can be removed without causing unacceptable neurological deficits. Candidacy for surgery is
determined by a constellation of tests including video/EEG monitoring, neuroimaging, and
neuropsychometric studies. In some cases, palliative surgical procedures are performed to reduce
seizure frequency or severity even though there is a low expectation of cure. These procedures typically
involve disconnections, such as cutting the corpus callosum, rather than removing brain tissue.
Vagus Nerve Stimulator
 Intermittent programmed electrical stimulation of left vagus nerve
 Option of magnet activated stimulation
 Adverse effects local, related to stimulus
(hoarseness, throat discomfort, dyspnea)
 Mechanism unknown
 Clinical trials show that 35% of patients have a 50% reduction in
seizure frequency and 20% experience a 75% reduction after 18
months of therapy.
 May improve mood and allow AED reduction
 FDA approved for refractory partial onset seizures and refractory
depression
The vagus nerve stimulator (VNS), a device that provides intermittent electrical stimulation of the vagus
nerve, was shown in several studies to be effective in reducing the frequency of complex partial
seizures, and received FDA approval in 1997. The stimulator is similar to a cardiac pacemaker and is
surgically implanted subcutaneously. Intermittent stimulation is delivered every 0.3-10 minutes for 7-30
seconds, but patients who experience a seizure warning can trigger the device manually, with anecdocal
success for some. The mechanism by which stimulation reduces seizures is not well established.
Adverse effects include hoarseness, throat pain, or a feeling of dyspnea during stimulation; these are
generally mild. Central nervous system side effects typical of AEDs are not present. The stimulator has
been studied only in combination with AED treatment, but in this setting, efficacy against medication-
resistant partial seizures was comparable to that of some of the new AEDs. The cost of the device and
its implantation may be limiting factors. Clinical trials demonstrate that <5% of patients become seizure
free with VNS placement but approximately 1/3 of patients experience a clinically significant decrease in
their seizure frequency.
The FDA has approved the device for partial onset seizures, but it may have value for generalized
epilepsies, especially Lennox Gastaut syndrome and specifically atonic seizures. Many centers will try a
VNS prior to a callostomy for intractable atonic seizures. VNS has a responder rate of 40% (i.e. 40% of
patients have a 50% or more decrease in their seizures). The VNS was approved in late 2005 for
treatment-resistant depression by the FDA
Status Epilepticus
 Definition
• More than 10 minutes of continuous seizure activity
or
• Two or more sequential seizures without full
recovery between seizures
Status epilepticus is defined as: 1) an episode of more than 10 minutes of continuous seizure activity, or
2) two or more sequential seizures spanning this period without full recovery between seizures.
Clinically, however, most seizures last less than 5 minutes, and those persisting longer are unlikely to
stop spontaneously. Therefore, one should initiate treatment for the seizures lasting longer than 5
minutes.
The incidence of status epilepticus is at least 60,000 cases/year in the U.S. with higher rates among the
very young and very old. Status epilepticus is an emergency because of its morbidity and mortality, and
any seizure type may manifest as status epilepticus. The outcome of convulsive status epilepticus
largely depends on etiology, but prompt treatment can improve outcome.
From a practical standpoint, status epilepticus may be divided into convulsive and non-convulsive forms.
The convulsive forms may be generalized or partial. The non-convulsive forms are difficult to classify on
clinical grounds but are often divided electroencephalographically into absence status (in which the EEG
demonstrates generalized spike-wave activity) and complex partial status (in which the EEG may show
a variety of localized rhythmic discharges).
Status Epilepticus (SE)
 A medical emergency
• Adverse consequences can include hypoxia,
hypotension, acidosis, hyperthermia, rhabdomyolysis
and neuronal injury
• Know the recommended sequential protocol for
treatment and distribute a written protocol to
emergency rooms, ICUs and housestaff.
• Goal: stop seizures as soon as possible
First Aid
Tonic-Clonic Seizure
 After seizure ends, turn person on side with face
turned toward ground to keep airway clear, protect
from nearby hazards
 Transfer to hospital needed for:

• Multiple seizures or status epilepticus
• Person is pregnant, injured, diabetic
• New onset seizures
 DO NOT put any object in mouth or restrain

Pregnancy and Epilepsy
 96% of pregnancies in mothers with epilepsy produce
normal children
 Spontaneous abortions and pre-term birth are more
common in women with epilepsy
 There is an increased rate of fetal malformations
associated with antiepileptic drug exposure
 Seizures during pregnancy may be harmful
 Tonic-clonic seizures associated with intracranial hemorrhage, fetal
bradycardia and lower IQ in children
 Status associated with increased fetal and maternal mortality in some
studies
 Insufficient data on non-convulsive seizures
A major concern of women of childbearing age is the teratogenic potential of AEDs. Whereas the
incidence of major birth defects (those requiring medical or surgical intervention) in the normal
population is approximately 2-3%, approximately twice as many, or 4-7%, of the offspring of women on
AED monotherapy have recognizable major birth defects, with another 5-10% having minor cosmetic
anomalies such as shortened distal digits. AEDs are felt to be the major reason for the increased risk of
fetal malformations, though some may be related to injury imposed by seizures during the pregnancy or
genetic abnormalities carried by the mother. While physicians can do little about the later, there is an
obvious tension between the first two risk factors, optimal control of maternal seizures vs. teratogenicity
of AEDs (particularly in early pregnancy).

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Control and Communication in

the Nervous System

Yazan M. Dweiri, Ph.D.

The Nervous System

• Convolutions = folding= gyri (gyrus)

• White matter – fiber tracts

• 1400g (~2% body weight)

• Convolutions = folding= gyri (gyrus)

• White matter – fiber tracts

Mental Processes Are Represented in the Brain by Their

Peripheral Nervous System

• Release adrenaline and Dilates pupil

skeletal muscles Inhibits activity Stomach

• Inhibits digestive Pancreas

functions Stimulates glucose Liver

Secretion of adrenaline, Adrenal

Sympathetic Stimulates ejaculation

system Contracts pupil

conserve and cord

maintain energy Slows heartbeat

• Lowers heartbeat, Stimulates activity

breathing rate, &

The basic functional unit in the microcontrollers and computers

The basic functional unit in the NS is the neuron

How neurons communicate

• Neurons communicate by means of an

Types of glial cells

Types of glial cells

Astrocytes form the blood-brain barrier (BBB)

• It is a physical barrier between the local Blood vessels and

• The BBB is permeable to alcohol, and some heavy metals can

Types of glial cells

Oligodendrocyte, Schwan cells and Astrocytes are categorized as

Microglia is the brain’s phagocytes

Control and Communication in

Yazan M. Dweiri, Ph.D.

Transient electrical signals—receptor potentials, synaptic potentials, and

Two types of ion channels—resting and gated—

Resting channels are primarily important in maintaining the resting

The Resting Membrane Potential Results from the

Recording the Membrane Potential

The equilibrium potential for any ion X can be calculated

Or: z is the valence of the ion

Ion current vs net current

The Functional Properties of the Neuron Can Be Represented as an Electrical

Cytoplasmic Equilibrium Relative

Sodium Channels are time dependent

Membrane Conductance During an AP

The main ionic currents in an AP are Na and K currents

• Voltage gated 𝑁𝑎+ and 𝐾 + channels

Excitability Properties Vary Between

• Peripheral myelinated axons: Repolarization at

• Central myelinated axons have significant

Both central and peripheral myelinated axons K+

Voltage-gated 𝑁𝑎+ 𝑎𝑛𝑑 𝑘 +channels

High density voltage gated 𝑁𝑎+channels

Model neuron section by section and

Resistance inside the cell through the cytoplasm

Model neuron section by section and

Resistance outside the cell through the extracellular space is << ra . It