Memory - A Marvel of Nature: Dr David Weintrob - Epilepsy Australia

PAPERS FROM THE EPILEPSY & SOCIETY SYMPOSIUM, Melbourne 2010Memory – A marvel of natureDr David WeintrobSenior Clinical Neuropsychologist, Department of Neuropsychology, Austin Health, MelbourneAs with walking and breathing, weoften take our memory for grantedand barely spend time marvelling atthe astounding evolutionary feat itrepresents. I have three aims in thistalk: (1) to remind you of the marvel thatis memory; (2) to take you on a briefjourney through the recent history ofmemory research and to outline the vitalcontribution that people with epilepsyhave made to our modern understandingof how the brain makes memorypossible, and; (3) to leave you with asense of the nature and cause of memorydysfunction in epilepsy. That is, what arethe kinds of things people with epilepsyforget and why.At the outset, we need to understandwhat memory is. For most of us, itreflects the ability to remember an eventthat occurred in the past. Our 21st. Ourmarriage. The birth of our child. And,indeed, this is how memory is oftendefined by respected dictionaries. Forthose who study memory, however,memory is a much more diffuse, andindeed nebulous, phenomenon.In general, for the neuroscientist,memory reflects the capacity of theorganism to benefit from experience.It is, therefore, a ubiquitous presencein many very different life forms andassumes many different guises. Forexample, the ability of the earthworm tohabituate to its environment representsa legitimate memory. So too is a dog’sconditioned salivation in response to abell.In humans, memory ranges fromsimple (“his name is David”) to complex(“she can recite all Shakespeare’ssonnets”), from highly specific (“Thetalk starts at 11am”) to the most general(“A lion is a kind of animal”), fromthe trifling (“I need to buy milk”) tothe vitally important (“which buttonlaunches the nuclear missile?”), fromthe visual (face recognition/paintingrecognition) to verbal (remembering apoem) to the spatial (“How do I get …there?”) to the musical (“I can hum 20different Beatles songs”) to the active (Ican kick a football without even thinkingabout it). It underpins our ability to ride6 THE EPILEPSY REPORT JUNE 2011a bike, obey traffic signals, identifyobjects by name, use language, andbehave appropriately when in church.Moreover, and perhaps even moreastoundingly, it encompasses the abilityto be consciously aware now of an eventthat occurred seconds-minutes-hoursyears-decadesago, and to re-experiencethat event – even if it occurreddecades ago – with a vitality and fullreawakening of the colors, textures,and emotions we felt at the time ... andto recall when and where the eventoccurred.In that it underpins our personalautobiographies, memory is integral topersonal identity. That is, it is integral toour sense of who we are.Note too, that a special kind ofconsciousness accompanies memory.When we recall events from ourpast, our conscious awareness ofthat experience is different from ourordinary ‘online’ awareness of ourenvironment. We seldom confusethe feeling that we are rememberingan event with the feeling that we areadmiring a sunset, dreaming, solving aSudoku problem, or wondering what weshould have for lunch. We are certainlyconscious while doing those activities,but that consciousness is plainly andrecognizably different. Endel Tulving,one of the doyens of memory research,has used the term “autonoesis” to referto the special kind of consciousness thatallows us to be aware of the subjectivetime in which events occurred.Paradoxically, therefore, not onlydoes memory allow us to travel backin time, it allows us to recollect futurearrangements and to project ourselvesinto the future. That is, it seems tobe closely linked with our ability toperceive the present moment as acontinuation of preceding events and asa prelude to future activities. This lastability is probably unique to humans andis a vital precondition for human culturalevolution – awareness of the existenceof a past is a necessary precondition forchanging the future.Memory is truly a remarkableevolutionary achievement.The complexity of memory:refining the questionIn all its variety and glory, memory isbeing investigated across many differentspecies, at many levels of analysis(molecular – cellular – anatomical –cognitive), using many different andoften highly sophisticated techniques.Novel findings are reported almost dailyin journals devoted solely to memoryresearch. Any literature search will yieldliterally tens of thousands of studies.What is indisputable is that memorydid not evolve for the convenience ofthe neuroscientist. While significantprogress has been made, EndelTulving – one of the doyens of memoryresearch- has noted rather prosaicallythat the main finding is that memory is“extraordinarily complicated”.Epilepsy and memoryNonetheless, the study of memoryin people with epilepsy, and temporallobe epilepsy in particular, has beenenormously influential in attempts toimpose scientific order on this amazingability. It has also played a vital rolein helping us understand how thebrain makes memory possible. This isbecause in TLE, epilepsy and memoryco-habit the same space. Indeed,Snyder has commented that the studyof memory in individuals with temporallobe epilepsy has provided “the mostsingularly important natural laboratoryfor uncovering the neuroanatomic basesof human memory.” (Snyder, 1997). Theremarkable patient H.M. is regarded asthe index case and our story really startswith him.H.M.After being introduced to the medicalworld in 1957, H.M. went on to becomeone of the most studied of all patientsin medical and psychological history.In 1953, aged 27, H.M. underwentsurgery in Canada to relieve hisseverely disabling epilepsy. In whathis surgeon described as a “franklyexperimental procedure”, H.M. hadthe front-most end of both his temporallobes removed. H.M’s epilepsy wassubstantially improved by this operation.

PAPERS FROM THE EPILEPSY & SOCIETY SYMPOSIUM, Melbourne 20102. Semantic memory, i.e., memory forfacts or general information about theworld. It is impersonal, i.e., the contentof this kind of memory is not specificto the individual but may be shared byliterally billions of people. Moreover,it contains no record of the contextin which the memory was formed.It encompasses, for example, ourknowledge of the meaning of the word‘testify’, the usual colour of a banana,the taste of an apple, the chemicalformula for table salt, the knowledgethat the summer months in Brisbane areusually quite humid, and how to behavewhen you enter a restaurant. Billions ofpeople know and can declare this kindof memory without remembering theoccasion on which it was learned.To reinforce the distinction: Beingable to state that Princess Diana died inParis in a car accident reflects semanticmemory; being able to state that one waseating breakfast at 7am in the kitchenand that you felt very sad when youlearned this from the TV news broadcastreflects episodic memory.An evolutionary asideSemantic memory is the kind ofmemory that makes it possible fororganisms to store a kind of “generalknowledge” of the world and thenuse this information flexibly andappropriately. All kinds of animalshave excellent semantic memory – thatis, they know a lot about the kind ofworld they live in. Our evolutionaryancestors were like this, but at somepoint in human evolution, possibly ratherrecently, episodic memory emerged asan embellishment of semantic memory.As far as we know, no species otherthan humans has episodic memory ofthe kind just described. That is, no otherspecies has any subjective sense of selfas existing in time with the ability tore-experience discrete events in one’spersonal history.H.M. revisitedIn respect of Temporal LobeEpilepsy (TLE), it is really declarativememory we’re concerned with. Morespecifically, and particularly in lightof its significance for everyday life, itis episodic memory that is usually ofmost concern to neuropsychologists andpeople with TLE.As we’ve seen, episodic memory wasprofoundly impaired in H.M. Afternearly 40 years he could recollect few, if8 THE EPILEPSY REPORT JUNE 2011episodic(events)MEMORYDeclarative Non- Declarativesemantic(facts)any, events he’d personally experiencedsince his operation. Fortunately,however, unlike H.M., the overwhelmingmajority of people with TLE havedamage confined to one temporal lobe.Consequently, any accompanyingmemory impairment tends to be verymuch milder than that of H.M’s.This is not to downplay thesignificance of memory impairment forpatients and family, but fortunately wedon’t see the dense, disabling gaps inmemory for recent personal activitiesthat H.M exhibited. Having said asmuch, however, what kinds of memorydifficulties do patients with TLEtypically experience?The nature of forgetting inTLEThe paradox of H.M. is that throughhim we have learned a great dealabout human memory, but because ofthe unexpected tragic results of hissurgery the sample size of one willnever increase. That is, no one has everattempted removal of both temporallobes again.Following H.M., however, attentionturned to patients with epilepsy who’dundergone unilateral resections of onetemporal lobe only. These patients alsoshowed memory impairments, albeitvery much milder than that of H.M.Moreover, the nature of the deficit variedas a function of side, with memory forverbal information, i.e., informationconveyed through the medium oflanguage, being most affected bysurgery on the left temporal lobe andmemory for non-verbal information,i.e., information with a prominent visualor spatial emphasis that is not easilyrepresented in language, being affectedby surgery on the right temporal lobe.For example, the ability to learn a list of15 words was depressed in people who’dundergone a left temporal lobectomy, butnormal in those who’d had a right-sidedoperation. In contrast, the ability toremember an abstract geometric figurewas depressed in people who’d had aright temporal lobectomy, but normal inskillshabitsprimingclassical conditioningnon-associativethose who’d had a left-sided operation.Subsequent studies showed that, evenprior to any temporal lobe surgery,similar problems affected peoplewith either left or right temporal lobeepilepsy. These observations led to thematerial-specific model of memory, atheoretical framework which, althoughquestioned in more recent times, stillguides practice in many epilepsy centresaround the world.To summarise: Unlike H.M., peoplewith unilateral TLE retain the abilityto lay down personal memories andtherefore generally retain an ongoingand coherent autobiographical record.Against this backdrop, however, theindividual with unilateral TLE may wellhave difficulty remembering the finedetails of events they experience andnew information they encounter. This ismost pronounced for verbal informationwhen the left temporal lobe is involvedand most pronounced for non-verbal (i.e.,visual and spatial information) when theright is involved.Thus far, I’ve been referring tomemory as it applies to a person’sperformance on a standardised,objective test of memory. That is, I’vebeen referring to their performance ontasks that require them, for example,to learn a list of words or memorise anabstract figure. Relatively little workhas been done attempting to understandhow memory impairment on testingtranslates into deficits in everydaylife. As broad pass, however, the kindsof things people with temporal lobeepilepsy tend to struggle with include:Left temporal lobe epilepsy andhippocampal damage: retrieve skeletalautobiographical memories for whichthe gist of the memory is maintained,but some of the specific details arelost (St-Laurent et al, 2010; Thaiss andPetrides, 2008); they may rememberhaving the conversation, but find thattheir memory for the details of what wasspoken about is unreliable; details ofinstructions; details of information readin books and newspapers.

Right temporal lobe epilepsy: memorycomplaint less frequent; route aroundthe city centre or local shopping centre;the layout of their local supermarket;location of their car on leavingthe supermarket; less often, facialrecognitionIn both, there may be a denser andmore encompassing disruption ofmemory for events that occurred shortlybefore or after a seizure.TLE, memory, and somegeneral observationsAt this point, I will briefly canvass afew other pertinent issues:Severity – what determines theseverity of memory impairment in TLE?Earlier age at onset of seizures, longerduration of epilepsy, and greater seizurefrequency tends to be associated witha somewhat more severe impairmentof memory (although exceptions areseen, raising the possibility that in somepatients memory has transferred to theother temporal lobe);Memory decline after temporallobectomy – this issue is always takenextremely seriously and is always verycarefully considered. The first pointto note is that for most people withright TLE, a right Anterior TemporalLobectomy (ALT) does not causeany discernible change in memory onspecific testing. However, given that theleft hemisphere of the brain is typicallydominant for language, and given thatmost of what we need to rememberis embedded in language, left ATL isusually much more of a concern. Again,however, as a general principle thedamage, so to speak, is often done bythe time a left ATL is contemplated andremoving a part of the temporal lobedoes not place people at great risk of afurther disabling decline in memory.A recent study (Williams, Martin,& McGlone, 2009) looking at thesubjective experience of memory changeafter surgery found that most patientsdenied any significant change in theirmemory after temporal lobe surgery.Indeed, a small number of patientsreport (Williams, Martin, & McGlone,2009) and exhibit (Baxendale et al,2008) a modest improvement in memory.This converges on our experience atAustin Health.In a small number of patients,however, the possibility of a significantchange in verbal memory does exist.This is true especially of people withlate-onset left TLE, no or only very mildhippocampal pathology, or normal oronly mildly impaired verbal memorybeforehand. The guiding philosophyin our program is that this needn’t ruleout surgery. Rather, any risk to memoryneeds to weighed against the benefits ofseizure freedom and, moreover, needs tobe understood in terms of what the likelyfunctional consequences of memorydecline will be. That is, althoughwe might expect to see a change forthe worse on our memory measures,this doesn’t automatically translateinto difficulties in everyday life. Forexample, a QC who relies very heavilyon verbal memory might be a differentprospect to someone with a more routineor repetitive occupation, even if thedecline seen on our tests is equivalent.Decline with time – there is evidencethat refractory TLE may be associatedwith a slow but progressive decline incognitive abilities (e.g., Jokeit & Ebner,2002; Hermann et al, 2002; Cascino,2009). That is, poorly controlled seizuresmay cause cumulative cognitive deficitsover time. There is, therefore, a growingbelief that epilepsy surgery may not bea procedure of last resort in suitablecandidates. Time may mean neurons.Immediate, short-term,working, and long termmemoryUp until now, we have consideredmemory in terms of the nature ofthe information to be remembered.That is, whether its verbal or spatialor musical or autobiographical orsemantic. However, memories can alsobe distinguished in terms of the timeinterval across which the informationneeds to be remembered. When weconsider this time dimension, memorycan again be divided into categories.In particular, a distinction is drawnbetween immediate, working, and longtermmemory.Immediate memory refers to a systemthat makes it possible to store smallamounts of information over very briefperiods of time. Its capacity is verylimited – e.g., it cannot deal with morethan one or two sentences or about 6-9digits at a time – and its contents decayrapidly to make way for the next itemsin the continuous stream of informationthat enters our awareness. For example,if I read out 7 digits and ask you torepeat them, you’ve engaged immediatememory. In real life, taking down atelephone number from a friend is aprime example of immediate memory– as your friend speaks the number,you transiently keep the digits onlinewhile writing them down and, oncethat is completed, you promptly forgetthem as your attention is engaged bythe next item in the ongoing streamof consciousness. Indeed, one mightspeculate that this sort of task hasbecome more important of late becauseof the increasing use in our society ofdigit and letter sequences, in the formof telephone numbers, post codes, ATMPINs and internet passwords.Allied with immediate memory isworking memory. This system not onlyfacilitates the temporary maintenanceof information in mind, but providesthe mental workspace that allows usto simultaneously manipulate thatinformation for some purpose. Forexample, if I read out a series of 7digits and ask you to repeat themin reverse order, you have engagedworking memory. Similarly, if I askyou to multiply 27 by 3, you need tosimultaneously hold and manipulatevarious bits of information in mind untilthe answer is provided. Once you’vedone so, however, the mental workspaceof working memory will be taken up bysome other demand.Immediate and working memory arecrucial systems that make possible ourongoing awareness of the environmentand all the events therein. It is closelyallied, if not actually synonymouswith, the concept of attention. Indeed,many neuropsychologists regard theseprocesses as a part of the attentionalsystem, rather than memory per se.As noted, they are characterised bythe brief duration of the memory traceand by limited storage capacity. Incontrast, long-term memory is a systemor systems that underpin the capacityto store information over minuteshours-months-years-decades-alifetime.Storage capacity is virtually unlimited.The declarative and non-declarativememory systems I referred to earlier areforms of long-term memory.A model proposed by Atkinsonand Shifrin in the 1970s and that isprobably still useful for our purposeslinks these different memory systemsand suggests how information thatreaches us from the environment flowsthrough these various systems to endup as a permanent memory. Critically,THE EPILEPSY REPORT JUNE 2011 9

PAPERS FROM THE EPILEPSY & SOCIETY SYMPOSIUM, Melbourne 2010information from the environment isfirst processed by immediate memorybefore it enters a more durable long-termstore. In short, we need first to attend toinformation if we are to ever hope that itenters permanent storage.Why am I at pains to mentionthis? The answer is that under thismodel, disruption of this interveningattentional/memory system canrender long-term memory systemsless efficient. How is this relevant topresent discussion? The answer is thatin people with epilepsy several factorsand co-morbid conditions can impact,sometimes quite significantly, with thisintervening system. Chief among thesefactors are medication and mood.Anti-convulsant medicationAt its simplest, epilepsy represents anabnormal electrical discharge betweennerve cells in the brain. The aim of drugtreatment is to suppress this excitability.While AEDs are often effective atdoing just that, they unfortunately alsosuppress normal patterns of neuronalexcitability more diffusely in the brain.The cognitive manifestation of that issedation, a state in which normal levelsof energy, arousal, attention, vigilance,and mental processing speed give wayto drowsiness, slowness of thought,and lapses in focus and concentration.I often use a jogging analogy to makethis point – for the person with epilepsyon medication, thinking can often feellike wading through mud rather thansprinting on dry bitumen. Similarly,imagine you’ve been sleep-deprived fora few days and you’re asked to subtract17 from 35 – the challenge that wouldpose is what matters are chronicallylike for some people with epilepsyon medication. In short, the commonexperience of sedation can disrupt theintervening attention/memory systemand result in inefficiencies of memory.Different AEDs have different effectsin this regard. Certain medicationsare more likely than others to causesedation. The chance of sedation is alsoincreased with rapid initiation, higherdoses, and polytherapy.Clearly, disruption of this interveningsystem can further compound memorydisturbance in people with temporallobe epilepsy whose long-term memorysystem is already compromised.However, disruption of this interveningsystem might also cause attentionaland memory inefficiencies in peoplewhose epilepsy arises from outside10 THE EPILEPSY REPORT JUNE 2011of the temporal lobe. Indeed, I’d goso far as to suggest that disruption tothis intervening system is perhaps theprincipal source of cognitive difficultiesin people with extra-temporal lobeepilepsy. Fortunately, those difficultiestend to be much less disabling.An important point: This is not to say,however, that people should cease takingAEDs. Ongoing seizures of themselvescan be detrimental to both cognitionand quality of life and clearly the needto take AEDs to suppress seizures mostoften trumps any sedating effect theymay have. However, I raise this issuebecause it is important if we are to fullyappreciate the factors that can affectcognition in people with epilepsy.MoodI will touch briefly on the questionof mood disturbance because it too hasthe potential to disrupt the interveningimmediate/working memory systemand cause or exacerbate cognitivedysfunction.The incidence of mood disturbance,i.e., either depression and/or anxiety, iselevated in people with epilepsy. Thismay be a direct biological consequenceof their condition, it may reflect theoften significant psychosocial fearsand restrictions that accompanythe condition, or it may be somecombination of the two. Regardless ofcause, cognitive disruption frequentlyaccompanies both disorders.In people who are anxious,excessive and uncontrollable worryand pre-occupation with fears thatare irrelevant to the task they needto complete in the ‘here-and-now’crowd the mental landscape to thepoint where focussed attention onother matters is compromised. Thetendency to transiently forget one’sintention when walking into a roomis a common manifestation of this. Sotoo is the realisation that on reachingthe bottom of a page one has failed toabsorb what you’ve just read. So toois the phenomenon of losing track ofwhat one wishes to say mid-sentence.Not surprisingly, people often interpretthese sorts of attentional lapses asforgetfulness. Not surprisingly too,however, actual long-term memorybecomes unreliable in these contexts.Similarly, low energy levels andassociated motivation make it difficultfor some people with depression toinvest the effort needed for effectiveattention and concentration. Again, longtermmemory can become unreliablein this context. Indeed, in generalneuropsychological practice, and I’m notreferring just to epilepsy, anxiety anddepression are among the most commoncauses of a memory complaint.LanguageOne final consideration is worthmentioning. As I’ve already indicated,memory impairment is often present inpeople with TLE because their epilepsyand memory co-habit the same partof the brain. In addition to memory,another important cognitive domainthat is partially housed in the temporallobe, usually the left, is language. Notsurprisingly, therefore, some patientswith left TLE experience mild languagedifficulties. Typically this manifests as aword finding difficulty, that is, difficultyretrieving the name for a particularitem. Naturally, this can compound anyco-occurring memory deficit.ClosingH.M. died in December 2008 aged82. He was a quiet and courteous manwith a sense of humour who, referringto his neurosurgeon, once said “What helearned about me helped others, and I’mglad about that.”The early descriptions of H.M.’smemory impairment ushered in themodern era of memory research.They showed that memory could bedissociated from other intellectualand perceptual domains, that memoryitself can be subdivided into differentdomains, and that memory for theepisodes of everyday life is criticallydependent on the hippocampus andadjacent structures. Subsequent studiesshowed that people with damageconfined to one temporal lobe also havememory deficits, albeit much milderthan that of H.M. Typically, people withunilateral damage retain memory forthe event, and thus retain a coherentautobiographical record. Frustratinglyfor them, however, they often experiencea tendency to forget the fine detailsof events they experience and newinformation they encounter. This isusually most apparent when the damageis on the left and it can be a majorcontributor to the burden of epilepsy. Itcan also contribute to the restrictionsthat epilepsy sometimes imposes onacademic achievement and employment.Medication and mood may compoundunderlying memory impairment throughtheir impact on attention/concentration,focus, and motivation.