Table 1.
Characteristics of VBM studies
| Study | Diagnosis | Sample size | Mean age/Group | Insular region Atrophy | Functional domain | Correlation Volume/Atrophy vs function |
p value GM Multiple comparison |
MRI Field strength | Software | FWHM |
|---|---|---|---|---|---|---|---|---|---|---|
| (Li et al. 2016) | AD | AD = 21 HC = 25 |
AD = 68.19 ± 9.07 HC = 64.52 ± 6.44 |
Bilateral insula |
Affective-cognition: Impaired recognition of emotional images-emotional memory (EM) |
Positive: volume of bilateral insula and EM |
p < 0.05 FWE corrected | 3.0 T | SPM8 | 8 mm |
| (Amanzio et al. 2016) | bvFTD |
FTD = 15 HC = 15 |
bvFTD =68.65 ± 8.68 HC = 62.0 ± 4.4 |
Left insula |
Activity Instrumental Activities of daily living (iADL) |
Positive: Left insula volume and iADL scores |
p < 0.005 corrected | 1.5 T | SPM8 | 8 mm |
| (Alzahrani et al. 2016) | PD |
PD = 65 HC = 24 |
PD = 67.1 HC = 62.79 (9.77) |
Left insula |
Emotion: Apathy |
Negative: Left insula volume and apathy |
p < 0.001 corrected |
1.5 T | SPM8 | 8 mm |
| (Dermody et al. 2016) |
FTD AD |
bvFTD =24 AD = 25 HC = 22 |
bvFTD =63.0 AD = 66.1(8.0) HC = 68.2(6.7) |
Left insula |
Affective-Cognitive: Empathy |
Positive: Left insula volume and empathy in bvFTD |
p < 0.001 uncorrected |
3 T | FSL | 8 mm |
| (Blanc et al. 2016) | Pro-DLB and pro-AD |
Patients =55 HC = 33 |
Pro-DLB =67.5 Pro-AD 69.3= HC = 72.4 ± 10.4 |
Bilateral insula |
Cognitive: MCI |
No correlation assessed.Bilateral insular atrophy and pro-DLB diagnosis |
p < 0.05 FWE corrected |
3 T | SPM8 | 8 mm |
| (Mandelli et al. 2016) | FTD: nfvPPA and bvFTD |
FTD = 48 HC = 34 |
FTD = 64.8 HC = 62.3 |
1.nfvPPA: Left SPGI 2.bvFTD: bilateral insula |
1-Speech: verbal agility (nfvPPA) 2-Behavior: Aberrant eating (bvFTD) |
Positive: 1-Left SPGI and verbal agility in nfvPPA Negative 2- bvFTD: Bilateral VA insulae volume and aberrant eating |
p < 0.05 FWE corrected |
1.5/3 T | SPM8 | 8 mm |
| (Heitz et al. 2016) | DLB and AD |
Patients = 48 HC = 16 |
Patients =68.9 HC = 68.3 ± 10.5 |
Left insula |
Cognitive & affective-cognition: Theory of mind, faux pas recognition (social sensitivity) |
Positive: Left insula atrophy and Theory of mind deficits in DLB |
P < 0.05 | 3 T | SPM12 | 8 mm |
| (Chen et al. 2016) | PD |
Patients = 37 HC = 21 |
Patients =61.9 HC = 61.95 ± 5.40 |
Bilateral insula | Cognition & Disease severity |
Positive: right insula atrophy & disease duration,UPDRS score -No correlation with cognition |
p < 0.01 alphasim correction p < 0.05 Bonferroni correction |
3 T | SPM8 | 8 mm |
| (O'Callaghan et al. 2016) | FTD |
Patients = 22 HC = 22 |
Patients =64.8 ± 8.8 HC = 64.8 ± 11.1 |
Left anterior insula |
Behavior: Pro-social behavior |
Positive: left anterior insula volume & Prosocial behavior |
p < 0.05 FWE corrected |
3 T | FSL | 8 mm |
| (Zhang et al. 2015) | PD |
PD = 35 HC = 20 |
PD = 61.86 ± 8.98 HC = 59.36 ± 6.36 |
PD-MCI: Left insula | Cognition: Memory impairment |
No correlation assessed. PD-MCI and atrophy in the left insula |
p < 0.05 | 3 T | SPM5 | 8 mm |
| (Fletcher et al. 2015b) | FTD and AD |
FTD = 56 AD = 17 HC = 50 |
Patients = 64.7 HC = 67.5 |
1.Bilateral Mid- posterior insula |
Behavior: Music aversion |
Positive: Atrophy and music aversion in FTD |
p < 0.05 FWE corrected |
3 T | SPM8 | 6 mm |
| (Fletcher et al. 2015a) | FTD and PD |
Patients = 78 HC = 20 |
Patients =64.95 HC = 67.5 |
Right mid and posterior insula |
Autonomic: Pain & temperature |
Positive: Atrophy and pain and temperature changes in FTD |
p < 0.05 | 3 T | SPM8 | 6 mm |
| (Hu et al. 2015) | MCI and AD |
Patients = 293 HC = 131 |
Patients =74.6 ± 7.5 HC = 75.6 ± 5.0 |
Left Insula | Emotion: Agitation |
Positive: Atrophy and agitation in combined group MCI and AD |
P < 0.05 FWE corrected | 1.5 T | SPM8 | 8 mm |
| (Sturm et al. 2015) | FTD |
FTD = 96 HC = 34 |
FTD = 61.9 ± 7.3 HC = 64.9 ± 9.3 |
Left anterior insula |
Emotion: Happiness |
Positive: Atrophy & higher happiness behavior |
p < 0.05 FWE corrected |
1.5/3 T | SPM5 | 8 mm |
| (Ting et al. 2015) | MCI/early AD (delusional vs non-delusional) | Patients = 58 | Patients =74.4 | Right Insula | Perception: Delusions |
Positive: Insula atrophy and delusions |
p < 0.001 uncorrected p < 0.05 FWE and FDR corrected |
1.5 T | SPM8 | 10 mm |
| (Woolley et al. 2015) | AD, FTD |
Patients = 305 FM = 25 HC = 90 |
*Patients =61.8 FM = 48.2 ± 12.4 HC(69.4 ± 7.0) |
Bilateral Ventro-anterior Insula |
Behavior & affective- cognition: 1-Disgusting behavior 2- Disgust Recognition |
Positive: Bilateral anterior insula atrophy and disgust behavior/ recognition in FTD |
1-p < 0.05 FWE 2-p < 0.005 FWE uncorrected |
1.5,3,4 T | SPM5 | 8 mm |
| (Blanc et al. 2014) | AD |
Patients = 39 HC = 39 |
Patients =76.2 HC = 78.8 |
Right anterior insula | Perception: Hallucinations |
Positive: insula atrophy and hallucinations |
p < 0.001 uncorrected p < 0.05 FWE corrected |
1.5 T | SPM12b | 8 mm |
| (Cerasa et al. 2014) | PD |
Patients = 24 HC = 24 |
Patients =58.65 HC = 60.3 ± 9.1 |
Right insula |
Behavioral: Pathological Gambling |
No correlation between insula atrophy and test for gambling |
p < 0.05 FWE corrected |
3 T | SPM8 | 10 mm |
| (Kumfor et al. 2014) | FTD and AD |
Patients = 27 HC = 12 |
Patients =67.8 HC = 71.3 ± 5.0 |
Right Insula |
Affective-cognition: Emotional enhancement of memory |
Positive: Emotional enhancement of memory and integrity of right insula in FTD |
p < 0.005 uncorrected | 3 T | FSL | 8 mm |
| (Lee et al. 2014) | PD-MCI |
PD = 51 HC = 25 |
PD = 71.36 HC = 70.0 ± 3.4 |
Left insula- |
Cognitive: Frontal executive functions |
No correlation between insula atrophy and executive functions |
p < 0.001 uncorrected |
3 T | SPM8 | 6 mm |
| (Gama et al. 2014) | PD |
PD = 39 HC = 10 |
PD = 67.1 ± 8.4 HC = 68.1 ± 7.0 |
Left insula |
Perception: Visual hallucinations |
Positive: Atrophy of left insula and hallucinations | P < 0.05 | 1.5 T | SPM8 | 12 mm |
| (Mak et al. 2014) | PD- MCI vs no MCI | Patients = 90 | Patients = 64.95 ± 7.54 | Left insula |
Cognitive: Executive function & attention |
Negative: Left insula atrophy and executive function/ attention |
p < 0.001 uncorrected p < 0.05 |
3 T | SPM8 | 8 mm |
| (Perry et al. 2014) | bvFTD | FTD = 91 | FTD = 59.7 ± 8.4 | Right anterior insula |
Behavior: Aberrant Eating and sweet preference |
Positive: Insula volume and aberrant eating |
P < 0.05 FWE corrected |
1.5/ 3/ 4 T | SPM8 | 8 mm |
| (Shany-Ur et al. 2014) | AD and FTD |
Patients = 78 HC = 46 |
Patients = 62.1 HC = 69.9 ± 7.1 |
Right anterior and posterior insula |
Cognitive: Self-awareness |
Positive: 1- Right anterior insula & awareness of ADLs, cognitive abilities, and interpersonal abilities. 2- Bilateral insular atrophy & awareness of emotional control |
P < 0.05 FWE corrected P < 0.001 uncorrected |
1.5/3/4 T | SPM5 | – |
| (Shine et al. 2014) | PD (hallucinators vs non-hallucinators) | Patients = 22 | Patients = 63.21 | Bilateral anterior insula | Perception: hallucinations |
Positive: Bilateral anterior insula atrophy and BPP score (hallucinations) |
P < 0.05 FDR corrected |
3 T | SPM8 | 8 mm |
| (Cerami et al. 2014) | bvFTD | FTD = 14HC = 20 |
FTD = 63.4 ± 7.47 HC = 62.8 ± 7.9 |
Left posterior insula |
Emotion: Emotional attribution of empathy |
Positive: Left insula atrophy and emotion attribution |
p < 0.05 FWE corrected | 3.0 T | SPM8 | 8 mm |
| (Couto et al. 2013) | PNFA and bvFTD |
Patients =22 HC = 18 |
Patients = 67.57 HC = 69.8 ± 7.3 |
1-Bilateral insula- both groups 2- bilateral anterior insula- bvFTD |
1- Affective-Cognition: Face recognition, emotion recognition, 2- Cognition: theory of mind |
Negative1-bilateral insula atrophy & Face recognition in PNFA 2- Emotion & bilateral insula atrophy 3-TOM: bilateral insula atrophy in PNFA |
p < 0.05 | 1.5 T | SPM8 | 12 mm |
| (Stanton et al. 2013) | AD and PSP | Patients =17 | Patients = 72.68 | Left insula |
Emotion: Apathy Emotional blunting |
Positive: Left insular atrophy & emotional blunting and apathy |
p < 0.05 | 3 T | SPM5 | 8 mm |
| (Kumfor et al. 2013) | FTD (bvFTD, SD, PNFA) |
Patients =40 HC =27 |
Patients = 63.69 HC = 64.3 ± 3.7 |
Disgust recognition: left ventral anterior insula |
Affective-Cognition: Negative Emotion recognition |
Positive: Left ventral anterior insula volume with disgust recognition in bvFTD and SD |
p < 0.05 FWE corrected |
3 T | FSL | 8 mm |
| (Lee et al. 2013) | PD ± dementia |
Patients =32 HC = 16 |
Patients = 69.1 HC = 69.5 ± 6.3 |
Anterior insula: Short insular gyrus |
Cognition: Dementia |
Decreased anterior insula volume in PDD |
p < 0.001 uncorrected |
1.5 T | SPM2 | 8 mm |
| (Nakaaki et al. 2013) | AD (delusional vs non-delusional) | Patients = 53 | Patients = 76.94 | Left insula | Perception: Delusions |
Positive: Left insular atrophy & delusions |
p < 0.05 FDR corrected |
1.5 T | SPM5 | 12 mm |
| (Eslinger et al. 2012) | FTD(bvFTD, PNFA, SD) |
Patients = 26 HC = 16 |
FTD = 68.45 HC = 75.0 ± 6.6 |
Left anterior insula |
Emotion: Apathy |
Negative: Left anterior insular volume & apathy evaluation scale in bvFTD |
p < 0.0001 uncorrected p < 0.025 uncorrected |
3 T | SPM99 | 12 mm |
| (Hsieh et al. 2012) |
SD-FTD AD |
FTD = 9 AD = 12 HC = 15 |
FTD = 62.6 ± 5.4 AD = 62.9 ± 8.2 HC = 64.2 ± 6.4 |
Bilateral insula |
Affective-Cognitive: Emotion Recognition from faces and music |
Positive: Insula volume and emotion recognition |
p < 0.001 uncorrected | 3 T | FSL | 8 mm |
| (Vasconcelos et al. 2011) | Mild AD | Patients = 19 | Patients = 75.2 ± 4.7 | Right anterior insula |
Cognition: Global (MMSE) and disability assessment for dementia |
Positive: Right insular atrophy & disability assessment for dementia scores and MMSE |
P < 0.001 uncorrected | 1.5 T | SPM5 | 8 mm |
| (Omar et al. 2011) | FTD |
Patients = 26 HC = 21 |
Patients = 63.81 HC = 67.0 ± 8.8 |
Bilateral anterior insula | Affective-cognition: Emotion recognition | Positive: Anterior insula atrophy and impaired emotion recognition from music and faces |
p < 0.05 FDR corrected |
1.5 T | SPM2 | 8 mm |
| (Song et al. 2011) | PD (MCI vs PDD) | Patients = 68 | Patients = 70.76 | left insula (PD-MCI)& right insula (PDD) |
Cognitive: MCI and dementia |
Positive: cognitive impairment and insular atrophy | p < 0.05 | 3 T | SPM8 | 6 mm |
| (Hu et al. 2010) | LPA and PNFA (AD & FTD) | †Patients = 23 | Patients = 63.89 | left insula |
Speech: aphasia |
Positive: Left insula atrophy & aphasia in FTD |
p < 0.05 FWE corrected | 3 T | SPM5 | – |
| (Reijnders et al. 2010) | PD | Patients = 60 | Patients = 62.0 ± 10.1 | Bilateral insula |
Emotion: Apathy |
Positive: Bilateral insula atrophy & apathy scores |
p < 0.05 FDR corrected | 3 T | SPM8 | 10 mm |
| (Ash et al. 2009) | FTD (PNFA, SD, Soc/Exec) |
†Patients = 22 HC = 10 |
Patients = 67.34 HC = 69.5 ± 5.1 |
Left insula |
Speech: speech fluency |
Positive: Left atrophy and fluency in PNFA & SD |
p < 0.001 | 1.5/3 T | SPM5 | 8 mm |
| (Kipps et al. 2009) |
FTD AD |
FTD = 21 HC = 12 |
FTD = 62.1 ± 6.6 HC = 66.4 ± 4.9 |
Left insula |
Affective-cognition: Emotion Recognition |
No correlation assessed | P < 0.05 FDR | 3 T | SPM5 | 8 mm |
| (Hoefer et al. 2008) | AD & FTD |
†Patients = 37 HC = 17 |
Patients = 62.61 HC = 66.7 ± 8.6 |
Left insula |
Emotion: Fear conditioning & emotional blunting |
Positive: Left insular volume & reactivity to unconditioned stimulus in FTD |
p < 0.05 FWE corrected | 1.5 T | SPM2 | 12 mm |
| (Seeley et al. 2008) | FTD |
Patients =45 HC = 45 |
Patients = 64.16 HC = 68.3 ± 7.9 |
Bilateral Anterior and posterior insula |
Cognitive: CDR |
No correlation assessed: low CDR & anterior insula atrophy. high CDR & bilateral posterior insula |
p < 0.05 FWE corrected | 1.5 T | SPM2 | 12 mm |
| (Woolley et al. 2007) | FTD, AD, SD |
†Patients = 27 HC = 18 |
Patients = 59.5 HC = (57.2 ± 8.1) |
Right anterior insula |
Behavior: Binge Eating |
Positive: Binge eating and right anterior insula atrophy |
p < 0.05 corrected | 1.5 T | SPM2 | 12 mm |
| (Farrow et al. 2007) | Early AD |
Patients =7 HC = 11 |
Patients = 77 ± 7 HC = 70 ± 4 |
Bilateral insula | Cognitive: ADAS-TES performance |
Positive: Left insula volume and ADAS-TES score |
p < 0.05 | 1.5 T | SPM2 | 8 mm |
| (Whitwell et al. 2007) | FTD |
Patients =16 HC = 9 |
Patients = 62.9 ± 7.6 HC = 62.6 ± 15.1 |
Right anterior insula |
Behavior: Abnormal eating behavior |
Positive: Pathological sweet tooth & right anterior insula atrophy |
p < 0.05 corrected | 1.5 T | SPM99 | 12 mm |
| (Rosen et al. 2005) | FTD, SD, PNFA& AD | Patients = 148 | Patients = 64.8 ± 9.4 | Anterior insula |
Behavior: Apathy, eating disorders and aberrant motor behavior |
Positive: Anterior insula atrophy and all behaviors. No correlation with specific function |
p < 0.05 FWE corrected | 1.5 T | SPM | 12 mm |
Characteristics of studies included in systematic review ane meta-analysis. All studies assessed and their corresponding subject demographics, insular atrophy and relationship with functional deficit, as well as technical details related to MRI and VBM are shown. ADAS Alzheimer’s disease assessment scale, AD Alzheimer’s disease, ADL activities of daily living BPP Bistable percept paradigm bvFTD behavioral variant FTD, CDR Clinical Dementia Rating scale, DLB Dementia with Lewy bodies, EM emotional memory, FDR False Discovery Rate, FM family member, FTD frontotemporal dementia, FWE family wise error, FWHM full width half maximum, HC healthy controls, LPA logopenic progressive aphasia, MCI mild cognitive impairment, MMSE mini-mental status examination, nfvPPA non-fluent variant primary progressive aphasia, PD Parkinson’s disease, PDD Parkinson’s disease with dementia, PNFA Progressive non-fluent aphasia, pro Prodromal, PSP progressive supranuclear palsy, SD semantic dementia, Soc/Exec FTD subjects with social/executive deficits, SPGI superior precentral region of the dorsal anterior insula, T Tesla, TOM Theory of mind test; VBM voxel based morphometry
†Subjects that had an MRI (not total number of subjects)