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Epilepsy Research 32 (1998) 233–253

Review

Amygdala damage in experimental and human temporallobe epilepsy

Asla Pitkanen a,*, Jarkko Tuunanen a, Reetta Kalviainen b, Kaarina Partanen c,Tuuli Salmenpera b

a A.I.Virtanen Institute, Uni6ersity of Kuopio, P.O. Box 1627, FIN-70 211 Kuopio, Finlandb Department of Neurology, Kuopio Uni6ersity Hospital, P.O. Box 1777, FIN-70 211 Kuopio, Finland

c Department of Clinical Radiology, MRI Unit, Kuopio Uni6ersity Hospital, P.O. Box 1777, FIN-70 211 Kuopio, Finland

Abstract

The amygdala complex is one component of the temporal lobe that may be damaged unilaterally or bilaterally inchildren and adults with temporal lobe epilepsy (TLE) or following status epilepticus. Most MR (magnetic resonance)imaging studies of epileptic patients have shown that volume reduction of the amygdala ranges from 10–30%. In thehuman amygdala, neuronal loss and gliosis have been reported in the lateral and basal nuclei. Studies in rats havemore specifically identified the amygdaloid regions that are sensitive to status epilepticus-induced neuronal damage.These areas include the medial division of the lateral nucleus, the parvicellular division of the basal nucleus, theaccessory basal nucleus, the posterior cortical nucleus, and portions of the anterior cortical and medial nuclei.Otherwise, other amygdala nuclei, such as the magnocellular and intermediate divisions of the basal nucleus and thecentral nucleus, remain relatively well preserved. Amygdala kindling studies in rats have shown that the density of asubpopulation of GABAergic inhibitory neurons that also contain somatostatin may be reduced even after a lownumber of generalized seizures. While analyses of histological sections and MR images indicate that in approximately10% of TLE patients, seizure-induced damage is isolated to the amygdala, more often amygdala damage is combinedwith damage to the hippocampus and/or other brain areas. Moreover, recent data from rodents and nonhumanprimates suggest that structural and functional alterations caused by seizure activity originating in the amygdala arenot limited to the amygdala itself, but may also affect other temporal lobe structures. The information gathered sofar on damage to the amygdala in epilepsy or after status epilepticus suggests that local alterations in inhibitorycircuitries may contribute to a lowered seizure threshold and greater excitability within the amygdala. Furthermore,damage to select nuclei in the amygdala may predict impairment of performance in behavioral tasks that depend onthe integrity of the amygdaloid circuits. © 1998 Elsevier Science B.V. All rights reserved.

Keywords: Amygdaloid complex; Magnetic resonance imaging; Pathology; Primate; Rat; Seizure; T2 relaxometry;Volumetry

* Corresponding author. Tel.: +358 17 163296; fax: +358 17 163025; e-mail: [email protected]

0920-1211/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.

PII S0920-1211(98)00055-2

A. Pitkanen et al. / Epilepsy Research 32 (1998) 233–253234

1. Introduction

The temporal lobe is composed of the amyg-dala, the hippocampus, and the surrounding cor-tex. These areas are interconnected by a myriad oftopographically organized pathways which or-chestrate the various functions assigned to thetemporal lobe, including the formation of memo-ries and emotions (Amaral, 1987). Damage to thehippocampus and its association with the symp-tomatology of temporal lobe epilepsy (TLE) havebeen appreciated since 1825 (Bouchet and Cazau-vieilh, 1825). Since then, an increasing volume ofdata has been collected in the epileptic hippocam-pus. As a result, our current understanding of themechanisms underlying epileptogenesis andseizure generation is largely based on informationobtained in the hippocampus. Damage to theother components of the temporal lobe network,however, and their contributions to epileptogene-sis as well as to the behavioral impairments asso-ciated with TLE, have remained relativelyunexplored.

Interest in TLE-associated structural damage inthe amygdala grew in the 1950s when severalauthors reported damage to the amygdala in pa-tients who had died from status epilepticus (Table1; for review, see Gloor (1992)). However, itwasn’t until the observations of Feindel andPenfield (1954) and Penfield and Jasper (1954)who stimulated the amygdala of patients undergo-ing surgery for TLE that the specific involvementof the amygdala in the symptomatology of theseizures of temporal lobe origin was demon-strated. Another landmark discovery for the roleof the amygdala in epilepsy was the finding byGoddard et al. (1969), who showed that theamygdala had one of the lowest thresholds forkindling. In recent years, research interest in theamygdala has experienced a renaissance of discov-eries, providing us with new insights into itsanatomy and function which undoubtedly willhave an impact on studies of epilepsy. For exam-ple, in humans the amygdala has been shown tobe involved in functions such as the recognition ofemotion in visual and auditory stimuli (Adolphset al., 1994; Young et al., 1995; Bonda et al.,1996; Breiter et al., 1996; Irwin et al., 1996; Mor-

ris et al., 1996; Scott et al., 1997), the acquisitionof conditioned responses to sensory stimuli(Bechara et al., 1995; LaBar et al., 1995), and theacquisition (Cahill et al., 1996) and retrieval(Rauch et al., 1996) of memories for emotionallyarousing events. Using the rat as an experimentalsystem, investigators have found that the func-tions of the amygdala range from emotion toattention to memory (Davis, 1992; Gallagher andHolland, 1994; Cahill et al., 1996; Rogan andLeDoux, 1996).

In this review, we will first summarize the majoraspects of the anatomical organization of theamygdala. We will then describe the pattern ofamygdala damage that is known to be associatedwith seizures and epilepsy in primates and ro-dents, and identify the conditions that are neces-sary to generate such damage. Finally, we willpropose some hypotheses regarding how damageto the amygdala may impair intra-amygdala in-formation processing; we will focus primarily onTLE since most of the information available onthis topic comes from epileptic patients of thistype.

2. Organization of the connections of theamygdala

2.1. Nuclei and nuclear subdi6isions

The amygdala or rather the ‘amygdala com-plex’ in rat, monkey, and human is composed ofmore than ten nuclei and their subdivisions (Fig.1) which have different cytoarchitectonic,chemoarchitectonic, and connectional characteris-tics. We will consider each subdivision to repre-sent a functional unit in the amygdala (Pitkanenet al., 1997).

2.2. Input projections terminate in selecti6e nucleiof the amygdala

Tract-tracing studies in rodents and primateshave shown that information from different brainareas enters the amygdaloid complex via selectnuclei (Amaral et al., 1992). For example, corticaland thalamic sensory information enters the

A. Pitkanen et al. / Epilepsy Research 32 (1998) 233–253 235

Fig. 1. Brightfield photomicrographs from coronal sections of the (A) rat, (B) monkey, and (C) human amygdala. In all species, theamygdaloid complex is composed of more than ten nuclei and their subdivisions. In humans, the amygdaloid complex can be dividedinto the deep nuclei, which include the lateral (medial and lateral divisions), basal (magnocellular, intermediate, and parvicellulardivisions), accessory basal (magnocellular, parvicellular, and ventromedial divisions), and paralaminar nuclei. The superficial nucleiinclude the anterior cortical nucleus, the medial nucleus, the periamygdaloid cortex (divided into PACs, PACo, PAC1, and PAC3),the posterior cortical nucleus, and the nucleus of the lateral olfactory tract. The other nuclei include the central nucleus (medial andlateral divisions), anterior amygdaloid area, amygdalohippocampal area, and intercalated nuclei (Sorvari et al., 1995). Thepartitioning of the monkey amygdala was recently presented by Amaral et al. (1992) and the rat amygdala by Pitkanen et al. (1997)(see Figs. 5 and 6). Abbreviations: AB, accessory basal nucleus; B, basal nucleus; CE, central nucleus; L, lateral nucleus, M, medialnucleus; PAC, periamygdaloid cortex; PL, paralaminar nucleus. Scale bar of 2 mm applies to all panels.


Table 1Histopathological studies on the amygdala damage in humans

PatientsAuthor ObservationSpecimen

AutopsyBrockhaus (1938) Two children ‘Status marmoratus’ of the amygdala. No clear association of damagewith epilepsy.

Autopsy 29 adults Amygdala gliosis in 11/29 patients with HC sclerosis. Amygdala damageSano and Mala-mud (1953) was bilateral in 8/11 cases

Meyer et al. Autopsy One child Bilateral amygdala damage in a 9-year old boy who died from SE(1955) (seizures and several episodes of SE over a period of 1 year). Damage

was located in ‘the ventral half of the amygdala’.Surgery Six children/34 Amygdala was analyzed in 10/17 patients with HC sclerosis. Six casesCavanagh and

had amygdala damage characterized as a focal cell loss in ‘the basaladultsMeyer (1956)group’. Other cases had severe gliosis in the amygdala.

Fowler (1957) Four childrenAutopsy Three of four children with SE associated with fever had amygdaladamage analyzed within 18 weeks after the initial insult. In one case theamygdala damage was bilateral.

Falconer et al. Surgery 100 patients (ma- Patchy nerve cell loss and gliosis in the amygdala.jority adults)(1964)

Norman (1964) 11 children Amygdala was damaged in 6/11 cases (4/6 52 years of age) who hadAutopsyexperienced SE associated with fever within the past 2 weeks beforeautopsy. Two patients with amygdala damage had no prior history ofepilepsy.

AutopsyMargerison and 55 patients Amygdala damage was found in 15/55 patients. It was bilateral in fiveCorsellis (1966) cases. Amygdala damage was always associated with HC damage. In(adults/children)

13/15 cases with amygdala damage also the thalamus, cerebellum orcortex was damaged. Patchy nerve cell loss and gliosis were most clearin ‘the basolateral nuclear group’.

Autopsy One childOunstedt et al. A child with recurrent generalized seizures and mental retardation died(1966) at the age of 12 months (case M.H.). Bilateral neuronal loss and fibrous

gliosis were found in ‘the ventral part of the amygdaloid nucleus’.Bruton (1988) 249 patients Amygdala damage was found in 81/92 patients with HC sclerosis. De-Surgery

(adults/children) pending on the severity of the HC damage they report amygdala damagein 1/3 patients with ‘end folium sclerosis’, 43/52 patients with ‘classical’Ammon’s horn sclerosis, and in 37/37 patients with ‘total’ Ammon’shorn sclerosis.

Hudson et al. Surgery 16 adults Neuronal loss and gliosis was found in the lateral nucleus also without(1993) concomittant hippocampal pathology.

Surgery 113 patientsMiller et al. Isolated amygdala sclerosis in 10% (11/113) of the patients. In 53% of(adults/children) cases, both the amygdala and HC were damaged.(1994)

Autopsy Patchy neuronal loss in ‘the medial and basal portions’ of the amygdalaOne adultCendes et al.(1995) in a man who died 3 1/4 years after developing TLE due to domoic acid

intoxication.

HC, hippocampus; SE, status epilepticus, TLE, temporal lobe epilepsy.

amygdala largely, though not exclusively, via thelateral nucleus. Projections from the frontal cor-tex terminate primarily in the lateral, basal, andaccessory basal nuclei. Inputs from the hippocam-pal formation terminate in the basal nucleus,those from the hypothalamus in the accessorybasal, medial, and central nuclei, and projectionsfrom the brainstem in the central nucleus (for

details, see Price et al. (1987), Amaral et al.(1992)).

2.3. Three le6els of intra-amygdaloid connecti6ity

The major principles of the organization of theintra-amygdaloid circuitries in rat are summarizedin Fig. 2 (Pitkanen et al., 1997). After entering the


Fig. 2. Summary of the major principles of the organization of the amygdaloid circuitry in rat. The inputs enter the amygdala viaselect nuclei or nuclear subdivisions. From these nuclei, the information is distributed to different locations within the amygdala byintra-amygdaloid circuitries. Finally, the outputs originating in select amygdaloid areas convey the information to other functionalsystems in the brain like the temporal lobe memory system, autonomic centers in the brainstem, or to the motor system.Abbreviations: AB, accessory basal nucleus; B, basal nucleus; CE, central nucleus; COa, anterior cortical nucleus; Ldl, dorsolateraldivision of the lateral nucleus; Lm, medial division of the lateral nucleus; Lvl, ventrolateral division of the lateral nucleus; M, medialnucleus; PAC, periamygdaloid cortex.

amygdala, the information may travel to otherlocations within the amygdala via intra-amygdalaconnections. These local pathways have three dif-ferent levels. Intradivisional connections transferinformation within a subdivision. For example,the rostral portion of the magnocellular division isheavily connected with other neurons in that divi-sion. Interdivisional connections are links betweenregions of a particular nucleus. For example, thedorsolateral division of the lateral nucleusprojects to the medial division of the lateral nu-cleus. Internuclear pathways connect variousamygdaloid nuclei with each other. For example,the lateral nucleus, which provides the most sub-stantial intra-amygdala connections, innervatesthe basal nucleus, the accessory basal nucleus, themedial nucleus, the amygdalohippocampal area,the central nucleus, the posterior cortical nucleus,and the periamygdaloid cortex. Via these differentintra-amygdala connections, information enteringone nucleus of the amygdala may have represen-tations in various locations within the amygdala,

and consequently become associated with inputfrom other functional systems of the brain.

2.4. Reciprocal intra-amygdala connections

Many of the intra-amygdala connections arereciprocal (Fig. 2). For example, most of theamygdala nuclei that receive input from the lat-eral nucleus (e.g. the basal nucleus, the accessorybasal nucleus, the periamygdaloid cortex) projectback to the lateral nucleus. These pathways mayprovide routes by which target neurons can regu-late the responsiveness of their input regions.

2.5. Con6ergence of intra-amygdala connectionsin select regions

There are a few nuclei, such as the centralnucleus and the amygdalohippocampal area, thatreceive convergent inputs from several amygdalanuclei but do not send any substantial inputs backto the other amygdala areas (Fig. 2). These nuclei


are presumed to act primarily as output stationsfrom the amygdala to other brain regions, toevoke the appropriate behavioral responses tostimuli entering the amygdala.

2.6. Output projections to other brain areasoriginate in select regions of the amygdala

The outputs to various functional systems ofthe brain leave the amygdala from different loca-tions. For example, the lateral nucleus projectsheavily to the entorhinal and perirhinal cortices.The basal nucleus projects to the basal forebrain,hippocampus, striatum and frontal cortex. Theaccessory basal nucleus provides substantial pro-jection to the temporal and orbitofrontal corticesas well as to the striatum, hypothalamus, andbasal forebrain. The medial nucleus projects heav-ily to the hypothalamus, and the central nucleussends prominent projections to the brainstem (fordetails of these connections in different species,see Price et al. (1987) for rat and monkey; Amaralet al. (1992) for monkey).

2.7. Amygdala anatomy and seizure generation

What is there in the anatomy of the amygdalathat would link it so closely with epileptogenesisand seizure generation in TLE? First, as tract-tracing studies have shown, the amygdala com-plex receives monosynaptic inputs from largeareas of the frontal and temporal cortices thatmay generate and propagate seizure activity to theamygdala from foci located in these regions. Sec-ond, the smallest functional units of the amyg-dala, the nuclear subdivisions, often have a denseintradivisional network of connections. This sug-gests that activation of a small portion of adivision by afferent inputs could rapidly recruit alarge number of neurons within that division.Third, via intra-amygdala connections, the seizureactivity may become monosynaptically distributedin parallel to various amygdala nuclei. Fourth,outputs from the amygdala to the extrapyramidalsystem, cortex, and hippocampal formation areeven more widespread than the inputs from theseareas to the amygdala; these pathways mayprovide routes by which the amygdala activity can

rapidly recruit other regions of the brain. Fifth, inrodents the two amygdalae are interconnectedmonosynaptically, which may explain the rapidcontralateral activation produced by seizures elic-ited in one amygdala (Savander et al., 1997). Inprimates, however, monosynaptic inter-amygdalaconnections have not been described (Amaral etal., 1992). Sixth, recent electrophysiological stud-ies have proposed that interconnections betweenthe amygdala and the entorhinal cortex underliethe coherent oscillations observed in amygdala-hippocampal circuitries (Pare and Gaudreau,1996). And finally, the fact that each of the amyg-dala nuclei has unique anatomical characteristicssuggests that the functional consequences ofseizure-induced neuronal damage to the amygdalaare largely dependent on the nuclear location ofthe damage within the amygdala.

3. Amygdaloid damage in epilepsy

3.1. Human studies

3.1.1. HistopathologyNeuronal loss and gliosis in the amygdala have

been reported in a large number of histopatholog-ical studies in which amygdala tissue from hu-mans with chronic epilepsy or status epilepticuswas available for analysis either from autopsy orepilepsy surgery (Table 1). Amygdala damage wasfound both in adults (Sano and Malamud, 1953;Cavanagh and Meyer, 1956; Falconer et al., 1964;Margerison and Corsellis, 1966; Bruton, 1988;Hudson et al., 1993; Miller et al., 1994; Cendes etal., 1995) as well as in children, some of whomwere under 2 years of age (Meyer et al., 1955;Fowler, 1957; Norman, 1964; Ounstedt et al.,1966). In many of the early studies, amygdaladamage was found in patients who had experi-enced recent status epilepticus (Meyer et al., 1955;Fowler, 1957; Norman, 1964; Fujikawa and Ita-bashi, 1994), which in some studies was associatedwith fever (Fowler, 1957; Norman, 1964). Inter-estingly, some of these patients did not haveepilepsy prior to the episode of status (Norman,1964). Based on the data available, amygdaladamage may become apparent over a period of a


few days or a few weeks following status epilepti-cus (Fowler, 1957; Norman, 1964). However,many studies show that amygdala damage mayalso occur in patients with TLE but who have noprior history of status epilepticus (Margerison andCorsellis, 1966; Bruton, 1988; Hudson et al.,1993).

Amygdala damage may be either unilateral orbilateral (Sano and Malamud, 1953; Fowler,1957; Margerison and Corsellis, 1966). Most of-ten, it has been reported to occur in combinationwith hippocampal damage or with damage to thecerebral cortex, cerebellum, or thalamus. In mate-rial analyzed by Bruton (1988), the percentage ofpatients with amygdala damage increased with theseverity of the hippocampal damage (Table 1).More recently, however, Hudson et al. (1993)described eight patients with amygdala damagewho did not have any apparent neuronal loss inthe hippocampus. Miller et al. (1994) investigateda series of 113 patients undergoing temporal lobesurgery and also found isolated amygdala sclero-sis in approximately 10% of the patients.

Even though we do not have a detailed analysisavailable of the distribution of damage to variousnuclei of the human amygdala, there is someevidence showing nuclear specificity. Early reportsmention that the ‘ventral part of the amygdala’ or‘the basal group of the amygdala’ was the mostdamaged portion of the amygdala (Meyer et al.,1955; Cavanagh and Meyer, 1956; Ounstedt et al.,1966). Moreover, Margerison and Corsellis (1966)found neuronal loss and/or gliosis in ‘the basolat-eral nuclear group’. In Fig. 11 of Meyer et al.(1955) and Fig. 25 of Ounstedt et al. (1966), itappears that most of the gliosis is in a region thatinvolves the lateral (medial division) and basal(parvicellular division) nuclei. In a study by Hud-son et al. (1993), neuronal damage and gliosiswere identified in the lateral nucleus. Also in ourmaterial, we found substantial gliosis in the me-dial division of the lateral nucleus in patients withTLE (Fig. 3B–D).

3.1.2. MR 6olumetryDetection of amygdala damage in vivo using

volumetric measurements of the amygdala by MR(magnetic resonance) imaging has provided us

with a new tool to investigate in more detail thefactors that lead to amygdala damage. One exam-ple of the appearance of the amygdala damage inMR image is shown in Fig. 3A. Caution shouldbe taken when interpreting data from volumetrystudies because the relative sensitivity of thismethod in detecting amygdala damage, comparedto histological analysis, has not yet been estab-lished. For example, in a study by Miller et al.(1994), none of the 11 patients with histologicallyverified amygdala damage had definitive atrophyor an increased T2 signal in the amygdala.

MR volumetric measurements of the amygdalarevealed that the reduction in the amygdala vol-ume in patients with drug-refractory TLE variesbetween 10–30% (Cendes et al., 1993a,b,c;Saukkonen et al., 1994; Bronen et al., 1995;Kalviainen et al., 1997). In our ongoing studywhere we have measured the volume of the amyg-dala by MR imaging in 147 patients with TLE,the volume of the smallest amygdala was 57% ofthat in control subjects (Salmenpera, Kalviainen,Partanen, Vainio and Pitkanen, unpublisheddata). In a study by Cendes et al. (1993a), themost pronounced atrophy of the amygdala (a 30%volume reduction) was found in drug-refractorypatients with TLE who had experienced pro-longed febrile convulsions in childhood. In 26%(10/39) of all patients, the amygdala damage (]2S.D. reduction)1 was bilateral (i.e. in 45% ofpatients with any amygdala damage).

As in histopathological studies, MR volumetryhas demonstrated that amygdala damage typicallyappears in combination with hippocampal dam-age. For example, in the patients of Cendes et al.(1993a), a large majority with amygdala damagealso had hippocampal damage. More recently,Bronen et al. (1995) reported by visually inspect-ing the MR images that amygdala damage was

1 In MR volumetry, \1 S.D. or \2 S.D. reduction in thevolume of the amygdala refers to the volume of the amygdalathat was one or two standard deviations smaller than the meanamygdala volume in controls, respectively. In our material, a 1S.D. volume reduction equals a 16% volume reduction on theleft and a 11% volume reduction on the right, compared to themean volume on the left or right amygdala in controls, respec-tively. A 2 S.D. volume reduction equals a 32% volumereduction on the left and a 22% volume reduction on the right.


Fig. 3. Amygdala damage in MR image and histological sections. (A) A coronal MR image from a 46-year-old male who wasoperated due to drug-refractory TLE. The right amygdala (open arrow) is atrophied and its normalized volume is 75% of that incontrol subjects. Also, the T2 relaxation time of the right amygdala was prolonged (108 ms). The patient had a 4-year history ofepilepsy, during which he was estimated to have experienced 1200 seizures. Also, the volume of his right hippocampus was reduced(55% of that in controls, not shown). The asterisk indicates the location of the lateral nucleus. (B) Brightfield photomicrograph ofa thionin-stained section from the lateral nucleus of the amygdala of the patient illustrated in panel A. (C) Brightfieldphotomicrograph from an adjacent section stained with an antibody raised against parvalbumin (PARV) or (D) glial fibrillary acidprotein (GFAP). The level of histological section is rostral to that in the MR image. Note the increased astrocytosis in theventromedial aspect of the lateral nucleus in panel D (area between the arrowheads) which corresponds to a region that is lightlystained in parvalbumin preparations in panel C. Abbreviations: L, lateral nucleus; ec, external capsule. Scale bars: A, 10 mm; B–D,2 mm.


Table 2MR volumetry of the amygdala in patients with TLE

Patients with volume reduction of theamygdala (%)

]2 S.D.]1 S.D.

6All patients with TLE (147) 29

Etiology28From patients with cryptogenic etiology 5

831From patients with symptomatic etiology

Duration of epilepsy318From newly diagnosed patients7From chronic patients 33

Amygdala damage bilateral 08Associated with

8956]1 S.D. volume reduction of the HC]2 S.D. volume reduction of the HC 42 67

Isolated volume reduction of the amygdala (simultaneous HC damage 51 S.D.) 113

The data comes from an ongoing study, in which we have analyzed the amygdala volumes of 147 patients with temporal lobeepilepsy by using MR volumetry (Salmenpera, Kalviainen, Partanen, Vainio, and Pitkanen, in preparation). For methodology andclinical criteria for classification of patients, see Kalviainen et al. (1997). A 1 S.D. volume reduction equals a 16% volume reductionon the left and a 11% volume reduction on the right compared to the mean volume of the left or right amygdala in controls,respectively. A 2 S.D. volume reduction equals a 32% volume reduction on the left and a 22% volume reduction on the right.HC, hippocampus; MR, magnetic resonance; S.D., standard deviation of the mean; TLE, temporal lobe epilepsy.

present in 12% (7/52) of the patients with patho-logically proven hippocampus sclerosis. However,amygdala damage was apparent in MR imagesalso in cases where no evidence of hippocampalatrophy was detected. Cendes et al. (1993a) re-ported three patients out of 39 (8%) in whichamygdala damage was more pronounced than thehippocampal damage. In our series of 147 patientswith TLE, isolated ]1 S.D. reduction in theamygdala volume was found in 13% of the pa-tients with TLE, whereas isolated ]2 S.D. reduc-tion in the amygdala volume was found in lessthan 1% of the patients (Table 2) (Salmenpera,Kalviainen, Partanen, Vainio and Pitkanen, un-published data).

Tract-tracing studies have shown that theamygdala receives monosynaptic inputs from vari-ous extratemporal cortical regions in primates(Amaral et al., 1992). This connectivity leads tothe question of whether the amygdala is damagedin extratemporal epilepsy. Cendes et al. (1993b)found no amygdala damage in six patients with

an extratemporal seizure focus. However, theiroriginal finding was challenged in a later study(Cendes et al., 1993c) in which they describedbilateral amygdala damage in two out of sevenpatients with an extratemporal focus. In our ownstudies, ]1 S.D. reduction in the amygdala vol-ume was found in 3% (1/36) of the patients withan extratemporal seizure focus (Salmenpera,Kalviainen, Partanen, Vainio and Pitkanen, un-published data).

Is amygdala damage already present at the timeof epilepsy diagnosis or does it appear later? Inour series of patients, which included both newlydiagnosed and chronic patients, we found that18% of the newly diagnosed patients had ]1S.D. reduction in the amygdala volume, whereas33% of the patients with chronic TLE showed asimilar volume reduction. Over 2 S.D. volumereduction was found in only 3% of the newlydiagnosed and in 7% of the chronic patients(Table 2) (Salmenpera, Kalviainen, Partanen,Vainio and Pitkanen, unpublished data). Interest-


ingly, there was a significant correlation betweenlifetime seizure number and volume reduction inthe amygdala (Fig. 4) (Kalviainen et al., 1997),which suggests that amygdala damage progressesas the number of seizures over a lifetime increases.

Another interesting question is whether amyg-dala damage is associated with the etiology ofTLE. Previous MR imaging studies have shownthat, for example, herpes encephalitis, which maybe a preceding cerebral insult leading to epilepsy,causes widespread damage to various brain areasincluding the amygdala (Kapur et al., 1994).Moreover, according to Cendes et al. (1993a),prolonged febrile seizures in childhood may beassociated with pronounced damage to the amyg-dala. This contrasts with the observations ofMiller et al. (1994) who found that in patientswith isolated amygdala sclerosis, their first seizureappeared later than in patients with amygdala-hippocampus sclerosis, and they had no clinicalhistory of seizures in early childhood. In ourseries of patients, amygdala damage ]1 S.D.

over control was found in 28% of patients withcryptogenic TLE and in 31% of patients withsymptomatic TLE, which suggests that amygdaladamage is not any more common in patients witha defined seizure etiology (Table 2) (Salmenpera,Kalviainen, Partanen, Vainio and Pitkanen, un-published data).

What are the symptoms associated with amyg-dala damage? Cendes et al. (1994) studied 50patients with drug-refractory TLE, and foundthat 34% of the patients recognized fear as acomponent of their seizures. The volume of theamygdala in patients experiencing fear was 75%of that in control subjects, whereas the patientshaving no fear had an amygdala volume 91% ofthat in controls. Miller et al. (1994) investigatedpatients with isolated amygdala sclerosis andfound that amygdala damage was associated witha more widespread EEG abnormality and with ahigher tendency of seizures to become generalizedcompared to patients with amygdala-hippocampalsclerosis. Moreover, the patients with amygdalasclerosis did not show improvement in IQ follow-ing surgery, and they had a greater tendencytowards postoperative seizures than did thosewith amygdala-hippocampal sclerosis.

3.1.3. T2 relaxometryT2 relaxation time is another measure obtained

by MR imaging that is used to locate structuralchanges in epileptic brain. Van Paesshen et al.(1996) investigated T2 relaxation times in 82 pa-tients with intractable TLE. They found that 54%(44/82) of the patients had an abnormal amygdalaT2 time which was bilateral in 22% (18/82) of thepatients. Interestingly, of the patients with unilat-eral prolongation of T2 in the hippocampus, 57%also had an abnormal amygdala T2 time. More-over, isolated prolongation of amygdala T2 wasfound unilaterally in 18% (15/82) and bilaterallyin 8% (7/82) of the patients. These authors foundthat patients with isolated amygdala T2 prolonga-tion were older at the onset of epilepsy and rarelyexperienced febrile convulsions. We recentlyfound ]2 S.D. prolongation of amygdala T2relaxation time in approximately 20% of patientswith TLE (Kalviainen et al., 1997). Like the vol-umetry findings, T2 prolongation occurred both

Fig. 4. The reduction of the right amygdala volume as afunction of the logarithm of lifetime seizure number. It can beestimated that a 20% volume reduction of the amygdalarequired approximately 4000 seizures. Abbreviations: C, con-trols; n, number of patients with TLE; P, statistical signifi-cance (Pearson’s correlation test); r, correlation coefficient.Original data was presented in Kalviainen et al. (1997).


in newly diagnosed and in chronic patients. More-over, T2 prolongation was also not clearly associ-ated with either cryptogenic or symptomaticetiology.

To summarize, histological, MR volumetry,and MR T2 relaxometry studies on humans showthat unilateral or bilateral amygdala damage mayoccur both in adults and children with epilepsy.Seizure-associated neuronal loss and gliosis havebeen generally described in humans to be in theventral portion (the lateral and basal nuclei) ofthe amygdala complex. Several types of braininsults may cause amygdala damage, includingstatus epilepticus, encephalitis, and prolongedfebrile seizures, each of which has been reportedto be associated with a volume reduction of theamygdala. In line with these observations, ourcross-sectional study showed that the amygdalavolume may be reduced in patients with symp-tomatic epilepsy, though this was shown to be nodifferent from patients with cryptogenic epilepsy.TLE-associated damage is isolated to the amyg-dala in approximately 10% of the patients. Moretypically it occurs in combination with damage toother structures of the brain. In extratemporalepilepsy where the seizure focus lies outside of thetemporal lobe, amygdala damage is rare.

3.2. Nonhuman primates

Studies in nonhuman primates have providedus with more detailed information on the patternof seizure-induced damage to the amygdala.Wasterlain et al. (1996) described damage to thebasolateral amygdala in 3–4 week-old marmosetmonkeys following status epilepticus induced withlithium chloride and pilocarpine. Meldrum andBrierley (1973) induced seizures in adult baboonswith bicuculline. They found damage to ‘the baso-lateral portions of the amygdala’ in seven of tenanimals. ‘The centromedial portion’ was alsodamaged in four of the seven baboons. The dura-tion of the seizures leading to damage in thetemporal lobe of these animals lasted for 82–299min. In another study, Meinini et al. (1980) in-jected kainic acid into the amygdala of adultPapio papio baboons. They found that damage tothe amygdala was unilateral, but the accompany-

ing mild hippocampal damage was bilateral insome cases. It should be noted, that in all casesdamage was also observed in several extra-amyg-daloid brain areas.

3.3. Rats

Studies of a number of rat seizure models haveprovided us with even more details of the specificpattern of seizure-induced damage to differentamygdaloid nuclei and neuronal populations. Inadult rats, amygdala damage has been reported invarious epilepsy models, including those whereseizures were induced by either kainic acid(Schwob et al., 1980; Tuunanen et al., 1996) orpilocarpine (Houser and Obenaus, 1994) injectionor by electrical stimulation of the perforant path-way (Tuunanen et al., 1996) or the lateral nucleusof the amygdala (Nissinen et al., 1996). In addi-tion, Baram and Ribak (1995) recently reportedamygdala damage in 10–13 day-old infant ratsthat had experienced status epilepticus induced byintracerebroventricular injection of corticotropin-releasing hormone. Electrophysiological studieshave also shown that the amygdala is prone toseizure-induced alterations. For example, theamygdala has one of the lowest thresholds forkindled seizures (Goddard et al., 1969). More-over, after kainate-induced status epilepticus,spontaneous bursting activity first appears in thebasal nucleus of the amygdala (Smith and Dudek,1996). White and Price (1993) also showed thatthe activation of the basal nucleus is primarilyresponsible for the generation of widespreadstatus epilepticus activity in models where seizureswere evoked even in extra-amygdaloid regions.Furthermore, feed-forward GABAergic inhibitionwas found to be impaired in the kindled amygdala(Rainnie et al., 1992).

What have we learned about the nucleus specifi-city of seizure-induced damage in the amygdala?Studies in the hippocampus have shown that thehilar neurons are among the first to die, whereasthe cells in the CA2 region are relatively resistantto seizure-induced damage (Babb and Pretorius,1993). Similarly in the amygdala, some regionsseem to be more resistant to seizure damage thanare others which is illustrated in Figs. 5–7A–C.


Fig. 5. Brightfield photomicrographs of thionin-stained sections showing the distribution of damage in the rat amygdala after statusepilepticus was induced with kainic acid. (A) Rostral section from the normal rat amygdala. (B) Rostral section from the amygdalaof a rat that was injected with kainic acid two days earlier. Note the damage to layer III of the anterior cortical nucleus (arrow).Otherwise, the magnocellular divisions of the basal nucleus and the central nucleus are well preserved. Abbreviations; Bmc,magnocellular division of the basal nucleus; CE, central nucleus (c, capsular division; CEl, lateral division; m, medial division); Ldl,dorsolateral division of the lateral nucleus; M, medial nucleus (Mcd, dorsal portion of the central division; Mr, rostral division),PAC, periamygdaloid cortex. Scale bar: 500 mm.

In models where status epilepticus was induced bysystemically injecting kainic acid or electricallystimulating the perforant pathway, the amygdalaregions most seriously damaged were the deeplayers of the anterior cortical and medial nuclei,

the medial division of the lateral nucleus, theparvicellular division of the basal nucleus, theaccessory basal nucleus, and the posterior corticalnucleus (Tuunanen et al., 1996). The most pre-served regions were the magnocellular division of


Fig. 6. See legend to Fig. 5. (A) Caudal section from the normal rat amygdala. (B) Caudal section from a rat injected with kainicacid 2 days earlier. Note the preservation of the dorsolateral division of the lateral nucleus. Otherwise, the medial division of thelateral nucleus (arrow), the parvicellular division of the basal nucleus, the accessory basal nucleus, and the posterior cortical nucleusare heavily damaged. Abbreviations; ABmc, magnocellular division of the accessory basal nucleus; ABpc, parvicellular division ofthe accessory basal nucleus; AHAl, lateral division of the amygdalohippocampal area; AHAm, medial division of the amygdalo-hippocampal area; Bpc, parvicellular division of the basal nucleus; COp, posterior cortical nucleus; PAC, periamygdaloid cortex(PACm, medial division; PACs, sulcal division). Scale bar: 500 mm.

the basal nucleus, the dorsolateral division of thelateral nucleus, and the central nucleus (Tuunanenet al., 1996).

How much seizure activity is sufficient to causedamage to the amygdala? Generally, seizure-in-duced structural damage has been assessed in

models of status epilepticus. Whether a singleepileptic seizure can cause structural damage tothe amygdala or to any other region of the brainis under dispute. Callahan et al. (1991) showedthat amygdala-kindled rats perfused for histologi-cal purposes 2–6 months after experiencing three


Fig. 7. (A–C) Schematic drawings summarizing the distribution of damage in various nuclei and nuclear subdivisions of theamygdala in rat two weeks after the induction of status epilepticus with kainic acid. Panel A is the most rostral and Panel C is themost caudal. The darkness of the shading indicates the severity of damage (dotted pattern=mild, grey=moderate, black=severedamage). Panel D shows the correlation of the number of TUNEL positive neurons in the medial division of the lateral nucleus withthe duration of epileptic EEG seizure activity (generalized rhythmic high-voltage sharp waves). Abbreviations: n, number of rats; P,statistical significance (Pearson’s correlation test); r, correlation coefficient. Anatomic abbreviations as in Figs. 5 and 6.

to five generalized seizures (not including theseizures that occurred during the induction ofkindling) had a 37–64% loss of GABA-im-munoreactive neurons in ‘the basolateral’ amyg-dala. We recently reinvestigated amygdaladamage in an amygdala kindling model in whichthe animals had experienced five class 5 seizuresby the end of the kindling procedure, which re-quired eight to 11 stimulations. The total durationof the after-discharges varied between 343–628 s.We could not find any reduction in the totalnumber of neurons in the lateral, basal, or acces-sory basal nuclei (Tuunanen and Pitkanen, un-

published data) or in the overall density ofGABA-immunoreactive neurons (Fig. 8) (Tuu-nanen et al., 1997). Surprisingly, however, wefound over a 35% decrease in the density ofsomatostatin-immunoreactive neurons, pre-sumably GABAergic inhibitory neurons (McDon-ald and Pearson, 1989), in the medial division ofthe lateral nucleus and in the magnocellular divi-sion of the basal nucleus in the amygdala con-tralateral to the stimulation site (Tuunanen et al.,1997). These observations support the idea that arelatively low number of seizures may damage asubpopulation of inhibitory neurons in the amyg-


Fig. 8. (A) The percentage of GABA-immunoreactive (GABA-ir) neurons remaining in the lateral nucleus of the rat amygdala aftervarious treatments. Note that kainate-treated animals had a substantial decrease in the density of GABA-ir neurons. (B) Thepercentage of somatostatin-immunoreactive neurons (SOM-ir) remaining in the lateral nucleus after various treatments. GroupsKind and KA correspond to those in panel A. Group WDS: rats that experienced wet-dog shakes (WDS) after a low dose of kainicacid was injected (5 mg/kg, intraperitoneally); Group Kind: rats that were amygdala-kindled 6 months earlier; Group PP: rats thathad experienced status epilepticus induced by electrical stimulation of the perforant pathway 2 weeks earlier; Group KA: rats thathad experienced kainate-induced status epilepticus (9 mg/kg, intraperitoneally) 2 weeks earlier. Statistical significances: * PB0.05,** PB0.01 compared to controls (Mann-Whitney U-test). Details of the studies can be found in the original publications (Tuunanenet al., 1996, 1997).

dala, which could contribute to the low kindlingthreshold in the amygdala. However, the moresevere seizure activity that is associated withstatus epilepticus may cause damage not only tothe somatostatin-ir neurons, but also to the gen-eral GABA-ir neuron population and to the pyra-midal cells as well (see Fig. 8) (Tuunanen et al.,1996).

What is the mechanism of seizure-induced neu-ronal damage in the amygdala? Data from recentstudies of kainic acid model indicate that, inaddition to necrotic cell death, apoptosis maycontribute to neuronal damage. In our hands, ratsthat were killed 8 h after kainate injection hadTUNEL positive neurons (an indicator of DNAfragmentation) in amygdaloid nuclei that are sen-sitive to seizure-induced damage. Moreover, thenumber of TUNEL positive neurons correlatedwith the duration of epileptiform activity in elec-troencephalogram (Fig. 7D) (Tuunanen and

Pitkanen, unpublished data). In silver-stained sec-tions, damaged (presumably necrotic) neurons canbe seen as early as 4 h after kainate injection(Tuunanen and Pitkanen, unpublished data).

4. Functional aspects

4.1. Nuclei targeted in seizure-induced amygdaladamage

Studies in rats have shown that the amygdala isa critical component of a network which generatesappropriate behavioral responses to emotionallysignificant sensory stimuli (Rogan and LeDoux,1996). In humans, the amygdala is also involvedin the interpretation of emotional aspects of sen-sory stimuli. For example, patients with amygdalalesions have difficulties in recognizing fear in fa-cial expressions (Adolphs et al., 1994) and in


perceiving changes in intonation in speech pat-terns (Scott et al., 1997). Anatomical studies haveshown that the lateral nucleus of the amygdala isthe major recipient of sensory information di-rected to the amygdala (Amaral et al., 1992). Asan example, the dorsolateral division of the lateralnucleus that is relatively undamaged after statusepilepticus, receives auditory information fromthe thalamus (Price et al., 1987). Via interdivi-sional connections the dorsolateral division con-veys the representation of a tone to the medialdivision of the lateral nucleus, which is one of themost sensitive regions of the amygdala to seizure-induced neuronal damage. The medial division inturn provides substantial projections to the otheramygdaloid nuclei (Pitkanen et al., 1995). There-fore, even though the neurons receiving the sen-sory information may reside in unaffectedportions of the lateral nucleus, damage to themedial division interferes with the connections ofthe lateral nucleus with the rest of the amygdala,and consequently impairs processing of sensoryinformation within the amygdaloid circuits. Aschematic diagram summarizing the presumedpattern of disrupted amygdaloid circuits is pre-sented in Fig. 9.

The pattern of amygdaloid damage that can beextracted from the little data available in humanssuggests that it is the ventral portion of the lateralnucleus that is damaged in human epilepsy (Oun-stedt et al., 1966; Hudson et al., 1993). Interest-

ingly, previous anatomic studies suggest that thechemoarchitectonic and connectional characteris-tics of the ventral portion of the lateral nucleus inprimates resemble that of the medial division ofthe lateral nucleus in rodents (Amaral et al., 1992;Pitkanen et al., 1997). For example, like in ro-dents, also in nonhuman primates the ventralportion of the lateral nucleus gives origin to wide-spread intra-amygdala projections (Pitkanen andAmaral, 1991). It remains to be determinedwhether the recognition of emotions in sensorysignals is impaired in patients with epilepsy andamygdala damage.

The preservation of the magnocellular divisionof the basal nucleus and of the central nucleus isof interest since they project to the striatum andthe brainstem autonomic areas, respectively(Amaral et al., 1992). Preservation of the amyg-dala input to the striatum would suggest that thepathways mediating the spread of the motor com-ponent of behavioral seizures remain intact withinthe epileptic amygdala (Fig. 9). Motor and auto-nomic components of the fear response shouldalso remain, since the central nucleus mediatesthese behaviors via its projections to the brain-stem and hypothalamus. Therefore, though someof the amygdaloid nuclei may be damaged byseizures, the remaining areas may still convey thebehavioral manifestations of seizure activity towide areas of the motor and autonomic centers inthe brain.

Fig. 9. Schematic diagram summarizing the seizure-induced disruption of the amygdaloid circuitries in the lateral, basal, accessorybasal, and central nuclei and how the damage may compromise the functions of the amygdala. Panel A shows how in the normalamygdaloid complex the sensory information enters the amygdala via the lateral nucleus. A substantial portion of the lateral nucleusoutputs are directed to the other amygdaloid nuclei, including the basal nucleus (B), accessory basal nucleus (AB), and centralnucleus (CE). These nuclei, on the other hand, send outputs to the extra-amygdaloid areas where many of the symptoms of theamygdaloid seizures are generated. The basal nucleus projects to the striatum. It is also reciprocally connected with thesubiculum/CA1 border of the hippocampus and the ventral subiculum. The accessory basal nucleus also projects to thehippocampus. The central nucleus projects to the brainstem and to the hypothalamic autonomic and endocrine centers (data takenfrom Price et al. (1987), Pitkanen et al. (1997). In Panel B the dark shading indicates the seizure-induced damage to selective regionsof the lateral, basal, and accessory basal nuclei. Dashed lines indicate impaired connectivity. We hypothesize that damage to theventrolateral and medial divisions of the lateral nucleus may impair access of sensory information from the lateral nucleus to therest of the amygdala. Damage to the parvicellular division of the basal nucleus and to the accessory basal nucleus may interfere withthe information flow between the amygdala and the hippocampal formation, and thus, impair the memory processing. Lightershading shows the amygdaloid regions that were found to be relatively well preserved after status epilepticus that was induced bykainic acid injection or by electrical stimulation of the perforant pathway (Tuunanen et al., 1996). The magnocellular andintermediate divisions of the basal nucleus project to the striatum, which may be a pathway by which amygdaloid seizures manifestthemselves as secondarily generalized convulsions. On the other hand, outputs from the almost undamaged central nucleus maymediate the autonomic and endocrine symptoms of fear associated with amygdaloid seizures. Abbreviations as in Figs. 5 and 6.


Fig. 9.


4.2. Epileptic acti6ity originating in the amygdalamay cause damage to the other regions ofthe temporal lobe

The loss of inhibitory neurons in select subdivi-sions of the amygdala nuclei may underlie the lowseizure threshold that is observed in this region inamygdala-kindling or kainate-induced statusepilepticus in rat. The remaining excitatory neu-rons presumably transfer the seizure activity fromone amygdaloid nucleus to another as well aswhen the seizures spread from the amygdala to avariety of other brain areas monosynaptically. Infact, although this is not always appreciated, theseizure activity that is initiated by the stimulationof the amygdala has on several occasions beenreported to cause secondary damage in thehippocampus. For example, we found that loss ofhilar neurons and sprouting of mossy fibers in thedentate gyrus occurred in rats that developedspontaneous seizures after a self-sustained statusepilepticus was induced by electrical stimulationof the lateral nucleus of the amygdala (Nissinen etal., 1996). Damage was also found in the entorhi-nal cortex. Loss of hilar cells and mossy fibersprouting has also been reported in amygdala-kin-dled rats (Sutula et al., 1988; Cavazos et al., 1991)or after injecting kainic acid into the rat amygdala(Mascott et al., 1994). Similarly in nonhumanprimates, pathological findings in the hippocam-pus were reported after injecting kainic acid(Meinini et al., 1980) or alumina gel (Ribak et al.,1995) into the amygdala. More recently, Behr etal. (1996) reported an altered electrophysiologicalresponsiveness of CA1 pyramidal cells to the stim-ulation of the entorhinal cortex in slices that wereprepared from amygdala-kindled rats. Also, inhumans, there is evidence that seizure activitymay spread from the epileptic amygdala to thehippocampus or to the surrounding cortex(Quesney, 1986; So et al., 1989; Wilson et al.,1990; Gotman and Levtova, 1996; Bertram, 1997).These observations raise the question of what thespecific role is of each of the temporal lobe struc-tures in the generation and propagation of seizureactivity among the myriad of connections whichlink these areas together.

5. Conclusions

The amygdaloid complex is one component ofthe temporal lobe that is damaged in a largesubpopulation of patients with TLE. Future stud-ies will show if amygdala pathology plays a criti-cal role in epileptogenesis, and how amygdalainteracts with other components of the temporallobe network to generate temporal lobe seizures.

Acknowledgements

This study was supported by the Academy ofFinland, the Vaajasalo Foundation, and theSigrid Juselius Foundation. The help from DrDavid G. Amaral (UC at Davis, CA) in thepreparation of Fig. 1 is greatly appreciated.

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