NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis.

NGF is a well-studied neurotrophic factor, and TrkA is a receptor tyrosine kinase for NGF. The NGF-TrkA system supports the survival and maintenance of NGF-dependent neurons during development. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder due to loss-of-function mutations in the NTRK1 gene encoding TrkA. Individuals with CIPA lack NGF-dependent neurons, including NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. Thus, the pathophysiology of CIPA can provide intriguing findings to elucidate the unique functions that NGF-dependent neurons serve in humans, which might be difficult to evaluate in animal studies. Preceding studies have shown that the NGF-TrkA system plays critical roles in pain, itching and inflammation. This review focuses on the clinical and neurobiological aspects of CIPA and explains that NGF-dependent neurons in the peripheral nervous system play pivotal roles in interoception and homeostasis of our body, as well as in the stress response. Furthermore, these NGF-dependent neurons are likely requisite for neurobiological processes of 'emotions and feelings' in our species.

Emotional pain without sensory pain--dream on?

The article by Danziger and colleagues in this issue of Neuron evaluates empathy in a unique population--individuals with congenital insensitivity to pain. As such, it provides insights into the brain's ability to evaluate others' feeling to observed pain without having a specific sensory experience of pain itself.

Can we share a pain we never felt? Neural correlates of empathy in patients with congenital insensitivity to pain.

Theories of empathy differ regarding the relative contributions of automatic resonance and perspective taking in understanding others' emotions. Patients with the rare syndrome of congenital insensitivity to pain cannot rely on "mirror matching" (i.e., resonance) mechanisms to understand the pain of others. Nevertheless, they showed normal fMRI responses to observed pain in anterior mid-cingulate cortex and anterior insula, two key regions of the so-called "shared circuits" for self and other pain. In these patients (but not in healthy controls), empathy trait predicted ventromedial prefrontal responses to somatosensory representations of others' pain and posterior cingulate responses to emotional representations of others' pain. These findings underline the major role of midline structures in emotional perspective taking and understanding someone else's feeling despite the lack of any previous personal experience of it--an empathic challenge frequently raised during human social interactions.

[Congenital insensitivity to pain]. / L'insensibilité congénitale à la douleur.

Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions, characterized by a dramatic impairment of pain perception since birth. In the 1980s, progress in nerve histopathology allowed to demonstrate that CIP was almost always a manifestation of hereditary sensory and autonomic neuropathies (HSAN) involving the small-calibre (A-delta and C) nerve fibres which normally transmit nociceptive inputs along sensory nerves. Identification of the genetic basis of several clinical subtypes has led to a better understanding of the mechanisms involved, emphasizing in particular the crucial role of nerve growth factor (NGF) in the development and survival of nociceptors. Recently, mutations of the gene coding for the sodium channel Nav1.7--a voltage-dependent sodium channel expressed preferentially on peripheral nociceptors and sympathetic ganglia--have been found to be the cause of CIP in patients showing a normal nerve biopsy. This radical impairment of nociception mirrors the hereditary pain syndromes associated with "gain of function" mutations of the same ion channel, such as familial erythromelalgia and paroxysmal extreme pain disorder. Future research with CIP patients may identify other proteins specifically involved in nociception, which might represent potential targets for chronic pain treatment. Moreover, this rare clinical syndrome offers the opportunity to address interesting neuropsychological issues, such as the role of pain experience in the construction of body image and in the empathic representation of others' pain.

Arthritis in a child secondary to congenital insensitivity to pain and self-aggression. Why and when pain is good?

A 9 year-old female child presented with recurrent arthritis of ankles, left knee and unequal leg length. Clinical examination revealed mild valgus deformity in her left knee with grade 2 effusion, arthritis of both ankles and deformity in her left wrist. Examination of the affected joints showed no evidence of tenderness upon active or passive movements and the patient did not show any limping upon gait analysis. Past history of the patient revealed evidence of previous dislocation of her left hip and previous fibular fracture. Revision of her previous x-rays showed left hip dislocation, fracture left fibula and fracture of right metatarsal bone after repetitive trauma which pass unnoticed. Recent x-ray of her left knee showed osteochondral injury. Laboratory investigations were done to rule out common causes of childhood arthritis and revealed: ESR 12 1st hours, CRP negative, negative rheumatoid factor, and negative ANA. Neurological evaluation of the patient documented congenital insensitivity to pain and EMG studies confirmed evidence of sensory neuropathy. Traumatic arthritis resulting from congenital insensitivity to pain with self-aggression is rarely encountered in children but should be considered in the differential diagnosis specially if radiological features point to repetitive trauma with attempts of healing.

Is pain the price of empathy? The perception of others' pain in patients with congenital insensitivity to pain.

Empathy is a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. Recent findings suggest that empathy for pain may involve a 'mirror-matching' simulation of the affective and sensory features of others' pain. Despite such evidence for a shared representation of self and other pain at the neural level, the possible influence of the observer's own sensitivity to pain upon his perception of others' pain has not been investigated yet. The aim of this study was to explore how patients with congenital insensitivity to pain (CIP), who are largely deprived of common stimulus-induced pain experiences, perceive the pain of others. Ratings of verbally presented imaginary painful situations showed that CIP patients' semantic knowledge regarding the pain of others did not differ from control subjects. Moreover, the propensity to infer pain from facial expressions was very similar between CIP patients and control subjects. On the other hand, when asked to rate pain-inducing events seen in video clips in the absence of visible or audible pain-related behaviour, CIP patients showed more variable and significantly lower pain ratings, as well as a reduction in aversive emotional responses, compared with control subjects. Interestingly, pain judgements, inferred either from facial pain expressions or from pain-inducing events, were strongly related to inter-individual differences in emotional empathy among CIP patients, while such correlation between pain judgement and empathy was not found in control subjects. The results suggest that a normal personal experience of pain is not necessarily required for perceiving and feeling empathy for others' pain. In the absence of functional somatic resonance mechanisms shaped by previous pain experiences, others' pain might be greatly underestimated, however, especially when emotional cues are lacking, unless the observer is endowed with sufficient empathic abilities to fully acknowledge the suffering experience of others in spite of his own insensitivity.

Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain.

Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth and is generally caused by a hereditary sensory and autonomic neuropathy (HSAN) with loss of the small-calibre, nociceptive nerve fibres. We report the case of a 32-year-old woman with CIP and a presumptive diagnosis of HSAN type V, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother. This patient had sustained innumerable painless injuries during childhood, including bone fractures and severe burns. The only pain she ever felt consisted in an intense headache, which took place in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. The description of this inaugural episode of headache fulfilled the diagnostic criteria of episodic tension-type headache. This case strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception and despite the lack of previous pain experience. In the light of recent experimental data showing that the same neural mechanisms that regulate physical pain may also control the expression of separation distress and the feeling of social exclusion, this unique case helps to better understand why some patients may feel physically hurt after the loss of someone they love.

Consciousness and body image: lessons from phantom limbs, Capgras syndrome and pain asymbolia.

Words such as 'consciousness' and 'self' actually encompass a number of distinct phenomena that are loosely lumped together. The study of neurological syndromes allows us to explore the neural mechanisms that might underlie different aspects of self, such as body image and emotional responses to sensory stimuli, and perhaps even laughter and humour. Mapping the 'functional logic' of the many different attributes of human nature on to specific neural circuits in the brain offers the best hope of understanding how the activity of neurons gives rise to conscious experience. We consider three neurological syndromes (phantom limbs, Capgras delusion and pain asymbolia) to illustrate this idea.

Orthopaedic manifestations in congenitally insensate patients.

The spectrum of orthopaedic problems in eight congenitally insensate patients was reviewed. The conditions included congenital insensitivity to pain, Riley-Day syndrome, and Lesch-Nyhan syndrome. In each of these conditions, the patient has an abnormality of interpretation of painful stimuli or lacks normal pain avoidance, leading to self-inflicted damage. The orthopaedic problems and complications included fracture, self-mutilation, autoamputation, osteomyelitis, septic arthritis, Charcot joints, scoliosis, and dislocation. Effective management consists of early diagnosis and patient/parent education to prevent as many complications as possible. Fractures may be treated conservatively, while progressive scoliosis requires operative intervention. Osteomyelitis, septic arthritis, and Charcot joints require appropriate operative treatment.

Dominantly transmitted congenital indifference to pain.

Two patients from a family with dominantly inherited indifference to pain were investigated. Perception of the other sensory modalities was normal as was the remainder of the neurological examination. Electrophysiological studies and morphometric evaluation of myelinated and unmyelinated fibers of nerve biopsy specimens were normal. This is the first morphometric study of peripheral nerve in dominantly inherited indifference to pain.