Topographically organized projection to posterior insular cortex from the posterior portion of the ventral medial nucleus in the long-tailed macaque monkey.

Prior anterograde tracing work identified somatotopically organized lamina I trigemino- and spinothalamic terminations in a cytoarchitectonically distinct portion of posterolateral thalamus of the macaque monkey, named the posterior part of the ventral medial nucleus (VMpo; Craig [2004] J. Comp. Neurol. 477:119-148). Microelectrode recordings from clusters of selectively thermoreceptive or nociceptive neurons were used to guide precise microinjections of various tracers in VMpo. A prior report (Craig and Zhang [2006] J. Comp. Neurol. 499:953-964) described retrograde tracing results, which confirmed the selective lamina I input to VMpo and the anteroposterior (head to foot) topography. The present report describes the results of microinjections of anterograde tracers placed at different levels in VMpo, based on the anteroposterior topographic organization of selectively nociceptive units and clusters over nearly the entire extent of VMpo. Each injection produced dense, patchy terminal labeling in a single coherent field within a distinct granular cortical area centered in the fundus of the superior limiting sulcus. The terminations were distributed with a consistent anteroposterior topography over the posterior half of the superior limiting sulcus. These observations demonstrate a specific VMpo projection area in dorsal posterior insular cortex that provides the basis for a somatotopic representation of selectively nociceptive lamina I spinothalamic activity. These results also identify the VMpo terminal area as the posterior half of interoceptive cortex; the anterior half receives input from the vagal-responsive and gustatory neurons in the basal part of the ventral medial nucleus.

Modular architectonic organization of the insula in the macaque monkey.

In order to provide a framework for ongoing analyses of the neuronal connections of the insular cortex of the macaque monkey using modern high-resolution methods, we examined its anatomical organization in serial coronal sections stained alternately with Nissl and Gallyas (myelin) techniques. We observed the same 15 distinct architectonic areas in 10 brains. Within the granular, dysgranular, and agranular regions described in prior studies, we identified 4, 4, and 7 distinct areas, respectively. Across brains, these areas have consistent architectonic characteristics, and in flat map reconstructions they display a consistent topological or neighborhood arrangement, despite variations in the size of individual areas between cases. The borders between areas are generally rather sharply defined. Some areas, in particular the dysgranular areas, appear to consistently contain subtle transitions that suggest possible subareas or modules within the well-delimited areas. The presence of a distinct granular area that straddles the fundus of the superior limiting sulcus over its entire posterior-to-anterior extent is consistent with the available evidence on interoceptive thalamocortical projections, and also with the tensile anchor theory of species-specific cortical gyrification. These observations are consonant with the model of homeostatic afferent processing in the primate insula, and they suggest that discrete modules within insular cortex provide the basis for its polymodal integration of all salient activity relevant to ongoing emotional behavior.

Evidence of Conjoint Activation of the Anterior Insular and Cingulate Cortices during Effortful Tasks.

The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).

Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression.

BACKGROUND: Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD. OBJECTIVE: (17)Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months. METHODS: Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders. RESULTS: A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (P(uncorrected) = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders. CONCLUSIONS/LIMITATIONS: VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications.

Distinctive neurons of the anterior cingulate and frontoinsular cortex: a historical perspective.

Human anterior cingulate and frontoinsular cortices participate in healthy social-emotional processing. These regions feature 2 related layer 5 neuronal morphotypes, the von Economo neurons and fork cells. In this paper, we review the historical accounts of these neurons and provide a German-to-English translation of von Economo's seminal paper describing the neurons which have come to bear his name. We close with a brief discussion regarding the functional and clinical relevance of these neurons and their home regions.

Psychological and neural mechanisms of subjective time dilation.

For a given physical duration, certain events can be experienced as subjectively longer in duration than others. Try this for yourself: take a quick glance at the second hand of a clock. Immediately, the tick will pause momentarily and appear to be longer than the subsequent ticks. Yet, they all last exactly 1 s. By and large, a deviant or an unexpected stimulus in a series of similar events (same duration, same features) can elicit a relative overestimation of subjective time (or "time dilation") but, as is shown here, this is not always the case. We conducted an event-related functional magnetic neuroimaging study on the time dilation effect. Participants were presented with a series of five visual discs, all static and of equal duration (standards) except for the fourth one, a looming or a receding target. The duration of the target was systematically varied and participants judged whether it was shorter or longer than all other standards in the sequence. Subjective time dilation was observed for the looming stimulus but not for the receding one, which was estimated to be of equal duration to the standards. The neural activation for targets (looming and receding) contrasted with the standards revealed an increased activation of the anterior insula and of the anterior cingulate cortex. Contrasting the looming with the receding targets (i.e., capturing the time dilation effect proper) revealed a specific activation of cortical midline structures. The implication of midline structures in the time dilation illusion is here interpreted in the context of self-referential processes.

Significance of the insula for the evolution of human awareness of feelings from the body.

An ascending sensory pathway that underlies feelings from the body, such as cooling or toothache, terminates in the posterior insula. Considerable evidence suggests that this activity is rerepresented and integrated first in the mid-insula and then in the anterior insula. Activation in the anterior insula correlates directly with subjective feelings from the body and, strikingly, with all emotional feelings. These findings appear to signify a posterior-to-anterior sequence of increasingly homeostatically efficient representations that integrate all salient neural activity, culminating in network nodes in the right and left anterior insulae that may be organized asymmetrically in an opponent fashion. The anterior insula has appropriate characteristics to support the proposal that it engenders a cinemascopic model of human awareness and subjectivity. This review presents the author's views regarding the principles of organization of this system and discusses a possible sequence for its evolution, as well as particular issues of historical interest.

Insular cortex activation in a patient with "sensed presence"/ecstatic seizures.

OBJECTIVE: Seizures with an aura of a "sensed presence," a religious emotion, or feelings of euphoria (ecstatic seizures) are characterized by heightened self-awareness. A previous case report on a patient with epilepsy and "sensed presence" as an aura described hypoperfusion in both temporal lobes and a local ictal increase in the left frontoparietal area. A reexamination of the data was suggested by a recent study of patients with ecstatic seizures, which proposed that hyperactivation of the left anterior insula might be a potential cause. METHODS: We reanalyzed the laboratory data on the case with "sensed presence" aura using a fusion of SPECT and MR images of the brain, which had not previously been available, and a close examination of the subdural ictal EEG registrations. RESULTS: Examination of the ictal EEG recordings from subdural strip electrodes implanted subtemporally and temporally on both sides showed that seizure activity occurred first at the most medial subtemporal electrode on the left side. From an anatomical point of view, this electrode position is close to the ventral aspect of the left anterior insula, and it is possible that the seizure activity was initiated there. Reexamination of the SPECT data after fusion with contemporary MR images clearly indicated that the region of strong hyperactivation overlies the left anterior insula. Hyperactive regions also appear on the midinsula bilaterally. Together with the neurophysiological ictal EEG, this evidence supports a reinterpretation that this aura of "sensed presence" can be attributed to hyperactivation of the left anterior insula. CONCLUSION: The present findings support the proposal that ecstatic seizures or "sensed presence" auras can originate from the left anterior insula, a region that has been suggested to engender self-awareness associated with positive feelings.

The sentient self.

This article addresses the neuroanatomical evidence for a progression of integrative representations of affective feelings from the body that lead to an ultimate representation of all feelings in the bilateral anterior insulae, or "the sentient self." Evidence for somatotopy in the primary interoceptive sensory cortex is presented, and the organization of the mid-insula and the anterior insula is discussed. Issues that need to be addressed are highlighted. A possible basis for subjectivity in a cinemascopic model of awareness is presented.

The neural substrates of subjective time dilation.

An object moving towards an observer is subjectively perceived as longer in duration than the same object that is static or moving away. This "time dilation effect" has been shown for a number of stimuli that differ from standard events along different feature dimensions (e.g. color, size, and dynamics). We performed an event-related functional magnetic resonance imaging (fMRI) study, while subjects viewed a stream of five visual events, all of which were static and of identical duration except the fourth one, which was a deviant target consisting of either a looming or a receding disc. The duration of the target was systematically varied and participants judged whether the target was shorter or longer than all other events. A time dilation effect was observed only for looming targets. Relative to the static standards, the looming as well as the receding targets induced increased activation of the anterior insula and anterior cingulate cortices (the "core control network"). The decisive contrast between looming and receding targets representing the time dilation effect showed strong asymmetric activation and, specifically, activation of cortical midline structures (the "default network"). These results provide the first evidence that the illusion of temporal dilation is due to activation of areas that are important for cognitive control and subjective awareness. The involvement of midline structures in the temporal dilation illusion is interpreted as evidence that time perception is related to self-referential processing.

The neurocircuitry of impaired insight in drug addiction.

More than 80% of addicted individuals fail to seek treatment, which might reflect impairments in recognition of severity of disorder. Considered by some as intentional deception, such 'denial' might instead reflect dysfunction of brain networks subserving insight and self-awareness. Here we review the scant literature on insight in addiction and integrate this perspective with the role of: (i) the insula in interoception, self-awareness and drug craving; (ii) the anterior cingulate in behavioral monitoring and response selection (relevant to disadvantageous choices in addiction); (iii) the dorsal striatum in automatic habit formation; and (iv) drug-related stimuli that predict emotional behavior in addicted individuals, even without conscious awareness. We discuss implications for clinical treatment including the design of interventions to improve insight into illness severity in addiction.

Emotional moments across time: a possible neural basis for time perception in the anterior insula.

A model of awareness based on interoceptive salience is described, which has an endogenous time base that might provide a basis for the human capacity to perceive and estimate time intervals in the range of seconds to subseconds. The model posits that the neural substrate for awareness across time is located in the anterior insular cortex, which fits with recent functional imaging evidence relevant to awareness and time perception. The time base in this model is adaptive and emotional, and thus it offers an explanation for some aspects of the subjective nature of time perception. This model does not describe the mechanism of the time base, but it suggests a possible relationship with interoceptive afferent activity, such as heartbeat-related inputs.

How do you feel--now? The anterior insula and human awareness.

The anterior insular cortex (AIC) is implicated in a wide range of conditions and behaviours, from bowel distension and orgasm, to cigarette craving and maternal love, to decision making and sudden insight. Its function in the re-representation of interoception offers one possible basis for its involvement in all subjective feelings. New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.

Retrograde analyses of spinothalamic projections in the macaque monkey: input to the ventral lateral nucleus.

The distribution of retrogradely labeled spinothalamic tract (STT) neurons was analyzed in monkeys following variously sized injections of cholera toxin subunit B (CTb) in order to determine whether different STT termination sites receive input from different sets of STT cells. This report focuses on STT input to the ventral lateral nucleus (VL), where prior anterograde tracing studies identified dense or moderately dense STT terminations. Large and very large injections in VL produced large numbers of labeled cells predominantly in laminae V and VII (more than half as many as from massive injections in the entire thalamus). Medium-sized and small injections in VL labeled STT cells almost exclusively in laminae V and VII, in segments consistent with the coarse mediolateral VL topography; few or no cells were labeled in lamina I. All injections labeled the deep cerebellar nuclei (see accompanying article: Evrard and Craig, 2008). Notably, even the most anterior injection in VL that produced dense pallidal labeling still labeled both STT and deep cerebellar cells. These observations indicate that VL receives STT input originating from laminae V and VII neurons that may be coextensive with its cerebellothalamic input. These findings support the role of laminae V and VII STT cells in sensorimotor integration and suggest a significant ongoing influence on both motor and premotor thalamocortical function. Together with the preceding observations of selective STT projections to other thalamic regions, these results provide compelling evidence that the primate STT consists of anatomically and functionally differentiable components.

Retrograde analyses of spinothalamic projections in the macaque monkey: input to posterolateral thalamus.

The distribution of retrogradely labeled spinothalamic tract (STT) neurons was analyzed in macaque monkeys following variously sized, physiologically guided pressure or iontophoretic injections of cholera toxin subunit B (CTb) in order to determine whether different STT termination sites receive input selectively from different sets of STT cells. This report focuses on posterolateral thalamus, where prior anterograde tracing observations identified the posterior part of the ventromedial nucleus (VMpo) as the major projection target of lamina I STT neurons. Large injections in posterolateral thalamus labeled predominantly STT cells in lamina I throughout the spinal cord. In cases with medium-sized or small injections centered in VMpo, almost all labeled STT cells ( approximately 90%) were lamina I neurons. Small injections revealed a posteroanterior (foot to hand) somatotopographic organization consistent with that observed in prior anterograde tracing work; injections in posterior VMpo labeled primarily lumbosacral lamina I cells, whereas injections placed more anteriorly in VMpo labeled primarily cervical lamina I cells. These findings support the concept that VMpo is a primate lamina I spinothalamocortical relay nucleus important for pain, temperature, itch, muscle ache, sensual touch, and other interoceptive feelings from the body, and they provide strong evidence for the general hypothesis that the STT consists of several functionally and anatomically differentiable components.

Laser-evoked potentials are graded and somatotopically organized anteroposteriorly in the operculoinsular cortex of anesthetized monkeys.

The operculoinsular cortical region has a major role in the representation of noxious stimuli, based on functional imaging observations, clinical lesion studies, and EEG recordings of specifically pain-related laser-evoked potentials (LEPs) in humans. The source of LEPs has not been identified, and several somatic representations and cytoarchitectonic areas may be present in this complex region. To overcome the limitations of human studies, a primate model is needed in which the main LEP generator in this region can be localized and characterized using invasive methods. We obtained EEG recordings of evoked responses to noxious laser stimulation at different intensities and performed dipole source analyses in three anesthetized macaque monkeys. We show that LEPs can be recorded that 1) grade with stimulus intensity, 2) display two distinct responses corresponding to the "late" (Adelta-fiber) and the "ultralate" (C-fiber) LEPs recorded in humans, and 3) originate deep within the operculoinsular region, thus establishing a valid primate model for experimental analysis of LEPs. Further, we found that LEPs elicited from the leg, arm, and ear display a global somatotopy organized in the posteroanterior direction (leg posterior and arm and ear anterior), which contrasts starkly with the mediolateral (leg to face) gradient of the somatotopic representations in primary and secondary somatosensory cortices. These results provide evidence that the main generator of pain-related activity in operculoinsular cortex may participate in both the somatic localization and the intensity discrimination of pain sensations, and they indicate that it may be distinct from the traditional somatosensory cortices.

Forebrain emotional asymmetry: a neuroanatomical basis?

There is considerable psychophysiological evidence to indicate that the left and right halves of the human forebrain differentially associate with particular emotions and affective traits. A neurobiological model is needed. Here I propose that forebrain emotional asymmetry is anatomically based on an asymmetrical representation of homeostatic activity that originates from asymmetries in the peripheral autonomic nervous system. This proposal builds on recent evidence indicating that lateralized, higher-order re-representations of homeostatic sensory activity provide a foundation for subjective human feelings. It can subsume differing views of emotion and the forebrain because it suggests that emotions are organized according to the fundamental principle of autonomic opponency for the management of physical and mental energy.