Emotional processing impairments in patients with insula lesions following stroke

Functional imaging has helped to understand the role of the human insula as a major processing network for integrating input with the current state of the body. However, these studies remain at a correlative level. Studies that have examined insula damage show lesion-specific performance deficits. Case reports have provided anecdotal evidence for deficits following insula damage, but group lesion studies offer a number of advances in providing evidence for functional representation of the insula. We conducted a systematic literature search to review group studies of patients with insula damage after stroke and identified 23 studies that tested emotional processing performance in these patients. Eight of these studies assessed emotional processing of visual (most commonly IAPS), auditory (e.g., prosody), somatosensory (emotional touch) and autonomic function (heart rate variability). Fifteen other studies looked at social processing, including emotional face recognition, gaming tasks and tests of empathy. Overall, there was a bias towards testing only patients with right-hemispheric lesions, making it difficult to consider hemisphere specificity. Although many studies included an overlay of lesion maps to characterise their patients, most did not differentiate lesion statistics between insula subunits and/or applied voxel-based associations between lesion location and impairment. This is probably due to small group sizes, which limit statistical comparisons. We conclude that multicentre analyses of lesion studies with comparable patients and performance tests are needed to definitively test the specific function of parts of the insula in emotional processing and social interaction.


Introduction
In recent years, there has been increasing evidence that the insula plays a central role in the integration and processing of emotional states of experience (e.g. in the case of fear see Stein et al., 2007; in the case of disgust see Calder et al., 2000).In functional imaging studies, the insula is one of the most consistently activated areas in paradigms testing emotional processing (Dosenbach et al., 2006; for a meta-analysis on emotional processing see Kober et al., 2008; for a more general metaanalysis see Kurth et al., 2010).The role of the insula in the perception and evaluation of bodily signals is an integral part of the encoding of emotional information, but also of the activation of emotional states (cf.Craig, 2009;Critchley, 2005).This review aims to summarize findings from imaging studies of the human insula in order to provide a data base for better understanding the function of the insula and its interaction with other brain areas.

Anatomy of the insula
The insula is located bilaterally under the posterior part of the frontal lobe and the anterior part of the temporal lobe and is anatomically divided into anterior (gyri breves insulae) and posterior (gyri longi insulae) regions.The anterior and posterior regions of the insula differ not only in their cytoarchitecture (Quabs et al., 2022), but also in their afferent and efferent connections.While the posterior insula is connected to the thalamus, somatosensory cortex, and superior temporal gyrus, the anterior insula maintains close connections with the limbic system, particularly the amygdala and anterior cingulate, but also with the prefrontal cortices and basal ganglia (Dupont et al., 2003).The posterior insula is involved in various visceral functions (including pain) and physiological bodily processes (cf.Craig, 2009) due to spinothalamic afferents.Because the anterior insula receives both gustatory and olfactory inputs, it has long been thought to be involved only in gustatory and olfactory processing (Mesulam and Mufson, 1982).An isolated insula lesion is quite unlikely since its arterial supply is part (pars insularis) of the arteria cerebri media.Therefore, following partial E-mail address: martin.lotze@uni-greifswald.de.Using cytoarchitectural mapping Quabs et al. (2022) (see Fig. 1 right) reported three distinct regions within the insula: a granular (dorsal posterior insula; ig1-3), an agranular (ventral posterior insula, ld1, ld3, ld5) and a dysgranular region (dorsal anterior insula; ld 4, 6, 7).

Subdivision of the insula based on connectivity
The functional specialisation of the insula can be expressed its projections to other brain regions.To this end, several methods have been used (Van Den Heuvel and Sporns, 2011).Peng et al. (2018) described three different connectivity maps based on resting state functional MRI (rsfMRI) from insula seeds, distinguishing two anterior (ventral and dorsal) and one posterior seed with characteristic functional connectivity at rest.Using cluster analysis on functional connectivity rsfMRI data, Deen et al. (2011) identified three insula subregions with distinct connectivity patterns: a posterior region functionally connected to sensorimotor cortices, a dorsal anterior to middle region connected to the dorsal anterior cingulate cortex, and a ventral anterior region primarily connected to the anterior cingulate cortex.Uddin et al. (2014) used coactivation mapping and network analysis to define categories of insula function.They again proposed three subregions of the insula: (1) "the anterior ventral region, which processes peripheral physiological responses to emotional experience (see also Mutschler et al., 2009); (2) the anterior dorsal region with cognitive control functions, such as attention, inhibitory control, and goal-directed cognitive tasks (Dosenbach et al., 2006); and (3) the posterior insula, which mediates sensorimotor-interoceptive functions (Craig, 2002).Using intracortical recordings Frot and colleagues (2022) investigated the role of the insula in the processing of facial expressions, particularly in the right hemisphere.While the posterior insula cortex and the fusiform gyrus responded to all facial expressions, including neutral expressions, the anterior insula was specifically active in response to emotional faces, especially to expressions of pain and fear.In terms of self-monitoring, neural activity in the anterior insula predicted the accuracy of one´s own heart rate perception (Wiens, 2005).Accordingly, Adolfi et al. (2017) highlighted interoception as an element for emotional processing and self-awareness.
With regard to structural connectivity, the separation in 19 different ROIs, as suggested by Ghaziri et al. (2017), might be unfavourable with respect to a multiple comparison correction.In addition, adjacent ROIs show comparable projections.Centanni et al. (2021) suggested four subregions of the insula: a ventral anterior region mostly involved in limbic processing, a dorsal anterior region for prefrontal interactions, a middle region predominantly involved in cognitive processing and a posterior region predominantly involved in sensory-discriminative processing.In our recent study (Klepzig et al., 2023), we identified four major connectivity groups.Tracking was tested by tractography performed in the human connectome database (see Fig. 2) and published masks can now be used for applying them for white matter diffusionality quantification (e.g., by applying fractional anisotropy) in datasets of patients with possible damage of these structures.

Functional representation in the human insula
While the amygdala primarily reflects the motivational relevance of environmental stimuli, the insula appears to be crucial for the representation of bodily signals elicited by emotional stimuli.This is also supported by findings showing that the amygdala is activated by emotionally relevant stimuli, even when these stimuli are difficult to recognize (Carlsson et al., 2004) or when the subjects are instructed to perform another distracting task (Straube et al., 2006).An early Fig. 1. provides an overview on the structural differentiation of the human insula.Outer left: Practical illustration of the differentiation in an anterior (green) and posterior (red) insula part as demonstrated on a cut of a rendered MNI-brain (Neuromorphometrics, Inc).Dotted line: the central sulcus of the insula is in line with the rolandic sulcus for 95 % of hemispheres investigated (Bakhaidar et al., 2022).Middle: Macroscopic differentiation of the human insula after Clarck (1986) (with permission by Quabs et al., 2022).Abbreviations for the sulci: postCS: postcentral sulcus; CS: central sulcus; preCS: precentral sulcus; SIS: short insular sulcus.Abbreviations for the gyri: ALG: anterior long gyrus; PLG: posterior long gyrus; PSG: posterior short gyrus; MSG: middle short gyrus; ASG: anterior short gyrus; AC: accessory gryrus.Inner Right: Microscopic clustered cytoarchitectural differentiation of the human insula (with permission; Quabs et al., 2022).

Fig. 2.
Projections of four seeds for each hemisphere as tested with the human connectome dataset.Suggestion for a differentiation of four different insula tracts with seeds from the anterior (blue: superior; green: inferior) and posterior (white: superior; red: inferior) insula.The following cortical projections (light blue) have been selected: 1: parietal; 2: prefrontal; 3: occipital; 4: temporal pole.Tracking had been obtained for the Human connectome dataset (VanEssen et al., 2013).
M. Lotze meta-analysis (Wager et al., 2003) did not confirm a lateralization with respect to a valence dimension in emotional processing but reported increased involvement of the left insula in the processing of withdrawal to unpleasant stimuli.A left-hemispheric functional lateralization for the anterior insula representation has been reported for the processing of emotional faces indicating negative valence, such as expressions of anger, sadness and fear (Lukito et al., 2023).Levine et al. (2018) described a left superior-anterior insula activation maxima indicating highest association with individual affective ratings to IAPS pictures in healthy volunteers.The right insula, on the other hand, seems to be more involved in the representation of positive emotions (Duerden et al., 2013).However, emotional vocalizations increasingly activate the right insula without a valence effect (for crying: Sander and Scheich, 2005; for laughing: Wattendorf et al., 2019).For functional studies, subtle lateralization effects are difficult to verify, since interscanner and fMRI sequence effects are high (Seghier, 2008).Fig. 3 provides a schematic overview of the representation of (emotional) insula processing as described in different meta-analyses.

Most prominent models and theories of insula function
Many psychological theories of emotion postulate a close relationship between the perception of bodily changes and emotional experience (Lotze, 1852).There are mainly two traditional models for this relationship; the first theory proposed by James (James, 1884) and Lange (1885) formulated the perception of vegetative patterns as a central mechanism.The second theory, suggested by Schachter and Singer (Schachter and Singer, 1962) suggested that the perception of a more unspecific physical state is integrated into an emotional experience through an evaluation or attribution process triggered by the situation.Critchley (Critchley, 2005) provided a model on how autonomic and visceral information -which are processed on the brain stem level -are interacting with a network of the insula, the anterior cingulate and the orbitofrontal cortex.This network processes basic states of comfort and discomfort which results in essential modification of the behavioural response on a given stimulus.
In his "somatic marker" hypothesis, Damasio explains how interoceptive processes can influence the decision-making process.By anticipating a potentially negative consequence, vegetative and somatic reactions are triggered via the so-called body loop, which are then represented in the somatosensory and insular cortex.The insula thus has the task of a monitor of visceral processes, which are triggered either directly by emotional relevant stimuli, but also by the anticipation of aversive or appetitive consequences.Therefore, bodily physiological signals influence the richness of perceived emotions and can be used to guide decision making (Damasio, 1996).
Apart from the anterior insula relating regional activation patterns with the monitored and corresponding affective state (Phillips et al., 2019), it does also have an important function in recognizing emotionally relevant stimuli (for an early case study see Calder et al., 2000).Singer et al. (2009) assigned the insula as an important function for emotional empathy.People with high introspection and awareness for their own feelings are therefore more prone to develop empathy for other people.The representation of the physiological responses when looking at emotional facial expressions may be an important element that supports the encoding of these emotional stimuli.
Especially the posterior-dorsal insula is associated with autonomic function regulation: patients with stroke in that area experience less heart rate variability than before stroke but increase the amount of complex tachyarrhythmia (Abboud et al., 2006).That points to an active regulative function of the insula for autonomic response (Ozdemir and Hachinski, 2008).
The insula is essential for both valence and arousal processing in interaction with the monitoring of bodily responses.It is therefore not astonishing that the insula has an important role in craving behaviour for drugs and the effect of insula damage on cessation of smoking following stroke has been repeatedly reported.Smokers with insular lesions following stroke were able to quit smoking more easily and more permanently than smokers whose post-stroke lesions did not involve the insular cortex (Abdolahi et al., 2015;Naqvi et al., 2007).This suggests that the perception of visceral cues is not only important for emotional learning and decision-making, but may be an important component of craving for an addictive substance.For a recent review of cessation of smoking following insula stroke see Regner et al. (2019).

Models and experimental evidence for lateralization of insula function
There had been some models on lateralization of insula function.The right hemisphere hypothesis postulates that emotions are preferentially processed in the right hemisphere (Borod et al., 1998).Earlier (Borod, 1992), this author already formulated that posterior (occipito-temporal) sites are important for perception and anterior ones (fronto-temporal) for the expression of emotions.The Valence-Specific Hypothesis (Ahern and Schwartz, 1979) postulates left hemisphere specialization for processing positive emotions (e.g., happiness, surprise) and right hemisphere dominance for processing negative emotions (e.g., anger, fear, disgust, sadness).The approach-withdrawal theory (Davidson et al., 1990) assumes that the left prefrontal lobe is specialized in "approach" emotions, whereas the right prefrontal lobe is increasingly active during "withdrawal" emotions, therefore being a modification of the Valence-Specific Hypothesis.Najt et al. (2013) tested theories about lateralization of insula function by presenting faces with different emotional expressions (sadness, anger, disgust, fear, surprise and happiness but also neutral expressions) in the left or right visual half field in healthy volunteers.To largely exclude speech and language lateralization effects participants were asked to indicate as quickly and correctly as possible whether the presented stimuli showed an "emotional" or "emotionally neutral" face.They found a left hemispheric effect for happy facial recognition but a right hemispheric for anger, fear and surprise.Since disgust and neutral were not lateralized in performance, the authors conclude that none of the three theories could be supported by their trial.Overall, surprise and disgust have some specific additional characteristics in comparison to other basic emotions (surprise increases startle effect which is different to other pleasant emotions; disgust has also been perceived as a funny expression) which do not fit in a mere valence hypothesis.From that study it might be expected that facial expressions of anger, fear, and surprise should be processed more intensively in the right hemisphere and that patients with right-hemispheric lesions might show more impairment in recognition of these emotional facial expressions.Studies  on patients with specific unilateral lesions provide a more specific investigation of parts of the hemispheres and impairment in emotional recognition.However, several factors, such as small samples, different testing methods, and selective patient inclusion hamper consistent effects between centres.

Lateralization for emotional processing in brain damaged patients apart from stroke
Although I here focus on brain damage caused by stroke, other causes of brain damage might also be sensitive for detecting lateralization effects for emotional processing.Previous studies on patients following surgical interventions after medication treatment resistant epilepsy found an impairment for fearful expressions for those with right temporal lobe resection (Benuzzi et al., 2004;Burton et al., 2003).Weniger & Irle (2002), investigating patients following tumour resection or intracerebral haemorrhage, reported highest impairments for fear, sadness and surprise recognition in patients with right-hemispheric damage.One study investigated traumatic brain injured patients (TBI) with contribution of the insula (Dal Monte et al., 2013).They reported impairment in recognition of unpleasant emotional facial expressions for left-sided lesions (insula, temporal pole, medial prefrontal lobe including ACC).These data sets support the view of valence lateralization of insula function since patients with bilateral lesions showed impairments of positively valanced facial expressions.Since TBI has different lesion locations and recovery processes than stroke, this study was not inserted in Table 1.

Case studies involving participants with insula damage following stroke
In an early case study, Calder et al. (2000) showed that a patient with a lesion of the insular cortex and basal ganglia in the left hemisphere had marked impairments in the encoding of disgusted faces and corresponding prosody.However, the patient had no difficulties in assigning images from the International Affective Picture System (IAPS) to different emotion categories, even images with disgusting content.When asked about his disgust reactions in typically disgusting situations, the patient reported significantly fewer disgust reactions than comparable controls.This impairment was not found for other emotions.Adolphs et al. (2003) studied a patient with extensive bilateral lesions of various brain areas including the insular cortex.This patient showed general impairments in recognizing emotional facial expressions, with the encoding of expressions of disgust being particularly impaired.Straube et al. (2010), investigating a patient with a lesion of the right insula and the right basal ganglia found no significant impairment in the recognition of emotional facial expressions.However, in agreement with Calder's findings, there was also no impairment in the categorization of emotional scenes (IAPS images).Nijboer and Jellema (2012) described a case with extensive right hemispheric temporo-occipito-parietal damage who had an impairment in recognizing negatively valanced facial emotions but was not impaired in happy facial expressions.Borg et al. (2013) reported a case with left posterior insula and SII damage following stroke and compared testing with those of 16 healthy controls (HC).The patient showed impairment in the recognition of facial expression of disgust and assessed them as less intense.Grunkina et al. ( 2017) investigated a patient with a complete left hemispheric arteria media infarction who presented impaired bodily response (skin conductance response, SCR) but comparable ratings to a matched HC in response to sounds eliciting chills.Kirsch et al. (2020) reported a case of right large damage (amygdala, thalamus, basal ganglia, precentral gyrus) including the right insula with an impairment of recognizing affective touch but intact tactile acuity.Furthermore, single patient reports were published on a loss of hunger lasting for 15 months after left medial insula damage following stroke (Hébert-Seropian et al., 2021) and on a patient with right anterior insula and temporal pole damage with impairment in fear and disgust facial perception and visceral negative feelings on visual complex scenes (Cantone et al., 2019).Overall, although case studies can help to formulate hypotheses for conducting group studies, they are only of anecdotical value.Since lesion pattern is usually not limited to one anatomical structure, voxel-based group studies offer more possibilities in functional assignments especially when interested in subdivisions of one anatomical area.

Methods
We performed a systematic literature search in January 2024 using the following search terms in PubMed: (1) emotional processing, stroke, insula (PUBMed: 38 hits), (2) emotional processing, insula damage (PUBMed: 67 hits), (3) insula, stroke, psychophysiology, emotion (PUBMed: 37 hits).We identified duplicate records and excluded studies which were not original studies, did not test emotional processing, did not evaluate lesions with brain MRI or CCT, and/or investigated other patient groups apart from stroke patients.Additionally, we checked the reference sections of published articles and included articles describing testing of emotional processing following stroke.
We identified 23 studies who tested these patients for emotional processing performance.Eight of these studies investigated emotional processing of visual (most used IAPS), auditory (prosody or chilling stimuli), somatosensory (emotional touch) and autonomic function (heart rate variability).Fifteen additional studies were related to social processing which comprised emotional facial recognition, gaming tasks and testing of empathy.A PRISM graph illustrating the literature selection process is shown in Supplementary Figure 1.Berntson et al. (2011) presented pictures from the IAPS to seven patients with and nine patients without damage of the insula following stroke (chronic stage).Rating of valence and arousal and the emotional category (e.g., disgust) revealed that insula-damaged patients showed a relevant decrease of their valence and arousal ratings for both very pleasant and very unpleasant stimuli.This study did not differentiate for hemisphere, did not measure psychophysiology and did not perform statistical voxel-wise lesion mapping.An effect for lower rating of the valence dimension in patients with insula damage was also reported by Vijayaraghaven et al., 2013 andParadisoet al., 2011 but not for the arousal dimension.Both reported higher effects for right-hemispheric brain lesions also covering the insula (Paradisoet al., 2011;Vijayaraghavan et al., 2013).For the latter, impaired pleasantness ratings were predominantly based on sexual stimuli, which were rated more aversive and were significantly viewed for shorter times when viewing times could be selected individually.Adolfi et al. (2017) demonstrated impairments in interoception accuracy (heartbeat detection) and emotion recognition (prosody recognition) testing 17 patients (14 right-hemispheric) with insula damage following stroke (chronic stage) compared to 20 HCs.Kirsch et al. (2020) investigated 59 patients with right-hemispheric damage including the insula using different touch including affective touch on the ipsi-and contralesional forearm.In patients with right posterior insula damage, affective touch was less accurately indicated for the contralateral forearm.

Studies on processing of emotional stimuli and interoception
Stroke patients with right-hemispheric insula damage show more often autonomic dysregulations resulting in arrythmias and sudden death (Tokgözoglu et al., 1999).This underlines possible regulatory function of the right insula on autonomic balance.Such autonomic dysfunction can be also mirrored by abnormal skin conductance response (SCR) during emotion induction paradigms.In fact, Holtmann et al. (2020) presented photos from the IAPS and found a SCR reduction and reduction in arousal ratings in nine right-sided insula lesion patients compared to 18 HCs and 10 left-sided insula lesion patients.The authors concluded that their "data suggest an idiosyncratic involvement of the left and right insula in emotional processing, with a role of the right insula as integral node for sympathetic arousal and cognitive-affective processing."Witt and colleagues (2023) presented highly arousing sounds, such as scratching chalk on the blackboard and measured 28 patients in the chronic stage following unilateral stroke (18 with insula lesions).They reported that patients with left-hemispheric insula lesions showed impairments in bodily responses as measured with SCR although arousal ratings were not different to matched HCs.Interestingly, voxelwise lesion mapping revealed no significant associations of SCR impairments and insula damage.However, SCR impairments were associated with white matter integrity of the left inferior anterior insula tract projecting into anterior temporal areas and amygdala (uncinate tract).The authors interpreted their findings that coupling of psychophysiology and rating is transferred by left inferior anterior insula tracts (Witt et al., 2023).
In sum, the right insula seems to be increasingly involved in the processing of autonomic integration and subjective experience during emotional stimulation.In contrast, the bodily response (SCR) in the arousal dimension seems to be integrated in the interaction of left anterior insula to temporal pole.
Table 1 summarizes the findings of studies of samples of stroke survivors with damage of the insula overviewing sample sizes, testing performed, MRI measurements, and main results.
Table 1A comprises general emotional processing (pictures, sounds, somatosensory stimuli) whereas Table 1B those stimuli relevant for social recognition and interaction (facial recognition, empathy, competitive gaming behaviour).Since this differentiation is somehow artificial (emotional faces are for instance included in the IAPS) it is summarized in one Table but differentiated in an A and B part.

Studies on facial recognition, social behaviour and empathy
Usually, facial expressions of six basic emotions are tested which comprise anger, fear, happiness, sadness, surprise and disgust.For pleasant facial expressions, happy faces are easily recognized and even patients perform well (Calvo and Beltrán, 2013).Therefore, unpleasant facial expressions, such as fear and anger, seem to be the best candidates for providing (1) significant between-group effects, and (2) performing well in lesion mapping analysis.There is a discussion on the recognition of disgust, since it seems to be more difficult than the recognition of other basic emotions.This is expressed in decreased hit rates and higher performance variation (as measured with SD) already for healthy participants (see Klepzig et al., 2023).Higher cognitive effort is often related to an increasing amount of working memory resources and therefore performance impairment is not restricted to the insula.As an example for more prefrontal resources needed, lesion mapping in a group of 29 stroke patients showed a higher left BA47 contribution during the recognition for disgusted facial expressions (Klepzig et al., 2023).Kucharska-Pietura et al. (2003) investigated patients following unilateral stroke resulting in left (n = 30) or right (n = 30) hemispheric damage in different parts of the brain presenting visual (emotional facial expressions) and auditory emotional stimuli (recognition for prosody) and compared performance data to those of 50 HCs.The results clearly supported the right-hemisphere hypothesis for emotional processing: all emotional stimuli were less accurately recognized in right-hemispheric damaged patients.Since that study had been conducted quite early and lesions were mostly based on CCT scans (only 33 % had MRIs), there was no voxelwise lesion mapping involved.In addition, there was no differentiation of groups with respect to a present or absent insula or amygdala damage.Terasawa et al. (2015), investigating three patients with right anterior insula damage, did not identify a specific impairment of the facial recognition of basic emotional expression.Especially no clear trends have been recognized for disgust recognition.The authors instead reported a decrease of facial recognition performance across all patients.
Adolfi et al. ( 2017) applied a facial expression recognition task featuring basic emotions and sadness in 17 patients (14 right insula-affected).They found impaired emotional facial recognition for the patient group, especially for sadness.Tippett et al. (2018) investigated 30 right-hemispheric affected stroke patients in the acute stage and compared testing for emotional facial expression to 30 HCs.They reported that patients were less accurate than HCs in identifying emotional and neutral facial expressions.In a more detailed analysis, patients with right amygdala (happy and angry faces) and insula damage (angry faces) were more affected than those with other right-sided lesions.Again, this study did not apply voxelwise lesion mapping.
Holtmann et al. ( 2020) used a comprehensive emotional test battery including testing of facial expressions for happiness, disgust, sadness, fear and surprise, investigating 4 right-and 4 left-hemispheric insula damaged patients versus 19 HCs.This test did not result in relevant group effects.However, in a composite score (calculating an averaged z-score for all applied tasks on emotional processing) the authors identified an impairment for disgust only in the left insula-affected group.Statistical voxelwise lesion mapping was not performed and therefore no exact location of the lesion in association of impairment could be performed.Klepzig et al. (2023) investigated a group of 29 stroke patients in the chronic stage and 14 healthy age-and gender-matched controls and reported that facial recognition deficits of emotional faces expressing fear were associated with left anterior insula lesions, for anger recognition lesion mapping also revealed left insula lesions but more superiorly than for fear.Disgust recognition was associated with right-hemispheric insula and putamen damage, but also left ventrolateral prefrontal damage.Correct recognition of neutral facial expressions was associated with left posterior insula damage.Additional analyses for four tracts deriving from insula seeds of each hemisphere showed an association with integrity of the left superior anterior tract (reaching into the prefrontal lobe) with impairments in the recognition of anger.
Overall, lesion location using voxelwise mapping identified three different locations in the left insula that were associated with recognition impairments.This finding is in concordance with results obtained in patients with brain tumour resection (Dal Monte et al., 2013), but also with data using intraoperative direct electrical stimulation (Frot et al., 2022).
One test for understanding emotions in others is the "Reading the Mind in the Eyes Test" (RMET) (Baron-Cohen et al., 2001).It is more complex than the recognition of the basis emotion in facial expressions since participants are also asked to judge cognitive states of the person depicted.Consequently, additionally to a strong bilateral fronto-insula representation, it involves a disseminated network (temporoparietal, emotion processing areas; Molenberghs et al., 2016) and therefore can easily be affected by various stroke locations.Adolfi et al. (2017), applied this task in 14 right insula affected and three left insula affected participants and found a non-lateralized accuracy impairment in the RMET task when compared to matched controls.Dominguez and colleagues (2019) investigated essential and associated substrates for processing of the RMET.Patients selected (n = 64; mostly right hemispheric affected because those with language impairments were excluded) showed severe impairments in the RMET.They used three different evaluation strategies: parcel-based lesion-symptom (PLSM) technique, tract-wise statistical analysis, and disconnectome symptom mapping.By using the PLSM technique they identified the right inferior frontal gyrus (pars opercularis), insula, precentral gyrus and caudate tail as the regions, which were associated with impairments in the RMET.Highest impairments were observed in the right posterior insula.Disconnectome symptom mapping revealed a location for highest impairments in the right frontal aslant tract interconnecting inferior with superior prefrontal areas.Overall, this study is the first to combine three imaging techniques (fMRI, lesion mapping; white matter affection) for the evaluation of brain regions involved in social-emotional processing.
Emotional empathy includes two different processes: one is the sharing of one´s other emotion and the other is a more cognitive perspective, making interferences about the emotional state of others (Decety and Jackson, 2004).Whereas the first is based predominantly on insula processing, the second is located in the parieto-temporal junction (Decety and Lamm, 2007;Shamay-Tsoory et al., 2004).Right-hemispheric insula lesions have demonstrated higher impairments of affective empathy than left insula damage (Shamay-Tsoory et al., 2005).Consistently, right anterior insula and temporal pole affection resulted in an impairment in affective empathy if compared to HCs (Leigh et al., 2013).Holtmann and colleagues (2023) found an effect for the affective processing of empathy in insula damaged patients but not for the cognitive aspect of empathy (interference of emotional states; Shamay-Tsoory and Lamm, 2018).They did not observe any lateralization effects in their group of 13 left and 7 right-damaged post-stroke patients when compared to 24 HCs.Oishi et al. (2015) were the first who included diffusion weighted imaging quantification strategies for white matter connectivity in emotional testing of 30 right hemispheric stroke patients.They showed that right uncinate fascicle damage (tract between inferior anterior insula and temporal pole/amygdala) was related to an impairment in empathy.
For gambling tasks, it might well be the case that not only prefrontal control but also monitoring of bodily response on emotional situations have an impact on risky behaviour.Clark et al. (2008) showed that not only patients with lesions of the medial frontal lobe, but also patients with lesions of the insula made more risky decisions in the Cambridge Gamble Task.In consideration of data of patients with prefrontal lesions, this finding points to the strong interaction between parts of the anterior insula and the prefrontal cortex for risky decision making.Later Clark and colleagues investigated 4 patients with left and 4 with right insula lesions in the chronic stage following stroke.Whereas HCs demonstrated a riskier behaviour when confronted with near win results, insula patients did not show an impact of these "near to win results" on their future behaviour (Clark et al., 2014).Weller and colleagues (2009) found a comparable effect (reduction of cognitive biases and risky decisions) during gambling in patients with insula lesions no matter on the lateralization of lesion.Kim and colleagues (2017) investigated nine patients and matched HCs with right hemispheric insula stroke in a roulette game.The found that SCR during winning or losing negatively correlated with lesion of the right insula, together with the operculum and medial PFC.Nitsch et al. (2022) investigated 30 patients with insula lesion and 30 patients without who were involved in an Ultimatum Game.Insula lesion patients accepted offers of an unequal disadvantageous split significantly more often than comparison lesion patients.
In conclusion, most lesion studies on empathy, gambling tasks, and tasks on social cognition reported an association of insula damage and deficits.Again, several studies reported an effect stronger for those patients with right hemispheric damage.

Summary
Different methods applied for testing and lesion statistics and small group sizes of cohorts do only enable a very preliminary summary.There seems to be a moderate valence effect in response to emotional pictures (IAPS; Berntson et al., 2011;Paradisoet al., 2011;Vijayaraghaven et al., 2013) for patients with insula damage indicating less positive ratings than HCs.With respect to arousal and related psychophysiology, an SCR reduction and reduction in arousal ratings in right-sided insula lesion patients during presentation of IAPS has been described (Holtmann et al., 2020), whereas emotional sounds elicited a lower SCR amplitude in patients with damage of the anterior-inferior tracts deriving from the left anterior insula (Witt et al., 2023).With respect to autonomic function right-hemispheric insula damage show more often autonomic dysregulations resulting in arrythmias and sudden death (Tokgözoglu et al., 1999).Important for the discriminative function of the posterior insula patients with right posterior insula damage showed less accuracy in affective pleasantness ratings following affective touch for their left forearm (Kirsch et al., 2020).
For facial recognition right sided lesions showed an impairment for recognition of sadness (Adolfi et al., 2017;Tippett et al., 2018) whereas left sided lesions showed an impairment for recognition of fear and anger (Klepzig et al., 2023).The expression of disgust showed bilateral effects in VBLM but for the left hemisphere effects were located more anterior (in BA 47) to the insula (Klepzig et al., 2023).
For the "Reading the Mind in the Eyes Test" (RMET) strongest impairments were observed in the right posterior insula (Domínguez et al., 2019).
With respect to affective empathy right-hemispheric lesions have demonstrated higher impairments than left insula damage (Shamay-Tsoory et al., 2005).Holtmann and colleagues (2023) found an effect for the processing of affective empathy in insula damaged patients but not for the cognitive aspect of empathy.Oishi and colleagues (2015) showed that right uncinate fascicle damage (tract between inferior anterior insula and temporal pole/amygdala) was related to an impairment in empathy.
For gambling tasks both patients with lesions of medial frontal lobe, but also patients with lesions of the insula made more risky decisions (Cambridge Gamble Task; Clark et al., 2008).In addition, there is a smaller "near to win bias" in risky behaviour decisions for all insula damaged patients (Weller et al., 2009;Clark et al., 2014).SCR during winning or losing in a roulette game negatively correlated with lesion of the right insula, together with the operculum and mPFC (Kim et al., 2017).Insula lesion patients accepted offers of an unequal disadvantageous split in an ultimatum game more often than comparison lesion patients (Nitsch et al., 2022).
What models raised for emotional processing and the role of the insula have been supported by these findings?Overall, the models which are considering the insula as part of a network integrating bodily monitoring, autonomic function and emotional processing and recognition are more powerful and stood the proof of time.This comprehends the perception of bodily changes and emotional experience suggested more than one and a half century ago (Lotze, 1852).This also comprehends the role of the insula for monitoring function of bodily responses as proposed by Damasio: 1996.Lesions in the insula or it ´s anterior-ventral pathways result in SCR-decrease in emotional picture and sound processing (e.g., Holtmann et al., 2020;Witt et al., 2023).
The theories of James and Lange but also by Schachter and Singer can be integrated as a bodily reaction which has an impact on the experience but is somehow independently going on besides of a cognitive evaluation process.It could not fully be demonstrated what is the hen and what the egg but it became quite clear that they both interact in a monistic model integrating bodily response and experience of emotions.
The anterior insula is processing the emotional content whereas the posterior the discriminative aspects of experience.This is already supported by anatomical structural and functional connectivity of the two insula parts but also by findings that anterior insula lesions result in deficits in facial expression recognition (Holtmann et al., 2020;Klepzig et al., 2023).In addition, according to Abboud et al., 2006 the right posterior insula is especially important for processing autonomic function (see also Ozdemir and Hachinski, 2008;Tokgözoglu et al., 1999).In contrast, theories which were quite simplistic and were built only on one dimension of emotional experience (e.g., valence) could not be reproduced.Borod et al. (1998) suggested that the right hemisphere is processing all emotions which was not supported by most of the studies.The Valence-Specific Hypothesis (Ahern and Schwartz, 1979) which postulates left hemisphere specialization for processing positive emotions (e. g., happiness, surprise) and right hemisphere dominance for processing negative emotions (e.g., anger, fear, disgust, sadness) and the Approach-Withdrawal Theory (Davidson et al., 1990) could not fully be verified by lesion studies.
Overall, a right hemisphere bias of patients in studies testing emotional recognition following stroke can be stated.Therefore, only some studies are available for comparisons between hemispheres.In detail, disgust was not lateralized in the study of Naqui et al., 2013 and studies using VLSM (e.g., Klepzig et al., 2023) described that negatively valenced emotions like anger and fear were lateralized to the left anterior insula.This has also been shown in TBI patients (Dal Monte et al., 2013) and by direct cortical stimulation of the insula (Frot et al., 2022).
Much more promising seems to be based on a network approach: Critchley (2005) describes a network interacting for basic states of comfort and discomfort contributing the brain stem, insula, ACC, OFC.This seems to be proven by most fMRI studies and partially also by lesion studies.

Perspective
Since it has become quite clear that subregions of the insula are differentially interconnected with other brain areas and functionally specialized a mere differentiation in lesion with or without damage of the insula is of limited value.Parcel-based lesion-symptom mapping (PLSM) may be more promising for increasing power of patient studies with low numbers of participants whereas for VLSM a restriction on the insula as a region of interest might be warranted for smaller group sizes.In addition, adding information about integrity of white matter tracts for interactions between different brain subsystems is an important issue.Only a small number of studies includes these different aspects which are essential to understand the contribution of insula subregions for emotional processing.Overall, this topic definitely calls for data aggregations between study centers, e.g. with new multicentre studies in centres with comparable testing.Besides the patient selection bias, the issue of different testing tools and scores used between study centres will challenge this endeavour.

Disclosures
The study was funded by a grant from the "Deutsche Forschungsgemeinschaft" (DFG).ML is a paid editor for the journal "Neuroreha" (Thieme Verlag).There is nothing else to disclose.

Declaration of competing interest
None.

Table 1 A: Emotional picture processing, emotional sounds, chill and addiction, interoception and psychophysiology
B: Facial recognition, social processing (empathy and competitive games) PLSM: right insula showed highest impairments in the RMET (CD=1.27),right (continued on next page) M. Lotze