Working Memory and Transcranial-Alternating Current Stimulation-State of the Art: Findings, Missing, and Challenges.

Working memory (WM) is a cognitive process that involves maintaining and manipulating information for a short period of time. WM is central to many cognitive processes and declines rapidly with age. Deficits in WM are seen in older adults and in patients with dementia, schizophrenia, major depression, mild cognitive impairment, Alzheimer's disease, etc. The frontal, parietal, and occipital cortices are significantly involved in WM processing and all brain oscillations are implicated in tackling WM tasks, particularly theta and gamma bands. The theta/gamma neural code hypothesis assumes that retained memory items are recorded via theta-nested gamma cycles. Neuronal oscillations can be manipulated by sensory, invasive- and non-invasive brain stimulations. Transcranial alternating-current stimulation (tACS) and repetitive transcranial magnetic stimulation (rTMS) are frequency-tuned non-invasive brain stimulation (NIBS) techniques that have been used to entrain endogenous oscillations in a frequency-specific manner. Compared to rTMS, tACS demonstrates superior cost, tolerability, portability, and safety profile, making it an attractive potential tool for improving cognitive performance. Although cognitive research with tACS is still in its infancy compared to rTMS, a number of studies have shown a promising WM enhancement effect, especially in the elderly and patients with cognitive deficits. This review focuses on the various methods and outcomes of tACS on WM in healthy and unhealthy human adults and highlights the established findings, unknowns, challenges, and perspectives important for translating laboratory tACS into realistic clinical settings. This will allow researchers to identify gaps in the literature and develop frequency-tuned tACS protocols with promising safety and efficacy outcomes. Therefore, research efforts in this direction should help to consider frequency-tuned tACS as a non-pharmacological tool of cognitive rehabilitation in physiological aging and patients with cognitive deficits.

10 Minutes Frontal 40 Hz tACS-Effects on Working Memory Tested by Luck-Vogel Task.

Working memory is a cognitive process that involves short-term active maintenance, flexible updating, and processing of goal- or task-relevant information. All frequency bands are involved in working memory. The activities of the theta and gamma frequency bands in the frontoparietal network are highly involved in working memory processes; theta oscillations play a role in the temporal organization of working memory items, and gamma oscillations influence the maintenance of information in working memory. Transcranial alternating current stimulation (tACS) results in frequency-specific modulation of endogenous oscillations and has shown promising results in cognitive neuroscience. The electrophysiological and behavioral changes induced by the modulation of endogenous gamma frequency in the prefrontal cortex using tACS have not been extensively studied in the context of working memory. Therefore, we aimed to investigate the effects of frontal gamma-tACS on working memory outcomes. We hypothesized that a 10-min gamma tACS administered over the frontal cortex would significantly improve working memory outcomes. Young healthy participants performed Luck-Vogel cognitive behavioral tasks with simultaneous pre- and post-intervention EEG recording (Sham versus 40 Hz tACS). Data from forty-one participants: sham (15 participants) and tACS (26 participants), were used for the statistical and behavioral analysis. The relative changes in behavioral outcomes and EEG due to the intervention were analyzed. The results show that tACS caused an increase in the power spectral density in the high beta and low gamma EEG bands and a decrease in left-right coherence. On the other hand, tACS had no significant effect on success rates and response times. Conclusion: 10 min of frontal 40 Hz tACS was not sufficient to produce detectable behavioral effects on working memory, whereas electrophysiological changes were evident. The limitations of the current stimulation protocol and future directions are discussed in detail in the following sections.

Working Memory and Cross-Frequency Coupling of Neuronal Oscillations.

Working memory (WM) is the active retention and processing of information over a few seconds and is considered an essential component of cognitive function. The reduced WM capacity is a common feature in many diseases, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). The theta-gamma neural code is an essential component of memory representations in the multi-item WM. A large body of studies have examined the association between cross-frequency coupling (CFC) across the cerebral cortices and WM performance; electrophysiological data together with the behavioral results showed the associations between CFC and WM performance. The oscillatory entrainment (sensory, non-invasive electrical/magnetic, and invasive electrical) remains the key method to investigate the causal relationship between CFC and WM. The frequency-tuned non-invasive brain stimulation is a promising way to improve WM performance in healthy and non-healthy patients with cognitive impairment. The WM performance is sensitive to the phase and rhythm of externally applied stimulations. CFC-transcranial-alternating current stimulation (CFC-tACS) is a recent approach in neuroscience that could alter cognitive outcomes. The studies that investigated (1) the association between CFC and WM and (2) the brain stimulation protocols that enhanced WM through modulating CFC by the means of the non-invasive brain stimulation techniques have been included in this review. In principle, this review can guide the researchers to identify the most prominent form of CFC associated with WM processing (e.g., theta/gamma phase-amplitude coupling), and to define the previously published studies that manipulate endogenous CFC externally to improve WM. This in turn will pave the path for future studies aimed at investigating the CFC-tACS effect on WM. The CFC-tACS protocols need to be thoroughly studied before they can be considered as therapeutic tools in patients with WM deficits.

Impact of severe oral mucositis in pediatric cancer patients on resource utilization and cancer treatment plans.

BACKGROUND: Oral mucositis is a common chemotherapy-related adverse event that may result in serious complications. Few studies have evaluated mucositis in pediatric patients. OBJECTIVE: To evaluate the impact of severe mucositis on resource utilization and on treatment plans of pediatric cancer patients. SETTING: Comprehensive cancer center in Amman, Jordan. METHOD: Retrospective study on pediatric patients undergoing active cancer treatment with a hospital admission diagnosis of severe oral mucositis (January 2015-December 2019). Patients undergoing bone marrow transplant were excluded. Severe oral mucositis was defined as interfering with oral intake and requiring intravenous opioids. MAIN OUTCOME MEASURE: We reviewed the electronic billing system and patient medical charts to determine the resources utilized during hospitalization, cost, and the impact on subsequent treatment protocols. RESULTS: During the study period, 200 patients were eligible; the average age was 8.6±5.6 years (SD) and 45% had acute lymphoblastic leukemia. The median hospital stay was 6 days (range 2-21) with a total median cost of US$ 2,176 (range 635-13,976) per admission. The median medication cost was US$ 1,075 (range 135-9010), and 85% of the patients received antibiotics during hospitalization, at a median cost of US$ 487 (range 23-2,193). Modification of the chemotherapy treatment protocol was required in 110 patients, which included dose reduction (60%), delay (38%), and discontinuation (2%). CONCLUSION: Severe oral mucositis is associated with significant resource utilization and modification of the treatment protocols. Further studies are needed to identify strategies to reduce the impact of mucositis in this patient population.

Thrombosis and Anticoagulant Therapy Among Pediatric Cancer Patients: Real-Life Data.

BACKGROUND: Venous thromboembolism (VTE) in children is relatively rare, and more so among those with cancer. In this study, we report the characteristics and outcomes of children with cancer-associated thrombosis. METHODS: We reviewed institutional databases for all children with cancer and a diagnosis of VTE at King Hussein Cancer Center in Jordan. Variables reviewed are patients' clinical characteristics, treatment for cancer, and anticoagulation therapy. RESULTS: Between January 2011 and December 2018, a total of 45 patients fulfilled the inclusion criteria, and the median age was 10.4 (0.8-17.9) years. The most common underlying diagnosis was acute lymphoblastic leukemia (n = 13, 29%). At the time of VTE, 29 (64.4%) patients were receiving chemotherapy, and eight (17.8%) had a central venous catheter (CVC). The majority of patients (n = 37, 82%) developed VTE within 30 days of hospitalization. Thrombosis mostly involved the extremities (n = 23, 51%) and sagittal vein (n = 12, 26.7%). All patients were treated with low-molecular-weight heparin (LMWH), complicated by bleeding in three (6.6%) patients. CONCLUSION: In contrast to adults, VTE in pediatric cancer patients is more associated with chemotherapy and recent hospitalization. LMWH is a safe and effective therapy for children with cancer who develop VTE.

Early versus delayed administration of granulocyte-colony stimulating factor following chemotherapy in pediatric patients with Ewing sarcoma.

BACKGROUND: The optimal timing of initiating granulocyte-colony stimulating factor following chemotherapy in pediatric patients has not been clearly defined. This study aimed to compare the administration of granulocyte-colony stimulating factor on day 1 versus day 3 postchemotherapy in pediatric patients with Ewing sarcoma. METHOD: A retrospective study of pediatric patients with Ewing sarcoma who received granulocyte-colony stimulating factor following chemotherapy between January 2016 and September 2018 at a comprehensive cancer center. The institution's chemotherapy protocol for Ewing sarcoma was modified in April 2017 to include granulocyte-colony stimulating factor initiation on day 3 instead of day 1 post-chemotherapy. Febrile neutropenia requiring hospitalization, duration of hospital stay, and chemotherapy delay were compared for patients before and after the protocol change. RESULTS: Over the study period, 250 cycles were evaluated with day 1 granulocyte-colony stimulating factor and 221 cycles with day 3 granulocyte-colony stimulating factor. There were no differences between the day 1 and day 3 groups in the number of cycles associated with Febrile neutropenia requiring hospitalization (34 vs. 19, p = 0.086), and the length of Febrile neutropenia-related hospitalization (mean 4 ± 2.1 vs. 4.6 ± 1.8, p = 0.123). However, delay in chemotherapy due to neutropenia was reported in significantly more cycles in the day 1 group, compared to the day 3 group (37 vs. 16, p = 0.01). CONCLUSIONS: Febrile neutropenia resulting in hospital admission and the length of hospital stay was not different between pediatric patients with Ewing sarcoma who received granulocyte-colony stimulating factor on day 1 or day 3 post-chemotherapy. Chemotherapy delay due to neutropenia was higher in patients who received granulocyte-colony stimulating factor on day 1. Larger studies are required to fully determine the impact of delayed initiation of granulocyte-colony stimulating factor.

Bacterial Infections in Children With Acute Myeloid Leukemia Receiving Ciprofloxacin Prophylaxis.

BACKGROUND: The aim of the study was to describe the incidence and type of bacterial infections associated with the use of ciprofloxacin prophylaxis as single agent in pediatric patients with acute myeloid leukemia (AML). PROCEDURE: This was a retrospective review of all patients with AML, who were treated according to the AML02 protocol between 2011 and 2015. The medical records were reviewed for any positive cultures from the initiation of the protocol until death or protocol discontinuation. Patient demographics, type of infections, type of isolated bacteria, and intensive care unit admissions were recorded. RESULTS: A total of 50 patients were evaluated, who were of a mean age of 8 years±5.1 (SD). We identified 77 episodes of bacterial infections in 42 (84%) patients. Among those bacterial infections, 73 episodes were with bacteremia and included 45 (62%) gram-positive bacterial infections, 24 (33%) gram-negative bacterial infections, and 4 (6%) mixed gram-negative and gram-positive bacterial infections. Coagulase-negative Staphylococcus and Viridans streptococci were the most commonly isolated bacteria in 33% and 30% of the episodes, respectively. Seventeen (45%) patients with bacteremia required intensive care unit admission. CONCLUSIONS: A high rate of bacterial infection was detected in patients who received the AML02 protocol, mainly gram-positive bacterial infections. The prophylactic regimen should be reconsidered for its efficacy, and other antibacterial prophylaxis may be used.