Carta Acesso aberto Revisado por pares

A stress-system model for functional neurological symptoms

2017; Elsevier BV; Volume: 383; Linguagem: Inglês

10.1016/j.jns.2017.10.044

ISSN

1878-5883

Autores

Kasia Kozlowska,

Tópico(s)

Obsessive-Compulsive Spectrum Disorders

Resumo

In "Physical Precipitating Factors in Functional Movement Disorders" (2014), Pareés et al. present a Bayesian approach to functional neurological symptom disorder (FND) and the role that physical events potentially play in triggering functional neurologic symptoms in adults. In this letter we quickly review our own, similar findings with children and adolescents, describe a stress-system model of FND, and suggest that, from a clinical perspective, this model is especially useful in explaining functional neurological symptoms to child and adolescent patients and families. As background, nineteenth-century clinicians recognized that functional neurological symptoms arose in the context of stress, pain, fatigue, injury, or psychological trauma, and in response to sudden intense and overwhelming emotions [1Eulenburg A. Lehrbuch der Nervenkrankheiten.Bde. 1, 2. August Hirschwald, Berlin1878Google Scholar, 2Janet P. L'Automatisme Psychologique. Alcan, Paris1889Google Scholar]. In the twentieth century, diagnostic classification systems for FND disregarded physical events and focused solely on psychological stressors. In this century, things have come full circle. In 2013, DSM-5 dropped psychological stressors as a diagnostic requirement [[3]American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5thed. American Psychiatric Association, 2013Crossref Google Scholar]. The following year, this journal published the article by Pareés et al. mentioned above. That study documented that in 50 adult patients with functional motor symptoms, physical events triggered about 80% of the FND presentations. Consistent with earlier clinical observations, they also found that 70% of patients experienced symptoms of panic—symptoms of autonomic arousal and motor activation (nausea, numbness, and tremor)—at the onset of FND symptoms. Likewise, and more broadly, numerous studies suggest that adult patients with FND present in a state of hyperarousal [[4]Apazoglou K. Mazzola V. Wegrzyk J. Polara G.F. Aybek S. Biological and perceived stress in motor functional neurological disorders.Psychoneuroendocrinology. 2017; 85: 142-150Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. And neuroimaging studies suggest that arousal/emotion-processing regions are overactive and overly dominant in patients with FND: arousal/emotion-processing regions appear to overconnect with motor regions, thereby disrupting motor function (see Blakemore et al. [[5]Blakemore R.L. Sinanaj I. Galli S. Aybek S. Vuilleumier P. Aversive stimuli exacerbate defensive motor behaviour in motor conversion disorder.Neuropsychologia. 2016; 93: 229-241Crossref PubMed Scopus (49) Google Scholar] for review). In our work with children and adolescent patients from three different research cohorts, we have obtained results similar to those of Pareés et al. (2014). We documented high rates of physical events (49%–60%) preceding the onset of functional neurological symptoms [6Kozlowska K. Scher S. Williams L.M. Patterns of emotional-cognitive functioning in pediatric conversion patients: implications for the conceptualization of conversion disorders.Psychosom. Med. 2011; 73: 775-788Crossref PubMed Scopus (56) Google Scholar, 7Kozlowska K. Griffiths K.R. Foster S.L. Linton J. Williams L.M. Korgaonkar M.S. Grey matter abnormalities in children and adolescents with functional neurological symptom disorder.Neuroimage Clin. 2017; 15: 306-314Crossref PubMed Scopus (37) Google Scholar, 8Kozlowska K. Rampersad R. Cruz C. Shah U. Chudleigh C. Soe S. Gill D. Scher S. Carrive P. The respiratory control of carbon dioxide in children and adolescents referred for treatment of psychogenic non-epileptic seizures.Eur. Child Adolesc. Psychiatry. 2017; Crossref PubMed Scopus (28) Google Scholar], with a minor physical injury over a fifth of patients) or a viral illness (in over a tenth of patients) being the most common. Taken together, family reports of cumulative antecedent stressors and assessments of attachment (indicative of long-term relational stressors) suggest that, most typically, physical events trigger FND in the wake of other stressors [6Kozlowska K. Scher S. Williams L.M. Patterns of emotional-cognitive functioning in pediatric conversion patients: implications for the conceptualization of conversion disorders.Psychosom. Med. 2011; 73: 775-788Crossref PubMed Scopus (56) Google Scholar, 7Kozlowska K. Griffiths K.R. Foster S.L. Linton J. Williams L.M. Korgaonkar M.S. Grey matter abnormalities in children and adolescents with functional neurological symptom disorder.Neuroimage Clin. 2017; 15: 306-314Crossref PubMed Scopus (37) Google Scholar]. Across the three cohorts we have also found high rates of non-specific somatic symptoms (60%–88%) 1In our three separate cohorts, one or more non-specific somatic symptoms were present in 44/76 (60% with documented dizziness, breathlessness, nausea, or fatigue), 22/25 (88%, with documented dizziness, breathlessness, nausea, or fatigue), and 53/60 (88% with documented dizziness, breathlessness, nausea, fatigue, or pounding heart), as presented in Kozlowska et al. [6–8], respectively.1In our three separate cohorts, one or more non-specific somatic symptoms were present in 44/76 (60% with documented dizziness, breathlessness, nausea, or fatigue), 22/25 (88%, with documented dizziness, breathlessness, nausea, or fatigue), and 53/60 (88% with documented dizziness, breathlessness, nausea, fatigue, or pounding heart), as presented in Kozlowska et al. [6–8], respectively.—somatic manifestations of increased autonomic arousal/motor activation—and high rates of comorbid pain (61%–84%). Using biological markers, we have confirmed that our patients present in a state of increased brain-body arousal and motor readiness (see Kozlowska et al. [[8]Kozlowska K. Rampersad R. Cruz C. Shah U. Chudleigh C. Soe S. Gill D. Scher S. Carrive P. The respiratory control of carbon dioxide in children and adolescents referred for treatment of psychogenic non-epileptic seizures.Eur. Child Adolesc. Psychiatry. 2017; Crossref PubMed Scopus (28) Google Scholar] for review). The further question, with both adults and children, is "how physical events related to the onset of FND could play an important role in generation of functional symptoms" (Pareés et al. (2014, p 177)). Pareés et al. (2014) propose a Bayesian model in which disordered attentional modulation of sensory and motor feedback from the body results in a mismatch between bottom-up sensory evidence and top-down prior beliefs, with these "prediction errors" driving FND symptoms. When FND is triggered by a physical event, the new sensory data arising from the physical event is likely to combine with many other predisposing factors (including past illness experiences and beliefs, and cognitive and affective biases) to facilitate development of abnormal predictions regarding movement. Pareés et al. suggest that the presence of symptoms related to panic during the physical event is likely to increase the salience of any sensory information occurring during a coincident physical event. In our work with children and adolescents, we have followed a different approach from that of Pareés et al. (2014). Rather than drawing on the Bayesian model of FND, we have found that contemporary advances about the workings of the body's stress systems provide the basis for a stress-system model of FND. This model is useful in understanding FND symptoms and, clinically, both in explaining those symptoms to our patients and their families, and in designing treatment programs [9Kozlowska K. Chudleigh C. Cruz C. Lim M. McClure G. Savage B. Shah U. Cook A. Scher S. Carrive P. Gill D. Psychogenic non-epileptic seizures in children and adolescents. Part I: diagnostic formulations.Clin. Child Psychol. Psychiatry. 2017; (1359104517732118)Google Scholar, 10Kozlowska K. Chudleigh C. Cruz C. Lim M. McClure G. Savage B. Shah U. Cook A. Scher S. Carrive P. Gill D. Psychogenic non-epileptic seizures in children and adolescents: part II - explanations to families, treatment, and group outcomes.Clin. Child Psychol. Psychiatry. 2017; (1359104517730116)Google Scholar]. The brain-body stress systems—the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system, immune-inflammatory system, and brain systems underpinning pain, arousal, and emotional states—are interconnected and form part of a larger integrated system that protects the individual from a broad range of threats. Activation of any single part of the system, whether by emotional stress, pain, injury, infection, or psychological trauma, can trigger the body's stress response, resulting in a cascade of stress-induced changes in the brain, which prompt, in turn, brain-wide network reorganization that prioritizes automatic responses to threat [11Hermans E.J. van Marle H.J. Ossewaarde L. Henckens M.J. Qin S. van Kesteren M.T. Schoots V.C. Cousijn H. Rijpkema M. Oostenveld R. Fernandez G. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration.Science. 2011; 334: 1151-1153Crossref PubMed Scopus (408) Google Scholar, 12Arnsten A.F. Stress weakens prefrontal networks: molecular insults to higher cognition.Nat. Neurosci. 2015; 18: 1376-1385Crossref PubMed Scopus (366) Google Scholar]. According to the perspective presented here, functional neurological symptoms emerge when aberrant patterns of functional connectivity between arousal/emotion-processing regions and motor-processing regions are incidentally co-opted in the process of this stress-induced network reorganization. Finally, there is the important issue of comorbidities. The majority of our child and adolescent patients with FND suffer with comorbid anxiety and depression as well as chronic functional pain. Research suggests that stress and inflammation have a role in all these presentations. It is now well established that inflammation plays a causative role in depression and that psychosocial stressors, which activate immune-inflammatory processes, are a risk factor in depression [[13]Raison C.L. Miller A.H. Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment.Mod. Trends Pharmacopsychiatry. 2013; 28: 33-48Crossref PubMed Scopus (56) Google Scholar]. Likewise, stress-induced activation of glial cells—part of the brain's immune-inflammatory system—and stress-induced changes in glial cell numbers and morphology appear to play an important role in the neurobiology of depression [13Raison C.L. Miller A.H. Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment.Mod. Trends Pharmacopsychiatry. 2013; 28: 33-48Crossref PubMed Scopus (56) Google Scholar, 14Rajkowska G. Miguel-Hidalgo J.J. Gliogenesis and glial pathology in depression.CNS Neurol. Disord. Drug Targets. 2007; 6: 219-233Crossref PubMed Scopus (492) Google Scholar]. Emerging data from animal studies show that non-neural cells, including glial cells, play an important role in inducing the neuroplastic changes that maintain chronic pain [[15]Ji R.R. Chamessian A. Zhang Y.Q. Pain regulation by non-neuronal cells and inflammation.Science. 2016; 354: 572-577Crossref PubMed Scopus (638) Google Scholar]. More generally, glial cells are involved in priming the brain's sensitivity to stress [16Frank M.G. Weber M.D. Watkins L.R. Maier S.F. Stress-induced neuroinflammatory priming: a liability factor in the etiology of psychiatric disorders.Neurobiol. Stress. 2016; 4: 62-70Crossref PubMed Scopus (87) Google Scholar, 17Brenhouse H.C. Schwarz J.M. Immunoadolescence: neuroimmune development and adolescent behavior.Neurosci. Biobehav. Rev. 2016; 70: 288-299Crossref PubMed Scopus (70) Google Scholar, 18von Bernhardi R. Eugenin-von Bernhardi J. Flores B. Eugenin Leon J. Glial cells and integrity of the nervous system.Adv. Exp. Med. Biol. 2016; 949: 1-24Crossref PubMed Scopus (34) Google Scholar], in facilitating neural synapse formation and function, and in network configuration (via synaptic and non-synaptic routes) [14Rajkowska G. Miguel-Hidalgo J.J. Gliogenesis and glial pathology in depression.CNS Neurol. Disord. Drug Targets. 2007; 6: 219-233Crossref PubMed Scopus (492) Google Scholar, 19Volterra A. Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues.Nat. Rev. Neurosci. 2005; 6: 626-640Crossref PubMed Scopus (1338) Google Scholar]. In this way, stress-induced activation, priming, and (mal)adaption of non-neuronal cells may play a key role in holding immunological memory for past stressors, and in facilitating and maintaining network changes patients with in FND. Accordingly, early-life stressors combined with more recent cumulative adverse life events (predisposing factors) would prime the stress system into a state of readiness, and antecedent events (precipitating factors)—even if relatively minor—would trigger an overly robust (potentiated) brain-body stress response. Interestingly, there is an overlap between the stress-system model proposed here and the neurobiological model of somatosensory amplification that Perez and Barsky and colleagues (2015) have developed for patients with non-specific somatic symptoms [[20]Perez D.L. Barsky A.J. Vago D.R. Baslet G. Silbersweig D.A. A neural circuit framework for somatosensory amplification in somatoform disorders.J. Neuropsychiatry Clin. Neurosci. 2015; 27: e40-50Crossref PubMed Scopus (67) Google Scholar]. Both models highlight the complex interactions between the different components of the brain-body stress system—including the likely importance of inflammation and stress-related neuroplastic changes—with the somatosensory model giving particular attention to the roles of attention (negative attentional bias) and expectations (negative expectation bias) in symptom amplification. Though scientifically and clinically feasible and attractive, the stress-system model raises as many questions as it answers. No studies have examined cortisol levels in child and adolescent patients with FND, and no studies have tracked patterns of HPA dysregulation from childhood into adulthood in FND patients. 2Of interest in this context is that, whereas cortisol response increases in girls who have been sexually abused, that response is attenuated in adulthood [[21]Trickett P.K. Noll J.G. Susman E.J. Shenk C.E. Putnam F.W. Attenuation of cortisol across development for victims of sexual abuse.Dev. Psychopathol. 2010; 22: 165-175Crossref PubMed Scopus (270) Google Scholar].2Of interest in this context is that, whereas cortisol response increases in girls who have been sexually abused, that response is attenuated in adulthood [[21]Trickett P.K. Noll J.G. Susman E.J. Shenk C.E. Putnam F.W. Attenuation of cortisol across development for victims of sexual abuse.Dev. Psychopathol. 2010; 22: 165-175Crossref PubMed Scopus (270) Google Scholar]. Likewise, we have limited understanding of stress-related neuroplastic changes in FND and of how illness duration and course affect the pattern of changes. Recent studies suggest that the neuroplastic changes seen in children and adolescent patients with short illness duration [[7]Kozlowska K. Griffiths K.R. Foster S.L. Linton J. Williams L.M. Korgaonkar M.S. Grey matter abnormalities in children and adolescents with functional neurological symptom disorder.Neuroimage Clin. 2017; 15: 306-314Crossref PubMed Scopus (37) Google Scholar] may not be the same as those found in adult patients with chronic illness duration [22Aybek S. Nicholson T.R. Draganski B. Daly E. Murphy D.G. David A.S. Kanaan R.A. Grey matter changes in motor conversion disorder.J. Neurol. Neurosurg. Psychiatry. 2014; 85: 236-238Crossref PubMed Scopus (50) Google Scholar, 23Perez D.L. Williams B. Matin N. LaFrance Jr., W.C. Costumero-Ramos V. Fricchione G.L. Sepulcre J. Keshavan M.S. Dickerson B.C. Corticolimbic structural alterations linked to health status and trait anxiety in functional neurological disorder.J. Neurol. Neurosurg. Psychiatry. 2017; Crossref Scopus (48) Google Scholar]. Finally, the applicability of the stress-system model to adult patients with FND—and in particular, those who do not identify antecedent stressors [[24]Nicholson T.R. Aybek S. Craig T. Harris T. Wojcik W. David A.S. Kanaan R.A. Life events and escape in conversion disorder.Psychol. Med. 2016; 46: 2617-2626Crossref PubMed Scopus (71) Google Scholar]—is an open question. It is also an open question, however, whether child, adolescent, and adult patients who identify no such stressors may nonetheless have primed stress systems, either epigenetically or from events early during development that are not remembered. In the future, as we learn more about how the brain responds to stress—and about the genetic and epigenetic variations that modulate individual differences in the brain's stress response—we will be able to start filling in the details of the stress-system model and to gain further insights into how to translate that model into effective treatments. The current work was not supported by any funding.

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