Brain Research Reviews 42 (2003) 143154www.elsevier.com/ locate /brainresrev

Review

T he insula (Island of Reil) and its role in auditory processingLiterature reviewa , b a*Doris-Eva Bamiou , Frank E. Musiek , Linda M. Luxon

aNeuro-Otology Department, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UKbCommunication Sciences, DCP Comm Center, Unit 1085, University of Connecticut, Storrs, CT, USA

Accepted 11 March 2003

Abstract

The insular cortex is a complex structure which contains areas that subserve visceral sensory, motor, vestibular, and somatosensoryfunctions. The role of the insular cortex in auditory processing was poorly understood until recently. However, recent case studies indicatethat bilateral damage to the insulae may result in total auditory agnosia. Functional imaging studies demonstrate that the insulaeparticipate in several key auditory processes, such as allocating auditory attention and tuning in to novel auditory stimuli, temporalprocessing, phonological processing and visualauditory integration. These studies do not clarify the issue of further specialisation withinthe insular cortex, e.g. whether the posterior insulae are primarily sensory areas, while the anterior insulae serve mainly asintegration /association auditory areas, two hypotheses that would be compatible with the cytoarchitectonic structure and connectivity ofthe insulae. The functional characterisation of the insulae remains incomplete, underlining the need for further studies. 2003 Elsevier Science B.V. All rights reserved.

Theme: Sensory systems

Topic: Auditory systems: central physiology

Keywords: Insula; Auditory processing; Agnosia; Temporal; Phonological; Visualauditory integration

Contents

1 . Introduction ............................................................................................................................................................................................ 1442 . Anatomy................................................................................................................................................................................................. 1443 . Cytoarchitecture ...................................................................................................................................................................................... 1454 . Connections ............................................................................................................................................................................................ 1455 . Case reports in humans ............................................................................................................................................................................ 1466 . PET and fMRI studies.............................................................................................................................................................................. 148

6 .1. Sound detection and non-verbal processing ....................................................................................................................................... 1496 .1.1. The insulae are activated by passive listening to sounds and may thus participate in sound processing with access to abstract

knowledge about non-verbal sound material ............................................................................................................................ 1496 .1.2. Target and novel auditory stimuli activate the insulae bilaterally, with greater activation for target than for the novel stimuli ........ 1496 .1.3. The right insula is a multimodally responsive area that responds to visual, tactile and auditory stimuli (anterior.posterior) and

shows a significantly greater response to a novel versus a familiar stimulus ............................................................................... 1496 .2. Temporal processing ....................................................................................................................................................................... 150

6 .2.1. The insulae may contribute in auditory temporal processing with the left insula as a non-linear high pass filter and the rightinsula as a linear low-pass filter .............................................................................................................................................. 150

6 .2.2. The left insula is involved in musical rhythm processing .......................................................................................................... 1516 .2.3. The right insula is involved in auditory sequencing and sound movement detection .................................................................... 151

6 .3. Phonological processing .................................................................................................................................................................. 151

*Corresponding author. Tel.: 144-207-837-3611x3275; fax: 144-207-829-8775.E-mail addresses: doris-eva.bamiou@uclh.org (D.-E. Bamiou), frank.musiek@uconn.edu (F.E. Musiek), l.luxon@ich.ucl.ac.uk (L.M. Luxon).

0165-0173/03/$ see front matter 2003 Elsevier Science B.V. All rights reserved.doi:10.1016/S0165-0173(03)00172-3

144 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

6 .3.1. Phonological verbal short-term memory activates both insulae .................................................................................................. 1516 .3.2. Dyslexics have less activation of the insulae bilaterally than normal controls when performing a phonological (rhyming) task ...... 1526 .3.3. The left insula is activated by phonological recognition of words .............................................................................................. 152

6 .4. Visualauditory integration.............................................................................................................................................................. 1526 .4.1. The right insula is involved in detection of temporal mismatch (onset asynchrony) between simple stationary auditory and visual

stimuli .................................................................................................................................................................................. 1526 .4.2. The left anterior insula will be activated by a cross-modal speed comparison of an auditory versus visual motion task .................. 1536 .4.3. The insulae may mediate temporally defined crossmodal auditoryvisual interactions................................................................. 153

7 . Comments and conclusion........................................................................................................................................................................ 153References................................................................................................................................................................................................... 154

2 . Anatomy1 . Introduction

The insula lies deep inside the lateral sulcus in theThe insula (Island of ReilBroadman areas 1316) is aSylvian fissure under the operculum. Removal of thecomplex structure with increased complexity in the coursefronto-orbital, frontoparietal and temporal opercula willof primate evolution that is characterised by a strikingreveal the pyramid-shaped insula in its entirety (Fig. 1)heterogeneity in architecture, physiology and connectivity[35]. The extreme capsule consists of the insular subcorti-with other areas of the brain. Thus it subserves a widecal white matter and is united with the white matter of therange of neural processes in all species. The role of theopercula. The insular cortex and extreme capsule cover thehuman insular cortex as visceral sensory, motor, motorclaustrum, external capsule, putamen and globus pallidusassociation, vestibular, and somatonsensory areas is well(Fig. 2) [35]. The insula contains five to seven sulci inknown [2,3]. In contrast, its role in auditory processing ishumans, who possess a larger left than right insula bypoorly understood. The aim of this review paper is toadulthood [24]. Both insulae have an intricate vascularisa-summarise and discuss the available information on thetion pattern, with an average of 96 arteries that originateauditory functions of the human insulae.

Fig. 1. Photograph of brain specimen. The insula has been exposed following excision of the opercula. aps5anterior periinsular sulcus; alg5anterior longinsular gyrus; asg5anterior short insular gyrus; cis5central insular sulcus; cs5central sulcus of Rolando; F25middle frontal gyrus; f25inferior frontalsulcus; ips5inferior periinsular sulcus; li5limen insula; mog5medial orbital gyrus; msg5middle short insular gyrus; pcg5precentral gyrus; pcis5precentral insular sulcus; pcs5precentral sulcus; pg5postcentral gyrus; pis5postcentral insular sulcus; plg5posterior long insular gyrus; psg5posteriorshort insular gyrus; ps5postcentral sulcus; sps5superior periinsular sulcus; sis5short insular sulcus; T25middle temporal gyrus; tg5transverse insular

gyrus. From Ture et al. [35], with kind permission of the Journal of Neurosurgery.

D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154 145

from the middle cerebral artery and predominantly its M2 diaphorase staining indicates the presence of two putativesegment [36]. The fronto-opercular artery is the main cortical areas [30]:insular artery. The insular arteries supply the insularcortex, extreme capsule and occasionally the claustrum and 1. A darkly-stained region on the posterior insula thatexternal capsule, but not the putamen, globus pallidus or contains few stained fibres and a small number ofinternal capsule, which are supplied by the lateral len- neurons, with a profile compatible with a primaryticulostriate arteries (LLA) with no gross communications sensory areabetween the insular arteries and the LLA [36]. 2. A lightly-stained region on the anteriorinferior part

of the insula where neuronal somata predominate, withan intermediate profile between that of a primary

3 . Cytoarchitecture sensory area and a high order association area

The insular cortex is divided into three belts fromanterior to posterior on the basis of a gradual cytoarchitec- 4 . Connectionstonic change. These include (a) an agranular belt on theanterior one-third of the insula (b) a transitional dysgranu- Regional cytoarchitectonic differences correspond welllar belt in layers without complete laminar differentiation, to the thalamic connectivity of the insula. Jones andand (c) a posterior granular belt with well defined granule Burton [21] studied the cortical connections of thecell layers that occupies the posterior third [3]. Further thalamus in 66 rhesus and squirrel monkey brains byanalysis of the cortical architecture of the human insula in injecting isotopically labelled aminoacids in the thalamiccytochrome oxidase, acetylcholinesterase and NSDPH- nuclei complexes, including the medial geniculate body.

Fig. 2. Coronal section of the brain through the foramen of Monro and the amygdala. a5amygdala; ac5anterior commissure; ahg5anterior Heschlsgyrus; alg5anterior long insular gyrus; bcc5body of corpus callosum; bf5body of fornix; c5claustrum; cg5cingulate gyrus; cis5central insular sulcus;cn5caudate nucleus; cs5central sulcus of Rolando; ec5external capsule; exc5extreme capsule; fg5fusiform gyrus; gp5globus pallidus; ic5internalcapsule; ot5optic tract; p5putamen; ph5pes hippocampi; phg5posterior Heschls gyrus; phig5parahippocampal gyrus; psg5posterior short insular gyrus;scg5subcentral gyrus; T15superior temporal gyrus; T25middle temporal gyrus; T35inferior temporal gyrus; t15superior tempolar sulcus; t25inferior

temporal sulcus. From Ture et al. [35], with kind permission.

146 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

While no axoplasmically transported label could be traced Spreen et al. [33] presented the case of a 65-year-oldin the anterior-third agranular area, the posterior-third man with a cerebrovascular accident that involved the rightgranular insular field had a dense, coarse thalamic plexus, hemisphere, including the right Sylvian fissure, parietalwhile the middle dysgranular field had a fine thalamic lobe and long and short gyri of the insula (Fig. 3). Theplexus. Injecting the medial geniculate body resulted in patient had normal language and normal speech receptionintense labelling of the parainsular field throughout its thresholds, but a significant environmental sound agnosia.extent [5]. Physiological experiments using auditory His pitch discrimination in a task that required him toevoked potentials in awake squirrel monkeys have similar- differentiate whether two sounds were of the same orly identified the presence of auditory responsive units in different frequency was normal at low frequencies (250the insular cortex, with response latencies that would be Hz), but deteriorated and was markedly abnormal as thecompatible with direct connections from the medial frequency of the presented sounds increased up to 2000geniculate body, and with higher concentrations of audit- Hz. He was also thought to have amusia, although this wasory units in the caudal (posterior) than rostral (anterior) not formally examined, due to his limited interest in music.parts [34]. However, Mesulam and Mufson [24] labelled While this was one of the first cases to present withbrains of Old World monkeys and found comparable auditory agnosia due to a unilateral, non-dominant hemi-connections of both anterior and posterior part of the insula sphere rather than a bilateral lesion, the particular deficitswith the parvicellular medial geniculate nucleus. for which the insular lesion was responsible are unclear, as

The insula and its posterior part in particular also has the pathology had also affected other auditory areas of thewidespread and well-developed connections with the audit- right hemisphere.ory cortex. Mesulam and Mufson [24] labelled brains of Hyman and Tranel [20] subsequently discussed the caseOld World monkeys with tritiated aminoacids or horserad- of a 61-year-old right-handed man with lacunar cerebro-ish peroxide injections and showed projections from the vascular disease that resulted in a more circumscribeddysgranular area of the insula to the parainsular area and lesion of the left posterior insula and thalamocorticalsuperior temporal cortex, and from the postauditory cortex connections with a spared thalamus (Fig. 4). This patientto the posterior insula (especially the granular areas). There developed a conduction aphasia (disproportionate impair-were additional connections with AIAII (primary and ment of repetition and multiple phonemic paraphasias),association auditory area), and reciprocal connections with with intact aural and reading comprehension of single andthe temporal pole and superior temporal sulcus [2]. In short phrases, but impaired comprehension with moreaddition, the extensive work of Pandya and colleagues complex material. His speech and linguistic functions[25,26] has identified the presence of several interhemis- almost completely resolved several months later, but hepheric connection routes through the corpus callosum, was left with a severe right ear deficit with a near normalwhere it was interesting to note the close proximity of left ear result on dichotic listening to word pairs (52 andauditory fibres and posterior insular fibres. Pandya and 90 of 110, respectively). Dichotic tests, in which the twocolleagues utilized isotope tracers in the rhesus monkey ears are presented with different but simultaneous signals,and found that the anterior aspect of the insula projects are based on the premise that in humans, the contralateralfibres through the posterior aspect of the anterior half of auditory pathway is more robust than the ipsilateral. Forthe corpus callosum, while the posterior segment of the monaural input, the ipsilateral or the contralateral auditoryinsula sends fibre tracts through the anterior part of the pathway is sufficient for the appropriate response, but insulcus of the corpus callosum (which is posterior half of dichotic situations the weaker ipsilateral pathways arethis structure). The fibres from the posterior part of the suppressed and the stronger contralateral pathways remaininsula combined with fibres from regions around and active. This will result in a contralateral deficit if oneincluding the primary auditory areas. hemisphere is compromised and bilateral deficit if the

language-dominant hemisphere is compromised. Thus,Hyman and Tranels case indicates that the lesion of the

5 . Case reports in humans left posterior insula was sufficient to result in a right eardichotic deficit, indicating compromised function of the

Over the last few decades, single case reports in humans left auditory pathway, despite good recovery of languagehave thrown some further light onto the role that the insula function, due to the fact that areas on the left important forhas in auditory processing. Subjects with vascular events language were spared. An alternative hypothesis is that thisthat include the insulae on one or both sides may present patient, who had a 20-year history of diabetes and a 5-yearwith auditory agnosia contralaterally to the affected side, history of hypertension as well as raised cholesterol, hadto environmental sounds [33], speech [20], music [18], or more wide-spread damage of the auditory cortex thanto all three of the above [15,16,19] and this agnosia will depicted on CT.resolve to a varying degree over a few months to years, Similarly to Hyman and Tranel [20], Fifer [16] de-depending on the extent of the lesion and on which other scribed a patient with a stroke in the right inferiorstructures have been affected. temporoparietal area, that involved the insula, extreme

D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154 147

Fig. 3. A photograph with an approximate location of the lesion in Spreen et al. [33]. 15insula; 25external capsule; 35internal capsule; 45Heschlsgyrus.

capsule, claustrum and external capsule and possibly the patient did not react to any sound or speech stimuli andthalamocortical fibres, but that spared Heschls gyrus and was totally mute. Two months later, she had near-normalinternal capsule (Fig. 5). One week post discharge, the language but continued complaining of subtle auditorypatient presented with normal hearing thresholds, but with problems. At that time, she had typical features of non-a left auditory agnosia with poor speech recognition in the verbal auditory agnosia, on the basis of poor identificationleft ear, in quiet as well as in the presence of ipsilateral of environmental sounds and recognition of famous voices,competing message. Six months later, his speech recogni- receptive aprosodia and receptive amusia, as demonstratedtion in the left ear was normal, both in quiet and in the by an auditory agnosia battery. Eight months later, herpresence of an ipsilateral competing message. Fifer thus audiometric thresholds were normal, and while tone in-suggested that the insula may be involved in pre-process- tensity discrimination was also normal, pitch discrimina-ing auditory stimuli prior to Heschls gyrus and Wer- tion was impaired. She had a near total left ear extinctionnickes area, an hypothesis that may be consistent with on a dichotic task with 100% right ear score. Binauralwhat is known about insula connectivity (see previous stimulation middle latency response was present, but poor,Section 4). However, the lesion was imaged by 5 mm cut with Na at 19 ms and Pa at 29 ms, and the recordingCT, that allowed for suboptimal spatial resolution, while obtained from electrodes over the left hemisphere werelocal oedema or metabolic effects of the lesion may well slightly better than from the recording obtained fromhave extended to adjacent auditory cortex structures. electrodes over the right hemisphere. Similarly, the N100

Habib et al. [19] reported the case of a 44-year-old auditory event related response, that is elicited by thefemale who suffered two consecutive embolic cerebrovas- expectation of a rare stimulus, showed a very strongcular accidents, that involved the insulae bilaterally. The asymmetricity in favour of the left hemisphere in thisfirst stroke affected the right insula extending towards the patient, while N100 is usually symmetrically recorded inopercular cortex and temporal lobe while the second stroke the two hemispheres in normals. The authors attributed theaffected the left insula almost in isolation (Fig. 6). Whereas total auditory agnosia to the discrete lesion on the leftthe first strokes single observable deficit was a rapidly insula and significantly, the auditory agnosia persisted afterimproving left hemiparesis, after the second stroke the 1 year, in contrast to previous reports. However, a subtle

148 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

Fig. 4. An illustration of the approximate location of the lesion in Hymanand Tranel [20].

Fig. 5. An illustration of the approximate location of the lesion in Fifer[16].auditory deficit after the first stroke may have escaped

unnoticed, as no test was carried out at that time. They alsosuggested that the two insulae may represent a key station parietal lobe and long gyri of the insula had nofor auditory attention, required to process verbal and non- language deficit, but environmental and probablyverbal stimuli findings, and that this process is mediated music perception deficits. Taken together, this mayvia the callosal connections between the two insulae. This indicate that the right insula and the thalamocorticalhypothesis would explain the dichotic test deficit to the projections it receives are important pre-processingleft, i.e. contralaterally to the more widely damaged right relay stations for all aspects of audition, includingside, but it would not explain the better MLR on the left, music and speechnor the shifting of the N100 to the left hemisphere, as these 2. Habib et al.s case [19] with total agnosia in thetwo potentials are minimally affected by attention. Similar- presence of bilateral insulae damage may indicate thatly, the study has some further limitations, in that initial pre-processing at the level of the insulae on both sidesimaging was done by CT, while MRI was conducted 6 of the brain is vital for auditory processing, as the leftmonths after the second stroke. However, the reported insulathalamocortical projection damage of Hymanamusia is of interest, as there are other case reports of this and Tranels case [20] was not sufficient to producesymptom in the presence of a right insula lesion [18,33]. total agnosia

These case studies are not directly comparable due tothe different and developing imaging techniques over thethree decades spanned by these case reports and to patient 6 . PET and fMRI studiesassessment differences. Moreover, more widespread effectsof the lesion than actually depicted by imaging should also The single case studies of the previous section providebe considered. However, a synthesis of these reports allow abundant support for a major role for the human insulae infor two inferences to be made: auditory processing. However, the specific functional

deficits that are caused by the insular lesions cannot be1. Fifers case [16] with a right temporo-parietal, insular firmly established, due to methodology differences that

and probably thalamocortical projection lesion had a include patient testing and radiology, involvement ofcontralateral speech perception deficit, while Spreens adjacent auditory structures to a varying extent, and thecase [33] with a lesion at the right Sylvian fissure, patients own inherent characteristics pre-stroke. More

D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154 149

subject had had two consecutive strokes in the perisylvianareas that included the insulae bilaterally, leading tocomplete auditory agnosia immediately after the secondstroke. At the time of the PET study, 8 years after hissecond stroke, the patient could discriminate all soundsand categorize and occasionally identify environmentalsounds, but not linguistic stimuli. He had normal auditorybrainstem evoked responses, present but abnormal patternmiddle and long latency auditory evoked potentials andabsent P300s. PET while passively listening to soundsshowed activation of the spared auditory cortex withrecruitment of adjacent areas with homologous function,including the left insula. The authors postulated that theareas that were activated to passive listening to sounds,including the insulae, may be candidates for sound pro-cessing with access to abstract knowledge about non-verbal sound material. Other factors that need to beconsidered include the possibility that the activation seenin the insulae reflects inhibition of a motor response, eitherarticulation, as the patients were asked not to verbalise thesound internally, or raising the arm, as this response wasrequired of the subjects before the scanning, but not duringthe scanning. Unfortunately, control PET data with thesetwo conditions (internal verbalising and arm raising) werenot performed.

6 .1.2. Target and novel auditory stimuli activate theinsulae bilaterally, with greater activation for target

Fig. 6. A photograph with an approximate location of the lesion in Habib than for the novel stimuliet al. [19]. Kiel et al. [22] used event-related functional magnetic

resonance imaging (erfMRI) to assess the cerebral sitessophisticated imaging techniques, such as PET or func- that participate in auditory target detection and noveltytional MRI, that explore the neuronal networks that processing. They used a 1500-Hz tone as target and aparticipate in perceptual cognitive processing in more 1000-Hz tone as non-target stimuli, with non-repeatingdetail, help to further enhance our understanding of the random digital noises, such as whistles, as novel stimuli.functional specialisation of the insulae. Results of these Haemodynamic responses revealed that concurrently withstudies indicate that the human insulae may contribute to other auditory areas, the insulae were bilaterally activatedthe following auditory processes (Table 1): to the target stimuli as well as to the novel stimuli, but

activation was greater for the target versus novel stimuli,6 .1. Sound detection and non-verbal processing and this activation would thus correspond to a larger P3b,

an event related potential response that is elicited byThere is converging evidence that the insulae are expected, task-relevant stimuli [12]. However, one also

involved in sound detection and in entry of the sound into needs to consider whether this greater activation by theawareness, as well as in other non-verbal processing. target versus novel stimuli is due to the entirely different

nature of the stimuli, i.e. digital noises versus pure tones,6 .1.1. The insulae are activated by passive listening to or by the motor task required of the subjects in response tosounds and may thus participate in sound processing the novel stimuli (finger raising), particularly as the insulawith access to abstract knowledge about non-verbal is a motor and motor association area.sound material

Engelien et al. [15] assessed the neural network underly- 6 .1.3. The right insula is a multimodally responsive areaing passive listening to sounds and categorisation of that responds to visual, tactile and auditory stimulienvironmental sounds in six normal volunteers and in a (anterior.posterior) and shows a significantly greatersubject who had sustained a stroke, using PET. In the response to a novel versus a familiar stimulusnormal subjects, passive listening to sounds activated the Downar et al. [14] conducted an fMRI study to identifyauditory cortices bilaterally, but more prominently on the the neuroanatomical network that underlies the detection ofright, where it included the anterior insula. The stroke changes in the visual, auditory and tactile environment, in

150 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

Table 1Summary of the major auditory functions of the insulaeFunctions R insula L insula Reference

(A) Sound detection and non-verbal processingActivation by passive listening to sounds(R.L) 1 1 [15]Activation by target and by novel stimuli, withtarget.novel stimuli activation (P3b generator site) 1 1 [22]Novel.familiar auditory stimulus activation 1 [14]

(B) Temporal processingAuditory temporal processing 1 1 [1]Musical rhythm processing 1 [28]Auditory sequencing 1 [18]Sound movement detection 1 [18]

1 1 [23](C) Phonological processing

Phonological verbal short-term memory 1 1 [27]Phonological rhyming task 1 1 [11]Phonological word recognition 1 [31]

[37]Activation by time-reversed sentences?reflecting short-term memory?sub-vocal rehearsal 1 1 [37]

(D) Visualauditory integrationTemporal onset mismatch detectionbetween visualauditory stimuli 1 [6]Cross-modal speed comparison(auditoryvisual motion task) 1 [23]Mediation of temporally definedcross-modal auditoryvisual interactions 1 1 [7]

the absence of any task. To exclude potential confounding Downar et al. [13] conclude that the insula forms part offactors of response selection, planning and working mem- the network that serves to detect events in the sensoryory on the study results, no response was required during environment across multiple modalities and to identifythe experiment, although this strategy may have the salient (novel) events, in order to mediate attention anddrawback that it could not be checked whether the subjects plan the necessary responses.of the study were actually adhering to the instructions toobserve the stimuli. The authors used continuous trains of 6 .2. Temporal processingstimuli for each modality that alternated independentlybetween two different states, and each alternation was Temporal processing is a prominent function of thelabelled as a transition. The right insula emerged as a central auditory nervous system, and forms one of themultimodally responsive area that responds to visual, bases of speech perception. Some aspects of temporaltactile and auditory stimuli (anterior.posterior), although processing include temporal sequencing (ordering acousticthis activation was less prominent than in other areas such stimuli), pattern perception (ordering acoustic stimuli andas the right temporoparietal junction. processing these as a gestalt rather than as individual

In a subsequent study, Downar et al. [13] sought to components), frequency discrimination, and tasks such asassess whether multimodally responsive areas, including sound localisation are also dependent on temporal process-the insulae, are sensitive to the salience of stimuli across ing in a major way [4,29]. Both insulae appear to besensory modalities independent of behavioural context. responsible for many aspects of auditory temporal process-They used fMRI in 10 right-handed individuals, who were ing that include sequencing of sounds, musical rhythmpresented with an oddball paradigm of a baseline combina- processing, as well as detection of a moving sound.tion of visual, auditory and tactile stimuli, interspersedwith identical deviant stimuli, and after the stimulus had 6 .2.1. The insulae may contribute in auditory temporalbecome familiar, with a combination of visual, auditory processing with the left insula as a non-linear high passand tactile stimuli interspersed with the familiar deviant as filter and the right insula as a linear low-pass filterwell as non-familiar deviant stimuli, in pseudo-random Ackerman et al. [1] assessed rateresponse profilesorder. The right anterior insula showed a significantly across a 26-Hz frequency band by means of functionalgreater response to the novel versus the familiar stimulus. MRI in eight normal right-handed volunteers. They used as

D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154 151

stimuli 6-s trains of synthetic clicks of 26 Hz at a 6 .2.3. The right insula is involved in auditorycomfortable loudness level and instructed the subjects to sequencing and sound movement detectionpassively listen to the stimuli. They found a significant Griffiths et al. [18] investigated central auditory functionnegative linear correlation with a decline of the blood- in a patient with a right hemisphere infarction involvingoxygen level dependent (BOLD) haemodynamic response the insula, 1 year after the stroke, using behavioural tests.when the click train rate increased within the right insular The initial MRI showed diffuse mild atrophy and alteredcortex and a non-linear rateresponse function at the left T2 signal in the right hemisphere and along the rightanterior insular cortex. Thus, they documented a profile of insula, consistent with infarction between the right middlea non-linear high pass filter at the level of the left insula, and posterior cerebral artery territories. One year later, theand of a linear low-pass filter for the right insula, that may MRI showed regional atrophy in the right temporal lobewell underlie the cerebral laterality of auditory processing and altered signal in the right insula, while the patient onlywith longer time frames on the right temporal hemisphere complained of the lack of musical appreciation at that time.(e.g. intonation contours-prosody) versus auditory process- He was found to have a dissociated amusia, with gooding with short time frames on the left temporal hemisphere environmental sound and language perception skills, but(e.g. consonant sounds). However, this difference of non- with poor tune recognition. He was successful in perform-linear high pass filter of the left insula, and of a linear ing, albeit with significantly lower thresholds than inlow-pass filter for the right insula, may also be due to the normal controls, a two-alternative forced choice frequencyBOLD effect showing a progressive attenuation at higher modulation detection task, with low and high modulationfrequencies .1 Hz of stimuli presentation, as has been rates (at 1 and 2 Hz, that would correspond to orchestraldocumented for words. They argue that insulae contribute music, and at 40 Hz, that would correspond to speechin the processing of temporal aspects of verbal utterances, sounds such as consonantvowel transition). He was alsoalthough alternative explanations of their findings, as able to discriminate sequences of different frequency tonesdiscussed by the authors, include the possibility that these presented at a slow rate, but not at a fast rate. Assessmentfindings reflect inner speech, or the activation of an of his auditory spatial processing revealed auditory laterali-internal clock that provides temporal computations across sation deficits both for amplitude and phase cues, moredifferent sensory domains. prominent for sound displacement to the left, and deficits

in sound movement detection tasks for interaural phase andamplitude cues. His amusia was, thus, attributed to the

6 .2.2. The left insula is involved in musical rhythm deficits in auditory sequencing and sound movementprocessing detection, while speech and environmental sound percep-

Platel et al. [28] explored the cerebral structures in- tion were preserved due to their different than musicvolved in the appreciation of music and, in particular, of acoustic structure.the different sub-components of music expression, in aPET study of six young healthy subjects. They found that 6 .3. Phonological processingtimbre appreciation, which involved a same or differenttask, mapped to the right hemisphere, while pitch, rhythm Both insulae are involved in aspects of phonologicaland the judgement that the music sequence sounded processing, such as rhyming and phonological verbalfamiliar were processed in the left hemisphere. In par- short-term memory, while the left insula is involved inticular, rhythm judgement, that involved a task of identify- phonological word recognition.ing whether the lengths of the intervals and notes in thegiven music sequence were regular or irregular, mapped to 6 .3.1. Phonological verbal short-term memory activatesthe left insula and left Brocas area. They attributed the both insulaeactivation of the left insula in the rhythm task, to memory Paulesu et al. [27] assessed the verbal short-termprocessing of sound sequences in this area, and the memory and its phonological component in particular inactivation of Brocas area (BA 6 and 44) to the subjects six right-handed normal subjects using PET. They ex-inner strategy to recall the sounds by articulating. Alter- amined the main effect of phonological processing bynatively, the activation of the left insula may also have to combining the results on two experimental tasks anddo with other demands of the task, such as perceiving the comparing these to the control tasks. The first experimentgiven music sequence (temporal pattern) as a whole and required the subjects to remember visually displayedlabelling this sequence as regular or irregular. Ablation English letters, based on the assumption that these lettersexperiments in cats have shown that the insulartemporal would be transformed into a phonological code andregion of the cat brain is crucial for the animals ability to subvocally rehearsed, while the control task used Koreandiscriminate temporal auditory patterns (e.g. ABA letters for the same task. The second experiment requiredversus BAB) by attending to the entire pattern [10] and the subjects to make rhyming judgements about visuallyit may well be that the human insula is also involved in presented consonants, based on the assumption that visual-temporal auditory pattern discrimination. ly rhyming decisions engage the subvocal rehearsal system

152 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

but not the phonological store. The control task required task, whereas subjects were asked to decide which word inthe subjects to decide whether visually displayed Korean a pair sounded like a real word (phonological decision) orletters looked similar. Phonological processing elicited which word was a real word (orthographical decision).statistically significant activation foci in the insulae bilater- Both orthographic and phonological pronunciation tasksally. Similarly, Wong et al. [37], found that both speech activated the left insula, among other areas of the brain,and non-speech stimuli in the form of time-reversed with a local maximum during orthographic pronunciationsentences activated the anterior insulae on both sides, in a and with both deactivation and significant activation intask that required the subjects to listen to stimulus patterns. different insular areas during phonological pronunciation.They attributed this finding to the necessity to maintain the Phonological, but not orthographic, decision making acti-complex stimulus pattern in short-term memory, or alter- vated the insula near its border with the inferior frontalnatively to sub-vocal rehearsal of the speech signal or the cortex, with this insular region being superior and morepitch patterns in non-speech. The tasks of both of these laterally located than the area deactivated by phonologicalstudies require some form of temporal processing, such as pronunciation, and this activation was the second mostsequencing and pattern recognition, and the findings from striking and robust difference in phonological versusboth these studies may again highlight the insulas signifi- orthographic lexical decision activation after greater acti-cance for temporal processing. vation of the left inferior frontal cortex. This activation

could also be due to the task requiring subvocal articula-6 .3.2. Dyslexics have less activation of the insulae tion. Similarly, Wong et al. [37] found that the left anteriorbilaterally than normal controls when performing a insula was activated on PET by speech as well as non-phonological (rhyming) task speech (time-reversed speech) stimuli, compared to silent

Dyslexics have less activation of the insulae bilaterally baseline. The results of both these studies may indicate thatthan normal controls when performing both a phonological the left insula is an important site for phonologicaltask (judging whether aurally presented pairs of real recognition of words, particularly as an fMRI study [32]words, pseudo-words, or a pair of real and pseudo-word, found that imagining ones voice saying a phrase elicitsrhyme) and a lexical judgement task (judging whether both significantly more activation of the left insula than silentlyaurally presented words were real in a pair of real words or articulating the phrase.pseudo-words or a pair of real and pseudo-words) [11].The lexical task activated the left insula in all seven 6 .4. Visualauditory integrationcontrols but only in two out of eight dyslexics. The authorssuggested that dyslexics differ from able readers in audit- In the cat, the anterior Sylvian area, that contains theory language processes that do not require reading, but anterior Sylvian gyrus and dorsal lip of the pseudo-Sylvianmay interfere with learning to read, and also may interfere sulcus, caudally to the insular areas [8] has multiplewith executive control and attention processes used to auditory and visual connections and may integrate highlyco-ordinate language codes as well as in lexical access. elaborate auditory and visual information [9]. Similarly,They propose that activation of the insulae may reflect the the human insula is a multimodally responsive area thatproblems experienced by individuals with dyslexia, such as integrates information from the visual and auditory sensoryarticulatory coding, phonological decision or rapid auto- modalities.matic naming. The study would have benefited by somemore information on the reading strategies used by both 6 .4.1. The right insula is involved in detection ofthe dyslexic subjects and the normal controls, as dyslexia temporal mismatch (onset asynchrony) between simpleis a diverse clinical entity. In addition, one need consider stationary auditory and visual stimulihow the well-documented brain structural abnormalities in Bushara et al. [6] examined the network activated bydyslexic subjects [17] may have affected these results detection of temporal mismatch (onset asynchrony) be-

tween simple stationary auditory and visual stimuli using6 .3.3. The left insula is activated by phonological PET in twelve right-handed healthy subjects that wererecognition of words asked to indicate whether the stimuli were synchronous or

Rumsey et al. [31] examined the neural pathway in- asynchronous. The task activated the right insula, as wellvolved in phonological versus orthographic strategies of as right prefrontal cortex, inferior parietal lobule and leftword recognition, i.e. sounding out the word versus cerebellar hemisphere. Increasing the task demand, byvisually and/or linguistically analysing the written word in reducing the time-interval between presentation of the twoorder to read it. They measured regional cerebral blood stimuli, correlated with increased regional cerebral bloodflow (rCBF) using PET in 14 healthy male adults. The flow response only in the right insula, indicating that thistasks involved a pronunciation task of items that were area is more actively involved in this process than prefron-specifically constructed to favour orthographic pronuncia- tal and parietal regions. These authors suggest that thistion (e.g. words with irregular spelling) or phonological inter-sensory temporal processing is mediated via subcorti-pronunciation (e.g. pseudowords), and a lexical decision cal tecto-thalamo-insular pathways and may underlie phe-

D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154 153

nomena such as the McGurk illusion, whereby when the imposition of unimodal auditory and visual activationsound of a syllable is synchronised with the image of lip maps revealed no significant areas of tautochronous activa-movements of another syllable, this leads to the perception tion, similarly to the Sudakov et al. [34] results in squirrelof a third syllable. This also may explain the ventriloquist monkeys that auditory responsive and visual responsiveeffect, in which temporally synchronous, but spatially insular areas do not overlap. Conversely, an enhanceddisparate, visual and auditory stimuli will be perceived as response with simultaneous presentation of the two stimulilocalised towards their apparent visual source. or response depression when the stimuli were asynchron-

ously presented were observed in the superior colliculi,6 .4.2. The left anterior insula will be activated by a and less prominently in the insulae bilaterally. Thesecross-modal speed comparison of an auditory versus results would have been more valid if the study had used avisual motion task stepwise stimulus increment to establish the relationship

Lewis et al. [23] investigated the neural substrates of between stimulus level and area activation. In addition, theintegration of visual and auditory motion information by depressed BOLD response could be the result of an activemeans of functional MRI in 11 healthy subjects, who were inhibition at an earlier relay station of the auditoryasked to perform an auditory and a visual motion task in pathway that is required for the task. However, theseisolation or concurrently. In the auditory motion task, the results, together with Busharas study [6], may wellsubjects were required to listen to a 300-Hz square wave of indicate that the insulae have a particular role in mediating300 ms that was presented to both ears with interaural temporally defined crossmodal interactions.intensity differences, in order to elicit the perception ofsound moving to the left or to the right, through or behindthe head. The apparent velocity of the sound was propor- 7 . Comments and conclusiontional to the interaural intensity difference. The subjectswere asked to judge successive presentation of the sounds The insular cortex has been largely ignored as anas slower or faster. The visual motion task involved a auditory centre until recently. However, the finding of verydynamic random dot stimulus, and the subjects were asked prominent auditory deficits in patients with strokes thatto identify the part of the annulus that contained the dots involved the insulae, but spared Heschls gyrus [16,20],with the highest velocity motion. Both tasks elicited indicate that the insulae are not only an integral componentactivation of the anterior insulae bilaterally, but while of the central auditory nervous system, but vital relayactivation of the insulae by the isolated auditory motion stations, as its bilateral damage may result in total agnosiatask was only moderate, it was stronger and more exten- [19]. Sophisticated neuroimaging studies have helped tosive than the insulae activation by the visual motion task. establish the insulas specific auditory functions. There isThe pathways activated by the auditory motion task were converging evidence that the insula is not only involved inbroadly similar to those activated by a pitch discrimination sound detection and in entry of the sound into awareness,task. To further explore the area of cross-modal inter- but also in allocating auditory attention, and in processingaction, the authors asked four subjects to perform a cross- novel versus familiar auditory stimuli. Both insulae appearmodal speed comparison, by presenting visual and auditory to be responsible for many aspects of auditory temporalstimuli simultaneously and asking the subjects to compare processing that include sequencing of sounds, musicalthe speeds of the visual and auditory target. This cross- rhythm processing, prosody, as well as detection of amodal auditory versus visual speed comparison elicited moving sound, while both insulae also seem to be criticalenhancement of the left anterior insula in three of four for music appreciation. Not surprisingly, in view of theirsubjects. However, as Lewis et al. pointed out, this temporal processing functions, both insulae are involved inpolymodal effect could have reflected specific task factors, aspects of phonological processing, such as rhyming andsuch as attentional tracking of the target, selection /compu- phonological verbal short-term memory, while the lefttation of the relevant motion parameter (speed), com- insula is involved in phonological word recognition. Inparison of speeds, selection of response, or non specific addition, the insula appears to be a major multi-sensorytask factors such as storage and retrieval of information integration site that contributes to the detection of temporalfrom working memory. onset mismatch between visualauditory stimuli, auditory

visual speed comparison and temporally defined auditory6 .4.3. The insulae may mediate temporally defined visual interaction, and may thus participate in both thecrossmodal auditoryvisual interactions McGurk phenomenon and the ventriloquists effect. The

Calvert et al. [7] assessed the areas responsible for question is raised whether the posterior part of the insula,non-speech auditoryvisual stimuli integration using the which mainly receives many afferents from the thalamusBOLD effect of fMRI in 10 right-handed normal subjects, and has a staining profile of a primary sensory area, isusing white noise and visual chequerboard as stimuli. involved in basic, important auditory processing [20],Presentation of the auditory stimuli in isolation activated while the anterior insula, which has an intermediate profilethe right insula, amongst other auditory areas. Super- between a primary sensory area and a high order associa-

154 D.-E. Bamiou et al. / Brain Research Reviews 42 (2003) 143154

[18] T.D. Griffiths, A. Rees, C. Witton, P.M. Cross, R.A. Shakir, G.G.R.tion area, is more involved in integration of auditoryGreen, Spatial and temporal auditory processing deficits followinginformation with other associative functions [6,23]. Atright hemisphere infarction. A psychophysical study, Brain 120present, there is no definitive answer to this question, while (1997) 785794.

the functional characterisation of the insula remains incom- [19] M. Habib, G. Daquin, L. Milandre, M.L. Royere, M. Rey, A.plete, underlining the need for further studies. Lanteri, G. Salamon, R. Khalil, Mutism and auditory agnosia due to

bilateral insular damage-role of the insula in human communication,Neuropsychologia 3 (1995) 327339.

[20] B.T. Hyman, D. Tranel, Hemianesthesia and Aphasia. An ana-R eferencestomical and behavioural study, Arch. Neurol. 46 (1989) 816819.

[21] E.G. Jones, H. Burton, Areal differences in the laminar distribution[1] H. Ackermann, A. Riecker, K. Mathiak, M. Erb, W. Grodd, D. of thalamic afferents in cortical fields of the insular, parietal andWildgruber, Rate dependent activation of a prefrontal insular temporal regions of primates, J. Comp. Neurol. 168 (1976) 197cerebellar network during passive listening to trains of click stimuli: 248.an fMRI study, Neuroreport 12 (2001) 40874092. [22] K.A. Kiehl, K.R. Laurens, T.L. Duty, B.B. Forster, P.F. Liddle,[2] J.R. Augustine, The insular lobe in primates including humans, Neural sources involved in auditory target detection and noveltyNeurol. Res. 7 (1985) 210. processing: an event-related fMRI study, Psychophysiology 38[3] J.R. Augustine, Circuitry and functional aspects of the insular lobe (2001) 133142.in primates including humans, Brain. Res. Rev. 22 (1996) 229244. [23] J.W. Lewis, M.S. Beauchamp, E.A. DeYoe, A comparison of visual[4] S.P. Bornstein, F.E. Musiek, Implications of temporal processing for

and auditory motion processing in human cerebral cortex, Cereb.children with learning and language problems, in: D. Beasley (Ed.),

Cortex 10 (2000) 873888.Audition in Childhood: Methods of Study, College Hill Press, San[24] M.M. Mesulam, E.J. Mufson, The insula of Reil in man andDiego, 1980.

monkey. Architectonics, connectivity and function, in: E.G. Jones,[5] H. Burton, E.G. Jones, The posterior thalamic region and its corticalA. Peters (Eds.), Cerebral Cortex, Vol. 4, Plenum Press, New York,projection in New World and Old World monkey, J. Comp. Neurol.1985, pp. 179226.168 (1976) 248302.

[25] D. Pandya, E. Karol, D. Heilbronn, The topographical distribution of[6] K. Bushara, J. Grafman, M. Hallett, Neural correlates of auditoryinterhemispheric connections in the rhesus monkey, Brain Res. 32visual stimulus onset asynchrony detection, J. Neurosci. 21 (2001)(1971) 3143.300304.

[26] D. Pandya, D. Rosene, Some observations on trajectories and[7] G.A. Calvert, P.C. Hansen, S.D. Iversen, M.J. Brammer, Detectiontopography of commissural fibers, in: A. Reeves (Ed.), Epilepsy andof audiovisual integration sites in humans by application ofthe Corpus Callosum, Plenum Press, New York, 1985, pp. 2135.electrophysiological criteria to the BOLD effect, NeuroImage 14

(2001) 427438. [27] E. Paulesu, C.D. Frith, R.S.J. Frackowiak, The neural correlates of[8] F. Clasca, A. Llamas, F. Reinoso-Suarez, Insular cortex and the verbal component of working memory, Nature 362 (1993)

neighboring fields in the cat: a redefinition based on cortical 342345.microarchitecture and connections with the thalamus, J. Comp. [28] H. Platel, J.C. Baron, R. Wise, J. Lambert, R.S.J. Frackowiak, B.Neurol. 384 (1997) 456482. Lechevalier, F. Eustache, The structural components of music

[9] F. Clasca, A. Llamas, F. Reinoso-Suarez, Cortical connections of the perception. A functional anatomical study, Brain 120 (1997) 229insular and adjacent parieto-temporal fields in the cat, Cereb. Cortex 243.10 (2000) 371399. [29] M.L. Pinheiro, F.M. Musiek, Sequencing and temporal ordering in

[10] F.B. Collavita, F.V. Szeligo, S.D. Zimmer, Temporal discrimination the auditory system, in: M.L. Pinheiro, F.M. Musiek (Eds.), Assess-in cats with insulartemporal lesions, Brain Res. 79 (1974) 153 ment of Central Auditory Dysfunction. Foundations and Clinical156. Correlates, Wakeley Press, Baltimore, 1985.

[11] D.P. Corina, T.L. Richards, S. Serafini, A.L. Richards, K. Steury, [30] F. Rivier, S. Clarke, Cytochrome oxidase, acetylcholinesterase andR.D. Abbott, D.R. Echelard, K.R. Maravilla, V.W. Berninger, FMRI NADPH-diaphorase staining in human supratemporal and insularauditory language differences between dyslexic and able reading cortex: evidence for multiple auditory areas, NeuroImage 6 (1997)children, Brain Imaging 12 (2001) 11951201. 288304.

[12] J.T. Coull, Neural correlates of attention and arousal: insights from [31] M. Rumsey, B. Horwitz, B.C. Donohue, K. Nace, J.M. Maisog, P.electrophysiology, functional neuroimaging and psychopharmacolo- Andreason, Phonological and orthographic components of wordgy, Progr. Neurobiol. 55 (1998) 343361.

recognition. A PET-rCBF study, Brain 120 (1997) 739759.[13] J. Downar, A.P. Crawley, D.J. Mikulis, K.D. Davis, A cortical [32] S.S. Shergill, E.T. Bullmore, M.J. Brammer, S.R.C. Williams, R.M.network sensitive to stimulus salience in a neutral behavioural Murry, P.K. McGuire, A functional study of auditory verbalcontext across multiple sensory modalities, J. Neurophysiol. 87 imagery, Psychol. Med. 31 (2001) 241253.(2001) 615620. [33] O. Spreen, A.L. Benton, R.W. Fincham, Auditory agnosia without[14] J. Downar, A.P. Crawley, D.J. Mikulisand, K.D. Davis, A multimod-

aphasia, Arch. Neurol. 13 (1965) 8492.al cortical network for the detection of changes in the sensory

[34] K. Sudakov, P.D. McLean, A. Reeves, R. Marino, Unit study ofenvironment, Nature Neurosci. 3 (2000) 277283.exteroceptive inputs to claustrocortex in awake sitting squirrel[15] A. Engelien, D. Silbersweig, E. Stern, W. Huber, W. Doring, C. Frith,monkeys, Brain Res. 28 (1971) 1934.R.S.J. Frackowiak, The functional anatomy from recovery from

[35] U. Ture, M.G.G. Yasargil, O. Al-Mefty, D.C.H. Yasargil, Topog-auditory agnosia. A PET study of sound categorisation in araphic anatomy of the insular region, J. Neurosurg. 90 (1999)neurological patient and normal controls, Brain 118 (1995) 1395720733.1409.

[36] U. Ture, M.G.G. Yasargil, O. Al-Mefty, D.C.H. Yasargil, Arteries of[16] R.C. Fifer, Insular stroke causing unilateral auditory processingthe insula, J. Neurosurg. 92 (2000) 676687.disorder: case report, J. Am. Acad. Audiol. 4 (1993) 364369.

[17] A.M. Galaburda, G.F. Shermann, G.D. Rosen, F. Aboitiz, M. [37] D. Wong, D.B. Pisoni, J. Learn, J.T. Gandour, R.T. Miyamoto, G.D.Geschwind, Developmental dyslexia: four consecutive patients with Hutchins, PET imaging of differential cortical activation by monaur-cortical abnormalities, Ann. Neurol. 18 (1985) 222233. al speech and non-speech stimuli, Hear. Res. 166 (2002) 923.

The insula (Island of Reil) and its role in auditory processingLiterature reviewIntroductionAnatomyCytoarchitectureConnectionsCase reports in humansPET and fMRI studiesSound detection and non-verbal processingThe insulae are activated by passive listening to sounds and may thus participate in sound pTarget and novel auditory stimuli activate the insulae bilaterally, with greater activation The right insula is a multimodally responsive area that responds to visual, tactile and audi

Temporal processingThe insulae may contribute in auditory temporal processing with the left insula as a non-linThe left insula is involved in musical rhythm processingThe right insula is involved in auditory sequencing and sound movement detection

Phonological processingPhonological verbal short-term memory activates both insulaeDyslexics have less activation of the insulae bilaterally than normal controls when performiThe left insula is activated by phonological recognition of words

Visual-auditory integrationThe right insula is involved in detection of temporal mismatch (onset asynchrony) between The left anterior insula will be activated by a cross-modal speed comparison of an auditory The insulae may mediate temporally defined crossmodal auditory-visual interactions

Comments and conclusionReferences