Possible Biological Mechanisms Linking Mental Health and Heat—A Contemplative Review

This review provides examples of possible biological mechanisms that could, at least partly, explain the existing epidemiological evidence of heatwave-related exacerbation of mental disease morbidity. The author reviews the complicated central processes involved in the challenge of maintaining a stable body temperature in hot environments, and the maladaptive effects of certain psychiatric medicines on thermoregulation. In addition, the author discusses some alternative mechanisms, such as interrupted functional brain connectivity and the effect of disrupted sleep, which may further increase the vulnerability of mental health patients during heatwaves.

Related papers:

title: Death toll exceeded 70,000 in Europe during the summer of 2003.
abstract: Daily numbers of deaths at a regional level were collected in 16 European countries. Summer mortality was analyzed for the reference period 1998-2002 and for 2003. More than 70,000 additional deaths occurred in Europe during the summer 2003. Major distortions occurred in the age distribution of the deaths, but no harvesting effect was observed in the months following August 2003. Global warming constitutes a new health threat in an aged Europe that may be difficult to detect at the country level, depending on its size. Centralizing the count of daily deaths on an operational geographical scale constitutes a priority for Public Health in Europe.

title: Deaths of psychiatric patients during heat waves.
abstract: Deaths of patients in state psychiatric hospitals in the New York City area during heat waves and control periods from 1950 to 1984 were compared with those in the overall New York City population during the same periods. Psychiatric patients had twice the risk of dying during a heat wave than the general population. The risk for patients was higher in the 1950s, before the introduction of antipsychotic medications, than in the 1980s, but was highest in the 1970s, when higher dosages of antipsychotic medication were commonly used. During 1980 to 1984 the risk was the same for both populations, suggesting that both psychiatric illness and antipsychotic medications increase patients' risk of dying during heat waves but that risk can be eliminated with preventive measures.

title: Heat-related deaths during the July 1995 heat wave in Chicago.
abstract: During a record-setting heat wave in Chicago in July 1995, there were at least 700 excess deaths, most of which were classified as heat-related. We sought to determine who was at greatest risk for heat-related death.



We conducted a case-control study in Chicago to identify risk factors associated with heat-related death and death from cardiovascular causes from July 14 through July 17, 1995. Beginning on July 21, we interviewed 339 relatives, neighbors, or friends of those who died and 339 controls matched to the case subjects according to neighborhood and age.



The risk of heat-related death was increased for people with known medical problems who were confined to bed (odds ratio as compared with those who were not confined to bed, 5.5) or who were unable to care for themselves (odds ratio, 4.1). Also at increased risk were those who did not leave home each day (odds ratio, 6.7), who lived alone (odds ratio, 2.3), or who lived on the top floor of a building (odds ratio, 4.7). Having social contacts such as group activities or friends in the area was protective. In a multivariate analysis, the strongest risk factors for heat-related death were being confined to bed (odds ratio, 8.2) and living alone (odds ratio, 2.3); the risk of death was reduced for people with working air conditioners (odds ratio, 0.3) and those with access to transportation (odds ratio, 0.3). Deaths classified as due to cardiovascular causes had risk factors similar to those for heat-related death.



In this study of the 1995 Chicago heat wave, those at greatest risk of dying from the heat were people with medical illnesses who were socially isolated and did not have access to air conditioning. In future heat emergencies, interventions directed to such persons should reduce deaths related to the heat.

title: Excess hospital admissions during the July 1995 heat wave in Chicago.
abstract: This study describes medical conditions treated in all 47 non-VA hospitals in Cook County, IL during the 1995 heat wave. We characterize the underlying diseases of the susceptible population, with the goal of tailoring prevention efforts.



Primary and secondary discharge diagnoses made during the heat wave and comparison periods were obtained from computerized inpatient hospital discharge data to determine reasons for hospitalization, and comorbid conditions, respectively.



During the week of the heat wave, there were 1072 (11%) more hospital admissions than average for comparison weeks and 838 (35%) more than expected among patients aged 65 years and older. The majority of this excess (59%) were treatments for dehydration, heat stroke, and heat exhaustion; with the exception of acute renal failure no other primary discharge diagnoses were significantly elevated. In contrast, analysis of comorbid conditions revealed 23% (p = 0.019) excess admissions of underlying cardiovascular diseases, 30% (p = 0.033) of diabetes, 52% (p = 0.011) of renal diseases, and 20% (p = 0.027) of nervous system disorders. Patient admissions for emphysema (p = 0.007) and epilepsy (p = 0.009) were also significantly elevated during the heat wave week.



The majority of excess hospital admissions were due to dehydration, heat stroke, and heat exhaustion, among people with underlying medical conditions. Short-term public health interventions to reduce heat-related morbidity should be directed toward these individuals to assure access to air conditioning and adequate fluid intake. Long-term prevention efforts should aim to improve the general health condition of people at risk through, among other things, regular physician-approved exercise.

title: Excess mortality related to the August 2003 heat wave in France
abstract: From August 1st to 20th, 2003, the mean maximum temperature in France exceeded the seasonal norm by 11–12°C on nine consecutive days. A major increase in mortality was then observed, which main epidemiological features are described herein.  The number of deaths observed from August to November 2003 in France was compared to those expected on the basis of the mortality rates observed from 2000 to 2002 and the 2003 population estimates.  From August 1st to 20th, 2003, 15,000 excess deaths were observed. From 35 years age, the excess mortality was marked and increased with age. It was 15% higher in women than in men of comparable age as of age 45 years. Excess mortality at home and in retirement institutions was greater than that in hospitals. The mortality of widowed, single and divorced subjects was greater than that of married people. Deaths directly related to heat, heatstroke, hyperthermia and dehydration increased massively. Cardiovascular diseases, ill-defined morbid disorders, respiratory diseases and nervous system diseases also markedly contributed to the excess mortality. The geographic variations in mortality showed a clear age-dependent relationship with the number of very hot days. No harvesting effect was observed.  Heat waves must be considered as a threat to European populations living in climates that are currently temperate. While the elderly and people living alone are particularly vulnerable to heat waves, no segment of the population may be considered protected from the risks associated with heat waves.

title: The Effect of Heat Waves on Mental Health in a Temperate Australian City
abstract: The goal of this study was to identify mental, behavioral, and cognitive disorders that may be triggered or exacerbated during heat waves, predisposing individuals to heat-related morbidity and mortality.  Using health outcome data from Adelaide, South Australia, for 1993–2006, we estimated the effect of heat waves on hospital admissions and mortalities attributed to mental, behavioral, and cognitive disorders. We analyzed data using Poisson regression accounting for overdispersion and controlling for season and long-term trend, and we performed threshold analysis using hockey stick regression.  Above a threshold of 26.7°C, we observed a positive association between ambient temperature and hospital admissions for mental and behavioral disorders. Compared with non–heat-wave periods, hospital admissions increased by 7.3% during heat waves. Specific illnesses for which admissions increased included organic illnesses, including symptomatic mental disorders; dementia; mood (affective) disorders; neurotic, stress related, and somatoform disorders; disorders of psychological development; and senility. Mortalities attributed to mental and behavioral disorders increased during heat waves in the 65- to 74-year age group and in persons with schizophrenia, schizotypal, and delusional disorders. Dementia deaths increased in those up to 65 years of age.  Our results suggest that episodes of extreme heat pose a salient risk to the health and well-being of the mentally ill. Relevance to Clinical or Professional Practice: Improvements in the management and care of the mentally ill need to be addressed to avoid an increase in psychiatric morbidity and mortality as heat waves become more frequent.

title: Acute impacts of extreme temperature exposure on emergency room admissions related to mental and behavior disorders in Toronto, Canada.
abstract: The purpose of this study was to assess the effects of extreme ambient temperature on hospital emergency room visits (ER) related to mental and behavioral illnesses in Toronto, Canada.



A time series study was conducted using health and climatic data from 2002 to 2010 in Toronto, Canada. Relative risks (RRs) for increases in emergency room (ER) visits were estimated for specific mental and behavioral diseases (MBD) after exposure to hot and cold temperatures while using the 50th percentile of the daily mean temperature as reference. Poisson regression models using a distributed lag non-linear model (DLNM) were used. We adjusted for the effects of seasonality, humidity, day-of-the-week and outdoor air pollutants.



We found a strong association between MBD ER visits and mean daily temperature at 28°C. The association was strongest within a period of 0-4 days for exposure to hot temperatures. A 29% (RR=1.29, 95% CI 1.09-1.53) increase in MBD ER vists was observed over a cumulative period of 7 days after exposure to high ambient temperature (99th percentile vs. 50th percentile). Similar associations were reported for schizophrenia, mood, and neurotic disorers. No significant associations with cold temperatures were reported.



The ecological nature and the fact that only one city was investigated.



Our findings suggest that extreme temperature poses a risk to the health and wellbeing for individuals with mental and behavior illnesses. Patient management and education may need to be improved as extreme temperatures may become more prevalent with climate change.

title: Relationship between mean daily ambient temperature range and hospital admissions for schizophrenia: Results from a national cohort of psychiatric inpatients.
abstract: Environmental temperature is known to correlate with schizophrenia, but little is known about the association with changes in temperature. This 12-year study aimed to evaluate the relationship between the mean daily range of ambient temperature and schizophrenia admissions in a national cohort of psychiatric inpatients in Taiwan. Meteorological data provided by the Central Weather Bureau of Taiwan were interpolated to create representative estimates. Psychiatric inpatient admissions in all hospitals with medical services enrolled in the current health care insurance system were retrieved from the 1996-2007 Psychiatric Inpatient Medical Claim dataset of the National Health Insurance Research Database. Generalized linear models with Poisson distributions were used to analyze the impact of mean diurnal change of temperature on schizophrenia admissions, controlling for internal correlations and demographic covariates. The daily temperature range varied between 1.7°C and 12.1°C (1st to 99th percentile). The relative risk of schizophrenia admission was significantly increased at a temperature range of 3.2°C (10th percentile), and the maximum was at 12.1°C (99th percentile); however, no such association was found with schizoaffective disorder. When restricted to the capital and largest city, the effects of temperature range were prominent and may correlate with temperature itself. The joint effect of temperature and temperature range was associated with elevated risk, particularly at cooler temperatures. A positive correlation was found between increasing temperature range and schizophrenia admissions. The increase in morbidity at high percentiles suggests that the increasing dynamics of temperature range are a valid reflection of risk, highlighting the need for precautionary action.

title: Is greater temperature change within a day associated with increased emergency admissions for schizophrenia?
abstract: Diurnal temperature range (DTR), as an important index of climate change, has been increasingly used to evaluate the impacts of temperature variability on human health. However, little is known about the effects of DTR on schizophrenia.



The present study aims to examine the relationship between DTR and schizophrenia admissions, and further, to explore whether the association varied by individual characteristics and study periods.



A Poisson generalized linear regression combined with distributed lag non-linear model (DLNM) was applied to analyze daily DTR and schizophrenia data from Hefei, China during 2005 to 2014, after adjusting for long-term and seasonal trends, mean temperature, relative humidity and other confounding factors.



An acute adverse effect of extremely high DTR on schizophrenia was observed, with a 2.7% (95% CI: 1.007-1.047) increase of daily schizophrenia admissions after exposure to extremely high DTR (95th percentile vs. 50th percentile). The risk for schizophrenia onset due to large DTR exposure increased from the first five years (2005-2009) to the second five years (2010-2014). Additionally, the patient aged 15-29 and 50-64years, male patients, patients born in spring/autumn, and married patients appeared to be more vulnerable to DTR effect. However, there was no significant association between moderately high DTR (75th percentile) and schizophrenia.



This study suggests that extremely high DTR is a potential trigger for schizophrenia admissions in Hefei, China. Our findings may provide valuable information to decisions-makers and guidance to health practitioners.

title: Weather Variations and Hospital Admissions for Depressive Disorders : A Case Study in Hanoi
abstract: Studies from developed countries have shown season and weather influencing mood disorders, but it is not known whether such associations exist in tropical/sub-tropical low- and middle-income countr ...

title: General and specific mortality among the elderly during the 2003 heat wave in Genoa (Italy).
abstract: The effects of heat waves on health can be serious for elderly persons, especially those in urban areas. We investigated in-depth the mortality excess during the 2003 heat wave among elderly persons (>74 years) in the City of Genoa (Italy). The excess in general mortality was calculated for the period July 16-August 31, as the ratio of observed to expected deaths. To evaluate "harvesting", we compared observed and expected mortality in the period September 2003-April 2004. We also studied the relationship between mortality and climatic conditions considering daily maximum temperature and Humidex discomfort degrees, as well as "lag-time". For cause-specific mortality, we considered all pathologies reported on the death certificate. The excess in general mortality was significant and was greatest in the first half of August. During Summer 2003, in Genoa the climatic conditions (described in terms of maximum temperature and Humidex Index) were extremely hot; regarding lag-time, the greatest correlation between the number of observed deaths and the maximum temperature values was observed for the three preceding days (rho=0.568; significance level<0.01). The prominent causes of death, for which an excess was observed, were cerebrovascular diseases, severe respiratory diseases, severe renal diseases, dementia; moreover, certain pathologic conditions and symptoms, usually not lethal, were also frequent causes of death (e.g., hypovolemia, hyperpyrexia, decubitus ulcers and immobilization syndrome). The results of this study confirm the relationship between the heat waves and death among elderly, stressing that, because of their poorer physical health and the prevalence of cognitive disturbances that hinder risk perception, it is necessary to properly care for them during heat waves.

title: Short‐term association between environmental factors and hospital admissions due to dementia in Madrid
abstract: Spain has one of the highest proportions of dementia in the world among the population aged 60 years or over. Recent studies link various environmental factors to neurocognitive‐type diseases. This study sought to analyse whether urban risk factors such as traffic noise, pollutants and heat waves might have a short‐term impact on exacerbation of symptoms of dementia, leading to emergency hospital admission.  We conducted a longitudinal ecological time‐series study, with the dependent variable being the number of daily dementia‐related emergency (DDE) hospital admissions to Madrid municipal hospitals (ICD‐10 codes 290.0–290.2, 290.4–290.9, 294.1–294) from 01 to 01‐2001 to 31‐12‐2009, as obtained from the Hospital Morbidity Survey (National Statistics Institute). The measures used were as follows: for noise pollution, Leqd, equivalent diurnal noise level (from 8 to 22 h), and Leqn, equivalent nocturnal noise level (from 22 to 8 h) in dB(A); for chemical pollution, mean daily NO2, PM2.5, PM1 as provided by the Madrid Municipal Air Quality Monitoring Grid; and lastly, maximum daily temperature (°C), as supplied by the State Meteorological Agency. Scatterplot diagrams were plotted to assess the type of functional relationship existing between the main variable of analysis and the environmental variables. The lags of the environmental variables were calculated to analyse the timing of the effect. Poisson regression models were fitted, controlling for trends and seasonalities, to quantify relative risk (RR).  During the study period, there were 1175 DDE hospital admissions. These admissions displayed a linear functional relationship without a threshold in the case of Leqd. The RR of DDE admissions was 1.15 (1.11–1.20) for an increase of 1 dB in Leqd, with impact at lag 0. In the case of maximum daily temperature, there was a threshold temperature of 34 °C, with an increase of 1 °C over this threshold posing an RR of 1.19 (1.09–1.30) at lag 1. The only pollutant to show an association with DDE hospital admissions was O3 at lag 5, with an RR of 1.09 (1.04–1.15) for an increase of 10 &mgr;g/m3  Diurnal traffic noise, heat waves and tropospheric ozone may exacerbate the symptoms of dementia to the point of requiring emergency admission to hospital. Lowering exposure levels to these environmental factors could reduce dementia‐related admissions in Madrid. HighlightsSpain has one of the highest proportions of dementia in the world.The RR of DDE admissions was 1.15 (1.11–1.20) for an increase of 1 dB in Leqd.The RR of DDE admissions was 1.19 (1.09–1.30) for an increase of 1 °C above 34 °C in Tmax.The RR of DDE admissions was 1.09 (1.04–1.15) for an increase of 10 &mgr;g/m3 in O3a concentrations.Diurnal traffic noise, heat waves and tropospheric ozone can exacerbate the symptoms of dementia.

title: Seasonal variations in hospital admissions for mania: Examining for associations with weather variables over time.
abstract: Bipolar disorder is characterized by a seasonal pattern with emerging evidence that weather conditions may trigger symptoms. Thus, our aims were to investigate if year-to-year variations in admissions with mania correlated with year-to-year variations in key meteorological variables, if there was a secular trend in light of climate change and if gender or admission status influenced the seasonal pattern.



We undertook a Danish register-based nationwide historical cohort study. We included all adults hospitalized to psychiatric care from 1995 to 2012 with mania using the Danish Psychiatric Central Research Register. The Danish Meteorological Institute provided the meteorological variables. The association between weather and admissions was tested using linear regression.



Our database comprised 24,313 admissions with mania. There was a seasonal pattern with admission rates peaking in summer. Higher admission rates were associated with more sunshine, more ultraviolet radiation, higher temperature and less snow but were unassociated with rainfall. We did not find a secular trend in the seasonal pattern. Finally, neither gender nor admission status impacted on the overall seasonal pattern of admissions with mania.



Only patients in psychiatric care were included. We could not subdivide by type of bipolar disorder.



This cohort study based on more than 24,000 admissions identified a distinct seasonal pattern in hospital admissions for those with mania. We found no secular trend. This could indicate that the climate change is not impacting on seasonal patterns, that there is no link between the proposed variables or that change is currently not sufficiently distinctive.

title: Effect of heat waves on morbidity and mortality due to Parkinson's disease in Madrid: A time-series analysis.
abstract: Parkinson's disease (PD) is one of the factors which are associated with a higher risk of mortality during heat waves. The use of certain neuroleptic medications to control some of this disease's complications would appear to be related to an increase in heat-related mortality.



To analyse the relationship and quantify the short-term effect of high temperatures during heat wave episodes in Madrid on daily mortality and PD-related hospital admissions.



We used an ecological time-series study and fit Poisson regression models. We analysed the daily number of deaths due to PD and the number of daily PD-related emergency hospital admissions in the city of Madrid, using maximum daily temperature (°C) as the main environmental variable and chemical air pollution as covariates. We controlled for trend, seasonalities, and the autoregressive nature of the series.



There was a maximum daily temperature of 30°C at which PD-related admissions were at a minimum. Similarly, a temperature of 34°C coincides with an increase in the number of admissions. For PD-related admissions, the Relative Risk (RR) for every increase of 1°C above the threshold temperature was 1.13 IC95%:(1.03-1.23) at lags 1 and 5; and for daily PD-related mortality, the RR was 1.14 IC95%:(1.01-1.28) at lag 3.



Our results indicate that suffering from PD is a risk factor that contributes to the excess morbidity and mortality associated with high temperatures, and is relevant from the standpoint of public health prevention plans.

title: Association between environmental factors and emergency hospital admissions due to Alzheimer's disease in Madrid.
abstract: There are scarce studies of time series that analysed the short-term association between emergency hospital admissions due to Alzheimer's disease (AD) and environmental factors. The objective is to analyse the effect of heat waves, noise and air pollutants on urgent hospital admissions due to AD in Madrid.



Longitudinal ecological time series study was performed. The dependent variable was the emergency AD hospital admissions occurred in Madrid during the period 2001-2009.  Daily mean concentrations (μg/m3) of air pollutants (PM2.5 and PM10; O3 and NO2); maximum daily temperature (°C) and daily and night noise levels (dB(A)). Relative Risk (RR) for an increment in interquartile range, and Attributable Risk (AR) values were calculated through GLM with Poisson link.



Our findings indicated that only PM2.5 concentrations at lag 2 with a RR: 1.38 (95% CI: 1.15-1.65); AR 27.5% (95% CI: 13.0-39.4); and heat wave days at lag 3 with a RR: 1.30 (95% CI: 1.12-1.52); AR 23.1% (95% CI: 10.7-34.2) were associated with AD hospital admissions.



A reduction in AD patients' exposure levels to PM2.5 and special care of such patients during heat wave periods could result in a decrease in both emergency AD admissions and the related health care costs.

title: The number of emergency department visits for psychiatric emergencies is strongly associated with mean temperature and humidity variations. Results of a nine year survey
abstract: Several disorders, such as renal colics, stroke, atrial fibrillation and others, are epidemiologically associated with seasonality and microclimatic variations. Although evidence is still limited, an association between psychiatric emergencies and seasonality has also been previously described. In order to elucidate the possible association between weather and incidence of psychiatric emergencies in a country with temperate climate, we analyzed the influence of day by day climate changes on the number of visits for psychiatric emergencies in an urban emergency department (ED) of northern Italy. All ED visits for psychiatric emergencies were retrieved from the hospital database from 2002 to 2010. The total number of ED visits was 725,812 throughout the study period, 11,786 of which for emergency psychiatric problems. We found a strong seasonal distribution of emergency psychiatric visits, peaking in summer and at the beginning of spring. The linear regression analysis showed a strong positive association between number of daily emergency psychiatric visits and mean daily air temperature (R=0.82; P<0.001), and an inverse association with mean daily air humidity (R=-0.52; P<0.001). These findings suggest that psychiatric disorders follow a significant seasonal variation, so that it may be advisable to strengthen psychiatric emergency services during the hottest months.

title: Heatwaves and Hospital Admissions for Mental Disorders in Northern Vietnam
abstract: Studies in high-income countries have shown an association between heatwaves and hospital admissions for mental disorders. It is unknown whether such associations exist in subtropical nations like Vietnam. The study aim was to investigate whether hospital admissions for mental disorders may be triggered, or exacerbated, by heat exposure and heatwaves, in a low- and middle-income country, Vietnam. For this, we used data from the Hanoi Mental Hospital over five years (2008–2012) to estimate the effect of heatwaves on admissions for mental disorders. A zero-inflated negative binomial regression model accounting for seasonality, time trend, days of week, and mean humidity was used to analyse the relationship. Heatwave events were mainly studied as periods of three or seven consecutive days above the threshold of 35°C daily maximum temperature (90th percentile). The study result showed heatwaves increased the risk for admission in the whole group of mental disorders (F00-79) for more persistent heatwaves of at least 3 days when compared with non-heatwave periods. The relative risks were estimated at 1.04 (0.95–1.13), 1.15 (1.005–1.31), and 1.36 (1–1.90) for a one-, three- and seven-day heatwave, respectively. Admissions for mental disorders increased among men, residents in rural communities, and the elderly population during heatwaves. The groups of organic mental disorders, including symptomatic illnesses (F0-9) and mental retardation (F70-79), had increased admissions during heatwaves. The findings are novel in their focus on heatwave impact on mental diseases in a population habituating in a subtropical low- and middle-income country characterized by rapid epidemiological transitions and environmental changes.

title: Heat stress in older individuals and patients with common chronic diseases
abstract: Scientists have predicted that extremes in climate are likely to increase in frequency and severity.  These changes may have a direct impact on population health, as heat waves can exceed the physiological adaptive capacity of vulnerable population groups. Individuals over the age of 60 years

title: Central neural pathways for thermoregulation.
abstract: Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.

title: Responses to hyperthermia. Optimizing heat dissipation by convection and evaporation: Neural control of skin blood flow and sweating in humans
abstract: Under normothermic, resting conditions, humans dissipate heat from the body at a rate approximately equal to heat production. Small discrepancies between heat production and heat elimination would, over time, lead to significant changes in heat storage and body temperature. When heat production or environmental temperature is high the challenge of maintaining heat balance is much greater. This matching of heat elimination with heat production is a function of the skin circulation facilitating heat transport to the body surface and sweating, enabling evaporative heat loss. These processes are manifestations of the autonomic control of cutaneous vasomotor and sudomotor functions and form the basis of this review. We focus on these systems in the responses to hyperthermia. In particular, the cutaneous vascular responses to heat stress and the current understanding of the neurovascular mechanisms involved. The available research regarding cutaneous active vasodilation and vasoconstriction is highlighted, with emphasis on active vasodilation as a major responder to heat stress. Involvement of the vasoconstrictor and active vasodilator controls of the skin circulation in the context of heat stress and nonthermoregulatory reflexes (blood pressure, exercise) are also considered. Autonomic involvement in the cutaneous vascular responses to direct heating and cooling of the skin are also discussed. We examine the autonomic control of sweating, including cholinergic and noncholinergic mechanisms, the local control of sweating, thermoregulatory and nonthermoregulatory reflex control and the possible relationship between sudomotor and cutaneous vasodilator function. Finally, we comment on the clinical relevance of these control schemes in conditions of autonomic dysfunction.

title: Psychotropic drugs use and risk of heat-related hospitalisation
abstract: To assess if use of psychotropic drugs is associated with an increased risk of admission for heat-related pathologies during a heat wave period.  We conducted a matched case–control study. Cases were defined as subjects admitted to an emergency department for heat-related pathology (hyperthermia or heat stroke) over the August 2003 heat wave. Controls were defined as subjects living in the same area but not hospitalised over the same period and who had at least one prescription form submitted for refunding by the social security insurance in July 2003. Multivariate analyses were used to identify psychotropic drugs independently associated with hospital referral during the heat wave period.  Out of the 1405 patients admitted to the emergency department, 56 (4%) presented with heat-related pathology. The mean age of cases was 83 years. Multivariate analyses showed that cases were more likely than controls to be treated with anticholinergic drugs (OR 6.0, 95% CI 1.8–19.6), antipsychotics (OR 4.6, 95% CI 1.9–11.2) or anxiolytics (OR 2.4, 95% CI 1.3–4.4).  In special risk situations such as heat waves, the risk/benefit ratio of psychotropic drugs which could interfere with body temperature regulation has to be carefully assessed, particularly in the elderly.

title: Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation.
abstract: A fundamental discovery of modern human brain imaging with positron-emission tomography that the blood flow to activated regions of the normal human brain increases substantially more than the oxygen consumption has led to a broad discussion in the literature concerning possible mechanisms responsible for this phenomenon. Presently no consensus exists. It is well known that oxygen delivery is not the only function of systemic circulation. Additional roles include delivery of nutrients and other required substances to the tissue, waste removal, and temperature regulation. Among these other functions, the role of regional cerebral blood flow in local brain temperature regulation has received scant attention. Here we present a theoretical analysis supported by empirical data obtained with functional magnetic resonance suggesting that increase in regional cerebral blood flow during functional stimulation can cause local changes in the brain temperature and subsequent local changes in the oxygen metabolism. On average, temperature decreases by 0.2 degrees C, but individual variations up to +/-1 degrees C were also observed. Major factors contributing to temperature regulation during functional stimulation are changes in the oxygen consumption, changes in the temperature of incoming arterial blood, and extensive heat exchange between activated and surrounding brain tissue.

title: Hyperthermia induced pathophysiology of the central nervous system
abstract: This review is focused on the pathophysiology of the central nervous system (CNS) associated with mild-to-moderate hyperthermia (body temperature > 37°C but <40°C) induced thermal stress in Human cases as well as whole body hyperthermia (WBH) in animal studies. Pathological changes can be observed in the nerve cells and glial cells in Humans following mild-to-moderate thermal exposure. On the other hand, morphological changes in the axons, nerve cells, glial cells and vascular endothelium is seen at the cellular and the molecular levels in rats subjected to heat exposure at 38°C for 4 h (body temperature > 40°C but <42°C). This effect depends on the age of the animals and their prior thermal experiences. Taken together, heat stress induced hyperthermia, once believed to be non-toxic in the mammalian CNS, do produce specific alterations in the CNS that may have long-term behavioural, physiological and neuropathological consequences. The probable mechanism(s) underlying hyperthermia induced brain pathology is discussed.

title: Central neural control of thermoregulation and brown adipose tissue
abstract: Central neural circuits orchestrate the homeostatic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response. This review summarizes the experimental underpinnings of our current model of the CNS pathways controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction controlling heat loss, and shivering and brown adipose tissue for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific, core efferent pathways within the CNS that share a common peripheral thermal sensory input. Via the lateral parabrachial nucleus, skin thermal afferent input reaches the hypothalamic preoptic area to inhibit warm-sensitive, inhibitory output neurons which control heat production by inhibiting thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to thermogenesis-controlling premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation of spinal circuits necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation and elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation.

title: Cholinergic mechanisms of cutaneous active vasodilation during heat stress in cystic fibrosis.
abstract: To test the hypothesis that cutaneous active vasodilation in heat stress is mediated by a redundant cholinergic cotransmitter system, we examined the effects of atropine on skin blood flow (SkBF) increases during heat stress in persons with (CF) and without cystic fibrosis (non-CF). Vasoactive intestinal peptide (VIP) has been implicated as a mediator of cutaneous vasodilation in heat stress. VIP-containing cutaneous neurons are sparse in CF, yet SkBF increases during heat stress are normal. In CF, augmented ACh release or muscarinic receptor sensitivity could compensate for decreased VIP; if so, active vasodilation would be attenuated by atropine in CF relative to non-CF. Atropine was administered into skin by iontophoresis in seven CF and seven matched non-CF subjects. SkBF was monitored by laser-Doppler flowmetry (LDF) at atropine treated and untreated sites. Blood pressure [mean arterial pressure (MAP)] was monitored (Finapres), and cutaneous vascular conductance was calculated (CVC = LDF/MAP). The protocol began with a normothermic period followed by a 3-min cold stress and 30-45 min of heat stress. Finally, LDF sites were warmed to 42 degrees C to effect maximal vasodilation. CVC was normalized to its site-specific maximum. During heat stress, CVC increased in both CF and non-CF (P < 0.01). CVC increases were attenuated by atropine in both groups (P < 0.01); however, the responses did not differ between groups (P = 0.99). We conclude that in CF there is not greater dependence on redundant cholinergic mechanisms for cutaneous active vasodilation than in non-CF.

title: Clinical aspects of changes in water and sodium homeostasis in the elderly
abstract: The population of elderly individuals is increasing worldwide. With aging, various hormonal and kidney changes occur, both affecting water homeostasis. Aging is a risk factor for chronic kidney disease (CKD) and many features of CKD are reproduced in the aging kidney. Dehydration and hyperosmolarity can be triggered by diminished thirst perception in this population. Elderly with dementia are especially susceptible to abnormalities of their electrolyte and body water homeostasis and should be (re-)assessed for polypharmacy. Hypo- and hypernatremia can be life threatening and should be diagnosed and treated promptly, following current practice guidelines. In severe cases of acute symptomatic hyponatremia, a rapid bolus of 100 to 150 ml of intravenous 3% hypertonic saline is appropriate to avert catastrophic outcomes; for asymptomatic hyponatremia, a very gradual correction is preferred. In summary, the body sodium (Na+) balance is regulated by a complex interplay of environmental and individual factors. In this review, we attempt to provide an overview on this topic, including dehydration, hyponatremia, hypernatremia, age-related kidney changes, water and sodium balance, and age-related changes in the vasopressin and renin-angiotensin-aldosterone system.

title: Thirst and hydration status in everyday life.
abstract: Water is an essential nutrient for all persons; thus, maintaining a chronic state of optimal hydration is recognized to provide health benefits. Fluid balance is maintained via thirst, a feedback-controlled variable, regulated acutely by central and peripheral mechanisms. However, voluntary drinking is also a behavior influenced by numerous social and psychological cues. Therefore, whether "thirst-guided" drinking maintains optimal hydration status is a multifactorial issue. Thirst perception is typically assessed by subjective ratings using either categorical or visual analog scales; however, which instrument yields greater sensitivity to change in hydration status has not been examined. Ratings of thirst perception do not always yield predictable patterns of voluntary drinking following dehydration; therefore, perceived thirst and ad libitum drinking are not equivalent measures of human thirst. The recommendation "drink to thirst" is frequently given to healthy individuals during daily life. However, factors and conditions (e.g., age, disease) that influence thirst should be recognized and probed further.

title: Heat stress-induced neuroinflammation and aberration in monoamine levels in hypothalamus are associated with temperature dysregulation
abstract: Heat Stress (HS) induces diverse pathophysiological changes, which include brain ischemia, oxidative stress and neuronal damage. The present study was undertaken with the objective to ascertain whether neuroinflammation in Hypothalamus (HTH) caused under HS affects monoamine levels and hence, its physiological role in thermoregulation. Rats were exposed to HS in a heat simulation environmental chamber (Ambient temperature, Ta=45±0.5°C and Relative Humidity, RH=30±10%) with real-time measurement of core temperature (Tc) and skin temperature (Ts). Animals were divided into two subgroups: Moderate HS (MHS) (Tc=40°C) and Severe HS (SHS)/Heat stroke (Tc=42°C). Rats with MHS showed an increase in Mean Arterial Pressure (MAP) and Heart Rate (HR) while fall in MAP and rise in HR was observed in rats with SHS. In addition, oxidative stress and an increase in pyknotic neurons were observed in HTH. High levels of Adrenocorticotropic-hormone (ACTH), Epinephrine (EPI), Norepinephrine (NE) and Dopamine (DA) in the systemic circulation and progressive increase in EPI and DA levels in HTH were recorded after the thermal insult. Moreover, a substantial increase in Glutamate (Glu) level was observed in HTH as well as in systemic circulation of heat stroke rats. We found a rise in NE whereas a fall in Serotonin (5-HT) level in HTH at MHS, without perturbing inflammatory mediators. However, rats with SHS exhibited significant elevations in NF-kB, IL-1β, COX2, GFAP and Iba1 protein expression in HTH. In conclusion, the data suggest that SHS induces neuroinflammation in HTH, which is associated with monoamines and Glu imbalances, leading to thermoregulatory disruption.

title: Heat stress, plasma concentrations of adrenaline, noradrenaline, 5-hydroxytryptamine and cortisol, mood state and cognitive performance.
abstract: The primary aims of this paper were to examine the effect of heat stress on working memory, choice reaction time and mood state, and to investigate the relationship between heat induced changes in plasma concentrations of selected neurotransmitters and hormones, and cognition. Heat stress resulted in a deterioration of performance on a central executive task (random movement generation) but not on verbal and spatial recall, and choice reaction time tasks. Perceptions of vigour decreased and fatigue increased following exposure to heat stress. Plasma concentrations of cortisol and 5-hydroxytryptamine significantly increased following exposure to heat. Regression analyses showed that percent body mass loss and change from baseline (Delta) concentrations of cortisol, post-exposure to heat, were significant predictors of Delta random movement generation and Delta fatigue. A secondary purpose was to examine the effect of recovery on cognition and mood. Following recovery, the performance of the central executive task was poorer than pre-treatment. Mood states, catecholamines and 5-hydroxytryptamine concentrations returned to pre-treatment values, but cortisol fell to a level significantly lower. Regression correlations showed that Delta adrenaline and Delta scores, post-recovery, on the central executive task were significantly correlated. Delta noradrenaline correlated significantly with Delta fatigue. It was concluded that heat stress results in deterioration in the performance of central executive tasks and perceptions of mood state, and that this can be predicted by changes in body mass loss and plasma concentrations of the hormones cortisol and adrenaline.

title: Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia
abstract: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenance treatment with olanzapine 20 mg/day, trihexyphenidyl 4 mg/day, and trazodone 50 mg/day, suffered from heat stroke in a heat wave and required intensive care. He recovered with the medical treatment provided.  Several factors could have contributed to the impaired thermoregulation and the occurrence of heat stroke in this case: schizophrenia, the psychotropic regimen, and lack of preventive measures. Possible differential diagnoses of heat stroke in this case include infection, neuroleptic malignant syndrome, and serotonin syndrome.  Heat stroke can occur during the maintenance treatment of olanzapine, trihexyphenidyl, and trazodone for schizophrenia. Clinicians should be proactive to reduce the risk of heat stroke in psychiatric patients.

title: Involvement of serotonin in the ventral tegmental area in thermoregulation of freely moving rats
abstract: We have recently reported that the serotonin (5-HT) projections from the midbrain's raphe nuclei that contains 5-HT cell bodies may play a role both in heat production and in heat loss. The purpose of the present study was to clarify the involvement of 5-HT in the ventral tegmental area (VTA), where 5-HT is suggested to participate in thermoregulation, using the combined methods of telemetry, microdialysis, and high performance liquid chromatography, with a special emphasis on regulation of the body temperature (Tb) in freely moving rats. First, we measured changes in Tb, tail skin temperature (Ttail; an index of heat loss), heart rate (HR; an index of heat production), locomotor activity (Act), and levels of extracellular monoamines in the VTA during cold (5°C) or heat (35°C) exposure. Subsequently, we perfused citalopram (5-HT re-uptake inhibitor) into the VTA and measured the thermoregulatory parameters and monoamines release. Although Tb, Ttail, and HR changed during both exposures, significant changes in extracellular level of 5-HT (138.7±12.7% baseline, p<0.01), but not dopamine (DA) or noradrenaline (NA) were noted in the VTA only during heat exposure. In addition, perfusion of citalopram into the VTA increased extracellular 5-HT levels (221.0±52.2% baseline, p<0.01), but not DA or NA, while Tb decreased from 37.4±0.1°C to 36.8±0.2°C (p<0.001),Ttail increased from 26.3±0.4°C to 28.4±0.4°C (p<0.001), and HR and Act remained unchanged. Our results suggest that the VTA is a key area for thermoregulation, and 5-HT, but not DA or NA, modulates the heat loss system through action in the VTA.

title: Central dopaminergic neurotransmission plays an important role in thermoregulation and performance during endurance exercise
abstract: Dopamine (DA) has been widely investigated for its potential role in determining exercise performance. It was originally thought that DA's ergogenic effect was by mediating psychological responses. Recently, some studies have also suggested that DA may regulate physiological responses, such as thermoregulation. Hyperthermia has been demonstrated as an important limiting factor during endurance exercise. DA is prominent in the thermoregulatory centre, and changes in DA concentration have been shown to affect core temperature regulation during exercise. Some studies have proposed that DA or DA/noradrenaline (NA) reuptake inhibitors can improve exercise performance, despite hyperthermia during exercise in the heat. DA/NA reuptake inhibitors also increase catecholamine release in the thermoregulatory centre. Intracerebroventricularly injected DA has been shown to improve exercise performance through inhibiting hyperthermia-induced fatigue, even at normal ambient temperatures. Further, caffeine has been reported to increase DA release in the thermoregulatory centre and improves endurance exercise performance despite increased core body temperature. Taken together, DA has been shown to have ergogenic effects and increase heat storage and hyperthermia tolerance. The mechanisms underlying these effects seem to involve limiting/overriding the inhibitory signals from the central nervous system that result in cessation of exercise due to hyperthermia.

title: A role for an indoleamine other than 5‐hydroxytryptamine in the hypothalamic thermoregulatory pathways of the rat
abstract: 1. Intrahypothalamic injection of either 5‐hydroxytryptamine (5‐HT) (20 μg) or tryptamine (1 μg) caused hypothermia and hyperthermia respectively in lightly restrained rats maintained at an ambient temperature of 20 ± 1 °C.

title: Changes of body temperature and extracellular serotonin level in the preoptic area and anterior hypothalamus after thermal or serotonergic pharmacological stimulation of freely moving rats.
abstract: Although many studies has been shown that serotonin (5-HT) in the preoptic area and anterior hypothalamus (PO/AH) is important for regulating body temperature (Tb), the exact role is not established yet due to conflicting results probably related to experimental techniques or conditions such as the use of anesthesia. The purpose of present study was to clarify the role of 5-HT in the PO/AH using the combined methods of telemetry, microdialysis and high performance liquid chromatography (HPLC), with a special emphasis on the regulation of Tb in freely moving rats. Firstly, we measured changes in Tb and levels of extracellular 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the PO/AH during cold (5 degrees C) and heat (35 degrees C) exposure. We also perfused fluoxetine (5-HT re-uptake inhibitor) and 8-hydroxy-2-(Di-n-propylamino)tetralin (8-OH-DPAT: 5-HT1A agonist) into the PO/AH. During both exposures, although Tb changed significantly, no significant changes were noted in extracellular levels of 5-HT and 5-HIAA in the PO/AH. In addition, although perfusion of fluoxetine or 8-OH-DPAT into the PO/AH increased or decreased extracellular 5-HT and 5-HIAA levels in the PO/AH respectively, but Tb did not change at all. Our results suggest that 5-HT in the PO/AH may not mediate acute changes in thermoregulation.

title: Effect of Midbrain Stimulations on Thermoregulatory Vasomotor Responses in Rats
abstract: 1 Efferent projections eliciting vasodilatation when the preoptic area is warmed were investigated by monitoring tail vasomotor responses of ketamine‐anaesthetized rats when brain areas were stimulated electrically (0.2 mA, 200 μs, 0 Hz) or with the excitatory amino acid D,L‐homocysteic acid (1 mM, 0.3 μM). 2 Both stimulations elicited vasodilatation when applied within a region extending from the most caudal part of the lateral hypothalamus to the ventrolateral periaqueductal grey matter (PAG) and the reticular formation ventrolateral to the PAG. 3 Vasodilatation elicited by preoptic warming was suppressed when either stimulation was applied within the rostral part of the ventral tegmental area (VTA). 4 Sustained vasodilatation was elicited by knife cuts caudal to the VTA, and vasodilatation elicited by preoptic warming was suppressed by cuts either rostral to the VTA or in the region including the PAG and the reticular formation ventrolateral to it. 5 These results, together with the results of earlier physiological and histological studies, suggest that warm‐sensitive neurones in the preoptic area send excitatory signals to vasodilatative neurones in the caudal part of the lateral hypothalamus, ventrolateral PAG and reticular formation, and send inhibitory signals to vasoconstrictive neurones in the rostral part of the VTA.

title: Control of cutaneous blood flow by central nervous system
abstract: Hairless skin acts as a heat exchanger between body and environment, and thus greatly contributes to body temperature regulation by changing blood flow to the skin (cutaneous) vascular bed during physiological responses such as cold- or warm-defense and fever. Cutaneous blood flow is also affected by alerting state; we ‘go pale with fright’. The rabbit ear pinna and the rat tail have hairless skin, and thus provide animal models for investigating central pathway regulating blood flow to cutaneous vascular beds. Cutaneous blood flow is controlled by the centrally regulated sympathetic nervous system. Sympathetic premotor neurons in the medullary raphé in the lower brain stem are labeled at early stage after injection of trans-synaptic viral tracer into skin wall of the rat tail. Inactivation of these neurons abolishes cutaneous vasomotor changes evoked as part of thermoregulatory, febrile or psychological responses, indicating that the medullary raphé is a common final pathway to cutaneous sympathetic outflow, receiving neural inputs from upstream nuclei such as the preoptic area, hypothalamic nuclei and the midbrain. Summarizing evidences from rats and rabbits studies in the last 2 decades, we will review our current understanding of the central pathways mediating cutaneous vasomotor control.

title: Dopamine neuron systems in the brain: an update
abstract: The basic organization of the catecholamine-containing neuronal systems and their axonal projections in the brain was initially worked out using classical histofluorescence techniques during the 1960s and 1970s. The introduction of more versatile immunohistochemical methods, along with a range of highly sensitive tract-tracing techniques, has provided a progressively more detailed picture, making the dopamine system one of the best known, and most completely mapped, neurotransmitter systems in the brain. The purpose of the present review is to summarize our current knowledge of the diversity and neurochemical features of the nine dopamine-containing neuronal cell groups in the mammalian brain, their distinctive cellular properties, and their ability to regulate their dopaminergic transmitter machinery in response to altered functional demands and aging.

title: Dopamine and thermoregulation: An evaluation with special reference to dopaminergic pathways
abstract: The complex role of dopamine (DA) in the diencephalic mechanisms involved in the control of body temperature is reviewed and evaluated. In the context of the monoamine theory of thermoregulation, catecholaminergic synapses in the anterior hypothalamic pre-optic area, are proposed mediate the pathways in the brain-stem which subserve heat dissipation. Within this theoretical framework, hypothalamic DA is considered to underlie a portion of the functional component of the heat loss system. This deduction is based on pharmacological studies in which both the catecholamine and receptor antagonists have been infused directly into the hypothalamus. In view of the action of DA applied to the substantia nigra and other subcortical structures, the unique anatomical circuitry of the central dopaminergic projections has also been analyzed in terms of specific connections within critical morphological regions related to thermal functions. In particular, the nigro-striatal pathway could be involved in the mediation of one or more of the different aspects of the thermoregulatory system integrating both autonomic and behavioral responses. Finally, an anatomical schema which portrays the suggested mechanisms of DA activity is presented.

title: Dopamine effects on thermosensitive neurons in hypothalamic tissue slices
abstract: To understand the role of hypothalamic dopamine in thermoregulation, single unit activity was recorded in vitro, from constantly perfused tissue slices of rat preoptic area and anterior hypothalamus, PO/AH. The firing rate and thermosensitivity of individual PO/AH neurons were determined before, during and after tissue perfusion with media containing dopamine. Dopamine excited 41% of the warm-sensitive neurons, inhibited 100% of the cold-sensitive neurons, and had no effect on 83% of the temperature-insensitive neurons. In addition, dopamine decreased the local thermosensitivity of most cold-sensitive neurons. There were no major differences between these neuronal types in terms of the time course or latency of dopamine's effect. These results are consistent with the hypothesis that dopamine is involved in hypothalamic synapses controlling thermoregulatory responses which oppose increases in body temperature.

title: Temperature regulation and dopaminergic systems in the brain: Does the substantia nigra play a role?
abstract: Male Sprague-Dawley rats (250-300 g) were stereotaxically implanted above the substantia nigra (SN) and preoptic/anterior hypothalamus (PO/AH) with 23 gauge stainless-steel guide tubes. Microinjections of apomorphine (APO), pimozide, or 0.9% saline were made bilaterally in 0.5 or 1.0 microliter vols. using a Harvard infusion pump. Oxygen consumption, and colonic (Tc), tail-skin, and ambient temperatures were monitored each minute. Microinjections of APO into the SN produced a dose dependent hypothermia that was antagonized by the central (1.0 microgram) or systemic (0.5mg/kg i.p.) injection of pimozide. This hypothermia was associated with increased heat loss and decreased heat production and occurred at ambient temperatures of 15, 23 and 25 degree C indicating that APO did not produce a poikilothermic state. Injecting 20 microgram APO into the PO/AH or SN produced similar hypothermic responses; Tc fell 0.87 /+- 0.10 degree C and 1.02 /+- 0.08 degree C, respectively. Pimozide injected into the SN failed to alter thermoregulation during exercise or exogenous heating. Moreover, systemic injections of APO before and after electrolytic lesioning of the SN produced similar hypothermic responses. However, when the SN was lesioned, (a) resting Tc was significantly reduced, and (b) during exposure to a 35 degree C environment for 55 min, Tc rose to 39.5 /+- 0.68 degree C before the lesion compared with a rise to only 38.5 /+- 0.13 degree C after the lesion. We conclude that the pharmacological data implicate a thermoregulatory role for dopamine receptors in the rat, but the functional significance of this central location in temperature regulation remains to be elucidated.

title: Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation, metabolic rate and running performance.
abstract: To assess the effects of a blockade of central D1- and D2-dopaminergic receptors on metabolic rate, heat balance and running performance, 10 nmol (2 microl) of a solution of the D(1) antagonist SCH-23390 hydrochloride (SCH, n = 6), D2 antagonist eticlopride hydrochloride (Eti, n = 6), or 2 microl of 0.15 M NaCl (SAL, n = 6) was injected intracerebroventricularly into Wistar rats before the animals began graded running until fatigue (starting at 10 m/min, increasing by 1 m/min increment every 3 min until fatigue, 5% inclination). Oxygen consumption and body temperature were recorded at rest, during exercise and following 30 min of recovery. Control experiments with injection of two doses (10 and 20 nmol/rat) of either SCH or Eti solution were carried out in resting rats as well. Body heating rate, heat storage, workload and mechanical efficiency were calculated. Although SCH and Eti treatments did not induce thermal effects in resting animals, they markedly reduced running performance (-83%, SCH; -59% Eti, p < 0.05) and decreased maximal oxygen uptake (-79%, SCH; -45%, Eti, p < 0.05) in running rats. In addition, these treatments induced a higher body heating rate and persistent hyperthermia during the recovery period. Our data demonstrate that the alteration in dopamine transmission induced by the central blockade of dopamine- D1 and D2 receptors impairs running performance by decreasing the tolerance to heat storage. This blockade also impairs the dissipation of exercise-induced heat and metabolic rate recovery during the post-exercise period. Our results provide evidence that central activation of either dopamine- D1 or D2 receptors is essential for heat balance and exercise performance.

title: Developmental origins of central norepinephrine neuron diversity
abstract: Central norepinephrine-producing neurons comprise a diverse population of cells differing in anatomical location, connectivity, function and response to disease and environmental insult. The mechanisms that generate this diversity are unknown. Here we elucidate the lineal relationship between molecularly distinct progenitor populations in the developing mouse hindbrain and mature norepinephrine neuron subtype identity. We have identified four genetically separable subpopulations of mature norepinephrine neurons differing in their anatomical location, axon morphology and efferent projection pattern. One of the subpopulations showed an unexpected projection to the prefrontal cortex, challenging the long-held belief that the locus coeruleus is the sole source of norepinephrine projections to the cortex. These findings reveal the embryonic origins of central norepinephrine neurons and provide multiple molecular points of entry for future study of individual norepinephrine circuits in complex behavioral and physiological processes including arousal, attention, mood, memory, appetite and homeostasis.

title: Changes in body temperature after administration of adrenergic and serotonergic agents and related drugs including antidepressants: II
abstract: This survey continues a second series of compilations of data regarding changes in body temperature induced by drugs and related agents. The information listed includes the species used, the route of administration and dose of drug, the environmental temperature at which experiments were performed, the number of tests, the direction and magnitude of change in body temperature and remarks on the presence of special conditions, such as age or brain lesions. Also indicated is the influence of other drugs, such as antagonists, on the response to the primary agent. Most of the papers were published from 1980 to 1984 but data from many earlier papers are also tabulated.

title: Effect of amine on temperature-responsive neuron in slice preparation of rat brain stem.
abstract: Using slice preparations we investigated the effect of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) on thermoresponsive neurons in the hypothalamus, midbrain, and the medulla oblongata. NE inhibits the activities of most of the warm-responsive neurons (11 out of 13 neurons) but 5-HT activates the warm-responsive neurons (10 out of 11 neurons) in the hypothalamus. However, the direction of neuronal response of the midbrain was opposite of that in the hypothalamus when 5-HT was applied. In the medulla oblongata, 5-HT facilitates both warm- and cold-responsive neurons and NE facilitates or inhibits these neurons in equal proportions. Furthermore, the dose-response relationships were determined using slice preparations. In the hypothalamus and the midbrain, NE and 5-HT started to effect the warm-responsive neurons at the minimum concentration of 5 X 10(-6) M, whereas the maximum responses were obtained at the concentration of 5 X 10(-5) M. In the medulla oblongata, NE or 5-HT changed the activities of the warm-responsive neurons in the range of 5 X 10(-5) to 10(-3) M or 10(-6) to 10(-5) M, respectively. It is concluded that the thermoresponsive neurons respond to 5-HT and NE in different ways, at both various levels in the central nervous system and the applied concentration of amines.

title: Central fatigue and neurotransmitters, can thermoregulation be manipulated?
abstract: Fatigue is a complex phenomenon that can be evoked by peripheral and central factors. Although it is obvious that fatigue has peripheral causes such as glycogen depletion and cardiovascular strain, recent literature also focuses on the central origin of fatigue. It is clear that different brain neurotransmitters – such as serotonin, dopamine and noradrenaline – are implicated in the occurrence of fatigue, but manipulation of these neurotransmitters produced no conclusive results on performance in normal ambient temperature. Exercise in the heat not only adds an extra challenge to the cardiorespiratory system, but also to the brain. This provides a useful tool to investigate the association between exercise‐induced hyperthermia and central fatigue. This review focuses on the effects of pharmacological manipulations on performance and thermoregulation in different ambient temperatures. Dopaminergic reuptake inhibition appears to counteract hyperthermia‐induced fatigue in 30 °C, while noradrenergic neurotransmission shows negative effects on performance in both normal and high temperature, and serotonergic manipulations did not lead to significant changes in performance. It is, however, unlikely that one neurotransmitter system is responsible for the delay or onset of fatigue. Further research is required to determine the exact mechanisms of fatigue in different environmental conditions.

title: Microdialysis of norepinephrine into preoptic area of guinea pigs: characteristics of hypothermic effect.
abstract: This study was designed to characterize the previously described hypothermic action of norepinephrine (NE) microdialyzed into the medial preoptic area (MPO) of conscious guinea pigs. To this end, the effects on core temperature (Tco) of isotonic pyrogen-free saline (PFS), hypotonic PFS, inactive (oxidized) NE (hypertonic), 5-hydroxytryptamine (5-HT, 10 and 20 micrograms/microliter), PFS with or without 2.4 mM Ca2+, 10 micrograms/microliters NE with Ca2+, and various doses of NE (0.05-60 micrograms/microliters) were compared in a series of studies at an ambient temperature (Ta) of 24 degrees C. The Tco responses to 10 micrograms/microliters NE in a cold (15 +/- 2 degrees C) and a warm (31 +/- 1 degrees C) Ta and during the night in the dark in Ta 24 degrees C were also measured. Bromophenol blue (0.2%) was microdialyzed to assess the extent of diffusion of these dialysates. A stain was found in the MPO, which increased in density but did not spread beyond this region over 3 h of continuous microdialysis. Neither PFS nor the hypotonic and hypertonic solutions had any obvious effect on Tco. Similarly, neither dose of 5-HT evoked a thermal response. Ca2+ added to either PFS or NE did not alter the usual Tco responses to these two solutions. NE induced dose-dependent hypothermia in Ta 24 degrees C. NE microdialyzed in Ta 15 degrees C also produced Tco falls, but these responses were smaller than those in 24 degrees C. NE had no effect in the warm Ta. During the night, NE elicited similar Tco falls, but their recoveries after dialysis ended were slower than during the day.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Preoptic norepinephrine-induced hypothermia is mediated by alpha 2-adrenoceptors.
abstract: We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area of conscious guinea pigs evokes a fall in core temperature (Tco) that is mediated by a reduction in metabolic rate. To identify the adrenoceptor subtype(s) involved in this effect, we microdialyzed intrapreoptically various adrenergic agonists or antagonists singly or in combinations. Tco and ear skin temperatures of the animals were monitored throughout the experiments. alpha 1-, beta-, beta 1-, and beta 2-agonists and antagonists did not induce significant Tco changes. Although the alpha 2-antagonists yohimbine (Yoh) and rauwolscine (Rau) did not have thermal effects per se, the alpha 2-agonist clonidine evoked dose-dependent Tco falls that were abolished by codialyzed Yoh and Rau. The microdialysis of NE evoked, as before, a 0.7 +/- 0.2 degrees C Tco fall; it was abolished by the codialyzed alpha-antagonist phentolamine, Yoh, and Rau but not by the beta-antagonist propranolol. No adrenoceptor agonist induced changes in ear skin temperature. These results indicate that the hypothermizing effect of intrapreoptically microdialyzed NE is achieved by a reduction in metabolic heat production, mediated by alpha 2-adrenoceptors.

title: Heat stroke. Keeping your clients cool in the summer.
abstract: Persons with persistent, disabling mental illness have an increased risk of heat-related illness. Mental health care providers must be aware of this risk, and should be educated regarding detection and prevention. A high level of awareness and monitoring for symptoms of heat-related illness is indicated during the initial days of a heat wave. Health professionals must ensure that consumers know about the risk of heat stroke and have a plan in place to deal with hot weather. Plans must be practical, affordable, and take into account the preferences, habits, and psychiatric symptoms of the individual who will carry them out. Thoughtful planning and education can help reduce the risk of heat-related illness in this vulnerable group.

title: Managing anticholinergic side effects.
abstract: Atypical antipsychotics are associated with a lower risk of extrapyramidal symptoms (EPS) and tardive dyskinesia than the conventional antipsychotics; however, many atypical antipsychotics can cause other potentially harmful side effects such as anticholinergic side effects. Peripheral and central anticholinergic side effects can cause physical and mental impairment. Awareness of the medications that have the potential to cause anticholinergic side effects as well as proper management of these symptoms can aid physicians in treating patients who need antipsychotic therapy.

title: Recurrent Heat-Related Illnesses During Antipsychotic Treatment
abstract: To report a case of recurrent heat-related illnesses associated with the use of benzhexol, chlorpromazine, and zuclopenthixol decanoate.  During the summer of 2004, a 48-year-old man with a history of diabetes mellitus and schizophrenia was twice admitted to the hospital because of heat-related illnesses. On both occasions, he had been working under the sun in an open car park. His medications included benzhexol 2 mg twice daily, chlorpromazine 650 mg at bedtime, and zuclopenthixol decanoate intramuscular injection 600 mg every 4 weeks. In the first admission, the clinical diagnosis was heat stroke. He was discharged home on day 14, with precautionary advice against heat stroke. In the second admission, the clinical diagnosis was heat exhaustion. He was discharged home on day 4 and reminded of the precautions against heat stroke. An objective causality assessment revealed that the adverse event was possibly drug related in the first admission and probably drug related in the second admission.  Several drugs can impair thermoregulation during exercise or under conditions of environmental heat stress. Anticholinergic drugs or drugs with anticholinergic effects can inhibit sweating and reduce heat elimination. Neuroleptics (antipsychotics), such as phenothiazines, have combined anticholinergic and central thermoregulatory effects. The set point of the temperature regulation center can be elevated by the antidopaminergic effect of antipsychotics, such as phenothiazines and thioxanthenes.  Certain drugs may induce or worsen heat-related illnesses. During a heat wave, special attention should be given to those most at risk, and the importance of preventive measures should be emphasized.

title: Drug-induced hyperthermic syndromes: part I. Hyperthermia in overdose.
abstract: Drugs and natural compounds that affect the thermoregulatory system can induce or contribute to hyperthermia when used in excess. Hyperthermia associated with drug overdose is dangerous and potentially lethal. This article reviews the body's process of maintaining thermodynamic equilibrium, and describes the mechanisms by which it is influenced by sympathomimetic and anticholinergic drugs, salicylates, and thyroid replacement medications. Appropriate treatment strategies such as cooling and the administration of counteractive medications are discussed.

title: Drug-associated heat stroke.
abstract: During the June 1998 heat wave in New Orleans, 8 patients came to the emergency department of a large public hospital over a 14-day period. They were subsequently admitted to the intensive care unit with a diagnosis of heat stroke. On each of these days, the ambient temperature exceeded 33.3 degrees C (91.9 degrees F). Although the highest recorded temperature was only 35.6 degrees C (96 degrees F), the heat index reached a high of 44.5 degrees C (112 degrees F). Weather-related heat illnesses are well documented, but the reports rarely address contributing medications or drugs. In this series, 6 patients (75%) had been using medication or drugs known to induce or worsen hyperthermia. A seventh patient had been prescribed a phenothiazine, but actual use could not be established. An eighth patient had an unidentified agent detected on toxicologic screening. The most common drug identified was cocaine. Other drugs included diphenhydramine, tricyclic antidepressants, and phenothiazines. Six patients (75%) had rhabdomyolysis; 3 of them also had disseminated intravascular coagulation. There were 2 deaths, yielding a 25% mortality rate.

title: Performance and thermoregulatory effects of chronic bupropion administration in the heat
abstract: The combination of acute dopamine/noradrenaline reuptake inhibition (bupropion; BUP) and heat stress (30°C) significantly improves performance (9%). Furthermore the maintenance of a higher power output resulted in the attainment of significantly higher heart rates and rectal temperatures—above 40°C—in the BUP trial compared to the placebo trial. Since BUP is an aid to cease smoking that is taken for longer periods, question remains if similar performance and thermoregulatory effects are found following administration of BUP over several days (10 days). The purpose of the present study was to examine the effects of chronic BUP on exercise performance, thermoregulation and hormonal variables in the heat. Eight trained male cyclists participated in the study. Subjects completed two trials consisting of 60 min fixed intensity exercise (55% Wmax) followed by a time trial (TT) in a double-blind randomized crossover design. Exercise was performed in 30°C. Subjects took either placebo (PLAC) or BUP (Zyban™) for 3 days (150 mg), followed by 300 mg for 7 days. Chronic BUP did not influence TT performance (BUP 40′42″ ± 4′18″; PLAC 41′36″ ± 5′12″), but significantly increased core temperature (P = 0.030). BUP significantly increased circulating growth hormone levels (PLAC: 9.8 ± 5.8 ng L−1; BUP: 13 ± 6.8 ng L−1; P < 0.008).  Chronic BUP did not influence TT performance in 30°C and subjects did not reach core temperature values as high as observed during the acute BUP study. It seems that chronic administration results in an adaptation of central neurotransmitter homeostasis, resulting in a different response to the drug.

title: Acute dopamine/norepinephrine reuptake inhibition increases brain and core temperature in rats.
abstract: The purpose of the present study was to examine the effects of an acute dose of the dual dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (Bup) on brain (T(brain)), body core (T(core)), and tail skin (T(tail)) temperature in freely moving rats and to simultaneously monitor the extracellular neurotransmitter concentrations in the preoptic area and anterior hypothalamus (PO/AH). A microdialysis probe was inserted in the PO/AH, and samples for NE, DA, and serotonin (5-HT) were collected every 20 min before and after the injection of 17 mg/kg of Bup, for a total sampling time of 180 min. T(core) was monitored using a biotelemetry system. T(brain) and T(tail), an index of heat loss response, were also measured. Both NE and DA levels in the PO/AH significantly increased after Bup injection compared with the baseline levels, reaching approximately 450 and 230%, respectively, 40 min after injection. There was no effect on 5-HT release. The neurotransmitter changes were accompanied by a significant decrease in T(tail) and an increase in both T(brain) and T(core) compared with the baseline levels. The present results demonstrate that inhibition of NE and DA reuptake suppresses heat loss mechanisms and elevates T(brain) and T(core) in freely moving rats.

title: Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor.
abstract: The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.

title: Bupropion occupancy of the dopamine transporter is low during clinical treatment
abstract: AbstractRationale. Bupropion is thought to treat major depression by blocking the dopamine transporter (DAT) because bupropion appears to have a selective affinity for the DAT. The validity of this mechanism has been questioned because the affinity of bupropion for the DAT is quite low.
 Objective. To determine the occupancy of bupropion for the DAT during clinical treatment of patients with depression.
 Methods. Positron emission tomography with [11C]-RTI32 was used to determine the striatal DAT binding potential (BP) of eight depressed patients before and during treatment with bupropion. BP is proportional to available receptor density (receptors not blocked by drug). Occupancy is the percent change in BP. Eight healthy subjects were similarly studied in a test-retest design.
 Results. No significant difference in DAT BP was found after bupropion treatment in comparison to the test-retest data. The occupancy after bupropion treatment was 14% (confidence interval 6–22%) as compared to 7% in the test-retest condition.
 Conclusions. Bupropion treatment occupies less than 22% of DAT sites. This raises the question as to whether a DAT occupancy of less than 22% is therapeutic or whether there is another mechanism involved during treatment with bupropion.

title: Evidence that the Acute Behavioral and Electrophysiological Effects of Bupropion (Wellbutrin®) Are Mediated by a Noradrenergic Mechanism
abstract: Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg IP) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg IP). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg IP) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxy-bupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after IV doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing. The effects of clonidine, a direct acting α2 agonist, were not significantly changed by reserpine. Likewise, a reduction in the effect of bupropion on LC firing was observed in vitro after depletion of catecholamines with reserpine or tetrabenazine. These results suggest that bupropion preferentially affects NE neurons in locus coeruleus at doses that are active in animal antidepressant tests. The doses of bupropion required to inhibit DA cell firing were associated with inhibition of DA uptake and behavioral stimulation and were significantly higher than those selectively producing behavioral effects in animal antidepressant tests. The acute electrophysiological actions of bupropion on NE cells require a reserpine-sensitive store of NE and occur at doses having activity in antidepressant screening tests.

title: Heat‐related side‐effects of neurological and non‐neurological medication may increase heatwave fatalities
abstract: During the 2003 French heatwave 15 000 excess deaths were registered. One fifths died from the combination of dehydration, heatstroke, and hyperthermia and one tenth from dehydration, despite abundant water.

title: Increased Risk of Drug-Induced Hyponatremia during High Temperatures
abstract: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA).  All individual adverse drug reactions (ADR) reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case-crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases.  During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR) with increasing temperature in the warm season with a highest odds ratio, with delays of 1–5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 °C. The change in sodium per 1 °C increase in temperature was estimated to be −0.37 mmol/L (95% CI: −0.02, −0.72).  Warm weather appears to increase the risk of drug-induced hyponatremia.

title: Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults.
abstract: Hyponatremia may occur after initiation of a second-generation antidepressant drug. However, the magnitude of this risk among older adults in routine care is not well characterized.



Retrospective, population-based, matched-cohort study.



In Ontario, Canada, 2003 to 2012, we compared older adults with a mood or anxiety disorder who were dispensed 1 of 9 second-generation antidepressant drugs with matched adults with comparable indicators of baseline health who were not dispensed an antidepressant drug (n=138,246 per group). A similar comparison was made in a subpopulation with available laboratory data (n=4,186 per group).



Second-generation antidepressant prescription versus no antidepressant prescription.



The primary outcome was hospitalization with hyponatremia. A secondary outcome was hospitalization with both hyponatremia and delirium.



We assessed hospitalization with hyponatremia using a diagnosis code and, in the subpopulation, serum sodium values. We assessed hospitalization with hyponatremia and delirium using a combination of diagnosis codes.



Second-generation antidepressant use versus nonuse was associated with higher 30-day risk for hospitalization with hyponatremia (450/138,246 [0.33%] vs 84/138,246 [0.06%]; relative risk [RR], 5.46 [95% CI, 4.32-6.91]). This association was consistent in the subpopulation with serum sodium values (73/4,186 [1.74%] vs 18/4,186 [0.43%]; RR, 4.23 [95% CI, 2.50-7.19]; absolute risk increase, 1.31% [95% CI, 0.87%-1.75%]). Second-generation antidepressant use versus nonuse was also associated with higher 30-day risk for hospitalization with both hyponatremia and delirium (28/138,246 [0.02%] vs 7/138,246 [0.005%]; RR, 4.00 [95% CI, 1.75-9.16]).



Measures of serum sodium could be ascertained in only a subpopulation.



Use of a second-generation antidepressant in routine care by older adults is associated with an approximate 5-fold increase in 30-day risk for hospitalization with hyponatremia compared to nonuse. However, the absolute increase in 30-day incidence is low.

title: Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people.
abstract: To establish the incidence, time course and risk factors of hyponatraemia complicating treatment with fluoxetine or paroxetine in an elderly population.



Retrospective descriptive and case control study in an inpatient/outpatient assessment and rehabilitation service for people aged 65 years and over. Fourteen elderly patients with hyponatraemia complicating treatment with fluoxetine or paroxetine, matched with 56 controls drawn from 845 patients treated with fluoxetine or paroxetine over 3.5 years. No other SSRI antidepressants were used over the study period.



The incidence of hyponatraemia was 4.7/1000 people treated/year (6.3/1000 for fluoxetine and 3.5/1000 for paroxetine). Hyponatraemia was detected at a median 13.5 (mean 18.6, range 4-64) days after commencing the drug. Mean (95% confidence intervals) body weights were lower in cases at 53.0 (95% CI 46.5-59.5) kg compared with controls at 64.5 (95% CI 60.1-68.4) kg (P<0.01). 71% of cases were women compared with 45% of controls (P=0.07) but the effect of gender was confounded by body weight. There were trends for cases to be older (odds ratio 1.10: 95% CI 0.99, 1.23) and lighter (odds ratio 0.92, 95% CI 0.86, 0.99).



Approximately 1 in 200 elderly people treated per year with fluoxetine or paroxetine developed complicating hyponatraemia. Low body weight was a particular risk factor. Most cases occurred within 3 weeks of treatment.

title: Serum Sodium Changes in Fluoxetine Users at Different Age Groups
abstract: Fluoxetine, a widely used antidepressant, can affect the serum sodium level. The aim of this study was to evaluate and compare changes in the serum sodium level of depressive patients taking fluoxetine according to age.  This quasi-experimental study was conducted on 126 patients with depression, dividing the patients into two age groups of 15 to 35 years, and above 55 years, who referred to psychiatric clinics of the Isfahan University of Medical Sciences. Serum sodium level was measured prior to fluoxetine therapy and at the first and third week after; adverse symptoms were recorded. Serum sodium level, hyponatremia, and other adverse effects were compared between the two age groups.  There was a significant decrease in serum sodium levels in the older patients at the first and third week after the therapy; but the serum sodium levels decreased only after the third week of therapy in the younger patients (p<0.05). Serum sodium level was significantly lower in older than in younger patients at the third week of the therapy (140.8±2.26 vs. 135.2±2.06; p<0.05), and hyponatremia was detected only in the older patients after the first and third week of therapy, 4.7% and 15.8%, respectively.  Using fluoxetine can decrease serum sodium level, which is more frequent, more severe, and more clinically manifested in older than younger patients. Monitoring serum sodium level is recommended in early weeks of fluoxetine therapy especially for patients older than 55 years of age.

title: Syndrome of inappropriate ADH secretion (SIADH) associated with citalopram use
abstract: Selective serotonin reuptake inhibitors (SSRIs) can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH is associated with hyponatraemia without oedema. We report the case of a patient who developed acute-onset hyponatraemia that progressed rapidly to serious neurological dysfunction shortly after the introduction of citalopram. All SSRIs including citalopram should be used with care in the elderly. The water and electrolyte balance should be monitored carefully during SSRI therapy.

title: Hyponatremia Associated with Selective Serotonin-Reuptake Inhibitors in Older Adults
abstract: To review the incidence, risk factors, mechanism, times of onset and resolution, and treatment of hyponatremia associated with selective serotonin-reuptake inhibitors (SSRIs).  An English-language literature search was conducted using MEDLINE (1966–December 2005) using the search terms selective serotonin-reuptake inhibitor, hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Additional references were identified by reviewing bibliographies of articles retrieved. Study Selection and Data Extraction: Relevant data were extracted from published reports, letters, and studies of humans with hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to SSRIs. All articles identified from data sources were reviewed for relevant information. Applicable information was included in this review.  Numerous case reports, observational studies, and case-controlled studies, as well as one prospective clinical trial, have reported hyponatremia associated with SSRI use, with the incidence varying from 0.5% to 32%. Risk factors for the development of hyponatremia with SSRIs include older age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium concentration. In published reports, hyponatremia developed within the first few weeks of treatment and resolved within 2 weeks after therapy was discontinued. The mechanism by which SSRIs cause hyponatremia is thought to be secondary to development of SIADH. Treatment of isovolemia hypotonic hyponatremia associated with SSRI use includes water restriction and mild diuresis with a loop diuretic. More severe cases may be treated with higher doses of loop diuretics and hypertonic saline. There have been few reports of rechallenge with the same or another SSRI or substitution of another agent from a different therapeutic class. In some, but not all, cases hyponatremia recurred.  Practitioners should be on the alert for this potentially life-threatening adverse event, especially in older adults with other risk factors for developing hyponatremia.

title: Hyperthermia-Induced Disruption of Functional Connectivity in the Human Brain Network
abstract: Passive hyperthermia is a potential risk factor to human cognitive performance and work behavior in many extreme work environments. Previous studies have demonstrated significant effects of passive hyperthermia on human cognitive performance and work behavior. However, there is a lack of a clear understanding of the exact affected brain regions and inter-regional connectivities.  We simulated 1 hour environmental heat exposure to thirty-six participants under two environmental temperature conditions (25°C and 50°C), and collected resting-state functional brain activity. The functional connectivities with a preselected region of interest (ROI) in the posterior cingulate cortex and precuneus (PCC/PCu), furthermore, inter-regional connectivities throughout the entire brain using a prior Anatomical Automatic Labeling (AAL) atlas were calculated. We identified decreased correlations of a set of regions with the PCC/PCu, including the medial orbitofrontal cortex (mOFC) and bilateral medial temporal cortex, as well as increased correlations with the partial orbitofrontal cortex particularly in the bilateral orbital superior frontal gyrus. Compared with the normal control (NC) group, the hyperthermia (HT) group showed 65 disturbed functional connectivities with 50 of them being decreased and 15 of them being increased. While the decreased correlations mainly involved with the mOFC, temporal lobe and occipital lobe, increased correlations were mainly located within the limbic system. In consideration of physiological system changes, we explored the correlations of the number of significantly altered inter-regional connectivities with differential rectal temperatures and weight loss, but failed to obtain significant correlations. More importantly, during the attention network test (ANT) we found that the number of significantly altered functional connectivities was positively correlated with an increase in executive control reaction time.  We first identified the hyperthermia-induced altered functional connectivity patterns. The changes in the functional connectivity network might be a possible explanation for the cognitive performance and work behavior alteration.

title: Clinical utility of resting-state functional connectivity magnetic resonance imaging for mood and cognitive disorders
abstract: Although functional magnetic resonance imaging (fMRI) has long been used to assess task-related brain activity in neuropsychiatric disorders, it has not yet become a widely available clinical tool. Resting-state fMRI (rs-fMRI) has been the subject of recent attention in the fields of basic and clinical neuroimaging research. This method enables investigation of the functional organization of the brain and alterations of resting-state networks (RSNs) in patients with neuropsychiatric disorders. Rs-fMRI does not require participants to perform a demanding task, in contrast to task fMRI, which often requires participants to follow complex instructions. Rs-fMRI has a number of advantages over task fMRI for application with neuropsychiatric patients, for example, although applications of task fMR to participants for healthy are easy. However, it is difficult to apply these applications to patients with psychiatric and neurological disorders, because they may have difficulty in performing demanding cognitive task. Here, we review the basic methodology and analysis techniques relevant to clinical studies, and the clinical applications of the technique for examining neuropsychiatric disorders, focusing on mood disorders (major depressive disorder and bipolar disorder) and dementia (Alzheimer’s disease and mild cognitive impairment).

title: Integration of multimodal neuroimaging methods: a rationale for clinical applications of simultaneous EEG-fMRI.
abstract: Functional magnetic resonance imaging (fMRI), which has high spatial resolution, is increasingly used to evaluate cerebral functions in neurological and psychiatric diseases. The main limitation of fMRI is that it detects neural activity indirectly, through the associated slow hemodynamic variations. Because neurovascular coupling can be regionally altered by pathological conditions or drugs, fMRI responses may not truly reflect neural activity. Electroencephalography (EEG) recordings, which directly detect neural activity with optimal temporal resolution, can now be obtained during fMRI data acquisition. Therefore, there is a growing interest in combining the techniques to obtain simultaneous EEG-fMRI recordings. The EEG-fMRI approach has several promising clinical applications. The first is the detection of cortical areas involved in interictal and ictal epileptic activity. Second, combining evoked potentials with fMRI could be an accurate way to study eloquent cortical areas for the planning of neurosurgery or rehabilitation, circumventing the above-mentioned limitation of fMRI. Finally, the use of this approach to evaluate the functional connectivity of resting-state networks would extend the applications of EEG-fMRI to uncooperative or unconscious patients. Integration of multimodal neuroimaging methods: a rationale for clinical applications of simultaneous EEG-fMRI.

title: Investigating the Blood Oxygenation Level-Dependent Functional MRI Response to a Verbal Fluency Task in Early Stroke before and after Hemodynamic Scaling
abstract: Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) has been extensively used as a marker of brain dysfunction and subsequent recovery following stroke. However, growing evidence suggests that straightforward interpretation of BOLD fMRI changes with aging and disease is challenging. In this study, we investigated the effect of calibrating task fMRI data by applying a hemodynamic calibration method using the resting-state fluctuation amplitude (RSFA). Task fMRI responses were obtained during a covert verbal fluency task in a group of early stage stroke patients and matched healthy normal controls.  Fifteen acute left hemisphere stroke patients (less than 7 days from stroke; aged 44–84 years, average ~64 years) and 21 healthy controls (aged 55–77 years, average ~61 years) were prospectively studied. All subjects completed a 3-min covert verbal fluency task, and a 10-min eyes-closed resting-state fMRI scan, from which the calibration factor (RSFA) was computed. A behavioral measure on the verbal fluency task was also collected outside the scanner. Whole brain activation volumes and region-of-interest (ROI)-wise percent signal change and activation volumes before and after calibration were computed.  Between-group differences in whole brain activation volumes, although statistically significant before calibration failed to be significant after calibration. There were significant within-group differences before and after calibration with RSFA. Statistically significant between-group differences on ROI-wise measures before calibration also significantly reduced after calibration. Exploratory brain-behavior correlations revealed a similar pattern: significant correlations before calibration failed to survive after calibration.  BOLD fMRI changes with aging and disease is confounded by changes in neurofunctional coupling leading to challenges in the straightforward interpretation of task fMRI results. Application of the hemodynamic calibration using the RSFA technique in the current study appeared to mitigate any differences between stroke and age-matched healthy controls. Our study indicates that estimating neural activity after applying hemodynamic scaling is important for studies of aging and for studies tracking post-stroke changes. We recommend that further investigation of hemodynamic calibration with RSFA in healthy subjects and in stroke in larger samples is necessary.

title: Neuroimaging methods in affective neuroscience: selected methodological issues.
abstract: A current goal of affective neuroscience is to reveal the relationship between emotion and dynamic brain activity in specific neural circuits. In humans, noninvasive neuroimaging measures are of primary interest in this endeavor. However, methodological issues, unique to each neuroimaging method, have important implications for the design of studies, interpretation of findings, and comparison across studies. With regard to event-related brain potentials, we discuss the need for dense sensor arrays to achieve reference-independent characterization of field potentials and improved estimate of cortical brain sources. Furthermore, limitations and caveats regarding sparse sensor sampling are discussed. With regard to event-related magnetic field (ERF) recordings, we outline a method to achieve magnetoencephalography (MEG) sensor standardization, which improves effects' sizes in typical neuroscientific investigations, avoids the finding of ghost effects, and facilitates comparison of MEG waveforms across studies. Focusing on functional magnetic resonance imaging (fMRI), we question the unjustified application of proportional global signal scaling in emotion research, which can greatly distort statistical findings in key structures implicated in emotional processing and possibly contributing to conflicting results in affective neuroscience fMRI studies, in particular with respect to limbic and paralimbic structures. Finally, a distributed EEG/MEG source analysis with statistical parametric mapping is outlined providing a common software platform for hemodynamic and electromagnetic neuroimaging measures. Taken together, to achieve consistent and replicable patterns of the relationship between emotion and neuroimaging measures, methodological aspects associated with the various neuroimaging techniques may be of similar importance as the definition of emotional cues and task context used to study emotion.

title: Resting-state functional connectivity reflects structural connectivity in the default mode network.
abstract: Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations in spontaneous blood oxygen level-dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the default mode network, a set of brain regions--including medial prefrontal cortex (MPFC), medial temporal lobes (MTLs), and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)--implicated in episodic memory processing. Using seed regions from the functional connectivity maps, the DTI analysis revealed robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC). The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.

title: Structural and Functional Brain Networks: From Connections to Cognition
abstract: The human brain presents a puzzling and challenging paradox: Despite a fixed anatomy, characterized by its connectivity, its functional repertoire is vast, enabling action, perception, and cognition. This contrasts with organs like the heart that have a dynamic anatomy but just one function. The resolution of this paradox may reside in the brain's network architecture, which organizes local interactions to cope with diverse environmental demands—ensuring adaptability, robustness, resilience to damage, efficient message passing, and diverse functionality from a fixed structure. This review asks how recent advances in understanding brain networks elucidate the brain’s many-to-one (degenerate) function-structure relationships. In other words, how does diverse function arise from an apparently static neuronal architecture? We conclude that the emergence of dynamic functional connectivity, from static structural connections, calls for formal (computational) approaches to neuronal information processing that may resolve the dialectic between structure and function. Schematic of the multiscale hierarchical organization of brain networks. Brain function or cognition can be described as the global integration of local (segregated) neuronal operations that underlies hierarchical message passing among cortical areas, and which is facilitated by hierarchical modular network architectures. Advances Much of our understanding of brain connectivity rests on the way that it is measured and modeled. We consider two complementary approaches: the first has its basis in graph theory that aims to describe the network topology of (undirected) connections of the sort measured by noninvasive brain imaging of anatomical connections and functional connectivity (correlations) between remote sites. This is compared with model-based definitions of context-sensitive (directed) effective connectivity that are grounded in the biophysics of neuronal interactions. Recent topological network analyses of brain circuits suggest that modular and hierarchical structural networks are particularly suited for the functional integration of local (functionally specialized) neuronal operations that underlie cognition. Measurements of spontaneous activity reveal functional connectivity patterns that are similar to structural connectivity, suggesting that structural networks constrain functional networks. However, task-related responses that require context-sensitive integration disclose a divergence between function and structure that appears to rest mainly on long-range connections. In contrast to methods that describe network topology phenomenologically, model-based theoretical and computational approaches focus on the mechanisms of neuronal interactions that accommodate the dynamic reconfiguration of effective connectivity. We highlight the consilience between hierarchical topologies (based on structural and functional connectivity) and the effective connectivity that would be required for hierarchical message passing of the sort suggested by computational neuroscience. Outlook In summary, neuronal interactions represent dynamics on a fixed structural connectivity that underlie cognition and behavior. Such divergence of function from structure is, perhaps, the most intriguing property of the brain and invites intensive future research. By studying the dynamics and self-organization of functional networks, we may gain insight into the true nature of the brain as the embodiment of the mind. The repertoire of functional networks rests upon the (hidden) structural architecture of connections that enables hierarchical functional integration. Understanding these networks will require theoretical models of neuronal processing that underlies cognition. How rich functionality emerges from the invariant structural architecture of the brain remains a major mystery in neuroscience. Recent applications of network theory and theoretical neuroscience to large-scale brain networks have started to dissolve this mystery. Network analyses suggest that hierarchical modular brain networks are particularly suited to facilitate local (segregated) neuronal operations and the global integration of segregated functions. Although functional networks are constrained by structural connections, context-sensitive integration during cognition tasks necessarily entails a divergence between structural and functional networks. This degenerate (many-to-one) function-structure mapping is crucial for understanding the nature of brain networks. The emergence of dynamic functional networks from static structural connections calls for a formal (computational) approach to neuronal information processing that may resolve this dialectic between structure and function.

title: Segregated Systems of Human Brain Networks
abstract: The organization of the brain network enables its function. Evaluation of this organization has revealed that large-scale brain networks consist of multiple segregated subnetworks of interacting brain areas. Descriptions of resting-state network architecture have provided clues for understanding the functional significance of these segregated subnetworks, many of which correspond to distinct brain systems. The present report synthesizes accumulating evidence to reveal how maintaining segregated brain systems renders the human brain network functionally specialized, adaptable to task demands, and largely resilient following focal brain damage. The organizational properties that support system segregation are harmonious with the properties that promote integration across the network, but confer unique and important features to the brain network that are central to its function and behavior.

title: Cingulate-Precuneus Interactions: A New Locus of Dysfunction in Adult Attention-Deficit/Hyperactivity Disorder
abstract: Pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. On the basis of evidence that negative interactions between frontal foci involved in cognitive control and the non-goal-directed "default-mode" network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD.



Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers.



Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and precuneus/posterior cingulate cortex regions (p < .0004, corrected). Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex (p < 3 x 10(-11), corrected) and portions of posterior cingulate (p < .02, corrected).



Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD.

title: Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI
abstract: Recent functional imaging studies have revealed coactivation in a distributed network of cortical regions that characterizes the resting state, or default mode, of the human brain. Among the brain regions implicated in this network, several, including the posterior cingulate cortex and inferior parietal lobes, have also shown decreased metabolism early in the course of Alzheimer's disease (AD). We reasoned that default-mode network activity might therefore be abnormal in AD. To test this hypothesis, we used independent component analysis to isolate the network in a group of 13 subjects with mild AD and in a group of 13 age-matched elderly controls as they performed a simple sensory-motor processing task. Three important findings are reported. Prominent coactivation of the hippocampus, detected in all groups, suggests that the default-mode network is closely involved with episodic memory processing. The AD group showed decreased resting-state activity in the posterior cingulate and hippocampus, suggesting that disrupted connectivity between these two regions accounts for the posterior cingulate hypometabolism commonly detected in positron emission tomography studies of early AD. Finally, a goodness-of-fit analysis applied at the individual subject level suggests that activity in the default-mode network may ultimately prove a sensitive and specific biomarker for incipient AD.

title: Altered corticostriatal functional connectivity in obsessive-compulsive disorder.
abstract: Neurobiological models of obsessive-compulsive disorder (OCD) emphasize disturbances in the function and connectivity of brain corticostriatal networks, or "loops." Although neuroimaging studies of patients have supported this network model of OCD, very few have applied measurements that are sensitive to brain connectivity features.



Using resting-state functional magnetic resonance imaging, we tested the hypothesis that OCD is associated with disturbances in the functional connectivity of primarily ventral corticostriatal regions, measured from coherent spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal.



Case-control cross-sectional study.



Hospital referral OCD unit and magnetic resonance imaging facility.



A total of 21 patients with OCD (10 men, 11 women) and 21 healthy control subjects matched for age, sex, and estimated intelligence.



Voxelwise statistical parametric maps testing the strength of functional connectivity of 4 striatal seed regions of interest (dorsal caudate nucleus, ventral caudate/nucleus accumbens, dorsal putamen, and ventral putamen) with remaining brain areas.



For both groups, there was a clear distinction in the pattern of cortical connectivity of dorsal and ventral striatal regions, consistent with the notion of segregated motor, associative, and limbic corticostriatal networks. Between groups, patients with OCD had significantly increased functional connectivity along a ventral corticostriatal axis, implicating the orbitofrontal cortex and surrounding areas. The specific strength of connectivity between the ventral caudate/nucleus accumbens and the anterior orbitofrontal cortex predicted patients' overall symptom severity (r(2) = 0.57; P < .001). Additionally, patients with OCD showed evidence of reduced functional connectivity of the dorsal striatum and lateral prefrontal cortex, and of the ventral striatum with the region of the midbrain ventral tegmental area.



This study directly supports the hypothesis that OCD is associated with functional alterations of brain corticostriatal networks. Specifically, our findings emphasize abnormal and heightened functional connectivity of ventrolimbic corticostriatal regions in patients with OCD.

title: Activity and Connectivity of Brain Mood Regulating Circuit in Depression: A Functional Magnetic Resonance Study
abstract: Functional imaging studies indicate that imbalances in cortico-limbic activity and connectivity may underlie the pathophysiology of MDD. In this study, using functional Magnetic Resonance Imaging (fMRI), we investigated differences in cortico-limbic activity and connectivity between depressed patients and healthy controls.



Fifteen unmedicated unipolar depressed patients and 15 matched healthy subjects underwent fMRI during which they first completed a conventional block-design activation experiment in which they were exposed to negative and neutral pictures. Next, low frequency blood oxygenation dependent (BOLD) related fluctuations (LFBF) data were acquired at rest and during steady-state exposure to neutral, positive and negative pictures. LFBF correlations were calculated between anterior cingulate cortex (ACC) and limbic regions--amygdala (AMYG), pallidostriatum (PST) and medial thalamus (MTHAL) and used as a measure of cortico-limbic connectivity.



Depressed patients had increased activation of cortical and limbic regions. At rest and during exposure to neutral, positive, and negative pictures cortico-limbic LFBF correlations were decreased in depressed patients compared to healthy subjects.



The finding of increased activation of limbic regions and decreased LFBF correlations between ACC and limbic regions is consistent with the hypothesis that decreased cortical regulation of limbic activation in response to negative stimuli may be present in depression.

title: Functional and Structural Connectivity Between the Perigenual Anterior Cingulate and Amygdala in Bipolar Disorder
abstract: Abnormalities in the morphology and function of two gray matter structures central to emotional processing, the perigenual anterior cingulate cortex (pACC) and amygdala, have consistently been reported in bipolar disorder (BD). Evidence implicates abnormalities in their connectivity in BD. This study investigates the potential disruptions in pACC-amygdala functional connectivity and associated abnormalities in white matter that provides structural connections between the two brain regions in BD.



Thirty-three individuals with BD and 31 healthy comparison subjects (HC) participated in a scanning session during which functional magnetic resonance imaging (fMRI) during processing of face stimuli and diffusion tensor imaging (DTI) were performed. The strength of pACC-amygdala functional connections was compared between BD and HC groups, and associations between these functional connectivity measures from the fMRI scans and regional fractional anisotropy (FA) from the DTI scans were assessed.



Functional connectivity was decreased between the pACC and amygdala in the BD group compared with HC group, during the processing of fearful and happy faces (p < .005). Moreover, a significant positive association between pACC-amygdala functional coupling and FA in ventrofrontal white matter, including the region of the uncinate fasciculus, was identified (p < .005).



This study provides evidence for abnormalities in pACC-amygdala functional connectivity during emotional processing in BD. The significant association between pACC-amygdala functional connectivity and the structural integrity of white matter that contains pACC-amygdala connections suggest that disruptions in white matter connectivity may contribute to disturbances in the coordinated responses of the pACC and amygdala during emotional processing in BD.

title: Overall brain connectivity maps show cortico‐subcortical abnormalities in schizophrenia
abstract: Abnormal interactions between areas of the brain have been pointed as possible causes for schizophrenia. However, the nature of these disturbances and the anatomical location of the regions involved are still unclear. Here, we describe a method to estimate maps of net levels of connectivity in the resting brain, and we apply it to look for differential patterns of connectivity in schizophrenia. This method uses partial coherences as a basic measure of covariability, and it minimises the effect of major physiological noise. When overall (net) connectivity maps of a sample of 40 patients with schizophrenia were compared with the maps from a matched sample of 40 controls, a single area of abnormality was found. It is an area of patient hyper‐connectivity and is located frontally, in medial and orbital structures, clearly overlapping the anterior node of the default mode network (DMN). When this area is used as a region of interest in a second‐level analysis, it shows functional hyper‐connections with several cortical and subcortical structures. Interestingly, the most significant abnormality is found with the caudate, which has a bilateral pattern of abnormality, pointing to a possible DMN–striatum deviant relation in schizophrenia. However, hyper‐connectivity observed with other regions (right hippocampus and amygdala, and other cortical structures) suggests a more pervasive alteration of brain connectivity in this disease.

title: Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder.
abstract: Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD.



To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD.



Cross-sectional study.



Academic medical center.



Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.



Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry.



Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network.



Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

title: Amygdala and ventrolateral prefrontal cortex function during anticipated peer evaluation in pediatric social anxiety.
abstract: Amygdala and ventrolateral prefrontal cortex (vlPFC) dysfunction manifests in adolescents with anxiety disorders when they view negatively valenced stimuli in threatening contexts. Such fear-circuitry dysfunction may also manifest when anticipated social evaluation leads socially anxious adolescents to misperceive peers as threatening.



To determine whether photographs of negatively evaluated smiling peers viewed during anticipated social evaluation engage the amygdala and vlPFC differentially in adolescents with and without social anxiety.



Case-control study.



Government clinical research institute.



Fourteen adolescents with anxiety disorders associated with marked concerns of social evaluation and 14 adolescents without a psychiatric diagnosis matched on sex, age, intelligence quotient, and socioeconomic status.



Blood oxygenation level-dependent signal measured with event-related functional magnetic resonance imaging. Before and during neuroimaging scans, participants anticipating social evaluation completed peer- and self-appraisals. Event-related analyses were tailored to participants' ratings of specific peers.



Participants classified 40 pictures of same-age peers as ones with whom they did or did not want to engage in a social interaction. Anxious adolescents showed greater amygdala activation than healthy adolescents when anticipating evaluation from peers previously rated as undesired for an interaction. Psychophysiological interaction connectivity analyses also revealed a significant positive association between amygdala and vlPFC activation in anxious vs healthy adolescents in response to these stimuli.



Anticipating social evaluation from negatively perceived peers modulates amygdala and vlPFC engagement differentially in anxious and healthy adolescents. Amygdala and vlPFC dysfunction manifests in adolescent anxiety disorders in specific contexts of anticipated peer evaluation.

title: Altered default mode network activity in patient with anxiety disorders: an fMRI study.
abstract: Anxiety disorder, a common mental disorder in our clinical practice, is characterized by unprovoked anxiety. Medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC), which closely involved in emotional processing, are critical regions in the default mode network. We used functional magnetic resonance imaging (fMRI) to investigate whether default mode network activity is altered in patients with anxiety disorder. Ten anxiety patients and 10 healthy controls underwent fMRI while listening to emotionally neutral words alternating with rest (Experiment 1) and threat-related words alternating with emotionally neutral words (Experiment 2). In Experiment 1, regions of deactivation were observed in patients and controls. In Experiment 2, regions of deactivation were observed only in patients. The observed deactivation patterns in the two experiments, which included MPFC, PCC, and inferior parietal cortex, were similar and consistent with the default model network. Less deactivation in MPFC and greater deactivation in PCC were observed for patients group comparing to controls in Experiment 1. Our observations suggest that the default model network is altered in anxiety patients and dysfunction in MPFC and PCC may play an important role in anxiety psychopathology.

title: Disentangling the web of fear: Amygdala reactivity and functional connectivity in spider and snake phobia
abstract: The objective was to study effects of fear on brain activity, functional connectivity and brain-behavior relationships during symptom provocation in subjects with specific phobia. Positron emission tomography (PET) and (15)O water was used to measure regional cerebral blood flow (rCBF) in 16 women phobic of either snakes or spiders but not both. Subjects watched pictures of snakes and spiders serving either as phobic or fear-relevant, but non-phobic, control stimuli depending on phobia type. Presentation of phobic as compared with non-phobic cues was associated with increased activation of the right amygdala and cerebellum as well as the left visual cortex and circumscribed frontal areas. Activity decreased in the prefrontal, orbitofrontal and ventromedial cortices as well as in the primary somatosensory cortex and auditory cortices. Furthermore, amygdala activation correlated positively with the subjective experience of distress. Connectivity analyses of activity in the phobic state revealed increased functional couplings between voxels in the right amygdala and the periamygdaloid area, fusiform gyrus and motor cortex. During non-phobic stimulation, prefrontal activity correlated negatively with amygdala rCBF, suggesting a phobia-related functional decoupling. These results suggest that visually elicited phobic reactions activate object recognition areas and deactivate prefrontal areas involved in cognitive control over emotion-triggering areas like the amygdala, resulting in motor readiness to support fight or flight.

title: Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder
abstract: Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment. Although the amygdala has a central role in perception and processing of threatening cues, little is known about the involved networks and corresponding dysfunctions in social anxiety. Therefore, this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways. Ten patients with anxiety disorders (social and/or panic) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state. Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region. Group comparisons were done by random-effects analysis in SPM. Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus. The strength of this functional connectivity showed a negative association with the severity of state anxiety. In addition, an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group. Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder. Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing.

title: The impact of passive hyperthermia on human attention networks: An fMRI study
abstract: An attention network test (ANT) provides a behavioral measure of the efficiency of the three attention networks (alerting, orienting and executive networks) within a single task. In the present study, we investigated the effect of passive hyperthermia on the attention network with event-related functional magnetic resonance imaging (fMRI). The behavioral results showed that passive hyperthermia of 50 °C and 40% relative humidity impaired the executive function, but showed no effect on the alerting and orienting networks. The fMRI results showed that: (i) passive hyperthermia enhanced the activity in the right superior frontal gyrus and depressed the activity in the right middle occipital gyrus, left inferior parietal lobule and left culmen in the alerting network, (ii) passive hyperthermia enhanced the activity in the temporal lobe and depressed the activity in the frontal lobe, parietal lobe and occipital lobe in the orienting network, and (iii) passive hyperthermia enhanced the activity in the dorsolateral prefrontal cortex but did not affect the activity in the anterior cingulate. We concluded that passive hyperthermia impaired executive function, especially the efficiency of resolving conflict and the negative effects of passive hyperthermia on alerting and orienting were overcome through variant regional brain activation.

title: The AttentionTrip: A game-like tool for measuring the networks of attention
abstract: Recognizing that attention is not a unitary system, the Attention Network Test (ANT) and its variants were developed to measure the efficacy of the multiple components of attention. One potential weakness of these tests (ANTs) is that they are unengaging. This poses a problem when particular groups are tested (e.g., young children), when more stable measures of performance are desirable (and can only be achieved in longer testing sessions) and when repeated testing is necessary.


NEW METHOD
Here we describe the evolution of a game-like tool, which we call the AttentionTrip©, that is suitable for investigating three isolable attentional networks (alerting, orienting, and executive functions).



Utilizing this tool we were able to generate reasonable network scores for alerting, executive control (from both the flanker and Simon effects), endogenous orienting and, after some motivated modifications, exogenous orienting.


COMPARISON WITH EXISTING METHOD(S)
Split-half reliabilities of the alerting and executive (flanker) network scores were considerably higher than those reported by MacLeod et al. (2010) in their psychometric review of the ANT. Informal observations (e.g., some participants asking if they could keep doing the task when their session was over) suggesting that the AttentionTrip is considerably more engaging than the traditional ANT have been confirmed in a head-to-head comparison (Vallis & Klein, 2016).



The AttentionTrip@ is available now for research purposes. A tablet version, which will have greater clinical utility, is under development.

title: The attention system of the human brain: 20 years after.
abstract: Here, we update our 1990 Annual Review of Neuroscience article, "The Attention System of the Human Brain." The framework presented in the original article has helped to integrate behavioral, systems, cellular, and molecular approaches to common problems in attention research. Our framework has been both elaborated and expanded in subsequent years. Research on orienting and executive functions has supported the addition of new networks of brain regions. Developmental studies have shown important changes in control systems between infancy and childhood. In some cases, evidence has supported the role of specific genetic variations, often in conjunction with experience, that account for some of the individual differences in the efficiency of attentional networks. The findings have led to increased understanding of aspects of pathology and to some new interventions.

title: Attention and executive functions in remitted major depression patients.
abstract: Although deficits in attention and executive functions in patients with Major Depressive Disorder (MDD) are well confirmed [Veiel, H.O.F., 1997. A preliminary profile of neuropsychological deficits associated with major depression.  The database regarding the relationship between impairments and the duration of disease or the number of episodes is inconsistent. Furthermore, the role of long-term cognitive impairments in MDD during remitted state is not well understood [Elliott, R., 2002. The neuropsychological profile in primary depression. Taylor and Francis, London, pp. 273-293.]. There is consequently a lack of studies accounting for different courses of illness in the euthymic state and considering the influence of possible attentional deficits on executive performance.



40 euthymic patients with MDD diagnosis according to DSM-IV (20 patients with 1-2 episodes and 20 severe depressives with at least three episodes) as well as 20 healthy controls matched for education and age were administered three tests for attention (attentional shift, Stroop task, sustained attention) and three for executive functions (BADS, word fluency, memory span). The methods selected were theory based with regard to an involvement of frontal-subcortical networks in MDD, attention, and executive functions, respectively.



Euthymic patients with MDD showed deficits in all tests related to attentional and executive functions compared to healthy controls. The patient groups did not differ with regard to attentional performance. Executive functions in severe depressives were more impaired than in mild depressives.



Differing performances of the patient groups in the subtests of the executive test battery (BADS) can only be interpreted to a limited extent.



The results support the assumption that deficits in attention and executive functions in MDD show an increase in trait character and executive function during chronic course. Implications for differential diagnosis and cognitive psychotherapy are discussed.

title: Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder.
abstract: Attention-deficit/hyperactivity disorder (ADHD) has been associated with structural alterations in brain networks influencing cognitive and motor behaviors. Volumetric studies in children identify abnormalities in cortical, striatal, callosal, and cerebellar regions. In a prior volumetric study, we found that ADHD adults had significantly smaller overall cortical gray matter, prefrontal, and anterior cingulate volumes than matched controls. Thickness and surface area are additional indicators of integrity of cytoarchitecture in the cortex. To expand upon our earlier results and further refine the regions of structural abnormality, we carried out a structural magnetic resonance imaging study of cortical thickness in the same sample of adults with ADHD (n = 24) and controls (n = 18), hypothesizing that the cortical networks underlying attention and executive function (EF) would be most affected. Compared with healthy adults, adults with ADHD showed selective thinning of cerebral cortex in the networks that subserve attention and EF. In the present study, we found significant cortical thinning in ADHD in a distinct cortical network supporting attention especially in the right hemisphere involving the inferior parietal lobule, the dorsolateral prefrontal, and the anterior cingulate cortices. This is the first documentation that ADHD in adults is associated with thinner cortex in the cortical networks that modulate attention and EF.

title: Separable Learning Systems in the Macaque Brain and the Role of Orbitofrontal Cortex in Contingent Learning
abstract: Orbitofrontal cortex (OFC) is widely held to be critical for flexibility in decision-making when established choice values change. OFC's role in such decision making was investigated in macaques performing dynamically changing three-armed bandit tasks. After selective OFC lesions, animals were impaired at discovering the identity of the highest value stimulus following reversals. However, this was not caused either by diminished behavioral flexibility or by insensitivity to reinforcement changes, but instead by paradoxical increases in switching between all stimuli. This pattern of choice behavior could be explained by a causal role for OFC in appropriate contingent learning, the process by which causal responsibility for a particular reward is assigned to a particular choice. After OFC lesions, animals' choice behavior no longer reflected the history of precise conjoint relationships between particular choices and particular rewards. Nonetheless, OFC-lesioned animals could still approximate choice-outcome associations using a recency-weighted history of choices and rewards.

title: Roles of Medial Prefrontal Cortex and Orbitofrontal Cortex in Self-evaluation
abstract: Empirical investigations of the relation of frontal lobe function to self-evaluation have mostly examined the evaluation of abstract qualities in relation to self versus other people. The present research furthers our understanding of frontal lobe involvement in self-evaluation by examining two processes that have not been widely studied by neuroscientists: on-line self-evaluations and correction of systematic judgment errors that influence self-evaluation. Although people evaluate their abstract qualities, it is equally important that perform on-line evaluations to assess the success of their behavior in a particular situation. In addition, self-evaluations of task performance are sometimes overconfident because of systematic judgment errors. What role do the neural regions associated with abstract self-evaluations and decision bias play in on-line evaluation and self-evaluation bias? In this fMRI study, self-evaluation in two reasoning tasks was examined; one elicited overconfident self-evaluations of performance because of salient but misleading aspects of the task and the other was free from misleading aspects. Medial PFC (mPFC), a region associated with self-referential processing, was generally involved in on-line self-evaluations but not specific to accurate or overconfident evaluation. Orbitofrontal cortex (OFC) activity, a region associated with accurate nonsocial judgment, negatively predicted individual differences in overconfidence and was negatively associated with confidence level for incorrect trials.

title: Alterations in cognitive performance during passive hyperthermia are task dependent
abstract: The objectives of this study were to (1) assess the effect of passive heating upon attention and memory task performance, and (2) evaluate the effectiveness of the application of cold packs to the head on preserving these functions. Using a counter-balance design 16 subjects underwent three trials: a control (CON, 20°C, 40% rH), hot (HOT, 50°C, 50% rH) and hot with the head kept cool (HHC). In each condition, three attention tests and two memory tests were performed. Mean core, forehead and tympanic temperatures were all significantly higher (p < 0.05) during HOT (38.6° ± 0.1°, 39.6° ± 0.2° and 38.8° ± 0.1°C, respectively) and HHC (38° ± 0.2, 37.7° ± 0.3° and 37.7°C, respectively) than in CON (37.1° ± 0.6°, 33.3° ± 0.2° and 35.9° ± 0.3°C, respectively). Results indicate that there was impairment in working memory with heat exposure (p < 0.05) without alteration in attentional processes. The regular application of cold packs only prevented the detrimental effect of hyperthermia on short-term memory. Our results show that impairments in cognitive function with passive hyperthermia and the beneficial effect of head cooling are task dependent and suggests that exposure to a hot environment is a competing variable to the cognitive processes.

title: Hyperthermia impairs short-term memory and peripheral motor drive transmission
abstract: The aims of this study were to determine (i) the effect of passive hyperthermia on motor drive and cognitive function, and (ii) whether head cooling can limit the hyperthermia‐induced alterations. Sixteen subjects were randomly exposed for 2 h to three different conditions: control (Con, 20°C), hot (Hot, 50°C) and hot head cool (HHC – where cold packs were applied to the head under Hot conditions). Three cognitive tests measuring attention and two measuring memory were performed. Neuromuscular testing included electrically evoked muscle action potentials (M‐waves) and reflex waves (H‐reflex) at rest and during brief (4–5 s) and sustained (120 s) maximal voluntary contractions (MVC) of the plantar flexors. All the tests were performed in the environmental room. During brief MVC, torque was significantly lower in both Hot and HHC as compared to Con (P < 0.05). The decrease in muscle activation was significant in Hot (P < 0.05) but not in HBC (P= 0.07). This was accompanied by peripheral failures in the transmission of the neural drive at both spinal (significant decrements in H‐reflexes and V‐waves, P < 0.05) and neuromuscular junction (significant decrements in M‐waves, P < 0.05) levels. During sustained MVC, muscle activation was further depressed (P < 0.05) without any concomitant failures in M‐waves, suggesting neural activation adjustments occurring probably at the supraspinal level. Cerebral perturbations were confirmed by significant decrements in both memory tests in Hot as compared with Con (P < 0.05) but not in simple tests (attention tests) that were not affected by hyperthermia. The decrement in memory capacity suggested the existence of frontal lobe activity impairments. Thus, HHC preserved memory capacity but not the visual memory.

title: Altered topological patterns of large-scale brain functional networks during passive hyperthermia
abstract: In this study, we simulated environmental heat exposure to 18 participants, and obtained functional magnetic resonance image (fMRI) data during resting state. Brain functional networks were constructed over a wide range of sparsity threshold according to a prior atlas dividing the whole cerebrum into 90 regions. Results of graph theoretical approaches showed that although brain networks in both normal and hyperthermia conditions exhibited economical small-world property, significant alterations in both global and nodal network metrics were demonstrated during hyperthermia. Specifically, a lower clustering coefficient, maintained shortest path length, a lower small-worldness, a lower mean local efficiency were found, indicating a tendency shift to a randomized network. Additionally, significant alterations in nodal efficiency were found in bilateral gyrus rectus, bilateral parahippocampal gyrus, bilateral insula, right caudate nucleus, bilateral putamen, left temporal pole of middle temporal gyrus, right inferior temporal gyrus. In consideration of physiological system changes, we found that the alterations of normalized clustering coefficient, small-worldness, mean normalized local efficiency were significantly correlated with the rectal temperature alteration, but failed to obtain significant correlations with the weight loss. More importantly, behavioral attention network test (ANT) after MRI scanning showed that the ANT effects were altered and correlated with the alterations of some global metrics (normalized shortest path length and normalized global efficiency) and prefrontal nodal efficiency (right dorsolateral superior frontal gyrus, right middle frontal gyrus and left orbital inferior frontal gyrus), implying behavioral deficits in executive control effects and maintained alerting and orienting effects during passive hyperthermia. The present study provided the first evidence for human brain functional disorder during passive hyperthermia according to graph theoretical analysis using resting-state fMRI.

title: Disturbed resting state EEG synchronization in bipolar disorder: A graph-theoretic analysis☆
abstract: Disruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity.

title: Effects of short-term environmental hyperthermia on patterns of cerebral blood flow
abstract: Environmental hyperthermia is a very common risk factor for many occupations, however, its potential influences on cerebral circulation remain obscure. In this study, 20 participants underwent two simulated environmental thermal conditions (50 °C/25 °C, 1 h), and their cerebral blood flows (CBFs) were quantified using a pseudo-continuous arterial spin labeling (ASL) MR imaging. During the experiment, the physiological parameters, including rectal temperature, arterial blood pressure and weight loss, heart rate and respiration rate, were recorded, and a visual analog scale (VAS) test was performed during both conditions to evaluate the psychological state including vigilance, anxiety, vigor, confidence, anger, nervousness, drowsiness, and loquacity. After scanning, a highly-demanding attentional task--the psychomotor vigilance test (PVT) was performed for behavioral performance evaluation. Compared with that during normothermic condition, the global CBF (gCBF) during hyperthermic condition showed a tendency of decrease, but no significant differences. Regional CBFs (rCBFs) were significantly altered mainly in the prefrontal cortex, somatosensory areas and limbic system. Physiological detection revealed significantly decreased diastolic pressure and systolic pressure and accelerated respiration rate. Furthermore, linear multivariate regression analysis showed that altered rCBFs in several regions could be predicted by physiological (systolic pressure, rectal temperature) and psychological (vigilance, drowsiness, nervousness, anger) changes. And PVT revealed significantly slower attentional reaction during hyperthermia, and the longer reaction time was correlated with the altered rCBF in the left dorsolateral prefrontal cortex (DLPFC). These findings suggested that during short-term hyperthermia gCBF might remain relatively stable under the integrated effect of physiological changes and cerebral auto-regulation, rather than decreased solely dependently on hyperthermia-induced physiological changes. Furthermore, altered regional blood distribution might be accounted for neural activity of thermal sensation and regulation, mood state and cognitive changes.

title: Heat stress reduces cerebral blood velocity and markedly impairs orthostatic tolerance in humans.
abstract: Orthostatic tolerance is reduced in the heat-stressed human. This study tested the following hypotheses: 1) whole body heat stress reduces cerebral blood velocity (CBV) and increases cerebral vascular resistance (CVR); and 2) reductions in CBV and increases in CVR in response to an orthostatic challenge will be greater while subjects are heat stressed. Fifteen subjects were instrumented for measurements of CBV (transcranial ultrasonography), mean arterial blood pressure (MAP), heart rate, and internal temperature. Whole body heating increased both internal temperature (36.4+/-0.1 to 37.3+/-0.1 degrees C) and heart rate (59+/-3 to 90+/-3 beats/min); P<0.001. Whole body heating also reduced CBV (62+/-3 to 53+/-2 cm/s) primarily via an elevation in CVR (1.35+/-0.06 to 1.63+/-0.07 mmHg.cm-1.s; P<0.001. A subset of subjects (n=8) were exposed to lower-body negative pressure (LBNP 10, 20, 30, 40 mmHg) in both normothermic and heat-stressed conditions. During normothermia, LBNP of 30 mmHg (highest level of LBNP achieved by the majority of subjects in both thermal conditions) did not significantly alter CBV, CVR, or MAP. During whole body heating, this LBNP decreased MAP (81+/-2 to 75+/-3 mmHg), decreased CBV (50+/-4 to 39+/-1 cm/s), and increased CVR (1.67+/-0.17 to 1.92+/-0.12 mmHg.cm-1.s); P<0.05. These data indicate that heat stress decreases CBV, and the reduction in CBV for a given orthostatic challenge is greater during heat stress. These outcomes reduce the reserve to buffer further decreases in cerebral perfusion before presyncope. Increases in CVR during whole body heating, coupled with even greater increases in CVR during orthostasis and heat stress, likely contribute to orthostatic intolerance.

title: Cerebrovascular and corticomotor function during progressive passive hyperthermia in humans.
abstract: The present study examined the integrative effects of passive heating on cerebral perfusion and alterations in central motor drive. Eight participants underwent passive hyperthermia [0.5°C increments in core temperature (Tc) from normothermia (37 ± 0.3°C) to their limit of thermal tolerance (T-LIM; 39.0 ± 0.4°C)]. Blood flow velocity in the middle cerebral artery (CBFv) and respiratory responses were measured continuously. Arterial blood gases and blood pressure were obtained intermittently. At baseline and each Tc level, supramaximal femoral nerve stimulation and transcranial magnetic stimulation (TMS) were performed to assess neuromuscular and cortical function, respectively. At T-LIM, measures were (in a randomized order) also made during a period of breathing 5% CO(2) gas to restore eucapnia (+5% CO(2)). Mean heating time was 179 ± 51 min, with each 0.5°C increment in Tc taking 40 ± 10 min. CBFv was reduced by ∼20% below baseline from +0.5°C until T-LIM. Maximal voluntary contraction (MVC) of the knee extensors was decreased at T-LIM (-9 ± 10%; P < 0.05), and cortical voluntary activation (VA), assessed by TMS, was decreased at +1.5°C and T-LIM by 11 ± 8 and 22 ± 23%, respectively (P < 0.05). Corticospinal excitability (measured as the EMG response produced by TMS) was unaltered. Reductions in cortical VA were related to changes in ventilation (Ve; R(2) = 0.76; P < 0.05) and partial pressure of end-tidal CO(2) (Pet(CO(2)); R(2) = 0.63; P < 0.05) and to changes in CBFv (R(2) = 0.61; P = 0.067). Interestingly, although CBFv was not fully restored, MVC and cortical VA were restored towards baseline values during inhalation of 5% CO(2). These results indicate that descending voluntary drive becomes progressively impaired as Tc is increased, presumably due, in part, to reductions in CBFv and to hyperthermia-induced hyperventilation and subsequent hypocapnia.

title: Reductions in cerebral blood flow during passive heat stress in humans: partitioning the mechanisms
abstract: Heat stress reduces brain blood flow and impairs orthostatic tolerance. Brain blood flow is largely controlled by the partial pressure of arterial . Indeed, hyperthermia‐induced over‐breathing and related reductions in arterial account for ∼50% of the reduction in brain blood flow. This investigation tested the unique hypothesis that the distribution of cardiac output during heat stress (challenged by thermoregulatory increases in skin blood flow and sweat loss) contributes to the remaining 50%. We show that cardiac output is not related to brain blood flow, but rather arterial plays a much larger role than previously suggested. These findings help us understand the mechanisms relating heat stress with an increased likelihood of fainting, and are also relevant to pathological conditions that are accompanied by elevations in body temperature.

title: Cerebral Autoregulation: An Overview of Current Concepts and Methodology with Special Focus on the Elderly
abstract: Cerebral autoregulation (CA) refers to the properties of the brain vascular bed to maintain cerebral perfusion despite changes in blood pressure (BP). Whereas classic studies have assessed CA during changes in BP that have a gradual onset, dynamic studies quantify the fast modifications in cerebral blood flow (CBF) in relation to rapid alterations in BP. There is a lack of standardization in the assessment of dynamic CA. This review provides an overview of the methods that have been applied, with special focus on the elderly. We will discuss the relative merits and shortcomings of these methods with regard to the aged population. Furthermore, we summarize the effects of variability in BP on CBF in older people. Of the various dynamic assessments of CA, a single sit-to-stand procedure is a feasible and physiologic method in the elderly. The collection of spontaneous beat-to-beat changes in BP and CBF allows estimation of CA using the technique of transfer function analysis. A thorough search of the literature yielded eight studies that have measured dynamic CA in the elderly aged <75 years. Regardless of the methods used, it was concluded from these studies that CA was preserved in this population.

title: Sleep under extreme environments: Effects of heat and cold exposure, altitude, hyperbaric pressure and microgravity in space
abstract: Human sleep is sensitive to the individual's environment. The present review examines current knowledge of human sleep patterns under different environments: heat exposure, cold exposure, altitude, high pressure and microgravity in space. Heat exposure has two effects. In people living in temperate conditions, moderate heat loads (hot bath, sauna) prior to sleep provoke a delayed reaction across time (diachronic reaction) whereby slow-wave sleep (SWS) augments in the following night (neurogenic adaptive pathway). Melanoids and Caucasians living in the Sahel dry tropical climate experience diachronic increases in SWS throughout seasonal acclimatization. Such increases are greater during the hot season, being further enhanced after daytime exercise. On the contrary, when subjects are acutely exposed to heat, diachronic decreases in total sleep time and SWS occur, being often accompanied by synchronic (concomitant) diminution in REM sleep. Stress hormones increase. Nocturnal cold exposure provokes a synchronic decrease in REM sleep along with an activation of stress hormones (synchronic somatic reaction). SWS remains undisturbed as it still occurs at the beginning of the night before nocturnal body cooling. Altitude and high pressure are deleterious to sleep, especially in non-acclimatized individuals. In their controlled environment, astronauts can sleep well in microgravity. Exercise-induced sleep changes help to understand environmental effects on sleep: well-tolerated environmental strains may improve sleep through a neurogenic adaptive pathway; when this "central" adaptive pathway is overloaded or bypassed, diachronic and synchronic sleep disruptions occur.

title: Metabolism and thermoregulation during stages of sleep in humans exposed to heat and cold.
abstract: Electrophysiological stages of sleep, oxygen consumption (VO2), and skin (Tsk) and rectal (Tre) temperatures were recorded from six virtually naked male subjects exposed to ambient temperatures (Ta) of 21, 24, 29, 34, and 37 degrees C. VO2 increased during sleep as a whole as Ta departed from thermoneutrality (29 degrees C) and was significantly greater during rapid-eye-movement (REM) sleep than during adjacent nonrapid-eye-movement (NREM) periods at low and high Ta but not at 29 degrees C. Tsk showed small but significant increases during REM sleep at 29, 34, and 37 degrees C, but Tre did not change during REM sleep at any Ta. Shivering was present during wakefulness at 21 and 24 degrees C but occurred only occasionally during stages 1 and 2 sleep at 21 degrees C. The increases in VO2 and the absence of marked changes in vasomotor tone during REM sleep in the cold were unexpected and possibly indicate that REM sleep is not as thermally disruptive in humans as in other mammals.

title: Variations in evaporation and body temperatures during sleep in man.
abstract: The thermal balance in man was investigated during nocturnal sleep in neutral and warm environments (from 32 to 39.5 degrees C, 45%rh). Changes of body temperatures and skin evaporation were continuously monitored throughout the whole night. In neutral conditions (32 and 34 degrees C) body temperature and skin evaporation decreased during the night, following the circadian rhythm deltaT sk = -0.34 degrees C; deltaT re = -0.52 degrees C;deltaE = -12 W-m-2. In warm conditions, body temperatures and evaporation remained steady. Marked fluctuations of body temperatures and evaporation occurred synchronously with the rapid eye movement (REM) periods. Each REM period induced phasic increase of Tsk reaching +2 degrees C in some cases, with a cessation of evaporation. Tre showed upward and downward rhythmical waves synchronously with REM sleep occurrence. The nocturnal variations of thermal balance were characterized by two rhythms: a basal circadian rhythm and superimposed on it a rhythm conditioned by occurrence of REM sleep every 80-90 min. The phasic changes of body temperatures and evaporation only appeared with REM's. The results suggest that the nervous integrative function conditioning the patterns of sleep, conditions also the phasic cyclic changes of thermoregulatory function.

title: Body movements of the elderly during sleep and thermal conditions in bedrooms in summer.
abstract: The frequency of body movement in the elderly and young people during sleep was measured in order to investigate the effect of hot thermal environments on sleep in summer. Simultaneously, room temperature and humidity were also measured. In the morning after measuring body movements, the subjects completed a questionnaire about their night's sleep. The results obtained were as follows: 1) The time of going to bed and rising in the elderly was significantly earlier than the young. 2) The elderly had a tendency to judge their sleep as "good", however, there were no significant differences between the two groups. 3) The room temperature for the elderly during sleep ranged from 25 to 28 degrees C (mean 26.5 degrees C). On the other hand, it was between 20 and 30 degrees C (mean 27.1 degrees C) in the young, which was significantly higher than that of the elderly. 4) Body movement in the elderly during sleep was significantly greater than those in the young. 5) A significant relation between body movement and room temperature was found within each group. Under conditions of less than 28 degrees C of room temperature, there were significantly higher rates of body movement in the elderly.

title: Effects of thermal environment on sleep and circadian rhythm
abstract: The thermal environment is one of the most important factors that can affect human sleep. The stereotypical effects of heat or cold exposure are increased wakefulness and decreased rapid eye movement sleep and slow wave sleep. These effects of the thermal environment on sleep stages are strongly linked to thermoregulation, which affects the mechanism regulating sleep. The effects on sleep stages also differ depending on the use of bedding and/or clothing. In semi-nude subjects, sleep stages are more affected by cold exposure than heat exposure. In real-life situations where bedding and clothing are used, heat exposure increases wakefulness and decreases slow wave sleep and rapid eye movement sleep. Humid heat exposure further increases thermal load during sleep and affects sleep stages and thermoregulation. On the other hand, cold exposure does not affect sleep stages, though the use of beddings and clothing during sleep is critical in supporting thermoregulation and sleep in cold exposure. However, cold exposure affects cardiac autonomic response during sleep without affecting sleep stages and subjective sensations. These results indicate that the impact of cold exposure may be greater than that of heat exposure in real-life situations; thus, further studies are warranted that consider the effect of cold exposure on sleep and other physiological parameters.

title: The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults
abstract: Inflammatory cytokines are released in response to stress, tissue damage, and infection. Acutely, this response is adaptive; however, chronic elevation of inflammatory proteins can contribute to health problems including cardiovascular, endocrine, mood, and sleep disorders. Few studies have examined how sleep deprivation acutely affects inflammatory markers, which was the aim of the current study. Nineteen healthy men and women aged 28.05+/-8.56 (mean+/-SD) were totally sleep deprived for 40 h under constant routine conditions. Pro-inflammatory markers: intracellular adhesion molecule-1 (ICAM-1), E-selectin, vascular adhesion molecule-1 (VCAM-1), c-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), and the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) were assayed in plasma. Daytime levels during baseline (hours 1-15 of scheduled wakefulness) were compared to daytime levels during sleep deprivation (hours 25-39 of scheduled wakefulness), thus controlling for circadian phase within an individual. Repeated measures ANOVA with planned comparisons showed that 40 h of total sleep deprivation induced a significant increase in E-selectin, ICAM-1, IL-1beta, and IL-1ra, a significant decrease in CRP and IL-6, and no significant change in VCAM-1. Alterations in circulating levels of pro- and anti-inflammatory cytokines and cell adhesion molecules during sleep deprivation were consistent with both increased and decreased inflammation. These findings suggest that one night of sleep loss triggers a stress response that includes stimulation of both pro- and anti-inflammatory proteins in the healthy young subjects tested under our experimental conditions.

title: The human emotional brain without sleep — a prefrontal amygdala disconnect
abstract: Sleep deprivation is known to impair a range of functions, including immune regulation and metabolic control, as well as neurocognitive processes, such as learning and memory . But evidence for the role of sleep in regulating our emotional brain-state is surprisingly scarce, and while the dysregulation of affective stability following sleep loss has received subjective documentation [2,3], any neural examination remains absent. Clinical evidence suggests that sleep and emotion interact; nearly all psychiatric and neurological disorders expressing sleep disruption display corresponding symptoms of affective imbalance . Independent of sleep, knowledge of the basic neural and cognitive mechanisms regulating emotion is remarkably advanced. The amygdala has a well-documented role in the processing of emotionally salient information, particularly aversive stimuli [5,6]. The extent of amygdala engagement can also be influenced by a variety of connected systems, particularly the medial-prefrontal cortex (MPFC); the MPFC is proposed to exert an inhibitory, top-down control of amygdala function, resulting in contextually appropriate emotional responses [5,6]. We have focused on this network and using functional magnetic resonance image (fMRI) have obtained evidence, reported here, that a lack of sleep inappropriately modulates the human emotional brain response to negative aversive stimuli (see Supplemental data available on-line with this issue).

title: Does improving sleep lead to better mental health? A protocol for a meta-analytic review of randomised controlled trials
abstract: Sleep and mental health go hand-in-hand, with many, if not all, mental health problems being associated with problems sleeping. Although sleep has been traditionally conceptualised as a secondary consequence of mental health problems, contemporary views prescribe a more influential, causal role of sleep in the formation and maintenance of mental health problems. One way to evaluate this assertion is to examine the extent to which interventions that improve sleep also improve mental health.  Randomised controlled trials (RCTs) describing the effects of interventions designed to improve sleep on mental health will be identified via a systematic search of four bibliographic databases (in addition to a search for unpublished literature). Hedges’ g and associated 95% CIs will be computed from means and SDs where possible. Following this, meta-analysis will be used to synthesise the effect sizes from the primary studies and investigate the impact of variables that could potentially moderate the effects. The Jadad scale for reporting RCTs will be used to assess study quality and publication bias will be assessed via visual inspection of a funnel plot and Egger’s test alongside Orwin’s fail-safe n. Finally, mediation analysis will be used to investigate the extent to which changes in outcomes relating to mental health can be attributed to changes in sleep quality. Ethics and dissemination This study requires no ethical approval. The findings will be submitted for publication in a peer-reviewed journal and promoted to relevant stakeholders.

title: Insomnia, worry, anxiety and depression as predictors of the occurrence and persistence of paranoid thinking
abstract: PurposeOur theoretical model proposes that insomnia, worry, and negative affect are important determinants of paranoid thinking. Anxiety produces anticipation of threat, depression increases the sense of vulnerability, worry leads to implausible ideas, and insomnia exacerbates negative affect and creates an altered perceptual state. The study objective was to examine for the first time these factors as predictors of the onset of new paranoid thinking and of the persistence of existing paranoid thinking.MethodA total of 2,382 participants in the 2000 British National Psychiatric Morbidity Survey were followed-up 18 months after their first assessment. Baseline assessments were used to predict the development and persistence of paranoid thinking at follow-up. Data were weighted to be representative of the general household population.ResultsInsomnia, worry, anxiety, depression and depressive ideas were each substantial predictors both of new inceptions of paranoia and of the persistence of existing paranoid thinking. Worry and insomnia were the strongest predictors. For example, insomnia at the first assessment led to a more than threefold increase in later inceptions of paranoid thinking.ConclusionsThe study indicates that insomnia, worry, anxiety and depression are potential risk factors for new inceptions of paranoid thinking. The results also corroborate an emerging literature indicating that anxiety, worry and depression may encourage the persistence of paranoid thinking. The study provides the first longitudinal evidence linking insomnia and paranoia. The important clinical implication is that the use of interventions for common mental health difficulties in people with psychosis may have the additional benefit of reducing paranoia.

title: Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies.
abstract: In many patients with depression, symptoms of insomnia herald the onset of the disorder and may persist into remission or recovery, even after adequate treatment. Several studies have raised the question whether insomniac symptoms may constitute an independent clinical predictor of depression. This meta-analysis is aimed at evaluating quantitatively if insomnia constitutes a predictor of depression.



PubMed, Medline, PsycInfo, and PsycArticles databases were searched from 1980 until 2010 to identify longitudinal epidemiological studies simultaneously investigating insomniac complaints and depressed psychopathology. Effects were summarized using the logarithms of the odds ratios for insomnia at baseline to predict depression at follow-up. Studies were pooled with both fixed- and random-effects meta-analytic models in order to evaluate the concordance. Heterogeneity test and sensitivity analysis were computed.



Twenty-one studies met inclusion criteria. Considering all studies together, heterogeneity was found. The random-effects model showed an overall odds ratio for insomnia to predict depression of 2.60 (confidence interval [CI]: 1.98-3.42). When the analysis was adjusted for outliers, the studies were not longer heterogeneous. The fixed-effects model showed an overall odds ratio of 2.10 (CI: 1.86-2.38).



The main limit is that included studies did not always consider the role of other intervening variables.



Non-depressed people with insomnia have a twofold risk to develop depression, compared to people with no sleep difficulties. Thus, early treatment programs for insomnia might reduce the risk for developing depression in the general population and be considered a helpful general preventive strategy in the area of mental health care.

title: Sleep and mental disorders: A meta-analysis of polysomnographic research.
abstract: Investigating sleep in mental disorders has the potential to reveal both disorder-specific and transdiagnostic psychophysiological mechanisms. This meta-analysis aimed at determining the polysomnographic (PSG) characteristics of several mental disorders. Relevant studies were searched through standard strategies. Controlled PSG studies evaluating sleep in affective, anxiety, eating, pervasive developmental, borderline and antisocial personality disorders, attention-deficit-hyperactivity disorder (ADHD), and schizophrenia were included. PSG variables of sleep continuity, depth, and architecture, as well as rapid-eye movement (REM) sleep were considered. Calculations were performed with the "Comprehensive Meta-Analysis" and "R" software. Using random effects modeling, for each disorder and each variable, a separate meta-analysis was conducted if at least 3 studies were available for calculation of effect sizes as standardized means (Hedges' g). Sources of variability, that is, sex, age, and mental disorders comorbidity, were evaluated in subgroup analyses. Sleep alterations were evidenced in all disorders, with the exception of ADHD and seasonal affective disorders. Sleep continuity problems were observed in most mental disorders. Sleep depth and REM pressure alterations were associated with affective, anxiety, autism and schizophrenia disorders. Comorbidity was associated with enhanced REM sleep pressure and more inhibition of sleep depth. No sleep parameter was exclusively altered in 1 condition; however, no 2 conditions shared the same PSG profile. Sleep continuity disturbances imply a transdiagnostic imbalance in the arousal system likely representing a basic dimension of mental health. Sleep depth and REM variables might play a key role in psychiatric comorbidity processes. Constellations of sleep alterations may define distinct disorders better than alterations in 1 single variable.

title: A bidirectional relationship between anxiety and depression, and insomnia? A prospective study in the general population.
abstract: The purpose of this study was to examine whether there is a bidirectional relationship between, on one hand, anxiety and depression and, on the other hand, insomnia over the course of a year.



A randomly selected sample of 3000 participants from the general population filled out a baseline survey (N=1812) and a 1-year follow-up survey (N=1498) on anxiety, depression, and insomnia.



On cross-sectional analyses, bivariate correlations showed that anxiety, depression, and insomnia were significantly intercorrelated (varphi=.31-.54). On prospective analyses, logistic regression analyses demonstrated that anxiety at baseline [odds ratio (OR)=4.27 (8% of variance)] and depression at baseline [OR=2.28 (2% of variance)] were related to new cases of insomnia on follow-up. Furthermore, insomnia at baseline was related to new episodes of high anxiety and high depression on follow-up [OR=2.30 (2% of variance) and OR=3.51 (4% of variance), respectively].



Evidence suggests that there is a bidirectional relationship between, on one hand, anxiety and depression and, on the other hand, insomnia. This suggests that anxiety, depression, and insomnia are intertwined over time, implying implications for theoretical conceptualizations and interventions.

title: Sleep and emotions: a focus on insomnia.
abstract: Insomnia disorder is defined as difficulties in initiating/maintaining sleep and/or non-restorative sleep accompanied by decreased daytime functioning, persisting for at least four weeks. For many patients suffering from depression and anxiety, insomnia is a pervasive problem. Many of the aetiological theories of insomnia postulate that heightened emotional reactivity contributes to the maintenance of symptoms. This review focuses on the role of emotional reactivity in insomnia, and how the relationship between insomnia and depression and anxiety may be mediated by emotional reactivity. Furthermore, studies investigating the valence of emotions in insomnia are reviewed. Overall, there is empirical evidence that dysfunctional emotional reactivity might mediate the interaction between cognitive and autonomic hyperarousal, thus contributing to the maintenance of insomnia. Moreover, dysfunctions in sleep-wake regulating neural circuitries seem to be able to reinforce emotional disturbances. It seems plausible that dysfunctional emotional reactivity modulates the relationship between insomnia and depression and anxiety. Considering the interaction between sleep and emotional valence, poor sleep quality seems to correlate with high negative and low positive emotions, both in clinical and subclinical samples. Good sleep seems to be associated with high positive emotions, but not necessarily with low negative emotions. This review underlines the need for future research on emotions in insomnia.

title: Relationships between affect, vigilance, and sleepiness following sleep deprivation
abstract: This pilot study examined the relationships between the effects of sleep deprivation on subjective and objective measures of sleepiness and affect, and psychomotor vigilance performance. Following an adaptation night in the laboratory, healthy young adults were randomly assigned to either a night of total sleep deprivation (SD group; n = 15) or to a night of normal sleep (non‐SD group; n = 14) under controlled laboratory conditions. The following day, subjective reports of mood and sleepiness, objective sleepiness (Multiple Sleep Latency Test and spontaneous oscillations in pupil diameter, PUI), affective reactivity/regulation (pupil dilation responses to emotional pictures), and psychomotor vigilance performance (PVT) were measured. Sleep deprivation had a significant impact on all three domains (affect, sleepiness, and vigilance), with significant group differences for eight of the nine outcome measures. Exploratory factor analyses performed across the entire sample and within the SD group alone revealed that the outcomes clustered on three orthogonal dimensions reflecting the method of measurement: physiological measures of sleepiness and affective reactivity/regulation, subjective measures of sleepiness and mood, and vigilance performance. Sleepiness and affective responses to sleep deprivation were associated (although separately for objective and subjective measures). PVT performance was also independent of the sleepiness and affect outcomes. These findings suggest that objective and subjective measures represent distinct entities that should not be assumed to be equivalent. By including affective outcomes in experimental sleep deprivation research, the impact of sleep loss on affective function and their relationship to other neurobehavioral domains can be assessed.

title: The effects of sleep loss on medical residents' emotional reactions to work events: a cognitive-energy model.
abstract: This study investigated the relationship between sleep loss and emotional reactivity in medical residents. We hypothesized that this relationship is shaped by the effect of sleep loss on cog-nitive-energy resources required for coping with goal-disruptive events or for capitalizing on new opportunities offered by goal-enhancing events.



15 medical wards in 4 large hospitals in Israel.



78 medical residents, 67% men, aged 26 to 39 years.



Actigraphic sleep-wake cycles were measured for 5- to 7-day periods, surrounding nightshifts, every 6 months, covering the first 2 years of residency. During each study period, emotional reactivity was investigated using the experience-sampling methodology by which residents received 3 phone calls at random times during their working day for 3 consecutive days. These calls reminded them to fill out brief questionnaires concerning change of circumstances over the previous 15 minutes and to rate their emotional response to these circumstances using the Positive Affect and Negative Affect Scales. Fatigue at those times was measured by a subscale of the Profile of Mood States.



Multilevel regression analysis was used to determine the influence of sleep duration and sleep fragmentation on the emotional reactions to goal-disruptive and goal-enhancing daytime events. We found that sleep loss intensified negative emotions and fatigue following daytime disruptive events, while positive emotion was mitigated following goal-enhancing events. Sleep loss also resulted in an overall elevated baseline for positive emotion.



Sleep loss amplifies the negative emotive effects of disruptive events while reducing the positive effect of goal-enhancing events. Methodologically, the study highlights the utility and advantages of event-level analysis as opposed to the current practice of random sampling of emotion states during waking hours, disregarding contextual factors associated with purposeful, goal-oriented behavior episodes.

title: Sleep problems and self-harm in adolescence
abstract: Although self-harm and sleep problems are major public health problems in adolescence, detailed epidemiological assessment is essential to understand the nature of this relationship.  To conduct a detailed assessment of the relationship between sleep and self-harm in adolescence.  A large population-based study in Norway surveyed 10 220 adolescents aged 16–19 years on mental health, including a comprehensive assessment of sleep and self-harm.  Adolescents with sleep problems were significantly more likely to report self-harm than those without sleep problems. Insomnia, short sleep duration, long sleep onset latency, wake after sleep on set as well as large differences between weekdays versus weekends, yielded higher odds of self-harm consistent with a dose–response relationship. Depressive symptoms accounted for some, but not all, of this association.  The findings highlight a strong relationship between sleep problems and self-harm. Interventions to reduce adolescent self-harm ought to incorporate sleep problems as a treatment target.

title: Sleep, Plasticity and Memory from Molecules to Whole-Brain Networks
abstract: Despite the ubiquity of sleep across phylogeny, its function remains elusive. In this review, we consider one compelling candidate: brain plasticity associated with memory processing. Focusing largely on hippocampus-dependent memory in rodents and humans, we describe molecular, cellular, network, whole-brain and behavioral evidence establishing a role for sleep both in preparation for initial memory encoding, and in the subsequent offline consolidation of memory. Sleep and sleep deprivation bidirectionally alter molecular signaling pathways that regulate synaptic strength and control plasticity-related gene transcription and protein translation. At the cellular level, sleep deprivation impairs cellular excitability necessary for inducing synaptic potentiation and accelerates the decay of long-lasting forms of synaptic plasticity. In contrast, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep enhance previously induced synaptic potentiation, although synaptic de-potentiation during sleep has also been observed. Beyond single cell dynamics, large-scale cell ensembles express coordinated replay of prior learning-related firing patterns during subsequent NREM sleep. At the whole-brain level, somewhat analogous learning-associated hippocampal (re)activation during NREM sleep has been reported in humans. Moreover, the same cortical NREM oscillations associated with replay in rodents also promote human hippocampal memory consolidation, and this process can be manipulated using exogenous reactivation cues during sleep. Mirroring molecular findings in rodents, specific NREM sleep oscillations before encoding refresh human hippocampal learning capacity, while deprivation of sleep conversely impairs subsequent hippocampal activity and associated encoding. Together, these cross-descriptive level findings demonstrate that the unique neurobiology of sleep exerts powerful effects on molecular, cellular and network mechanisms of plasticity that govern both initial learning and subsequent long-term memory consolidation.

title: The Impact of Sleep Quality on Cognitive Functioning in Parkinson's Disease
abstract: In healthy individuals and those with insomnia, poor sleep quality is associated with decrements in performance on tests of cognition, especially executive function. Sleep disturbances and cognitive deficits are both prevalent in Parkinson's disease (PD). Sleep problems occur in over 75% of patients, with sleep fragmentation and decreased sleep efficiency being the most common sleep complaints, but their relation to cognition is unknown. We examined the association between sleep quality and cognition in PD. In 35 non-demented individuals with PD and 18 normal control adults (NC), sleep was measured using 24-hr wrist actigraphy over 7 days. Cognitive domains tested included attention and executive function, memory and psychomotor function. In both groups, poor sleep was associated with worse performance on tests of attention/executive function but not memory or psychomotor function. In the PD group, attention/executive function was predicted by sleep efficiency, whereas memory and psychomotor function were not predicted by sleep quality. Psychomotor and memory function were predicted by motor symptom severity. This study is the first to demonstrate that sleep quality in PD is significantly correlated with cognition and that it differentially impacts attention and executive function, thereby furthering our understanding of the link between sleep and cognition.

title: The association between insomnia-related sleep disruptions and cognitive dysfunction during the inter-episode phase of bipolar disorder.
abstract: Sleep disturbance and cognitive dysfunction are two domains of impairment during inter-episode bipolar disorder. Despite evidence demonstrating the importance of sleep for cognition in healthy and sleep-disordered samples, this link has been minimally examined in bipolar disorder. The present study tested the association between insomnia-related sleep disruptions and cognitive dysfunction during inter-episode bipolar disorder. Forty-seven participants with bipolar disorder and a comorbid insomnia diagnosis (BD-Insomnia) and 19 participants with bipolar disorder without sleep disturbance in the last six months (BD-Control) participated in the study. Two domains of cognition were assessed: working memory and verbal learning. Insomnia-related sleep disruptions were assessed both categorically (i.e., insomnia diagnosis) and dimensionally (i.e., total wake time, total sleep time, total wake time variability, and total sleep time variability). Hierarchical linear regressions, adjusting for participant age, demonstrated that insomnia diagnosis did not have an independent or interactive effect on cognition. However, regardless of insomnia diagnosis, greater total sleep time variability predicted poorer working memory and verbal learning performance. Further, following sleep treatment, a reduction in total wake time predicted improved working memory performance and a reduction in total sleep time variability predicted improved verbal learning performance. These findings raise the possibility that sleep disturbance may contribute to cognitive dysfunction in bipolar disorder and highlight the importance of treating sleep disturbance in bipolar disorder.