Ebook Brain and behavior (4E): Part 2

(BQ) Part 2 book “Brain and behavior” has contents: Learning and memory, intelligence and cognitive functioning, psychological disorders, sleep and consciousness.

Part IV Complex Behavior

At the age of 7, Henry Molaison’s life was forever changed by a seeminglyminor incident: He was knocked down by a bicycle and was unconscious for

5 minutes Three years later, he began to have minor seizures, and his firstmajor seizure occurred on his 16th birthday Still, Henry had a reasonablynormal adolescence, taken up with high school, science club, hunting, and roller-skating, except for a 2-year furlough from school because the other boys teasedhim about his seizures

“

Discovering the physical basis of learning in humans and other mammals is among the greatest remaining challenges facing the neurosciences.

—Brown, Chapman,Kairiss, & Keenan, 1988

”After high school, he took a job in a factory, but eventually the seizures made

it impossible for him to work He was averaging 10 small seizures a day and 1major seizure per week Because anticonvulsant medications were unable tocontrol the seizures, Henry and his family decided on an experimental operationthat held some promise In 1953, when he was 27, a surgeon removed much ofboth of his temporal lobes, where the seizure activity was originating Thesurgery worked, for the most part: With the help of medication, the petit malseizures were mild enough not to be disturbing, and major seizures were reduced

to about one a year Henry returned to living with his parents He helped withhousehold chores, mowed the lawn, and spent his spare time doing difficultcrossword puzzles Later, he worked at a rehabilitation center, doing routinetasks like mounting cigarette lighters on cardboard displays

Henry’s intelligence was not impaired by the operation; his IQ testperformance even went up, probably because he was freed from the interference

of the abnormal brain activity However, there was one important andunexpected effect of the surgery Although he could recall personal and publicevents and remember songs from his earlier life, Henry had difficulty learningand retaining new information He could hold new information in memory for ashort while, but if he were distracted or if a few minutes passed, he could nolonger recall the information When he worked at the rehabilitation center, hecould not describe the work he did He did not remember moving into a nursinghome in 1980, or even what he ate for his last meal And although he watchedtelevision news every night, he could not remember the day’s news events later

or even recall the name of the president (Corkin, 1984; B Milner, Corkin, &Teuber, 1968)

he was more than two or three blocks away, he was able to draw a floor plan ofthe house, which he had navigated many times daily (Corkin, 2002) Over theyears he became aware of his condition, and he was very insightful about it Inhis own words,

Every day is alone in itself, whatever enjoyment I’ve had, and whateversorrow I’ve had Right now, I’m wondering Have I done or said anythingamiss? You see, at this moment everything looks clear to me, but whathappened just before? That’s what worries me It’s like waking from a dream;

I just don’t remember (B Milner, 1970, p 37)

Over a period of 55 years, Henry would be the subject of a hundred scientificstudies that he could not remember; he was known to the world as patient HM toprotect his privacy In the next several pages, you will see why many considerHM’s surgery the most significant single event in the study of learning

Learning as the Storage of Memories

Some one-celled animals “learn” surprisingly well, for example, to avoidswimming toward a light where they have received an electric shock before I

have placed the term learn in quotation marks because such simple organisms

lack a nervous system; their behavior changes briefly, but if you take a lunchbreak during your subject’s training, when you return, you will have to start allover again Such a temporary form of learning may help an organism avoid anunsafe area long enough for the danger to pass or linger in a place where food ismore abundant But without the ability to make a more or less permanent record,you could not learn a skill, and experience would not help shape who you are

We will introduce the topic of learning by examining the problem of storage

How does studying amnesia help us understand memory?

Amnesia: The Failure of Storage and Retrieval

HM’s symptoms are referred to as anterograde amnesia, an impairment in

forming new memories (Anterograde means “moving forward.”) This was notHM’s only memory deficit; the surgery also caused retrograde amnesia, the

inability to remember events prior to impairment His retrograde amnesiaextended from the time of surgery back to about the age of 16; he had a fewmemories from that period, but he did not remember the end of World War II orhis own graduation, and when he returned for his 35th high school reunion, herecognized none of his classmates Better memory for earlier events than forrecent ones may seem implausible, but it is typical of patients who have braindamage similar to HM’s How far back the retrograde amnesia extends depends

FIGURE 12.1 Temporal Lobe Structures Involved in Amnesia.

(a) HM’s brain (top left) and a normal brain (below) You can see that the

amygdala (A), hippocampus (H), and other structures labeled in the normalbrain are partly or completely missing in HM’s brain (b) Structures of the

medial temporal lobe, which are important in learning (The frontal lobe is tothe left.)

SOURCES: (a) From “HM’s Medial Temporal Lobe Lesion: Findings FromMagnetic Resonance Imaging,” by S Corkin, D G Amaral, R G González,

HM’s surgery damaged or destroyed the hippocampus, nearby structures that

along with the hippocampus make up the hippocampal formation, and the

amygdala Figure 12.1 shows the location of these structures; because they are

on or near the inside surface of the temporal lobe, they form part of what is

known as the medial temporal lobe (remember that medial means “toward the

middle”) Because HM’s surgery was so extensive, it is impossible to tell whichstructures are responsible for the memory functions that were lost Studies ofpatients with varying degrees of temporal lobe damage have helped determinewhich structures are involved in amnesia and, therefore, in memory Henry died

in 2008 at the age of 82, but he continues to make a contribution, as theaccompanying Application explains

APPLICATION The Legacy of HM

SOURCE: Wikimedia Commons

Not only did Henry Moliason devote much of his life to numerousscientific investigations, but his brain will continue to be the subject ofstudy for many years to come (Lafee, 2009) Soon after his death,Henry’s preserved brain was in a plastic cooler strapped in a seat on aflight from Boston to San Diego; in the next seat was Jacopo Annese,director of the Brain Observatory at the University of California at SanDiego After several months of preparation, Annese and his colleaguesdissected Henry’s brain into slices as thin as the width of a hair Eachslice was microscopically photographed with such resolution that thedata from each slice would fill 200 DVDs The data were then combinedinto a three-dimensional reconstruction of the brain, which is availableonline Scientists can navigate through it to the area of their interest andthen zoom in to the level of individual neurons Ironically, the man whocould not remember will never be forgotten

1 HM and His Brain

The hippocampus consists of several substructures with different functions

The part known as CA1 provides the primary output from the hippocampus to

other brain areas; damage in that part of both hippocampi results in moderateanterograde amnesia and only minimal retrograde amnesia If the damageincludes the rest of the hippocampus, anterograde amnesia is severe Damage tothe entire hippocampal formation results in retrograde amnesia extending back

15 years or more (J J Reed & Squire, 1998; Rempel-Clower, Zola, Squire, &Amaral, 1996; Zola-Morgan, Squire, & Amaral, 1986) More extensiveretrograde impairment occurs with broader damage or deterioration, like thatseen in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease,apparently because memory storage areas in the cortex are compromised (Squire

“

Most memories, like humans and wines, do not mature instantly Instead they are gradually stabilized in a process referred to as consolidation.

divide memory into two stages, short-term memory and long-term memory.

Long-term memory, at least for some kinds of learning, can be divided into twostages that have different durations and occur in different locations (see Figure12.2), as we will see later (McGaugh, 2000)

FIGURE 12.2 Stages of Consolidation.

Making a memory permanent involves multiple stages and different processes

Science, 287, pp 248–251 Reprinted with permission from AAAS.

An animal study clearly demonstrates that the hippocampus participates inconsolidation Rats were trained in a water maze, a tank of murky water fromwhich they could escape quickly by learning the location of a platformsubmerged just under the water’s surface (Figure 12.3; Riedel et al., 1999).Then, for 7 days the rats’ hippocampi were temporarily disabled by a drug thatblocks receptors for the neurotransmitter glutamate Eleven days later—plenty oftime for the drug to clear the rats’ systems—they performed poorly comparedwith control subjects (Riedel et al.) Researchers have been able to “watch” theconsolidation happening in humans, using brain scans and event-relatedpotentials Presenting words or pictures activated the hippocampus and adjacentcortex; how well the material was remembered later could be predicted fromhow much activation occurred in those areas during stimulus presentation(Figure 12.4; Alkire, Haier, Fallon, & Cahill, 1998; Brewer, Zhao, Desmond,Glover, & Gabrieli, 1998; Fernández et al., 1999)

FIGURE 12.3 A Water Maze.

The rat learns to escape the murky water by finding the platform hidden justbelow the surface

The arrow is pointing to the hippocampal region Reds and yellows indicatepositive correlations of activity at the time of learning with later recall; bluesindicate negative correlations

FIGURE 12.5 Hippocampal Activity in the Human Brain During

Retrieval.

(a) As participants tried to recall visually presented words that had been

activated both hippocampal areas

SOURCE: Reprinted with permission from “Conscious Recollection and theHuman Hippocampal Formation: Evidence From Positron Emission

Tomography,” by D L Schacter et al., Proceedings of the National Academy of Sciences, USA, 93, pp 321–325 Copyright 1996 National Academy of

Where Memories Are Stored

The hippocampal area is not the permanent storage site for memories If itwere, patients like HM would not remember anything that happened before theirdamage occurred According to most researchers, the hippocampus storesinformation temporarily in the hippocampal formation; then, over time, a morepermanent memory is consolidated elsewhere in the brain A study of mice thathad learned a spatial discrimination task supported the hypothesis: Over 25 days

of retention testing, metabolic activity progressively decreased in thehippocampus and increased in the cortical areas (Bontempi, Laurent-Demir,

Is there a place where memories are stored?

To explore further the relationship between these two areas, Remondes andSchuman (2004) severed the pathway that connects CA1 of the hippocampuswith the cortex The lesions did not impair the rats’ performance in a water mazeduring training or 24 hours (hr) later, but after 4 weeks the rats had lost theirmemory for the task The results supported the hypothesis that short-termmemory depends on the hippocampus but long-term memory requires the cortexand an interaction over time between the two To pin down the window ofvulnerability of the memory, the researchers lesioned two additional groups of

animals at different times following training Those lesioned 24 hr after training

were impaired in recall 4 weeks later, but those whose surgery was delayed until

3 weeks after training performed as well as the controls This progressionapparently occurs over a longer period of time in humans Christine Smith andLarry Squire (2009) used fMRI to image the brain’s activity while subjectsrecalled news events from the past 30 years Activity was greatest in thehippocampus and related areas as subjects recalled recent events, with levelsdeclining over a period of 12 years and stabilizing after that At the same time,activity increased progressively with older memories in the prefrontal, temporal,and parietal cortex So your brain works rather like your computer when ittransfers volatile memory from RAM to the hard drive—it just takes a lot longer

In Chapter 3, you learned that when Wilder Penfield (1955) stimulatedassociation areas in the temporal lobes of surgery patients, he often evokedvisual and auditory experiences that seemed like memories We speculated thatmemories might be stored there, and more recent research has supported thatidea, with memories for sounds activating auditory areas and memories forpictures evoking activity in the occipital region (see Figure 12.6; M E Wheeler,Petersen, & Buckner, 2000) You also saw in Chapter 9 that when we learn anew language, it is stored near Broca’s area Naming colors (which requiresmemory) activates temporal lobe areas near where we perceive color; identifyingpictures of tools activates the hand motor area and an area in the left temporallobe that is also activated by motion and by action words (A Martin, Haxby,Lalonde, Wiggs, & Ungerleider, 1995; A Martin et al., 1996); and spatialmemories appear to be stored in the parietal area and verbal memories in the leftfrontal lobe (F Rösler, Heil, & Henninghausen, 1995) Thus, all memories arenot stored in a single area, nor is each memory distributed throughout the brain.Rather, different memories are located in different cortical areas, apparentlyaccording to where the information they are based on was processed

FIGURE 12.6 Functional MRI Scans of Brains During Perception and Recall.

Memories of pictures and sounds evoked responses in the same general areas(arrows) as the original stimuli

& Moser, 2004; Wilson & McNaughton, 1993) The fields are dependent onspatial cues in the environment, including visual, tactile, and even olfactory cues(Shapiro, Tanila, & Eichenbaum, 1997) Place cells do more than indicate anindividual’s current location For example, they contribute the context oflocation that is so important in memories of events (Smith & Mizumori, 2006).They also provide spatial memory required for planning navigation; as ratspaused at choice points in a maze with which they were well experienced, cellswith place fields in the alternative sections fired in sequence, as if the rats were

simulating the two choices (Johnson & Redish, 2007) Functional MRI hasconfirmed that humans have place cells; their activity is so precise that theinvestigators could determine the subject’s “location” in a computer-generatedvirtual environment (Hassabis et al., 2009).

FIGURE 12.7 Recordings From Place Cells in a Rat in a Circular Runway.

The recordings are from seven different place cells, indicated by different

colors Note that each cell responds when the rat is in a particular part of therunway (Due to cue similarities in a circular apparatus, cells occasionally

in which the individual uses a pencil to trace a path around a pattern, relyingsolely on a view of the work surface in a mirror HM improved in mirror-drawing ability over 3 days of training, and he learned to solve the Tower ofHanoi problem (Figure 12.8) But he could not remember learning either task,and on each day of practice he denied even having seen the Tower puzzle before(N J Cohen, Eichenbaum, Deacedo, & Corkin, 1985; Corkin, 1984) What thismeans, researchers realized, is that there are two categories of memoryprocessing Declarative memory involves learning that results in memories of

facts, people, and events that a person can vebalize or declare For example, youcan remember being in class today, where you sat, who was there, and what was

discussed Declarative memory includes a variety of subtypes, such as episodic memory (events), semantic memory (facts), autobiographical memory (information about oneself), and spatial memory (the location of the individual

and of objects in space) Nondeclarative memory involves memories for

behaviors; these memories result from procedural or skills learning, emotionallearning, and stimulus-response conditioning Learning mirror tracing or how toride a bicycle or solve the Tower of Hanoi problem are examples ofnondeclarative learning or, more specifically, procedural or skills learning;remembering having practiced the tasks involves declarative learning Anotherway of putting it, which is admittedly a bit oversimplified, is that declarativememory is informational, while nondeclarative memory is more concerned with

the control of behavior; just as we have what and where pathways in vision and audition, we have a what and a how in memory.

What are the two kinds of learning?

The main reason to distinguish between the two types of learning is that theyhave different origins in the brain; studying them can tell us something abouthow the brain carries out its tasks For years it looked like we were limited tostudying the distinction in the rare human who had brain damage in just the rightplace; hippocampal lesions did not seem to affect learning in rats, so researchersthought that rats did not have an equivalent of declarative memory But it justtook selecting the right tasks R J McDonald and White (1993) used anapparatus called the radial arm maze, a central platform with several armsradiating from it (Figure 12.9) Rats with damage to both hippocampi could learnthe simple conditioning task of going into any lighted arm for food But if everyarm was baited with food, the rats could not remember which arms they hadvisited and repeatedly returned to arms where the food had already been eaten

FIGURE 12.8 The Tower of Hanoi Problem.

The task is to relocate the rings in order onto another post by moving themone at a time and without ever placing a larger ring over a smaller one

Conversely, rats with damage to the striatum could remember which arms

they had visited but could not learn to enter lighted arms Because Parkinson’sdisease and Huntington’s disease damage the basal ganglia (which include the

striatum), people with these disorders have trouble learning procedural tasks,such as mirror tracing or the Tower of Hanoi problem (Gabrieli, 1998).

Incidentally, the term declarative seems inappropriate with rats; researchers have often preferred the term relational memory, which implies that the individual

must learn relationships among cues, an idea that applies equally well to humansand animals

he could not tell the researchers which color the loud sound was paired with.This neural distinction between declarative learning and nondeclarativeemotional learning may well explain how an emotional experience can have along-lasting effect on a person’s behavior even though the person does notremember the experience

The amygdala has an additional function that cuts across learning types Bothpositive and negative emotions enhance the memorability of any event; theamygdala strengthens even declarative memories about emotional events,apparently by increasing activity in the hippocampus Electrical stimulation ofthe amygdala activates the hippocampus, and it enhances learning of anonemotional task, such as a choice maze (McGaugh, Cahill, & Roozendaal,1996) In humans, memory for both pleasant and aversive emotional material isrelated to the amount of activity in both amygdalas while viewing the material(Cahill et al., 1996; Hamann, Ely, Grafton, & Kilts, 1999).

Working Memory

The brain stores a tremendous amount of information, but information that ismerely stored is useless It must be available, not just when it is being recalledinto awareness but when the brain needs it for carrying out a task Working memory provides a temporary “register” for information while it is being used.

Working memory holds a phone number you just looked up or that you recallfrom memory while you dial the number; it also holds information retrievedfrom long-term memory while it is integrated with other information for use inproblem solving and decision making Without working memory, we could not

—G M Stratton, 1919

”Think of working memory as similar to the RAM in your computer The RAMholds information temporarily while it is being processed or used, but theinformation is stored elsewhere on the hard drive But we should not take anyanalogy too far Working memory has a very limited capacity (with no upgradesavailable), and information in working memory fades within seconds So if youdial a new phone number and get a busy signal, you’ll probably have to look upthe number again And if you have to remember the area code, too, you’d betterwrite it down in the first place

Why is working memory important?

The delayed match-to-sample task described in Chapter 11 provides an

excellent means of studying working memory During the delay period, cellsremain active in one or more of the association areas in the temporal and parietallobes, depending on the nature of the stimulus (Constantinidis & Steinmetz,1996; Fuster & Jervey, 1981; Miyashita & Chang, 1988) Cells in these areasapparently help maintain the memory of the stimulus, but they are not thelocation of working memory If a distracting stimulus is introduced during thedelay period, the altered firing in these locations ceases abrupty, but the animalsare still able to make the correct choice (Constantinidis & Steinmetz, 1996; E K.Miller, Erickson, & Desimone, 1996) Cells in the prefrontal cortex have severalattributes that make them better candidates as working memory specialists Notonly do they increase firing during a delay, but they also maintain the increase inspite of a distracting stimulus (E K Miller et al., 1996) Some respondselectively to the correct stimulus (di Pellegrino & Wise, 1993; E K Miller etal., 1996) Others respond to the correct stimulus, but only if it is presented in aparticular position in the visual field; they apparently integrate information fromcells that respond only to the stimulus with information from cells that respond

to the location (Rao, Rainer, & Miller, 1997) Prefrontal damage impairshumans’ ability to remember a stimulus during a delay (D’Esposito & Postle,1999) All these findings suggest that the prefrontal area plays the major role inworking memory

Although the prefrontal cortex serves as a temporary memory register, itsfunction is apparently more than that of a neural blackboard In Chapters 3 and

8, you learned that damage to the frontal lobes impairs a person’s ability togovern his or her behavior in several ways Many researchers believe that theprimary role of the prefrontal cortex in learning is as a central executive That is,

it manages certain kinds of behavioral strategies and decision making andcoordinates activity in the brain areas involved in the perception and responsefunctions of a task, all the while directing the neural traffic in working memory(Wickelgren, 1997)

Take a Minute to Check Your Knowledge and Understanding

What determines the symptoms and the severity of symptoms of amnesia? Describe the two kinds of learning and the related brain structures

Working memory contributes to learning and to other functions How?

Learning is a form of neural plasticity that changes behavior by remodelingneural connections Specialized neural mechanisms have evolved to make themost of this capability We will look at them in the context of long-termpotentiation

Long-Term Potentiation

More than 50 years ago, Donald Hebb (1940) stated what has become known

as the Hebb rule: If an axon of a presynaptic neuron is active while the

postsynaptic neuron is firing, the synapse between them will be strengthened

We saw this principle in action during the development of the nervous system,when synaptic strengthening helped determine which neurons would survive;some of that plasticity is retained in the mature individual Researchers havelong believed that in order to understand learning as a physiological process,they would have to figure out what happens at the level of the neuron and,particularly, at the synapse Since its discovery four decades ago (T Bliss &Lømo, 1973), long-term potentiation has been the best candidate for explainingthe neural changes that occur during learning

How do neurons change during learning?

Long-term potentiation (LTP) is an increase in synaptic strength resulting

from the simultaneous activation of presynaptic neurons and postsynapticneurons (Cooke & Bliss, 2006) LTP is usually induced in the laboratory bystimulating the presynaptic neurons with pulses of high-frequency electricity for

a few seconds (W R Chen et al., 1996; Dudek & Bear, 1992); temporalsummation of these high-frequency stimuli ensures that the postsynaptic neuronswill fire along with the presynaptic neurons As you can see in Figure 12.10a,the postsynaptic neuron’s response to a test stimulus is much stronger followinginduction of LTP What is remarkable about LTP is that it can last for hours intissue cultures and months in laboratory animals (Cooke & Bliss) LTP has beenstudied mostly in the hippocampus, but it also occurs in several other areas,including the visual, auditory, and motor cortex So LTP appears to be acharacteristic of much of neural tissue, at least in the areas most likely to beinvolved in learning

FIGURE 12.10 LTP and LTD in the Human Brain.

The graphs show excitatory postsynaptic potentials in response to a test

stimulus before and after repeated stimulation (a) 100-hertz (Hz) stimulationproduced LTP (b) 1-Hz stimulation produced LTD, which blocked the

potentiation established earlier

Inferior and Middle Temporal Cortex,” by W R Chen et al., Proceedings of the National Academy of Sciences, USA, 93, pp 8011–8015 Copyright 1996

National Academy of Sciences, USA Used with permission

Neural functioning requires weakening synapses as well as strengtheningthem Long-term depression (LTD) is a decrease in the strength of synapses thatoccurs when stimulation of presynaptic neurons is insufficient to activate thepostsynaptic neurons (S H Cooke & Bliss, 2006) In the laboratory, LTD isusually produced by a low-frequency stimulus; you can see in Figure 12.10b thatstimulation at 1 Hz for 15 minutes (min) blocked the potentiation that had beeninduced earlier; the result was a postsynaptic potential even smaller than theoriginal LTD is believed to be the mechanism the brain uses to modifymemories and to clear old memories to make room for new information(Stickgold, Hobson, Fosse, & Fosse, 2001)

Activity in presynaptic neurons also influences the sensitivity of nearbysynapses If a weak synapse and a strong synapse on the same postsynapticneuron are active simultaneously, the weak synapse will be potentiated; thiseffect is called associative long-term potentiation (Figure 12.11) Associative

LTP is usually studied in isolated brain tissue with artificially created weak andstrong synapses, but it has important behavioral implications, which is why itinterests us Electric shock evokes a strong response in the lateral amygdala,where fear is registered, while an auditory stimulus produces only a minimalresponse there Rogan, Stäubli, and LeDoux (1997) repeatedly paired a tone withshock to the feet of rats As a result of this procedure, the tone alone began toevoke a significantly increased response in the amygdala, as well as anemotional “freezing” response in the rats You may recognize this scenario as an

example of classical conditioning; we could easily change the labels in Figure12.11 from “Strong synapse” to “Electric shock” and from “Weak synapse” to

“Auditory tone.” Researchers believe that associative LTP is the basis ofclassical conditioning, and Rogan et al.’s results support that view LTP, LTD,

and associative LTP can all be summed up in the expression “Cells that firetogether wire together.”

FIGURE 12.11 Associative LTP.

How LTP Happens

The long trains of stimulation experimenters use to induce LTP and LTD seemvery artificial, and they are; in the brain, these changes are more likely triggered

by theta EEG Theta rhythm is EEG activity with a frequency range of 4 to 7 Hz.This rhythm is interesting because it typically occurs in the hippocampus when

an animal is experiencing a novel situation, and any learning situation issomewhat novel (otherwise there would be nothing to learn) The researchersused a low-tech but effective method for producing theta in their experiment:They pinched the rats’ tails When electrical stimulation of the hypothalamuswas timed to coincide with the peaks of theta waves, LTP could be produced byjust five pulses of stimulation (Hölscher, Anwyl, & Rowan, 1997) Stimulationthat coincided with the trough of theta waves reversed LTP that had beeninduced 30 min before Suppressing theta EEG in the hippocampus with asedative drug eliminated rats’ ability to remember which way they turned on theprevious trial in a two-choice maze (Givens & Olton, 1990) Hölscher and hiscolleagues believed that the theta rhythm, by responding to novel situations,might emphasize important stimuli for the brain and facilitate LTP and LTD.LTP induction involves a cascade of events at the synapse In most locations,the neurotransmitter involved in LTP is glutamate Glutamate is detected by twotypes of receptors: the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor and the NMDA (N-methyl-d-aspartic acid) receptor.Initially, glutamate activates AMPA receptors but not NMDA receptors, becausethey are blocked by magnesium ions (Figure 12.12) During LTP induction,activation of the AMPA receptors by the first few pulses of stimulation partiallydepolarizes the membrane, which dislodges the magnesium ions The criticalNMDA receptor can then be activated, resulting in an influx of sodium and

calcium ions; not only does this further depolarize the neuron, but the calciumactivates CaMKII (calcium/calmodulin-dependent protein kinase Type II), anenzyme that is necessary for LTP (Lisman, Schulman, & Cline, 2002) CaMKIIapparently functions as a two-way switch that changes the strength of a synapse(O’Connor, Wittenberg, & Wang, 2005).

How does the brain grow during learning?

Neural Growth in Learning

LTP induction is followed by gene activation, gene silencing, and synthesis ofproteins, all of which result in functional changes in synapses and the growth ofnew connections (Kandel, 2001; C A Miller & Sweatt, 2007) When thepostsynaptic neuron is activated, it releases nitric oxide gas, which is aretrograde messenger, back into the synaptic cleft The nitric oxide diffusesacross the cleft to the presynaptic neuron, where it induces the neuron to releasemore neurotransmitter (Schuman & Madison, 1991) The nitric oxide lasts onlybriefly, but the increase in neurotransmitter release is long term (O’Dell,Hawkins, Kandel, & Arancio, 1991) Within 30 min after LTP, postsynapticneurons develop increased numbers of dendritic spines, outgrowths from the

dendrites that partially bridge the synaptic cleft and make the synapse moresensitive (see Figure 12.13; Engert & Bonhoeffer, 1999; Maletic-Savatic,Malinow, & Svoboda, 1999) Existing spines also enlarge or split down themiddle to form two spines (Matsuzaki, Honkura, Ellis-Davies, & Kasai, 2004;Toni, Buchs, Nikonenko, Bron, & Muller, 1999) Postsynaptic strength isincreased further as additional AMPA receptors are transported from thedendrites into the spines (Lisman et al., 2002; Shi et al., 1999) In addition, anincrease in dopamine unmasks previously silent synapses and, 12 to 18 hourslater, initiates the growth of new synapses (C H Bailey, Kandel, & Si, 2004).One further very important change that occurs in support of learning is thegeneration of new neurons in the hippocampus; though the rate of neurogenesis

is relatively low, over the life span they add up to an estimated 10% to 20% ofthe population (Jacobs, van Praag, & Gage, 2000) These young neuronsintegrate into already established neural networks, where they are more likely toparticipate in new learning than the older neurons (Kee, Teixeira, Wang, &Frankland, 2007)

FIGURE 12.12 Participation of Glutamate Receptors in LTP.

(a) Initially, glutamate activates the AMPA receptors but not the NMDA

receptors, which are blocked by magnesium ions (b) However, if the

activation is strong enough to partially depolarize the postsynaptic membrane,

With all that growth, you might suspect that there would be some increase inthe volume of the brain areas that are involved in LTP In fact, there is evidencethat this does happen London taxi drivers, who are noted for their ability tonavigate the city’s complex streets entirely from memory, spend about 2 yearslearning the routes before they can be licensed to operate a cab Maguire and hercolleagues (2000) used MRI to scan the brains of 16 drivers The posterior part

of their hippocampi, known to be involved in spatial navigation, was larger than

in males of similar age (Overall hippocampal volume did not change; theiranterior hippocampi were smaller.) The difference was greater for cabbies whohad been driving for the longest time, which we would expect if the differencewas caused by experience

FIGURE 12.13 Increase in Dendritic Spines Following LTP.

(a) A single synaptic spine on a dendrite (white) and a presynaptic terminal(red) (b) The same spine split into two following LTP

The hippocampus has the ability to acquire learning “on the fly” while theevent is in progress, but a longer time is needed for long-term storage ofdeclarative memories in the cortex Many researchers now believe that thehippocampus transfers information to the cortex during times when thehippocampus is less occupied, even during sleep (Lisman & Morris, 2001;McClelland, McNaughton, & O’Reilly, 1995) During sleep, neurons in the rats’hippocampus and cortical areas repeat the pattern of firing that occurred during

learning (Louie & Wilson, 2001; Y Qin, McNaughton, Skaggs, & Barnes, 1997).Human EEG and PET studies showed the hippocampus repeatedly activating thecortical areas that participated in the daytime learning, and this reactivation wasaccompanied by significant task improvement the next morning without furtherpractice (Figure 12.15; Maquet et al., 2000; Wierzynski, Lubenov, Gu, & Siapas,2009) Presumably, “off-line” replay provides the cortex the opportunity toundergo LTP at the more leisurely pace it requires (Lisman & Morris, 2001).During sleep more than 100 genes increase their activity; many of those havebeen identified as major players in protein synthesis, synaptic modification, andmemory consolidation (Cirelli, Gutierrez, & Tononi, 2004).

FIGURE 12.14 Retention in Normal and αCaMKII- Deficient Mice Over Time.

Mice were given three foot shocks in a conditioning chamber Subgroups ofmice were later tested for memory of the foot shocks (by observing emotional

“freezing”) at one of the retention delay times Note that in the mice

heterozygous for the mutant gene, memory had begun to decay after 3 daysand they failed to form permanent memory

The first is extinction The experimenter sounds a tone just before delivering a

puff of air to your eye; after just a few trials, you blink just because you hear thetone This doesn’t happen simply because you understand that the air blast iscoming; it occurs more quickly than you can make a voluntary response Thenthe experimenter sounds the tone several times without administering the puff ofair Slowly the tone loses its power to make you blink The memory is not gone;

if the experimenter repeats the puff of air, you will be back to blinking everytime you hear the tone Nor is this an example of forgetting Rather, extinctioninvolves new learning; one indication is that, like LTP, extinction requiresactivation of NMDA receptors, and blocking these receptors eliminatesextinction (Santini, Muller, & Quirk, 2001)

Forgetting

Most memories dissipate at least somewhat over time if they are not used

frequently We invariably regard memory loss from forgetting as a defect, but

researchers are finding clues that the brain actively removes useless information

to prevent the saturation of synapses with information that is not called upregularly or has not made connections with other stored memories One way the

a product of the PP1 gene To study PP1’s effect, researchers created transgenic

mice (see Chapter 4) with genes for a particularly active form of PP1 inhibitor(Genoux et al., 2002) The genes were inducible, which means that theresearchers could activate them at any time Mice were trained in a water maze,and then the genes were turned on in the transgenic animals; 6 weeks later, thecontrol subjects’ memory for the task was completely absent, while thetransgenic mice had forgotten very little You may remember from yourintroductory psychology course that for most tasks, spreading out practice

sessions (distributed practice) leads to better learning than massed practice.

When the inhibitor genes were turned on during training, this advantagedisappeared, which suggests that the reason distributed practice is superior is thatPP1’s effects accumulate over massed practice trials Another gene involved in

forgetting is Drac1(V12) Its protein product, Rac, causes memory to decay after

learning Interestingly, continued training suppresses Rac, which means thatadditional practice has a dual benefit (Shuai et al., 2010)

APPLICATION Total Recall

Most of us would like to remember more and forget less But a few yearsago Jill Price wrote to neuropsychologist James McGaugh at the

University of California, Irvine, asking for help because she couldn’t

forget; she can remember what she did and what was happening in theworld for practically every day of her life, and she is often tormented bybad memories (J Marshall, 2008; E S Parker, Cahill, & McGaugh,2006) Two years later two men with similar memory capabilities cameforward, but unlike Price, Brad Williams and Rick Baron can keep theirmemories at bay (Elias, 2008; D S Martin, 2008) Williams uses hismemory in his work as a radio news reporter; Baron is unemployed butsupports himself in part by winning contests that utilize his memory forfacts The researchers are eager to understand what fuels this unusualability, because the knowledge could help the memory impaired Of the

33 super-memory people confirmed by McGaugh’s lab, 11 haveundergone MRI scans; these revealed structural differences in nine brainareas, as well as greater white matter connections between areas (LePort

et al., 2012)

The interesting thing is that these individuals do no better than other

people on memorization tests; they just don’t suppress their memoriesonce they’re formed An indication that inadequate inhibition might beinvolved is that all three show signs of compulsive behavior They aredevoted collectors—years of TV guides, rare record albums, hundreds of

Reconsolidation

Consolidation is a progressive affair extending over a relatively long period oftime During that time, the memory is vulnerable to disruption from a number ofsources, including electroconvulsive shock and drugs that interfere with proteinsynthesis In recent years researchers have come to realize that each time a

memory is retrieved, it must be reconsolidated, and during that time the memory

becomes even more vulnerable (Dudai, 2004) For example, Nader, Schafe, andLeDoux (2000) conditioned a fear response (freezing) to a tone in mice bypairing the tone with electric shock to the feet Anisomycin will eliminate thefear memory if it is injected shortly after learning, but injection 24 hr aftertraining has no effect However, as much as 2 weeks later, anisomycineliminated the fear learning if the researchers induced retrieval of the memory bypresenting the tone again (without the shock) You might very well wonder whythe brain would give up protection of a consolidated memory during retrieval.Apparently, reopening a memory provides the opportunity to refine it, correcterrors, and modify your emotional response to redheaded acquaintances (Lee,2009) Reconsolidation may even have therapeutic usefulness It can be used toeliminate a learned fear response in humans, and (as you will see in Chapter 14)could provide an effective tool for erasing fear memories in people withposttraumatic stress disorder (D Schiller et al., 2009) Although retrieval makes

a memory vulnerable, reconsolidation during the labile period apparentlystrengthens the memory Rats given several brief exposures to the trainingapparatus during the first few days after they learned a shock avoidance taskshowed no forgetting when tested 55 days after training (Inda, Muravieva, &Alberini, 2011) In the News describes newfound evidence that retrieval andreconsolidation can be useful to humans as well

Memory practice is an important part of therapy forpatients with memory impairment following severetraumatic brain injury Shortly after patients had learned a

list of word pairs, members of a retrieval group were

quizzed by presenting one of the words and having thepatients respond with the paired word Two other groups

restudied the words, either through massed restudy (cramming) or spaced restudy (spread over a longer time).

When the patients were retested immediately after thestudy sessions were completed, the retrieval group remembered three times asmany word pairings as the other two groups; a week later, the retrieval groupstill remembered 11% of the words The massed restudy group recalled 1.3%and the spaced restudy subjects recalled none According to the leadinvestigator, “If these individuals learn to incorporate this compensatorystrategy into their daily routines, they can improve their memory Forexample, rather than rereading an article several times, it would be moreeffective if they quizzed themselves periodically, eg, after each paragraph orpage.”

2 Retrieval Aids Remembering

Of course, there is no way to guarantee that reconsolidation will always beadaptive; the opportunity to correct errors also allows the introduction of newerrors We have long known that memories get “reconstructed” over time,usually by blending with other memories Reconstruction can be a progressive

affair Evidence suggests that one reason for the “recovery” of false childhood

memories during therapy may be therapists’ repeated attempts to stimulate recall

at successive sessions Laboratory research has shown that people’s agreementwith memories planted by the experimenter can increase over multipleinterviews (E F Loftus, 1997) In one study, researchers using doctoredphotographs found that after being questioned three times, 50% of subjects weredescribing a childhood ride in a hot air balloon that never happened (Wade,Garry, Read, & Lindsay, 2002) More recently, Loftus and her colleagues (D M.Bernstein, Laney, Morris, & Loftus, 2005) were able to shift their subjects’ foodpreferences by giving them a bogus computer analysis of their responses to afood questionnaire For example, in a follow-up questionnaire, about 20% of thesubjects agreed with the analysis that they had, in fact, been made sick by eating

Does the brain age, too?

Until fairly recently, researchers believed that declining memory and cognitiveabilities were an inevitable consequence of aging Although various kinds ofcognitive deficits are typical of old age, they are not inevitable For example,college professors in their 60s perform as well as professors in their 30s on many

tests of learning and memory (Shimamura, Berry, Mangels, Rusting, & Jurica,1995) An active lifestyle in old age has been associated with this “successfulaging” (Schaie, 1994), but this fact does not necessarily tell us that staying activewill stave off decline Continued mental alertness may be the reason the personremains active, or health may be responsible for both good memory and a highactivity level However, we do know that rats reared in an enriched environmentdevelop increased dendrites and synapses on cortical neurons (Sirevaag &Greenough, 1987) Also, we will see in Chapter 13 that cognitive skill trainingproduces significant and enduring improvement in the elderly, which suggeststhat experience can affect the person’s cognitive well-being.

For many years, researchers believed that deficits in the elderly were caused

by a substantial loss of neurons, especially from the cortex and the hippocampus.However, the studies that led to this conclusion were based on flawed methods

of estimating cell numbers More recent investigations have found that thenumber of hippocampal neurons was not diminished in aged rats, even thosewith memory deficits, and that neuron loss from cortical areas was relativelyminor (see M S Albert et al., 1999, for a review) And, as we saw in Chapter 3,the number of synapses continues to increase with age in humans (Buell &Coleman, 1979)

On the other hand, certain circuits in the hippocampus do lose synapses andNMDA receptors with aging (Gazzaley, Siegel, Kordower, Mufson, & Morrison,1996; Geinisman, de Toledo-Morrell, Morrell, Persina, & Rossi, 1992) Probably

as a result of these changes, LTP is impaired in aged rats; it develops moreslowly and diminishes more rapidly (Barnes & McNaughton, 1985) The rats’memory capabilities parallel their LTP deficits: Learning is slower, andforgetting is more rapid There is also a decrease in metabolic activity in the

entorhinal cortex, the major input and output to the hippocampus (M J de Leon

et al., 2001) In normal elderly individuals, metabolic activity in the entorhinalcortex predicts the amount of cognitive impairment 3 years later Another likelycause of learning deficits is myelin loss (A R Jensen, 1998) Without myelin,neurons conduct more slowly and interfere with each other’s activity

One subcortical area does undergo substantial neuron loss during aging, at

least in monkeys It is the basal forebrain region (D E Smith, Roberts, Gage, &

Tuszynski, 1999), whose acetylcholine-secreting neurons communicate with thehippocampus, amygdala, and cortex Basal forebrain cell loss is much greater inAlzheimer’s disease, but the less pronounced degeneration that occurs in normalaging probably contributes to memory deficits as well

Some of the deficits in the elderly resemble those of patients with frontal lobedamage (Moscovitch & Winocur, 1995) In one study, elderly individuals

participated in the “gambling task” described in Chapter 8, choosing playingcards from two “safe” decks and two “risky” decks Like patients with prefrontalbrain damage, 35% of these elderly volunteers never learned to avoid the riskydecks, and another 28% were slow in doing so (Denburg, Tranel, & Bechara,2005).

Deficits occur at the molecular level as well One study, for example,examined the brains of deceased individuals and found 17 genes in the dentategyrus of the hippocampus that undergo changed levels of expression with aging(Pavlopoulos et al., 2013) Downregulation of one of these results in lessabundant production of the protein RbAp48 in humans and mice This proteinturns out to be important for memory: Young mice engineered to producereduced RbAp48 showed dysfunction in the dentate gyrus and performed likeold mice on memory tests

Can we improve memory in the aged? Earlier, we saw the suggestion thatforgetting useless memories is adaptive; however, when useful memories areeliminated as well, forgetting becomes a deficiency In the study describedearlier, Genoux and his colleagues (2002) found that aged mice weresignificantly impaired on the learning task after just 1 day without practice, butperformance in old mice with the enhanced PP1 inhibitor genes was still robust 4weeks later If we could find simple, safe ways to manipulate gene expression inhumans, we could reduce many of the burdens of aging

Alzheimer’s Disease

Substantial loss of memory and other cognitive abilities (usually, but notnecessarily, in the elderly) is referred to as dementia The most common cause ofdementia is Alzheimer’s disease, a disorder characterized by progressive brain

deterioration and impaired memory and other mental abilities Alzheimer’sdisease was first described by the neuroanatomist and neurologist AloisAlzheimer in 1906, after autopsying the brain of a 56-year-old patient withmemory problems Alzheimer’s is primarily a disorder of the aged, but it canstrike fairly early in life Of the nearly 5 million people in the United States withAlzheimer’s, 4.7 million are over the age of 65 (Hebert, Weuve, Scherr, &Evans, 2013) The earliest and most severe symptom is usually impaireddeclarative memory Initially, the person is indistinguishable from a normallyaging individual, though the symptoms may start earlier; the person has troubleremembering events from the day before, forgets names, and has trouble findingthe right word in a conversation Later, the person repeats questions and tells thesame story again during a conversation As time and the disease progress, theperson eventually fails to recognize acquaintances and even family members.Alzheimer’s disease is not just a learning disorder but a disorder of the brain, so

ultimately most behaviors suffer Language, visual-spatial functioning, andreasoning are particularly affected, and there are often behavioral problems such

as aggressiveness and wandering away from home Alzheimer’s researcherZaven Khachaturian (1997) eloquently described his mother’s decline: “Thedisease quietly loots the brain, nerve cell by nerve cell, like a burglar returning tothe same house each night” (p 21) Eventually, Alzheimer’s is fatal; it is thesixth leading cause of death in the United States (Murphy, Xu, & Kochanek,2013)

4 Alzheimer’s Resources

The Diseased Brain: Plaques and Tangles

There are two notable characteristics of the Alzheimer’s brain, though they arenot unique to the disease Plaques are clumps of beta amyloid (A β ), a type of

protein, that cluster among axon terminals and interfere with neural transmission(Figure 12.16a) The main component is Aβ42, so called because it is 42 aminoacids long; Aβ42 is particular “sticky,” so it clumps easily to form the plaques

In addition, abnormal accumulations of the protein tau form neurofibrillary tangles inside neurons; tangles are associated with the death of brain cells

(Figure 12.16b)

FIGURE 12.16 Neural Abnormalities in the Brain of a Person With

Alzheimer’s.

(a) The round clumps in the photo are plaques, which interfere with neuraltransmission (b) The dark, twisted features are neurofibrillary tangles, whichare associated with death of neurons

SOURCE: (a) © Dr M Goedert/Science Source (b) © SPL/Science Source

FIGURE 12.17 Alzheimer’s Brain (Left) and a Normal Brain.

The illustrations show the most obvious differences, the reduced size of gyriand increased size of sulci produced by cell loss in the diseased brain

What causes Alzheimer’s disease?

Figure 12.17 shows the brain of a deceased Alzheimer’s patient and a normalbrain Notice the decreased size of the gyri and the increased width of the sulci

in the diseased brain Internally, enlarged ventricles tell a similar story of severeneuron loss Many of the lesions are located in the temporal lobes; because oftheir location, they effectively isolate the hippocampus from its inputs andoutputs, which partly explains the early memory loss (B T Hyman, Van Horsen,Damasio, & Barnes, 1984) However, plaques and tangles also attack the frontallobes, accounting for additional memory problems as well as attention and motordifficulties The occipital lobes and parietal lobes may be involved as well;disrupted communication between the primary visual area and the visualassociation areas in the parietal and temporal lobes explains the visual deficitsthat plague some Alzheimer’s sufferers

While amyloid plaques have been considered the hallmark of Alzheimer’sdisease, the number of amyloid deposits is only moderately related to the degree

of cognitive impairment (Selkoe, 1997), and about 25% of the elderly haveplaques but suffer no dementia (Mintun et al., 2006) Over the past decaderesearchers have realized they need to distinguish between insoluble forms ofamyloid and soluble forms (Larson & Lesné, 2012) The soluble type ofamyloids reach 70-fold higher levels in the brains of people with Alzheimer’s,compared with the brains of control subjects In mice they have been linked tomemory failure, loss of synapses, and failure of LTP in the hippocampus (Gong

et al., 2003) Researchers are becoming increasingly convinced that solubleamyloids are the initiators of Alzheimer’s disease

Alzheimer’s and Heredity

Heredity is an important factor in Alzheimer’s disease The first clue to a genelocation came from a comparison of Alzheimer’s with Down syndrome (Lott,

1982) Down syndrome individuals also have plaques and tangles, and theyinvariably develop Alzheimer’s disease if they live to the age of 50 BecauseDown syndrome is caused by an extra chromosome 21, researchers zeroed in on

that chromosome; there they found mutations in the amyloid precursor protein (APP) gene (Goate et al., 1991) When aged mice were genetically engineered with an APP mutation that increased plaques, both LTP and spatial learning were

impaired (Chapman et al., 1999) Three additional genes that influenceAlzheimer’s had been confirmed by the end of the 1990s; all of those affectamyloid production or its deposit in the brain (Selkoe, 1997) As you can see inTable 12.1, the genes fall into two classes, those associated with early-onsetAlzheimer’s disease (often before the age of 60) and one found in patients with

late-onset Alzheimer’s The ε4 allele of the APOE gene is particularly interesting

because it contributes to so many Alzheimer’s cases It increases risk by three- toeightfold and is associated with plaques and tangles, but how it contributes topathology is not well understood Two recent studies indicate that nondementedcarriers have lower cerebral blood flow (Thambisetty, Beason-Held, An, Kraut,

& Resnick, 2010) and that 2- to 25-month-old children with the allele havereduced growth in temporal and parietal areas, which are affected in patientswith Alzheimer’s (Dean et al., 2014)

TABLE 12.1 Known Genes for Alzheimer’s Disease.

SOURCES: Marx (1998); Selkoe (1997)

The four genes in the table account for just a little over half the cases ofAlzheimer’s disease, and environmental causes seem to have little effect, sothere must be a number of additional genes that are difficult to detect because oftheir rarity or small effect Discovery of these genes would have to await whole-genome studies with large numbers of individuals Such studies have theadvantage that they allow gene searches without the need for a preconceivedtarget area Prior to 2009, 11 genes had been associated with Alzheimer’s, but in

3 years a whole-genome study of 74,000 individuals was able to add 11additional gene locations (Lambert et al., 2013) Although the genes themselveshave not been identified yet, genes near the loci are involved in amyloid and taupathways, inflammation, immune response, cell migration, and cellular

Genome-wide studies have also made it possible to do broad searches forepigenetic changes, and in the past few years the focus has been shifting in thatdirection; one study alone found more than 900 differently methylated genes inthe brains of Alzheimer’s patients (Lunnon & Mill, 2013) If we could identifythe environmental conditions that trigger these changes, then preventivemeasures could reduce the incidence of Alzheimer’s Lead exposure is

associated with changes in the expression of the APP gene; adding lead to the

formula given to infant monkeys resulted in elevated plaques and tangles in theirbrains 23 years later (Bihaqi & Zawia, 2013) Until regulations were put intoeffect, children in the United States were exposed to lead in the water, in the airfrom automobile emissions, and even from eating peeling paint; in some parts ofthe world children lack those protections Pesticides are also suspect, and bloodlevels of of a DDT metabolite have been found to be almost four times higher inpatients with Alzheimer’s disease (Richardson et al., 2014) In spite ofdemonstrated health and environmental hazards, DDT is still used agriculturallyand for malaria control in some countries Smoking is another environmentalrisk factor for Alzheimer’s (Cataldo, Prochaska, & Glantz, 2010), and stress isbelieved to be important The University of Southampton in England is takingmonthly stress measures on people with mild cognitive impairment to see ifstress contributes to the transition to Alzheimer’s (“Stress Link toAlzheimer’s ,” 2012)

Treatment of Alzheimer’s Disease

The annual cost of Alzheimer’s disease is estimated at $172 billion worldwide(“Changing the Trajectory,” 2010) With an aging population, the situation islikely to worsen significantly in the future By 2050, the population in the UnitedStates is expected to increase by 50%, while the number over the age of 85increases sixfold (Bureau of the Census, 2001); as a result, the number of peoplewith Alzheimer’s is projected to nearly triple (Figure 12.18; Hebert et al., 2013).Proportionate increases elsewhere will push the worldwide costs to $1 trillion ayear, but a treatment that delayed the onset of Alzheimer’s by 5 years wouldlower that cost to $631 billion (“Changing the Trajectory”)

FIGURE 12.18 Projected Increases in Alzheimer’s Disease in the United States.

Note that numbers begin to escalate rapidly after 2020

Five drugs are currently approved for the treatment of Alzheimer’s in theUnited States, but one of those is rarely prescribed due to side effects (Patoine &Bilanow, n.d.) Three of the ones in regular use are cholinesterase inhibitors;they restore acetylcholine transmission by interfering with the enzyme thatbreaks down acetylcholine at the synapse Acetylcholine-releasing neurons aresignificant victims of degeneration in Alzheimer’s disease, and experimentsshow that blocking acetylcholine activity eliminates hippocampal theta andimpairs learning in rats (J A Deutsch, 1983) and also impairs learning inhumans (Newhouse, Potter, Corwin, & Lenox, 1992) The fourth drug,memantine (marketed in the United States as Namenda), is the first approved foruse in patients with moderate and severe symptoms Some of the neuron loss inAlzheimer’s occurs when dying neurons trigger the release of the excitatorytransmitter glutamate; the excess glutamate produces excitotoxicity,overstimulating NMDA receptors and killing neurons Memantine limits theneuron’s sensitivity to glutamate, reducing further cell death Studies indicatemoderate slowing of deterioration and improvement in symptoms (“FDAApproves Memantine,” 2003; Reisberg et al., 2003) Unfortunately, these drugsprovide only modest relief for the memory and behavioral symptoms ofAlzheimer’s, and they are little or no help when degeneration is advanced

In their quest for more effective treatments, researchers are mounting efforts

on three major fronts: removing beta amyloid or blocking its formation,preventing tau from forming tangles, and reducing inflammation However, nonew drug has been approved by the FDA since 2003, and the disappointmentscontinue to accumulate The failure of two large trials of anti-amyloidantibodies, one of which was at the final phase 3 level, has some researchersnow thinking that once symptoms have appeared the treatment is too late; theyare shifting to pretreatment in asymptomatic individuals who are at genetic risk(Callaway, 2012) Similarly, a phase 3 trial attempting to treat inflammation withinjections of immunoglobulin has come up empty-handed (Weil Cornell Medical

College, 2014) However, the tangle-preventing drug LMTX is now in phase 3clinical trials, after reducing symptom progression by 90% in phase 2 trials(TauRx Therapeutics, n.d.).

Stem cell and gene therapy are obvious treatment possibilities, but work inthese areas is in its infancy Mice genetically engineered to have Alzheimer’sperformed better on a memory test a month after neural stem cells were injectedinto their brains (Blurton-Jones et al., 2009) However, only 6% of the stem cellsturned into neurons Instead, the stem cells secreted brain-derived neurotrophicfactor, which promoted the development of new synapses The gene therapyscene has not been very active lately, but in an interesting development, aChinese team has demonstrated that neural stem cells can be used to deliverRNA to silence the gene responsible for the key enzyme in beta amyloidproduction (Liu et al., 2013) An interesting alternative approach is nutritionalsupplementation; one of these supplements, Souvenaid, improved memory andincreased brain connectivity in phase 2 trials (Scheltens et al., 2012) and is nowundergoing phase 3 testing Finding a truly effective drug is a daunting task,which is why the National Institutes of Health is partnering with 10 drugcompanies in hopes of a breakthrough (See the accompanying In the News.)

National Institutes of Health Teams With Drug Companies

Drugs in development have a failure rate of 95%, whichmeans that developing a successful drug requires about 10years and a billion dollars Declaring that this is a job toobig for any single group, the National Institutes of Health(NIH) announced an unprecedented 5-year partnershipwith 10 drug companies and several nonprofitorganizations to develop new treatments for Alzheimer’sdisease, as well as for diabetes, lupus, and rheumatoidarthritis The partners will put up a total of $230 million;Alzheimer’s research will get the lion’s share, $130 million, which will beused to identify new therapeutic targets and to develop biomarkers that candetect the disease early and track treatment progress

battery of physical, neurological, and cognitive tests can do a reasonably goodjob, mostly by ruling out other forms of dementia that may be more treatable, ifnot reversible The physician may also order an MRI to look for atrophy in thetemporal and parietal areas For many years, patients were told that a definitediagnosis could be made only on autopsy, after examining the brain for plaquesand tangles, but recent advances in PET scanning and measurement ofbiomarkers is changing that Using new tracers that specifically target plaques,PET scans can identify 75% to 90% of individuals who are confirmed to haveAlzheimer’s at the time of autopsy; measuring Aβ42 and tau in the cerebrospinalfluid is equally accurate (Fraller, 2013) Biological assessment should lead tomore appropriate treatment planning by differentiating better betweenAlzheimer’s and other dementias; in addition, it will be possible to monitortherapeutic progress, detecting changes before they translate into cognitivegains But because current treatments only slow the progress of Alzheimer’s,researchers are interested in detecting the disease well before it is full-blown andbefore irreversible damage has occurred PET scanning for amyloid predictsabout one-third of individuals with mild cognitive impairment who will bediagnosed with Alzheimer’s during the next several months; among the normalelderly, 25% with high amyloid levels are diagnosed within 3 years, while thosewith low levels have a 98% chance of remaining cognitively stable (Gelossa &Brooks, 2012) Biomarkers found in cerebrospinal fluid and blood have shown90% to 100% accuracy in predicting progression to Alzheimer’s over the next 5

to 6 years (DeMeyer et al., 2010; Khan & Alkon, 2010; Ray et al., 2007)

A study of Roman Catholic sisters that has been going on since 1986 revealedcognitive differences as much as five decades before some of them werediagnosed with Alzheimer’s (Riley, Snowdon, Desrosiers, & Markesbery, 2005).Autobiographical essays were available for 180 of the study participants, writtenwhen they joined the order at an average age of 22 These were scored for ideadensity, defined as the number of ideas expressed for every 10 words Almost80% of the sisters with the lowest density scores eventually developedAlzheimer’s, compared with 10% among those who scored the highest Asurprising finding was the number of participants with high density scores and

no symptoms of Alzheimer’s who had neurofibrillary tangles when they wereautopsied (Iacono et al., 2009; Riley et al., 2009) Also, the sisters who remainedhealthy were just as likely as the ones with Alzheimer’s to have one or more

APOE4 alleles (Riley et al.) So what protected some of the women from

Alzheimer’s? This question leads us to the reserve hypothesis

Resistance to Alzheimer’s: The Reserve Hypothesis

According to the reserve hypothesis, individuals with greater cognitive or

brain capacity are able to compensate for brain changes due to aging, braindamage, or disorders such as Alzheimer’s There is some evidence for

compensation in the elderly through brain reserve, either by means of greater

activation in the network involved or by recruiting other brain areas (reviewed in

Stern, 2012) However, most studies have focused on cognitive reserve, by

assessing experiential factors and cognitive capabilities For example, the risk ofdeveloping dementia goes down 46% with higher educational and occupationallevels and higher IQ and mental activity in earlier life The protection, however,

is temporary; the delay may last the rest of the individual’s life but, if not,decline occurs more rapidly than in other Alzheimer’s patients

The elderly fare better if they have a history of both mental and physicalactivity, so they are frequently advised to stay active in order to stave off mentaldecline However, choosing an active lifestyle may simply be a reflection ofgeneral fitness, rather than the cause of better cognitive health later; we should

be careful about assuming cause until we have adequate experimental evidenceand, so far, the results have been mixed The most consistently positive resultshave been with exercise; cognitive training has not been very promising, withthe possible exception of complex computer games and role-playing games

Korsakoff’s Syndrome

Another form of dementia is Korsakoff’s syndrome, brain deterioration that isalmost always caused by chronic alcoholism The deterioration results from a

deficiency in the vitamin thiamine (B1), which has two causes: (1) the alcoholicconsumes large quantities of calories in the form of alcohol in place of anadequate diet, and (2) the alcohol reduces absorption of thiamine in the stomach.The most pronounced symptom is anterograde amnesia, but retrograde amnesia

is also severe; impairment is to declarative memory, while nondeclarativememory remains intact The hippocampus and temporal lobes are unaffected; butthe mammillary bodies (see Figures 3.20 and 8.4) and the medial part of thethalamus are reduced in size, and structural and functional abnormalities occur inthe frontal lobes (Gebhardt, Naeser, & Butters, 1984; Kopelman, 1995; Squire,Amaral, & Press, 1990) A bizarre accident demonstrated that damage limited tothe thalamic and mammillary areas can cause anterograde amnesia; a 22-year-old college student received a penetrating wound to the area when his roommateaccidentally thrust a toy fencing foil up his left nostril, producing an amnesiathat primarily affected verbal memory (Squire, Amaral, Zola-Morgan,Kritchevsky, & Press, 1989) Thiamine therapy can relieve the symptoms ofKorsakoff’s syndrome somewhat if the disorder is not too advanced, but thebrain damage itself is irreversible