Cognitive Cognitive EnhancementEnhancement

By Group 11: Steve, Natalie, By Group 11: Steve, Natalie, MayankMayank

What is Cognitive Enhancement?What is Cognitive Enhancement?

Aspects of CognitionAspects of Cognition Perception, attention, Perception, attention,

understanding, memoryunderstanding, memory

Types of interventionTypes of intervention TherapeuticTherapeutic

to repair dysfunctionto repair dysfunction EnhancementEnhancement

intervention in some way intervention in some way other than repairing a other than repairing a dysfunctiondysfunction

Normal and Deficit UseNormal and Deficit Use

Deficit and Normal use inseparableDeficit and Normal use inseparable

Cognitive EnhancementCognitive Enhancement

-positive change in cognitive skills or -positive change in cognitive skills or abilitiesabilities

Prescription or “Natural”Prescription or “Natural”

Prescription enhancers viewed as “cheating”Prescription enhancers viewed as “cheating” Beyond natural human endowmentBeyond natural human endowment

Herbal remedies perceived as natural enhancement Herbal remedies perceived as natural enhancement within the bounds of self improvementwithin the bounds of self improvement

Attention and ArousalAttention and Arousal

Difference between arousal and attentionDifference between arousal and attention Caffeine –arousalCaffeine –arousal Ritalin- attentionRitalin- attention

Mainly stimulantsMainly stimulants

Caffeine Caffeine Found in coffee bean Found in coffee bean and cola nutand cola nut

HistoryHistory In use since stone ageIn use since stone age

EffectsEffects Reaction time Reaction time prevents deterioration prevents deterioration flat dose responseflat dose response prevents boredomprevents boredom

Ritalin Ritalin UseUse

Treatment of ADHDTreatment of ADHD Nonprescription use Nonprescription use

among college studentsamong college students

HistoryHistory 11stst synthesized in 1940 synthesized in 1940

Effects Effects Narrowing of attentional Narrowing of attentional

spotlightspotlight Excitation of inhibitory Excitation of inhibitory

neurotransmitter neurotransmitter

MemoryMemory

Demand for memory Demand for memory improving productsimproving products Prevalence of Prevalence of

Ahlzimer’sAhlzimer’s Ginkgo BilobaGinkgo Biloba

Uniqueness of self Uniqueness of self in memory in memory

Less adverse effectsLess adverse effects

Memory: Mechanistic DetailsMemory: Mechanistic Details

OverviewOverview Memory as a function of consciousnessMemory as a function of consciousness LTPLTP

Short-term potentiationShort-term potentiation

Early LTPEarly LTP InductionInduction MaintenanceMaintenance

Late LTPLate LTP ExpressionExpression

Cognitive Enhancement Drugs: MemoryCognitive Enhancement Drugs: Memory

Memory and ConsciousnessMemory and Consciousness

Memory is our ability to be able to retain Memory is our ability to be able to retain andand recall past experiences recall past experiencesInitiation occurs in the hippocampus, Initiation occurs in the hippocampus, storage is considered to be distributed storage is considered to be distributed arbitrarily across the frontal cortical arbitrarily across the frontal cortical regions regions (Kemp (Kemp et al.et al. 2007) 2007)

Usually broken down into declarative Usually broken down into declarative (explicit) and procedural (implicit)(explicit) and procedural (implicit)(Wikipedia: (Wikipedia:

Memory, 2007)Memory, 2007)

LTP is the main basis for memory initiation LTP is the main basis for memory initiation and consolidationand consolidation

LTPLTPLong term potentiationLong term potentiationUtilizes glutamatergic synaptic Utilizes glutamatergic synaptic transmissiontransmission

AMPA and NMDA receptor AMPA and NMDA receptor

mediatedmediated(Lisman (Lisman et al.et al., 2006), 2006)

Glutamatergic release modulates Glutamatergic release modulates genetic transcription factors such as genetic transcription factors such as CREB through a second messenger CREB through a second messenger system, primarily involving cAMP system, primarily involving cAMP and PKAand PKA

LTP involves three phasesLTP involves three phases Short-term phaseShort-term phase Early phaseEarly phase Late phaseLate phase

Early and Late phaseEarly and Late phase Broken down into: induction, Broken down into: induction,

maintenance, and expressionmaintenance, and expressionHebbian Synaptic PlasticityHebbian Synaptic Plasticity

Images Courtesy of: Mann, 2004

Short-term PotentiationShort-term Potentiation

AMPA receptor mediation is required for LTP AMPA receptor mediation is required for LTP inductioninduction(Sweatt, 1999)(Sweatt, 1999)

AMPA receptors are excited on moment-to-AMPA receptors are excited on moment-to-moment activitymoment activityEPSP, or excitatory postsynaptic potential, is a EPSP, or excitatory postsynaptic potential, is a measure of the amount of electrical signal that measure of the amount of electrical signal that results from the activity of the aforementioned results from the activity of the aforementioned receptorsreceptors Magnitude and frequency are the main players in Magnitude and frequency are the main players in

LTP: high frequency of EPSPs with sufficient LTP: high frequency of EPSPs with sufficient electrical output are neededelectrical output are needed(Sweatt, 1999)(Sweatt, 1999)

Subsequent electrical stimuli need to give enough of Subsequent electrical stimuli need to give enough of electrical signals to prevent a previous EPSP electrical signals to prevent a previous EPSP response from dyingresponse from dying(Sweatt, 1999)(Sweatt, 1999)

Early LTPEarly LTP

E-LTP, a protein synthesis-independent pathwayE-LTP, a protein synthesis-independent pathwayThis phase of LTP is where the high frequency This phase of LTP is where the high frequency and sufficient electrical stimulus result in and sufficient electrical stimulus result in temporary changes to pre- and post-synaptic temporary changes to pre- and post-synaptic elementselementsNot sure what causes E-LTP to lead to L-LTP Not sure what causes E-LTP to lead to L-LTP (Late LTP)(Late LTP) Insertion of AMPA receptors or increase in Insertion of AMPA receptors or increase in

glutamatergic responseglutamatergic response(Wikipedia: Long-term Potentiation, 2007)(Wikipedia: Long-term Potentiation, 2007) Downstream cascading molecular events involve Downstream cascading molecular events involve

calmoldulin/calcium-dependent protein kinase II calmoldulin/calcium-dependent protein kinase II (CaMKII), protein kinase C (PKC), mitogen-activated (CaMKII), protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and tyrosine kinasesprotein kinase (MAPK), and tyrosine kinases(Lledo (Lledo et alet al., .,

1995), (Sweatt, 1999) 1995), (Sweatt, 1999)

Late LTPLate LTPL-LTP, an exceedingly protein L-LTP, an exceedingly protein dependent pathway of potentiationdependent pathway of potentiationHebbian Synaptic PlasticityHebbian Synaptic Plasticity(Sweatt, 1999)(Sweatt, 1999)

The formation of new synapses in The formation of new synapses in response to a repetitive and response to a repetitive and significant event/stimulus to certain significant event/stimulus to certain neuronal cellsneuronal cells

Two phase system: protein synthesis Two phase system: protein synthesis occurs then protein synthesis with occurs then protein synthesis with transcription modulationtranscription modulationCalmoldulin/calcium-Calmoldulin/calcium-independentindependent protein kinase IV (CaMKIV) and protein kinase IV (CaMKIV) and cAMP response element binding cAMP response element binding protein (CREB) are two significant protein (CREB) are two significant players in L-LTPplayers in L-LTP(Sweatt, 1999)(Sweatt, 1999)

Protein Kinase A (PKA) activates Protein Kinase A (PKA) activates second messenger system that second messenger system that involves cyclic adenosine involves cyclic adenosine monophosphate (cAMP)monophosphate (cAMP)cAMP reacts to CREB modulating cAMP reacts to CREB modulating transcription factors and inducing transcription factors and inducing protein synthesis that effectively protein synthesis that effectively results in the creation of new results in the creation of new synapsessynapses

Images Courtesy of: Mann, 2004

AmpakinesAmpakines

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 Could also treat normal age related deficits, or even augment the mental faculties of healthy individualsaugment the mental faculties of healthy individuals

MechanismMechanism

Ampakines work by allosterically binding Ampakines work by allosterically binding AMPA-type glutamate receptors.AMPA-type glutamate receptors.

Facilitate glutamatergic signaling Facilitate glutamatergic signaling Increase levels of trophic factors BDNF.Increase levels of trophic factors BDNF.

This promotes plasticity at the synapse, This promotes plasticity at the synapse, which could translate into better cognitive which could translate into better cognitive performanceperformance..

Synaptic MechanismSynaptic 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 RecallCX-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- 727CX- 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?Altered State?

Normal

Relief FromAnxiety

Disinhibition

Sedation

Hypnosis

General anesthesia

Coma

Death

SUPER NORMAL ?

• 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.

Bibliographic ReferencesBibliographic ReferencesKemp A, & Manahan-Vaughan D. Hippocampal long-term depression: Kemp A, & Manahan-Vaughan D. Hippocampal long-term depression: master or minion in declarative memory processes?. Trends in master or minion in declarative memory processes?. Trends in Neurosciences. 2007; 30(3):111-8. Neurosciences. 2007; 30(3):111-8. Mann MD. Learning and Memory. May 17, 2004, at 20:57 UTC. The Mann MD. Learning and Memory. May 17, 2004, at 20:57 UTC. The Nervous System in Action. Available at: Nervous System in Action. Available at: http://www.unmc.edu/Physiology/Mann/mann19.htmlhttp://www.unmc.edu/Physiology/Mann/mann19.html. Accessed June 5, . Accessed June 5, 2007. 2007. Lisman J, & Raghavachari S. A unified model of the presynaptic and Lisman J, & Raghavachari S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Science. 2006; postsynaptic changes during LTP at CA1 synapses. Science. 2006; 2006(356)2006(356)Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, et al. Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, et al. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proceedings of the National synaptic transmission by the same mechanism. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92(24):11175-Academy of Sciences of the United States of America. 1995; 92(24):11175-9.9.Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C.M., Kessler, M., Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C.M., Kessler, M., Schehr, R. (1997). Evidence That a Positive Modulator of AMPA-Type Schehr, R. (1997). Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Glutamate Receptors Improves Delayed Recall in Aged Humans. Humans. Experimental NeurologyExperimental Neurology, 145, 89–92., 145, 89–92.Lynch, G. (2002). Memory enhancement: the search for mechanism-based Lynch, G. (2002). Memory enhancement: the search for mechanism-based drugs. drugs. Neuroscience, Neuroscience, 5, 1035-1038.5, 1035-1038.

References (cont)References (cont)Sweatt JD. Toward a molecular explanation for long-term potentiation. Learning & Sweatt JD. Toward a molecular explanation for long-term potentiation. Learning & memory. 1999; 6(5):399-416. memory. 1999; 6(5):399-416. Wikipedia contributors. Memory. Wikipedia, The Free Encyclopedia. June 5, 2007, at Wikipedia contributors. Memory. Wikipedia, The Free Encyclopedia. June 5, 2007, at 22:36 UTC. Available at: 22:36 UTC. Available at: http://http://http://http://en.wikipedia.org/wiki/Memoryen.wikipedia.org/wiki/Memory. Accessed June 5, . Accessed June 5, 2007. 2007. Wikipedia contributors. Long-Term Potentiation. Wikipedia, The Free Encyclopedia. Wikipedia contributors. Long-Term Potentiation. Wikipedia, The Free Encyclopedia. May 23, 2007, at 23:42 UTC. Available at: May 23, 2007, at 23:42 UTC. Available at: http://en.wikipedia.org/wiki/Long-term_potentiationhttp://en.wikipedia.org/wiki/Long-term_potentiation. Accessed June 5, 2007. . Accessed June 5, 2007. Bostrom, Nick, and Sandberg, Anders. “Cognitive Enhancement :Methods, Ethics, Bostrom, Nick, and Sandberg, Anders. “Cognitive Enhancement :Methods, Ethics, Regulatory Challenges." Regulatory Challenges." Science and Engineering EthicsScience and Engineering Ethics, 2007., 2007.Smit, H.J., and Rogers, P.J. “Effects of Low Does of Caffeine on Cognitive Smit, H.J., and Rogers, P.J. “Effects of Low Does of Caffeine on Cognitive Performance , mood and thirst in low and high Consumers.” Performance , mood and thirst in low and high Consumers.” Pharmacology.Pharmacology. 28 July 28 July 2000.2000.Carroll, Bronwen C., et al. ”Patterns and Knowledge of Nonmedical Use of Stimulants Carroll, Bronwen C., et al. ”Patterns and Knowledge of Nonmedical Use of Stimulants Among College Students.” Among College Students.” Arch Pediatrics and Adolescent Medicine. Arch Pediatrics and Adolescent Medicine. Vol 160, May Vol 160, May 2007.2007.Munirathinam,S., Rogers, G., Bahr, B.A. (2002) Positive Modulation of _-imino-3-Munirathinam,S., Rogers, G., Bahr, B.A. (2002) Positive Modulation of _-imino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-Type Glutamate Receptors Elicits hydroxy-5-methyl-4-isoxazolepropionic Acid-Type Glutamate Receptors Elicits Neuroprotection after Trimethyltin Exposure in hippocampus. Neuroprotection after Trimethyltin Exposure in hippocampus. Toxicology and Applied Toxicology and Applied Pharmacology,Pharmacology, 185, 185, 111–118111–118