Postprandial portal glucose and lactate fluxes, insulin production, and portal vein-drained viscera oxygen consumption in growing pigs fed a high-fiber diet supplemented with a multi-enzyme cocktail.

Information on effects of supplementing fibrous diets with exogenous enzymes on nutrient absorption and energetic demands of visceral organs is scarce. Therefore, this study investigated the effects of supplementing a high-fiber (HF) diet with a multi-enzyme cocktail (MC) on net glucose and lactate portal fluxes, insulin production, and O consumption by the portal-drained viscera (PDV) and whole animal in growing pigs. The MC supplied (analyzed values) 5,397 U of xylanase, 162 U of ß-glucanase, and 2,000 U of protease per kg of diet, and guaranteed minimum activities of 1,000 U of α-amylase and 25 U of pectinase per kg of diet. Three isocaloric-nitrogenous diets based on corn and soybean meal with 0% (control) or 30% distillers' dried grains with solubles (DDGS; 1:1 corn and wheat mixture; HF) and HF supplemented with MC (HF + MC) were used. Five gilts (initial BW = 22.8 ± 1.6 kg) fitted with permanent catheters in the portal vein and carotid artery (for blood sampling), and ileal vein (to infuse para-amino hippuric acid to measure blood flow rate) were fed the 3 diets at 4% BW once daily at 0900 h for 7 d in a replicated 3 × 3 Latin square design. On d 7, pigs were placed in an open-circuit indirect calorimeter to measure whole-animal O consumption and sample blood for 7 h postprandial. Net glucose and insulin production were calculated from portal-arterial differences × portal blood flow, and PDV O consumption was calculated as arterial-portal O differences × portal blood flow. Diet had no effect on postprandial whole-animal O consumption, flow rate, and lactate flux. In addition, diet had no effect on overall mean postprandial PDV O consumption. Pigs fed control had greater ( < 0.05) portal insulin and glucose fluxes, from 90 to 300 min and net glucose flux from 90 to 240 min postprandial. However, pigs fed control and HF + MC had similar net glucose flux, which was greater ( < 0.05) than in pigs fed the HF diet. In conclusion, diets did not affect the energetic demand of the PDV but adding MC to the HF diet improved postprandial net glucose portal flux in growing pigs.

The potential role of Piezo2 in the mediation of visceral sensation.

Piezo2 is an important mechano-gated ion channel that is involved in light touch sensitivity and inflammatory allodynia. However, current research has focused on the function of Piezo2 in somatic sensation but not in visceral sensation. The present study aimed to investigate the role of Piezo2 in visceral sensation of mechanically innocuous and noxious stimuli under physiological and hyperalgesic conditions using rats as a model organism. Neonatal enema with acetic acid induced visceral hypersensitivity. Intrathecal administration of Piezo2-short hairpin RNA (shRNA) reduced Piezo2 expression in lumbosacral dorsal root ganglia (DRG) at both the mRNA and protein levels. Piezo2 knock-down in DRG attenuated visceral sensation to innocuous stimuli in control rats and to both innocuous and noxious stimuli in rats with neonatal irritation. Compared with control rats, Piezo2 was not up-regulated in irritated rats at the mRNA or protein levels in thoracolumbar or lumbosacral DRGs, while TRPV1 was up-regulated in lumbosacral DRGs. These data suggest a potential role of Piezo2 in the mediation of visceral sensation.

What is the Acupoint? A preliminary review of Acupoints.

BACKGROUND: According to traditional Chinese medicine (TCM) theory, acupoints are specifically chosen sites of acupuncture manipulation, and also the basis for studying the mechanism of acupuncture. Stimulating different acupoints on the body surface could provide various therapeutic benefits. However, what is the acupoint? This question is not clear. REVIEW SUMMARY: We focuse on examining the function of acupoints from different perspectives, including the local and the systemic effects of stimulating acupoints. For example, acupoints may release certain substances or incur some changes, which could adjust the function of organs, maintain homeostasis. Furthermore, the therapeutic effects of verum acupoints versus sham acupoints were discussed. However, due to insufficience in evidence and in current methodologies, research into mechanisms of acupuncture is still incomplete. CONCLUSION: This review might explain, to some extent, what an acupoint is. Further research into the identity of acupoints is warranted, and multidisciplinary methods using novel technologies may yield significant advances over existing knowledge.

[The central mechanisms underlying the phenomenon of acupoint sensitization evoked by visceral nociceptive afferent].

The physiological mechanism underlying the acupoint sensitization was evaluated systemically by using the method of electric physiology at spinal cord, medulla, and thalamus levels; the dynamic change of acupoint from the relative "silence" to the relative "activation" function was explained through the study on the dynamic process of acupoint sensitization; the biological process of the therapeutic effect of acupoint stimulation was illuminated through the research of the central mechanism underlining the dose effect relationship between the sensitive acupoint and the related brain area, thus scientific evidence for the functional link between the acupoint and internal organs as well as the nature of the acupoint were provided.

Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome.

BACKGROUND: Gut-directed hypnotherapy can reduce IBS symptoms, but the mechanisms underlying this therapeutic effect remain unknown. AIM: To determine the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients. METHODS: Forty-four women with moderate-to-severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high- (45 mmHg) and low-intensity (15 mmHg) rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). Thirty-one patients completed treatments and posttreatment fMRI. RESULTS: Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high-intensity distension in the dorsal and ventral anterior insula (cluster size 142, P = 0.006, and cluster size 101, P = 0.005 respectively). Moreover HYP responders demonstrated a pre-post treatment BOLD attenuation in posterior insula (cluster sizes 59, P = 0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, P = 0.05). Pre-post differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalising effect on the central processing abnormality of visceral signals in IBS. CONCLUSIONS: The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalised by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms. CLINICAL TRIAL NUMBER: NCT01815164.

Understanding the viscera-related theory that the lung and large intestine are exterior-interiorly related.

Pairing of the viscera and bowels is an important theory, which provides guidance to traditional Chinese medicine (TCM) clinical practice. Investigating this theory has been the focus of research on the basic theory of TCM. Recently, researchers have performed many studies on the theory that the lung and large intestine are exterior-interiorly related, which is a different point of view to that of previous literature, recent clinical studies and experimental studies, and these recent studies have enforced the theoretical connotation of the statement. However, there are problems in some of these studies including recent clinical studies and experimental studies. In the current article, literature on the viscera-related theory of the lung and large intestine are exterior-interiorly related is reviewed from physiological, pathological, and clinical views, and some opinions on the current research status are discussed.

The melanocortin system is involved in regulating autonomic nerve activity through central pituitary adenylate cyclase-activating polypeptide.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is highly expressed in the nervous system. We have previously reported that a central injection of PACAP leads to changes in the autonomic nervous system tones including sympathetic excitation and parasympathetic inhibition. An anatomical study revealed that melanocortin and PACAP are colocalized in some hypothalamic nuclei. Here, we investigated the possible role of the melanocortin system in autonomic control by PACAP using SHU9119, an antagonist of the melanocortin receptors (MC3-R/MC4-R). Pretreatment with SHU-9119 did not affect the activating neural responses of adrenal, renal, and lumbar sympathetic nerves following a PACAP injection However, SHU9119 significantly eliminated the suppressing effect of a PACAP injection on gastric vagal nerve activity and excitation effects on liver and brown adipose tissue sympathetic nerve activities. These results suggest that the brain melanocortin system might play a key role in the control of thermogenic sympathetic outflows and digestive parasympathetic outflow by PACAP, but this system does not participate in the central effects of PACAP on cardiovascular function and neural activities of renal, adrenal, and lumbar sympathetic nerves.

[Progress in the study on the mechanism underlying the correlation between acupoints/meridians and Zangfu organs].

In the present paper, the authors review development of studies on the mechanism underlying the correlation between acupoints/ meridians and internal organs in recent 10 years from (1) doctrine of "dynamic acupoint"; (2) effect of one acupoint-stimulation on multi-viscera, (3) effect of multi-acupoints/multi-meridians stimulation on one single internal organ, (4) specific reactions of visceral disorders on the body surface, (5) the therapeutic effect of acupoint-injection being better than muscular injection, (6) effect of acupuncture on the expression of some known intracellular genes/proteins of the related viscera, (7) effect of acupuncture on the expression or phosphorylation of whole genes/whole proteins of the related viscera, (8) peripheral pathways connecting acupoints and the associated internal organ, (9) central pathways connecting acupoints and the related viscera, and (10) overview of the similar researches in foreign countries. In addition, the authors also make a preliminary analysis on the research significance, current problems and the thoughts in the coming studies. Utilizing advanced knowledge and techniques of systems biology to study "the correlation between acupoints/meridians and internal organs" will greatly promote the development of acupuncturology.

Neurophysiologic basis of Back-Shu and Huatuo-Jiaji points.

Acupuncture, a method of traditional Chinese medicine that uses Back-Shu and Huatuo-Jiaji points, is especially effective for treating diseases of the visceral organs. Applying acupuncture on Back-Shu points affects visceral organs in many ways. For example, it dilates the bronchus, affects the heartbeat, stomach motility, urinary bladder contractions and so on. Acupuncture's effects can be explained as viscero-cutaneous, cutaneo-visceral, cutaneo-muscular, and viscero-muscular reflexes. Segmental dispersion of the sympathetic and parasympathetic systems is related to the location of Back-Shu points. Changes in visceral organs caused by application of acupuncture can be explained as modulation of the sympathetic and parasympathetic systems.

Dyspepsia in childhood and adolescence: insights and treatment considerations.

Functional dyspepsia (FD) is common in children, with as many as 80% of those being evaluated for chronic abdominal pain reporting symptoms of epigastric discomfort, nausea, or fullness. It is known that patients with persistent complaints have increased comorbidities such as depression and anxiety. The interaction with psychopathologic variables has been found to mediate the association between upper abdominal pain and gastric hypersensitivity. These observations suggest that abnormal central nervous system processing of gastric stimuli may be a relevant pathophysiologic mechanism in FD. Despite increased understanding, no specific therapy has emerged; however, recent nonpharmacological-based options such as hypnosis may be effective. Novel approaches, including dietary manipulation and use of nutraceuticals such as ginger and Iberogast (Medical Futures Inc., Ontario, Canada), may also be considered.

Estrogen rapidly modulates mustard oil-induced visceral hypersensitivity in conscious female rats: A role of CREB phosphorylation in spinal dorsal horn neurons.

This study investigated the effect of sex hormones on mustard oil (MO)-induced visceral hypersensitivity in female rats and analyzed possible involved signaling pathways. Female rats, either intact or ovariectomized (OVX), were prepared for abdominal muscle electromyography in response to colorectal distension after intracolonic instillation of MO. The effect of MO intracolonic sensitization was evaluated in intact rats, OVX rats, and OVX rats pretreated with a single injection of 17beta-estradiol (E), progesterone (P), E+P, or vehicle. cAMP-responsive element-binding protein (CREB) and phosphorylated CREB (pCREB) were detected in the superficial dorsal horn of L6 and S1 in MO or mineral oil-treated OVX rats with/without colorectal distension and estrogen replacement. The distal colorectum was removed for histological evaluation of inflammatory severity in MO-treated intact or OVX rats. The MO-treated rats had significantly higher visceromotor reflex than controls (enhanced visceral hypersensitivity), whereas OVX eliminated this hypersensitivity. After a single injection of E or E+P, the rats rapidly restored MO-induced visceral hypersensitivity within 2 h. Estrogen also rapidly induced a dose-dependent increase in pCREB expression in the superficial dorsal horn neurons in MO-treated, but not mineral oil-treated, OVX rats. The present study suggests that estrogen can rapidly modulate visceral hypersensitivity induced by MO intracolonic instillation in conscious female rats, which may involve spinal activation of the cAMP response element-mediated gene induction pathway.

[Relationship between female ages and the theory of five tones correlated with five zang viscera in Huangdi Neijing].

OBJECTIVE: To find out some evidence that may indicate the theory of voice pitch of the five tones being correlated with the five zang viscera in Huangdi Neijing, which was lost 2 000 years. METHODS: Eight-four healthy females were divided into younger group (<34 years old) and older group (> or =34 years old) according to their ages. The pronunciations of these females were examined by sono-frequency analysis facility. RESULTS: The frequency of Jiao tone was much higher than those of the other tones in both groups (P<0.01) and the frequency of Jiao tone increased as aging. The frequency of Zhi tone in the younger group was higher than that in the older group (P<0.05). CONCLUSION: The results of higher frequency of Jiao tone in females is in accordance with the theory put forward by Ye Gui (a famous doctor in Qing Dynasty of China) that the liver is the congenital base of female life. In traditional Chinese medicine, Jiao tone is correlated with the liver, and Zhi tone is correlated with the heart. The high frequency of Zhi tone in younger females implies that regulating the Small Intestine Meridian of Hand-Taiyang and Heart Meridian of Hand-Shaoyin may be beneficial to the health maintenance of younger female.

Water soluble fraction (<10 kDa) from bee venom reduces visceral pain behavior through spinal alpha 2-adrenergic activity in mice.

We have previously shown that subcutaneous bee venom (BV) injection reduces visceral pain behavior in mice, but it is not clear which constituent of BV is responsible for its antinociceptive effect. In the present study, we now demonstrate that a water-soluble subfraction of BV (BVA) reproduces the antinociceptive effect of BV in acetic acid-induced visceral pain model. We further evaluated three different BVA subfractions that were separated by molecular weight, and found that only the BVAF3 subfraction (a molecular weight of <10 kDa) produced a significant antinociceptive effect on abdominal stretches and suppressed visceral pain-induced spinal cord Fos expression. Injection of melittin (MEL), a major constituent of BVAF3, also produced a visceral antinociception. However, melittin's antinociception was completely blocked by boiling for 10 min at 100 degrees C, while boiling either whole BV or BVAF3 did not prevent their antinociception. The antinociceptive effect of BVAF3 was completely blocked by intrathecal pretreatment with the alpha2-adrenoceptor antagonist, yohimbine (YOH), while intrathecal pretreatment with the opioid antagonist, naloxone (NAL) or the serotonin antagonist, methysergide, had no effect. These data demonstrate that BVAF3 is responsible for the visceral antinociception of whole BV and further suggest that this effect is mediated in part by spinal alpha2-adrenergic activity.

Convergence of cutaneous, muscular and visceral noxious inputs onto ventromedial thalamic neurons in the rat.

We have recently described a population of neurons in the lateral part of the ventromedial thalamus (VMl), that respond exclusively to noxious cutaneous stimuli, regardless of which part of the body is stimulated. The purpose of the present study was to investigate the convergence of cutaneous, muscular and visceral noxious inputs onto single, VMl neurons in anesthetized rats. VMl neurons were characterized by their responses to Adelta- and C-fiber activation as well as noxious heat applied to the hindpaw. We investigated whether they responded also to colorectal distensions. In an additional series of experiments, we tested the effects of colorectal, intraperitoneal, intramuscular and subcutaneous applications of the chemical irritant mustard oil (MO). The present study shows that a population of neurons located within the thalamic VMl nucleus, carries nociceptive somatosensory signals from the entire body. All these neurons responded to noxious cutaneous and intramuscular stimuli but not to levels of distension that could be considered innocuous or noxious, of the intact and inflammed colon and rectum. Although colorectal distension did not elicit VMl responses, convergence of visceral as well as muscle and cutaneous nociceptors was demonstrated by the increases in ongoing (background) discharges following intracolonic MO. A distinct effect is seen after MO injection into the lumen of the colon: an increase in ongoing activity for 15min but still a lack of effect of colorectal distension. Moreover, following inflammation induced by subcutaneous injections of MO VMl neurons developed responses to both thermal and mechanical innocuous skin stimulation, reminiscent of allodynia phenomena. It is suggested that the VMl contributes to attentional aspects of nociceptive processing and/or to the integration of widespread noxious events in terms of the appropriate potential motor responses.

Structural characterization of a hypothalamic visceromotor pattern generator network.

A high resolution PHAL analysis of axonal connections suggests the existence of a visceromotor pattern generator network in the periventricular region of the rat hypothalamus (HVPG), and a preliminary account of its structure is provided here. Six nodes identified thus far include the dorsomedial nucleus and five small nuclei in the preoptic region (anteroventral and anterodorsal preoptic, parastrial, median preoptic, and anteroventral periventricular). Aside from its location between the neuroendocrine motor zone and the medial hypothalamic nuclei (behavior control column), three other primary features characterize the HVPG network. First, each HVPG nucleus generates a pattern of terminal fields that differentially targets a unique set of hypothalamic neuroendocrine motoneuron pools, and of preautonomic parts of the paraventricular nucleus. Second, the six HVPG nuclei are massively interconnected themselves. And third, the majority of projections from the HVPG nuclei remain within the medial half of the hypothalamus; additional outputs reach the septum, other parts of the diencephalon, and the brainstem central gray. Possible control of activity in the HVPG by neural inputs from the cerebral hemispheres, sensory systems, behavioral state-related cell groups, and the hypothalamic behavior or motivation control column is discussed, along with certain key functional data related to HVPG nuclei. Finally, the HVPG is incorporated into a working model of hypothalamic organization.

The role of endocannabinoids in the hypothalamic regulation of visceral function.

The hypothalamus plays an important role in the regulation of several visceral processes, including food intake, thermoregulation and control of anterior pituitary secretion. Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus. In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions. There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation. Cannabinoids can change body temperature in a dose-dependent manner. High doses cause hypothermia while low doses cause hyperthermia. Cannabinoid administration decreases heat production. It seems that the effects of can- nabinoids on thermoregulation is exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.THC and endocannabinoids have mainly inhibitory effects on the regulation of reproduction. Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels. AEA causes a prolongation of pregnancy in rats and temporarily inhibits the postnatal development of the hypothalamo-pituitary axis in offspring. The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level. CB(1) receptors have also been found in the anterior pituitary. Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice. Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.

Interoception: the inside story--a model for psychosomatic processes.

OBJECTIVE: To comprehend psychosomatic processes, it will be necessary to understand the brain's influences on bodily functions and also the body's afferent sensory input to the central nervous system, including the effects of this input on behavior and cognitive functions, especially emotion. The objective of this Presidential Address is to review what is known circa the year 2000 of the processes and mechanisms of visceral sensory psychobiology, often called interoception. METHODS: Over 1000 publications that have appeared since the 19th century were reviewed to prepare this review, including a group that are specifically cited here. RESULTS: Factors and data were reviewed that were identified as germane to understanding interoception. These included definitional issues, historical roots, the neural basis, studies and results in the cardiovascular-respiratory and alimentary-gastrointestinal systems, studies of emotion, and studies in people with mental disorders. Drug and hormone effects, pain, proprioception, and phantom limb or organ factors, and the role of awareness were briefly described. Methodological issues, methods of study including functional imaging, and possible future directions for study were identified. CONCLUSIONS: Understanding the physical basis of psychosomatic processes, including the so-called mind-body problem, will require a detailed understanding the psychobiology of interoception.

Localization of the melatonin-related receptor in the rodent brain and peripheral tissues.

Previous studies have provided a limited examination of the expression of the orphan melatonin-related receptor in the pituitary and hypothalamus of human and sheep and retinal tissue in the sheep. The present study reports evidence of conservation of expression in regions of the hypothalamus (dorsal medial hypothalamus, lateral hypothalamus, arcuate nucleus), the epithelial layer lining the third ventricle and the paraventricular thalamic nucleus of the mouse, rat and hamster. An extensive and detailed analysis of melatonin-related receptor mRNA expression in the mouse central nervous system and peripheral tissues is presented. Mapping the distribution throughout the entire mouse brain has revealed new sites of expression in a number of brain nuclei, including preoptic areas, parabrachial nuclei and widespread distribution in the olfactory bulb. Reverse transcriptase-polymerase chain reaction was performed with RNA isolated from peripheral tissues revealing expression of the melatonin-related receptor mRNA in the mouse kidney, adrenal gland, intestine, stomach, heart, lung, skin, testis and ovary. These results suggest a conserved function in neuroendocrine regulation and a potential role in coordinating physiological responses in the central nervous system and peripheral tissues.

Calcitonin gene-related peptide-like immunoreactivity marks putative visceral sensory pathways in human brain.

Calcitonin gene-related peptide serves as a neuromodulator in several ascending visceral sensory pathways from the parabrachial nucleus to the thalamus, amygdala and the visceral sensory cortex in rats, but these pathways have not been studied in primates. We have examined the distribution of calcitonin gene-related peptide-like immunoreactive innervation of the corresponding areas of the human brain, including the cortex, diencephalon and brainstem. We report the finding of three populations of calcitonin gene-related peptide-like immunoreactive cells that are homologous to those that have been characterized in the rat: the external lateral and external medial parabrachial subnuclei and the posterior intralaminar thalamic complex, including the subparafascicular, lateral subparafascicular and peripeduncular nuclei. In addition, scattered calcitonin gene-related peptide-like immunoreactive cells were found in the periventricular hypothalamus. Calcitonin gene-related peptide-like immunoreactive terminals were found in regions homologous to the projection areas of the external medial and external lateral parabrachial subnuclei in the rat, including the ventroposterior parvicellular nucleus of the thalamus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the insular cortex; and in the terminal field of the posterior intralaminar thalamic complex, including the amygdalo-striatal transition region and the insular cortex. These results suggest that, similarly to other species, calcitonin gene-related peptide may also serve as a marker for ascending visceral sensory pathways in the human brain.

Prefrontal cortical networks related to visceral function and mood.

At least twenty-two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct structure and connections, they can be grouped into two "networks," defined by cortico-cortical connections that primarily interconnect areas within each network. The networks also have different connections to the striatum, medial thalamus, and other brain regions. The orbital network consists of most of the areas in the orbital cortex. It receives several sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) that appear to be related to feeding. It also receives many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum, including a specific projection from the ventrolateral part of the basal amygdaloid nucleus. The orbital network may therefore serve as a substrate to integrate viscerosensory information with affective signals. The medial network consists of areas on the medial frontal surface together with a few select areas in the orbital cortex. These areas have few direct sensory inputs, and their limbic inputs are somewhat different than those to the orbital network (e.g., from the ventromedial part of the basal amygdaloid nucleus). However, they provide the major output from the OMPFC to the hypothalamus and brain stem (especially the periaqueductal gray). The medial network may therefore serve as a visceromotor system to provide frontal cortical influence over autonomic and endocrine function. Connections between the networks presumably allow information flow from viscerosensory to visceromotor systems. In addition to a probable role in eating behavior, this system appears to be involved in guiding behavior and regulation of mood. Lesions of the ventromedial prefrontal cortex result in sociopathic behavior and difficulty in making appropriate choices, whereas functional imaging studies indicate that subjects with unipolar and bipolar depression have abnormal activity in medial and orbital prefrontal areas. Many of these areas also show volume changes and decreased glial number and density in mood-disordered subjects.