Transcranial direct-current stimulation of the prefrontal cortex enhances working memory and suppresses pathological gamma power elevation in schizophrenia.

BACKGROUND: This investigation examines the clinical benefits of prefrontal cortex transcranial direct current stimulation (tDCS) treatment of working memory (WM) dysfunction in chronic schizophrenia patients. RESEARCH DESIGN AND METHODS: 34 schizophrenia (SZ) patients were evaluated at baseline, and 29 patients were randomly assigned to either active tDCS intervention or sham tDCS intervention. tDCS intervention applied 10 consecutive sessions (20 minutes, 2 mA, two sessions a day) over 5 days. WM performance (N = 25), symptom severity (N = 29), and resting EEG (N = 17) were assessed from pre- to post-tDCS intervention. Additionally, symptom severity was noted over a 12-week follow-up period. RESULTS: WM accuracy significantly improved in the active tDCS group while WM accuracy in the sham tDCS group was unchanged. Significant symptom-severity reduction was sustained for one week after active tDCS intervention. Sustained resting gamma stability (RGS) was noted from baseline to post tDCS in the active-treatment group versus a significant elevation in pathological gamma power in the sham-tDCS group. CONCLUSIONS: Examining treatment effects on RGS in SZ could be critical in identifying effective novel treatment strategies that promote left-DLPFC excitability and enhance WM functioning. Further empirical support is warranted to support the clinical benefits over longer periods of time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04637724. ETHICS APPROVAL REGISTRATION NO: 337-19.

Stress and Right Prefrontal Transcranial Direct Current Stimulation (tDCS) Interactive Effects on Visual Working Memory and Learning.

Stress impacts prefrontal cortex (PFC) activity and modulates working memory performance. In a recent study, stimulating the dorsolateral PFC (dlPFC) using transcranial direct current stimulation (tDCS) interacted with social stress in modulating participants' working memory. More specifically, stress disrupted the enhancing effects of dlPFC tDCS on working memory performance. The current study aimed to further explore these initial findings by randomizing healthy females to four experimental conditions (N = 130); stimulation (right dlPFC tDCS vs. sham) and stress manipulation (social stress vs. control). Participants performed cognitive tasks (i.e., visual working memory task and a visual declarative memory task) at baseline and post-stimulation. They also completed self-report measures of stress and anxiety. A significant stimulation × stress interaction was evident in the declarative memory (One-Card Learning, OCL) task, while working memory performance was unaffected. Though tDCS stimulation and stress did not interact to affect working memory, further research is warranted as these initial findings suggest that immediate visual-memory learning may be affected by these factors. The limited number of earlier studies, as well as the variability in their designs, provides additional impetus for studying the interactive effects of stress and tDCS on human visual learning.

Early Auditory Processing Predicts Efficient Working Memory Functioning in Schizophrenia.

Early auditory processing (EAP) deficits have been consistently documented in individuals diagnosed with schizophrenia (SZ). However, a relationship between EAP and executive attention has not been confirmed in SZ versus healthy controls (HC). The current study aimed to demonstrate that unlike HC, in SZ patients, auditory change-detection event-related potentials (ERPs) are significantly associated with executive working memory (WM) functioning. Additionally, correlational analyses investigated the relationships between patients' auditory ERPs, WM performance, and schizophrenia symptom severity scores. We examined verbal WM accuracy associated with "executive-control" prefrontal cortex mechanisms and EAP ERPs under midline prefrontal electrodes in 12 SZ patients versus 12 demographically matched HC. Mismatch negativity (MMN) amplitudes and latencies in SZ patients were not significantly different from HC, however, their verbal WM performance was significantly impaired versus HC. Importantly, prolonged MMN latencies in the SZ group were correlated with better WM accuracy. In the HC group, WM accuracy was unrelated to MMN latencies. Patients' MMN parameters were unrelated to schizophrenia symptom-domain severity. However, patients' WM RTs and accuracy were significantly related to illness severity and negative symptom severity, respectively. Therefore, inefficient sensory excitation related to EAP timing may underlie poor executive verbal WM functioning and might indirectly exacerbate the severity of negative symptoms in SZ. Treatments targeting prefrontal cortex dysfunction in schizophrenia are discussed.

Left-prefrontal alpha-dynamics predict executive working-memory functioning in elderly people.

Recent findings suggest that electroencephalography (EEG) oscillations in the theta and alpha frequency-bands reflect synchronized interregional neuronal activity and are considered to reflect cognitive-control, and executive working memory mechanisms in humans. Above the age of 50 years, hypothesized pronounced alterations in alpha and theta-band power at resting or across different WM-functioning brain states may well be due to pre-dementia cognitive impairments, or increasing severity of age-related neurological disorders. Executive working memory (EWM) functioning was assessed in older-adult participants (54 to 83 years old) by obtaining their WM-related EEG oscillations and WM performance scores. WM performance and WM brain-state EEG were recorded during online-WM periods as well as during specific online WM events within EWM periods, and during resting offline-WM periods that preceded online-WM periods. Left-prefrontal alpha-power was enhanced during offline-WM periods versus online-WM periods and was significantly related to WM accuracy. Left-prefrontal alpha power and left prefrontal-parietal theta power anterior-posterior difference-gradient during online WM activity were related to reaction times (RT's). Importantly, during active-storage events, WM-offset offline-periods, and preparatory pre-retrieval events, excessive left-prefrontal alpha activity was related to poor EWM performance. The potential for developing targeted noninvasive cognition-enhancing interventions and developing clinical-monitoring EEG-based biomarkers of pathological cognitive-decline in elderly people is discussed.

Advanced Dementia: Brain-State Characteristics and Clinical Indicators of Early Mortality.

There is an urgent need in advanced dementia for evidence-based clinical prognostic predictors that could positively influence ethical decisions allowing health provider and family preparation for early mortality. Accordingly, the authors review and discuss the prognostic utility of clinical assessments and objective measures of pathological brain states in advanced dementia patients associated with accelerated mortality. Overall, due to the paucity of brain-activity and clinical-comorbidity predictors of survival in advanced dementia, authors outline the potential prognostic value of brain-state electroencephalography (EEG) measures and reliable clinical indicators for forecasting early mortality in advanced dementia patients. In conclusion, two consistent risk-factors for predicting accelerated mortality in terminal-stage patients with advanced dementia were identified: pressure ulcers and paroxysmal slow-wave EEG parameters associated with cognitive impairment severity and organic disease progression. In parallel, immobility, malnutrition, and co-morbid systemic diseases are highly associated with the risk for early mortality in advanced dementia patients. Importantly, the authors' conclusions suggest utilizing reliable quantitative-parameters of disease progression for estimating accelerated mortality in dementia patients entering the terminal disease-stages characterized by severe intellectual deficits and functional disability.

Left prefrontal transcranial direct-current stimulation reduces symptom-severity and acutely enhances working memory in schizophrenia.

Recent studies indicated that left dorsolateral prefrontal cortex (DLPFC) transcranial direct current stimulation (tDCS) may improve clinical status and cognitive functioning in schizophrenia patients. The current study examined the effects of left prefrontal anodal tDCS on symptom-severity and on working memory performance in schizophrenia (SZ) patients. We conducted a double-blind, randomized sham-controlled parallel-group trial. Following baseline clinical and WM assessments, 19 chronic SZ patients were randomly assigned to receive 10 sessions of either active left dorsolateral prefrontal cortex (DLPFC) tDCS or sham DLPFC-tDCS across five consecutive days, followed by post-tDCS assessments every four weeks across 12 weeks. Active tDCS significantly alleviated symptom-severity versus baseline and versus sham tDCS. WM-performance improved versus baseline in the active tDCS group. Patients' symptom alleviation was maintained for four weeks after tDCS intervention. Patients' Post-tDCS WM scores were comparable to healthy controls' WM scores. The present findings highlight the benefits of left-prefrontal tDCS interventions and support the association between DLPFC dysfunction and symptom-severity in schizophrenia.

Neural reactivity parameters of awareness predetermine one-year survival in patients with disorders of consciousness.

Objective: The current investigation evaluated the sensitivity of neural-reactivity markers of awareness versus standard clinical assessments in predicting 1-year survival in nonresponsive-awake patients with disorders of consciousness (DOC).Methods: Pre-attentive auditory mismatch-negativity (MMN) event-related potentials (ERP's), globally induced electroencephalography (EEG) spectral power following verbal command, and clinical parameters were assessed. The study included 10 patients with DOC with mixed etiology and 10 healthy controls (HC) at baseline. The clinical status of patients with DOC was reassessed after 1 year.Results: Unlike baseline clinical assessment scores, baseline MMN amplitudes of non-survivors and induced theta-power following verbal-command clearly distinguished the non-surviving patients versus surviving patients. Baseline MMN peak-amplitude latencies in survivors with DOC were significantly related to clinical outcome over a 1-year period.Conclusion: Current findings underscore the increased sensitivity of EEG-reactivity markers of awareness versus standard clinical scores in predicting 1-year clinical outcome and survival in patients with DOC. Further longitudinal research in larger DOC samples is needed to confirm the prognostic-reliability, and validity of neural reactivity parameters of awareness in patients with DOC. Current finding may have implications for clinical care and medical-legal decisions in unresponsive-awake patients, and could assist clinicians to predict their survival up to 1 year from admission.

Integrated Development Environment for EEG-Driven Cognitive-Neuropsychological Research.

Background: EEG-driven research is paramount in cognitive-neuropsychological studies, as it provides a non-invasive window to the underlying neural mechanisms of cognition and behavior. A myriad collection of software and hardware frameworks has been developed to alleviate some of the technical barriers involved in EEG-driven research. Methods: we propose an integrated development environment which encompasses the entire technical "data-collection pipeline" of cognitive-neuropsychological research, including experiment design, data acquisition, data exploration and analysis in a state-of-the-art user interface. Our framework is based on a unique integration between a python-based web framework, time-oriented databases and object-based data schemes. Results: we demonstrated our framework with the recording and analysis of an n-Back task completed by 15 elderly (ages 50 to 80) participants. This case study demonstrates the highly utilized nature of our integrated framework with a challenging target population. Furthermore, our results may provide new insights into the correlation between brain activity and working memory performance in elderly people, who are prone to experience accelerated decline in executive prefrontal cortex functioning. Conclusion: our framework extends the range of EEG-driven experimental methods for assessing cognition available for cognitive-neuroscientists, allowing them to concentrate on the creative part of their work instead of technical aspects.

The effects of stress and transcranial direct current stimulation (tDCS) on working memory: A randomized controlled trial.

Recent reviews of transcranial direct current stimulation (tDCS) show limited support for its initially cited enhancing effects on working memory (WM). They highlight the need for additional research, assessing the specific circumstances that optimize stimulation outcome. Social stress is an attractive candidate in this regard, as it affects WM and is mediated by prefrontal cortex activity; tDCS that targets these neuronal networks may, therefore, interact with social stress to affect WM. Our objective was to explore the interaction between social stress and tDCS on WM performance in a healthy cohort, 69 female participants were randomized to four experimental conditions (i.e., 2 × 2 design): stimulation (dlPFC tDCS vs. sham stimulation) and stress manipulation (Trier Social Stress Test [TSST] procedure vs. a friendly control TSST). Participants' attention, WM (assessed using an n-back task), and subjective/objective indicators of stress were assessed. A significant Stimulation × Stress Manipulation interaction was found, F(1, 65) = 6.208, p = .015, suggesting that active tDCS may increase WM performance in the no-stress conditions, while decreasing it under stress. Follow-up analyses of variance, however, were not significant (i.e., ps=.083 / .093), and Bayesian analyses were inconclusive. In conclusion, stress seems to be a crucial factor in determining the effects of tDCS, and tDCS may have an enhancing effect on WM at lower levels of stress, while being detrimental at higher stress levels (i.e., reversing the direction of effect). Possible theoretical underpinnings of the findings are discussed, while acknowledging the need for further research.

Antiepileptic Effects of a Novel Non-invasive Neuromodulation Treatment in a Subject With Early-Onset Epileptic Encephalopathy: Case Report With 20 Sessions of HD-tDCS Intervention.

The current clinical investigation examined high-definition transcranial direct current stimulation (HD-tDCS) as a focal, non-invasive, anti-epileptic treatment in a child with early-onset epileptic encephalopathy. We investigated the clinical impact of repetitive (20 daily sessions) cathode-centered 4 × 1 HD-tDCS (1 mA, 20 min, 4 mm ring radius) over the dominant seizure-generating cortical zone in a 40-month-old child suffering from a severe neonatal epileptic syndrome known as Ohtahara syndrome (OS). Seizures and epileptiform activity were monitored and quantified using video-EEG over multiple days of baseline, intervention, and post-intervention periods. Primary outcome measures were changes in seizure frequency and duration on the last day of intervention versus the last baseline day, preceding the intervention. In particular, we examined changes in tonic spasms, tonic-myoclonic seizures (TM-S), and myoclonic seizures from baseline to post-intervention. A trend in TM-S frequency was observed indicating a reduction of 73% in TM-S frequency, which was non-significant [t(4) = 2.05, p = 0.1], and denoted a clinically significant change. Myoclonic seizure (M-S) frequency was significantly reduced [t(4) = 3.83, p = 0.019] by 68.42%, compared to baseline, and indicated a significant clinical change as well. A 73% decrease in interictal epileptic discharges (IEDs) frequency was also observed immediately after the intervention period, compared to IED frequency at 3 days prior to intervention. Post-intervention seizure-related peak delta desynchronization was reduced by 57%. Our findings represent a case-specific significant clinical response, reduction in IED, and change in seizure-related delta activity following the application of HD-tDCS. The clinical outcomes, as noted in the current study, encourage the further investigation of this focal, non-invasive neuromodulation procedure in other severe electroclinical syndromes (e.g., West syndrome) and in larger pediatric populations diagnosed with early-onset epileptic encephalopathy. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02960347, protocol ID: Meiron 2013-4.

Spasticity and dementia increase the risk of pressure ulcers.

The aim of this study was to identify and characterise the association between the prevalence of pressure ulcers, spasticity levels, and advanced dementia in disable elderly patients. Data were obtained from the patient medical files. Patients were hospitalised in the geriatric skilled nursing department. A total of 40 frail elderly patients, bedbound and suffering from advanced chronic diseases, advanced dementia, and high-grade pressure ulcers, were examined. Pressure ulcer grades and spasticity in advanced dementia versus non-dementia patients were evaluated. Logistic regression indicated that only advanced dementia and spasticity were significantly associated with the development of pressure ulcers versus those without dementia or without spasticity. Patients with advanced dementia displayed a significantly higher prevalence of severe spasticity. In multivariate logistic regression analyses, spasticity was significantly associated with pressure ulcers. The strong association of spasticity with the onset of pressure ulcers in advanced dementia should encourage clinicians to implement preventative measures to delay the onset of pressure ulcers.

High-Definition transcranial direct current stimulation in early onset epileptic encephalopathy: a case study.

PRIMARY OBJECTIVE: Early onset epileptic encephalopathy is characterized by high daily seizure-frequency, multifocal epileptic discharges, severe psychomotor retardation, and death at infancy. Currently, there are no effective treatments to alleviate seizure frequency and high-voltage epileptic discharges in these catastrophic epilepsy cases. The current study examined the safety and feasibility of High-Definition transcranial direct current stimulation (HD-tDCS) in reducing epileptiform activity in a 30-month-old child suffering from early onset epileptic encephalopathy. DESIGN AND METHODS: HD-tDCS was administered over 10 intervention days spanning two weeks including pre- and post-intervention video-EEG monitoring. RESULTS: There were no serious adverse events or side effects related to the HD-tDCS intervention. Frequency of clinical seizures was not significantly reduced. However, interictal sharp wave amplitudes were significantly lower during the post-intervention period versus baseline. Vital signs and blood biochemistry remained stable throughout the entire study. CONCLUSIONS: These exploratory findings support the safety and feasibility of 4 × 1 HD-tDCS in early onset epileptic encephalopathy and provide the first evidence of HD-tDCS effects on paroxysmal EEG features in electroclinical cases under the age of 36 months. Extending HD-tDCS treatment may enhance electrographic findings and clinical effects.

Systemic and Disease-Specific Risk Factors in Vascular Dementia: Diagnosis and Prevention.

In order to prevent the onset of vascular dementia (VaD) in aging individuals, it is critical to detect clinically relevant vascular and systemic pathophysiological changes to signal the onset of its preceding prodromal stages. Identifying behavioral and neurobiological markers that are highly sensitive to VaD classification vs. other dementias is likely to assist in developing novel preventive treatment strategies that could delay the onset of disruptive psychomotor symptoms, decrease hospitalizations, and increase the quality of life in clinically-high-risk aging individuals. In light of empirical diagnostic and clinical findings associated with VaD pathophysiology, the current investigation will suggest a few clinically-validated biomarker measures of prodromal VaD cognitive impairments that are correlated with vascular symptomology, and VaD endophenotypes in non-demented aging people. In prodromal VaD individuals, distinguishing VaD from other dementias (e.g., Alzheimer's disease) could facilitate specific early preventive interventions that significantly delay more severe cognitive deterioration or indirectly suppress the onset of dementia with vascular etiology. Importantly, the authors conclude that primary prevention strategies should examine aging individuals by employing comprehensive geriatric assessment approach, taking into account their medical history, and longitudinally noting their vascular, systemic, cognitive, behavioral, and clinical functional status. Secondary prevention strategies may include monitoring chronic medication as well as promoting programs that facilitate social interaction and every-day activities.

Dementia and Pressure Ulcers: Is There a Close Pathophysiological Interrelation?

The current theoretical investigation aimed to explore common pathophysiological mechanisms underlying dementia and pressure ulcers (PU). Along with the increased longevity, especially in frail elderly patients, there is a higher rate of functional and cognitive impairment with dementia coinciding with immobility, which results in a higher rate of PU. Understanding common etiological paths resulting in pressure ulcers and dementia is likely to produce new treatment strategies that could lead to the prevention of comorbid complications. Data collected from elderly dementia patients indicate a deterioration of several neurophysiological subsystems associated with motor, sensory, autonomic, cognitive, or behavioral pathways, supporting a "close pathophysiological interrelation" perspective linking PU with dementia progression. Overall, the authors' theoretical systemic-model of disease progression and PU comorbidity proposes that increased clinician awareness to PU in mild to moderate dementia may suppress the accelerated development of PU, resulting in less patient suffering, reduced long-term care hospitalization, and hopefully PU prevention.

The Effect of Pressure Ulcers on the Survival in Patients With Advanced Dementia and Comorbidities.

BACKGROUND/STUDY CONTEXT: The mortality rates for many leading causes of death have declined over the past decade. Advanced dementia with comorbidities has steadily increased to become one of the leading causes of death in the elderly population. Therefore, this study examined the effect of pressure ulcers on the survival time of patients with advanced dementia and comorbidities. METHODS: Data were reviewed from all the files of 147 patients hospitalized over a period of 3½ years. Ninety-nine tube-fed patients suffering from advanced dementia were assessed; 72 (66.5%) had pressure ulcers and 27 (33.5%) were without pressure ulcers at admission. Logistic regression analysis was used to estimate the odds ratio and 95% confidence intervals for pressure ulcers group versus non-pressure ulcers group. Unadjusted Cox model and Cox proportional hazards model were used to assess the hazard ratio for pressure ulcers and the association between pressure ulcers and survival time, respectively. Kaplan-Meier model was used to visually confirm the existence of proportional hazards of pressure ulcers on survival. RESULTS: The median survival of advanced dementia patients with pressure ulcers was significantly shorter, compared with those without pressure ulcers (96 vs. 863 days). Significant lower hemoglobin and serum albumin levels were found in the patients with pressure ulcers. CONCLUSION: Advance dementia and pressure ulcers in the same patient results in earlier mortality. Advanced dementia patients with pressure ulcers had significantly lower survival expectancy in comparison with similar patients without pressure ulcers. Clinical and ethical implications are discussed.

Prefrontal oscillatory stimulation modulates access to cognitive control references in retrospective metacognitive commentary.

OBJECTIVE: We intended to examine how theta-rhythm transcranial alternating current stimulation (tACS) (versus sham non-active stimulation) modulated associations between working memory accuracy and later retrospective self-evaluation scores. METHODS: Healthy participants were required to complete a verbal working memory task while receiving tACS bilaterally over the dorsolateral prefrontal cortex (DLPFC) versus sham DLPFC stimulation. After completion of the online and post-stimulation working memory tasks, participants were asked to rate the level of success-confidence on the two preceding working memory tasks. RESULTS: As expected, online working memory accuracy was improved in the active bilateral DLPFC condition versus sham stimulation. Importantly, this working memory enhancement was related to post-stimulation self-evaluation scores. CONCLUSIONS: Theoretically, our findings indicated that cognitive-control representations (e.g., working memory accuracy) could serve as the optimal frame of reference for later retrospective metacognitive judgments. SIGNIFICANCE: Noninvasive application of bi-frontal oscillatory currents might enhance functional connectivity between prefrontal regulatory components of working memory and retrospective monitoring in humans. Importantly, along with recent electrophysiological finding indicating interaction of tACS with ongoing oscillatory activity, our preliminary findings support the feasibility of utilizing tACS to treat theta-rhythm functional disconnectivity and related cognitive impairments in schizophrenia.

Unilateral prefrontal direct current stimulation effects are modulated by working memory load and gender.

BACKGROUND: Recent studies revealed that anodal transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) may improve verbal working memory (WM) performance in humans. In the present study, we evaluated executive attention, which is the core of WM capacity, considered to be significantly involved in tasks that require active maintenance of memory representations in interference-rich conditions, and is highly dependent on DLPFC function. OBJECTIVES: We investigated verbal WM accuracy using a WM task that is highly sensitive to executive attention function. We were interested in how verbal WM accuracy may be affected by WM load, unilateral DLPFC stimulation, and gender, as previous studies showed gender-dependent brain activation during verbal WM tasks. METHODS: We utilized a modified verbal n-Back task hypothesized to increase demands on executive attention. We examined "online" WM performance while participants received transcranial direct current stimulation (tDCS), and implicit learning performance in a post-stimulation WM task. RESULTS: Significant lateralized "online" stimulation effects were found only in the highest WM load condition revealing that males benefit from left DLPFC stimulation, while females benefit from right DLPFC stimulation. High WM load performance in the left DLPFC stimulation was significantly related to post-stimulation recall performance. CONCLUSIONS: Our findings support the idea that lateralized stimulation effects in high verbal WM load may be gender-dependent. Further, our post-stimulation results support the idea that increased left hemisphere activity may be important for encoding verbal information into episodic memory as well as for facilitating retrieval of context-specific targets from semantic memory.

Executive attention deficits in schizophrenia: putative mandatory and differential cognitive pathology domains in medicated schizophrenia patients.

Executive attention (EA) is a core-construct of working memory (WM) capacity. EA performance is directly related to dorsolateral prefrontal cortex (DLPFC) activation, a neural mechanism that is dysfunctional in schizophrenia. We examined the differences in particular types of EA failure in schizophrenia patients and healthy controls. We evaluated executive attention in 60 medicated schizophrenia patients and 60 matched healthy individuals. We used a standard WM task, a verbal n-Back task, to measure executive attention (WM accuracy). Our standard-version WM task (control block, 10min long) was designed to examine baseline executive attention function and was followed by one out of three different experimental blocks (revised n-Back tasks). Baseline executive attention performance was significantly related to psychosis severity and functional capacity in the psychiatric group. In both healthy and psychiatric groups, experimental-block conditions revealed that domain-general recall had a differential effect on WM scores, and was related to the patient's clinical condition. Only in the psychiatric group domain-specific recall impairments were mandatory, most severe, and independent of baseline WM scores. The results revealed the importance of domain-general recall WM scores in the evaluation of executive attention deficits in patients and controls. Disruption in domain-specific recall may represent a specifier of cognitive impairment in schizophrenia spectrum disorders.