Article

Unconscious amygdala fear conditioning in a subset of chronic fatigue syndrome patients

Authors:
To read the full-text of this research, you can request a copy directly from the author.

Abstract

Here, a novel hypothesis for chronic fatigue syndrome (CFS) is proposed. CFS may be a neurophysiological disorder focussing on the amygdala. During a 'traumatic' neurological event often involving acute psychological stress combined with a viral infection or other chemical or physiological stressor, a conditioned network or 'cell assembly' may be created in the amygdala. The unconscious amygdala may become conditioned to be chronically sensitised to negative symptoms arising from the body. Negative signals from the viscera or physiological, chemical and dietary stressors, become conditioned stimuli and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus. This cell assembly then produces the CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation, leading to sympathetic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. Recovery from CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala's expressions. I shall firstly discuss predisposing, precipitating, and perpetuating factors involved in the possible etiology of chronic fatigue syndrome (CFS), followed by the patient's experience of the illness. Finally, I shall look at a suggested explanation for the symptoms of CFS.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

... Zalcman, Savina, and Wise (1999) have found that immunogenic stimuli can alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli. In addition, stress might be a conditioned stimulus that leads to an impaired immune response (Gupta, 2002). Exposure to stress can induce long-term potentiation, such that the brain cells react more strongly in response to future exposures to a drug or stress (Saal et al., 2003). ...
... ability through normal synaptic pathways and intercellular communication. Therefore, different regions of the brain may become kindled in a secondary manner, separate from the initial kindling. These secondary sites could then affect different organ systems in a top-down fashion, leading to the diverse symptom patters found in patients with ME/CFS. Gupta (2002), borrowing on the work from LeDoux (1996), has suggested that an infection, chemical or physiological stressor can act to create a cell assembly within the unconscious amygdala, which can create sympathetic stimulation through the hypothalamus and other brain pathways involving the flight or fight response. The amygdala first determines ...
... Areas of the prefrontal cortex and anterior cingulate influence the amygdala (Gupta, 2002), and kindling in these areas and others could cause continuous sympathetic stimulation that would eventually lead to mental and physical exhaustion as well as glandular depletion. Kindling could cause CRH to be released from the paraventricular nucleus of the hypothalamus. ...
Article
Full-text available
Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems. Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness.
... It was also suggested that ME/CFS may be a neurophysiological disorder in the brain caused by repeated incidental or unnecessary stimuli in the limbic system, which is known as the threat response/protection center. These stimuli can be emotional, psychological, chemical, and/or physiological and they can keep the threat response center on a continuous high alert [105]. Connections between the amygdala and sympathetic, hypothalamic and other limbic brain systems can initiate a series of stimulations and uncontrolled reactions throughout the whole body, which could be considered as the root cause of CFS symptoms [105]. ...
... These stimuli can be emotional, psychological, chemical, and/or physiological and they can keep the threat response center on a continuous high alert [105]. Connections between the amygdala and sympathetic, hypothalamic and other limbic brain systems can initiate a series of stimulations and uncontrolled reactions throughout the whole body, which could be considered as the root cause of CFS symptoms [105]. ...
Article
Full-text available
Background and Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic condition distinguished by disabling fatigue associated with post-exertional malaise, as well as changes to sleep, autonomic functioning, and cognition. Mind-body interventions (MBIs) utilize the ongoing interaction between the mind and body to improve health and wellbeing. Purpose: To systematically review studies using MBIs for the treatment of ME/CFS symptoms. Materials and Methods: MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane CENTRAL were searched (inception to September 2020). Interventional studies on adults diagnosed with ME/CFS, using one of the MBIs in comparison with any placebo, standard of care treatment or waitlist control, and measuring outcomes relevant to the signs and symptoms of ME/CFS and quality of life were assessed for inclusion. Characteristics and findings of the included studies were summarized using a descriptive approach. Results: 12 out of 382 retrieved references were included. Seven studies were randomized controlled trials (RCTs) with one including three reports (1 RCT, 2 single-arms); others were single-arm trials. Interventions included mindfulness-based stress reduction, mindfulness-based cognitive therapy, relaxation, Qigong, cognitive-behavioral stress management, acceptance and commitment therapy and isometric yoga. The outcomes measured most often were fatigue severity, anxiety/depression, and quality of life. Fatigue severity and symptoms of anxiety/depression were improved in nine and eight studies respectively, and three studies found that MBIs improved quality of life. Conclusions: Fatigue severity, anxiety/depression and physical and mental functioning were shown to be improved in patients receiving MBIs. However, small sample sizes, heterogeneous diagnostic criteria, and a high risk of bias may challenge this result. Further research using standardized outcomes would help advance the field.
... A MR study examining a pediatric population of patients suffering from chronic EBV infection has shown evidence for the presence of lesions in the hippocampal region [65]. Areas of the prefrontal cortex and anterior cingulate influence the amygdala [66], and kindling in these areas and others could cause continuous sympathetic stimulation that would eventually lead to mental and physical exhaustion as well as glandular depletion. Administration of CRH in rats produces seizures in the amygdala and epileptiform discharges in the hippocampus, but the earliest CRH induced epileptiform discharges are produced in the amydgala and propagate to the hippocampus [16]. ...
... Lesions may then reappear under specific conditions of environmental stimuli, a process that fits well with the relapsing and remitting nature of ME/CFS. Within the brain, areas of the prefrontal cortex and anterior cingulate influence the amygdala [66], and kindling in these areas could cause continuous sympathetic nervous stimulation that would eventually lead to glandular depletion. Evidence reviewed above supports a pattern of HPA axis dysfunction in individuals with ME/CFS. ...
Article
Full-text available
Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.
... Specifically, amygdala and insula retraining (AIR), a mind-body approach, has preliminarily demonstrated improvements in physical health, energy, pain, distress, and fatigue in patients with FM and chronic fatigue syndrome (CFS) [16]. AIR was originally designed for patients with CFS [17] as a method of hypothetically reducing chronic over-sensitization and heightened fear response of the amygdala which may underlie some of the symptoms related to both CFS and FM [17,18]. These specific techniques aim to retrain conditioned somatic signaling in the brain which may keep the nervous system and the immune system in a state of heightened arousal. ...
... These specific techniques aim to retrain conditioned somatic signaling in the brain which may keep the nervous system and the immune system in a state of heightened arousal. This is achieved through specific and specialized interventions that seek to strengthen neurological inhibitory mechanisms in areas of the prefrontal and orbital cortices, the insula, and the anterior and posterior cingulate [16][17][18]. Retraining techniques involve repeatedly interrupting signals from the amygdala and insula using a variety of generative practices tailored to the individual patient [19]. The patient is taught to become aware of the internal signals of the symptoms, and then to act on these signals in a specific way that drastically interrupts the signaling. ...
Article
Full-text available
The lack of highly effective treatments for fibromyalgia (FM) represents a great challenge for public health. The objective of this parallel, pilot randomized controlled trial was two-fold: (1) to analyze the clinical effects of mindfulness plus amygdala and insula retraining (MAIR) compared to a structurally equivalent active control group of relaxation therapy (RT) in the treatment of FM; and (2) to evaluate its impact on immune-inflammatory markers and brain-derived neurotrophic factor (BDNF) in serum. A total of 41 FM patients were randomized into two study arms: MAIR (intervention group) and RT (active control group), both as add-on of treatment-as-usual. MAIR demonstrated significantly greater reductions in functional impairment, anxiety, and depression, as well as higher improvements in mindfulness, and self-compassion at post-treatment and follow-up, with moderate-to-large effect sizes. Significant decreases in pain catastrophizing and psychological inflexibility and improvements in clinical severity and health-related quality of life were found at follow-up, but not at post-treatment, showing large effects sizes. The number needed to treat was 3 based on criteria of ≥50% FIQ reduction post-treatment. Compared to RT, MAIR showed significant decreases in BDNF. No effect of MAIR was observed in immune-inflammatory biomarkers (i.e., TNF-α, IL-6, IL-10, and hs-CRP). In conclusion, these results suggest that MAIR as adjuvant of TAU appears to be effective for the management of FM symptoms and for reducing BDNF levels in serum.
... The similarities of the pathophysiological changes of posttraumatic stress disorders and chronic fatigue syndrome that are taking place in the central nervous system (particularly in the amygdala and hypothalamus), point to the great potential of future research about the correlation of posttraumatic stress disorder and chronic rhinosinusitis, among other things. This is because posttraumatic stress disorder is much more frequent in the general population than chronic fatigue syndrome.27–29 All three questionnaires that we used in our study have shown that posttraumatic stress disorder deteriorates the symptoms of chronic rhinosinusitis, which then classifies patients into the severe group. ...
Article
Full-text available
Severity of chronic rhinosinusitis (CRS), measured by disease-specific health-related quality-of-life questionnaires, is expected to increase in patients who also suffer from posttraumatic stress disorder (PTSD). Altered pain perception, sleep disorders, and fatigue may be associated with this comorbidity. Severity of CRS was compared between a group of 28 patients with CRS and a group of 28 patients with CRS and concomitant PTSD using different disease-specific and generic instruments, such as visual analog scale (VAS), Short Form-36 test (SF-36), and Sino-Nasal Outcome Test-22 (SNOT 22). SNOT-22 test showed significantly higher CRS severity in patients with CRS and PTSD, compared to patients with CRS without PTSD. Patients with less severe CRS, measured by objective outcome measures, due to the impact of comorbid PTSP, are classified as having severe rhinosinusitis, and are exposed to the risk of unnecessary diagnostic and therapeutic procedures. In patients with difficult-to-treat rhinosinusitis, diagnosis should be revised, and one item that should be evaluated is whether they suffer from PTSD.
... Zalcman et al. (1999) have found that immunogenic stimuli can alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli. In addition, stress might be a conditioned stimulus that leads to an impaired immune response (Cohen et al., 1994; Gupta, 2002). Exposure to most major drugs or stress can induce long-term potentiation, such that the brain cells react more strongly (and releases dopamine more abundantly) in response to future exposures to the drug or stress (Saal et al., 2003). ...
Article
Full-text available
Chronic fatigue syndrome (CFS) is an important condition confronting patients, clinicians, and researchers. This article provides information concerning the need for appropriate diagnosis of CFS subtypes. We first review findings suggesting that CFS is best conceptualized as a separate diagnostic entity rather than as part of a unitary model of functional somatic distress. Next, research involving the case definitions of CFS is reviewed. Findings suggest that whether a broad or more conservative case definition is employed, and whether clinic or community samples are recruited, these decisions will have a major influence in the types of patients selected. Review of further findings suggests that subtyping individuals with CFS on sociodemographic, functional disability, viral, immune, neuroendocrine, neurology, autonomic, and genetic biomarkers can provide clarification for researchers and clinicians who encounter CFS' characteristically confusing heterogeneous symptom profiles. Treatment studies that incorporate subtypes might be particularly helpful in better understanding the pathophysiology of CFS. This review suggests that there is a need for greater diagnostic clarity, and this might be accomplished by subgroups that integrate multiple variables including those in cognitive, emotional, and biological domains.
... Stress is also a risk factor for many diseases, e.g. depression, cardiovascular disease, etc. (Gupta 2002;McEwen 2002;Vanltallie 2002). The brain plays a critical role in determining stressful or non-stressful signals based on prior experience and the genetic background of each individual (McEwen 2000(McEwen , 2002. ...
Article
Stress is a part of daily life. However, molecular mechanisms underlying the activation of limbic-hypothalamic-pituitary-adrenal (LHPA) axis remains unknown. In this study, we explored whether activation of the mitogen-activated kinase kinase 4 (MKK4)-c-Jun-N-terminal kinase (JNK) signaling pathway may play a role in the activation of the LHPA axis. We found that forced-swim stress induced elevation of activated MKK4 in the hippocampal formation, amygdala, and hypothalamus. Unlike MKK4, a high basal level of JNK activity is present in many brain areas of unstressed mice. Forced-swim stress significantly elevated JNK activity in the hypothalamus and amygdala and, to a lesser extent, in the cortex, CA1 and CA3 regions, and the dentate gyrus. To further investigate the role of MKK4 and JNK in induction of stress responses, we investigated whether a different stress, namely, restraint stress, induced activation of MKK4 or JNK in the brain. We found that restraint stress also induced elevation of activated MKK4 and JNK in the hippocampal formation, amygdala, and hypothalamus. Because MKK4 and JNK were activated within 5 min following stress, we propose that the MKK4-JNK signaling may be an early neural event in the initiation of neuroendocrine, autonomic and behavioral stress responses.
... Although focusing primarily on a cognitive behavioral model of medically unexplained symptoms in general and CFS in particular, the importance of homeostatic dysregulation and perpetuating vicious circles has been recognized in recent papers [71,72] . Likewise , Gupta outlined the possibility of conditioned responses, but confined this process to the amygdala and emphasized a close relation to the emotional state of fear [73]. In fibromyalgia, a stress model related to ours was promoted by von Houdenhove [74]. ...
Article
Full-text available
We present an integrative model of disease mechanisms in the Chronic Fatigue Syndrome (CFS), unifying empirical findings from different research traditions. Based upon the Cognitive activation theory of stress (CATS), we argue that new data on cardiovascular and thermoregulatory regulation indicate a state of permanent arousal responses - sustained arousal - in this condition. We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning). Furthermore, sustained arousal may explain documented alterations by establishing vicious circles within immunology (Th2 (humoral) vs Th1 (cellular) predominance), endocrinology (attenuated HPA axis), skeletal muscle function (attenuated cortical activation, increased oxidative stress) and cognition (impaired memory and information processing). Finally, we propose a causal link between sustained arousal and the experience of fatigue. The model of sustained arousal embraces all main findings concerning CFS disease mechanisms within one theoretical framework.
... Participants were only impaired at recognising emotions from the eyes of others (RME task), and not in eToM ability to infer emotional or mental states in others (RMV and RMF tasks). Although these tasks all relate to emotional states in others, differences between these abilities exist (Ochsner, 2008); ability to recognise emotions in eyes relies on amygdala-driven threat processing (Adolphs, Baron-Cohen & Tranel, 2002) which has been proposed to be specifically affected in CFS (Gupta, 2002), while eToM for others is a cognitive ability related to frontal lobe function (Ochsner, 2008) which has been shown to be unaffected in CFS (Majer, Welberg et al. 2008). In addition to demonstrating that eToM in CFS is not significantly different to eToM in HCs, this study found no relationship between social functioning and eToM. ...
Article
Full-text available
Difficulties with social function have been reported in chronic fatigue syndrome (CFS), but underpinning factors are unknown. Emotion recognition, theory of mind (inference of another's mental state) and 'emotional' theory of mind (eToM) (inference of another's emotional state) are important social abilities, facilitating understanding of others. This study examined emotion recognition and eToM in CFS patients and their relationship to self-reported social function. CFS patients (n = 45) and healthy controls (HCs; n = 50) completed tasks assessing emotion recognition, basic or advanced eToM (for self and other) and a self-report measure of social function. CFS participants were poorer than HCs at recognising emotion states in the faces of others and at inferring their own emotions. Lower scores on these tasks were associated with poorer self-reported daily and social function. CFS patients demonstrated good eToM and performance on these tasks did not relate to the level of social function. CFS patients do not have poor eToM, nor does eToM appear to be associated with social functioning in CFS. However, this group of patients experience difficulties in emotion recognition and inferring emotions in themselves and this may impact upon social function.
... 40 Stimulation of the amygdala inhibits the hippocampus which in turn disinhibits the hypothalamus, hence causing excitation of the hypothalamus. Predominant sympathetic activity in hot water epilepsy might be due to stimulation of sympathetic center from the hypothalamus and amygdala 41,42 (Fig. 1). ...
Article
Full-text available
This study aimed to characterize the role of autonomic nervous system dysfunction in hot water epilepsy (HWE). Heart rate variability (HRV) has been established as a good index of cardio-autonomic regulation. Forty-five patients with HWE (age: 24.6±10.1 years; M:F=37:8) and 45 age and gender matched controls (age: 24.17±10.37 years; M:F=37:8) were studied. Five minutes resting lead II electrocardiogram (ECG) was obtained (AD instruments) under standard conditions and analyzed for time and frequency domain HRV parameters using LabChart software. Patients with hot water epilepsy showed significant increase in LF nu (Low frequency normalized unit) and LF/HF denoting an interictal increase in sympathetic activity. In addition, reductions were noted in parasympathetic function [RMSSD (root mean square successive difference of RR intervals), HF (High frequency) nu and LF/HF]. This study has demonstrated an impaired sympatho-vagal balance characterized by increased sympathetic activity and reduced parasympathetic activity in patients with HWE. The present study supports the notion that the hypothalamus is involved in both, the pathogenesis of HWE and autonomic regulation.
... The results from these multifaceted replicated research studies have established relationships for specific areas of the brain and their effect on acquisition or retention of fear conditioning [7,[9][10][11][12][13][14][15]. Learning and memory for single-cue fear conditioning does not require cortical involvement [16][17][18]. Also, fear-conditioned learning occurs very quickly via specific amygdala and thalamic subcortical pathways activating the hypothalamic and autonomic nervous systems (ANS) with associated organ responses [19]. ...
Article
Full-text available
Absence of memory or verbal recall for symptom acquisition in fear and trauma exposure, as well as absence of successful coping behavior for life events, is associated with a number of diagnoses, including traumatic brain injury, posttraumatic stress disorder, pain, and anxiety. The difficulty with diagnosis and treatment planning based on the absence of recall, memory, and successful coping behavior is threefold: (1) these assessments do not distinguish between disruption of behavior and lack of capacity, (2) the absence of verbal recall and memory complicates cognitive-based treatment, and (3) a confounding issue is the same absent behavior can be observed at different times and contexts. While memory of the specific details of the initial traumatic event(s) may not be available to verbal report, the existence of time- and context-dependent relationships for the initial as well as subsequent experiences is arguable. The absence of memory or lack of verbal recall does not rule out measurable physiological bodily responses for the initial trauma(s), nor does it help to establish the effects of subsequent experiences for symptom expression. Also, the absence of memory must include the prospect of fear-based learning that does not require or involve the cortex. It is posited that the literatures of fear conditioning and learned nonuse provide complementary illustrations of how the time and context of the initial trauma(s) and subsequent experiences affect behavior, which is not dependent on the effected individual being able to provide a memory-based verbal report. The replicated clinical application demonstrates that, without scientific demonstration, neither neuroanatomy nor verbal report can be assumed sufficient to predict overt behavior or physiologic responses. For example, while commonly assumed to be predictively so, autonomic nervous system innervation is insufficient to define the unique stimulus- and context-dependent physiological responses of an individual. By recording simultaneous physiological responses to the controlled presentation of a context-dependent stimulus, the unique relationships of physiology and overt behaviors for the individual can be demonstrated. Using this process also allows more complex virtual reality or other in vivo stimulus assessments to be incorporated for the development of individually tailored assessments and therapeutic plans. Thus, with or without memory or verbal recall, the use of multiple time- and context-specific simultaneous physiological measures and overt behavior can guide clinical effort as well as serve to objectively assess the ongoing treatment and its outcome.
... Within the brain, areas of the prefrontal cortex and anterior cingulate influence the amygdala, and kindling in these areas could cause continuous sympathetic nervous stimulation that would eventually lead to glandular depletion. [48] Other ME/CFS research suggests that long-term sensory receptor activation may lead to sensitization of the spinal cord and brain systems that transmit fatigue signals, causing long-term fatigue enhancement within the central nervous system. [49][50][51][52][53] Interventions that focus on energy balance and pacing might reduce the kindling and sensitization that could be occurring among patients with ME/CFS. ...
Article
Full-text available
Treatment approaches for patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been controversial. This paper provides the theoretical and conceptual background for the Energy Envelope Theory to assist patients with ME/CFS and reviews evidence of its treatment efficacy. Over a 15-year period, efforts were directed to develop a non-pharmacologic intervention that endeavored to help patients with ME/CFS self-monitor and self-regulate energy expenditures and learn to pace activities and stay within their energy envelope. Studies show that the energy envelope approach, which involves rehabilitation methods, helps patients with ME/CFS pace activities and manage symptoms and can significantly improve their quality of life.
... Böylece semptomlar daha kötüleflece¤i için hastan›n rahats›zl›-¤› artar. ‹flte bu fasit daire ancak hastan›n biraz iyileflmeye bafllamas› ile k›r›labilir (38). ...
Article
What is chronic fatigue immune dysfunction syndrome? Chronic fatigue immune dysfunction syndrome (CFIDS) is a central nervous system dysfunction characterized by profound disabling fatigue of at least 6 months and accompanied by multisystemic involvement manifesting itself with neuropsychiatric, neuroendocrinologic and immunologic symptoms. This review summarizes the current knowledge about CFIDS, which is little known in Turkish medical literature. Case definition, clinical presentation, evaluation, treatment and pathogenetic theories of CFIDS will be discussed in the light of the relevant literature. CFIDS is diagnosed on the basis of the clinically defined criteria. Patients with CFIDS experience profound functional impairment resulting in a significant decrease in their quality of life. Several research findings suggest that CFIDS is one of the stress-mediated disorders and should be distinct from psychiatric disorders. Existing pathophysiological abnormalities suggest that CFIDS is a heterogeneous condition of complex multifactorial etiology. Accumulating evidence also considers that dysfunction of HPA axis and serotonergic pathways in central nervous system may play an important role in the pathogenesis of CFIDS. Treatment for CFIDS is not specific but symptom-based and aimed at decreasing the level of stress. Graded exercise and cognitive behavioral therapy may be effective in increasing fitness and learning to cope with this disabling catastrophic syndrome, respectively. It has been reported that some experimental agents may be beneficial for treatment of some CFIDS patients. CFIDS is unlikely to be caused by a single agent. The data indicate that many environmental or psychological factors may precipitate or perpetuate the illness in genetically vulnerable subjects. The assessment and management of CFIDS patient should be multidimensional and psychiatrist should be a pervasive member of the multidisciplinary team for CFIDS.
... The amygdala receives direct projection from the thalamus, which monitors the sensory information and mediates the facilitation of attention (30). Neuroinflammation in this brain region may reduce cognitive activity through the deterioration of attentional function (31). Although our voxel-based morphometry studies demonstrated volume reduction of bilateral prefrontal cortices in CFS/ME patients (4), we did not focus on neuroinflammation in the prefrontal cortex and did not apply partial-volume correction since the BP ND range of 11 C-(R)-PK11195 in the prefrontal cortex was extremely small (0-0.0004). ...
Article
Full-text available
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region. The BPND values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BPND values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score. Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.
... LeDoux [387] refers to these cell assemblies as being particularly resistant to extinction; so, for some patients, this hard-wiring may only be regulated rather than extinguished. Gupta [388] believes that activation of the amygdala causes continuous sympathetic stimulation that is a predominantly unconscious process over which patients have little control, but it eventually leads to mental and physical exhaustion as well as glandular depletion. Wyller et al. [171] proposed compatible theories, stating that sustained arousal is the primary mechanism of ME. ...
Article
Full-text available
Myalgic Encephalomyelitis (ME) continues to cause significant morbiditiy worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson's Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to eludicate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers.This review, therefore, represents a synthesis of key discussions in the literature, andhas important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.
... However, as joint hypermobility was not assessed in the current study the degree to which it may have played a role the present findings remains unknown. Previous models of CFS have hypothesised a role for the amygdala in the pathophysiology of the condition (Gupta, 2002;Wyller et al., 2009). Its general role is perhaps best described as a salience and valence detector (Benarroch, 2015). ...
Article
Full-text available
Objective Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. Methods Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments. Results Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe. Conclusion Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.
... Its principles are based on Ledoux's neurobiological theory of conditioned fear that maintains that the amygdala has a key role in the symptomatology of various disorders (Ledoux, 2000;Maren & Quirk, 2004). In addition, this theory explains that the constant conditioned response of the amygdala and other neural centers when aversive and traumatic events happen, causes problems in the immune and sympathetic systems, and the person can suffer consequent physical and mental problems such as those described in FMS (Ehrlich et al., 2009;Gupta, 2002;Morris, Ohman, & Dolan, 1999). In fact, the theory says that the conditioning of the amygdala generates a state of hypervigilance to threat, real or not, leading to an imbalance of homeostasis, which causes the body to react constantly with high levels of alarm, and this feeds back onto the state of hypervigilance (Gupta, 2010). ...
Article
Full-text available
Fibromyalgia (FMS) is a prevalent, disabling syndrome characterized by chronic widespread musculoskeletal pain and symptoms such as sleep disturbance, fatigue, stiffness, and distress. Although no curative treatment has yet been found, various therapeutic approaches have been developed in the fields of pharmacology and psychology. The present paper aims to offer a narrative review and a description for clinicians and researchers of psychological therapies that have been applied in a format group in FMS with strong or promising empirical support: i.e., Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy (ACT), Mindfulness-Based Stress Reduction (MBSR), Psychoeducational program for FMS (FibroQoL), Amygdala Retraining Therapy (ART), and Attachment-Based Compassion Therapy (ABCT). This review will offer a brief practical summary of each therapy protocol (session-by-session), their rationale and available evidence of their effectiveness.
Article
Full-text available
ContextA novel mind–body approach (amygdala retraining) is hypothesized to improve symptoms related to fibromyalgia and chronic fatigue.Objective To examine the use of a mind–body approach for improving symptoms related to fibromyalgia and chronic fatigue.DesignThis was a single-blind, randomized controlled trial.SettingThe study was conducted in a tertiary-care fibromyalgia and chronic fatigue clinic.PatientsPatients with fibromyalgia, chronic fatigue, or both were included.InterventionsPatients were randomly assigned to receive amygdala retraining along with standard care or standard care alone. Standard care involved attending a 1.5-day multidisciplinary program. The amygdala retraining group received an additional 2.5-hour training course in which the key tools and techniques adapted from an existing program were taught to the patient. A home-study video course and associated text were provided to supplement the on-site program. Both groups received telephone calls twice a month to answer questions related to technique and to provide support.Main Outcome MeasuresValidated self-report questionnaires related to general health, well-being, and symptoms, including Short Form-36, Measure Yourself Medical Outcome Profile, Multidimensional Fatigue Inventory, Epworth Sleepiness Scale, and Fibromyalgia Impact Questionnaire.ResultsOf the 44 patients randomly assigned who completed baseline assessments, 21 patients completed the study (14 in the standard care group and 7 in the study group). Median age was 48 years (range, 27-56 years), and female subjects comprised 91% of the group. Analyses demonstrated statistically significant improvements in scores for physical health, energy, pain, symptom distress, and fatigue in patients who received the amygdala retraining compared with standard care.
Article
Implantable cardioverter defibrillators (ICD), despite an unequivocal clinical benefit, are known to have a complex psychosocial impact on the patients. ICD shocks and the resultant psychobiological changes are known to contribute to increased levels of anxiety, depression, and post-shock stress symptoms in these patients. Phantom shock is a patient-reported perception of an ICD shock in the absence of any actual shock; however, its pathophysiological understanding is poor. A retrospective chart review of the University hospital ICD patients' database from June 2006 to April 2010 was conducted. A total of 38 patients with documented phantom shocks as cases and 76 age- and sex-matched patients with no phantom shocks as controls were selected from the database. Patient characteristics were analyzed for their potential association with the occurrence of phantom shocks. Phantom shock patients had higher prevalence of documented depression (31.6%), anxiety (23.7%), and cocaine use (42.1%). Additionally, patients who had previous ICD shock storms were more likely to have phantom shocks (39.5%; p = 0.001). More importantly, no phantom shocks were reported in patients who did not receive defibrillation threshold testing or past ICD shock storms. Phantom shocks are primarily observed in ICD patients who had prior exposure to traumatic device shocks and are more common in patients with a history of depression, anxiety, or substance abuse. A pathophysiological mechanism is proposed as a guide to potential prevention.
Article
Chronic fatigue immune dysfunction syndrome (CFIDS) is a central nervous system dysfunction characterized by profound disabling fatigue of at least 6 months and accompanied by multisystemic involvement manifesting itself with neuropsychiatric, neuroendocrinologic and immunologic symptoms. This review summarizes the current knowledge about CFIDS, which is little known in Turkish medical literature. Case definition, clinical presentation, evaluation, treatment and pathogenetic theories of CFIDS will be discussed in the light of the relevant literature. CFIDS is diagnosed on the basis of the clinically defined criteria. Patients with CFIDS experience profound functional impairment resulting in a significant decrease in their quality of life. Several research findings suggest that CFIDS is one of the stress-mediated disorders and should be distinct from psychiatric disorders. Existing pathophysiological abnormalities suggest that CFIDS is a heterogeneous condition of complex multifactorial etiology. Accumulating evidence also considers that dysfunction of HPA axis and serotonergic pathways in central nervous system may play an important role in the pathogenesis of CFIDS. Treatment for CFIDS is not specific but symptom-based and aimed at decreasing the level of stress. Graded exercise and cognitive behavioral therapy may be effective in increasing fitness and learning to cope with this disabling catastrophic syndrome, respectively. It has been reported that some experimental agents may be beneficial for treatment of some CFIDS patients. CFIDS is unlikely to be caused by a single agent. The data indicate that many environmental or psychological factors may precipitate or perpetuate the illness in genetically vulnerable subjects. The assessment and management of CFIDS patient should be multidimensional and psychiatrist should be a pervasive member of the multidisciplinary team for CFIDS.
Article
Full-text available
A relationship between stress and sarcoidosis has been considered. However, studies concerning perceived stress, appraisal of life events, are scarce in sarcoidosis patients. Therefore, the aim of the present study was to further examine the role of perceived stress in sarcoidosis. Members of the Dutch Sarcoidosis Society (n = 1046; 59.0% females; the age range 40-49 contained the most persons) completed the Perceived Stress Scale (PSS), a symptom inventory, the Beck Depression Inventory (BDI), and the Fatigue Assessment Scale (FAS). The PSS score of sarcoidosis patients was high (p < 0.001), especially those of females (p < 0.001). Moreover, patients with psychological problems had higher PSS scores (p < 0.001). Notably, the presence of psychological problems and gender appeared to be unrelated. Furthermore, perceived stress was related to the BDI (r = 0.67, p < 0.001), especially to the cognitive subscale (r = 0.67, p < 0.001) and, to a lesser extent, to the physical depression subscale (r = 0.42, p < 0.001). Perceived stress was found to be high and related to symptoms in sarcoidosis. Moreover, depressive symptoms appeared to be related to perceived stress. Therefore, the management of sarcoidosis should include coping and appraisal therapy aiming to reduce stress and depressive symptoms.
Article
Do patients report specific physical symptoms in the presence of mental distress, taking into account the presence of somatic disease? Cross-sectional data were collected from 1458 participants in eight general practices in The Netherlands. Electronic patient records provided information on somatic disease. Questionnaires included the Hospital Anxiety and Depression Scale (HADS) to measure mental distress and the Physical Symptom Checklist (PSC). Patients reporting mental distress reported all types of physical symptoms more often than did patients without mental distress. Multivariate analyses in women, corrected for the presence of somatic disease, did not substantially change the univariate pattern. Odds ratios were particularly high (>6) for feeling tired or having low energy, fatigue without exertion and forgetfulness. It is the level of mental distress rather than gender or somatic disease that accounts for the reporting of any physical symptom. Fatigue might be an exception, but here, the classification as "physical" rather then "mental" is somewhat ambiguous.
Article
Although chronic stress is known to be linked with memory and other neurological disorders, little is known about the relationship between chronic stress and the onset or development of Alzheimer's disease (AD). In this study, we investigated the effects of long-term stress on the onset and severity of cognitive deficits and pathological changes in APPV717I-CT100 mice overexpressing human APP-CT100 containing the London mutation (V717I) after exposure to immobilization stress. We found that chronic immobilization stress accelerated cognitive impairments, as accessed by the Passive avoidance and the Social Transfer of Food Preference (STFP) tests. Moreover, the numbers and densities of vascular and extracellular deposits containing amyloid beta peptide (Abeta) and carboxyl-terminal fragments of amyloid precursor protein (APP-CTFs), which are pathologic markers of AD, were significantly elevated in stressed animals, especially in the hippocampus. Moreover, stressed animals, also showed highly elevated levels of neurodegeneration and tau phosphorylation and increased intraneuronal Abeta and APP-CTFs immunoreactivities in the hippocampus and in the entorhinal and piriform cortex. This study provides the first evidence that chronic stress accelerates the onset and severity of cognitive deficits and that these are highly correlated with pathological changes, which thus indicates that chronic stress may be an important contributor to the onset and development of AD.
Article
Full-text available
To examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with chronic fatigue syndrome in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity. Quadriceps needle muscle biopsies were obtained from 105 patients with chronic fatigue syndrome and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET). Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Patients with increased lactate responses to exercise did have significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found. Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.
Article
Full-text available
Phantom auditory perception--tinnitus--is a symptom of many pathologies. Although there are a number of theories postulating certain mechanisms of its generation, none have been proven yet. This paper analyses the phenomenon of tinnitus from the point of view of general neurophysiology. Existing theories and their extrapolation are presented, together with some new potential mechanisms of tinnitus generation, encompassing the involvement of calcium and calcium channels in cochlear function, with implications for malfunction and aging of the auditory and vestibular systems. It is hypothesized that most tinnitus results from the perception of abnormal activity, defined as activity which cannot be induced by any combination of external sounds. Moreover, it is hypothesized that signal recognition and classification circuits, working on holographic or neuronal network-like representation, are involved in the perception of tinnitus and are subject to plastic modification. Furthermore, it is proposed that all levels of the nervous system, to varying degrees, are involved in tinnitus manifestation. These concepts are used to unravel the inexplicable, unique features of tinnitus and its masking. Some clinical implications of these theories are suggested.
Article
Full-text available
In the classical Pavlovian conditioning paradigm, a stimulus that unconditionally elicits a physiological response is repeatedly paired with a neutral stimulus that does not elicit that same response. Eventually, the neutral stimulus becomes a conditioned stimulus in that it elicits the physiological response in the absence of an unconditioned stimulus. Here we summarize experiments in which Pavlovian conditioning has revealed an intimate relationship between the central nervous system and the immune system.
Article
Full-text available
The term functional somatic syndrome has been applied to several related syndromes characterized more by symptoms, suffering, and disability than by consistently demonstrable tissue abnormality. These syndromes include multiple chemical sensitivity, the sick building syndrome, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome, chronic whiplash, the chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Patients with functional somatic syndromes have explicit and highly elaborated self-diagnoses, and their symptoms are often refractory to reassurance, explanation, and standard treatment of symptoms. They share similar phenomenologies, high rates of co-occurrence, similar epidemiologic characteristics, and higher-than-expected prevalences of psychiatric comorbidity. Although discrete pathophysiologic causes may ultimately be found in some patients with functional somatic syndromes, the suffering of these patients is exacerbated by a self-perpetuating, self-validating cycle in which common, endemic, somatic symptoms are incorrectly attributed to serious abnormality, reinforcing the patient's belief that he or she has a serious disease. Four psychosocial factors propel this cycle of symptom amplification: the belief that one has a serious disease; the expectation that one's condition is likely to worsen; the "sick role," including the effects of litigation and compensation; and the alarming portrayal of the condition as catastrophic and disabling. The climate surrounding functional somatic syndromes includes sensationalized media coverage, profound suspicion of medical expertise and physicians, the mobilization of parties with a vested self-interest in the status of functional somatic syndromes, litigation, and a clinical approach that overemphasizes the biomedical and ignores psychosocial factors. All of these influences exacerbate and perpetuate the somatic distress of patients with functional somatic syndromes, heighten their fears and pessimistic expectations, prolong their disability, and reinforce their sick role. A six-step strategy for helping patients with functional somatic syndromes is presented here.
Article
Full-text available
The functional gastrointestinal disorders (FGID) are the most frequent conditions seen in gastroenterology practice and comprise a major portion of primary care. Psychosocial factors are important in these disorders with regard to: (1) their effects on gut physiology; (2) their modulation of the symptom experience; (3) their influence on illness behavior; (4) their impact on outcome; and (5) the choice of the therapeutic approach. This paper provides a review and consensus of the existing literature by gastroenterologists, psychiatrists, psychologists, physiologists, and health services investigators. Evidence is provided to support the biopsychosocial model as a basis for understanding and treating these disorders, and epidemiological and clinical information on the relations of psychosocial factors to gut physiology, symptom presentation, health behavior, and outcome is offered. Features of motility, personality, abuse history, health concerns, and treatment-seeking differ between patients with FGID and healthy controls, but they are not specific to FGID. They occur in other patients with chronic medical conditions and/or psychiatric disorders. Review of treatment trials indicates clear support for psychotherapeutic treatments, especially in the long term, as well as some evidence for the benefit of antidepressants in FGID, even in the absence of improvements in mood.
Article
Full-text available
The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.
Article
Full-text available
Patients with chronic fatigue syndrome (CFS) and depressive illness share many, but not all, features. To test the hypothesis that patients with CFS have abnormal cerebral perfusion, that differs from that in patients with depressive illness. We recruited 30 patients with CFS who were not depressed, 12 depressed patients and 15 healthy volunteers. Regional cerebral perfusion at rest was assessed using region of interest (ROI) and voxel-based statistical parametric mapping (SPM) techniques. On SPM analysis there was increased perfusion in the right thalamus, pallidum and putamen in patients with CFS and in those with depressive illness. CFS patients also had increased perfusion in the left thalamus. Depressed patients differed from those with CFS in having relatively less perfusion of the left prefrontal cortex. The results were similar on ROI analysis. Abnormal cerebral perfusion patterns in CFS subjects who are not depressed are similar but not identical to those in patients with depressive illness. Thalamic overactivity may be a correlate of increased attention to activity in CFS and depression; reduced prefrontal perfusion in depression may be associated with the greater neuropsychological deficits in that disorder.
Article
The term functional somatic syndrome has been applied to several related syndromes characterized more by symptoms, suffering, and disability than by consistently demonstrable tissue abnormality. These syndromes include multiple chemical sensitivity, the sick building syndrome, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome, chronic whiplash, the chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Patients with functional somatic syndromes have explicit and highly elaborated self-diagnoses, and their symptoms are often refractory to reassurance, explanation, and standard treatment of symptoms. They share similar phenomenologies, high rates of co-occurrence, similar epidemiologic characteristics, and higher-than-expected prevalences of psychiatric comorbidity. Although discrete pathophysiologic causes may ultimately be found in some patients with functional somatic syndromes, the suffering of these patients is exacerbated by a self-perpetuating, self-validating cycle in which common, endemic, somatic symptoms are incorrectly attributed to serious abnormality, reinforcing the patient's belief that he or she has a serious disease. Four psychosocial factors propel this cycle of symptom amplification: the belief that one has a serious disease; the expectation that one's condition is likely to worsen; the "sick role," including the effects of litigation and compensation; and the alarming portrayal of the condition as catastrophic and disabling. The climate surrounding functional somatic syndromes includes sensationalized media coverage, profound suspicion of medical expertise and physicians, the mobilization of parties with a vested self-interest in the status of functional somatic syndromes, litigation, and a clinical approach that overemphasizes the biomedical and ignores psychosocial factors. All of these influences exacerbate and perpetuate the somatic distress of patients with functional somatic syndromes, heighten their fears and pessimistic expectations, prolong their disability, and reinforce their sick role. A six-step strategy for helping patients with functional somatic syndromes is presented here.
Article
Background: Procaine activates limbic structures in animals. In humans, acute intravenous administration of procaine yields emotional and psychosensory experiences and temporal lobe fast activity. We studied procaine's acute effects on cerebral blood flow (CBF) in relationship to clinical responses. Methods: Cerebral blood flow was assessed by positron emission tomography with oxygen-15-labeled water in 32 healthy volunteers. Data were analyzed with statistical parametric mapping and magnetic resonance imaging-directed regions of interest. Results: Procaine increased global CBF and, to a greater extent, anterior paralimbic CBF. Subjects with intense procaine-induced fear compared with those with euphoria had greater increases in left amygdalar CBF. Absolute and normalized left amygdalar CBF changes tended to correlate positively with fear and negatively with euphoria intensity. Procaine-induced visual hallucinations appeared associated with greater global and occipital CBF increases. Absolute occipital CBF increases appeared to correlate positively with visual hallucination intensity. Conclusions: Procaine increased anterior paralimbic CBF, and different clinical responses appeared to be associated with different patterns of CBF changes.
Article
PURPOSE: Patients with fibromyalgia have been reported to display high rates of several concomitant medical and psychiatric disorders, including migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. To test further these and other possible associations, we assessed the personal and family histories of a broad range of medical and psychiatric disorders in patients with fibromyalgia. PATIENTS AND METHODS: Subjects were 33 women (mean age 42.1 years) who each met American College of Rheumatology criteria for fibromyalgia and presented to a rheumatologist at a tertiary referral center. They received the Structured Clinical Interview for DSM-III-R (SCID); a supplemental interview, in SCID format, for other medical and psychiatric disorders, including migraine, irritable bowel syndrome, and chronic fatigue syndrome; and an interview for family history of medical and psychiatric disorders. RESULTS: Patients with fibromyalgia displayed high lifetime rates of migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. They also exhibited high rates of familial major mood disorder. CONCLUSIONS: The finding that migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder are frequently comorbid with fibromyalgia is consistent with the hypothesis that these various disorders may share a common physiologic abnormality.
Article
Emotion and cognition are mediated by separate but interacting systems of the brain. The core of the emotional system is a network that evaluates (computes) the biological significance of stimuli, including stimuli from the external or internal environment or from within the brain (thoughts, images, memories). The computation of stimulus significance takes place prior to and independent of conscious awareness, with only the computational products reaching awareness, and only in some instances. The amygdala may be a focal structure in the affective network. By way of neural interactions between the amygdala and brain areas involved in cognition (particularly the neocortex and hippocampus), affect can influence cognition and cognition can influence affect. Emotional experiences, it is proposed, result when stimulus representations, affect representations, and self representations coincide in working memory.
Book
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
Article
argue . . . that worry is initiated as an attempt to control other unwanted experiences (both future environmental catastrophe and immediate somatic anxiety in response to perceived threat), but that it becomes an unwanted experience in itself that is in turn very difficult to control and contains within itself processes that are self-perpetuating / provide some insight into the role of unwanted cognitive activity in the maintenace of anxiety disorders (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
This article reviews findings of research examining the interaction of peripheral adrenergic systems with cholinergic, opioid peptidergic and GABAergic systems in modulating memory storage. It is well established that retention is enhanced by posttraining systemic or intra-amygdala injections of adrenergic agonists, opiate antagonists and GABAergic antagonists. These influences appear to be mediated by activation of NE receptors within the amygdala, as intra-amygdala injections of β-adrenergic antagonists block the memory-modulating effects of hormones and drugs affecting these systems. Furthermore, these influences also appear to involve, at a subsequent step, activation of a cholinergic system: atropine blocks the memory-enhancing effects of adrenergic agonists and opiate and GABAergic antagonists and oxotremorine attenuate the memory-impairing effects of opiate agonists and GABAergic agonists. These findings suggest that the amygdala integrates the memory-modulating effects of neuromodulatory systems activated by learning experiences.
Article
Patients with fibromyalgia have been reported to display high rates of several concomitant medical and psychiatric disorders, including migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. To test further these and other possible associations, we assessed the personal and family histories of a broad range of medical and psychiatric disorders in patients with fibromyalgia. Subjects were 33 women (mean age 42.1 years) who each met American College of Rheumatology criteria for fibromyalgia and presented to a rheumatologist at a tertiary referral center. They received the Structured Clinical Interview for DSM-III-R (SCID); a supplemental interview, in SCID format, for other medical and psychiatric disorders, including migraine, irritable bowel syndrome, and chronic fatigue syndrome; and an interview for family history of medical and psychiatric disorders. Patients with fibromyalgia displayed high lifetime rates of migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. They also exhibited high rates of familial major mood disorder. The finding that migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder are frequently comorbid with fibromyalgia is consistent with the hypothesis that these various disorders may share a common physiologic abnormality.
Article
There is much conflicting immunological and viral data about the causes of chronic fatigue syndrome (CFS); some findings support the notion that CFS may be due to one or more immune disorders that have resulted from exposure to an infectious agent. In the present study, flow cytometry and several different monoclonal antibodies recognising T, B, and natural killer (NK) cell populations as well as activation and cell adhesion antigens were used to study 147 individuals with CFS. Compared with healthy controls, a reduced CD8 suppressor cell population and increased activation markers (CD38, HLA-DR) on CD8 cells were found. The differences were significant (p = 0.01) in patient with major symptoms of the disease. These immunological indices were not observed in 80 healthy individuals, in 22 contacts of CFS patients, or in 43 patients with other diseases. No correlation of these findings in CFS patients with any known human viruses could be detected by serology. The findings suggest that immune activation is associated with many cases of CFS.
Article
The ability of chronic ethanol stress to alter hypothalamic-pituitary-adrenal (HPA) axis function in a manner similar to that previously reported for other chronic stress treatments was evaluated. Injection of male Sprague-Dawley or Long-Evans rats with ethanol (1-4 g/kg i.p., 20% v/v in saline) resulted in a rapid and large rise in serum corticosterone levels with maximal levels produced by a dose of 2 g/kg ethanol. Higher doses of ethanol did not increase the maximum corticosterone response above those produced by 2 g/kg ethanol but they extended the duration of the peak response. Chronic treatment with ethanol stress (1-3 weeks) produced signs of hyperstimulation of the HPA axis as indicated by adrenal hypertrophy and thymus involution. There was, however, adaptation of the HPA axis to the chronic ethanol treatment. The corticosterone response to ethanol on the last day of treatment was significantly less than on the first day of treatment, even though serum ethanol levels at the time of both measures were equivalent. There also were no signs of impaired negative feedback control of glucocorticoid secretion in the chronic-ethanol-treated rats. They exhibited a normal corticosterone response to 1 h of restraint and a normal shut-off of the stress response. There was also no down-regulation of type I or type II adrenal steroid receptors in the hippocampus of chronic ethanol-stress-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We have conducted studies in intact adult male rats, designed to examine the effect of a 3- or 7-day exposure to alcohol (EtOH) on the pituitary's response to corticotropin-releasing hormone (CRF) or stress, and on CRF expression in the hypothalamus. In a first series of experiments, rats exposed to EtOH vapors for 7 days had mean blood alcohol levels (BAL) of 127 +/- 12 mg%. At the end of the 7-day period, basal plasma ACTH levels were 69 +/- 10 pg/ml in control rats and 121 +/- 23 pg/ml in EtOH animals (P less than or equal to 0.01). Resting corticosterone levels were 39 +/- 11 ng/ml in control animals, and 101 +/- 24 ng/ml in EtOH rats (P less than or equal to 0.01). In all experiments described here, there was no statistical difference (P greater than 0.05) between the body weights of controls (animals kept in chambers with normal atmosphere) and EtOH-exposed animals. In control animals, the injection of 0.3-10 micrograms ovine CRF per rat caused dose-related increases in plasma ACTH levels measured 10 min later. All doses of CRF also significantly (P less than or equal to 0.01) stimulated ACTH secretion by EtOH rats, but there was no clear dose-response curve. Though EtOH-treated animals responded to the lower dose of CRF (0.3 microgram) with larger increases in plasma ACTH levels than control rats, the only statistical difference (P less than or equal to 0.01) between control and EtOH rats was observed following administration of 10 micrograms CRF, which caused a blunted response in EtOH animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances.
Article
Contrary to the common view that all panic attacks have a single etiology, it is shown that a distinction must be made between initial attacks, for which there are many causes, and recurrent attacks (panic disorder) which have a common basis. Most initial panic attacks are attributable to the physiological effects of hyperventilation resulting from severe and prolonged anxiety. It has been claimed that the attacks are due to such symptoms as dyspnea, tachycardia and dizziness being misattributed to deadly illness or incipient insanity. We reject this view on several grounds, and in particular because of a pilot study that showed that such attributions follow the onset of panic. Apart from some biological cases, the common initial panic is an unconditioned response to a bizarre stimulus complex produced by excessive hyperventilation, and panic disorder is the result of contiguous stimuli, especially endogenous stimuli, being conditioned to the elicited anxiety. Treatment accords with principles of conditioning.
Article
The involvement of the basal ganglia in motor functions has been well studied. Recent neurophysiological, clinical and behavioral experiments indicate that the basal ganglia also process non-noxious and noxious somatosensory information. However, the functional significance of somatosensory information processing within the basal ganglia is not well understood. This review explores the role of the striatum, globus pallidus and substantia nigra in nociceptive sensorimotor integration and suggests several roles of these basal ganglia structures in nociception and pain. Electrophysiological experiments have detailed the non-nociceptive and nociceptive response properties of basal ganglia neurons. Most studies agree that some neurons within the basal ganglia encode stimulus intensity. However, these neurons do not appear to encode stimulus location since the receptive fields of these cells are large. Many basal ganglia neurons responsive to somatosensory stimulation are activated exclusively or differentially by noxious stimulation. Indirect techniques used to measure neuronal activity (i.e., positron emission tomography and 2-deoxyglucose methods) also indicate that the basal ganglia are activated differentially by noxious stimulation. Neuroanatomical experiments suggest several pathways by which nociceptive information may reach the basal ganglia. Neuroanatomical studies have also indicated that the basal ganglia are rich in many different neuroactive chemicals that may be involved in the modulation of nociceptive information. Microinjection of opiates, dopamine and gamma-aminobutyric acid (GABA) into the basal ganglia have varied effects on pain behavior. Administration of these neurochemicals into the basal ganglia affects supraspinal pain behaviors more consistently than spinal reflexive behaviors. The reduction of pain behavior following electrical stimulation of the substantia nigra and caudate nucleus provides additional evidence for a role of the basal ganglia in pain modulation. Some patients with basal ganglia disease (e.g., Parkinson's disease, Huntington's disease) have alterations in pain sensation in addition to motor abnormalities. Frequently, these patients have intermittent pain that is difficult to localize. Collectively, these data suggest that the basal ganglia may be involved in the (1) sensory-discriminative dimension of pain, (2) affective dimension of pain, (3) cognitive dimension of pain, (4) modulation of nociceptive information and (5) sensory gating of nociceptive information to higher motor areas. Further experiments that correlate neuronal discharge activity with stimulus intensity and escape behavior in operantly conditioned animals are necessary to fully understand how the basal ganglia are involved in nociceptive sensorimotor integration.
Article
Patients with the sleep apnea/hypopnea syndrome suffer from impaired daytime function. This has been attributed to both sleep fragmentation and hypoxemia. To help understand which is casual, we studied the effects of sleep fragmentation alone on daytime function. Sixteen normal subjects were studied on two pairs of two nights. The first night of each pair was for acclimatization, and on the second the subject either slept undisturbed or had sleep fragmented with sound pulses every 2 min. Sound volume and duration was titrated to cause a return to theta or alpha rhythm on the EEG for at least 3 s. Study nights were followed by daytime testing of psychometric function and mood and by a multiple sleep latency test (MSLT) and a maintenance of wakefulness test (MWT). Total sleep time did not differ between study nights (400 +/- 20 SD min undisturbed, 396 +/- 24 min fragmented; p = 0.6). Fragmentation decreased sleep latency on both the MSLT (11 +/- 3, 7 +/- 2 min; p = 0.001) and the MWT (34 +/- 8, 24 +/- 10 min; p<0.001). Energetic arousal (22 +/- 4, 19 +/- 4; p = 0.005) and hedonic tone (29 +/- 4, 27 +/- 4; p = 0.05) decreased after fragmentation. Fragmentation impaired daytime function adjudged by the Trailmaking B (p = 0.05) and PASAT 4-s tests (p<0.03). One night of sleep fragmentation makes normal subjects sleepier during the day, impairs their subjective assessment of mood, and decreases mental flexibility and sustained attention.
Article
There are few data on the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in individuals with chronic GI symptoms. The current study was designed to describe and compare urine catecholamine (norepinephrine, epinephrine) and cortisol levels in women diagnosed with irritable bowel syndrome (IBS-patients), women who report similar symptom levels but had not sought health care services (IBS-nonpatients; IBS-NP), and asymptomatic (control) women. Seventy-three women (24 IBS; 24 IBS-NP; 25 controls) were interviewed for demographic, GI, gynecological, and psychological data and then followed for two menstrual cycles with a daily health diary. Urine samples were obtained in the evening and morning at specific phases across two menstrual cycles. Women in the IBS group had significantly higher PM and AM urine norepinephrine levels. Urine epinephrine and cortisol levels were also generally higher in women with IBS. Differences in neuroendocrine indicators of arousal were not accounted for by differences in demographic variables, lifestyle characteristics, menstrual distress, or average daily measures of anxiety or depression. Increases in indicators of sympathetic nervous system activation in women seeking health care for IBS may reflect greater symptom distress or may contribute to increased symptom distress.
Article
Many patients with chronic fatigue syndrome (CFS) display features of hypothalamic dysfunction. We have investigated aspects of circadian rhythmicity, an important hypothalamic function, in 20 CFS patients and in 17 age- and sex-matched healthy control subjects. There were no differences between the two groups in the amplitude, mesor (mean value) or timing of the peak (acrophase) of the circadian rhythm of core temperature, or in the timing of the onset of melatonin secretion. However, the CFS patients showed no significant correlation between the timing of the temperature acrophase and the melatonin onset (P < 0.5), whereas the normal significant correlation was observed in the controls (P < 0.05). Dissociation of circadian rhythms could be due to the sleep deprivation and social disruption, and/or the reduction in physical activity which typically accompany CFS. By analogy with jet-lag and shift-working, circadian dysrhythmia could be an important factor in initiating and perpetuating the cardinal symptoms of CFS, notably tiredness, impaired concentration and intellectual impairment.
Article
Posttraumatic stress disorder is a disorder with an identifiable etiological factor (exposure to a traumatic event) and with a complex symptomatology (i.e. intrusive memories, avoidance, hyperarousal) that suggests dysfunction in multiple psychobiological systems. This review considers studies of the neurobiological consequences of acute and chronic stress showing that traumatic experiences can produce long-lasting alterations in multiple neurochemical systems. The role of the locus coeruleus noradrenergic system, prefrontal cortex dopaminergic system, endogenous opiates, hypothalamic-pituitary-adrenal axis, and cortico-releasing factors are reviewed. Several models of PTSD are highlighted, including fear conditioning, kindling, and sensitization. In particular, fear conditioning to explicit and contextual cues is proposed as a model for intrusive memories reactivated by trauma-related stimuli and hyperarousal, respectively. It is argued that the amygdala plays a crucial role in the encoding and retrieval of fear memories activated by specific stimuli that have been associated with aversive events. Association involving more complex environmental stimuli and aversive events may require the involvement of the hippocampus and the bed nucleus of the stria terminalis. Repeated activation of conditioned fear memories may produce a kindling-like process which results in spontaneous intrusive memories.
Article
Ketter et al¹ report on an increase in anterior paralimbic cerebral blood flow (CBF) associated with procaine-induced affective and perceptual symptoms. Changes in CBF and increased activation of left anterior paralimbic structures were associated with procaine-induced fear. Superior temporal activation occurred in the entire group of subjects, most of whom experience "hallucinations." Intense unformed visual hallucinations were associated with greater global CBF. The clinical psychiatric symptoms of the toxic effects of lidocaine hydrochloride and procaine are similar, both showing dysphoric mood changes with fear of death or doom-related content and hallucinations.² Based on the work of Post et al,³ it had been previously hypothesized that activation of the amygdala, hippocampus, and related structures might be involved in producing the symptoms of lidocaine toxicity.⁴⁻⁶ The interesting finding by Ketter et al¹ that procaine-induced fear is related to activation of the left amygdala in experimental subjects
Article
Chronic fatigue syndrome (CFS) is associated with insidious and persistent immunologic abnormalities that have proved difficult to reproduce. The heterogeneity of CFS, the variable quality of immunologic assays and their performance, along with an almost complete absence of longitudinal studies of cellular immune abnormalities in CFS may explain this difficulty. However, in a significant proportion of cases, low levels of natural killer (NK) cell activity have been reported. This article will explore the mechanisms responsible for low NK cell activity, discuss the relation between levels of NK cell activity and health/disease, describe new findings on NK cell-brain interactions, and put forth a specific hypothesis for the role of NK cells in the pathogenesis of CFS.
Article
Our objective was to evaluate symptom patterns in patients with chronic fatigue syndrome (CFS) who were ill for 10 or more years. This cross-sectional self-report study compared patient groups with long-duration (median = 18 years; n = 258) and short-duration (median = 3 years; n = 28) CFS to a group of healthy significant others (n = 79) on symptomatic, neurocognitive, and psychological variables. Data were gathered from a 574-item postal questionnaire. A principal-components analysis of CFS symptom data yielded a three-factor solution: cognitive problems; flu-like symptoms; and neurologic symptoms. Compared with the short-duration CFS group, the long-duration group had significantly higher CFS symptom severity scores (p < 0.04), largely attributable to increased cognitive difficulties. A subgroup comparison of subjects ill for < 3 years versus those ill 4-7 years suggested that denial coping strategies were more likely in those participants with the shorter illness duration. Significant differences between both CFS groups and healthy controls were found in a number of comorbid disorders. Participants with CFS most often endorsed immune/viral abnormalities and persistent stress as important perceived causes of their illness. Participants with long-duration CFS reported a large number of specific cognitive difficulties that were greater in severity than those reported by participants with short-duration CFS. The pattern of comorbid disorders in the CFS groups was consistent with hypersensitivity and viral reactivation hypotheses.
Article
Traumatic events can result in a set of symptoms including nightmares, recurrent and intrusive recollections, avoidance of thoughts or activities associated with the traumatic event, and symptoms of increased arousal such as insomnia and hypervigilance. These posttraumatic stress disorder (PTSD)-like symptoms are frequently observed in persons with chronic pain syndromes. Little is known about how these two phenomena interact with one another. The present study evaluated PTSD-like symptoms in patients with fibromyalgia syndrome (FMS) and examined the relation between PTSD-like symptoms and problems associated with FMS. Ninety-three consecutive patients underwent a comprehensive FMS evaluation and completed self-report questionnaires measuring PTSD-like symptoms, disability, and psychosocial responses to their pain condition. Subjects were divided in two groups based on level of self-reported PTSD-like symptoms. Approximately 56% of the sample reported clinically significant levels of PTSD-like symptoms (PTSD+). The PTSD+ patients reported significantly greater levels of pain (p < 0.01), emotional distress (p < 0.01), life interference (p < 0.01), and disability (p < 0.01) than did the patients without clinically significant levels of PTSD-like symptoms (PTSD-). Over 85% of the PTSD+ patients compared with 50% of the PTSD- patients demonstrated significant disability. Based on response to the Multidimensional Pain Inventory, a significantly smaller percentage of PTSD+ patients were classified as adaptive copers (15%) compared with the PTSD- group (48.2%). Results suggest that PTSD-like symptoms are prevalent in FMS patients and may influence adaptation to this chronic illness. Clinicians should assess the presence of these symptoms, as the failure to attend to them in treatment may impede successful outcomes.
Article
Orthostatic hypotension during upright tilt is an important physical disorder in patients with chronic fatigue syndrome. We have tested its occurrence during prolonged standing, whether it is correctable, and whether reduced circulating erythrocyte volume is present. Fifteen patients were randomly selected from a large population of patients with chronic fatigue syndrome, studied, and observed for several years (by DSB). Blood pressure (BP) and heart rate (HR) measured with Dinamap every minute for 30 minutes supine and 60 minutes standing were compared with these findings in 15 healthy age- and gender-matched control subjects and later during lower body compression with military antishock trousers (MAST). Plasma catecholamines and circulating erythrocyte and plasma volumes were also measured by isotopic dilution methods. Abnormal findings in the patients included excessive orthostatic reductions in systolic (P < 0.001) and diastolic BP (P < 0.001) and excessive orthostatic tachycardia (P < 0.01), together with presyncopal symptoms in 11 of the 15 patients and in none of the control subjects after standing for 60 min. Lower body compression with the MAST restored all orthostatic measurements to normal and overcame presyncopal symptoms within 10 min. Circulating erythrocyte but not plasma volumes were subnormal in the 12 women (P < 0.01) and plasma norepinephrine concentration rose excessively after standing for 10 min. Delayed orthostatic hypotension and/or tachycardia caused by excessive gravitational venous pooling, which is correctable with external lower-body compression, together with subnormal circulating erythrocyte volume, are very frequent, although not invariably demonstrable, findings in moderate to severe chronic fatigue syndrome. When present, they may be involved in its pathogenesis.
Emotional Experience: A Neurological Model
  • K M Heilman
Heilman, K.M. (2000) “Emotional Experience: A Neurological Model”, in R.D. Lane and L. Nadel (eds) “Cognitive Neuroscience of Emotion”, (Oxford University Press
Tinnitus: Turning the Volume Down
  • Kevin Hogan
Kevin Hogan (1998), Tinnitus: Turning the Volume Down. (Network 3000 Publishing Company
The Emotional Brain " Weidenfeld and Nicolson p241
  • Kindly
  • J From Ledoux
Kindly reproduced from Ledoux, J. (1998) " The Emotional Brain " Weidenfeld and Nicolson p241
Cognitive-Emotional Interactions in Cognitive Neuroscience of Emotion Kindly reproduced from Ledoux The Emotional Brain " p170, Weidenfeld and Nicolson 76
  • J Ledoux
Ledoux, J. (2000) Cognitive-Emotional Interactions in Lane, R. D. (ed) Cognitive Neuroscience of Emotion, Oxford University Press 75. Kindly reproduced from Ledoux, J.,(1998) " The Emotional Brain " p170, Weidenfeld and Nicolson 76. Based on evidence cited by Ledoux, J., in " The Emotional Brain ", as well as general anatomy and physiology literature.
  • C Evidence Cited In Dancey
  • B Backhouse
Evidence cited in Dancey C., and Backhouse, B., (1997) IBS (Robinson), p2-5
  • Robert Ader
Robert Ader et al., Psychoneuroimmunology, 2d ed. (San Diego: Academic Press, 1990). See also Dozier, R., W., (1998), Fear Itself, (St. Martins Press) p210.
The Emotional Brain (Pheonix) chapters
  • See Ledoux
See Ledoux, J. (1998), The Emotional Brain (Pheonix) chapters 6-9
The effects of alcohol on selected regulatory aspects of the stress axis
  • R L Eskay
  • T Chautard
  • T Torda
  • D Hwang
Eskay, R.L.; Chautard, T.; Torda, T.; & Hwang, D. (1993)The effects of alcohol on selected regulatory aspects of the stress axis. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. Bethesda, MD
This process is described in " The Emotional Brain
  • Joseph Ledoux
This process is described in " The Emotional Brain ", Joseph Ledoux (1998) p260-261, and is currently hypothetical.
The Organisation of Behaviour
  • D O Hebb
Hebb D.O. (1949) The Organisation of Behaviour (New York: Wiley)
See also Wessely, Hotopf, Sharpe. Chronic Fatigue and its Syndromes
  • C Grillon
  • S M Southwick
  • D S Charney
The Emotional Brain (Pheonix)
  • J Ledoux