Cognitive
Enhancement
By Group 11: Steve, Natalie,
Mayank
What is Cognitive Enhancement?
Aspects of Cognition

Perception, attention,
understanding, memory
Types of intervention

Therapeutic
to repair dysfunction

Enhancement
intervention in some way
other than repairing a
dysfunction
Normal and Deficit Use
Deficit and Normal use inseparable
Cognitive Enhancement
-positive change in cognitive skills or
abilities
Prescription or “Natural”
Prescription enhancers viewed as “cheating”

Beyond natural human endowment
Herbal remedies perceived as natural enhancement

within the bounds of self improvement
Attention and Arousal
Difference between arousal and attention


Caffeine –arousal
Ritalin- attention
Mainly stimulants
Caffeine
Found in coffee bean
and cola nut
History

In use since stone age
Effects




Reaction time
prevents deterioration
flat dose response
prevents boredom
Ritalin
Use

Treatment of ADHD

Nonprescription use
among college students
History
1st synthesized in 1940
Effects

Narrowing of attentional
spotlight


Excitation of inhibitory
neurotransmitter
Memory
Demand for memory
improving products


Prevalence of
Ahlzimer’s
Ginkgo Biloba
Uniqueness of self
in memory
Less adverse effects
Memory: Mechanistic Details
Overview


Memory as a function of consciousness
LTP
Short-term potentiation
Early LTP


Induction
Maintenance
Late LTP

Expression
Cognitive Enhancement Drugs: Memory
Memory and Consciousness
Memory is our ability to be able to retain
and recall past experiences
Initiation occurs in the hippocampus,
storage is considered to be distributed
arbitrarily across the frontal cortical
regions (Kemp et al. 2007)
Usually broken down into declarative
(explicit) and procedural (implicit)(Wikipedia:
Memory, 2007)
LTP is the main basis for memory initiation
and consolidation
LTP
Long term potentiation
Utilizes glutamatergic synaptic
transmission


AMPA and NMDA receptor
mediated(Lisman et al., 2006)
Glutamatergic release modulates
genetic transcription factors such as
CREB through a second messenger
system, primarily involving cAMP
and PKA
LTP involves three phases



Short-term phase
Early phase
Late phase
Early and Late phase

Broken down into: induction,
maintenance, and expression
Hebbian Synaptic Plasticity
Images Courtesy of: Mann, 2004
Short-term Potentiation
AMPA receptor mediation is required for LTP
induction(Sweatt, 1999)
AMPA receptors are excited on moment-tomoment activity
EPSP, or excitatory postsynaptic potential, is a
measure of the amount of electrical signal that
results from the activity of the aforementioned
receptors


Magnitude and frequency are the main players in
LTP: high frequency of EPSPs with sufficient electrical
output are needed(Sweatt, 1999)
Subsequent electrical stimuli need to give enough of
electrical signals to prevent a previous EPSP
response from dying(Sweatt, 1999)
Early LTP
E-LTP, a protein synthesis-independent pathway
This phase of LTP is where the high frequency
and sufficient electrical stimulus result in
temporary changes to pre- and post-synaptic
elements
Not sure what causes E-LTP to lead to L-LTP
(Late LTP)


Insertion of AMPA receptors or increase in
glutamatergic response(Wikipedia: Long-term Potentiation, 2007)
Downstream cascading molecular events involve
calmoldulin/calcium-dependent protein kinase II
(CaMKII), protein kinase C (PKC), mitogen-activated
protein kinase (MAPK), and tyrosine kinases(Lledo et al.,
1995), (Sweatt, 1999)
Late LTP
L-LTP, an exceedingly protein
dependent pathway of potentiation
Hebbian Synaptic Plasticity(Sweatt, 1999)

The formation of new synapses in
response to a repetitive and
significant event/stimulus to certain
neuronal cells
Two phase system: protein synthesis
occurs then protein synthesis with
transcription modulation
Calmoldulin/calcium-independent
protein kinase IV (CaMKIV) and
cAMP response element binding
protein (CREB) are two significant
players in L-LTP(Sweatt, 1999)
Protein Kinase A (PKA) activates
second messenger system that
involves cyclic adenosine
monophosphate (cAMP)
cAMP reacts to CREB modulating
transcription factors and inducing
protein synthesis that effectively
results in the creation of new
synapses
Images Courtesy of: Mann, 2004
Ampakines
Increase attention span, alertness, and memory.
Lack side effects of many traditional stimulants.
Potential treatment for Alzheimers, Parkinsons’s,
and other neurodegenerative diseases.
Could also treat normal age related deficits, or even
augment the mental faculties of healthy individuals
Mechanism
Ampakines work by allosterically binding
AMPA-type glutamate receptors.
Facilitate glutamatergic signaling
Increase levels of trophic factors BDNF.
This promotes plasticity at the synapse,
which could translate into better cognitive
performance.
Synaptic Mechanism
• Potentiate induction of LTP,
by facilitating AMPA mediated
depolarization.
•Allows endogenously released
glutamate to bind AMPA
and NMDA receptors.
Lynch (2000)
CX-516 Increases Recall
• 24 subjects ages 65-76
• tested on recall of nonsense syllables after delay
• Increased performance seen 75 min after ingestion
• Greatest increase seen in 900 mg group
• Dosage dependent increase in recall ability
Lynch (1997)
CX- 727
• Hippocampal slices exposed to neurotoxic
TMT for 4 hrs
• Treated with different levels of CX 727 for
24 hrs after exposure.
• Slices exposed to higher dosage showed
highest optical density for AMPA receptor
subunit GluR.
• Dose dependent neuroprotection.
Munirathinam (2002)
Altered State?
• Yes. By increasing mental faculties
above “normal,” Ampakines and other
such drugs produce altered states.
• Cognitive enhancement may have far
reaching social implications and raises
serious ethical questions.
SUPER
NORMAL ?
Normal
Relief From
Anxiety
Disinhibition
Sedation
Hypnosis
General
anesthesia
Coma
Death
Bibliographic References
Kemp A, & Manahan-Vaughan D. Hippocampal long-term depression:
master or minion in declarative memory processes?. Trends in
Neurosciences. 2007; 30(3):111-8.
Mann MD. Learning and Memory. May 17, 2004, at 20:57 UTC. The
Nervous System in Action. Available at:
http://www.unmc.edu/Physiology/Mann/mann19.html. Accessed June 5,
2007.
Lisman J, & Raghavachari S. A unified model of the presynaptic and
postsynaptic changes during LTP at CA1 synapses. Science. 2006;
2006(356)
Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, et al.
Calcium/calmodulin-dependent kinase II and long-term potentiation
enhance synaptic transmission by the same mechanism. Proceedings of the
National Academy of Sciences of the United States of America. 1995;
92(24):11175-9.
Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C.M., Kessler, M.,
Schehr, R. (1997). Evidence That a Positive Modulator of AMPA-Type
Glutamate Receptors Improves Delayed Recall in Aged
Humans.
Experimental Neurology, 145, 89–92.
Lynch, G. (2002). Memory enhancement: the search for mechanism-based
drugs. Neuroscience, 5, 1035-1038.
References (cont)
Sweatt JD. Toward a molecular explanation for long-term potentiation. Learning &
memory. 1999; 6(5):399-416.
Wikipedia contributors. Memory. Wikipedia, The Free Encyclopedia. June 5, 2007, at
22:36 UTC. Available at: http://http://en.wikipedia.org/wiki/Memory. Accessed June 5,
2007.
Wikipedia contributors. Long-Term Potentiation. Wikipedia, The Free Encyclopedia.
May 23, 2007, at 23:42 UTC. Available at: http://en.wikipedia.org/wiki/Longterm_potentiation. Accessed June 5, 2007.
Bostrom, Nick, and Sandberg, Anders. “Cognitive Enhancement :Methods, Ethics,
Regulatory Challenges." Science and Engineering Ethics, 2007.
Smit, H.J., and Rogers, P.J. “Effects of Low Does of Caffeine on Cognitive
Performance , mood and thirst in low and high Consumers.” Pharmacology. 28 July
2000.
Carroll, Bronwen C., et al. ”Patterns and Knowledge of Nonmedical Use of Stimulants
Among College Students.” Arch Pediatrics and Adolescent Medicine. Vol 160, May
2007.
Munirathinam,S., Rogers, G., Bahr, B.A. (2002) Positive Modulation of _-imino-3hydroxy-5-methyl-4-isoxazolepropionic Acid-Type Glutamate Receptors Elicits
Neuroprotection after Trimethyltin Exposure in hippocampus. Toxicology and Applied
Pharmacology, 185, 111–118