Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT1AR) in the NTS. AT1AR-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT1AR-GFP mice to make targeted whole cell recordings from AT1AR-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT1AR-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT1AR-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT1AR-expressing viscerosensory neurons terminate on AT1AR-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT1AR-expressing NTS neurons.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT1AR-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT1AR-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT1AR-GFP neurons and TH-GFP neurons showed similar AT1AR-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT1AR-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing.

Neonatal basal ganglia and thalamic volumes: very preterm birth and 7-year neurodevelopmental outcomes.

BackgroundThis study aims to (i) compare volumes of individual basal ganglia nuclei (caudate nucleus, pallidum, and putamen) and the thalamus between very preterm (VP) and term-born infants at term-equivalent age; (ii) explore neonatal basal ganglia and thalamic volume relationships with 7-year neurodevelopmental outcomes, and whether these relationships differed between VP and term-born children.Methods210 VP (<30 weeks' gestational age) and 39 term-born (≥37 weeks' gestational age) infants underwent brain magnetic resonance imaging at term-equivalent age, and deep gray matter volumes of interest were automatically generated. 186 VP and 37 term-born children were assessed for a range of neurodevelopmental measures at age 7 years.ResultsAll deep gray matter structures examined were smaller in VP infants compared with controls at term-equivalent age; ranging from (percentage mean difference (95% confidence intervals) -6.2% (-10.2%, -2.2%) for the putamen, to -9.5% (-13.9%, -5.1%) for the caudate nucleus. Neonatal basal ganglia and thalamic volumes were positively related to motor, intelligence quotient, and academic outcomes at age 7 years, with mostly similar relationships in the VP and control groups.ConclusionVP birth results in smaller basal ganglia and thalamic volumes at term-equivalent age, and these smaller volumes are related to a range of 7-year neurodevelopmental deficits in VP children.

Post-liver transplant leptin results in resolution of severe recurrence of lipodystrophy-associated nonalcoholic steatohepatitis.

We describe the first case of a patient undergoing orthoptic liver transplantation for acquired generalized lipodystrophy-related nonalcoholic steatohepatitis who developed severe recurrence of nonalcoholic fatty liver disease in the first few months posttransplant but responded rapidly to the administration of exogenous leptin. The beneficial effects of therapy were supported by histology along with magnetic resonance spectroscopy studies, which demonstrated that leptin therapy greatly reduced fat deposition in the liver. Leptin therapy may have a role to play in preventing patients with lipodystrophy developing end-stage liver disease or in rescuing such patients who develop disease recurrence postliver transplantation.

Late-onset swallowing outcomes post-treatment for head and neck cancer in a UK-based population.

BACKGROUND: Adverse swallowing outcomes following head and neck squamous cell carcinoma treatment in the context of late-onset post-radiotherapy changes can occur more than five years post-treatment. METHODS: A retrospective study was conducted utilising patient records from March 2013 to April 2015. Patients were categorised into 'swallow dysfunction' and 'normal swallow' groups. Quality of life was investigated using the MD Anderson Dysphagia Inventory and EuroQol questionnaires. RESULTS: Swallow dysfunction was seen in 77 (51 per cent) of 152 patients. Twenty-eight patients (36 per cent) in the swallow dysfunction group reported symptoms in year five. Swallow dysfunction was associated with stage IV head and neck squamous cell carcinoma (p < 0.001) and radiotherapy (p < 0.001). MD Anderson Dysphagia Inventory global scores showed significant differences between swallow dysfunction and normal swallow groups (p = 0.01), and radiotherapy and surgery groups (p = 0.03), but there were no significant differences between these groups in terms of MD Anderson Dysphagia Inventory composite or EuroQol five-dimensions instrument scores. CONCLUSION: One-third of head and neck squamous cell carcinoma survivors with swallow dysfunction still show symptoms at more than five years post-surgery, a point at which they are typically discharged.

Differential effects of early hippocampal pathology on episodic and semantic memory.

Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.

Frailty Exists in Younger Adults Admitted as Surgical Emergency Leading to Adverse Outcomes.

BACKGROUND: Frailty is prevalent in the older adult population (≥65 years of age) and results in adverse outcomes in the emergency general surgical population. OBJECTIVE: To determine whether frailty exists in the younger adult emergency surgical population (<65 years) and what influence frailty may have on patient related outcomes. DESIGN: Prospective observational cohort study. SETTING: Emergency general surgical admissions. PARTICIPANTS: All patients ≥40 years divided into 2 groups: younger adults (40-64.9 years) and older adult comparative group (≥65). MEASUREMENTS: Over a 6-month time frame the following data was collected: demographics; Scottish Index of Multiple Deprivation (SIMD); blood markers; multi-morbidities, polypharmacy and cognition. Frailty was assessed by completion of the Canadian Study of Health and Ageing (CSHA). Each patient was followed up for 90 days to allow determination of length of stay, re-admission and mortality. RESULTS: 82 young adults were included and the prevalence of frailty was 16% (versus older adults 38%; p=0.001) and associated with: multi-morbidity; poly-pharmacy; cognitive impairment; and deprivation. Frailty in older adults was only significantly associated with increasing age. CONCLUSIONS: This novel study has found that frailty exists in 16% of younger adults admitted to emergency general surgical units, potentially leading to adverse short and long-term outcomes. Strategies need to be developed that identify and treat frailty in this vulnerable younger adult population.

Modifiable lifestyle factors are associated with lower pain levels in adults with knee osteoarthritis.

BACKGROUND: With no cure or effective treatments for osteoarthritis (OA), the need to identify modifiable factors to decrease pain and increase physical function is well recognized. OBJECTIVE: To examine factors that characterize OA patients at different levels of pain, and to investigate the relationships among these factors and pain. METHODS: Details of OA characteristics and lifestyle factors were collected from interviews with healthy adults with knee OA (n=197). The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess pain. Factors were summarized across three pain score categories, and χ(2) and Kruskal-Wallis tests were used to examine differences. Multiple linear regression analysis using a stepwise selection procedure was used to examine associations between lifestyle factors and pain. RESULTS: Multiple linear regression analysis indicated that pain was significantly higher with the use of OA medications and higher body mass index category, and significantly lower with the use of supplements and meeting physical activity guidelines (≥ 150 min/week). Stiffness and physical function scores, bilateral knee OA, body mass index category and OA medication use were significantly higher with increasing pain, whereas self-reported health, servings of fruit, supplement use and meeting physical activity guidelines significantly lower. No significant differences across pain categories were found for sex, age, number of diseases, duration of OA, ever smoked, alcoholic drinks/week, over-the-counter pain medication use, OA supplement use, physical therapy use, servings of vegetables or minutes walked/week. CONCLUSIONS: Healthy weight maintenance, exercise for at least 150 min/week and appropriate use of medications and supplements represent important modifiable factors related to lower knee OA pain.

Quantification of perfusion using bolus tracking magnetic resonance imaging in stroke: assumptions, limitations, and potential implications for clinical use.

BACKGROUND: MR techniques have been very powerful in providing indicators of tissue perfusion, particularly in studies of cerebral ischemia. There is considerable interest in performing absolute perfusion measurements, with the aim of improving the characterization of tissue "at risk" of stroke. However, some important caveats relating to absolute measurements need to be taken into account. The purpose of this article is to discuss some of the issues involved and the potential implications for absolute cerebral blood flow measurements in clinical use. SUMMARY OF COMMENT: In bolus tracking MRI, deconvolution of the concentration-time course can in theory provide accurate quantification. However, there are several important assumptions in the tracer kinetic model used, some of which may be invalid in cerebral ischemia. These can introduce significant errors in perfusion quantification. CONCLUSIONS: Although we believe that bolus tracking MRI is a powerful technique for the evaluation of perfusion in cerebral ischemia, interpretation of perfusion maps requires caution; this is particularly true when absolute quantification is attempted. Work is currently under way in a number of centers to address these problems, and with appropriate modeling they may be overcome in the future. In the interim, we believe that it is necessary for users of bolus tracking perfusion data to be aware of the current technical limitations if they are to avoid misinterpretation or overinterpretation of their findings.

MR perfusion imaging in Moyamoya Syndrome: potential implications for clinical evaluation of occlusive cerebrovascular disease.

BACKGROUND AND PURPOSE: Ischemic symptoms in patients with moyamoya syndrome (MMS) are usually due to hemodynamically mediated perfusion failure, and identification of abnormal tissue perfusion in these patients is therefore clinically important. Although dynamic susceptibility contrast (DSC) MRI can be used to study tissue perfusion, there are potential technical problems in MMS. This study investigates the scope and limitations of perfusion MRI in the clinical evaluation of such patients. METHODS: Thirteen patients with bilateral MMS were studied with the use of structural, diffusion, and perfusion MRI. The DSC MRI data were analyzed both visually and by a quantitative regional analysis, and the relationship between perfusion status and clinical symptoms was investigated. RESULTS: Extensive bilateral DSC MRI abnormalities were observed in all the patients. There was a very heterogeneous distribution of bolus arrival time. The areas of abnormality included the major arterial border zones in all cases, although these usually appeared normal on structural and diffusion MRI. Only the most clinically unstable patients had peak width (defined as time to peak minus bolus arrival time) >5 seconds on the quantitative regional analysis. Several technical limitations of perfusion quantification in MMS are described, as well as the implications of these limitations in patients with other forms of occlusive large-vessel disease. CONCLUSIONS: The technical limitations of DSC MRI described in this study are important for the accurate interpretation of perfusion MRI in MMS. Despite these limitations, these preliminary findings suggest that the use of quantitative regional analysis of summary parameters may provide clinically useful information in patients with MMS.

1H magnetic resonance spectroscopy in the investigation of intractable epilepsy.

We have been using proton magnetic resonance spectroscopy (1H MRS) in the investigation of adults and children with intractable epilepsy. Spectra were obtained from 2 x 2 x 2 cm cubes in the medial region of the temporal lobe, and were analyzed on the basis of signals from N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), and choline-containing compounds (Cho). In comparison with control subjects, the epilepsy patients as a group show significant reductions in the NAA signal and in the NAA/Cho+Cr ratio, with increases in the Cho and Cr signals. The reduction in NAA is interpreted in terms of neuronal loss or damage, while the increase in Cr and Cho signals may be a reflection of reactive astrocytosis.

The amygdala and intractable temporal lobe epilepsy: a quantitative magnetic resonance imaging study.

OBJECTIVE: To establish a quantitative MRI technique using T2 relaxation time mapping to study systematically the amygdala in patients with intractable temporal lobe epilepsy (TLE). BACKGROUND: Identification of a focal abnormality on MRI in patients with intractable TLE is important, because outcome from surgery depends largely on the removal of the underlying pathology. Hippocampal sclerosis (HS) is the most common cause of intractable TLE, but epileptogenic lesions can be confined to the amygdala. METHODS: Twenty control subjects and 82 patients with intractable TLE were studied. Patients who had foreign tissue lesions visible on routine MRI were excluded. All subjects had a hippocampal T2 map and volumetry and an amygdala T2 (AT2) map. RESULTS: Forty-four of the 82 patients (54%) had an abnormal AT2, which was bilateral in 18. Forty-four patients (54%) had unilateral HS on MRI, 25 (57%) of whom had an abnormal AT2. Seven patients (8%) had bilateral HS, four of whom had an abnormal AT2. Thirty-one patients (38%) had normal quantitative hippocampal measures, 15 of whom had an abnormal AT2, which was bilateral in seven. Fluid attenuated inversion recovery (FLAIR) imaging, where appropriate, confirmed that the increased AT2 signal was due to parenchymal changes. Neuropathologic correlates of an increased AT2 included microdysgenesis in one and gliosis in three patients. Patients with an isolated AT2 abnormality were significantly older at the onset of habitual epilepsy and rarely had a history of febrile convulsions, in comparison with patients who had HS. An isolated AT2 abnormality correlated well with interictal EEG findings. CONCLUSIONS: The combination of AT2 mapping and FLAIR is a sensitive method to detect lesions that are not seen on routine MRI in the amygdalae of patients with intractable TLE. Further correlational studies will be required to define the role of this technique in the presurgical evaluation of patients with intractable TLE.

Etiology and early prognosis of newly diagnosed partial seizures in adults: a quantitative hippocampal MRI study.

Sixty-three adult patients with newly diagnosed partial seizures underwent MRI of the brain including hippocampal quantitation. Seventy-six percent of patients had normal MRI findings, 10% had hippocampal sclerosis (HS), and 14% had MRI abnormalities other than HS. Patients with HS had a worse early prognosis than patients with other MRI findings with respect to seizures. The extent of hippocampal damage appeared to be an important mediating factor in frequency of seizures, secondary generalization, and resistance to antiepileptic drug treatment. Because MRI provides prognostic information and can alter management for the individual patient, high-resolution MRI should be performed in all patients with newly diagnosed partial seizures.

Magnetic resonance spectroscopy in temporal lobe epilepsy.

We used proton magnetic resonance spectroscopy (1H MRS) to investigate the temporal lobes of 25 patients with temporal lobe epilepsy. Spectra were obtained from 2 x 2 x 2 cm cubes in the medial region of the temporal lobe, and were analyzed on the basis of signals from N-acetylaspartate (NAA), creatine + phosphocreatine (Cr), and choline-containing compounds (Cho). In comparison with control subjects, the temporal lobes ipsilateral to the seizure focus showed a mean reduction of 22% in the NAA signal, with a 15% increase in the Cr signal and a 25% increase in the Cho signal. There were smaller effects in the contralateral temporal lobes. These spectral abnormalities may reflect neuronal loss or damage, together with reactive astrocytosis. The NAA/Cho+Cr ratio was abnormally low in 88% of the patients, 40% showing bilateral effects. On the basis of the NAA/Cho+Cr ratio, we correctly achieved lateralization in 15 cases, with three incorrect. Two of the incorrect lateralizations also had imaging abnormalities on the contralateral side, and the other had severe bilateral abnormalities on MRS. We conclude that 1H MRS provides useful information in the preoperative investigation of patients with temporal lobe epilepsy, contributing to lateralization and detecting bilateral abnormalities.

Detection of hippocampal pathology in intractable partial epilepsy: increased sensitivity with quantitative magnetic resonance T2 relaxometry.

Abnormal T2-weighted signal intensity in the hippocampus may be difficult to detect visually, and T2 mapping provides an objective means of assessing signal abnormality. We investigated 50 adult outpatients suffering from intractable partial epilepsy with MRI optimized to detect hippocampal and cortical gray matter abnormalities, and with MR T2 relaxation mapping. The range of normal hippocampal T2 relaxation times is small (99 to 106 msec), and the measurements are reproducible between observers. There were abnormal hippocampal T2 relaxation times in the hippocampus ipsilateral to the site of seizure origin in 70% of patients studied, with the more severe abnormality in the ipsilateral hippocampus in all cases. All hippocampal T2 measurements greater than 116 msec were associated with temporal lobe epilepsy and pathologic or MRI evidence of hippocampal sclerosis, or both. Bilateral abnormalities were present in 29% of cases with hippocampal sclerosis.

Functional magnetic resonance imaging of focal seizures.

Magnetic resonance imaging (MRI) can now provide maps of human brain function with high spatial and temporal resolution. We aimed to establish whether this noninvasive technique could also map the cortical activation that occurs during focal seizures. In order to do this, we used a conventional 1.5-tesla clinical MRI system for the investigation of a 4-year-old boy suffering from frequent partial motor seizures of his right side. We acquired FLASH images (TE = 60 msec) every 10 seconds over intervals of 10 minutes and derived activation images by subtracting baseline images from images obtained during clinical seizures. Functional MRI revealed sequential activation associated with specific gyri within the left hemisphere with each of five consecutive clinical seizures, and also during a period that was not associated with a detectable clinical seizure. The activated regions included gyri that were structurally abnormal. We concluded that functional MRI can provide new insights into the dynamic events that occur in the epileptic brain and their relationship to brain structure.

Lateralization of brain function in childhood revealed by magnetic resonance spectroscopy.

We used proton magnetic resonance spectroscopy (1H MRS) for the assessment of focal brain pathology in 22 right-handed children with a diagnosis of intractable temporal lobe epilepsy, and we related this pathology to cognitive dysfunction. Cognitive assessment was based on measurements of verbal IQ, performance IQ, and the Paired Associate Learning subtest of the Wechsler Memory Scale. Five of the 22 children showed no abnormalities of the temporal lobes on 1H MRS, seven showed unilateral pathology, and 10 showed bilateral abnormalities. We found that left-sided pathology is associated with a loss of verbal cognitive functions, whereas right-sided pathology is associated with a loss of nonverbal functions. These findings are consistent with the pattern of lateralization of brain function that has been observed in adults.

Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy.

OBJECTIVE: To determine the 1H MRS findings in patients with intractable temporal lobe epilepsy (TLE) who had no detectable abnormality on either qualitative or quantitative MRI. BACKGROUND: Previous work has indicated that approximately 20% of patients with TLE remain MRI negative after extensive qualitative and quantitative investigation. Single-voxel 1H MRS provides a means of identifying potentially diffuse disease. METHODS: Seven patients with intractable TLE, normal routine MRI, normal hippocampal volumes, and normal hippocampal and amygdala quantitative T2 values underwent single-voxel 1H MRS of the medial temporal lobes. The results are compared with those from 13 control subjects and 15 patients with evidence of hippocampal sclerosis (HS). RESULTS: The ratio N-acetylaspartate/(choline-creatine + phosphocreatine) was abnormally low in five of the seven MRI-negative patients. In two of these patients, the ratios were low bilaterally. The observed MRS ratios in the MRI-negative group with abnormal EEG were similar to those from temporal lobes ipsilateral to HS, suggesting the presence of widespread or diffuse disease of a similar degree in both groups. CONCLUSIONS: These results demonstrate that MRS can provide evidence of temporal lobe abnormalities in TLE patients who show no abnormality on extensive MRI investigation.

Quantitative magnetic resonance characterization of mesial temporal sclerosis in childhood.

OBJECTIVE: To investigate whether quantitative MR techniques can be used to distinguish between mesial temporal sclerosis in patients with a history of prolonged febrile convulsion and in patients without such a history. METHODS: Quantitative hippocampal T2 relaxometry, hippocampal volumetry, and single voxel (1)H-MRS data were acquired from 16 children who subsequently underwent temporal lobe resections for intractable temporal lobe epilepsy and histologically were shown to have sclerosis of the horn of Ammon. Eight children had a history of prolonged febrile convulsion in early childhood and eight children had other or no associations. RESULTS: Patients with a history of prolonged febrile convulsion had smaller hippocampi (p = 0.02) and prolonged T2 relaxation time (p = 0.03) ipsilateral to the seizure focus when compared with patients without such a history. There was also more side-to-side asymmetry of T2 relaxation time (p = 0.004) and hippocampal volume (p = 0.02) in the patients with a history of prolonged febrile convulsion than in those with other or no associations. No differences between the groups were identified using (1)H-MRS. CONCLUSIONS: These data support the view that there are at least two types of mesial temporal sclerosis. There may be several pathogenetic pathways from initial insult to later mesial temporal sclerosis, and these pathways are, at least in part, dependent on the initial insult.

Verbal memory impairment after right temporal lobe surgery: role of contralateral damage as revealed by 1H magnetic resonance spectroscopy and T2 relaxometry.

We assessed performance on selected tests of verbal memory in 48 patients who had undergone either anterior temporal lobectomy or selective amygdalo-hippocampectomy for the relief of pharmacologically intractable epilepsy. We related performance both to the side of surgical excision and to the presence or absence of abnormalities in the contralateral, unoperated, temporal lobe, as revealed by proton magnetic resonance spectroscopy (1H MRS) or T2 relaxometry. There were abnormalities on the unoperated side detected by 1H MRS in 50% of the 34 patients who successfully underwent spectroscopy, and by T2 relaxometry in 33% of the complete series of 48 patients. There was no systematic relationship between seizure outcome and the presence or absence of abnormalities on the unoperated side. Verbal memory deficits were present in patients with left-sided excision, regardless of whether there were abnormalities on the unoperated side. The patients with right-sided excision also had verbal memory deficits, but only in the group with magnetic resonance abnormalities on the contralateral (ie, left) side and only on delayed recall. The study extends previous findings on the role of the temporal lobes in memory and highlights the role of these new magnetic resonance techniques in relating cognitive processes to brain structures.