Participation of the insula in language revisited: A meta-analytic connectivity study

https://doi.org/10.1016/j.jneuroling.2014.02.001Get rights and content

Highlights

  • A meta-analytic connectivity study using the Activation Likelihood Estimation (ALE) technique was developed.

  • 26 papers corresponding to 39 paradigms, and including 522 participants were used in this study.

  • Thirteen different activation clusters were found.

  • The left insula represent a core area in language processing.

Abstract

Despite the insula's location in the epicenter of the human language area, its specific role in language is not sufficiently understood. The left insula has been related to a diversity of speech/language functions, including articulatory planning, language repetition ability, and phonological recognition. To further our understanding of the role of the insula in language, a meta-analytic connectivity study using the Activation Likelihood Estimation (ALE) technique was developed. By means of the BrainMap functional database, 26 papers corresponding to 39 paradigms, and including 522 participants were selected. Thirteen different activation clusters were found; insula connections included not only areas involved in language production (such as the Broca's area) and language understanding (such as the Wernicke's area), but also areas involved in language repetition (such as the supramarginal gyrus) and other linguistic functions, such as BA9 in the left prefrontal lobe (involved in complex language processes) and BA37 (involved in lexico-semantic associations). In conclusion, the insula represents a core area in language processing, as it was suggested during the 19th century.

Introduction

The insula (or Island of Reil) is a complex and not completely understood brain area. Its potential participation in language has been a topic of controversy since the 19th century (Freud, 1891, Wernicke, 1874/1970), even though currently it seems evident that it plays a crucial role in language processing (Price, 2010). The anterior segment of the insula extends to and interfaces with Broca's area while its posterior elements adjoin Wernicke's area (Flynn, Benson, & Ardila, 1999). The left insula is notably larger than the right in most humans (Greve et al., 2013, Mesulam and Mufson, 1985). Both the asymmetry and the location in the epicenter of the human language area (Benson & Ardila, 1996; Dejerine, 1914, Luria, 1976) suggest that the insula may be active in language processes. However, few papers have been specifically devoted to the analysis of the role of the insula in language (e.g., Ackermann and Riecker, 2004, Ardila, 1999, Ardila et al., 1997).

Since Wernicke (1874), the insula has frequently been implicated in the “major aphasic syndromes”: Broca's aphasia, conduction aphasia, and Wernicke's aphasia. In fact, Wernicke (1874) directly related insula damage with conduction aphasia. Involvement of the anterior part of the insula in Broca's aphasia was noted by Bernheim (1900) and Dejerine (1914) at the beginning of the 20th century. Furthermore, Liepmann and Storck (1902) associated the word-deafness component of Wernicke's aphasia with posterior insula pathology.

Pathology involving only the insular cortex and immediate sub-cortical structures, has been rarely reported however. Alexander, Benson, and Stuss (1989) presented two cases of pathology limited to the left insula and subjacent extreme-external capsules. Aphasia with mildly paraphasic production and agraphia was noted in both cases. Nielsen and Friedman (1942) reported several autopsy findings illustrating the association between left insula damage and aphasia. They noted, however, from their own cases and others in the literature, that a similar language syndrome followed isolated extreme capsule damage and postulated that insular damage without extreme capsule involvement would not produce aphasia. Habib et al. (1995) reported a case of bilateral insular damage, extending to a small part of the striatum on the left side, and to the temporal pole on the right. The patient presented mutism for about one month, did not respond to any auditory stimuli, and made no effort to communicate.

It is noteworthy that mutism has been frequently observed in individuals who suffered from insular damage. Transient mutism is found in cases of left inferior motor cortex damage extending to the insula (Alexander et al., 1989, Schiff et al., 1983), whereas lasting mutism appears to be associated with bilateral lesions of the frontal operculum and anterior insula (Cappa et al., 1987, Groswaser et al., 1988, Pineda and Ardila, 1992, Sussman et al., 1983). Alexander et al. (1989) suggested that left cortical and sub-cortical opercular lesions frequently result in a total speech loss associated with a right hemiparesis. Shuren (1993) described a patient who developed impaired speech initiation as a result of a left anterior insular infarct and suggested that anterior insular lesions in the left hemisphere could impair speech initiation. A possible interactive role of the left insula in speech initiation and language motivation could thus be conjectured (Ardila et al., 1997).

Dronkers (1996) showed that the left precentral gyrus of the insula is involved in motor planning of speech. Twenty-five stroke patients with a disorder in planning of articulatory movements (apraxia of speech), were compared with 19 individuals without such deficits. It was found that all patients with articulatory planning impairments presented lesions including the anterior insula. This area was completely spared in all patients without these articulatory defects. It was concluded that anterior insula represents a crucial brain area in motor planning and organization of speech. Verbal articulatory disruptions in some cases may be so severe as to result in mutism (Alexander et al., 1989, Pineda and Ardila, 1992).

Contemporary neuroimaging technique studies have supported the hypothesis regarding an active involvement of the insula in linguistic processes. Activation of the insula has been demonstrated in a diversity of verbal tests, including word generation (Baker et al., 1997, Bohland and Guenther, 2006, Gurd et al., 2002, Kemeny et al., 2005, McCarthy et al., 1993, Pihlajamaki et al., 2000, Rowan et al., 2004, Voets et al., 2006), naming (Berlingeri et al., 2008, Damasio et al., 2001, Price et al., 1996), and phonological discrimination (Booth et al., 2002, Rumsey et al., 1997, Tyler et al., 2005) (see Table 1). The insula has also been related to auditory processing (Bamiou, Musiek, & Luxon, 2003). Bates et al. (2003) analyzed the speech fluency and language comprehension of 101 patients with a left hemisphere stroke using voxel-based lesion symptom mapping the authors identified the insula as a crucial area in language; they observed that lesions involving the insula had a significant impact in verbal fluency.

These findings support the conclusion that the insula significantly participates in language. Furthermore, they suggest that the insula is not be involved in a single linguistic process, but simultaneously in several verbal processes. The anterior portion of the insula appears to be involved in the organization and planning of language articulation, and language initiation; while the middle and posterior portions appear to be involved with lexical knowledge, word retrieval, language understanding, and phonological discrimination.

Other studies have also suggested that the insula is involved in second language learning in bilinguals (e.g., Archila-Suerte et al., 2013, Buchweitz et al., 2012, Chan et al., 2008, Hernandez, 2009, Saur et al., 2009, Veroude et al., 2010). Chee, Soon, Lee, and Pallier (2004) analyzed the brain activity English/Chinese bilinguals. They observed that the left insula showed greater activation in equal bilinguals. Unequal bilinguals showed greater task-related deactivation in the anterior medial frontal region and greater anterior cingulate activation. These authors suggested that left insula activation can be regarded a marker for language attainment in bilinguals. Similar results were reported by Gandour et al. (2007).

The insula has also been related to the learning of grammar. Yang and Li (2012) analyzed the neural correlates of explicit and implicit learning of artificial grammar sequences. Using effective connectivity analyses of functional magnetic resonance imaging (fMRI) they found that different brain systems support these two types of learning: both activate some specific cortical and subcortical brain areas, but explicit learning is based in a circuit that includes the insula as a key mediator; implicit learning on the other hand activates a frontal-striatal circuit. There is no question that the insula plays a crucial role in grammar learning.

It is noteworthy that the insula possesses not only contralateral motor and sensory representation but also ipsilateral motor and sensory connections (Flynn et al., 1999). Connections have been described between the insula and the orbital cortex, frontal operculum, lateral premotor cortex, ventral granular cortex, and medial area 6 in the frontal lobe. The insula has been found to also connect with the temporal pole and the superior temporal sulcus. Significant projections to the cingulate gyrus, amygdaloid nucleus, perirhinal cortex, entorhinal and periamygdaloid cortex have been observed (Augustine, 1996; Flynn et al., 1999). The insula in consequence maintains a complex system of interconnections not only with classical cortical language regions in the temporal and frontal lobe, but with a variety of limbic structures as well, including the cingulate gyrus and the perirhinal and entorhinal cortex.

Bressler and Menon (2010) have emphasized that cognition results from the dynamic interactions of distributed brain areas operating in large-scale networks. They specifically refer to a “salience network” involved in monitoring the salience of external inputs and internal brain events. This salience network is proposed to be anchored in anterior insular and dorsal anterior cingulate cortices.

The analysis of the functional connectivity of the insula becomes most important in understanding its real contribution to the language brain system. Currently, there are several techniques that can potentially demonstrate brain networks. These techniques are grouped under the term “brain connectivity”. Recently, a new alternative to study brain connectivity has been proposed by Robinson, Laird, Glahn, Lovallo, and Fox (2010) known as meta-analytic connectivity modeling or MACM. MACM is based in automatic meta-analysis done by pooling co-activation patterns. The technique takes advantage of the Brainmap.org's repository of functional MRI studies, and of a special software (Sleuth) provided by the same group, to find, filter, organize, plot, and export the peaks coordinates for further statistical analysis of its results. Sleuth provides a list of foci, in Talairach or MNI coordinates, each one representing the center of mass of a cluster of activation. The method takes the region of interest (for instance, the insula), makes it the independent variable, and interrogates the database for studies showing activation of the chosen target. The query is easily filtered with different conditions (such as age, normal vs. patients, type of paradigm, domain of cognition, etc). By pooling the data with these conditions the tool provides a universe of co-activations that can be statistically analyzed for significant commonality. As a final step, Activation Likelihood Estimation (ALE) (Laird et al., 2005, Turkeltaub et al., 2002) that can be performed utilizing GingerALE, another software also provided by BrainMap, generating the probability of an event to occur at voxel level across the studies. Areas of coactivation will show a network related to the function and domains selected as filter criteria.

Considering the complex role of insula in language a meta-analytic connectivity utilizing MACM on the participation of the insula in language was developed. It was hypothesized that the left insula participated in different brain language circuits associated with different language functions.

Section snippets

Materials and methods

The DataBase of Brainmap (brainMap.org) was accessed utilizing Sleuth 2.2 on October 10, 2013. Sleuth is the software provided by BrainMap to query its database. The meta-analysis was intended to assess the network of coactivations in which the insula is involved.

The search conditions were: (1) studies reporting insula activation; (2) studies using fMRI; (3) context: normal subjects; (4) activations: activation only; (5) handedness: right-handed subjects; (6) age 20–60 years; (7) domain:

Results

Twenty-six papers corresponding to 39 experimental conditions with a total of 522 subjects were selected (subjects participating in two different experiments were counted as two subjects) (Table 1).

Table 2 presents the main loci of brain connectivity of insula by Meta-analytic Connectivity Modeling (MACM). Thirteen different clusters of activation were found, mostly related to the left hemisphere (Fig. 1).

The first cluster includes the claustrum (that is the insular subcortical gray matter);

Discussion

The current meta-analytic connectivity study reveals the participation of the left insula in a complex brain network involved in different aspects of language. Significant connections with left Broca's area (BA44) and the left middle frontal gyrus (area 9) clearly support attributing involvement of the insula in language production and complex language organization. This observation is congruent with the report that the anterior insula participates in motor planning of speech (Dronkers, 1996);

Acknowledgments

Our most sincere gratitude to Dr. Erika Hoff for her editorial support and valuable suggestions.

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