7. Glickman SE , Schiff BB . A biological theory of reinforcement . Psychol Rev 1967 ; 74 ( 2 ): 81 \200\223 109 . 8. Olds J , Milner P . Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain . J Comp Physiol Psychol 1954 ; 47 ( 6 ): 419 \200\223 27 . 9. Bartels A , Zeki S . The neural correlates of maternal and romantic love . Neuroimage 2004 ; 21 ( 3 ): 1155 \200\223 66 . 10. Zeki S . The neurobiology of love . FEBS Lett 2007 ; 581 : 2575 \200\223 9 . 11. Baird AD, Wilson SJ , Bladin PF , Saling MM , Reutens DC . Neurological control of human sexual behavior: insights from lesion studies . J Neurol Neur osurg Psychiatry 2007 ; 78 ( 10 ): 1042 \200\223 9 . 12. Rees PM , Fowler CJ , Maas CP . S exual function in men and women with neurological disorders . Lancet 2007 ; 369 ( 9560 ): 5 12 \200\223 25 . 13. Barbas H . Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices . Brain Res Bull 2000 ; 52 ( 5 ): 319 \200\223 30 . 14. Adolphs R . Recognizing emotion from facial expressions: psychological and neurological mechanisms . Behav Cogn Neurosci Rev 2002 ; 1 ( 1 ): 21 \200\223 62 . 15. Sheline YI , Price JL , Yan Z , Mintun MA . Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus . Proc N atl Acad Sci U S A 2010 ; 107 ( 24 ): 11020 \200\223 5 . 16. Mayberg HS , Liotti M , Brann an SK , McGinnis S , Mahurin RK , Jerabek PA , et al . Reciprocal limbic-cortical function and negative mood: converging PET \201 ndings in depression and normal sadness . Am J Psy chiatry 1999 ; 156 ( 5 ): 675 \200\223 82 . The comorbidity of emotional and sexual dysfunction in epi- lepsy has also been found to va ry with the medical treatment undertaken, with AEDs and temporal lobe resection having diff er- ential but well-documented effects. Although not the focus of this review, AEDs can alt er sex hormone concentrations and neuro- transmitter release that may have detrimental effe cts on sexual and reproductive function, and sedating effects on mood. Disruption of limbic system function via temporal lobe resection has also been associated with lowered mood, bu t increased sex drive, both of which are typically accompanied by impaired psychosocial fun c- tioning. These \201 ndings highlight the complexity of interactions underpinning emoti onal and sexual change in epilepsy and the need to consider individual differences in clini cal presentation. Greater understanding of this complexity promises improved treatments tha t may ultimately bene \201 t both the emotional and sexual functioning of people with epil epsy. At present, mood dis- orders remain underdiagnosed and sexual functioning is often no t discussed in clinical practice. Likewise in research, few studies have examined the links between emotional and sexual functioning in pre- or postoperative samples. As a \201 rst step, addressing these chal- lenges will move us towards identifying appropriate intervent ions that can better preserve sexual and emotional functioning, thereby enhancing quality o f life for people with epilepsy. 17. Johansen-Berg H , Gutman DA , Behrens TE , Matthews PM , Rushworth MF , Katz E , et al . Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimul ation for treatment-resistant depression . Cereb Cortex 2008 ; 18 ( 6 ): 1374 \200\223 83 . 18. Phillips ML , Drevets WC , Rauch SL , Lane R . Neurobiology of emotion perception II: Implications for major psychiatric disorders . Biol Psychiatry 2003 ; 54 ( 5 ): 515 \200 \223 28 . 19. Kennedy SH , Evans KR , Kr ger S , Mayberg HS , Meyer JH , McCann S , et al . 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Arch Se x Behav 1990 ; 19 ( 1 ): 1 \200\223 14 . CHAPTER 36 Epilepsy: Cognition and Memory in Adults Sallie Baxendale Introduction Epilepsy may be a condition de \201 ned by seizures, but seizures remain rare events for the majority of people with the diagnosis. Whilst up to two-thirds may become s eizure free on antiepileptic medications, dif \201 culties in memory and other cognitive p roblems associated with the condition (and its treatment) are encountered on a daily basis by many people with epilepsy. As the likelihood and concomitant fear of a seizure recedes f ollowing the instigation of an optimal antiepileptic treatment regimen, it is often the und er- lying cognitive dif \201 culties that become distressing daily reminders of the diagno sis. Thus, estimates of the prevalence of memory dif \201 culties in epi- lepsy based on self-r eport measures from patient samples may rep- resent a wide range of cognitive dif \201 cul ties and other factors associated with mood and psychological adjustment. Estimates based o n clinical studies using formal neuropsychological meas- ures may also overestimate the ext ent of the problem, as patients who undertake a formal assessment normally only do so follo wing concerns about their memory or a deterioration in other cognitive domains. Notwithstan ding these caveats, there is a general consen- sus that the prevalence of memory and other cognitive problems within the epilepsy population as a whole is high. Epilepsy is over-represented in people with a low intelligence quotient (IQ), often due to the extensive underlying cerebral abnormalities that lead to both limited cognitive abiliti es and recurrent seizures ( 8 ). However, when people with an IQ of 70 or below are discoun ted, the mean IQ of people with epilepsy falls slightly below, but within the average range of normative healthy samples and is distributed across a normal bell curve. The extent of the problem It is important to make a distinction between subjective complain ts and objective measures of cognitive impairment in epilepsy, par- ticularly in the memory domain. There is a poor correlation between scores on standardized neuropsychological test s of memory function and scores on self-report measures of everyday memory problems. Howeve r, patient ratings of memory com- plaints are closely related to measures of anxiety and de pression ( 1 \200\2233 ) and some have argued that memory complaints in epilepsy are a re \202 ection of dif \201 culties adjusting to, or coping with, the con- dition ( 4 ). Other s argue that the poor correlations re \202 ect the arti \201 - cial nature of standardize d memory tests and the fact that they bear little relation to either the demands placed on memory in everyday situations or the speci \201 c nature of the memory complaints of some patients. The poor ecological validity of pencil and paper memory tests is particularly rel evant for patients who complain of a loss of autobiographical memory ( 5 ). Amnesia for pas t events, such as holidays or weddings, can be a particular feature of patients with fronta l lobe epilepsy and is also commonly reported interictally by patients with transient epile ptic amnesia ( 5 , 6 ). Hermann and Lang \201 tt ( 7 ) point out that \200\230memory \200 \231 is often employed as a catchall phrase that patients use as a shorthand to describe a broad spec- trum of cognitive dif \201 culties. These can range from word- \201 nding dif \201 culties to dif \201 culties in recognizing faces; route \201 nding to remembering why you have come into the kitchen. From a neu- ropsychological perspective, different pro cesses and substrates may underpin each of these functions, but from a patient \200\231s pe rspective they all represent examples of \200\230a dreadful memory \200\231. Factors affecting cognition and memory There are many factors that contribute to cognitive dysfunction in epilepsy. Some of these factors may be \201 xed (e.g. the underlying patho logy) while others may be more \202 uid or transient (e.g. mood, side effects of antiepil eptic medications). Other factors may repre- sent the course of the disease (e.g. episodes of status epilepticus, the effects of aging). These factors all interact to shape the natur e and extent of the cognitive de \201 cits in each individual with epilepsy. See Table 36. 1 . Fixed factors Although a seizure is often the \201 rst overt sign of neurological dys- fu nction, there is increasing evidence that many people eventually diagnosed with epilepsy ha ve pre-existing signs of cerebral dys- function. Epilepsy has long been associated with dep ression and this has traditionally been understood as a response to the signi \201 - cant personal and practical changes a diagnosis of epilepsy brings. However, in a series of popu lation studies, Dale Hesdorffer and her colleagues from Columbia University, New York have demon- strated that depression is a risk factor for developing epilepsy and that mood distu rbance often predates the \201 rst seizure ( 9 \200\22311 ). oxford textbook of epilepsy and epileptic seizures 368 Table 36.1 Fixed, \202 uid, and cumulative factors that in \202 uence neuropsychological function in epilepsy common for people with pathology in the right temporal lobe to have some degree of verbal m emory impairment; similarly people with left temporal lobe pathology may demonstrate impair ments on memory tests involving both verbal and non-verbal material. Fig. 36. 1 represents the mean scores of 417 adult patients with medically intractable epilepsy and unilateral hi ppocampal sclerosis on a range of cognitive tasks including measures of intellectual functi on, verbal and visual learning, and expressive language func- tion. This \201 gure graphi cally illustrates the range and extent of cog- nitive de \201 cits associated with an appa rently discreet localized underlying lesion. On the memory tasks, the mean performance of t he epilepsy groups falls at about the 10th percentile of that of the normal population. Thu s whilst some patients with temporal lobe epilepsy (TLE) may have normal memory function, t hey will be in the minority. Fixed factors Variable factors History of the disease Nature of underlying pathology Laterality of pathology Locality of pathology Age onset of p athology/ seizures Age onset of treatment Impact on education Gender Intellectual capacity Medication Interictal/subclinical EEG abnormalities Seizure control Mood Motivation Quality of sleep Proximity of last seizure to assessment Episodes of status epilepticus Repeated generalized seizures Head injuries Adapted from Baxendale and Thompson ( 15 ). Hermann et al. ( 16 ) examined the neuropsychological pro \201 les of 96 patients with epi lepsy and compared them with matched healthy controls to determine whether distinct cogniti ve phenotypes could be identi \201 ed in TLE. They identi \201 ed three distinct types of cogni- tive pro \201 le. Almost half of the sample (47 % ) were minimally impaired. A sec ond group (24 % ) were impaired on memory meas- ures whilst the remainder (29 % ) were impa ired on a much broader range of tasks including measures of memory, executive function, and processing speed. Differences in brain structure are associated with each pro \201 le, wi th increasing abnormalities in temporal and extratemporal cortical thickness and decreasing volumes of the subcortical structures (hippocampus, thalamus, basal ganglia) dis- tinguish ing the cognitive phenotypes in a broadly step-wise fashion, according to the extent of the neuropsychological de \201 cits ( 17 ). In the Standard And New Antiepileptic Drugs (SANAD) study, researchers in Liverpool, UK exa mined the neuropsychological pro \201 les of 155 newly diagnosed people with epilepsy, bef ore they had started any treatments ( 12 ). They found that newly diagnosed patients with e pilepsy performed more poorly than healthy con- trols on six of 14 cognitive measures, with memory functions and psychomotor speed particularly affected. Cognitive performance was no t related to the type of epilepsy diagnosed or measures of low mood. The researchers conclu ded that many newly diagnosed, untreated patients with epilepsy are cognitively compromised before they start taking antiepileptic drugs. This is unsurprising given that the location , type, and extent of brain pathology are all significant factors in determining the associ ated cognitive dif \201 culties. Although it is in its infancy at present, this phenotypical approach may have important imp lications for the counseling of TLE patients regarding changes in cognition over time and a lso for the interpretation of the global declines in function often seen clini- cally in pa tients who have been followed for many years. Temporal lobe pathology The mesial temporal structures play a critical role in the learning and consolidation of new material. In patients with hippocampal sclerosis (one of the most common pathologies seen in focal tem- poral lobe epilepsies) the extent of hippocampal vol ume loss in the dominant hemisphere, quanti \201 ed using magnetic resonance imag- ing vol umetry, correlates with scores on tests of verbal learning and recall. These correlations h ave been corroborated with postopera- tive cell counting studies that have found signi \201 cant correlations between the neuronal densities in resected hippocampal specimens and preoperative scores on verbal memory tests. See Baxendale for a review ( 13 ). Whilst the role of the hippocampi in memory function has long been recognized, Saling has recently pre sented a persuasive argument that the perirhinal cortex is also a key node in a more extens ive memory network ( 14 ). Frontal lobe pathology Whilst people with frontal lobe epilepsy (FLE) may achieve comparabl e scores on formal tests of learning and recall to their counterparts with a temporal focus , their performance is often qualitatively very different. Frontal lesions are associated w ith dif- \201 culties in placing past events in order, or within the correct time frame. Confabulation and intrusions may be prominent, when recall of the original material is weak . Thus the FLE patient may be able to provide a fulsome (albeit inaccurate) recount of a st ory they have just heard, in stark contrast to TLE patients, who are often unable to provid e much detail and who are generally very aware of their poor recall. Recall is not always d isrupted in FLE. In some cases, recognition memory can be impaired in the context of intact recall abilities. This may be due to interference from distraction items in recognition me mory tests. Dif \201 culties in recalling the source of new information (the where, when, and how you learned something new) are also associated with frontal lobe disturbance. The material-speci \201 c model of memory function has been a dominant concept in the neur opsychological understanding of memory function for over 50 years ( 15 ). Based on postoper ative studies of early epilepsy surgery patients, this model postulates that verbal memory functions are associated with the dominant medial structures whilst non-verbal memory funct ions are associated with non-dominant mesial structures. However, this model has recently b een challenged on both theoretical and clinical grounds following critical re-evaluations o f the classic literature often cited in support of the model ( 14 , 15 ). The verbal versus non-verbal specialisms of the mesial temporal structures where they do exist, are just tha t \200\224 specialisms, they do not represent exclusive functions. Thus is it Cahn-Weiner et al. ( 18 ) compared the memory and executive functions of FLE and TLE patien ts on cognitively-based daily living tasks. They expected the TLE patients to be more impai red on memory tasks, whilst the FLE patients would be more impaired on tests that employed executive function. However, they did not \201 nd this double dissociation, but rather bo th groups were signi \201 cantly CHAPTER 36 epilepsy: cognition and memory in adults 369 Adapted from Baxendale et al (2010) (20) 45 Males RHS 40 Females RHS Males LHS Females LHS 35 n o i t a u p o p 30 l l a m r o n n 25 i k n a r 20 e l i t n e c r e P 15 10 5 0 Naming Verbal learning Verbal retention Visual learning Verbal IQ Visual retention Performance IQ Fig. 36.1 Mean scores of patients with unilateral hippocampal sclerosis (n = 417) on standa rdized neuropsychological tests of intellect, learning, memory, and language, plotted again st the percentile rank of healthy controls. Adapted from Baxendale et al. ( 20 ). recognition ( 19 ). However, gender may play a role in mediating the effects of underlying pathology on cognitive function, and females with left-sided hippocampal sclerosis may be p articularly vulnerable to more widespread cognitive dysfunction beyond the memory domain ( 20 ). impaired on the memory tasks whilst their executive function scores fell within normal limi ts. Language problems were also found in both groups. The authors concluded that a wide ran ge of cognitive problems were found in both groups, despite the appar- ent focal nature of their pathology. Etiology Whilst the focus of much early research was on the effects of the location of the underlying lesion in epilepsy, clinicians and researchers have recently begun to appreciate that the nature of the lesion may play just as important a role in shaping the characteris - tics and extent of any associated neuropsychological de \201 cit. Very early development al lesions, such as dysembroplastic neuroepithe- lial tumors (DNET), and other forms of cor tical dysplasia may be associated with relatively little cognitive disturbance as cognitive functions are reorganized during subsequent cognitive develop- ment. However, fast-growing tumors that occur in an adult brain that has developed normally can have a devastating imp act on neigh- bouring cortical functions. Thus similar-sized lesions, in the same location, can have a very different impact on cognitive function in different patients dependent on the etiology of the pathology. Fluid factors Seizure control can have a signi \201 cant impact on cognitive func- tion. C lusters of seizures may lead to temporarily reduced memory function and a reduced attention span. The proximity of a seizure to a neuropsychological assessment may have a signi \201 cant impact on the results. Nocturnal seizures disrupt sleep patterns, which can decrease cognitive ef \201 ciency the following day. Interictal subclinical electro- encephalogram (EEG) disturbances can signi \201 cantly interfere with normal brain function. Disruptions in cognitive processing cons e- quent on these otherwise subclinical abnormalities are sometimes detected when neuropsyc hological testing is conducted during a routine EEG recording. Low mood and anxiety (common comorbidities in epilepsy) are associated with reduced learnin g capacity and increased dif \201 culties in recall. Mood disturbance is also a signi \201 cant factor in self-reported memory function. Salas-Puig et al. ( 1 ) examined the con tribution of clinical and demographic factors to scores on a memory complaint questionnaire . They found that measures of anxiety and depression explained over a third of the variance in the self-perception of In the general population, women generally have better verbal abilities than men and this p attern appears to hold for women with epilepsy, whose verbal memory de \201 cits may not b e as marked as those observed in matched male groups. Female epilepsy patients also have a gender advantage over males in delayed facial oxford textbook of epilepsy and epileptic seizures 370 postoperative seizures on memory function is complex following surgery ( 32 \200\22336 ), t here are some patients who suffer the \200\230double whammy \200\231 of a signi \201 cant postoperative deterioration of memory functions and ongoing seizures following surgery. Th e lifetime risk of developing an amnesic syndrome is increased following surgery if the con tralateral hippocampal structures become damaged fol- lowing an episode of status or a seve re cluster of seizures. This is not just a theoretical risk; a number of such case studies have been reported in the literature ( 37 \200\22339 ). memory disturbance. Independent of formal neuropsychological test results, patients \200 \231 perceptions of cognitive dif \201 culties are also sig- ni \201 cantly correlated wi th measures of quality of life in epilepsy ( 21 ).