Posttraumatic Stress Disorder (PTSD) is highly co-morbid with chronic pain conditions. When present, PTSD significantly worsens chronic pain outcomes. Likewise, pain contributes to a more severe PTSD as evidenced by greater disability, more frequent use of harmful opioid analgesics and increased pain severity. The biomechanism behind this comorbidity is incompletely understood, however recent work strongly supports the widely-accepted role of expectation, in the entanglement of chronic pain and trauma symptoms. This work has shown that those with trauma have a maladaptive brain response while expecting stress and pain, whereas those with chronic pain may have a notable impairment in brain response while expecting pain relief. This dynamical expectation model of the interaction between neural systems underlying expectation of pain onset (traumatic stress) and pain offset (chronic pain) is biologically viable and may provide a biomechanistic insight into pain-trauma comorbidity. These predictive mechanisms work through interoceptive pathways in the brain critically the insula cortex. Here we highlight how the neural expectation-related mechanisms augment the existing models of pain and trauma to better understand the dynamics of pain and trauma comorbidity. These ideas will point to targeted complementary clinical approaches, based on mechanistically separable neural biophenotypes for the entanglement of chronic pain and trauma symptoms.

The thalamus is the final relay nucleus in the ascending pain pathway and receives its major nociceptive inputs from the spinothalamic and trigeminothalamic tracts (TTTs). These tracts terminate in several regions of medial and lateral thalamus. The terminations of nociceptive-specific neurons in lamina I of the spinal and medullary dorsal horn are to the posterior ventromedial nucleus (VMpo), ventroposterior inferior nucleus (VPI), and the ventrocaudal medial dorsal nucleus (MDvc), whereas the terminations of the nociceptive neurons in the deeper layers are in the ventroposterior nucleus (VP) as well as in VPI and the central lateral nucleus (CL). The main cortical targets of the thalamic regions receiving lamina I neuron projections are the insular cortex via the VMpo and the anterior cingulate cortex via the MDvc, whereas the VP that receives nociceptive inputs primarily from the deep dorsal horn is to primary somatosensory cortex. Nociceptive-specific neurons are located in VMpo and are topographically arranged. VP that contains primarily neurons responding to innocuous tactile stimuli also contains nociceptive neurons in register with the somatotopic pattern of the low-threshold neurons. Stimulation in the human VPI and VMpo region can produce pain, but stimulation in VP is rarely painful. Damage to the lateral thalamus, usually as a result of a stroke, can lead to chronic central pain. The thalamus may play a prominent role in the pathophysiology of central neuropathic pain.

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).

The insula lies hidden within the sylvian fissure, the first sulcus that forms during development. Its three general sectors each comprise several sharply delimited architectonic areas with different connections and functional roles. It is anchored by the interoceptive cortex, a high-resolution representation of the physiological condition of the body that is unique to primates. A posterior-to-mid-to-anterior progression of multimodal integration culminates in highly interconnected hubs in the anterior insula that underpin all subjective feelings. The anterior insula and the spindle-shaped von Economo neurons it contains contribute to embodied cognition and human self-awareness. Most pathologies of the insular cortex disrupt interoceptive and self-conscious feelings.

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: 17Fluorodeoxyglucose 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 (Puncorrected = 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.

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.

ABSTRACT 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. J. Comp. Neurol. 522:64–97, 2014. © 2013 Wiley Periodicals, Inc.

The main sensory input to the autonomic nervous system comes from small-diameter sensory fibers by way of lamina I neurons in the superficial dorsal horn. This pathway supports organotopic homeostatic control of the body's condition, but also human feelings from the body, such as temperature, pain, itch, affective touch, muscle ache, vascular flush, and so on. The anatomical pathways described in this chapter reveal that these feelings are correlates of behavioral homeostatic responses needed to maintain the health of the body. These findings suggest that bodily feelings provide important measures of the body's condition, support emotional well-being and awareness, and can be a significant therapeutic avenue.

A homeostatic energy model of awareness proposes that the anterior insular cortex engenders feelings that provide an amodal valuation of homeostatic energy utilization in an opponent, bivalent emotional control system. Feelings are the “common currency” which enable optimal utilization in the physical and mental behavior of a highly social primate. This model offers a different perspective.

ARTICLE Sir, In a recent publication in Brain , Garcia-Larrea et al . (2010) reported their identification of patients with post-stroke central pain and selective thermosensory dysfunction, but without other somatosensory abnormalities, and they suggested that the basis for such dissociated symptoms might be the presence of a ‘third somatosensory area’ specifically supporting temperature sensation in the operculo-insular region. In actuality, prior findings, which they did not cite, provide solid neurobiological evidence that the dorsal posterior insula contains the primary cortical sensory representation of temperature and pain in humans; indeed, these previous findings explain perfectly well these and other clinical observations by Garcia-Larrea and colleagues. In a carefully designed positron emission tomography study (Craig et al ., 2000), my colleagues and I examined cerebral activation associated with six different innocuous cool temperatures applied to the hand of awake human subjects, and by performing a regression analysis against stimulus temperature across scans, we obtained clear and unequivocal evidence that the only site in the contralateral cortex with activity directly (linearly) related to stimulus temperature was in the dorsal posterior insula (Fig. 1). We …

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.

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.

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.

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.

To celebrate the first 10 years of Nature Reviews Neuroscience, we invited the authors of the most cited article of each year to look back on the state of their field of research at the time of publication and the impact their article has had, and to discuss the questions that might be answered in the next 10 years. This selection of highly cited articles provides interesting snapshots of the progress that has been made in diverse areas of neuroscience. They show the enormous influence of neuroimaging techniques and highlight concepts that have generated substantial interest in the past decade, such as neuroimmunology, social neuroscience and the 'network approach' to brain function. These advancements will pave the way for further exciting discoveries that lie ahead.

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 neurophysiological literature on nociceptive neurons with ascending projections from the spinal cord has been riven for almost 40 years by a dogmatic controversy: many investigators professed that pain is subserved by so-called ‘wide dynamic range’ (WDR) neurons that respond to both low- and high-threshold cutaneous stimuli, whereas others preferred cells with nociceptive-specific (NS) response properties (reviewed in: Craig, 2003). WDR proponents claimed that such cells fulfilled the once popular (but now discredited: Inui et al. 2006) ‘gate control theory’ and that they could easily explain the allodynia commonly described by neuropathic pain patients (that is, pain elicited by low-threshold contact, as in sunburn). On the other hand, proponents of NS neurons claimed that such cells could serve as ‘labelled lines’ that required no central integration to signal pain. Attention has been focused in recent years on lamina I, which is the main output layer of the superficial dorsal horn, where the small-diameter afferents that innervate all tissues of the body terminate; lamina I contains an abundance of NS neurons (as well as neurons specific for cool, warm, itch, and so on), it contains the main concentration of spinal substance P-responsive neurons, and in primates it is a major source of the spinothalamic tract, which is classically associated with pain and temperature sensation. In rodents, which have a very diminutive spinothalamic projection, the major lamina I projection target is the brainstem parabrachial nucleus, consistent with the concept that the fundamental role of the small-diameter afferent/lamina I pathway is homeostasis (Craig, 2003). Molecular physiological evidence now indicates that rat lamina I spinoparabrachial neurons are normally mostly NS cells with few WDR cells, but that these proportions can be dramatically reversed by nerve injury, and most tellingly, that NS neurons can become WDR neurons following local glial activation or chloride channel disruption (Keller et al. 2007); this evidence provides a cogent role for NS-neurons-that-become-WDR-neurons in allodynia and hyperalgesia. Yet, such unmasked low-threshold input was presumed to be conveyed by large-diameter mechanoreceptors via an unknown polysynaptic route, because those fibres terminate in the deep dorsal horn, not the superficial dorsal horn. Low-threshold C-fibre tactile (CT or ‘slow brush’) afferents have been known for many years to terminate in the superficial dorsal horn, but across dozens of studies, no recordings of lamina I projection neurons responsive to ‘slow brush’ had been reported. Nevertheless, recent functional imaging work revealed that the human lamina I projection terminus in insular cortex is activated not only by pain and temperature, but also by CT fibres (Bjornsdotter et al. 2009). This evidence suggested strongly that lamina I projection neurons responsive to ‘slow brush’ must exist, consistent with a homeostatic role for CT fibres, which are thought to signal emotional safety (and promote bonding) in primates, rather than danger. The quantitative evidence provided now by Andrew in this issue of The Journal of Physiology (Andrew, 2010) convincingly demonstrates that rats indeed have lamina I spinoparabrachial neurons responsive to CT fibres, and by extension, that primates must have lamina I spinothalamic neurons sensitive to CT fibres. The surprise is that the neurons Andrew identified were not ‘labelled lines’ for ‘slow brush’, like NS and cool, warm and itch lamina I cells, rather they were all WDR cells! This finding has several potential ramifications. First, it suggests that the lamina I WDR neurons described in previous reports may in fact have responded to low-threshold brushing due to CT fibres, rather than large-diameter mechanoreceptors. That would be consistent with the often reported fact that few, if any, lamina I neurons respond to electrical stimulation of Aβ-fibres; it would provide a second way in which WDR cells can be misinterpreted (in addition to the confusion caused by the activation of polymodal nociceptive cells by forceps at room temperature), and it would differentiate WDR lamina I neurons from the WDR neurons in lamina V, which receive Aβ input and subserve skeletal motor control, because they receive small-diameter afferent input and subserve homeostatic emotion, like other lamina I cells. Second, it suggests that the homeostatic safety signal ascribed to CT fibres requires comparison with NS activity in order to guide behaviour. That implies that the hedonic valence of intimate conspecific contact can easily reverse under inappropriate circumstances, like the gentle touch that irritates instead of soothes. Third, and most significant clinically, this finding suggests that allodynia may be due to unmasked low-threshold activation of NS cells by CT fibres, not by mechanoreceptors, which in turn implies that a selective pharmaceutical target might exist for the alleviation of allodynic pain. Indeed, new molecular physiological and behavioural evidence has serendipitously just appeared in Nature (Seal et al. 2009) which confirms the critical role of CT fibres, and thus the neurons that Andrew identified, in allodynic pain. The absence of CT-specific lamina I neurons could of course be due to the anaesthesia or to sensitization by prior stimulation or the surgical trauma inherent in the acute experiments that Andrew performed, although earlier reports of ‘WDR’ lamina I trigeminothalamic neurons in awake monkeys suggest otherwise (see Craig, 2003). Perhaps recordings obtained from lamina I or parabrachial neurons while rats are grooming will provide evidence that confirms or denies the lack of specificity of CT-responsive lamina I neurons and the inherent potential shift in hedonic valuation that is implied. In the meantime, as we all learn eventually, it is important to keep an eye on someone who touches us softly.

In the present work, Natural rubber (NR) conventional composite containing 20phr black filler (CB) is taken for study. In order to reduce the utilization of CB, new hybrid nanocomposites containing a fixed content of 10phr CB and varied content of COOH functionalized multi-walled carbon nanotubes (CNT) (1phr-4phr) were developed by melt-blending on a twin roll mill and their morphology and mechanical properties were tested and compared with conventional composite. The prepared composites were examined for their morphology and various -mechanical properties. Studies revealed that incorporation of CNT in NR matrix resulted in superior mechanical properties in comparison to NR composites containing CB alone. Further NR hybrid nanocomposites containing 10phr of CB and 2phr of CNT exhibited an improvement of 15%, 10% and 3% in stress at break, elongation at rupture and resistance to crack propagation in comparison to the conventional composite containing 20phr CB. The same composite also exhibits superior hardness. The better performance of NR hybrid nanocomposites can be mainly attributed to high aspect ratio of functionalized CNT and its enhanced interactions with the NR matrix, enhanced CB-CNT interactions, improved dispersion of CNT in the elastomeric matrix due the existence of COOH group on the surface of CNT layers and formation of more cross-links between rubber and fillers with increase in nanofiller content. FESEM studies reveal the homogenous dispersion of hybrid fillers in the elastomeric matrix upto 2phr of CNT. These studies prove that partial replacement of CB with CNT is a promising approach to produce NR composites with superior mechanical properties.

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.