Gamma oscillations predict pro-cognitive and clinical response to auditory-based cognitive training in schizophrenia

AbstractCognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a “bottom-up” cognitive remediation intervention with efficacy for neurocognitive outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R2 = 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R2 = 0.40) and negative (SANS, R2 = 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R2 < 0.06). The results indicate that the capacity to support gamma oscillations, as well as the plasticity of the underlying ASSR circuitry after acute exposure to 1 h of TCT, reflect neural mechanisms underlying the efficacy of TCT, and may be used to predict individualized treatment outcomes. These findings suggest that gamma oscillatory biomarkers applied within the context of experimental medicine designs can be used to personalize individual treatment options for pro-cognitive interventions in patients with schizophrenia.

Download Full-text

Auditory-Based Cognitive Training Drives Short- and Long-Term Plasticity in Cortical Networks in Schizophrenia

Schizophrenia Bulletin Open ◽

10.1093/schizbullopen/sgaa065 ◽

2020 ◽

Vol 1 (1) ◽

Cited By ~ 1

Author(s):

Daisuke Koshiyama ◽

Makoto Miyakoshi ◽

Michael L Thomas ◽

Yash B Joshi ◽

Juan L Molina ◽

...

Keyword(s):

Cognitive Training ◽

Computer Games ◽

Effective Connectivity ◽

Gamma Oscillations ◽

Neural Substrates ◽

Cingulate Gyrus ◽

Treatment As Usual ◽

Short And Long Term ◽

The Right

Abstract Schizophrenia patients have widespread deficits in neurocognitive functioning linked to underlying abnormalities in gamma oscillations that are readily measured by the 40 Hz auditory steady-state response (ASSR). Emerging interventions such as auditory-based targeted cognitive training (TCT) improve neurocognitive function in patients. While acute ASSR changes after 1 hour of TCT predict clinical and cognitive gains after a 30-hour course of TCT, the neural substrates of underlying short- and long-term TCT interventions are unknown. To determine the neural substrates underlying TCT-associated ASSR changes, a novel data analysis method was applied to assess the effective connectivity of gamma-band ASSR among estimated cortical sources. In this study, schizophrenia patients (N = 52) were randomized to receive either a treatment as usual (TAU; N = 22) or TAU augmented with TCT (N = 30). EEG recordings were obtained immediately before (T0) and after 1 hour of either computer games (TAU) or cognitive training (TCT; T1), and at 65 ± 15 days (mean ± SD) post-randomization (T2). Results showed increased connectivity from the left ventral middle cingulate gyrus to the left posterior cingulate gyrus, accompanied by decreased connectivity from the left Rolandic operculum (a region that includes auditory cortex) to the right ventral middle cingulate gyrus after 1 hour of TCT. After 30 hours, decreased connectivity from the frontal cortex to a region near the calcarine sulcus were detected. Auditory-based cognitive training drives short- and long-term plasticity in cortical network functioning in schizophrenia patients. These findings may help us understand the mechanisms underlying cognitive training effects in schizophrenia patients and enhance the development of pro-cognitive therapeutics.

Download Full-text

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cancers ◽

10.3390/cancers13153708 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3708

Author(s):

Bhaba K. Das ◽

Aarthi Kannan ◽

Quy Nguyen ◽

Jyoti Gogoi ◽

Haibo Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Standard Of Care ◽

Aurora Kinase ◽

Selective Inhibition ◽

Potential Candidate ◽

Cycle Arrest

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

Download Full-text

Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211024460 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110244

Author(s):

Vanessa Wookey ◽

Axel Grothey

Keyword(s):

Colorectal Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Standard Of Care ◽

Cancer Type ◽

Cancer Therapies ◽

Multiple Cancer ◽

Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

Download Full-text

Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211031141 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110311

Author(s):

Chiun Hsu ◽

Lorenza Rimassa ◽

Hui-Chuan Sun ◽

Arndt Vogel ◽

Ahmed O. Kaseb

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Kinase Inhibitor ◽

Treatment Options ◽

Healthcare Providers ◽

Safety Data ◽

Standard Of Care ◽

Antiangiogenic Agents ◽

Efficacy And Safety ◽

First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

Download Full-text

Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

Pharmaceuticals ◽

10.3390/ph14010051 ◽

2021 ◽

Vol 14 (1) ◽

pp. 51

Author(s):

Brinda Balasubramanian ◽

Simran Venkatraman ◽

Kyaw Zwar Myint ◽

Tavan Janvilisri ◽

Kanokpan Wongprasert ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Drug Development ◽

Surgical Resection ◽

Treatment Options ◽

Standard Of Care ◽

Time Data ◽

Current Standard ◽

Innovative Drug ◽

Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

Download Full-text

Side effects of the metacognitive training for depression compared to a cognitive remediation training in patients with depression

Scientific Reports ◽

10.1038/s41598-021-87198-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mona Dietrichkeit ◽

Marion Hagemann-Goebel ◽

Yvonne Nestoriuc ◽

Steffen Moritz ◽

Lena Jelinek

Keyword(s):

Side Effects ◽

Side Effect ◽

Statistical Power ◽

Controlled Trial ◽

Treatment Options ◽

Cognitive Remediation ◽

Negative Effects ◽

Metacognitive Training ◽

To Receive

AbstractAlthough awareness of side effects over the course of psychotherapy is growing, side effects are still not always reported. The purpose of the present study was to examine side effects in a randomized controlled trial comparing Metacognitive Training for Depression (D-MCT) and a cognitive remediation training in patients with depression. 84 patients were randomized to receive either D-MCT or cognitive remediation training (MyBrainTraining) for 8 weeks. Side effects were assessed after the completion of each intervention (post) using the Short Inventory of the Assessment of Negative Effects (SIAN) and again 6 months later (follow-up) using the Negative Effects Questionnaire (NEQ). D-MCT and MyBrainTraining did not differ significantly in the number of side effects. At post assessment, 50% of the D-MCT group and 59% of the MyBrainTraining group reported at least one side effect in the SIAN. The most frequently reported side effect was disappointment in subjective benefit of study treatment. At follow-up, 52% reported at least one side effect related to MyBrainTraining, while 34% reported at least one side effect related to the D-MCT in the NEQ. The most frequently reported side effects fell into the categories of “symptoms” and “quality”. Our NEQ version was missing one item due to a technical error. Also, allegiance effects should be considered. The sample size resulted in low statistical power. The relatively tolerable number of side effects suggests D-MCT and MyBrainTraining are safe and well-received treatment options for people with depression. Future studies should also measure negative effects to corroborate our results.

Download Full-text

Frontal eye field microstimulation induces task-dependent gamma oscillations in the lateral intraparietal area

Journal of Neurophysiology ◽

10.1152/jn.00323.2012 ◽

2012 ◽

Vol 108 (5) ◽

pp. 1392-1402 ◽

Cited By ~ 15

Author(s):

Elsie Premereur ◽

Wim Vanduffel ◽

Pieter R. Roelfsema ◽

Peter Janssen

Keyword(s):

Spatial Attention ◽

Field Potential ◽

Gamma Oscillations ◽

Oculomotor Control ◽

Saccade Target ◽

Frontal Eye Field ◽

Alpha Power ◽

Lateral Intraparietal Area ◽

Electrical Microstimulation ◽

Gamma Power

Macaque frontal eye fields (FEF) and the lateral intraparietal area (LIP) are high-level oculomotor control centers that have been implicated in the allocation of spatial attention. Electrical microstimulation of macaque FEF elicits functional magnetic resonance imaging (fMRI) activations in area LIP, but no study has yet investigated the effect of FEF microstimulation on LIP at the single-cell or local field potential (LFP) level. We recorded spiking and LFP activity in area LIP during weak, subthreshold microstimulation of the FEF in a delayed-saccade task. FEF microstimulation caused a highly time- and frequency-specific, task-dependent increase in gamma power in retinotopically corresponding sites in LIP: FEF microstimulation produced a significant increase in LIP gamma power when a saccade target appeared and remained present in the LIP receptive field (RF), whereas less specific increases in alpha power were evoked by FEF microstimulation for saccades directed away from the RF. Stimulating FEF with weak currents had no effect on LIP spike rates or on the gamma power during memory saccades or passive fixation. These results provide the first evidence for task-dependent modulations of LFPs in LIP caused by top-down stimulation of FEF. Since the allocation and disengagement of spatial attention in visual cortex have been associated with increases in gamma and alpha power, respectively, the effects of FEF microstimulation on LIP are consistent with the known effects of spatial attention.

Download Full-text

Computerized Cognitive Training in Amnestic Mild Cognitive Impairment: A Randomized Clinical Trial

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211006472 ◽

2021 ◽

pp. 089198872110064

Author(s):

Kevin Duff ◽

Jian Ying ◽

Kayla R. Suhrie ◽

Bonnie C.A. Dalley ◽

Taylor J. Atkinson ◽

...

Keyword(s):

Clinical Trial ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Training ◽

Computer Games ◽

Brain Plasticity ◽

Amnestic Mild Cognitive Impairment ◽

Control Group ◽

Computerized Cognitive Training ◽

Secondary Outcomes

Objective: Computerized cognitive training has been successful in healthy older adults, but its efficacy has been mixed in patients with amnestic Mild Cognitive Impairment (MCI). Methods: In a randomized, placebo-controlled, double-blind, parallel clinical trial, we examined the short- and long-term efficacy of a brain-plasticity computerized cognitive training in 113 participants with amnestic MCI. Results: Immediately after 40-hours of training, participants in the active control group who played computer games performed better than those in the experimental group on the primary cognitive outcome (p = 0.02), which was an auditory memory/attention composite score. There were no group differences on 2 secondary outcomes (global cognitive composite and rating of daily functioning). After 1 year, there was no difference between the 2 groups on primary or secondary outcomes. No adverse events were noted. Conclusions: Although the experimental cognitive training program did not improve outcomes in those with MCI, the short-term effects of the control group should not be dismissed, which may alter treatment recommendations for these patients.

Download Full-text

The evolution of the education module for men with metastatic prostate cancer (mPC) in the prostate cancer supportive care (PCSC) program.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.279 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 279-279

Author(s):

Jennifer Marie Rauw ◽

Sunil Parimi ◽

Nikita Ivanov ◽

Jessica Noble ◽

Eugenia Wu ◽

...

Keyword(s):

Prostate Cancer ◽

Treatment Options ◽

Standard Of Care ◽

Primary Therapy ◽

Oncology Nurse ◽

Castration Resistant ◽

Medical Oncologists ◽

Hormone Sensitive ◽

Virtual Platform ◽

Satisfaction Surveys

279 Background: The PCSC Program was initiated in 2013 at the Vancouver Prostate Centre to provide a comprehensive program for patients and partners with prostate cancer. This program provides educational sessions (ES) and clinical services, including decision-making for primary therapy, sexual health, pelvic floor physiotherapy, hormone therapy, counseling, exercise, and nutrition for patients in BC, Canada. In 2016, the PCSC Program expanded to BC Cancer Victoria and in 2017 to other BC Cancer sites. In 2018, medical oncologists (MDs) in Victoria (JR, SP) developed an Education Module addressing treatment options for men with metastatic hormone sensitive (mHSPC) and metastatic castration resistant (mCRPC) disease. MDs delivered in-person ES in Victoria in 2018 and, in 2019, added a virtual platform (VP) option. From 3-5/2020, the ESs were on hold due to the COVID pandemic and parental leaves. In 6/2020, the ESs resumed only on VP, and the PCSC Oncology Nurse Practitioner (NP), NI, gave the presentations for the MDs on leave. In 10/2020, due to a changing standard of care for mHSPC, the PCSC team consolidated the two ESs into one. We report on the evolution of this Education Module in response to both the changing standard of care and the COVID pandemic. Methods: We prospectively collected attendance and patient characteristic metrics from all ES for men with mPC. We tracked presenter type (MD vs. NP) and prospectively collected anonymous patient satisfaction questionnaires. Results: From 1/2018 to 1/2021, 100 men registered for 27 ES; 81 men, 41 partners, and 2 family members actually attended. 48/75 (64%) men were white, 39/75 (52%) retired, and 56/75 (74.7%) married. 47 men attended 12 mHSPC ES, 13 men attended ten mCRPC ES, and 17 attended four consolidated ES. MDs presented 15 ES, and the NP presented 12 ES. Responses to questions on 70 satisfaction surveys were similar for MD vs. NP presenters. 9 responders to the recently added VP-specific questions said they agreed (4) or strongly agreed (5) that it was beneficial to watch the ES at home on a computer. The Table below shows attendance per site per year. Conclusions: The ESs for men with mPC were well-received. Although there was a VP option before COVID, attendance increased significantly after the lockdown as patients and providers became more familiar with VPs. Satisfaction surveys confirmed that an NP could deliver the ES rather than MD. Consolidation of the mHSPC and mCRPC ES reflected the changing standard of care and resulted in more efficient use of presenter time. Virtual delivery of the sessions provided greater access to those living in distant or remote areas of the province and those in lockdown during the COVID pandemic. [Table: see text]

Download Full-text

A Smartphone App to Monitor Mood Symptoms in Bipolar Disorder: Development and Usability Study

JMIR Mental Health ◽

10.2196/19476 ◽

2020 ◽

Vol 7 (9) ◽

pp. e19476

Author(s):

Kelly Ann Ryan ◽

Pallavi Babu ◽

Rebecca Easter ◽

Erika Saunders ◽

Andy Jinseok Lee ◽

...

Keyword(s):

Bipolar Disorder ◽

Treatment Options ◽

Treatment Decision ◽

Clinical Information ◽

Standard Of Care ◽

Text Messages ◽

Adherence Rate ◽

Mixed Effect ◽

Psychomotor Activity ◽

Measurement Based Care

Background There is considerable scientific interest in finding new and innovative ways to capture rapid fluctuations in functioning within individuals with bipolar disorder (BD), a severe, recurrent mental disorder associated with frequent shifts in symptoms and functioning. The use of smartphones can provide valid and real-world tools for use in measurement-based care and could be used to inform more personalized treatment options for this group, which can improve standard of care. Objective We examined the feasibility and usability of a smartphone to capture daily fluctuations in mood within BD and to relate daily self-rated mood to smartphone use behaviors indicative of psychomotor activity or symptoms of the illness. Methods Participants were 26 individuals with BD and 12 healthy control individuals who were recruited from the Prechter Longitudinal Study of BD. All were given a smartphone with a custom-built app and prompted twice a day to complete questions of mood for 28 days. The app automatically and unobtrusively collected phone usage data. A poststudy satisfaction survey was also completed. Results Our sample showed a very high adherence rate to the daily momentary assessments (91% of the 58 prompts completed). Multivariate mixed effect models showed that an increase in rapid thoughts over time was associated with a decrease in outgoing text messages (β=–.02; P=.04), and an increase in impulsivity self-ratings was related to a decrease in total call duration (β=–.29; P=.02). Participants generally reported positive experiences using the smartphone and completing daily prompts. Conclusions Use of mobile technology shows promise as a way to collect important clinical information that can be used to inform treatment decision making and monitor outcomes in a manner that is not overly burdensome to the patient or providers, highlighting its potential use in measurement-based care.

Download Full-text