Quantitative electroencephalogram analysis of frontal cortex functional changes in patients with migraine.

The functional abnormality of brain areas accounting for the migraine remains to be elucidated. Most related studies have used functional magnetic resonance imaging to investigate brain areas involved in migraine. However, the results are heterogeneous. In this study, we used a convenient tool to explore the brain regions involved in migraine. In this study, 40 children with migraine and 40 sex- and age-matched health controls were enrolled, and electroencephalogram was used to explore the functional abnormal areas of migraine through electroencephalogram bands and low-resolution electromagnetic tomography analysis. The results revealed that spectrum edge frequency 50 in all electroencephalogram channels in patients with migraine were lower than those in controls. Significant differences were discovered over frontal areas. In addition, significantly higher current density over the frontopolar prefrontal cortex and orbitofrontal cortex and higher connectivity over the left prefrontal cortex were observed in patients with migraine. We suggest that functional disturbance of the prefrontal cortex may play a potential role in children with migraine, and that low-resolution electromagnetic tomography is a reliable and convenient tool for studying the functional disturbance of migraine.

Central Nervous System Mechanisms of Nausea in Gastroparesis: An fMRI-Based Case-Control Study.

BACKGROUND/AIMS: Nausea is a major complaint of gastroparesis (GP), and the pathophysiology of this condition is poorly understood. Therefore, this study utilized fMRI to investigate the possible central nervous system (CNS) mechanisms of nausea in 10 GP patients versus 8 healthy controls (HCs). METHODS: Nausea severity was assessed on a 0-10 scale and presented as mean ± SD. Nausea was increased from baseline utilizing up to 30 min of visual stimulation (VS). Functional network connectivity was measured with fMRI at baseline and after 30 min of VS. fMRI data were preprocessed using statistical parametric mapping software. Thirty-four independent components were identified as meaningful resting-state networks (RSNs) by group independent component analysis. The Functional Network Connectivity (FNC) among 5 RSNs considered important in CNS nausea mechanisms was calculated as the Pearson's pairwise correlation. RESULTS: Baseline nausea score in GP patients was 2.7 ± 2.0 and increased to 7.0 ± 1.5 after stimulation (P < 0.01). In HCs nausea scores did not increase from baseline after stimulus (0.3 ± 0.5). When comparing GP patients to HCs after VS, a significant reduction (P < 0.001) in bilateral insula network connectivity compared to the right insula network was detected. No significant differences in connectivity were noted among the other RSNs. Additionally, the average gray matter volume was non-significantly reduced in the insula in GP patients compared to HC. CONCLUSIONS: The insula connectivity network is impaired in nauseated GP patients. This phenomenon could explain the susceptibility of GP patients to nausea or may have resulted from a state of chronic nausea.

Chronic unexplained nausea in adults: Prevalence, impact on quality of life, and underlying organic diseases in a cohort of 5096 subjects comprehensively investigated.

We evaluated to define the clinically significant chronic nausea in general population and to assess the prevalence of chronic unexplained nausea after exclusion of organic causes through the meticulous medical examination. Two phase studies were conducted. In phase 1, telephone survey was conducted to define the clinically significant nausea in 5000 representative subjects for a general population. Clinically significant nausea was identified by lowered quality of life if the frequency was 'more than one day per week'. Its prevalence was 1.6% (1.4-1.8%) and about 90% of nausea was not accompanied with vomiting. In phase 2, 5096 participants in a comprehensive health-screening cohort were enrolled. We investigated demographics, gastrointestinal symptoms, somatization symptoms and health related quality of life using validated questionnaire. All participants underwent meticulous medical examinations including endoscopy, abdominal ultrasound, thyroid function test, and blood testing. Among a total of 5096 subjects (men 51.8%, mean age 47.5 ± 10.0 years), organic diseases associated with chronic nausea were reflux esophagitis, duodenal ulcer and hyperthyroidism. The prevalence of chronic unexplained nausea was 0.6% (95% CI 0.4-0.8%) and there were significant overlap with functional dyspepsia and irritable bowel syndrome. HRQoL is significantly lower in people with nausea occurring 'more than one day per week' in a general population. Most chronic nausea was not accompanied with vomiting. Chronic unexplained nausea is uncommon affecting only 0.6% of the population but are more likely to report functional dyspepsia and irritable bowel syndrome.

Effects of acupuncture at Pericardium-6 and Stomach-36 on nausea, sedation and gastrointestinal motility in healthy dogs administered intravenous lidocaine infusions.

The objectives of this study were to assess gastrointestinal transit times, sedation, and signs of nausea associated with intravenous lidocaine infusions in dogs following targeted acupuncture at Pericardium-6 (PC6) and Stomach-36 (ST36). In a randomized, blind crossover design, 6 healthy, adult Beagles were fed thirty 1.5 mm barium-impregnated polyethylene spheres (BIPS), then were subject to 30 minutes of: 1) no acupuncture, 2) bilateral targeted acupuncture at PC6 and ST36, or 3) bilateral non-target acupuncture at Lung-5 (LU5) and Bladder-55 (BL55). Lidocaine was immediately administered at 1 mg/kg intravenously followed by 50 µg/kg/min. BIPS were tracked radiographically; sedation and nausea were scored at baseline (Time 0) and for 11 hours during lidocaine infusions. Transit times and sedation and nausea scores were analyzed with a linear mixed-effects model; the number of BIPS at defined time points was analyzed with a piecewise linear mixed-effects model. All P values were two-sided and P < 0.05 was considered significant. Sedation and nausea scores did not differ between treatments at any time point (all P > 0.05). However, nausea scores in all groups were significantly greater at Times 5 through 7 and at Time 11 compared to Time 0 whereas sedation scores in all groups were significantly greater at Times 2 through 11 compared to Time 0 (all P < 0.05). The number of BIPs found out of the stomach, the number found in the large intestine, gastric emptying and gastrointestinal transit times did not differ between treatments (all P > 0.05). Acupuncture at PC6 and ST36 did not alleviate nausea and sedation associated with lidocaine infusions in clinically normal animals or affect gastric emptying and gastrointestinal transit.

Vestibular symptoms in acute hemispheric strokes.

A prospective study focused on whether vestibular symptoms are seen in acute hemispheric strokes, and if so, the frequency and lateralization of causative lesions on MRI. Among 668 patients with hemispheric infarction, we prospectively included those with chief complaints of acute vestibular symptoms, such as vertigo/dizziness, nausea/vomiting and gait instability, in the "VS" group. We also retrospectively reviewed MRI of all stroke patients, and included cases with the findings of parieto-insular vestibular cortex (PIVC) or temporo-periSylvian vestibular cortex (TPSVC) lesion by diffusion-weighted MRI, in the "PIVC" group. Eight patients were found to belong to the VS group, and six other patients to the PIVC group. In the VS group, six patients had the responsible lesion on the right hemisphere, in the middle cerebral artery (MCA) territory except one case and two on the left MCA territory, particularly in the insula, retro-insular region, superior/middle temporal gyrus, angular gyrus, supra-marginal gyrus, putamen and hippocampus/para-hippocampal gyrus. In contrast, none of the six other patients of the PIVC group had vestibular symptoms. One of them had a lesion in the right hemisphere and five in the left hemisphere. Four lesions were located in the insular area and two within the temporal lobe. In conclusion, cerebral hemispheric infarction limited to the PIVC or TPSVC does not necessarily cause vertigo. However, unilateral hemispheric infarctions, restricted to the areas belonging to the vestibular cortical network may cause vestibular symptoms. The lesions responsible for vestibular symptoms are located more often in the right hemisphere.

Case Report: Severe back pain, epigastric distress and refractory nausea; an unusual presentation of mediastinal bronchogenic cyst.

Background: Bronchogenic cysts are congenital malformations from abnormal budding of embryonic foregut and tracheobronchial tree. We present a case of bronchogenic cyst with severe back pain, epigastric distress and refractory nausea and vomiting.   Case Presentation: A 44-year-old Hispanic female presented with a 3-week history of recurrent sharp interscapular pain radiating to epigastrium with refractory nausea and vomiting. She underwent cholecystectomy 2-years ago. Computed tomography (CT) abdomen at that time showed a subcarinal mass measuring 5.4 X 5.0 cm. Subsequent endoscopic ultrasound diagnosed it as a bronchogenic cyst. Endobronchial ultrasound (EBUS) guided aspiration resulted in incomplete drainage and she was discharged after partial improvement. Current physical examination showed tachycardia and tachypnea with labs showing leukocytosis, elevated inflammatory markers, and hypokalemic metabolic alkalosis. CT chest showed an increased size of the bronchogenic cyst (9.64 X 7.7 cm) suggestive of possible partial cyst rupture or infected cyst. X-ray esophagram ruled out esophageal compression or contrast extravasation. Patient's symptoms were refractory to conservative management. The patient ultimately underwent right thoracotomy with cyst excision that resulted in complete resolution of symptoms. Conclusion: Bronchogenic cysts are the most common primary cysts of mediastinum with the prevalence of 6%. The most common symptoms are chest pain, dyspnea, cough, and stridor. Diagnosis is made by chest X-Ray and CT chest. Magnetic resonance imaging chest and EBUS are more sensitive and specific. Symptomatic cysts should be resected unless surgical risks are high. Asymptomatic cysts in younger patients should be removed due to low surgical risk and potential late complications. Watchful waiting has been recommended for asymptomatic adults or high-risk patients. This case presents mediastinal bronchogenic cyst as a cause of back, nausea and refractory vomiting. Immediate surgical excision in such cases should be attempted, which will lead to resolution of symptoms and avoidance of complications.

Ictal nausea and vomiting - Is it left or right?

PURPOSE: Ictal nausea/vomiting has been linked to the non-dominant hemisphere and has been considered a lateralizing sign. However, small case series and single cases have reported seizure localisation in the dominant hemisphere. Here we aimed to determine the seizure localisation and lateralization in cases with ictal nausea/retching/vomiting to test the hypothesis that these signs are of lateralizing value. METHODS: We searched two large tertiary epilepsy-center video-EEG databases (period: 1980-2017) for reports on ictal nausea/retching/vomiting and retrieved ictal EEG seizure location, lateralization and clinical symptoms. RESULTS: We identified 13 patients with focal epilepsy and video-EEG-documented ictal nausea (n = 2), nausea and retching (n = 3), retching followed by vomiting (n = 5) or only vomiting (n = 3). Aetiology was genetic (n = 1), structural/metabolic (n = 7) or of unclear origin (n = 5). While in 12/13 patients epileptic discharges were temporal, a single case was parietal. A left-sided seizure origin was more frequent than a right-sided origin (62 vs. 38%). Assuming a left-sided language dominance in the single left-handed patient and in those two patients with unclear handedness (based on the known distribution of hemispheric speech-dominance), the distribution of ictal nausea/retching/vomiting to the dominant vs. non-dominant hemisphere was not significantly different from a random distribution (8 vs. 5, p = 0.581). CONCLUSION: Ictal nausea/retching/vomiting are most frequently of temporal origin. In contrast to previous studies, our ictal video-EEG data suggests that these signs have no lateralizing value. Thus, video-EEG should be performed and while this clinical sign points to a temporal seizure origin, it does not determine its lateralization.

Presenting Symptoms of Pituitary Apoplexy.

The classical term "pituitary apoplexy" (PA) describes a clinical syndrome usually characterized by abrupt onset of headache accompanied by neurologic and/or endocrinologic deterioration due to sudden expansion of a mass within the sella turcica as a result of hemorrhage or infarction within a pituitary tumor and adjacent pituitary gland. PA is a medical emergency and a difficult diagnosis to establish. Thus this article reviews the presenting symptoms of PA patients to help clinicians recognize or at least suspect this critical condition early on. PA commonly occurs in the setting of a preexisting adenoma, and several patients are unaware of its existence prior to the onset of apoplexy symptoms, which are mainly of a neurologic, ophthalmologic, and endocrinologic nature. Neurologic symptoms include sudden-onset severe headache and other symptoms of subarachnoid hemorrhage, symptoms from compression of the cavernous sinus contents, nausea/vomiting, impaired consciousness, and symptoms of meningeal irritation. Ophthalmologic symptoms include visual field defects, visual loss, diplopia, and ophthalmoplegia. Endocrinologic disturbances include pituitary adenoma symptoms, cortisol deficiency, panhypopituitarism, diabetes insipidus, and syndrome of inappropriate secretion of antidiuretic hormone. Magnetic resonance imaging is the imaging method of choice to aid the PA diagnosis. Its differential diagnoses include cerebrovascular accidents, infectious diseases, and other causes of endocrinologic imbalance. Transsphenoidal surgery is the treatment of choice, especially if there are associated visual abnormalities and ophthalmoplegia. Clinicians should be aware of the presenting symptoms because early diagnosis may reduce the morbidity and mortality of this neurosurgical emergency.

Emergency Department Treatment of Cannabinoid Hyperemesis Syndrome: A Review.

BACKGROUND: Cannabinoid hyperemesis syndrome (CHS) is a syndrome of cyclic vomiting associated with chronic cannabis use. As cannabis consumption steadily increases each year, CHS is becoming a commonplace and costly occurrence in hospitals nationwide. Currently, there are no best treatment strategies agreed upon universally. AREAS OF UNCERTAINTY: Thus far, most data about CHS have come from case reports and case series. Consequently, the pathophysiology of the syndrome is unclear, and its occurrence in some cannabis users, but not others, is not understood. DATA SOURCES: A literature search was conducted through PubMed, Embase, and Google Scholar from inception until 2017. Publications only in English describing the epidemiology, pathophysiology, diagnostic criteria, and treatments of CHS were incorporated after thorough evaluation. National government surveys were also referred to for current information about the CHS patient population. RESULTS: CHS should be considered in the differential diagnosis of any patient presenting with persistent nausea and vomiting. In particular, the diagnosis is suggested if the patient demonstrates regular and chronic cannabis use, intractable nausea and vomiting, cyclical vomiting, relief of symptoms with hot baths, and resolution of symptoms after cannabis cessation. There are currently many possible explanations regarding the mechanisms behind CHS. A variety of treatment options have also been examined, including hot water baths, haloperidol, capsaicin, and benzodiazepines. CONCLUSIONS: CHS is becoming an increasingly prevalent and complicated problem for health care providers and patients. Further research must be done to address the diagnostic and therapeutic challenges of this syndrome.

Ophthalmoscopy in the 21st century: The 2017 H. Houston Merritt Lecture.

Although the usefulness of viewing the ocular fundus is well-recognized, ophthalmoscopy is infrequently and poorly performed by most nonophthalmologist physicians, including neurologists. Barriers to the practice of ophthalmoscopy by nonophthalmologists include not only the technical difficulty related to direct ophthalmoscopy, but also lack of adequate training and discouragement by preceptors. Recent studies have shown that digital retinal fundus photographs with electronic transmission and remote interpretation of images by an ophthalmologist are an efficient and reliable way to allow examination of the ocular fundus in patients with systemic disorders such as diabetes mellitus. Ocular fundus photographs obtained without pharmacologic dilation of the pupil using nonmydriatic fundus cameras could be of great value in emergency departments (EDs) and neurologic settings. The Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) study showed that ED providers consistently failed to correctly identify relevant ocular funduscopic findings using the direct ophthalmoscope, and that nonmydriatic fundus photography was an effective alternate way of providing access to the ocular fundus in the ED. Extrapolating these results to headache clinics, outpatient neurology clinics, and adult and pediatric primary care settings seems self-evident. As technology advances, nonmydriatic ocular fundus imaging systems will be of higher quality and more portable and affordable, thereby circumventing the need to master the use of the ophthalmoscope. Visualizing the ocular fundus is more important than the method used. Ocular fundus photography facilitates nonophthalmologists' performance of this essential part of the physical examination, thus helping to reestablish the value of doing so.

Clinical features, outcome, and associated factors for posterior reversible encephalopathy in Thai patients with systemic lupus erythematosus: a case-control study.

Posterior reversible encephalopathy syndrome (PRES) in patients with systemic lupus erythematosus (SLE) has been recognized increasingly. This study aimed to determine the prevalence, clinical features, brain imaging findings, outcomes, and associated factors of PRES in Thai SLE patients. SLE patients with PRES were identified from the lupus cohort of Chiang Mai University. Controls were SLE patients with a hospital number close to and actually had SLE diagnosis within 5 years of the case (case:control ratio = 1:4). Of 1,332 SLE patients, 30 episodes of PRES were identified in 24 female SLE patients (prevalence 1.80%). The mean ± SD age at SLE diagnosis and at onset of PRES was 25.02 ± 13.78 and 28.31 ± 12.61 years, respectively. Seizure was the most common presenting symptom, as seen in 28 episodes, followed by acute severe headache in 17, alteration of consciousness in 17, nausea and vomiting in 10, blurred vision in 11, and hemiparesis in 3. Abrupt increase in blood pressure and active nephritis were seen in 29 and 26 of the episodes, respectively. Urine protein/creatinine ratio > 1.00 (OR 15.72, 95% CI 3.12-79.12, p = 0.001) and hemoglobin < 10 gm/dL (OR 5.12, 95% CI 1.37-19.15, p = 0.015) were associated factors for developing PRES. During the observation period, 7 patients in the PRES group and 8 in the control group died (p = 0.015). PRES was uncommon in SLE patients, but associated with a high mortality rate. Active nephritis and anemia were associated factors of PRES in Thai SLE patients.

Superficial Siderosis Associated with Pineal Cavernous Malformation.

BACKGROUND: Cavernous malformations in the pineal region are rare and difficult to anticipate from preoperative evaluation in patients with pineal apoplexy. We herein report the first case of a pineal cavernous malformation with superficial siderosis. Radiological findings were helpful in identifying the presence of the cavernous malformation. CASE DESCRIPTION: A 47-year-old female presented with a 4-month history of progressive headache, nausea, and dizziness. She complained of double vision and exhibited upward gaze palsy and papilledema on fundoscopy. Radiological examination revealed subacute hemorrhage in the pineal region and enlarged lateral ventricles. Furthermore, T2-star-weighted gradient-echo magnetic resonance imaging demonstrated a linear hypointensity along the pial surface of the cerebral cortex, brainstem, and cerebellum, indicating hemosiderin deposition consistent with superficial siderosis. Suspecting the presence of a cavernous malformation based on the radiological findings of superficial siderosis, we performed total mass resection. The postoperative course was uneventful and her preoperative symptoms resolved completely. CONCLUSION: Radiological findings of superficial siderosis on T2-star-weighted gradient-echo imaging are useful to making a diagnosis of cavernous malformation in cases of pineal apoplexy. They are also important for making the treatment decision to perform total mass resection, which is the best curative method for pineal cavernous malformations.

Clinical Manifestations of Huge Diaphragmatic Hernias.

Translocation of abdominal organs into the thoracic cavity may cause dyspnea, heart disorders, and gastric symptoms. Diaphragmatic hernias can cause diagnostic difficulties, since both clinical and radiological symptoms might imitate different disorders. In these cases computed tomography of the chest is the method of choice. The aim of this study was to assess clinical manifestations, risk factors, and prognosis in patients with huge diaphragmatic hernias with displacement of abdominal organs into the thorax, depending on the action taken. We carried out a retrospective study using data of patients hospitalized in the years 2012-2016. Ten patients were qualified for the study (8 women and 2 men). The mean age of the subjects was 86.5 ± 10.5 years. Thirty percent of the hernias were post-traumatic. All of the patients reported cardiovascular or respiratory symptoms. Upper gastrointestinal symptoms occurred in half of the patients. Twenty percent of patients underwent surgery with a positive outcome, while 30% of patients, who were not qualified for surgery due to numerous co-morbidities, died. The main risk factors predisposing to the occurrence of large diaphragmatic hernias were the following: old age, female gender, and thoracic cage deformities.

Gastric Motor Dysfunction in Patients With Functional Gastroduodenal Symptoms.

OBJECTIVES: The pathophysiology of dyspeptic symptoms is complex. The aim of this study was to evaluate the association of gastric emptying (GE), gastric accommodation (GA), and respiratory sinus arrhythmia (RSA, to assess vagal dysfunction) in a large cohort with functional gastroduodenal symptoms. METHODS: We reviewed demographic, clinical features, and results of gastric motor and vagal function studies of 1,287 patients (74.0% females, mean age 43.1±15.4 years) who had undergone both single photon emission computed tomography GA and scintigraphic GE. Accommodation was based on postprandial to fasting gastric volume ratio (VR). Electrocardiograms were available and analyzed for RSA in 300 patients. RESULTS: There were 29.8% patients with normal GE and GA, 21.9% with abnormal GA only, 27.1% with abnormal GE only, and 21.1% with abnormal GA and GE. There were numerical differences in GA among patients with normal, accelerated, and delayed GE (P=0.062, by χ2). Increased GA (VR >3.85) was more prevalent in patients with delayed GE compared to accelerated GE (14.0% vs. 6.8%, P=0.004). Decreased VRs (median 2.9) were observed with accelerated GE compared to normal GE (median 3.1, P<0.05). Nausea and vomiting were more prevalent (in contrast to the less prevalent bloating) in patients with delayed compared to accelerated or normal GE (all P<0.05). In patients with diminished RSA, there was higher prevalence of reduced GA (41.5%) compared to those with preserved RSA (29.2%, P=0.031). Multivariable analysis showed associations of the main abdominal symptoms with gender, body mass index, gastric emptying, diabetes, and prior abdominal surgery. CONCLUSIONS: Patients with symptoms of functional gastroduodenal disorders may have one or more gastric motor dysfunctions and reduced RSA; among the patients with abnormal gastric motor functions, vomiting suggests delayed GE, whereas reduced RSA is associated with reduced GA.

Motion sickness increases functional connectivity between visual motion and nausea-associated brain regions.

The brain networks supporting nausea not yet understood. We previously found that while visual stimulation activated primary (V1) and extrastriate visual cortices (MT+/V5, coding for visual motion), increasing nausea was associated with increasing sustained activation in several brain areas, with significant co-activation for anterior insula (aIns) and mid-cingulate (MCC) cortices. Here, we hypothesized that motion sickness also alters functional connectivity between visual motion and previously identified nausea-processing brain regions. Subjects prone to motion sickness and controls completed a motion sickness provocation task during fMRI/ECG acquisition. We studied changes in connectivity between visual processing areas activated by the stimulus (MT+/V5, V1), right aIns and MCC when comparing rest (BASELINE) to peak nausea state (NAUSEA). Compared to BASELINE, NAUSEA reduced connectivity between right and left V1 and increased connectivity between right MT+/V5 and aIns and between left MT+/V5 and MCC. Additionally, the change in MT+/V5 to insula connectivity was significantly associated with a change in sympathovagal balance, assessed by heart rate variability analysis. No state-related connectivity changes were noted for the control group. Increased connectivity between a visual motion processing region and nausea/salience brain regions may reflect increased transfer of visual/vestibular mismatch information to brain regions supporting nausea perception and autonomic processing. We conclude that vection-induced nausea increases connectivity between nausea-processing regions and those activated by the nauseogenic stimulus. This enhanced low-frequency coupling may support continual, slowly evolving nausea perception and shifts toward sympathetic dominance. Disengaging this coupling may be a target for biobehavioral interventions aimed at reducing motion sickness severity.

Clinical analysis of neuromyelitis optica presenting as intractable nausea, vomiting and hiccups.

Vomiting and hiccups can be the manifestations of numerous systemic and neurological illnesses. Intractable nausea, vomiting and hiccups (INH) are reported as possible initial manifestations of neuromyelitis optica (NMO), but not correctly identified. Awareness of these atypical presentations is conducive to NMO early diagnosis and proper treatment to prevent further disability. In this paper, 12 NMO were reported, whose intractable vomiting and hiccups were the sole manifestations of the first attack and other attacks involving spinal cord and optic nerves developed later. All the patients were women and serum aquaporin 4 antibody (AQP4-Ab) of 83% patients was positive. MRI of 50% patients showed T2-weighted imaging/fluid attenuated inversion recovery hyperintensity which were longitudinally extensive transverse myelitis or linear signal changes. Sixty-seven percent of patients had medulla lesions, in which dorsomedial and area postrema were involved.

Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.

Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.