Stimulation of distinct parietal locations differentiates frontal versus hippocampal network involvement in memory formation.

Adjacent regions of parietal cortex are thought to affiliate with distinct large-scale networks and thereby make different contributions to memory formation. We directly tested this putative functional segregation within parietal cortex by perturbing activity of anterior versus posterior parietal areas. We applied noninvasive theta-burst transcranial magnetic stimulation to these locations immediately before a semantic encoding task, and subsequently tested recollection memory. Consistent with previous findings, fMRI activity in left inferior frontal gyrus during semantic encoding correlated with subsequent high memory accuracy and strong subjective recollection. Stimulation of the posterior parietal cortex decoupled its network - the hippocampal-cortical network - from left inferior frontal gyrus. Furthermore, posterior parietal stimulation reduced highly accurate subjective recollection. Critically, both of these changes occurred relative to stimulation of the anterior parietal cortex. Stimulating anterior versus posterior parietal cortex therefore differentiated hippocampal network involvement in episodic memory. This provides direct evidence that distinct territories within close proximity of each other in parietal cortex make functionally distinct contributions to memory formation. Further, noninvasive stimulation has the spatial resolution required to differentially modulate the interaction of these adjacent parietal locations with distributed large-scale brain networks.

Evidence from theta-burst stimulation that age-related de-differentiation of the hippocampal network is functional for episodic memory.

Episodic memory is supported by hippocampal interactions with a distributed network. Aging is associated with memory decline and network de-differentiation. However, the role of de-differentiation in memory decline has not been directly tested. We reasoned that hippocampal network-targeted stimulation could test these theories, as age-related changes in the network response to stimulation would indicate network reorganization, and corresponding changes in memory would suggest that this reorganization is functional. We compared effects of stimulation on fMRI connectivity and memory in younger versus older adults. Theta-burst network-targeted stimulation of left lateral parietal cortex selectively increased hippocampal network connectivity and modulated memory in younger adults. In contrast, stimulation in older adults increased connectivity throughout the brain, without network selectivity, and did not influence memory. These findings provide evidence that network responses to stimulation are de-differentiated in aging and suggest that age-related de-differentiation is relevant for memory. This manuscript is part of the Special Issue entitled "Cognitive Neuroscience of Healthy and Pathological Aging" edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Cognitive control mediates age-related changes in flexible anticipatory processing during listening comprehension.

Effective listening comprehension not only requires processing local linguistic input, but also necessitates incorporating contextual cues available in the global communicative environment. Local sentence processing can be facilitated by pre-activation of likely upcoming input, or predictive processing. Recent evidence suggests that young adults can flexibly adapt local predictive processes based on cues provided by the global communicative environment, such as the reliability of specific speakers. Whether older comprehenders can also flexibly adapt to global contextual cues is currently unknown. Moreover, it is unclear whether the underlying mechanisms supporting local predictive processing differ from those supporting adaptation to global contextual cues. Critically, it is unclear whether these mechanisms change as a function of typical aging. We examined the flexibility of prediction in young and older adults by presenting sentences from speakers whose utterances were typically more or less predictable (i.e., reliable speakers who produced expected words 80% of the time, versus unreliable speakers who produced expected words 20% of the time). For young listeners, global speaker reliability cues modulated neural effects of local predictability on the N400. In contrast, older adults, on average, did not show global modulation of local processing. Importantly, however, cognitive control (i.e., Stroop interference effects) mediated age-related reductions in sensitivity to the reliability of the speaker. Both young and older adults with high cognitive control showed greater N400 effects of predictability during sentences produced by a reliable speaker, suggesting that cognitive control is required to regulate the strength of top-down predictions based on global contextual information. Critically, cognitive control predicted sensitivity to global speaker-specific information but not local predictability cues, suggesting that predictive processing in local sentence contexts may be supported by separable neural mechanisms from adaptation of prediction as a function of global context. These results have important implications for interpreting age-related change in predictive processing, and for drawing more generalized conclusions regarding domain-general versus language-specific accounts of prediction.

Cerebellar Theta and Beta Noninvasive Stimulation Rhythms Differentially Influence Episodic Memory versus Semantic Prediction.

The human cerebellum is thought to interact with distributed brain networks to support cognitive abilities such as episodic memory and semantic prediction. Hippocampal and fronto-temporo-parietal networks that respectively support episodic memory versus semantic prediction have been associated with distinct endogenous oscillatory activity frequency bands: theta (∼3-8 Hz) versus beta (∼13-30 Hz) respectively. We sought to test whether it is possible to toggle cerebellar participation in episodic memory versus semantic prediction by noninvasively stimulating with theta versus beta rhythmic transcranial magnetic stimulation. In human subjects of both sexes, cerebellar theta stimulation improved episodic memory encoding but did not influence neural signals of semantic prediction, whereas beta stimulation of the same cerebellar location increased neural signals of semantic prediction but did not influence episodic memory encoding. This constitutes evidence for double dissociation of cerebellar contributions to semantic prediction versus episodic memory based on stimulation rhythm, supporting the hypothesis that the cerebellum can be biased to support these distinct cognitive abilities at the command of network-specific rhythmic activity.SIGNIFICANCE STATEMENT The cerebellum interacts with several distinct large-scale brain networks for cognitive function, but the factors governing selectivity of such interactions for particular functions are not fully understood. We tested the hypothesis that cerebellar contributions to cognition are guided by neural oscillations with function-specific frequency bands. We demonstrated that matching noninvasive stimulation to network-specific frequencies selectively enhanced episodic memory versus semantic prediction. These findings suggest that cerebellar contributions to cognitive networks are selected based on corresponding activity rhythms and could be used to develop cerebellar stimulation interventions for specific neurocognitive impairments.

Fish oil-containing multicomponent lipid emulsion vs soy-based lipid emulsion and neurodevelopmental outcomes of children born < 29 weeks' gestation.

OBJECTIVE: To compare neurodevelopmental outcomes of extremely preterm children who received soy-medium chain triglycerides-olive-fish oil-containing lipid emulsion (SMOF-LE) vs soy-based LE. STUDY DESIGN: We conducted a pre-post comparative cohort study of children born < 29 weeks' gestation who received > 7 days of LE. Outcomes were mortality/significant neurodevelopmental impairment (NDI), mortality/any NDI, significant NDI, any NDI, and individual components of NDI. RESULTS: Among children with follow-up data (Intralipid: n = 340/442, 77%; SMOF-LE: n = 214/286, 75%), baseline characteristics were comparable except for postnatal steroids. There was no significant difference in death/significant NDI between groups. Adjusted odds of death/any NDI [0.68 (95% CI 0.48, 0.97)], any NDI [0.64 (95% CI 0.44, 0.93)] and Bayley-III language score < 85 and <70 were significantly lower in the SMOF-LE group. CONCLUSIONS: In extremely preterm children, a change from soy-based LE to SMOF-LE was not associated with deleterious effect on neurodevelopmental outcomes and may have been associated with some improvement.

Flexible predictions during listening comprehension: Speaker reliability affects anticipatory processes.

During listening comprehension, the identification of individual words can be strongly influenced by properties of the preceding context. While sentence context can facilitate both behavioral and neural responses, it is unclear whether these effects can be attributed to the pre-activation of lexico-semantic features or the facilitated integration of contextually congruent words. Moreover, little is known about how statistics of the broader language environment, or information about the current speaker, might shape these facilitation effects. In the present study, we measured neural responses to predictable and unpredictable words as participants listened to sentences for comprehension. Critically, we manipulated the reliability of each speaker's utterances, such that individual speakers either tended to complete sentences with words that were highly predictable (reliable speaker) or with words that were unpredictable but still plausible (unreliable speaker). As expected, the amplitude of the N400 was reduced for locally predictable words, but, critically, these context effects were also modulated by speaker identity. Sentences from a reliable speaker showed larger facilitation effects with an earlier onset, suggesting that listeners engaged in enhanced anticipatory processing when a speaker's behavior was more predictable. This finding suggests that listeners can implicitly track the reliability of predictive cues in their environment and use these statistics to adaptively regulate predictive processing.

Multi-component lipid emulsion vs soy-based lipid emulsion for very low birth weight preterm neonates: A pre-post comparative study.

OBJECTIVE: To examine the effectiveness of soybean oil-medium chain triglycerides-olive oil-fish oil lipid emulsion (SMOF-LE) on clinical outcomes of very-low-birth-weight neonates. STUDY DESIGN: We conducted a pre-post comparative study of very-low-birth-weight neonates, dividing them according to lipid emulsion received: Intralipid (soy-based; n = 680) or SMOF-LE (n = 617). Primary outcomes were mortality, chronic lung disease, severe retinopathy, infection, and necrotising enterocolitis. Secondary outcomes were cholestasis, osteopenia, time to full feeds, and time to regain birthweight. RESULTS: Baseline characteristics between groups were comparable. Primary outcomes did not differ significantly between groups, although any retinopathy was significantly lower in the SMOF-LE group. SMOF-LE group had lower odds of cholestasis, osteopenia, and lipid interruption, and reduced times to full feeds and to regain birthweight. CONCLUSIONS: Compared with Intralipid, SMOF-LE was not associated with differences in mortality and major morbidities but was associated with lower odds of any retinopathy, cholestasis, and osteopenia; and improved lipid tolerance.

Electrophysiological evidence for preserved primacy of lexical prediction in aging.

Young adults show consistent neural benefits of predictable contexts when processing upcoming words, but these benefits are less clear-cut in older adults. Here we disentangle the neural correlates of prediction accuracy and contextual support during word processing, in order to test current theories that suggest that neural mechanisms underlying predictive processing are specifically impaired in older adults. During a sentence comprehension task, older and younger readers were asked to predict passage-final words and report the accuracy of these predictions. Age-related reductions were observed for N250 and N400 effects of prediction accuracy, as well as for N400 effects of contextual support independent of prediction accuracy. Furthermore, temporal primacy of predictive processing (i.e., earlier facilitation for successful predictions) was preserved across the lifespan, suggesting that predictive mechanisms are unlikely to be uniquely impaired in older adults. In addition, older adults showed prediction effects on frontal post-N400 positivities (PNPs) that were similar in amplitude to PNPs in young adults. Previous research has shown correlations between verbal fluency and lexical prediction in older adult readers, suggesting that the production system may be linked to capacity for lexical prediction, especially in aging. The current study suggests that verbal fluency modulates PNP effects of contextual support, but not prediction accuracy. Taken together, our findings suggest that aging does not result in specific declines in lexical prediction.

In vitro differentiation of neural cells from human adipose tissue derived stromal cells.

BACKGROUND: Stem cells, including neural stem cells (NSCs), are endowed with self-renewal capability and hence hold great opportunity for the institution of replacement/protective therapy. We propose a method for in vitro generation of stromal cells from human adipose tissue and their differentiation into neural cells. MATERIALS AND METHODS: Ten grams of donor adipose tissue was surgically resected from the abdominal wall of the human donor after the participants' informed consents. The resected adipose tissue was minced and incubated for 1 hour in the presence of an enzyme (collagenase-type I) at 370C followed by its centrifugation. After centrifugation, the supernatant and pellets were separated and cultured in a medium for proliferation at 370C with 5% CO2 for 9-10 days in separate tissue culture dishes for generation of mesenchymal stromal cells (MSC). At the end of the culture, MSC were harvested and analyzed. The harvested MSC were subjected for further culture for their differentiation into neural cells for 5-7 days using differentiation medium mainly comprising of neurobasal medium. At the end of the procedure, culture cells were isolated and studied for expression of transcriptional factor proteins: orthodenticle homolog-2 (OTX-2), beta-III-tubulin (ß3-Tubulin), glial-fibrillary acid protein (GFAP) and synaptophysin-ß2. RESULTS: In total, 50 neural cells-lines were generated. In vitro generated MSC differentiated neural cells' mean quantum was 5.4 ± 6.9 ml with the mean cell count being, 5.27 ± 2.65 × 103/µl. All of them showed the presence of OTX-2, ß3-Tubulin, GFAP, synaptophysin-ß2. CONCLUSION: Neural cells can be differentiated in vitro from MSC safely and effectively. In vitro generated neural cells represent a potential therapy for recovery from spinal cord injuries and neurodegenerative disease.

Motherese, affect, and vocabulary development: dyadic communicative interactions in infants and toddlers.

Responsive parental communication during an infant's first year has been positively associated with later language outcomes. This study explores responsivity in mother-infant communication by modeling how change in guiding language between 7 and 11 months influences toddler vocabulary development. In a group of 32 mother-child dyads, change in early maternal guiding language positively predicted child language outcomes measured at 18 and 24 months. In contrast, a number of other linguistic variables - including total utterances and non-guiding language - did not correlate with toddler vocabulary development, suggesting a critical role of responsive change in infant-directed communication. We further assessed whether maternal affect during early communication influenced toddler vocabulary outcomes, finding that dominant affect during early mother-infant communications correlated to lower child language outcomes. These findings provide evidence that responsive parenting should not only be assessed longitudinally, but unique contributions of language and affect should also be concurrently considered in future study.

In vitro Generated Mesenchymal Stem Cells: Suitable Tools to Target Insulin Dependent Diabetes Mellitus?

A synergy of a pre-accumulated genes with an autoimmunity advancing to slow abolition of pancreatic beta-cells causes insulin deficiency and results enrooting insulin dependent diabetes mellitus (IDDM). As per WHO data worldwide about 150 million people are diabetic and the number may rise to more than double by the year 2025. Any absolute cure for IDDM is not available yet, and one of the credible advent in the field include cell-based therapy. At this conjecture, mesenchymal stem cells (MSC) seems to have a specific and beneficial characteristics due to their in vivo as well as in vitro potential to mimic a pancreatic endocrine phenotype and immune-regulatory actions. MSC have the capacity to tweak endogenous tissue and cells of immune system. They have been proven as secure and efficacious cell-based regenerative therapy, to treat diverse autoimmune, degenerative diseases and tissue injuries. By consolidating characteristics of MSC biology, MSC-based therapy, engineering and advances in the field, MSC have a great potential to bring us notably closer to a much-needed and long-time awaited cure of IDDM. The review discusses MSC-based cellular therapeutic strategies targeting at IDDM. MSC characteristics of immunomodulation and regeneration potential when used alone or in combination with islets or in differentiated form of insulin producing cells (IPC) are taken into consideration for the review purpose.

Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach.

BACKGROUND: Spinal cord injury (SCI) is not likely to recover by current therapeutic modalities. Stem cell (SC) therapy (SCT) has promising results in regenerative medicine. We present our experience of co-infusion of autologous adipose tissue derived mesenchymal SC differentiated neuronal cells (N-Ad-MSC) and hematopoietic SCs (HSCs) in a set of patients with posttraumatic paraplegia. MATERIALS AND METHODS: Ten patients with posttraumatic paraplegia of mean age 3.42 years were volunteered for SCT. Their mean age was 28 years, and they had variable associated complications. They were subjected to adipose tissue resection for in vitro generation of N-Ad-MSC and bone marrow aspiration for generation of HSC. Generated SCs were infused into the cerebrospinal fluid (CSF) below injury site in all patients. RESULTS: Total mean quantum of SC infused was 4.04 ml with a mean nucleated cell count of 4.5 × 10(4)/µL and mean CD34+ of 0.35%, CD45-/90+ and CD45-/73+ of 41.4%, and 10.04%, respectively. All of them expressed transcription factors beta-3 tubulin and glial fibrillary acid protein. No untoward effect of SCT was noted. Variable and sustained improvement in Hauser's index and American Spinal Injury Association score was noted in all patients over a mean follow-up of 2.95 years. Mean injury duration was 3.42 years against the period of approximately 1-year required for natural recovery, suggesting a positive role of SCs. CONCLUSION: Co-infusion of N-Ad-MSC and HSC in CSF is safe and viable therapeutic approach for SCIs.

Sensitivity to Referential Ambiguity in Discourse: The Role of Attention, Working Memory, and Verbal Ability.

The establishment of reference is essential to language comprehension. The goal of this study was to examine listeners' sensitivity to referential ambiguity as a function of individual variation in attention, working memory capacity, and verbal ability. Participants listened to stories in which two entities were introduced that were either very similar (e.g., two oaks) or less similar (e.g., one oak and one elm). The manipulation rendered an anaphor in a subsequent sentence (e.g., oak) ambiguous or unambiguous. EEG was recorded as listeners comprehended the story, after which participants completed tasks to assess working memory, verbal ability, and the ability to use context in task performance. Power in the alpha and theta frequency bands when listeners received critical information about the discourse entities (e.g., oaks) was used to index attention and the involvement of the working memory system in processing the entities. These measures were then used to predict an ERP component that is sensitive to referential ambiguity, the Nref, which was recorded when listeners received the anaphor. Nref amplitude at the anaphor was predicted by alpha power during the earlier critical sentence: Individuals with increased alpha power in ambiguous compared with unambiguous stories were less sensitive to the anaphor's ambiguity. Verbal ability was also predictive of greater sensitivity to referential ambiguity. Finally, increased theta power in the ambiguous compared with unambiguous condition was associated with higher working-memory span. These results highlight the role of attention and working memory in referential processing during listening comprehension.

Insulin-secreting adipose-derived mesenchymal stromal cells with bone marrow-derived hematopoietic stem cells from autologous and allogenic sources for type 1 diabetes mellitus.

BACKGROUND AIMS: Stem cell therapy (SCT) is now the up-coming therapeutic modality for treatment of type 1 diabetes mellitus (T1DM). METHODS: Our study was a prospective, open-labeled, two-armed trial for 10 T1DM patients in each arm of allogenic and autologous adipose-derived insulin-secreting mesenchymal stromal cells (IS-AD-MSC)+bone marrow-derived hematopoietic stem cell (BM-HSC) infusion. Group 1 received autologous SCT: nine male patients and one female patient; mean age, 20.2 years, disease duration 8.1 years; group 2 received allogenic SCT: six male patients and four female patients, mean age, 19.7 years and disease duration, 7.9 years. Glycosylated hemoglobin (HbA1c) was 10.99%; serum (S.) C-peptide, 0.22 ng/mL and insulin requirement, 63.9 IU/day in group 1; HbA1c was 11.93%, S.C-peptide, 0.028 ng/mL and insulin requirement, 57.55 IU/day in group 2. SCs were infused into the portal+thymic circulation and subcutaneous tissue under non-myelo-ablative conditioning. Patients were monitored for blood sugar, S.C-peptide, glutamic acid decarboxylase antibodies and HbA1c at 3-month intervals. RESULTS: Group 1 received mean SCs 103.14 mL with 2.65 ± 0.8 × 10(4) ISCs/kg body wt, CD34+ 0.81% and CD45-/90+/73+, 81.55%. Group 2 received mean SCs 95.33 mL with 2.07 ± 0.67 × 10(4) ISCs/kg body wt, CD34+ 0.32% and CD45-/90+/73+ 54.04%. No untoward effect was observed with sustained improvement in HbA1c and S.C-peptide in both groups with a decrease in glutamic acid decarboxylase antibodies and reduction in mean insulin requirement. CONCLUSIONS: SCT is a safe and viable treatment option for T1DM. Autologous IS-AD-MSC+ BM-HSC co-infusion offers better long-term control of hyperglycemia as compared with allogenic SCT.

Combined therapy of insulin-producing cells and haematopoietic stem cells offers better diabetic control than only haematopoietic stem cells' infusion for patients with insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a chronic condition characterised by impaired blood sugar metabolism and autoimmunity. We report two children: a 5-year-old girl on exogenous insulin therapy of 30 IU/day and a 9-year-old boy on short-acting insulin 30 IU/day, long-acting insulin 70 IU/day, with IDDM since 4 and 7 years, respectively. We infused in vitro-generated donor bone marrow (BM)-derived haematopoietic stem cells (HSC) in patient 1 and insulin-secreting cells trans-differentiated from autologous adipose tissue-derived mesenchymal stem cells along with BM-HSC in patient 2 under non-myeloablative conditioning. Patient 1 improved during the initial 6 months, but then again lost metabolic control with increased blood sugar levels and insulin requirement of 32 IU/day; we lost her to follow-up after 18 months. Patient 2, over follow-up of 24.87 months, has stable blood sugar levels with glycosylated haemoglobin of 6.4% and present insulin requirement of 15 IU/day.

Co-infusion of donor adipose tissue-derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation - single center experience.

BACKGROUND: Stem cell therapy (SCT) is used for immunosuppression minimization in renal transplantation (RT). We carried out a prospective study to evaluate the benefits of co-infusion of donor adipose-derived mesenchymal stem cells (AD-MSC) + hematopoietic stem cells (HSC) in living donor RT (LDRT) under non-myeloablative conditioning. METHODS: In a demographically balanced three-armed LDRT trial with 95 patients in each arm, group-1 received portal co-infusion of AD-MSC + HSC, group-2 received HSC and group-3 received no SCT. Lymphoid irradiation and anti-thyroglobulin were used for conditioning. RESULTS: SCT was safe. At 1 and 5 years post-transplant, patient survival was 100% and 94.7% in group-1, 100% and 95.7% in group-2, and 94.7% and 84% in group-3, death-censored graft survival was 100% and 94.6% in group-1, 100% and 91.3% in group-2, and 98.9% and 94.4% in group-3 with mean serum creatinine (mg/dL) of 1.38 and 1.39 in group-1, 1.48 and 1.51 in group-2, and 1.29 and 1.42 and in group-3. Rejection episodes and immunosuppression requirement were lesser in SCT groups versus controls with best results noted in group-1. CONCLUSION: Coinfusion of donor AD-MSC +HSC in portal circulation pre-transplant under non-myeloablative conditioning is safe and effective for immunosuppression minimization in LDRT.

Pre-transplant co-infusion of donor-adipose tissue derived mesenchymal stem cells and hematopoietic stem cells may help in achieving tolerance in living donor renal transplantation.

Transplantation tolerance is still a Utopian dream for many transplanters. Mesenchymal stem cells (MSC) have shown immuno-modulatory and tolerogenic effects in experimental models. We present a 29-year-old male with end stage renal disease (ESRD) who was transplanted with HLA 4/6 matched kidney from 51-year-old father in June 2010 preceded by co-infusion of donor-adipose tissue derived mesenchymal stem cells (AD-MSC) and bone marrow derived hematopoietic stem cells (BM-HSC) under non-myeloablative conditioning for deleting rejecting T and B-cells. He has maintained fairly stable graft function with serum creatinine (SCr) between 1.5 and 1.8 mg/dL at 3 years post-transplant with absence of donor specific antibodies (DSA), normal protocol graft biopsy, and peripheral T-regulatory cell levels (pTregs) (CD127(low/-)CD25(high)CD4+) of 4.57% on zero immunosuppression since 6 months.

In-vitro generation of human adipose tissue derived insulin secreting cells: up-regulation of Pax-6, Ipf-1 and Isl-1.

We present a study of up-regulation of genes responsible for pancreatic development in glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated and differentiated from human adipose tissue (h-AD), with use of our specific differentiation media and without use of any xenogenic material. Anterior wall abdominal fat was collected from 56 volunteers and cultured in self-designed proliferation medium for 10 days. Cells were harvested by trypsinization and differentiated into insulin-expressing cells using self-designed differentiation medium for 3 days followed by evaluation for transcriptional factors Pax-6, Ipf-1, Isl-1, C-peptide and insulin secretion. Generated IS-MSC showed expression of Pax-6, Pdx-6 and Isl-1. Non-differentiated MSC as well as their further culture in absence of differentiation medium were used as negative controls. Generated 56 IS-MSC cell-lines were glucose responsive i.e. mean C-Peptide and insulin secretion levels were measured 0.41 ng/ml and 13.13 µU/ml, respectively, in absence of glucose which rose to 1.18 ng/ml and 83.42 µU/ml, respectively, following glucose challenge (p < 0.001). The mean rise in C-peptide and insulin secretion levels was 2.88 and 6.35 fold, respectively. To conclude insulin-secreting h-AD-MSC can be generated safely and effectively with application of specific differentiation media without xenogeneic material/any genetic modification, showing expression of transcriptional factors Pax-6, Ipf-1 and Isl-1.