Beruflich Dokumente
Kultur Dokumente
DOI 10.1007/s11065-014-9246-9
REVIEW
P. G. Gasquoine (*)
Department of Psychology, University of TexasPan American,
1201 W. University Drive, Edinburg, TX 78541, USA
e-mail: drgdrg13@yahoo.com
Introduction
Many contemporary behavioral neuroscientists conceptualize
complex human behaviors as mediated by the flow of information (action potentials) through large scale distributed networks within the brain with modularization (specialized processing) taking place in various brain structures along the way
(e.g., Seeley et al. 2007). This may be little different from
previous conceptions of clinicians who followed in the tradition of Broca (1861) by investigating the effects on behavior
of naturally occurring brain lesions in humans. As illustration,
the influential Soviet neurologist Alexandra Luria wrote:
Each form of conscious activity is always a complex functional system and takes place through the combined working of
allbrain units, each of which makes its own contribution
(Luria 1973, p. 99: italics as in original).
Nowadays, behavioral neuroscientists have additional experimental techniques to supplement lesion/behavior change
analysis, especially the popular noninvasive neuroimaging
technique of functional magnetic resonance imaging (fMRI:
Ogawa et al. 1990). One benefit of the functional neuroimaging approach is that it has focused attention upon the brain
organization of human behaviors not assessed by traditional
neuropsychological tests of cognition that have dominated
lesion analysis studies. Such non-cognitive behaviors include
homeostatically incongruent states like hunger (e.g., Tataranni
et al. 1999) and self-generated emotional states (e.g., Damasio
et al. 2000). The role of brain structures that mediate such
behaviors have been poorly understood in the past. The insula
is one such structure.
A major reason for the historical lack of understanding of
the behavioral function of this enigmatic brain region is that
isolated lesions of the insula in humans are extremely rare. As
illustration, only 4 of 4,800 (0.0008 %) consecutive, first time
stroke patients recorded in the Lausanne Stroke Registry in
Switzerland between 1990 and 1999 had a lesion restricted to
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contribution the insula is making to these behaviors, a question that functional neuroimaging in isolation is poorly
equipped to address. There are general limitations in
interpreting variations in neuroimaged metabolic activity
levels in a given brain region in that they cannot be used to
determine exactly what contribution the brain region is making to the task (Coltheart 2006a, b). Neuroimaged metabolic
signals cannot distinguish between fundamental physiological
processes like excitatory/inhibitory or modulatory/
transmissive effects within a given neural region (Logothetis
2008). To circumvent such interpretational limitations, it has
been proposed that neuroimaging data be interpreted conservatively and combined with other sources of information to
better interpret brain-behavior relationships in a convergingmethods approach (e.g., Decety and Cacioppo 2010;
Gonsalves and Cohen 2010; Logothetis 2008; Stirling and
Elliott 2008). This review synthesizes information from brain
lesion/behavior change, stimulation, and functional neuroimaging studies on the insula with the goal of achieving a
parsimonious understanding of the contribution of the insula
to cognition and emotion. The preponderance of the evidence
suggests the insula acts as primary cortex for interoceptive
information that is critical for emotional feeling.
Fig. 1 Insular cortex shown in a lateral view of the left cerebral hemisphere with the overlying opercula of the temporal, parietal, and frontal
lobes removed (Source: Grays Anatomy)
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the other lobes of the cerebral cortex are named for bones of
the skull. It is the first region of cerebral cortex to develop and
differentiate, beginning at age 6 weeks of fetal life (Afif et al.
2007). In adults it comprises 2 % of the total cortical area
(Nieuwenhuys 2012).
The insula consists of five to six gyri arranged in a vertical
fan-like manner with the circular sulcus forming an upper
boundary. It has long been recognized that the number and
neuroanatomical arrangement of insula gyri varies naturally
among neurologically intact individuals, even between the
two sides of the same brain (Clark 1896; Craig 2010). Early
cytoarchitectonic studies on the human insula identified from
4 (areas 1316: Brodmann 1909) to 31 (Rose 1928) subregions. A frequently referenced subdivision of the insula based
on cytoarchitectonic study of Old World (rhesus) monkeys
defined concentric circular agranular (anterior/ventral),
dysgranular (medial), and granular (posterior/dorsal) subregions emanating from the lowest point (Mesulum and Mufson
1982). Variations in granularity pertain to the distribution of
neurons at layer IV, typically considered as having an input or
sensory function, of the cortical grey matter. The human insula
is much larger than that of the rhesus monkey and the boundaries of these subregions have not been precisely specified in
terms of sulci and gyri (Afif et al. 2007). Another oft used
subdivision is into anterior (three or four short gyri) and
posterior (two long gyri) subregions separated by the central
insular sulcus (Afif and Mertens 2010). The main branch of
the middle cerebral artery lies within this sulcus. Subdivision
of the human insula on the basis of cytoarchitecture remains
contentious (Nieuwenhuys 2012). Similarly, there is little
agreement on the functional specialization of subregions of
the insula from meta-analyses of functional neuroimaging
(Kurth et al. 2010; Mutschler et al. 2009) or electrical stimulation study (Stephani et al. 2011).
The insula has bidirectional connections with most of the
brain, but especially with orbitofrontal, anterior cingulate,
supplementary motor areas, parietal (primary and secondary
somatosensory areas), and temporal cortices and with subcortical structures that include especially the amygdala, globus
pallidus of the basal ganglia, and thalamus (Augustine 1985,
1996; Flynn et al. 1999: see Fig. 2). There is gradation of
connectivity throughout the region in that the anterior insula
has greater connectivity with the frontal lobe, while the posterior insula has greater connectivity with the parietal lobe.
Orbitofrontal cortex
Anterior cingulate
cortex
Supplementary motor
areas
Primary
somatosensory cortex
Insula
Secondary
somatosensory cortex
Temporal cortex
Thalamus
Amygdala
Globus pallidus
impairment of somatosensory, gustatory, and vestibular processing (Cereda et al. 2002). Insula injury has also been
implicated in patients who do not respond to painful stimulation by withdrawal or negative emotional response (Berthier
et al. 1988). Aside from sensory impairments, insula injury
has also been linked with cognitive impairment across all
neuropsychological domains. Many of the cognitive symptoms ascribed to insula injury likely reflect diaschisis (von
Monakow 1914) or disconnection syndromes (Geschwind
1965). In diaschisis uninjured regions of the brain that connect
with injured regions experience reduced neural activity especially in the early stages post-injury. Modern functional neuroimaging of cerebral blood flow and cell metabolism has
confirmed that diaschisis occurs (Pearce 1994), although the
exact mechanism of action is unknown. Disconnection syndromes are a related concept implying that injury to a region
of the brain can permanently adversely impact the performance of connected regions by restricting information flow.
Reasons for suspecting that diaschisis and/or disconnection
syndromes are involved in the production of certain cognitive
symptoms following insula lesions include: (a) the rarity of
reports of the symptom following insula injury; (b) a previous
strong link between the symptom and injury to other brain
regions; and (c) the transient nature of the symptom following
sudden onset neurological conditions like stroke. Examples of
probable diaschisis/disconnection effects after left insula
stroke include: (a) truncal ataxia (Liou et al. 2010), a symptom
historically associated with cerebellar injury; and (b) declarative verbal memory (Manes et al. 1999b), a symptom historically associated with dominant hippocampal injury. In the
latter study, six patients with left insula infarction showed
poorer immediate and delayed recall of a story from the
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volumes or hyper-and hypo-activity in the insula with schizophrenia, eating disorders, anxiety and mood disorders, conduct disorder, autism, addiction, and chronic pain.
Grey Matter Volumes in the Insula
Meta-analytic review has shown that insula grey matter volume is decreased bilaterally, especially in the anterior subregion, in patients with schizophrenia (Shepherd et al. 2012),
stimulant drug dependence (Ersche et al. 2013; Mackey and
Paulus 2013), and bipolar disorder (Selvaraj et al. 2012). This
is not the only brain structure so affected in these patients and
the significance of these finding is unclear. Some specific
hypotheses have been generated, for example that insula dysfunction may lead to internally generated sensory information
being misattributed to an external source contributing to hallucinations in schizophrenia (Wylie and Tregellas 2010).
Alternatively, it is possible that the insula dysfunction, whatever its nature, is generic across psychiatric conditions. Grey
matter volume reductions in the left anterior insula have also
been found in major depression (Takahashi et al. 2010) and
bilateral reductions have been reported in posttraumatic stress
disorder (Chen et al. 2009) and conduct disorder (Sterzer et al.
2007). Grey matter volume enlargement in the anterior insula
bilaterally has been reported in obsessive-compulsive disorder
(Nishida et al. 2011).
Hyper-and Hypo-Neuroimaged Activity in the Insula
Several functional neuroimaging studies have shown increased
activity within the insula in either hemisphere during conscious
urges to take drugs of all types (see Naqvi and Bechara 2008
for review). None of these studies implicated the insula specifically and increased activation in regions of orbitofrontal,
anterior cingulate, and dorsolateral prefrontal cortex also occurred. These findings have been supplemented by the lesion
studies of Naqvi et al. (2007) and Gaznick et al. (2013) that
implicated injury to the insula or the insula plus basal ganglia,
respectively, in a sudden loss of the urge to smoke immediately
following brain injury onset in nicotine addicts. Lesions were
not confined to the insula in either study but extended into
adjacent structures including orbitofrontal cortex.
Increased blood flow and metabolism has also been found
in the insula of patients with: psychosis (during auditory
hallucinations: Sommer et al. 2008); major depression
(Drevets 2000); generalized social anxiety disorder (Klumpp
et al. 2013); bulimia (in response to pictures of food: Schienle
et al. 2009); and chronic back pain (Apkarian et al. 2005). In
chronic back pain patients, neuroimaged hyper-activity
reflected the chronicity (as opposed to the intensity) of the
pain (Baliki et al. 2006), but abnormalities in other brain
regions, such as reduced grey matter volumes in dorsolateral
frontal cortex, were also noted.
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Table 1 Behavioral functions ascribed to the insula from selected studies
Study
Type of study
Ackermann and Riecker (2010)a posterior insularespiration-related metabolic (interoceptive) states rostral
componentsautonomic functions (p. 419)
part of the brain language area(and/or) verbal motivation and verbal affect (p. 79)
Ardila (1999)b
Baier et al. (2011)b
generation of speech motor execution (p. 1429)
b
Bamiou et al. (2003)
sound detectionallocating auditory attentionprocessing novel versus familiar
auditory stimuliauditory temporal processingmusic appreciation (p. 153)
tracking of risk (p. 645)
Bossaerts (2010)b
Brass and Haggard (2010)a
provide interoceptive signals that play an essential role in evaluating the
consequences of intentional action (p. 603: anterior insula)
neural correlate of consciousness (p. 59)
Craig (2009)c
Critchley et al. (2004)c
explicit awareness of, internal bodily processes (p. 193: right anterior
insula/operculum)
feelings of emotion (p. 260)
Damasio (2003)a
Dronkers (1996)b
motor planning of speech (p. 159)
Flynn et al. (1999)b
cardiovascular, gastrointestinal, vestibular, olfactory, gustatory, visual, auditory,
somatosensory, and motor modulationconditioned aversive learningpain
perception, stress induced immunosuppression, mood stability, sleep, and
language (p. 55)
Ibaez et al. (2010)a
coordination between internal and external information through emotional
subjective awareness (p. 397)
limb ownershipbeing involved in a movement (p. 411: right insula)
Karnath and Baier (2010)b
Manes et al. (1999b)b
verbal memory (p. 534: left insula)
c
Medford and Critchley (2010)
integrated awareness of cognitive, affective, and physical state (p. 540:
anterior insula)
interoceptive awareness, emotional responses,empathic processes
Menon and Uddin (2010)c
high-level cognitive control and attentional processes (p. 655).
conscious cue-induced urges (p. 61)
Naqvi and Bechara (2008)c
Penfield and Faulk (1955)a
gastric motility and stomach tone (p. 469)
Ronchi et al. (2012)b
perseveration (p. 588: right insula)
Seeley et al. (2007)a
personal salience, whether cognitive, homeostatic, or emotional, that requires
changes in sympathetic tone (p. 2349)
Small (2010)b
integrated oral sensory region that plays a role in feeding behavior (p. 551)
Stephani et al. (2011)a
somato-and viscerosensory cortex (p. 137)
a
Studies that implicate the insula in generic interoceptive reception and/or emotional feeling states
Resting state connectivity shows temporally correlated activity in neural regions in the absence of a stimulus/task
Review
Review
Lesion analysis
Review
Review
Review
Review
Functional neuroimaging
Review
Lesion analysis
Review
Review
Review
Lesion analysis
Review
Review
Review (drug addiction)
Electrical stimulation
Lesion analysis
Resting state connectivityd
Review
Electrical stimulation
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Summary
A synthesis of lesion/behavior change, stimulation, and functional neuroimaging studies of the insula suggests the following observations on its behavioral function:
1. The insula is commonly divided into anterior and posterior subregions. Some investigators also include a medial
subregion. There is not consistent agreement as to the
boundaries or the functional specialization of these subregions across studies. Divisions between anterior and
posterior subregions have been made on the basis of
cytoarchitechtonics or the central insular sulcus.
2. Historically conceived as a primary gustatory region, it is
now apparent that the insula processes a much wider
range of sensory stimuli. Most especially, it is the primary
reception area in the cerebral cortex for interoceptive
sensory information from the internal milieu associated
with changes in autonomic nervous system activity.
3. Lesion studies have implicated insula lesions with cognitive impairment across all neuropsychological domains,
but especially that of language. Although aphasic disturbances of various types frequently accompany dominant
insula injury, the exact role of the insula in language
processing remains unclear, as most cases involved lesions that extended into perisylvian language regions.
4. As the insula is the primary reception region of the brain
for interoceptive information reflecting changes in autonomic nervous system activity levels, it is considered as
critical for emotional feelings in accord with the JamesLange theory of emotion. This role was historically associated with the limbic system.
5. Lateralization effects in the insula reflect the wellestablished pattern of language processing in the dominant hemisphere, but also right sided processing of sympathetic effects and (possibly) left sided processing of
parasympathetic effects.
6. Neuroimaging has linked abnormal grey matter volumes
or hyper-and hypo-activity levels in the insula with
schizophrenia, eating disorders, anxiety and mood disorders, conduct disorder, autism, addiction, and chronic
pain. The significance of these abnormal activity patterns
remains theoretical.
7. Functional neuroimaging studies frequently show hyperactivations in the insula, typically in conjunction with
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