The role of the lateral prefrontal cortex and anterior cingulate in stimulus–response association reversals

Many complex tasks require us to flexibly switch between behavioral rules, associations, and strategies. The prefrontal cerebral cortex is thought to be critical to the performance of such behaviors, although the relative contribution of different components of this structure and associated subcortical regions are not fully understood. We used functional magnetic resonance imaging to measure brain activity during a simple task which required repeated reversals of a rule linking a colored cue and a left/right motor response. Each trial comprised three discrete events separated by variable delay periods. A colored cue instructed which response was to be executed, followed by a go signal which told the subject to execute the response and a feedback instruction which indicated whether to ‘‘hold’’ or ‘‘f lip’’ the rule linking the colored cue and response. The design allowed us to determine which brain regions were recruited by the specific demands of preparing a rule contingent motor response, executing such a response, evaluating the significance of the feedback, and reconfiguring stimulus–response (SR) associations. The results indicate that an increase in neural activity occurs within the anterior cingulate gyrus under conditions in which SR associations are labile. In contrast, lateral frontal regions are activated by unlikely/unexpected perceptual events regardless of their significance for behavior. A network of subcortical structures, including the mediodorsal nucleus of the thalamus and striatum were the only regions showing activity that was exclusively correlated with the neurocognitive demands of reversing SR associations. We conclude that lateral frontal regions act to evaluate the behavioral significance of perceptual events, whereas medial frontal–thalamic circuits are involved in monitoring and reconfiguring SR associations when necessary

Dynamic facial expressions evoke distinct activation in the face perception network:a connectivity analysis study

Very little is known about the neural structures involved in the perception of realistic dynamic facial expressions. In the present study, a unique set of naturalistic dynamic facial emotional expressions was created. Through fMRI and connectivity analysis, a dynamic face perception network was identified, which is demonstrated to extend Haxby et al.'s [Haxby, J. V., Hoffman, E. A., & Gobbini, M. I. The distributed human neural system for face perception. Trends in Cognitive Science, 4, 223–233, 2000] distributed neural system for face perception. This network includes early visual regions, such as the inferior occipital gyrus, which is identified as insensitive to motion or affect but sensitive to the visual stimulus, the STS, identified as specifically sensitive to motion, and the amygdala, recruited to process affect. Measures of effective connectivity between these regions revealed that dynamic facial stimuli were associated with specific increases in connectivity between early visual regions, such as the inferior occipital gyrus and the STS, along with coupling between the STS and the amygdala, as well as the inferior frontal gyrus. These findings support the presence of a distributed network of cortical regions that mediate the perception of different dynamic facial expressions

MEG responses to the perception of global structure within glass patterns

Background The perception of global form requires integration of local visual cues across space and is the foundation for object recognition. Here we used magnetoencephalography (MEG) to study the location and time course of neuronal activity associated with the perception of global structure from local image features. To minimize neuronal activity to low-level stimulus properties, such as luminance and contrast, the local image features were held constant during all phases of the MEG recording. This allowed us to assess the relative importance of striate (V1) versus extrastriate cortex in global form perception. Methodology/Principal Findings Stimuli were horizontal, rotational and radial Glass patterns. Glass patterns without coherent structure were viewed during the baseline period to ensure neuronal responses reflected perception of structure and not changes in local image features. The spatial distribution of task-related changes in source power was mapped using Synthetic Aperture Magnetometry (SAM), and the time course of activity within areas of maximal power change was determined by calculating time-frequency plots using a Hilbert transform. For six out of eight observers, passive viewing of global structure was associated with a reduction in 10–20 Hz cortical oscillatory power within extrastriate occipital cortex. The location of greatest power change was the same for each pattern type, being close to or within visual area V3a. No peaks of activity were observed in area V1. Time-frequency analyses indicated that neural activity was least for horizontal patterns. Conclusions We conclude: (i) visual area V3a is involved in the analysis of global form; (ii) the neural signature for perception of structure, as assessed using MEG, is a reduction in 10–20 Hz oscillatory power; (iii) different neural processes may underlie the perception of horizontal as opposed to radial or rotational structure; and (iv) area V1 is not strongly activated by global form in Glass patterns

Retinotopic mapping of the primary visual cortex – a challenge for MEG imaging of the human cortex

Magnetoencephalography (MEG) can be used to reconstruct neuronal activity with high spatial and temporal resolution. However, this reconstruction problem is ill-posed, and requires the use of prior constraints in order to produce a unique solution. At present there are a multitude of inversion algorithms, each employing different assumptions, but one major problem when comparing the accuracy of these different approaches is that often the true underlying electrical state of the brain is unknown. In this study, we explore one paradigm, retinotopic mapping in the primary visual cortex (V1), for which the ground truth is known to a reasonable degree of accuracy, enabling the comparison of MEG source reconstructions with the true electrical state of the brain. Specifically, we attempted to localize, using a beanforming method, the induced responses in the visual cortex generated by a high contrast, retinotopically varying stimulus. Although well described in primate studies, it has been an open question whether the induced gamma power in humans due to high contrast gratings derives from V1 rather than the prestriate cortex (V2). We show that the beanformer source estimate in the gamma and theta bands does vary in a manner consistent with the known retinotopy of V1. However, these peak locations, although retinotopically organized, did not accurately localize to the cortical surface. We considered possible causes for this discrepancy and suggest that improved MEG/magnetic resonance imaging co-registration and the use of more accurate source models that take into account the spatial extent and shape of the active cortex may, in future, improve the accuracy of the source reconstructions

Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: One- and two-year outcomes

BACKGROUND. Alemtuzumab (Campath-1H) induction with tacrolimus monotherapy has been shown to provide effective immunosuppression for kidney, liver, lung, and small bowel transplantation. This drug combination was evaluated in pancreas transplant recipients. METHODS. Sixty consecutive pancreas transplants (30 simultaneous pancreas-kidney, 20 pancreas after kidney, and 10 pancreas alone) were carried out under this protocol between July 2003 to January 2005. The mean follow-up was 22 months (range 17-33). RESULTS. One-year patient, pancreas, and kidney allograft survival were 95%, 93%, and 90%, respectively. With 22 months follow-up, patient, pancreas, and kidney survival were 94%, 89%, and 87%, respectively. The rejection rate was 30% (18/60), with four patients (7%) experiencing steroid-resistant rejection. Major infection occurred in three (5%) patients resulting in two (3.3%) deaths from disseminated histoplasmosis and a herpes virus infection. One patient with cryptococcal meningitis was successfully treated. Seven (11.7%) patients experienced cytomegalovirus infection, all of whom responded to treatment with ganciclovir. One (1.7%) case of polymorphic posttransplant lymphoproliferative disease was seen, which regressed with a temporary discontinuation of tacrolimus and high-dose ganciclovir. The mean serum creatinine of the 30 simultaneous pancreas-kidney transplants at one year posttransplant was 1.37±0.33 mg/ml. The preexisting creatinine in pancreas after kidney transplants was not adversely affected by this immunosuppressive protocol. CONCLUSION. A single dose of perioperative alemtuzumab followed by daily tacrolimus monotherapy provides effective immunosuppression for pancreas transplantation, but the optimal use of this drug combination is not yet clear. © 2006 Lippincott Williams & Wilkins, Inc

Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals:study protocol for a randomised controlled trial

BACKGROUND: Deviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis. METHODS/DESIGN: The study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18–60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain. DISCUSSION: Results of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics. TRIAL REGISTRATION: UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013

MEG Assessment of Expressive Language in Children Evaluated for Epilepsy Surgery

Establishing language dominance is an important step in the presurgical evaluation of patients with refractory epilepsy. In the absence of a universally accepted gold-standard non-invasive method to determine language dominance in the preoperative assessment, a range of tools and methodologies have recently received attention. When applied to pediatric age, many of the proposed methods, such as functional magnetic resonance imaging (fMRI), may present some challenges due to the time-varying effects of epileptogenic lesions and of on-going seizures on maturational phenomena. Magnetoencephalography (MEG) has the advantage of being insensitive to the distortive effects of anatomical lesions on brain microvasculature and to differences in the metabolism or vascularization of the developing brain and also provides a less intimidating recording environment for younger children. In this study we investigated the reliability of lateralized synchronous cortical activation during a verb generation task in a group of 28 children (10 males and 18 females, mean age 12 years) with refractory epilepsy who were evaluated for epilepsy surgery. The verb generation task was associated with significant decreases in beta oscillatory power (13–30 Hz) in frontal and temporal lobes. The MEG data were compared with other available presurgical non-invasive data including cortical stimulation, neuropsychological and fMRI data on language lateralization where available. We found that the lateralization of MEG beta power reduction was concordant with language dominance determined by one or more different assessment methods (i.e. cortical stimulation mapping, neuropsychological, fMRI or post-operative data) in 89% of patients. Our data suggest that qualitative hemispheric differences in task-related changes of spectral power could offer a promising insight into the contribution of dominant and non-dominant hemispheres in language processing and may help to characterize the specialization and lateralization of language processes in children

Состояние провоспалительного цитокинового звена у больных с нестабильной стенокарадией и сахарным диабетом 2-го типа в зависимости от функционального класса хронической сердечной недостаточности

Проанализировано состояние провоспалительного звена цитокинов у больных с нестабильной стенокардией (НС) и сопутствующим сахарным диабетом (СД) 2−го типа в зависимости от функционального класса хронической сердечной недостаточности (ХСН). Нарастание проявлений сердечной декомпенсации у больных с НС и СД 2−го типа ассоциируется с высокой активностью провоспалительного цитокинового звена, представленного фактором некроза опухолей−α и интерлейкином−6. Повышение функционального класса ХСН характеризуется увеличением инсулинорезистентности у больных с НС и СД 2−го типа.Проаналізовано стан прозапальної ланки цитокінів у хворих із нестабільною стенокардією (НС) та супутнім цукровим діабетом (ЦД) 2−го типу залежно від функціонального класу хронічної серцевої недостатності (ХСН). Наростання проявів серцевої декомпенсації у хворих із НС та СД 2−го типу асоціюється з високою активністю прозапальної цитокінової ланки, представленої фактором некрозу пухлин−α та інтерлейкіном−6. Підвищення функціонального класу ХСН характеризується зростанням інсулінорезистентності у хворих із НС та ЦД 2−го типу.The state of pro−inflammatory cytokines in patients with unstable angina (UA) and associated type 2 diabetes mellitus (DM) was analyzed depending on the functional class of chronic heart failure (CHF). The increase in manifestations of cardiac decompensation in patients with UA and type 2 DM is associated with high activity of pro−inflammatory cytokine level represented by tumor necrosis factor−β and interleukin−6. Increase of functional class of CHF is characterized by increased insulin resistance in patients with UA and type 2 DM

Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study

Background Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. Methods A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. Results The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19–10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01–174.3, p 5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. Conclusions Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes

Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial

Adrenal glucocorticoid secretion into the systematic circulation is characterised by a complex rhythm, composed of the diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of short duration hormonal pulses. To elucidate the potential neurobiological significance of glucocorticoid pulsatility in man, we have conducted a randomised, double-blind, placebo-controlled, three-way crossover clinical trial on 15 healthy volunteers, investigating the impact of different glucocorticoid rhythms on measures of mood and neural activity under resting conditions by recruiting functional neuroimaging, computerised behavioural tests and ecological momentary assessments. Endogenous glucocorticoid biosynthesis was pharmacologically suppressed, and plasma levels of corticosteroid restored by hydrocortisone replacement in three different regimes, either mimicking the normal ultradian and circadian profile of the hormone, or retaining the normal circadian but abolishing the ultradian rhythm of the hormone, or by our current best oral replacement regime which results in a suboptimal circadian and ultradian rhythm. Our results indicate that changes in the temporal mode of glucocorticoid replacement impact (i) the morning levels of self-perceived vigour, fatigue and concentration, (ii) the diurnal pattern of mood variation, (iii) the within-network functional connectivity of various large-scale resting state networks of the human brain, (iv) the functional connectivity of the default-mode, salience and executive control networks with glucocorticoid-sensitive nodes of the corticolimbic system, and (v) the functional relationship between mood variation and underlying neural networks. The findings indicate that the pattern of the ultradian glucocorticoid rhythm could affect cognitive psychophysiology under non-stressful conditions and opens new pathways for our understanding on the neuropsychological effects of cortisol pulsatility with relevance to the goal of optimising glucocorticoid replacement strategies