Thalamic regulation of frontal interactions in human cognitive flexibility.

Interactions across frontal cortex are critical for cognition. Animal studies suggest a role for mediodorsal thalamus (MD) in these interactions, but the computations performed and direct relevance to human decision making are unclear. Here, inspired by animal work, we extended a neural model of an executive frontal-MD network and trained it on a human decision-making task for which neuroimaging data were collected. Using a biologically-plausible learning rule, we found that the model MD thalamus compressed its cortical inputs (dorsolateral prefrontal cortex, dlPFC) underlying stimulus-response representations. Through direct feedback to dlPFC, this thalamic operation efficiently partitioned cortical activity patterns and enhanced task switching across different contingencies. To account for interactions with other frontal regions, we expanded the model to compute higher-order strategy signals outside dlPFC, and found that the MD offered a more efficient route for such signals to switch dlPFC activity patterns. Human fMRI data provided evidence that the MD engaged in feedback to dlPFC, and had a role in routing orbitofrontal cortex inputs when subjects switched behavioral strategy. Collectively, our findings contribute to the emerging evidence for thalamic regulation of frontal interactions in the human brain.

Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel.

Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, and HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.

Modulations of Insular Projections by Prior Belief Mediate the Precision of Prediction Error during Tactile Learning.

Awareness for surprising sensory events is shaped by prior belief inferred from past experience. Here, we combined hierarchical Bayesian modeling with fMRI on an associative learning task in 28 male human participants to characterize the effect of the prior belief of tactile events on connections mediating the outcome of perceptual decisions. Activity in anterior insular cortex (AIC), premotor cortex (PMd), and inferior parietal lobule (IPL) were modulated by prior belief on unexpected targets compared with expected targets. On expected targets, prior belief decreased the connection strength from AIC to IPL, whereas it increased the connection strength from AIC to PMd when targets were unexpected. Individual differences in the modulatory strength of prior belief on insular projections correlated with the precision that increases the influence of prediction errors on belief updating. These results suggest complementary effects of prior belief on insular-frontoparietal projections mediating the precision of prediction during probabilistic tactile learning.SIGNIFICANCE STATEMENT In a probabilistic environment, the prior belief of sensory events can be inferred from past experiences. How this prior belief modulates effective brain connectivity for updating expectations for future decision-making remains unexplored. Combining hierarchical Bayesian modeling with fMRI, we show that during tactile associative learning, prior expectations modulate connections originating in the anterior insula cortex and targeting salience-related and attention-related frontoparietal areas (i.e., parietal and premotor cortex). These connections seem to be involved in updating evidence based on the precision of ascending inputs to guide future decision-making.

Sharing and caring: The impact of social support on quality of life and health outcomes in hematopoietic stem cell transplantation.

BACKGROUND: Social support is crucial for successful recovery after hematopoietic stem cell transplantation (HSCT) and has the potential to affect patient quality of life (QOL) and health outcomes. However, there are limited data on the relationship between a patient's perception of his or her social support and these outcomes. METHODS: The authors conducted a secondary analysis of 250 autologous and allogeneic HSCT recipients enrolled in 2 supportive care trials at Massachusetts General Hospital from April 2011 through February 2016. They assessed social support as a patient's perception of his or her social well-being via the social well-being subscale of the Functional Assessment of Cancer Therapy. The authors used multivariate regression analyses to examine the relationship between pretransplant social well-being and QOL (Functional Assessment of Cancer Therapy-Treatment Outcome Index), psychological distress (Hospital Anxiety and Depression Scale), posttraumatic stress disorder [PTSD] symptoms (PTSD Checklist), fatigue (Functional Assessment of Cancer Therapy-Fatigue), and health care utilization (hospitalizations and days alive and out of the hospital) 6 months after HSCT. RESULTS: Participants were on average 56.4 years old (SD, 13.3 years); 44% (n = 110) and 56% (n = 140) received autologous and allogeneic HSCT, respectively. Greater pre-HSCT social well-being was associated with higher QOL (B = 0.10; 95% CI, 0.06-0.13; P < .001), lower psychological distress (B = -0.21; 95% CI, -0.29 to -0.12; P < .001), and lower PTSD symptoms (B = -0.12; 95% CI, -0.19 to -0.06; P < .001). Pre-HSCT social well-being was not significantly associated with fatigue or health care utilization 6 months after HSCT. CONCLUSIONS: Patients with higher pre-HSCT perceptions of their social support reported better QOL and lower psychological distress 6 months after HSCT. These findings underscore the potential for social support as a modifiable target for future supportive care interventions to improve the QOL and care of HSCT recipients.

Stimulus transformation into motor action: Dynamic graph analysis reveals a posterior-to-anterior shift in brain network communication of older subjects.

Cognitive performance slows down with increasing age. This includes cognitive processes that are essential for the performance of a motor act, such as the slowing down in response to an external stimulus. The objective of this study was to identify aging-associated functional changes in the brain networks that are involved in the transformation of external stimuli into motor action. To investigate this topic, we employed dynamic graphs based on phase-locking of Electroencephalography signals recorded from healthy younger and older subjects while performing a simple visually-cued finger-tapping task. The network analysis yielded specific age-related network structures varying in time in the low frequencies (2-7 Hz), which are closely connected to stimulus processing, movement initiation and execution in both age groups. The networks in older subjects, however, contained several additional, particularly interhemispheric, connections and showed an overall increased coupling density. Cluster analyses revealed reduced variability of the subnetworks in older subjects, particularly during movement preparation. In younger subjects, occipital, parietal, sensorimotor and central regions were-temporally arranged in this order-heavily involved in hub nodes. Whereas in older subjects, a hub in frontal regions preceded the noticeably delayed occurrence of sensorimotor hubs, indicating different neural information processing in older subjects. All observed changes in brain network organization, which are based on neural synchronization in the low frequencies, provide a possible neural mechanism underlying previous fMRI data, which report an overactivation, especially in the prefrontal and pre-motor areas, associated with a loss of hemispheric lateralization in older subjects.

Progressive gray matter hypertrophy with severity stages of insomnia disorder and its relevance for mood symptoms.

OBJECTIVE: To investigate the gray matter (GM) alterations in patients with insomnia disorder (ID) at different severity stages and the relationship between GM alterations and sleep, mood, and cognitive measures. METHODS: One hundred one ID patients and 63 healthy controls (HC) were included. Each patient underwent structural MRI and completed sleep-, mood-, and cognitive-related questionnaires. The ID patients were further grouped into subthreshold insomnia (SI) group and clinical insomnia (CI) group. We investigated changes in GM volumes in ID patients via diffeomorphic anatomical registration through exponentiated lie algebra voxel-based morphometry (DARTEL-VBM). We first compared voxel-wise differences in GM volumes between the HC group and the ID group. Analysis of variance was performed on individual GM maps in the SI, CI, and HC groups to further investigate the effects of different stages of ID severity on GM volumes. Multiple regression was used to model the relationship between altered GM volumes in SI and CI groups and clinical measures. RESULTS: GM hypertrophies in the left anterior and middle cingulate gyrus, right middle and inferior temporal gyrus, and right cerebellum Crus II were detected in ID. Increased GM volume in the right middle temporal gyrus was detected in the SI group, whereas all three regions in the CI group. Regression analysis showed that mood- and cognitive-related measures had a positive correlation with GM volumes, while sleep-related measures had a negative correlation with GM volumes in the CI group. CONCLUSIONS: Our findings of the progressively increased GM volumes in ID suggest that a hypertrophic cortical morphological mechanism may underlie the altered neuroanatomy induced by insomnia. KEY POINTS: • Insomnia-induced GM hypertrophies in the cingulate gyrus, temporal gyrus, and cerebellum Crus II. • The middle temporal gyrus was early detectable in the SI group. • The increased GM volumes in the CI group were correlated with clinical measures.

Confidence in Decision-Making during Probabilistic Tactile Learning Related to Distinct Thalamo-Prefrontal Pathways.

The flexibility in adjusting the decision strategy from trial to trial is a prerequisite for learning in a probabilistic environment. Corresponding neural underpinnings remain largely unexplored. In the present study, 28 male humans were engaged in an associative learning task, in which they had to learn the changing probabilistic strengths of tactile sample stimuli. Combining functional magnetic resonance imaging with computational modeling, we show that an unchanged decision strategy over successively presented trials related to weakened functional connectivity between ventralmedial prefrontal cortex (vmPFC) and left secondary somatosensory cortex. The weaker the connection strength, the faster participants indicated their choice. If the decision strategy remained unchanged, participant's decision confidence (i.e., prior belief) was related to functional connectivity between vmPFC and right pulvinar. While adjusting the decision strategy, we instead found confidence-related connections between left orbitofrontal cortex and left thalamic mediodorsal nucleus. The stronger the participant's prior belief, the weaker the connection strengths. Together, these findings suggest that distinct thalamo-prefrontal pathways encode the confidence in keeping or changing the decision strategy during probabilistic learning. Low confidence in the decision strategy demands more thalamo-prefrontal processing resources, which is in-line with the theoretical accounts of the free-energy principle.

Multimodal psychosocial intervention for family caregivers of patients undergoing hematopoietic stem cell transplantation: A randomized clinical trial.

BACKGROUND: Caregivers of patients undergoing hematopoietic stem cell transplantation (HCT) experience an immense caregiving burden before, during, and after HCT. METHODS: We conducted an unblinded, randomized trial of a psychosocial intervention (BMT-CARE) for caregivers of patients undergoing autologous and allogeneic HCT at Massachusetts General Hospital. Caregivers were randomly assigned to BMT-CARE or usual care. BMT-CARE was tailored to the HCT trajectory and integrated treatment-related education and self-care with cognitive-behavioral skills to promote coping. Caregivers assigned to BMT-CARE met with a trained interventionist (a psychologist or a social worker) in person, via telephone, or via videoconferencing for 6 sessions starting before HCT and continuing up to day +60 after HCT. The primary endpoint was feasibility, which was defined as at least 60% of eligible caregivers enrolling and completing 50% or more of the intervention sessions. We assesed caregiver quality of life (QOL; Caregiver Oncology Quality of Life Questionnaire), caregiving burden (Caregiver Reaction Assessment), psychological distress (Hospital Anxiety and Depression Scale), self-efficacy (Cancer Self-Efficacy Scale-Transplant), and coping (Measures of Current Status) at baseline and 30 and 60 days after HCT. We used mixed linear effect models to assess the effect of BMT-CARE on outcomes longitudinally. RESULTS: We enrolled 72.5% of eligible caregivers (100 of 138), and 80% attended 50% or more of the intervention sessions. Caregivers randomized to BMT-CARE reported improved QOL (B = 6.11; 95% CI, 3.50-8.71; P < .001), reduced caregiving burden (B = -6.02; 95% CI, -8.49 to -3.55; P < .001), lower anxiety (B = -2.18; 95% CI, -3.07 to -1.28; P < .001) and depression symptoms (B = -1.23; 95% CI, -1.92 to -0.54; P < .001), and improved self-efficacy (B = 7.22; 95% CI, 2.40-12.03; P = .003) and coping skills (B = 4.83; 95% CI, 3.04-6.94; P < .001) in comparison with the usual-care group. CONCLUSIONS: A brief multimodal psychosocial intervention tailored for caregivers of HCT recipients is feasible and may improve QOL, mood, coping, and self-efficacy while reducing the caregiving burden during the acute HCT period.

A response-locking protocol to boost sensitivity for fMRI-based neurochronometry.

The timeline of brain-wide neural activity relative to a behavioral event is crucial when decoding the neural implementation of a cognitive process. Yet, fMRI assesses neural processes indirectly via delayed and regionally variable hemodynamics. This method-inherent temporal distortion impacts the interpretation of behavior-linked neural timing. Here we describe a novel behavioral protocol that aims at disentangling the BOLD dynamics of the pre- and post-response periods in response time tasks. We tested this response-locking protocol in a perceptual decision-making (random dot) task. Increasing perceptual difficulty produced expected activity increases over a broad network involving the lateral/medial prefrontal cortex and the anterior insula. However, response-locking revealed a previously unreported functional dissociation within this network. preSMA and anterior premotor cortex (prePMV) showed post-response activity modulations while anterior insula and anterior cingulate cortex did not. Furthermore, post-response BOLD activity at preSMA showed a modulation in timing but not amplitude while this pattern was reversed at prePMV. These timeline dissociations with response-locking thus revealed three functionally distinct sub-networks in what was seemingly one shared distributed network modulated by perceptual difficulty. These findings suggest that our novel response-locked protocol could boost the timing-related sensitivity of fMRI.

High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML.

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated NPM1 in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than FLT3) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated NPM1 to evaluate the potential significance of NPM1 variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high NPM1 VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; P < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; P < .0001) compared with the other NPM1-mutated cases. In both univariate and multivariable analyses, high NPM1 VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission (P = .0004) and in patients with mutated DNMT3A (P < .0001). Our findings indicate that the prognostic effect of NPM1 mutation in de novo AML may be influenced by the relative abundance of the mutated allele.

Freely chosen and instructed actions are terminated by different neural mechanisms revealed by kinematics-informed EEG.

Neurophysiological accounts of human volition are dominated by debates on the origin of voluntary choices but the neural consequences that follow such choices remain poorly understood. For instance, could one predict whether or not an action was chosen voluntarily based only on how that action is motorically executed? We investigated this possibility by integrating scalp electroencephalograms and index-finger accelerometer recordings acquired while people chose between pressing a left or right button either freely or as instructed by a visual cue. Even though freely selected and instructed actions were executed with equal vigor, the timing of the movement to release the button was comparatively delayed for freely selected actions. This chronometric difference was six-times larger for the ß-oscillations over the sensorimotor cortex that characteristically accompany an action's termination. This surprising modulation of an action's termination by volition was traceable to volition-modulated differences in how the competing yet non-selected action was represented and regulated.

Frequency-specific modulation of connectivity in the ipsilateral sensorimotor cortex by different forms of movement initiation.

A consistent finding in motor EEG research is a bilateral attenuation of oscillatory activity over sensorimotor regions close to the onset of an upcoming unilateral hand movement. In contrast, little is known about how movement initiation affects oscillatory activity, especially in the hemisphere ipsilateral to the moving hand. We here investigated the neural mechanisms modulating oscillatory activity in the ipsilateral motor cortex prior to movement onset under the control of two different initiating networks, namely, Self-initiated and Visually-cued actions. During motor preparation, a contralateral preponderance of power over sensorimotor cortex (SM) was observed in α and ß bands during Visually-cued movements, whereas power changes were more bilateral during Self-initiated movements. Coherence between ipsilateral SM (iSM) and contralateral SM (cSM) in the α-band was significantly increased compared to the respective baseline values, independent of the context of movement initiation. However, this context-independent cSM-iSM coherence modulated the power changes in iSM in a context-dependent manner, that is, a stronger cSM-iSM coherence correlated with a larger decrease in high-ß power over iSM in the Self-initiated condition, in contrast to a smaller decrease in α power in the Visually-cued condition. In addition, the context-dependent coherence between SMA and iSM in the α-band and δ-θ-band for the Self-initiated and Visually-cued condition, respectively, exhibited a similar context-dependent modulation for power changes. Our findings suggest that the initiation of regional oscillations over iSM reflects changes in the information flow with the contralateral sensorimotor and premotor areas dependent upon the context of movement initiation. Importantly, the interaction between regional oscillations and network-like oscillatory couplings indicates different frequency-specific inhibitory mechanisms that modulate the activity in the ipsilateral sensorimotor cortex dependent upon how the movement is initiated.

Quality of life and mood predict posttraumatic stress disorder after hematopoietic stem cell transplantation.

BACKGROUND: During hospitalization for hematopoietic stem cell transplantation (HCT), patients experience a steep deterioration in quality of life (QOL) and mood. To our knowledge, the impact of this deterioration on patients' QOL and posttraumatic stress disorder (PTSD) symptoms after HCT is unknown. METHODS: We conducted a prospective longitudinal study of patients hospitalized for HCT. They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) and depression and anxiety symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) at the time of admission for HCT, during hospitalization, and 6 months after HCT. We also used the Hospital Anxiety and Depression Scale (HADS) to measure patients' anxiety and depression symptoms at baseline and during HCT hospitalization. The PTSD Checklist was used to assess for PTSD symptoms. Multivariable linear regression models were used to identify predictors of QOL and PTSD symptoms at 6 months. RESULTS: We enrolled 90 of 93 consecutively eligible patients (97%) undergoing autologous and allogeneic HCT. Data at 6 months were available for 67 participants. At 6 months, 28.4% of participants met the criteria for PTSD and 43.3% had clinically significant depression. On multivariable regression analyses adjusting for significant covariates, changes in QOL and depression scores from week 2 of HCT hospitalization to baseline predicted worse QOL (changes in scores between week 2 and baseline [Δ] QOL: ß, 0.94 [P<.0001] and Δ PHQ-9: ß, -2.59 [P = 0.001]) and PTSD symptoms (Δ QOL: ß, -0.40 [P<.0001] and Δ PHQ-9: ß, 1.26 [P<.0001]) at 6 months after HCT. CONCLUSIONS: Six months after HCT, a significant percentage of patients met the criteria for PTSD and depression. A decline in QOL and an increase in depressive symptoms during hospitalization for HCT were found to be the most important predictors of 6-month QOL impairment and PTSD symptoms. Therefore, managing symptoms of depression and QOL deterioration during HCT hospitalization may be critical to improving QOL at 6 months and reducing the risk of PTSD. Cancer 2016;122:806-812. © 2015 American Cancer Society.

Effect of Inpatient Palliative Care on Quality of Life 2 Weeks After Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

Importance: During hospitalization for hematopoietic stem cell transplantation (HCT), patients receive high-dose chemotherapy before transplantation and experience significant physical and psychological symptoms and poor quality of life (QOL). Objective: To assess the effect of inpatient palliative care on patient- and caregiver-reported outcomes during hospitalization for HCT and 3 months after transplantation. Design, Setting, and Participants: Nonblinded randomized clinical trial among 160 adults with hematologic malignancies undergoing autologous/allogeneic HCT and their caregivers (n = 94). The study was conducted from August 2014 to January 2016 in a Boston hospital; follow-up was completed in May 2016. Interventions: Patients assigned to the intervention (n=81) were seen by palliative care clinicians at least twice a week during HCT hospitalization; the palliative intervention was focused on management of physical and psychological symptoms. Patients assigned to standard transplant care (n=79) could be seen by palliative care clinicians on request. Main Outcomes and Measures: Primary: change in patient QOL from baseline to week 2; secondary: patient-assessed mood, fatigue, and symptom burden scores at baseline, 2 weeks, and 3 months after HCT and caregiver-assessed QOL and mood at baseline and 2 weeks after HCT. Results: Among 160 enrolled patients (mean age, 60 [SD, 13.3] years; 91 women [56.9%]; median hospital stay, 21 days) and 94 caregivers, 157 (98.1%) and 89 (94.7%), respectively, completed 2-week follow-up, and 149 patients (93.1%) completed 3-month follow-up. Patients in the intervention group reported a smaller decrease in QOL from baseline to week 2 (mean baseline score, 110.26; week 2 score, 95.46; mean change, -14.72) compared with patients in the control group (mean baseline score, 106.83; week 2 score, 85.42; mean change, -21.54; difference between groups, -6.82; 95% CI, -13.48 to -0.16; P = .045). Among the secondary outcomes, from baseline to week 2, patients in the intervention group vs those in the control group had less increase in depression (mean, 2.43 vs 3.94; mean difference, 1.52; 95% CI, 0.23-2.81; P = .02), lower anxiety (mean, -0.80 vs 1.12; mean difference, 1.92; 95% CI, 0.83-3.01; P < .001), no difference in fatigue (mean, -10.30 vs -13.65; mean difference, -3.34; 95% CI, -7.25 to 0.56; P = .09), and less increase in symptom burden (mean, 17.35 vs 23.14; mean difference, 5.80; 95% CI, 0.49-11.10; P = .03). At 3 months after HCT, intervention patients vs control patients had higher QOL scores (mean, 112.00 vs 106.66; mean difference, 5.34; 95% CI, 0.04-10.65; P = .048) and less depression symptoms (mean, 3.49 vs 5.19; mean difference, -1.70; 95% CI, -2.75 to -0.65; P = .002) but no significant differences in anxiety, fatigue, or symptom burden. From baseline to week 2 after HCT, caregivers of patients in the intervention group vs caregivers of patients in the control group reported no significant differences in QOL or anxiety but had a smaller increase in depression (mean, 0.25 vs 1.80; mean difference, 1.55; 95% CI, 0.14-2.96; P = .03). Conclusions and Relevance: Among adults at a single institution undergoing HCT for hematologic malignancy, the use of inpatient palliative care compared with standard transplant care resulted in a smaller decrease in QOL 2 weeks after transplantation. Further research is needed for replication and to assess longer-term outcomes and cost implications. Trial Registration: clinicaltrials.gov Identifier: NCT02207322.

Quality of life and mood of patients and family caregivers during hospitalization for hematopoietic stem cell transplantation.

BACKGROUND: We conducted a study to investigate the impact of hospitalization for hematopoietic stem cell transplantation (HCT) on the quality of life (QOL) and mood of patients and family caregivers (FC). METHODS: We conducted a longitudinal study of patients who were hospitalized for HCT and their FC. We assessed QOL (using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation) and mood (using the Hospital Anxiety and Depression Scale) at baseline (6 days before HCT), day +1, and day +8 of HCT. We administered the Medical Outcomes Study Health Survey Short Form-36 to examine FC QOL (Physical Component Scale and Mental Component Scale). To identify predictors of changes in QOL, we used multivariable linear mixed models. RESULTS: We enrolled 97% of eligible patients undergoing autologous (30 patients), myeloablative (30 patients), or reduced intensity (30 patients) allogeneic HCT. Patients' QOL markedly declined (mean Functional Assessment of Cancer Therapy-Bone Marrow Transplantation score, 109.6 to 96.0; P<.0001) throughout hospitalization. The percentage of patients with depression (Hospital Anxiety and Depression Scale-Depression score of >7) more than doubled from baseline to day +8 (15.6% to 37.8%; P<.0001), whereas the percentage of patients with anxiety remained stable (22.2%; P = .8). These results remained consistent when data were stratified by HCT type. Baseline depression (ß, -2.24; F, 42.2 [P<.0001]) and anxiety (ß, -0.63; F, 4.4 [P =.03]) were found to independently predict worse QOL throughout hospitalization. FC QOL declined during the patient's hospitalization (physical component scale: 83.1 to 79.6 [P =.03] and mental component scale: 71.6 to 67.4 [P =.04]). CONCLUSIONS: Patients undergoing HCT reported a steep deterioration in QOL and substantially worsening depression during hospitalization. Baseline anxiety and depression predicted worse QOL during hospitalization, underscoring the importance of assessing pre-HCT psychiatric morbidity.

Difficulties in hematopoietic progenitor cell collection from a patient with TEMPI syndrome and severe iatrogenic iron deficiency.

BACKGROUND: Collection of hematopoietic progenitor cells by apheresis (HPC-A) requires separation of cells by density. Previous studies highlighted the challenges of HPC-A collection from patients with abnormal red blood cells (RBCs). TEMPI syndrome is a recently described condition defined by teleangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Patients with TEMPI syndrome have responded to therapies used to treat plasma cell dyscrasias and may benefit from autologous HPC transplantation. We report HPC-A collection from a patient with TEMPI syndrome that was complicated by severe iron deficiency. STUDY DESIGN AND METHODS: The patient received granulocyte-colony-stimulating factor (G-CSF) and plerixafor for HPC mobilization and underwent 3 days of HPC-A collection. RESULTS: The patient presented for collection with a microcytic erythrocytosis. Over 3 days, approximately 50 L of whole blood was processed, and 2 × 10(8) CD34+ cells were collected (2.8 × 10(6) CD34+ cells/kg). The mean collection efficiency (CE), percentage of mononuclear cells, hematocrit (Hct), and RBC count were 18%, 90%, 14%, and 9 × 10(11) , respectively. Altering collection variables to avoid RBC contamination reduced CE. Ficoll preparations of the products after freeze-thaw showed RBC contamination and hemolysis. Postthaw viability exceeded 95%. The products were not RBC reduced or washed. There were no adverse reactions during or after infusion. CONCLUSIONS: HPC-A collection from a patient with TEMPI syndrome was complicated by microcytic erythrocytosis, leading to RBC contamination and hemolysis in the product. Adequate HPCs were collected and the patient tolerated infusion without RBC depletion or washing. Our report highlights difficulties of HPC-A collection from iron-deficient patients.

[Unusual behaviors in sleep as "compensatory" reactions, aimed at normalizing sleep-alertness cycles].

The present article is an attempt to perform a conceptual clinical and physiological analysis of a large spec- trum of sleep-related phenomena called parasomnias in children, based on data from three independent in- stitutions. Parasonmias appear in the process of falling asleep, at the time of sleep stage changes, and upon awakening. They are common for both healthy children and those with neurological and psychiatric disorders. Brief descriptions of clinical pictures of several groups of parasomnias and their polysomnographic characteristics are presented. Instances of stereotyped rhythmic movements (e.g. head rocking), paroxysmal somatic and behavioral episodes (night terrors and nightmares), "static" phenomena (sleep with open eyes, strange body positions), as well as somnambulism are specifically described. Common features of parasomnias as a group have been identified (the "Parasomnia syndrome"). It was found that sleep architecture frequently normalizes after a parasomnia episode, whereas parasomnias are self-liquidated after sleep matures (self-cure). The significance of gender differences in parasomnias have been reviewed. Possible compensatory physiological functions of parasomnias acting as "switches" or "stabilizers" of sleep stages to "off-set" deviated or immature sleep-wake mechanisms were discussed.

Human orbitofrontal cortex signals decision outcomes to sensory cortex during behavioral adaptations.

The ability to respond flexibly to an ever-changing environment relies on the orbitofrontal cortex (OFC). However, how the OFC associates sensory information with predicted outcomes to enable flexible sensory learning in humans remains elusive. Here, we combine a probabilistic tactile reversal learning task with functional magnetic resonance imaging (fMRI) to investigate how lateral OFC (lOFC) interacts with the primary somatosensory cortex (S1) to guide flexible tactile learning in humans. fMRI results reveal that lOFC and S1 exhibit distinct task-dependent engagement: while the lOFC responds transiently to unexpected outcomes immediately following reversals, S1 is persistently engaged during re-learning. Unlike the contralateral stimulus-selective S1, activity in ipsilateral S1 mirrors the outcomes of behavior during re-learning, closely related to top-down signals from lOFC. These findings suggest that lOFC contributes to teaching signals to dynamically update representations in sensory areas, which implement computations critical for adaptive behavior.

Analogous cognitive strategies for tactile learning in the rodent and human brain.

Evolution has molded individual species' sensory capacities and abilities. In rodents, who mostly inhabit dark tunnels and burrows, the whisker-based somatosensory system has developed as the dominant sensory modality, essential for environmental exploration and spatial navigation. In contrast, humans rely more on visual and auditory inputs when collecting information from their surrounding sensory space in everyday life. As a result of such species-specific differences in sensory dominance, cognitive relevance and capacities, the evidence for analogous sensory-cognitive mechanisms across species remains sparse. However, recent research in rodents and humans yielded surprisingly comparable processing rules for detecting tactile stimuli, integrating touch information into percepts, and goal-directed rule learning. Here, we review how the brain, across species, harnesses such processing rules to establish decision-making during tactile learning, following canonical circuits from the thalamus and the primary somatosensory cortex up to the frontal cortex. We discuss concordances between empirical and computational evidence from micro- and mesoscopic circuit studies in rodents to findings from macroscopic imaging in humans. Furthermore, we discuss the relevance and challenges for future cross-species research in addressing mutual context-dependent evaluation processes underpinning perceptual learning.

Modulation of prefrontal couplings by prior belief-related responses in ventromedial prefrontal cortex.

Humans and other animals can maintain constant payoffs in an uncertain environment by steadily re-evaluating and flexibly adjusting current strategy, which largely depends on the interactions between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). While the ventromedial PFC (vmPFC) represents the level of uncertainty (i.e., prior belief about external states), it remains unclear how the brain recruits the PFC-MD network to re-evaluate decision strategy based on the uncertainty. Here, we leverage non-linear dynamic causal modeling on fMRI data to test how prior belief-dependent activity in vmPFC gates the information flow in the PFC-MD network when individuals switch their decision strategy. We show that the prior belief-related responses in vmPFC had a modulatory influence on the connections from dorsolateral PFC (dlPFC) to both, lateral orbitofrontal (lOFC) and MD. Bayesian parameter averaging revealed that only the connection from the dlPFC to lOFC surpassed the significant threshold, which indicates that the weaker the prior belief, the less was the inhibitory influence of the vmPFC on the strength of effective connections from dlPFC to lOFC. These findings suggest that the vmPFC acts as a gatekeeper for the recruitment of processing resources to re-evaluate the decision strategy in situations of high uncertainty.