YEBEH-04687; No of Pages 4 Epilepsy & Behavior xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Epilepsy treatment and creativity Sarah Zubkov, Daniel Friedman ⁎ Comprehensive Epilepsy Center, New York University Langone Medical Center, 223 East 34th St, New York, NY 10016, USA
a r t i c l e
i n f o
Article history: Accepted 31 December 2015 Available online xxxx Keywords: Epilepsy Antiepileptic medications Epilepsy surgery Creativity
a b s t r a c t Creativity can be defined as the ability to understand, develop, and express, in a systematic fashion, novel orderly relationships. It is sometimes difficult to separate cognitive skills requisite for the creative process from the drive that generates unique new ideas and associations. Epilepsy itself may affect the creative process. The treatment of epilepsy and its comorbidities, by altering or disrupting the same neural networks through antiseizure drugs (ASDs), treatment of epilepsy comorbidities, ablative surgery, or neurostimulation may also affect creativity. In this review, we discuss the potential mechanisms by which treatment can influence the creative process and review the literature on the consequences of therapy on different aspects of creativity in people with epilepsy. This article is part of a Special Issue entitled “Epilepsy, Art, and Creativity”. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The ability to generate ideas is uniquely human. Diversity of ideas in our society can be attributed, in part, to a wide range of genetic expressions and life experiences. It has also been well documented that diseases of the brain and/or mind can influence creativity. However, the impact of treatment of these disorders is less well studied and is the subject of this review. 2. Creativity in epilepsy Creativity can be defined as the ability to understand, develop, and express, in a systematic fashion, novel orderly relationships [1]. In the scientific study of creativity, one must objectify creative expression to draw standardized comparisons. It is sometimes difficult to separate cognitive skills requisite for the creative process from the drive that generates unique new ideas and associations. A combination of both talent and motivation fuels creativity [1,2]. In considering the effects of treatment of neurological illness on creativity, more evidence exists for an impact on motivation, mediated by subcortical circuits, than for effects on talent, likely mediated by cortical networks. In addition, a certain degree of cognition is required for the creative process [3]. Creative artwork, for example, be it painting, sculpture, or music, requires an understanding of the individual components of the whole and how they fit together and builds on these principles in an original and/or unusual way. Dissociating the effects of the disorder or its treatment on creativity from effects on the expression of the creative process such as ⁎ Corresponding author. Tel.: +1 646 558 0868, fax: +1 646 385 7164. E-mail addresses: [email protected] (S. Zubkov), [email protected] (D. Friedman).
drawing, music perception, playing an instrument, or writing is challenging, making studies of creativity difficult to design and interpret. Before considering the effects of epilepsy treatment on the creative process, it is worthwhile to note that epilepsy itself may affect creativity in multiple domains. For example, one study found that patients with epilepsy demonstrated poor control over drawing, making disorganized lines [4]. In addition, patients with temporal lobe epilepsy (TLE) and complex partial seizures produced drawings with highly detailed individual components that were not well related to one another. Children with epilepsy were found to draw less-developed human figures than normal for their chronological age, with impaired selfconcept, distorted body image, low self-esteem, and a sense of vulnerability and lack of control [5]. Creativity depends, in part, on motivation, i.e., an inner drive to produce. Geschwind's description of an interictal behavioral syndrome in patients with temporal lobe epilepsy included hypergraphia, increased religiosity, and philosophical concerns (as well as hyposexuality and aggression) [6]. Though hypergraphia itself does not necessarily imply creative output, the increased productivity raises the chance that a percentage of the output will be deemed creative. Hypergraphia may be responsible for prolific writings of people with epilepsy (Fyodor Dostoevsky is a prominent example). 3. Anatomy of creativity Creativity involves processing diffuse heteromodal, or higher-order, outputs, which is most understood to occur in the frontal and temporal lobes [2,7,8]. The frontal lobes have both facilitatory and inhibitory effects on creative processing. They are involved in motivation, planning, and interpretation of stimuli [7]. As mentioned above, the creative innovator must think in a different direction than what is accepted, a process
http://dx.doi.org/10.1016/j.yebeh.2015.12.048 1525-5050/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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S. Zubkov, D. Friedman / Epilepsy & Behavior xxx (2016) xxx–xxx
termed divergent thinking [1]. One measure of creativity is the “brick test”, in which subjects must come up with as many uses of a brick as they can think of, both common and uncommon. Subjects who thought of more uses of a brick were found to have more activation of their frontal lobes [9]. Functional MRI studies have implicated the inferior prefrontal cortex in idea generation during creative tasks, as well as the default mode network, which is active during internal thought, mental imagery, and mind wandering, and which consists of the medial prefrontal cortex, posterior cingulate cortex, precuneus, and bilateral inferior parietal lobes [10]. The frontal lobe networks are also important for initiating actions; lesions to the frontal lobes result in apathy and depression. The frontal lobes, in turn, project broadly to areas of higherorder processing in the temporal and parietal lobes, perhaps inhibiting commonly used connections and favoring alternate pathways [1]. The temporal lobes process sensory output from association cortices adjacent to the primary cortex, assigning meaning [11] and emotion [8], the latter via limbic connections. The argument that TLE may be linked with creativity is based upon the observation in some cases and speculation in others that important writers, musicians, and visual artists have suffered from epilepsy [8,12–14]. While TLE best fits the description of strong emotion, déjà vu, hallucinations, delusions, and other symptoms of psychosis that many artists have described, little to no proof of diagnosis exists in most cases. However, there are fundamental properties of TLE that may foster creativity. Firstly, neurochemical lability in epilepsy may be the neural correlate of cognitive overinclusiveness (or increased associations between seemingly unrelated concepts), leading to original and unusual yet useful ideas [8]. Secondly, interictal limbic discharges may lead to emotionalization of internal and external stimuli via a process similar to kindling in animal models of epilepsy [8,15]. Thus, TLE may promote unusual relationships between concepts while simultaneously infusing emotion and meaningfulness into them. It follows that disruption of neural activity in the temporal lobes may affect processing of sensory inputs. Snyder [16] reported on the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the dominant anterior temporal lobe. Low-frequency rTMS creates virtual lesions by transiently disrupting neural activity in the region to which it is applied [17]. When applied to the dominant anterior temporal lobe of healthy subjects, rTMS can induce savant skills such as realistic drawing. The implication is that disrupting activity in the left temporal lobe allows for the bottom-up processing that savants rely on to produce incredibly detailed drawings [16]. Temporal lobe rTMS has also led to improved error detection in proofreading and an increased ability to accurately estimate the size of a large number of objects. The temporal lobes, in turn, project reciprocal inhibitory connections to the frontal lobes [2]. Thus, a temporal lobe lesion can result in frontal disinhibition, resulting in increased generation of ideas that may be suboptimally judged [2]. Such is the case in Wernicke's aphasia, where patients produce prolific, yet meaningless, speech. 4. Medical treatment of the epilepsies and creativity Geschwind proposed that antiseizure drugs (ASDs) should not diminish the traits of the interictal syndrome he described [6], as the treatment does not restore the function of the disordered temporal lobe network involved in the seizure focus. However, his proposal is purely speculative. In fact, ASDs, by reducing the frequency and severity of seizures, may limit the degree of temporal lobe neuronal injury and volume loss, preserving limbic function. Several authors have proposed that low arousal states are associated with creativity [1,18]. An experiment where subjects were given either ephedrine or propranolol, a centrally-acting beta-blocker, before solving anagrams revealed that those treated with the latter outperformed the former [18]. Sympathomimetic agents provoke a “fight-or-flight” response, attuning us to stimuli in the external world while dampening
internal signals. Notably, the frontal lobes, in addition to promoting setshifting responses, project to the locus coeruleus, inhibiting widespread norepinephrine release [19], another mechanism by which frontal activity may foster creativity. Although some ASDs, such as benzodiazepines and barbiturates, lower arousal, they can also lower motivation, making them counterproductive to the creative process. However, no studies examining the effects of individual ASDs on the creative process have been performed. 5. Medical treatment of epilepsy comorbidities and creativity Psychiatric disorders are significant comorbidities of epilepsy. People with epilepsy have high rates of depression, anxiety, and postictal and interictal psychotic symptoms [20]. Psychiatric comorbidities themselves may influence creativity. Hermann [21] studied 50 patients, 84% of whom had temporal lobe epilepsy, and rated their writing to determine whether they displayed traits of hypergraphia. The degree of hypergraphia was significantly inversely correlated with age of onset and directly correlated with disease duration. Additionally, severity of depression was inversely correlated, and severity of hypomania was directly correlated with the rating of hypergraphia. Treatment of psychiatric comorbidities may alter the creative process. Selective serotonin reuptake inhibitors (SSRIs) can foster creativity, as may be the case in patients with severe depression [2,22]. However, in some cases, SSRIs can also hinder goal-directed activity via inhibition of the dopaminergic system [20,23]. Therefore, treatment with SSRIs may also lead to apathy [24]. Antipsychotic medications, commonly used to treat interictal and postictal psychotic symptoms, can also influence creative behavior. Dopamine pathways play a central role in motivation behaviors. The dopaminergic system is involved in mania, compulsive gambling, and substance abuse; it drives action without judgmental thinking. An elevated dopaminergic state would be expected to cause generation of ideas without the screen of meaningfulness. Treatment with dopamine agonists can lead to increase in motivation; however, the work produced may differ from the patient's original interests [25,26]. For example, one man who developed Parkinson's disease changed his painting style from realistic to more impressionistic after starting a dopamine agonist [25]. Conversely, traditional neuroleptics may lead to a decrease in creativity. Atypical antipsychotics improve negative symptoms, allowing for creative work to flourish [25]. Other mood-stabilizing or antidepressant medications, such as lamotrigine, bupropion, or mirtazapine, may be better alternatives to preserve creativity in patients with psychiatric symptoms [2]. One case series [27] reported cognitive dulling, apathy, and loss of “spark” in seven patients on lithium, which improved after they were partially or fully switched to divalproex sodium. 6. Surgical treatment of the epilepsies and creativity As the anatomical substrates of creativity, the temporal and frontal lobe are also the most common location of the epileptogenic zone, and it is reasonable to postulate that ablative epilepsy surgery may alter the creative process. Only a few case series examining the effects of epilepsy surgery on the creative process exist. 6.1. Corpus callosotomy Because creative expression requires simultaneous use of the brain's specialized regions, epilepsy and its treatment, particularly through ablative surgery, may disrupt the creative process. In addition, as interactions between cortical regions are important for associations of seemingly unrelated concepts, the generation of novel ideas may rely to some extent on intact white matter tracts both within and between cerebral hemispheres. Early conceptual models of creativity postulated that the right hemisphere fostered creativity while the left worked to inhibit it
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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[28]. In this scenario, corpus callosotomy would be expected to increase creativity, as the right hemisphere is protected against the suppressive effects of the left hemisphere. However, these patients have been found to be less creative. For example, when asked to describe an emotionally evocative film, patients who had undergone cerebral commissurotomy used significantly fewer affective words, expressed themselves more passively, and tended not to interpret symbols [29]. The authors concluded that these patients were unimaginative because of poor cerebral connectivity. These findings suggest that white matter tracts, in particular the corpus callosum, play a role in the creative process by uniting various regions of the brain. 6.2. Anterior temporal lobectomy A small case series examined the effects of the laterality of anterior temporal lobectomy (ATL) on different aspects of creativity in 18 right-handed subjects with treatment-resistant TLE [30]. Six months following either right or left ATL, the subjects were administered the verbal and figural subtests of the Torrance Test of Creative Thinking. In the verbal subtests, subjects had to describe what was occurring in a drawing, list how to improve a toy depicted in a drawing, and come up with unusual uses for objects such as a brick or piece of cardboard. In the figural subtests, subjects were asked to make significant pictures out of incomplete figures and name them. There was no significant effect of side of surgery on overall creativity, nor was there an interaction between the side of surgery and the type of creativity. However, patients who had undergone right ATL had higher figural than verbal creativity scores. The authors questioned whether right TLE itself had led to increased figural creativity. They reasoned that focal epilepsies involve synchronous activation of different brain regions, potentially facilitating connections between areas that would not normally work together. It is also worth noting that because there was no preresection testing, one cannot draw any conclusions on the effects of the surgery itself on creativity. In assessing the impact of epilepsy surgery on the creative process, one must be careful to distinguish the ability to generate new ideas and associations important to the art-making process from the cognitive skills required to make the art. For instance, innovation in playing or composing music requires the ability to understand pitch, timbre, tempo, and rhythm and epilepsy surgery may affect these perceptual abilities. Kester and colleagues [31] studied 21 right-handed musically inexperienced patients with unilateral TLE who underwent ATL and compared them with healthy controls, also musically inexperienced. Prior to resection and two weeks afterwards, subjects underwent the Musical Aptitude Profile, or MAP, a seven-subtest exam designed to quantify tonal imagery (melody and harmony), rhythm imagery (tempo and meter), and musical sensitivity (phrasing, balance, and style). Prior to ATL, subjects with epilepsy performed below the level of the control subjects in overall musical processing, suggesting that TLE itself impairs musical ability. Patients who underwent right ATL performed worse on the tempo, meter, and style subtests of the MAP than those who underwent left ATL. The authors postulated that in musically inexperienced individuals, these aspects of music might be analogous to the prosody of speech, which also localizes to the right hemisphere, and these patients are at risk of decline in music processing skills following right ATL. In another study of the effects of ATL on musical perception, Zatorre and Halpern [32] studied 28 patients with epilepsy with left hemispheric language-dominance who had undergone temporal lobectomy (14 in each side) and compared them with 14 control subjects. Most were musical novices. Everyone was shown lyrics to a familiar song and asked to judge whether a highlighted word was higher or lower in pitch than another, either while actually listening to the song or imagining it. Overall, subjects performed worse on the second task. The subjects who had undergone right ATL performed significantly worse on both tasks than either the control or the left ATL subjects, who did not
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perform significantly different from one another. The study implicated an important role of the right temporal lobe in pitch judgment, though likely other areas such as the prefrontal cortex, particularly on the right, are involved. 6.3. Tailored temporal resection Single case reports constitute much of the literature on the effect of surgical treatment of epilepsy on creativity. Sellal and colleagues [33] described an 18-year-old right-handed man with intractable epilepsy due to a left inferior temporal gyrus ganglioglioma who experienced a significant change in esthetic tastes following a resection of the left anterior pole, middle temporal gyrus, inferior temporal gyrus, and fusiform gyrus, sparing the mesial temporal cortex. In the year following surgery, he could no longer stand to listen to the rock music that he had enjoyed preoperatively, complaining it was “too hard, too fast, and too violent.” Instead, he preferred Celtic or Corsican polyphonic singing. Likewise, he shunned his former taste for science fiction in favor of novels and developed an interest in the fine detail of realistic paintings. Otherwise, his personality remained unchanged, and his verbal IQ and performance IQ improved. He was surprised by and complained about his new artistic preferences, as he now had difficulty fitting in with his friends. The authors postulated that his new artistic preferences were the consequence of altered connections between neocortical areas involved in object processing and mesial structures involved in emotional labeling. 6.4. Frontal lobectomy McChesney-Atkins and colleagues [34] described a 31-year-old right-handed choir director with no formal musical training who lost his ability to musically express himself following right posterior parasagittal frontal lobectomy for intractable seizures. He was unable to sing familiar, simple songs. While he could neither produce pitch or rhythm accurately, he could understand pitch relationships, identify known songs and errors, if present, in their tunes, and discriminate between tempi, changes in volume, and articulation. He also had preserved prosody in spoken speech. The authors proposed that the right posterior parasagittal frontal lobe is important in musical expression and serves a distinct function from prosody of spoken language. While this alteration in musical expression might have gone unnoticed by most, it would be of particular importance to a musician relying on these creative abilities. 7. Neurostimulation and creativity Neurostimulation is another treatment option for some individuals with refractory epilepsy. Neurostimulation is thought to modulate the neural networks underlying the seizure focus, either directly or through activation of brainstem/subcortical structures with widespread projections to the cortex [35]. It is possible that this modulation can also influence networks underlying creativity. 7.1. Vagus nerve stimulation Vagus nerve stimulation (VNS) is an effective adjunctive treatment for refractory epilepsy [36]. The exact mechanism by which it helps reduce seizure frequency is unclear, though it is postulated to act via several central pathways and neurotransmitter systems to modulate cortical hyperexcitability [37]. Vagus nerve stimulation was found to reduce creativity and cognitive flexibility, without any evidence of causing a superimposed encephalopathy, in ten subjects who had had VNS implanted at least 3 months prior to testing [37]. The authors postulated that VNS stimulation leads to upregulation of widespread cortical norepinephrine release, heightening sensitivity to external stimuli but
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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reducing the internal cerebral connectivity that has been postulated as critical for the creative process [1,16,37]. 7.2. Deep brain stimulation Flaherty [2,38] additionally reported that deep brain stimulation (DBS) targeting the anterior internal capsule for treatment of obsessive compulsive disorder or Tourette syndrome affected mood. High-voltage stimulation of leads near the nucleus accumbens produced apathy and depression, whereas high-voltage stimulation of leads in the body of the internal capsule produced hypomania. It is unknown whether targeting other structures with DBS, such as the anterior nucleus of the thalamus for epilepsy treatment [39], can impact creativity. 8. Conclusions Any mechanism affecting chemical and structural connectivity in the brain has the potential to affect cognition, motivation, talent, and, therefore, creativity. While epilepsy itself may affect the content and mode of artistic expression, the same has not been shown for nonsedating antiepileptic medications. Epilepsy surgery, on the other hand, has the potential to affect or even disrupt the creative process. While some reports point to improved memory and intelligence following right temporal lobectomy, the opposite may be true for musical interpretation, especially in musically inexperienced individuals. In rare cases, tailored right frontal and left temporal resections have affected musical perception and tastes. Neurostimulation also has the potential to alter cortical, subcortical, and brainstem networks, and, thus, creativity. There is some evidence that VNS may impair the creative process, while DBS of the anterior internal capsule or nucleus accumbens may alter mood and, by extension, creativity. Further research is needed to guide general principles. However, the broad range of disease pathology and creative expression, as well as the diversity of treatment options, will ultimately require an individualized approach when addressing the potential complications of epilepsy treatment. Disclosures S.Z. and D.F. have no relevant disclosures. References [1] Heilman KM, Nadeau SE, Beversdorf DO. Creative innovation: possible mechanisms. Neurocase 2003;9:369–79. [2] Flaherty AW. Brain illness and creativity: mechanisms and treatment risks. Can J Psychiatry 2011;56:132–43. [3] Kalbfleisch ML. Functional neuroanatomy of talent. Anat Rec B New Anat 2004;277: 21–36. [4] Anschel DJ, Dolce S, Schwartzman A, Fisher RS. A blinded study of artwork in a comprehensive epilepsy center population. Epilepsy Behav 2005;6:196–202. [5] Stafstrom CE, Havlena J. Seizure drawings: insight into the self-image of children with epilepsy. Epilepsy Behav 2003;4:43–56. [6] Geschwind N. Interictal behavioral changes in epilepsy. Epilepsia 1983;24(Suppl. 1): S23–30. [7] Bogousslavsky J. Artistic creativity, style, and brain disorders. Eur Neurol 2005;54: 103–11. [8] Cartwright M, Clark-Carter D, Ellis SJ, Matthews C. Temporal lobe epilepsy and creativity: a model of association. Creat Res J 2004;16:27–34.
[9] Carlsson I, Wendt PE, Risberg J. On the neurobiology of creativity. Differences in frontal activity between high and low creative subjects. Neuropsychologia 2000;38: 873–85. [10] Beaty RE, Benedek M, Wilkins R, Jauk E, Fink A, Silvia PJ, et al. Creativity and the default network: a functional connectivity analysis of the creative brain at rest. Neuropsychologia 2014;64:92–8. [11] Spitsyna G, Warren JE, Scott SK, Turkheimer FE, Wise RJS. Converging language streams in the human temporal lobe. J Neurosci 2006;26:7328–36. [12] Bryant JE. Genius and epilepsy: brief sketches of twenty great men who had both. Concord, MA: Ye Old Depot Press; 1953. [13] Thomas RH, Mullins JM, Waddington T, Nugent K, Smith PEM. Epilepsy: creative sparks. Pract Neurol 2010;10:219–26. [14] Schachter SC. The visual art of contemporary artists with epilepsy. Int Rev Neurobiol 2006;74:119–31. [15] Bear DM. Temporal lobe epilepsy — a syndrome of sensory-limbic hyperconnection. Cortex 1979;15:357–84. [16] Snyder A. Explaining and inducing savant skills: privileged access to lower level, less-processed information. Philos Trans R Soc B 2009;364:1399–405. [17] Walsh V, Cowey A. Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci 2000;1:73–9. [18] Beversdorf GQ, Hughes JD, Steinberg BA, Lewis LD, Heilman KM. Noradrenergic modulation of cognitive flexibility in problem solving. NeuroReport 1999;10: 2763–7. [19] Sara SJ, Herve-Minvielle A. Inhibitory influence of frontal cortex on locus coeruleus neurons. Proc Natl Acad Sci 1995;92:6032–6. [20] Verrotti A, Carrozzino D, Milioni M, Minna M, Fulcheri M. Epilepsy and its main psychiatric comorbidities in adults and children. J Neurol Sci 2014;343:23–9. [21] Hermann BP, Whitman S, Wyler AR, Richey ET, Dell J. The neurological, psychosocial and demographic correlates of hypergraphia in patients with epilepsy. J Neurol Neurochir Psychiatr 1988;51:203–8. [22] Bolling MY, Kohlenberg RJ. Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patient satisfaction. Psychother Psychosom 2004;73:380–5. [23] Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic transmission of dopamine neurotransmission. Pharmacol Ther 2007;113:296–320. [24] Barnhart WJ, Latocha Makela EH, MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract 2004;10:196–9. [25] Kulisevsky J, Pagonabarraga J, Martinez-Corral M. Changes in artistic style and behavior in Parkinson’s disease: dopamine and creativity. J Neurol 2009;256:816–9. [26] Walker RH, Warwick R, Cercy SP. Augmentation of artistic productivity in Parkinson’s disease. Mov Disord 2006;21:285–6. [27] Stoll AL, Locke CA, Vuckovic A, Mayer PV. Lithium-associated cognitive and functional deficits reduced by a switch to divalproex sodium: a case series. J Clin Psychiatry 1996;57:356–9. [28] Zaidel DW. Split-brain, the right hemisphere, and art: fact and fiction. Prog Brain Res 2013;204:3–17. [29] Hoppe KD. Hemispheric specialization and creativity. Psychiatr Clin N Am 1988;11: 303–15. [30] Ghacibeh GA, Heilman KM. Creative innovation with temporal lobe epilepsy and lobectomy. J Neurol Sci 2013;324:45–8. [31] Kester DB, Saykin AJ, Sperling MR, O’Connor MJ, Robinson LJ, Gur RC. Acute effect of anterior temporal lobectomy on musical processing. Neuropsychologia 1991;29: 703–8. [32] Zatorre RJ, Halpern AR. Effect of unilateral temporal-lobe excision on perception and imagery of songs. Neuropsychologia 1993;31:221–32. [33] Sellal F, Andriantseheno M, Vercueil L, Hirsch E. Dramatic changes in artistic preference after left temporal lobectomy. Epilepsy Behav 2003;4:449–51. [34] McChesney-Atkins S, Davies KG, Montouris GD, Silver JT, Menkes DL. Amusia after right frontal resection for epilepsy with singing seizures: case report and review of the literature. Epilepsy Behav 2003;4:343–7. [35] Fisher RS, Velasco AL. Electrical brain stimulation for epilepsy. Nat Rev Neurol 2014; 10:261–70. [36] The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45:224–30. [37] Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM. Effect of vagus nerve stimulation on creativity and cognitive flexibility. Epilepsy Behav 2006;8:720–5. [38] Flaherty AW, Williams ZM, Amirnovin R, Kasper E, Rauch SL, Cosgrove GR, Eskandar EN. Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report. Neurosurgery 2005;57(Suppl. 3):E403. [39] Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, et al. Electrical stimulation of the anterior nucleus of the thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908.
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Epilepsy treatment and creativity Sarah Zubkov, Daniel Friedman ⁎ Comprehensive Epilepsy Center, New York University Langone Medical Center, 223 East 34th St, New York, NY 10016, USA
a r t i c l e
i n f o
Article history: Accepted 31 December 2015 Available online xxxx Keywords: Epilepsy Antiepileptic medications Epilepsy surgery Creativity
a b s t r a c t Creativity can be defined as the ability to understand, develop, and express, in a systematic fashion, novel orderly relationships. It is sometimes difficult to separate cognitive skills requisite for the creative process from the drive that generates unique new ideas and associations. Epilepsy itself may affect the creative process. The treatment of epilepsy and its comorbidities, by altering or disrupting the same neural networks through antiseizure drugs (ASDs), treatment of epilepsy comorbidities, ablative surgery, or neurostimulation may also affect creativity. In this review, we discuss the potential mechanisms by which treatment can influence the creative process and review the literature on the consequences of therapy on different aspects of creativity in people with epilepsy. This article is part of a Special Issue entitled “Epilepsy, Art, and Creativity”. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The ability to generate ideas is uniquely human. Diversity of ideas in our society can be attributed, in part, to a wide range of genetic expressions and life experiences. It has also been well documented that diseases of the brain and/or mind can influence creativity. However, the impact of treatment of these disorders is less well studied and is the subject of this review. 2. Creativity in epilepsy Creativity can be defined as the ability to understand, develop, and express, in a systematic fashion, novel orderly relationships [1]. In the scientific study of creativity, one must objectify creative expression to draw standardized comparisons. It is sometimes difficult to separate cognitive skills requisite for the creative process from the drive that generates unique new ideas and associations. A combination of both talent and motivation fuels creativity [1,2]. In considering the effects of treatment of neurological illness on creativity, more evidence exists for an impact on motivation, mediated by subcortical circuits, than for effects on talent, likely mediated by cortical networks. In addition, a certain degree of cognition is required for the creative process [3]. Creative artwork, for example, be it painting, sculpture, or music, requires an understanding of the individual components of the whole and how they fit together and builds on these principles in an original and/or unusual way. Dissociating the effects of the disorder or its treatment on creativity from effects on the expression of the creative process such as ⁎ Corresponding author. Tel.: +1 646 558 0868, fax: +1 646 385 7164. E-mail addresses: [email protected] (S. Zubkov), [email protected] (D. Friedman).
drawing, music perception, playing an instrument, or writing is challenging, making studies of creativity difficult to design and interpret. Before considering the effects of epilepsy treatment on the creative process, it is worthwhile to note that epilepsy itself may affect creativity in multiple domains. For example, one study found that patients with epilepsy demonstrated poor control over drawing, making disorganized lines [4]. In addition, patients with temporal lobe epilepsy (TLE) and complex partial seizures produced drawings with highly detailed individual components that were not well related to one another. Children with epilepsy were found to draw less-developed human figures than normal for their chronological age, with impaired selfconcept, distorted body image, low self-esteem, and a sense of vulnerability and lack of control [5]. Creativity depends, in part, on motivation, i.e., an inner drive to produce. Geschwind's description of an interictal behavioral syndrome in patients with temporal lobe epilepsy included hypergraphia, increased religiosity, and philosophical concerns (as well as hyposexuality and aggression) [6]. Though hypergraphia itself does not necessarily imply creative output, the increased productivity raises the chance that a percentage of the output will be deemed creative. Hypergraphia may be responsible for prolific writings of people with epilepsy (Fyodor Dostoevsky is a prominent example). 3. Anatomy of creativity Creativity involves processing diffuse heteromodal, or higher-order, outputs, which is most understood to occur in the frontal and temporal lobes [2,7,8]. The frontal lobes have both facilitatory and inhibitory effects on creative processing. They are involved in motivation, planning, and interpretation of stimuli [7]. As mentioned above, the creative innovator must think in a different direction than what is accepted, a process
http://dx.doi.org/10.1016/j.yebeh.2015.12.048 1525-5050/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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termed divergent thinking [1]. One measure of creativity is the “brick test”, in which subjects must come up with as many uses of a brick as they can think of, both common and uncommon. Subjects who thought of more uses of a brick were found to have more activation of their frontal lobes [9]. Functional MRI studies have implicated the inferior prefrontal cortex in idea generation during creative tasks, as well as the default mode network, which is active during internal thought, mental imagery, and mind wandering, and which consists of the medial prefrontal cortex, posterior cingulate cortex, precuneus, and bilateral inferior parietal lobes [10]. The frontal lobe networks are also important for initiating actions; lesions to the frontal lobes result in apathy and depression. The frontal lobes, in turn, project broadly to areas of higherorder processing in the temporal and parietal lobes, perhaps inhibiting commonly used connections and favoring alternate pathways [1]. The temporal lobes process sensory output from association cortices adjacent to the primary cortex, assigning meaning [11] and emotion [8], the latter via limbic connections. The argument that TLE may be linked with creativity is based upon the observation in some cases and speculation in others that important writers, musicians, and visual artists have suffered from epilepsy [8,12–14]. While TLE best fits the description of strong emotion, déjà vu, hallucinations, delusions, and other symptoms of psychosis that many artists have described, little to no proof of diagnosis exists in most cases. However, there are fundamental properties of TLE that may foster creativity. Firstly, neurochemical lability in epilepsy may be the neural correlate of cognitive overinclusiveness (or increased associations between seemingly unrelated concepts), leading to original and unusual yet useful ideas [8]. Secondly, interictal limbic discharges may lead to emotionalization of internal and external stimuli via a process similar to kindling in animal models of epilepsy [8,15]. Thus, TLE may promote unusual relationships between concepts while simultaneously infusing emotion and meaningfulness into them. It follows that disruption of neural activity in the temporal lobes may affect processing of sensory inputs. Snyder [16] reported on the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the dominant anterior temporal lobe. Low-frequency rTMS creates virtual lesions by transiently disrupting neural activity in the region to which it is applied [17]. When applied to the dominant anterior temporal lobe of healthy subjects, rTMS can induce savant skills such as realistic drawing. The implication is that disrupting activity in the left temporal lobe allows for the bottom-up processing that savants rely on to produce incredibly detailed drawings [16]. Temporal lobe rTMS has also led to improved error detection in proofreading and an increased ability to accurately estimate the size of a large number of objects. The temporal lobes, in turn, project reciprocal inhibitory connections to the frontal lobes [2]. Thus, a temporal lobe lesion can result in frontal disinhibition, resulting in increased generation of ideas that may be suboptimally judged [2]. Such is the case in Wernicke's aphasia, where patients produce prolific, yet meaningless, speech. 4. Medical treatment of the epilepsies and creativity Geschwind proposed that antiseizure drugs (ASDs) should not diminish the traits of the interictal syndrome he described [6], as the treatment does not restore the function of the disordered temporal lobe network involved in the seizure focus. However, his proposal is purely speculative. In fact, ASDs, by reducing the frequency and severity of seizures, may limit the degree of temporal lobe neuronal injury and volume loss, preserving limbic function. Several authors have proposed that low arousal states are associated with creativity [1,18]. An experiment where subjects were given either ephedrine or propranolol, a centrally-acting beta-blocker, before solving anagrams revealed that those treated with the latter outperformed the former [18]. Sympathomimetic agents provoke a “fight-or-flight” response, attuning us to stimuli in the external world while dampening
internal signals. Notably, the frontal lobes, in addition to promoting setshifting responses, project to the locus coeruleus, inhibiting widespread norepinephrine release [19], another mechanism by which frontal activity may foster creativity. Although some ASDs, such as benzodiazepines and barbiturates, lower arousal, they can also lower motivation, making them counterproductive to the creative process. However, no studies examining the effects of individual ASDs on the creative process have been performed. 5. Medical treatment of epilepsy comorbidities and creativity Psychiatric disorders are significant comorbidities of epilepsy. People with epilepsy have high rates of depression, anxiety, and postictal and interictal psychotic symptoms [20]. Psychiatric comorbidities themselves may influence creativity. Hermann [21] studied 50 patients, 84% of whom had temporal lobe epilepsy, and rated their writing to determine whether they displayed traits of hypergraphia. The degree of hypergraphia was significantly inversely correlated with age of onset and directly correlated with disease duration. Additionally, severity of depression was inversely correlated, and severity of hypomania was directly correlated with the rating of hypergraphia. Treatment of psychiatric comorbidities may alter the creative process. Selective serotonin reuptake inhibitors (SSRIs) can foster creativity, as may be the case in patients with severe depression [2,22]. However, in some cases, SSRIs can also hinder goal-directed activity via inhibition of the dopaminergic system [20,23]. Therefore, treatment with SSRIs may also lead to apathy [24]. Antipsychotic medications, commonly used to treat interictal and postictal psychotic symptoms, can also influence creative behavior. Dopamine pathways play a central role in motivation behaviors. The dopaminergic system is involved in mania, compulsive gambling, and substance abuse; it drives action without judgmental thinking. An elevated dopaminergic state would be expected to cause generation of ideas without the screen of meaningfulness. Treatment with dopamine agonists can lead to increase in motivation; however, the work produced may differ from the patient's original interests [25,26]. For example, one man who developed Parkinson's disease changed his painting style from realistic to more impressionistic after starting a dopamine agonist [25]. Conversely, traditional neuroleptics may lead to a decrease in creativity. Atypical antipsychotics improve negative symptoms, allowing for creative work to flourish [25]. Other mood-stabilizing or antidepressant medications, such as lamotrigine, bupropion, or mirtazapine, may be better alternatives to preserve creativity in patients with psychiatric symptoms [2]. One case series [27] reported cognitive dulling, apathy, and loss of “spark” in seven patients on lithium, which improved after they were partially or fully switched to divalproex sodium. 6. Surgical treatment of the epilepsies and creativity As the anatomical substrates of creativity, the temporal and frontal lobe are also the most common location of the epileptogenic zone, and it is reasonable to postulate that ablative epilepsy surgery may alter the creative process. Only a few case series examining the effects of epilepsy surgery on the creative process exist. 6.1. Corpus callosotomy Because creative expression requires simultaneous use of the brain's specialized regions, epilepsy and its treatment, particularly through ablative surgery, may disrupt the creative process. In addition, as interactions between cortical regions are important for associations of seemingly unrelated concepts, the generation of novel ideas may rely to some extent on intact white matter tracts both within and between cerebral hemispheres. Early conceptual models of creativity postulated that the right hemisphere fostered creativity while the left worked to inhibit it
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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[28]. In this scenario, corpus callosotomy would be expected to increase creativity, as the right hemisphere is protected against the suppressive effects of the left hemisphere. However, these patients have been found to be less creative. For example, when asked to describe an emotionally evocative film, patients who had undergone cerebral commissurotomy used significantly fewer affective words, expressed themselves more passively, and tended not to interpret symbols [29]. The authors concluded that these patients were unimaginative because of poor cerebral connectivity. These findings suggest that white matter tracts, in particular the corpus callosum, play a role in the creative process by uniting various regions of the brain. 6.2. Anterior temporal lobectomy A small case series examined the effects of the laterality of anterior temporal lobectomy (ATL) on different aspects of creativity in 18 right-handed subjects with treatment-resistant TLE [30]. Six months following either right or left ATL, the subjects were administered the verbal and figural subtests of the Torrance Test of Creative Thinking. In the verbal subtests, subjects had to describe what was occurring in a drawing, list how to improve a toy depicted in a drawing, and come up with unusual uses for objects such as a brick or piece of cardboard. In the figural subtests, subjects were asked to make significant pictures out of incomplete figures and name them. There was no significant effect of side of surgery on overall creativity, nor was there an interaction between the side of surgery and the type of creativity. However, patients who had undergone right ATL had higher figural than verbal creativity scores. The authors questioned whether right TLE itself had led to increased figural creativity. They reasoned that focal epilepsies involve synchronous activation of different brain regions, potentially facilitating connections between areas that would not normally work together. It is also worth noting that because there was no preresection testing, one cannot draw any conclusions on the effects of the surgery itself on creativity. In assessing the impact of epilepsy surgery on the creative process, one must be careful to distinguish the ability to generate new ideas and associations important to the art-making process from the cognitive skills required to make the art. For instance, innovation in playing or composing music requires the ability to understand pitch, timbre, tempo, and rhythm and epilepsy surgery may affect these perceptual abilities. Kester and colleagues [31] studied 21 right-handed musically inexperienced patients with unilateral TLE who underwent ATL and compared them with healthy controls, also musically inexperienced. Prior to resection and two weeks afterwards, subjects underwent the Musical Aptitude Profile, or MAP, a seven-subtest exam designed to quantify tonal imagery (melody and harmony), rhythm imagery (tempo and meter), and musical sensitivity (phrasing, balance, and style). Prior to ATL, subjects with epilepsy performed below the level of the control subjects in overall musical processing, suggesting that TLE itself impairs musical ability. Patients who underwent right ATL performed worse on the tempo, meter, and style subtests of the MAP than those who underwent left ATL. The authors postulated that in musically inexperienced individuals, these aspects of music might be analogous to the prosody of speech, which also localizes to the right hemisphere, and these patients are at risk of decline in music processing skills following right ATL. In another study of the effects of ATL on musical perception, Zatorre and Halpern [32] studied 28 patients with epilepsy with left hemispheric language-dominance who had undergone temporal lobectomy (14 in each side) and compared them with 14 control subjects. Most were musical novices. Everyone was shown lyrics to a familiar song and asked to judge whether a highlighted word was higher or lower in pitch than another, either while actually listening to the song or imagining it. Overall, subjects performed worse on the second task. The subjects who had undergone right ATL performed significantly worse on both tasks than either the control or the left ATL subjects, who did not
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perform significantly different from one another. The study implicated an important role of the right temporal lobe in pitch judgment, though likely other areas such as the prefrontal cortex, particularly on the right, are involved. 6.3. Tailored temporal resection Single case reports constitute much of the literature on the effect of surgical treatment of epilepsy on creativity. Sellal and colleagues [33] described an 18-year-old right-handed man with intractable epilepsy due to a left inferior temporal gyrus ganglioglioma who experienced a significant change in esthetic tastes following a resection of the left anterior pole, middle temporal gyrus, inferior temporal gyrus, and fusiform gyrus, sparing the mesial temporal cortex. In the year following surgery, he could no longer stand to listen to the rock music that he had enjoyed preoperatively, complaining it was “too hard, too fast, and too violent.” Instead, he preferred Celtic or Corsican polyphonic singing. Likewise, he shunned his former taste for science fiction in favor of novels and developed an interest in the fine detail of realistic paintings. Otherwise, his personality remained unchanged, and his verbal IQ and performance IQ improved. He was surprised by and complained about his new artistic preferences, as he now had difficulty fitting in with his friends. The authors postulated that his new artistic preferences were the consequence of altered connections between neocortical areas involved in object processing and mesial structures involved in emotional labeling. 6.4. Frontal lobectomy McChesney-Atkins and colleagues [34] described a 31-year-old right-handed choir director with no formal musical training who lost his ability to musically express himself following right posterior parasagittal frontal lobectomy for intractable seizures. He was unable to sing familiar, simple songs. While he could neither produce pitch or rhythm accurately, he could understand pitch relationships, identify known songs and errors, if present, in their tunes, and discriminate between tempi, changes in volume, and articulation. He also had preserved prosody in spoken speech. The authors proposed that the right posterior parasagittal frontal lobe is important in musical expression and serves a distinct function from prosody of spoken language. While this alteration in musical expression might have gone unnoticed by most, it would be of particular importance to a musician relying on these creative abilities. 7. Neurostimulation and creativity Neurostimulation is another treatment option for some individuals with refractory epilepsy. Neurostimulation is thought to modulate the neural networks underlying the seizure focus, either directly or through activation of brainstem/subcortical structures with widespread projections to the cortex [35]. It is possible that this modulation can also influence networks underlying creativity. 7.1. Vagus nerve stimulation Vagus nerve stimulation (VNS) is an effective adjunctive treatment for refractory epilepsy [36]. The exact mechanism by which it helps reduce seizure frequency is unclear, though it is postulated to act via several central pathways and neurotransmitter systems to modulate cortical hyperexcitability [37]. Vagus nerve stimulation was found to reduce creativity and cognitive flexibility, without any evidence of causing a superimposed encephalopathy, in ten subjects who had had VNS implanted at least 3 months prior to testing [37]. The authors postulated that VNS stimulation leads to upregulation of widespread cortical norepinephrine release, heightening sensitivity to external stimuli but
Please cite this article as: Zubkov S, Friedman D, Epilepsy treatment and creativity, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2015.12.048
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reducing the internal cerebral connectivity that has been postulated as critical for the creative process [1,16,37]. 7.2. Deep brain stimulation Flaherty [2,38] additionally reported that deep brain stimulation (DBS) targeting the anterior internal capsule for treatment of obsessive compulsive disorder or Tourette syndrome affected mood. High-voltage stimulation of leads near the nucleus accumbens produced apathy and depression, whereas high-voltage stimulation of leads in the body of the internal capsule produced hypomania. It is unknown whether targeting other structures with DBS, such as the anterior nucleus of the thalamus for epilepsy treatment [39], can impact creativity. 8. Conclusions Any mechanism affecting chemical and structural connectivity in the brain has the potential to affect cognition, motivation, talent, and, therefore, creativity. While epilepsy itself may affect the content and mode of artistic expression, the same has not been shown for nonsedating antiepileptic medications. Epilepsy surgery, on the other hand, has the potential to affect or even disrupt the creative process. While some reports point to improved memory and intelligence following right temporal lobectomy, the opposite may be true for musical interpretation, especially in musically inexperienced individuals. In rare cases, tailored right frontal and left temporal resections have affected musical perception and tastes. Neurostimulation also has the potential to alter cortical, subcortical, and brainstem networks, and, thus, creativity. There is some evidence that VNS may impair the creative process, while DBS of the anterior internal capsule or nucleus accumbens may alter mood and, by extension, creativity. Further research is needed to guide general principles. However, the broad range of disease pathology and creative expression, as well as the diversity of treatment options, will ultimately require an individualized approach when addressing the potential complications of epilepsy treatment. Disclosures S.Z. and D.F. have no relevant disclosures. References [1] Heilman KM, Nadeau SE, Beversdorf DO. Creative innovation: possible mechanisms. Neurocase 2003;9:369–79. [2] Flaherty AW. Brain illness and creativity: mechanisms and treatment risks. Can J Psychiatry 2011;56:132–43. [3] Kalbfleisch ML. Functional neuroanatomy of talent. Anat Rec B New Anat 2004;277: 21–36. [4] Anschel DJ, Dolce S, Schwartzman A, Fisher RS. A blinded study of artwork in a comprehensive epilepsy center population. Epilepsy Behav 2005;6:196–202. [5] Stafstrom CE, Havlena J. Seizure drawings: insight into the self-image of children with epilepsy. Epilepsy Behav 2003;4:43–56. [6] Geschwind N. Interictal behavioral changes in epilepsy. Epilepsia 1983;24(Suppl. 1): S23–30. [7] Bogousslavsky J. Artistic creativity, style, and brain disorders. Eur Neurol 2005;54: 103–11. [8] Cartwright M, Clark-Carter D, Ellis SJ, Matthews C. Temporal lobe epilepsy and creativity: a model of association. Creat Res J 2004;16:27–34.
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