Visceral brain-body information transfer.

Organisms interact with their environments through various afferent (sensory) and efferent (motor) mechanisms. While the usual environment of interest has been external to the organism, the internal environment is also of fundamental importance. This article briefly reviews many of the interactive mechanisms between the brain and the visceral environment, along with identification of relevant brain structures and linkages related to these peripheral functions (particularly the hypothalamus). Afferent and efferent neural (autonomic nervous system) and chemical (endocrine, immune, and blood-brain barrier and circumventricular organs) pathways are described, and potential unifying principles (emotion and, especially, homeostasis, including allostasis and stress) are identified. The importance of bidirectional (afferent, efferent) communication is emphasized. These systems of visceral brain-body information transfer are major connections between the central nervous system and the body through which and by which many psychosomatic processes occur.

The rebirth of neuroscience in psychosomatic medicine, Part I: historical context, methods, and relevant basic science.

Neuroscience was an integral part of psychosomatic medicine at its inception in the early 20th century. Since the mid-20th century, however, psychosomatic research has largely ignored the brain. The field of neuroscience has burgeoned in recent years largely because a variety of powerful new methods have become available. Many of these methods allow for the noninvasive study of the living human brain and thus are potentially available for integration into psychosomatic medicine research at this time. In this first paper we examine various methods available for human neuroscientific investigation and discuss their relative strengths and weaknesses. We next review some basic functional neuroanatomy involving structures that are increasingly being identified as relevant for psychosomatic processes. We then discuss, and provide examples of, how the brain influences end organs through "information transfer systems," including the autonomic, neuroendocrine, and immune systems. The evidence currently available suggests that neuroscience holds great promise for advancing the goal of understanding the mechanisms by which psychosocial variables influence physical disease outcomes. An increased focus on such mechanistic research in psychosomatic medicine is needed to further its acceptance into the field of medicine.

The rebirth of neuroscience in psychosomatic medicine, Part II: clinical applications and implications for research.

During the second half of the last century, biopsychosocial research in psychosomatic medicine largely ignored the brain. Neuroscience has started to make a comeback in psychosomatic medicine research and promises to advance the field in important ways. In this paper we briefly review select brain imaging research findings in psychosomatic medicine in four key areas: cardiovascular regulation, visceral pain in the context of functional gastrointestinal disorders, acute and chronic somatic pain and placebo. In each area, there is a growing literature that is beginning to define a network of brain areas that participate in the functions in question. Evidence to date suggests that cortical and subcortical areas that are involved in emotion and emotion regulation play an important role in each domain. Neuroscientific research is therefore validating findings from previous psychosomatic research and has the potential to extend knowledge by delineating the biological mechanisms that link mind and body more completely and with greater specificity. We conclude with a discussion of the implications of this work for how research in psychosomatic medicine is conducted, the ways in which neuroscientific advances can lead to new clinical applications in psychosomatic contexts, the implications of this work for the field of medicine more generally, and the priorities for research in the next 5 to 10 years.

Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder.

CONTEXT: Benzodiazepine drugs are highly effective anxiolytic medications, but the role of the benzodiazepine-gamma-aminobutyric acid(A)-chloride ion channel macromolecular complex in the pathophysiologic mechanism of anxiety is not well understood. Previous human imaging studies have indicated involvement of specific regions of the brain in anxiety disorders, especially the frontal-prefrontal, temporal, and cingulate cortical and the limbic areas. OBJECTIVE: To identify potential abnormalities of brain benzodiazepine receptor binding number and distribution in anxiety disorders. SETTING AND PARTICIPANTS: At the University of Michigan positron emission tomography facility, 11 individuals with DSM-IV-defined anxiety syndrome panic disorder were compared with 21 unaffected healthy control subjects. Design and Main Outcome Measure In a between-group comparison, we used positron emission tomography and the benzodiazepine receptor ligand flumazenil labeled with carbon 11 to assess the regional brain pattern of receptor binding. RESULTS: We observed decreased binding specifically in the insular cortex bilaterally. No binding abnormality was observed in any other brain region, and there was no evidence of abnormal cerebral blood flow anywhere in the brain. Individuals with panic disorder and comorbid depression, indicative of a more severe disorder, had the lowest binding. No significant correlations were observed for binding with age, sex, or duration of disorder. CONCLUSIONS: A previous smaller study with the same ligand reported a probable binding abnormality in the right insula. Because gamma-aminobutyric acid is a major inhibitory neurotransmitter in the brain and because benzodiazepines facilitate this effect of gamma-aminobutyric acid, decreased benzodiazepine binding is consistent with localized brain activation (ie, loss of inhibition). Because the insula is strongly involved in visceral-somatic afferent and efferent function, activation of the insula is consistent with the occurrence of the physical symptoms prominently associated with panic disorder.

Interoception and Mental Health: A Roadmap.

Interoception refers to the process by which the nervous system senses, interprets, and integrates signals originating from within the body, providing a moment-by-moment mapping of the body's internal landscape across conscious and unconscious levels. Interoceptive signaling has been considered a component process of reflexes, urges, feelings, drives, adaptive responses, and cognitive and emotional experiences, highlighting its contributions to the maintenance of homeostatic functioning, body regulation, and survival. Dysfunction of interoception is increasingly recognized as an important component of different mental health conditions, including anxiety disorders, mood disorders, eating disorders, addictive disorders, and somatic symptom disorders. However, a number of conceptual and methodological challenges have made it difficult for interoceptive constructs to be broadly applied in mental health research and treatment settings. In November 2016, the Laureate Institute for Brain Research organized the first Interoception Summit, a gathering of interoception experts from around the world, with the goal of accelerating progress in understanding the role of interoception in mental health. The discussions at the meeting were organized around four themes: interoceptive assessment, interoceptive integration, interoceptive psychopathology, and the generation of a roadmap that could serve as a guide for future endeavors. This review article presents an overview of the emerging consensus generated by the meeting.

Delirium, depression, and other psychosocial and neurobehavioral issues in cardiovascular disease.

Understanding relevant psychosocial (neural, behavioral, psychiatric) issues is essential to optimal care of individuals who have cardiovascular disorders. Delirium, a condition of diffuse cerebral dysfunction caused by underlying systemic or central nervous system pathology, and often requiring measures of acute neurobehavioral management with nonpharmacological and pharmacological means, in addition to treatment of the underlying medical disorder, often occurs in association with severe cardiovascular disease. Depression is a psychiatric disorder known to be associated with cardiovascular disease. Substantial improvement in understanding the nature of this association has occurred in the past 10 to 20 years, including very preliminary data suggesting that pharmacological treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants might improve postmyocardial infarction cardiac prognosis. Numerous other factors-anxiety, stress, social support, anger, and other personality factors-also are implicated in the relationship of psychosocial issues to cardiovascular disease.

Anxious-depressive comorbidity: effects on HPA axis and CNS noradrenergic functions.

Psychiatric comorbidity is all too common. An important example is the high comorbidity frequency of depressive and anxiety disorders, 25%-50%, much higher than the 5% or less expected by chance. Possible reasons for this comorbidity include definitional, environmental, and biological factors. Few previous studies have assessed, with proper methodology, potential biological changes associated with this co-occurrence. We assessed both hypothalamic-pituitary-adrenocortical axis (HPA) responses to the Trier Social Stress Test and growth hormone (GH) responses to clonidine, a centrally active alpha-2 adrenoreceptor agonist, in 15 persons with major depression without anxiety, 15 with an anxiety disorder without depression, 18 comorbid for anxiety and depression, and 48 individually matched control subjects. Individuals with depression only were normal on both tests, while those with anxiety only had normal HPA responses but blunted GH responses. Comorbid individuals showed elevated HPA responses and only those comorbid persons with anxiety symptoms predominant also showed blunted GH responses. Controls and anxiety-only subjects showed significant correlations between the results of the two tests. This association was disrupted by the presence of depression with or without comorbidity. Comorbidity is fundamental to understanding the pathophysiologies of depression and anxiety.

Interaction of brain noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in man.

BACKGROUND: Numerous interactions between the brainstem locus coeruleus system and the HPA axis have been shown in experimental animals. This relationship is less well characterized in humans and little is known about the influence of psychiatric disorders, which disturb one of these systems, on this relationship. METHODS: Untreated subjects with pure MDD (n = 13), MDD with comorbid anxiety disorders (n = 17), and pure anxiety disorders (n = 15) were recruited by advertising. Age and sex matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 45). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for ACTH assay. These same subjects also underwent a clonidine challenge study for assessment of growth hormone release as a marker of tonic noradrenergic activation. RESULTS: Examining log transformed area under the curve response for each hormone, a significant negative relationship (simple regression) was observed between systems in normal subjects. This relationship was preserved in anxiety subjects. However, both pure depressed and comorbid depressed and anxiety subjects demonstrated disruption of this relationship. CONCLUSIONS: Under normal circumstances, noradrenergic systems can influence the magnitude of the HPA axis response to stress. However, in subjects with major depression, HPA axis activation appears autonomous of noradrenergic influence.

Validation of retrospective reports of early experiences with smoking.

Initial sensitivity to the pharmacological effects of a drug may affect patterns of future use and dependence for a wide variety of drugs. Retrospective reports of sensations experienced upon early experimentation, however, may be limited by recall bias based on time elapsed and subsequent experiences. To validate reports of early experiences with nicotine, we studied 34 smokers who had contributed retrospective data on early experiences with smoking. Half had reported experiencing a buzz from smoking their first cigarette (the "yes" group), the other half had not (the "no" group). To simulate initial sensitivity to nicotine, we asked participants to remain abstinent from smoking for 5 days to allow for the dissipation of tolerance. They then participated in a laboratory session in which they were reexposed to nicotine in an unfamiliar form (nicotine nasal spray) and asked to indicate pleasurable responses by depressing a foot pedal if and when they experienced a "pleasurable buzz." Smokers in the "yes" group were marginally more likely to be male. The two groups did not differ significantly on age or race. The "yes" group smoked significantly more cigarettes/day than the "no" group. When the two groups were compared for response to nasal spray following 5 days' abstinence, smokers in the "yes" group were marginally more likely to have signaled experiencing at least one pleasurable buzz and rated "pleasurable sensation from spray" on a 100-mm visual analogue scale administered 10 min after nicotine dosing significantly higher than were those in the "no" group. To the extent that several days' abstinence can serve as a model for initial sensitivity to nicotine, our findings validate retrospective reports of pleasurable sensations upon early smoking experimentation.

Anxious and depressive disorders and their comorbidity: effect on central nervous system noradrenergic function.

BACKGROUND: Although comorbidity of anxiety with depression is common, investigations of physiologic abnormalities related specifically to comorbidity are rare. This study examined relationships of DSM-IV-defined depression, anxiety, and their comorbidity to noradrenergic function measured by blunting of the growth hormone (GH) response to the alpha2 adrenoreceptor agonist (and imidazoline receptor agent) clonidine and by blood pressure and symptom responses. METHODS: Fifteen subjects with pure social anxiety or panic disorder, 15 with pure major depression, and 18 with both depression and anxiety were compared with healthy control subjects matched for age and gender. Other factors known to affect GH (weight, menstrual status, prior antidepressant, or other drug exposure) were controlled. RESULTS: Anxiety produced GH blunting, but depression was associated with normal GH responses. The comorbid state did not affect results beyond the impact of anxiety. Preclonidine stress-related GH elevations were observed, to the greatest degree in anxious subjects. Relevant symptom, but not blood pressure, changes were significantly associated with blunting. CONCLUSIONS: With use of pure depression and anxiety groups and careful control of other factors known to affect GH, these results demonstrate central nervous system noradrenergic dysfunction in anxiety disorders. In contrast to less rigorously controlled studies, noradrenergic function in depression was normal.

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.

Relative rectal bioavailability of fluoxetine in normal volunteers.

This study was conducted to determine the relative rectal bioavailability of fluoxetine capsules as well as the acceptability of the rectal route of fluoxetine capsule administration. Using a 2-period, crossover design with a 30-day washout between study sessions, 20 mg fluoxetine capsules were administered to 7 healthy, drug-free, nonsmoking volunteers by the oral and rectal routes. Blood samples were collected at baseline, and 1, 2, 4, 6, 8, 10, 12, 24 hours, as well as 2, 3, 4, 5, 7, 14, 21, 28 days following drug administration. Plasma concentrations of fluoxetine and norfluoxetine were determined using high performance liquid chromatography with ultraviolet detection. The area under the plasma concentration versus time curve could not be determined for fluoxetine following rectal administration due to very low fluoxetine plasma levels. The relative rectal bioavailability was determined for norfluoxetine and total (fluoxetine + norfluoxetine) in each individual. Six subjects completed both phases of the study. The relative bioavailability of rectally administered fluoxetine was approximately 15% [norfluoxetine, 95% CI 9-21%, and total (fluoxetine + norfluoxetine), 95% CI 8-22%]. The rectal route of administration was rated as reasonably tolerable by all subjects. Although rectal bioavailability of fluoxetine capsules is considerably less than oral, the rectal route of administration might be an option in patients who cannot take oral medications.

Regional brain activation due to pharmacologically induced adrenergic interoceptive stimulation in humans.

OBJECTIVE: Identifying the brain regions associated with visceral sensory activation and awareness (interoception) was a neglected area of neural science until quite recently despite being essential to a comprehensive understanding of psychosomatic processes, baroreception, and higher brain functions such as fear and anxiety, other emotions, and pain. METHODS: In this study regional changes in the cerebral metabolic rate for glucose were determined with positron emission tomography in response to cardiovascular-respiratory activation induced in healthy humans by beta-adrenergic stimulation produced with intravenous isoproterenol, which acts predominantly in the periphery because of minimal transport across the blood-brain barrier. RESULTS: Interoceptive activation raised heart rate to approximately 120 beats per minute, produced somatic and to a lesser extent psychological symptoms, and significantly increased cerebral glucose metabolism in the left primary somatosensory cortex and medial portion of the cingulate gyrus; right insular cortex showed a trend toward an increase that was significant in homogeneous subgroups of right-handed or female subjects. CONCLUSIONS: These results demonstrate the involvement of specific brain regions as well as hemispheric laterality of function in visceral perception, and they suggest that during emotional reactions involving changes in visceral organ function, activation of some of the brain regions observed could be due specifically to interoceptive processes.

Depression, smoking abstinence and HPA function in women smokers.

To determine whether smokers with a history of depression are differentially susceptible to smoking withdrawal, depressed mood induction and/or hypothalamic-pituitary-adrenal (HPA) axis dysregulation during smoking abstinence, 24 women smokers with and without such a history were studied. During one 5-day interval, participants smoked ad libitum; during a second they abstained. On day 4, the participants were exposed to the Velten mood induction procedure (VMIP). Participants were then instructed to take 1 mg dexamethasone at 11 pm. At 4 pm on day 5, blood samples were withdrawn to determine the cortisol and ACTH response. Despite lower baseline cotinine levels, history-positive participants displayed more pronounced overall withdrawal distress than did history-negative participants, regardless of condition. The VMIP increased depression as well as negative responses on other profile of mood states subscales. Despite many overall group differences, no significant main effects for smoking condition nor interaction effects emerged. All participants evinced cortisol suppression in response to dexamethasone during both conditions, but the degree of suppression did not differ as a function of either abstinence or depression history. In history-positive smokers, however, ACTH levels trended toward overall elevation and showed almost no suppression during abstinence; thus exacerbation of HPA dysregulation in history-positive smokers during smoking abstinence cannot be ruled out.