Psychophysics of Pain: A Methodological Introduction.

For over 100 years, psychophysics ..÷ the scientific study between physical stimuli and sensation ... has been successfully employed in numerous scientific and healthcare disciplines, as an objective measure of sensory phenomena. This manuscript provides an overview of fundamental psychophysical concepts, emphasizing pain and research application..÷defining common terms, methods, and procedures.Psychophysics can provide systematic and objective measures of sensory perception that can be used by nursing scientists to explore complex, subjective phenomena..÷such as pain perception. While there needs to be improved standardization of terms and techniques, psychophysical approaches are diverse and may be tailored to address or augment current research paradigms. The interdisciplinary nature of psychophysics..÷like nursing..÷provides a unique lens for understanding how our perceptions are influenced by measurable sensations. While the quest to understand human perception is far from complete, nursing science has an opportunity to contribute to pain research by using the techniques and methods available through psychophysical procedures.

A Cross-Sectional Study of Pain Sensitivity and Unpleasantness in People with Vascular Dementia.

OBJECTIVE: Advanced age is associated with a higher risk of both pain and dementia, with many studies finding that dementia often heightens sensitivity to pain. Vascular dementia (VaD) is the second most common type of dementia. Only a few observational or retrospective studies have examined pain responsiveness in VaD, suggesting that it could increase pain unpleasantness (i.e., pain affect). This study compared thermal pain psychophysics between a cohort of patients with VaD and healthy control (HC) subjects. DESIGN: Single-center, cross-sectional, between-subjects design. SUBJECTS: Verbally communicative patients with probable VaD (n = 23) and age- and sex-matched HCs (n = 23). METHODS: A thermal psychophysics protocol assessed "mild pain" and "moderate pain" thresholds (temperature in degrees Celsius) and associated unpleasantness ratings (0-20 scale) in both the VaD and HC groups. Psychophysics were compared between groups by way of a mixed-effects analysis, controlling for depressive symptoms. RESULTS: There were no significant differences between groups for pain thresholds (main effect P = 0.086, Cohen's d: mild = 0.55, moderate = 0.27). However, unpleasantness ratings were higher in the VaD group than in the HC group (main effect P = 0.003; mild pain P = 0.022, Cohen's d = 0.79; moderate pain P = 0.057, Cohen's d = 0.6). CONCLUSIONS: These results are consistent with prior observational findings suggesting that VaD could make patients more susceptible to pain, particularly its affective component.

Determining the impact of age and sex on the psychophysical and neurophysiological response to thermal pain across the adult lifespan.

AIMS: Determine sex- and age-associated psychophysical and neurophysiological differences in the processing of pain across the adult lifespan. DESIGN: Preliminary, exploratory, cross-sectional study. METHODS: Using psychophysics (to measure intensity and unpleasantness) and functional magnetic resonance imaging blood oxygenation level dependent methods (to measure stimulus-evoked brain activation), we will examine sex- and age-associated differences in thermal pain processing and their underlying neurophysiology in a broad range of healthy adults (ages 30-89). We will acquire resting state functional connectivity data for secondary analyses exploring whether resting state connectivity predicts psychophysical and neurophysiological responses to thermal pain. To examine the effects of altered blood flow, we will acquire resting-state arterial spin labeling magnetic resonance imaging data to quantify resting cerebral blood flow. We will interpret findings in the context of a proposed neural model of pain, ageing, and sex. Study funding was received in June of 2014. Ethical approval was obtained from the Vanderbilt University IRB prior to study initiation. CONCLUSION: Exploring the biological reasons for age- and sex-associated differences in pain processing will increase our understanding of pain in older adults. The paucity of neurobiological evidence to support best practice pain management in older adults places these individuals at risk for poor pain management. IMPACT: Poorly treated pain in older adults is a critical public health problem associated with a poor quality of life and increased healthcare costs. Understanding how age and sex have an impact on central processing of pain across the lifespan is a critical step toward improving personalized pain medicine.

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior.

Thermal Psychophysics and Associated Brain Activation Patterns Along a Continuum of Healthy Aging.

OBJECTIVE: To examine psychophysical and brain activation patterns to innocuous and painful thermal stimulation along a continuum of healthy older adults. DESIGN: Single center, cross-sectional, within-subjects design. METHODS: Thermal perceptual psychophysics (warmth, mild, and moderate pain) were tested in 37 healthy older adults (65-97 years, median = 73 years). Percept thresholds (oC) and unpleasantness ratings (0-20 scale) were obtained and then applied during functional magnetic resonance imaging scanning. General linear modeling assessed effects of age on psychophysical results. Multiple linear regressions were used to test the main and interaction effects of brain activation against age and psychophysical reports. Specifically, differential age effects were examined by comparing percent-signal change slopes between those above/below age 73 (a median split). RESULTS: Advancing age was associated with greater thresholds for thermal perception (z = 2.09, P = 0.037), which was driven by age and warmth detection correlation (r = 0.33, P = 0.048). Greater warmth detection thresholds were associated with reduced hippocampal activation in "older" vs "younger" individuals (>/<73 years; beta < 0.40, P < 0.01). Advancing age, in general, was correlated with greater activation of the middle cingulate gyrus (beta > 0.44, P < 0.01) during mild pain. Differential age effects were found for prefrontal activation during moderate pain. In "older" individuals, higher moderate pain thresholds and greater degrees of moderate pain unpleasantness correlated with lesser prefrontal activation (anterolateral prefrontal cortex and middle-frontal operculum; beta < -0.39, P < 0.009); the opposite pattern was found in "younger" individuals. CONCLUSIONS: Advancing age may lead to altered thermal sensation and (in some circumstances) altered pain perception secondary to age-related changes in attention/novelty detection and cognitive functions.

Neuroimaging Methods for Nursing Science.

BACKGROUND: Since the inception of magnetic resonance imaging, thousands of studies have appeared in the literature reporting on multiple imaging techniques. However, there is a paucity of neuroimaging research programs developed by nurse scientists. OBJECTIVES: The purpose of this article is to introduce the nurse scientist to complex neuroimaging methods with the ultimate goal of creating impetus for future use of brain imaging in nursing research. METHODS: This article reviews common neuroimaging methods, presents vocabulary frequently used in neuroimaging work, provides information on access to resources in neuroimaging education, and discusses considerations for use of neuroimaging in research. RESULTS: Ten imaging modalities are reviewed, including structural and functional magnetic resonance imaging, computed tomography, positron emission tomography, and encephalography. DISCUSSION: Choosing an imaging modality for research depends on the nature of the research question, needs of the patient population of interest, and resources available to the novice and seasoned nurse scientist. Neuroimaging has the potential to innovate the study of symptom science and encourage interdisciplinary collaboration in research.

Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age.

Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age-related change in function across cortical and subcortical sub-regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross-sectional adult age differences in estimates of D2-like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [18 F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6-16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3-5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0-2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging.

Individual differences in dopamine D2 receptor availability correlate with reward valuation.

Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D2 receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [18F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [18F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.

Sex Differences in Brain Regions Modulating Pain Among Older Adults: A Cross-Sectional Resting State Functional Connectivity Study.

Objective: A long-standing hypothesis is that when compared with males, females may be at increased risk of experiencing greater pain sensitivity and unpleasantness. The purpose of this study was to examine sex differences in pain psychophysics and resting state functional connectivity (RSFC) in core pain regions in an age- and sex-matched sample of healthy older adults. Design: Between groups, cross-sectional. Setting: Vanderbilt University and Medical Center. Subjects: The sample in the analyses reported here consisted of 19 cognitively intact males matched with 19 cognitively intact females of similar ages (median ages: females = 70 years, males = 68 years). Methods: Psychophysical assessment of experimental thermal pain and RSFC. Results: There were no significant differences in perceptual thresholds or unpleasantness ratings in response to thermal stimuli. Older males showed greater RSFC between the affective and sensory networks and between affective and descending modulatory networks. Conversely, older females showed greater RSFC between the descending modulatory network and both sensory and affective networks. The strongest evidence for sex differences emerged in the associations of thermal pain with RSFC between the anterior cingulate cortex (ACC) and amygdala and between the ACC and periaqueductal gray matter in older females relative to older males. Conclusions: We found no differences in pain sensitivity or pain affect between older males and older females. Additionally, we found that older females exhibited a greater association between thermal pain sensitivity and RSFC signal between regions typically associated with pain affect and the descending modulatory system. One interpretation of these findings is that older females may better engage the descending pain modulatory system. This better engagement possibly translates into older females having similar perceptual thresholds for temperature sensitivity and unpleasantness associated with mild and moderate pain. These findings contrast with studies demonstrating that younger females find thermal pain more sensitive and more unpleasant.

Pain interference and depressive symptoms in communicative people with Alzheimer's disease: a pilot study.

OBJECTIVES: To examine pain interference in verbally communicative older adults with mild to moderate Alzheimer's disease (AD) and to examine the association of pain interference with cognitive function and depressive symptoms. METHOD: For this pilot study, we used a cross-sectional design to examine pain interference (Brief Pain Inventory-Short Form), cognitive function (Mini-Mental State Exam), and depressive symptoms (15-item Geriatric Depression Scale) in 52 older (≥65) communicative adults with AD who reported being free from chronic pain requiring daily analgesics. RESULTS: Pain was reported to interfere with general activity (13.5%), mood (13.5%), walking ability (13.5%), normal work (11.5%), enjoyment of life (11.5%), relationships with other people (9.6%), and sleep (9.6%). Pain interference was significantly positively correlated with both cognitive function (rs = 0.46, p = 0.001) and depressive symptomology (rs = 0.45, p = 0.001), indicating that greater reported pain interference was associated with better cognitive function and more depressive symptoms. CONCLUSION: Among older people with AD who report being free from chronic pain requiring daily analgesics, 2 in 10 are at risk of pain interference and depressive symptoms. Those with better cognitive function reported more pain interference and depressive symptoms, meaning pain is likely to be under-reported as AD progresses. Clinicians should regularly assess pain interference and depressive symptoms in older persons with AD to identify pain that might be otherwise overlooked..

Reduced effects of age on dopamine D2 receptor levels in physically active adults.

Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.

Associations between dopamine D2 receptor availability and BMI depend on age.

OBJECTIVE: The dopamine D2/3 receptor subtypes (DRD2/3) are the most widely studied neurotransmitter biomarker in research on obesity, but results to date have been inconsistent, have typically involved small samples, and have rarely accounted for subjects' ages despite the large impact of age on DRD2/3 levels. We aimed to clarify the relation between DRD2/3 availability and BMI by examining this association in a large sample of subjects with BMI spanning the continuum from underweight to extremely obese. SUBJECTS: 130 healthy subjects between 18 and 81years old underwent PET with [18F]fallypride, a high affinity DRD2/3 ligand. RESULTS: As expected, DRD2/3 availability declined with age. Critically, age significantly interacted with DRD2/3 availability in predicting BMI in the midbrain and striatal regions (caudate, putamen, and ventral striatum). Among subjects under 30years old, BMI was not associated with DRD2/3 availability. By contrast, among subjects over 30years old, BMI was positively associated with DRD2/3 availability in the midbrain, putamen, and ventral striatum. CONCLUSION: The present results are incompatible with the prominent dopaminergic hypofunction hypothesis that proposes that a reduction in DRD2/3 availability is associated with increased BMI, and highlights the importance of age in assessing correlates of DRD2/3 function.

Contact heat sensitivity and reports of unpleasantness in communicative people with mild to moderate cognitive impairment in Alzheimer's disease: a cross-sectional study.

BACKGROUND: Compared to healthy controls, people with Alzheimer's disease (AD) have been shown to receive less pain medication and report pain less frequently. It is unknown if these findings reflect less perceived pain in AD, an inability to recognize pain, or an inability to communicate pain. METHODS: To further examine aspects of pain processing in AD, we conducted a cross-sectional study of sex-matched adults ≥65 years old with and without AD (AD: n = 40, female = 20, median age = 75; control: n = 40, female = 20, median age = 70) to compare the psychophysical response to contact-evoked perceptual heat thresholds of warmth, mild pain, and moderate pain, and self-reported unpleasantness for each percept. RESULTS: When compared to controls, participants with AD required higher temperatures to report sensing warmth (Cohen's d = 0.64, p = 0.002), mild pain (Cohen's d = 0.51, p = 0.016), and moderate pain (Cohen's d = 0.45, p = 0.043). Conversely, there were no significant between-group differences in unpleasantness ratings (p > 0.05). CONCLUSIONS: The between-group findings demonstrate that when compared to controls, people with AD are less sensitive to the detection of thermal pain but do not differ in affective response to the unpleasant aspects of thermal pain. These findings suggest that people with AD may experience greater levels of pain and potentially greater levels of tissue or organ damage prior to identifying and reporting injury. This finding may help to explain the decreased frequency of pain reports and consequently a lower administration of analgesics in AD.

Specific Physician Orders Improve Pain Detection and Pain Reports in Nursing Home Residents: Preliminary Data.

Despite evidence that many nursing home residents' pain is poorly managed, reasons for this poor management remain unanswered. The aim of this study was to determine if specific order sets related to pain assessment would improve pain management in nursing home (NH) residents. Outcomes included observed nurse pain assessment queries and resident reports of pain. The pretest/post-test study was performed in a 240-bed for-profit nursing home in the mid-southern region of the United States and participants were 43 nursing home residents capable of self-consent. Medical chart abstraction was performed during a 2-week (14-day) period before the implementation of specific order sets for pain assessment (intervention) and a 2-week (14-day) period after the intervention. Trained research assistants observed medication administration passes and performed participant interviews after each medication pass. One month after intervention implementation, 1 additional day of observations was conducted to determine data reliability. Nurses were observed to ask residents about pain more frequently, and nurses continued to ask about pain at higher rates 1 month after the intervention was discontinued. The proportion of residents who reported pain also significantly increased in response to increased nurse queries (e.g., "Do you have any pain right now?"), which underscores the importance of nurses directly asking residents about pain. Notably 70% of this long-stay NH population only told the nurses about their pain symptoms when asked directly. Findings uncover that using specific pain order sets seems to improve the detection of pain, which should be a routine part of nursing assessment.

Neurocircuitry underlying risk and resilience to social anxiety disorder.

BACKGROUND: Almost half of children with an inhibited temperament will develop social anxiety disorder by late adolescence. Importantly, this means that half of children with an inhibited temperament will not develop social anxiety disorder. Studying adults with an inhibited temperament provides a unique opportunity to identify neural signatures of both risk and resilience to social anxiety disorder. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activation during the anticipation of viewing fear faces in 34 young adults (17 inhibited, 17 uninhibited). To identify neural signatures of risk, we tested for group differences in functional activation and connectivity in regions implicated in social anxiety disorder, including the prefrontal cortex, amygdala, and insula. To identify neural signatures of resilience, we tested for correlations between brain activation and both emotion regulation and social anxiety scores. RESULTS: Inhibited subjects had greater activation of a prefrontal network when anticipating viewing fear faces, relative to uninhibited subjects. No group differences were identified in the amygdala. Inhibited subjects had more negative connectivity between the rostral anterior cingulate cortex (ACC) and the bilateral amygdala. Within the inhibited group, those with fewer social anxiety symptoms and better emotion regulation skills had greater ACC activation and greater functional connectivity between the ACC and amygdala. CONCLUSIONS: These findings suggest that engaging regulatory prefrontal regions during anticipation may be a protective factor, or putative neural marker of resilience, in high-risk individuals. Cognitive training targeting prefrontal cortex function may provide protection against anxiety, especially in high-risk individuals, such as those with inhibited temperament.

Traumatic brain injury-related attention deficits: treatment outcomes with lisdexamfetamine dimesylate (Vyvanse).

BACKGROUND AND OBJECTIVES: Attention deficits are often among the most persistent and debilitating impairments resulting from traumatic brain injury (TBI). This study examined the effects of lisdexamfetamine dimesylate (Vyvanse) in treating attention deficits due to moderate-to-severe TBI. It was the first study of lisdexamfetamine dimesylate with this population and, in fact, was the first controlled trial in this area examining a stimulant medication option other than methylphenidate. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, cross-over trial. A total of 22 rigorously selected cases were enrolled, 13 of whom completed the trial. They were 16-42 years of age and had newly acquired attention deficits persisting for 6-34 months post-injury. They were assessed on a broad range of neuropsychological and behavioural measures at baseline, 6-weeks and at 12-weeks. RESULTS AND CONCLUSIONS: Positive treatment effects were found involving selective measures of sustained attention, working memory, response speed stability and endurance and in aspects of executive functioning. No major problems with safety or tolerability were observed. Some moderating treatment effects were found from a broad range of pre-treatment subject characteristics and injury variables examined. Avenues for further research and treatment applications in this area are discussed.

Gender Differences in Pain Threshold, Unpleasantness, and Descending Pain Modulatory Activation Across the Adult Life Span: A Cross Sectional Study.

The neurobiological underpinnings of gender differences in pain perception, and how these differences may be modified by age, are incompletely understood, placing patients at risk of suboptimal pain management. Using functional magnetic resonance imaging, we examined brain responses in the descending pain modulatory system (DPMS, specifically, dorsolateral prefrontal cortex, anterior cingulate cortex, insula, hypothalamus, amygdala, and periaqueductal gray, during an evoked pain task. We investigated the interaction of age and gender in our sample of healthy adults (27 females, 32 males, 30-86 years) on DPMS response. In a perceptually matched thermal pain paradigm, we investigated pain unpleasantness and neural responses for 3 heat pain percepts: just noticeable pain, weak pain, and moderate pain (MP). Females reported just noticeable pain at a lower temperature, but reported less unpleasantness at weak pain and MP percepts, compared to males. There was a significant age-by-gender interaction during moderate pain in the right anterior cingulate cortex and bilateral insula, such that, males had a stronger positive relationship between DPMS response and age compared to females in these regions. Our results indicate that differences in DPMS responses may explain some gender differences in pain perception and that this effect may change across the adult lifespan. PERSPECTIVE: Gender differences in pain have been well-documented but the brain mechanisms for these differences are still unclear. This article describes potential differences in brain functioning during different levels of pain that could explain differences in pain responses between men and women across the adult lifespan.

Mobile Delivery Program to Prevent Relapse and Improve Functioning in Patients With Psychiatric Diseases.

The term "revolving door patients" refers to those who are frequently rehospitalized for relapse. This phenomenon can be explained by a multitude of factors, including a lack of medical and/or social support. On the basis of a review of various modalities of psychiatric treatment, such as long-acting injectables, assisted outpatient treatment, and telehealth, it is clear that a major underlying issue among people with psychiatric diseases who lack insight into their mental and physical health is medication nonadherence. Therefore, we propose a mobile delivery program (MDP) in which health care professionals deliver medications and care to psychiatric patients in their own homes. The target patient population for MDP is patients with medication nonadherence, frequent emergency department visits, and missed appointments. Patients with mental illnesses, especially schizophrenia, are disproportionately represented among the homeless and incarcerated populations. By implementing MDP, we can help break the cycle of incarceration for patients with mental illnesses and homelessness. In addition, the cost of transportation and salaries for the mobile delivery team would be considerably lower than the billions of dollars spent each year due to relapses, emergency department visits, inpatient admissions, and crime leading to long-term stays in correctional facilities. This model has the potential to reduce relapse, improve functioning, and reduce excess morbidity and mortality. Substantial cost savings for health services can, in turn, be expected.

Dopaminergic mechanisms of individual differences in human effort-based decision-making.

Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

Oscillatory serotonin function in depression.

Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 min for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting-state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy, 3,4-methylenedioxy-N-methylamphetamine) users because of their chronically diminished 5HT function compared with non-MDMA polysubstance users (Karageorgiou et al., 2009). Compared with a non-MDMA using cohort, MDMA users showed diminished fMRI intra-regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated.