A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Effects of repetitive paired associative stimulation on brain plasticity and working memory in Alzheimer's disease: a pilot randomized double-blind-controlled trial.

DESIGN: Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation. OBJECTIVES: To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer's disease (AD). METHODS: Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta-gamma coupling were assessed at the same time points using the N-back task and EEG. RESULTS: There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta-gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta-gamma coupling. CONCLUSIONS: This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586).

Assessing the Longitudinal Relationship between Theta-Gamma Coupling and Working Memory Performance in Older Adults.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD.

Insights of neurophysiology on unconscious state using combined transcranial magnetic stimulation and electroencephalography: A systematic review.

Unconscious state has been investigated in numerous studies so far, but pathophysiology of this state is not fully understood. Recently, combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been developed to allow for non-invasive assessment of neurophysiology in the cerebral cortex. We conducted a systematic literature search for TMS-EEG studies on human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including one article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. This review demonstrated that TMS-EEG could represent a promising neuroscientific tool to investigate various unconscious states. Further TMS-EEG research may help elucidate the neural basis of unconscious state.

Theta-gamma coupling and ordering information: a stable brain-behavior relationship across cognitive tasks and clinical conditions.

Ordering of information is a critical component that underlies several cognitive functions. Prefrontal theta-gamma coupling (TGC) is a neurophysiologic measure associated with ordering of information during the performance of a working memory task (N-back). Little is known about the relationship between TGC and ordering during other cognitive tasks or whether the relationship between TGC and ordering of information is independent of clinical condition. This study aimed to determine whether the relationship between TGC and ordering of information exists independent of a task and its timing, and whether this relationship is the same in different clinical conditions. A total of 311 participants were assessed using a neuropsychological battery that included the N-back during which TGC was measured; two other tasks that also require ordering; and three tests that do not require ordering. All non-N-back tasks were completed several days separate from the N-back by a mean interval (SD) of 5.14 (8.03). Our three hypotheses were that TGC during the N-back task would be associated with performance on N-Back and other cognitive tasks that also require ordering, but not with performance on cognitive tasks that do not require ordering; and that these relationships will be independent of clinical diagnosis. Multivariate linear regression results show that TGC was associated with performance on the ordering tasks but not the non-ordering tasks. In addition, there was no interaction between TGC and diagnosis. Our study is the first to demonstrate that TGC is a neurophysiologic measure of ordering information across several cognitive tasks that require ordering, and this TGC-ordering relationship is stable over time even when several days separate the measurement of TGC and the performance of the ordering tasks. Our results also show that this relationship is independent of clinical diagnosis, supporting the brain-behavior nature of this relationship. These results highlight the importance of TGC in ordering-based cognition, and suggest that TGC could be a valid target for interventions that aim to enhance this function across cognitive tasks and clinical conditions.

Changes in Theta but not Alpha Modulation Are Associated with Impairment in Working Memory in Alzheimer's Disease and Mild Cognitive Impairment.

While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n = 29), MCI (n = 100), and healthy controls (HCs; n = 40). Theta (4-7 Hz) and alpha (7.5-12 Hz) modulation was measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD.

Theta-Gamma Coupling and Working Memory in Alzheimer's Dementia and Mild Cognitive Impairment.

Working memory deficits are common among individuals with Alzheimer's dementia (AD) or mild cognitive impairment (MCI). Yet, little is known about the mechanisms underlying these deficits. Theta-gamma coupling-the modulation of high-frequency gamma oscillations by low-frequency theta oscillations-is a neurophysiologic process underlying working memory. We assessed the relationship between theta-gamma coupling and working memory deficits in AD and MCI. We hypothesized that: (1) individuals with AD would display the most significant working memory impairments followed by MCI and finally healthy control (HC) participants; and (2) there would be a significant association between working memory performance and theta-gamma coupling across all participants. Ninety-eight participants completed the N-back working memory task during an electroencephalography (EEG) recording: 33 with AD (mean ± SD age: 76.5 ± 6.2), 34 with MCI (mean ± SD age: 74.8 ± 5.9) and 31 HCs (mean ± SD age: 73.5 ± 5.2). AD participants performed significantly worse than control and MCI participants on the 1- and 2-back conditions. Regarding theta-gamma coupling, AD participants demonstrated the lowest level of coupling followed by the MCI and finally control participants on the 2-back condition. Finally, a linear regression analysis demonstrated that theta-gamma coupling (ß = 0.69, p < 0.001) was the most significant predictor of 2-back performance. Our results provide evidence for a relationship between altered theta-gamma coupling and working memory deficits in individuals with AD and MCI. They also provide insight into a potential mechanism underlying working memory impairments in these individuals.

Extent of Dorsolateral Prefrontal Cortex Plasticity and Its Association With Working Memory in Patients With Alzheimer Disease.

Importance: The extent of dorsolateral prefrontal cortex (DLPFC) plasticity in Alzheimer disease (AD) and its association with working memory are not known. Objectives: To determine whether participants with AD had impaired DLPFC plasticity compared with healthy control participants, to compare working memory between participants with AD and controls, and to determine whether DLPFC plasticity was associated with working memory. Design, Setting, and Participants: This cross-sectional study included 32 participants with AD who were 65 years or older and met diagnostic criteria for dementia due to probable AD with a score of at least 17 on the Mini-Mental State Examination and 16 age-matched control participants. Participants were recruited from a university teaching hospital from May 2013 to October 2016. Main Outcomes and Measures: Plasticity of the DLPFC measured as potentiation of cortical-evoked activity using paired associative stimulation (a combination of peripheral nerve electrical stimulation and transcranial magnetic stimulation) combined with electroencephalography. Working memory was assessed with the n-back task (1- and 2-back) and measured using the A' statistic. Results: Among the 32 participants with AD, 17 were women and 15 were men (mean [SD] age, 76.3 [6.3] years); among the 16 controls, 8 were men and 8 were women (mean [SD] age, 76.4 [5.1] years). Participants with AD had impaired DLPFC plasticity (mean [SD] potentiation, 1.18 [0.25]) compared with controls (mean [SD] potentiation, 1.40 [0.35]; F1,44 = 5.90; P = .02; between-group comparison, Cohen d = 0.77; P = .01). Participants with AD also had impaired performances on the 1-back condition (mean [SD] A' = 0.47 [0.30]) compared with controls (mean [SD] A' = 0.96 [0.01]; Cohen d = 1.86; P < .001), with similar findings for participants with AD on the 2-back condition (mean [SD] A' = 0.29 [0.2]) compared with controls (mean [SD], A' = 0.85 [0.18]; Cohen d = 2.83; P < .001). Plasticity of DLPFC was positively associated with working memory performance on the 1-back A' (parameter estimate B [SE] = 0.32 [0.13]; standardized ß = 0.29; P = .02) and 2-back A' (B [SE] = 0.43 [0.15]; ß = 0.39; P = .006) across both groups after controlling for age, education, and attention. Conclusions and Relevance: This study demonstrated impaired in vivo DLPFC plasticity in patients with AD. The findings support the use of DLPFC plasticity as a measure of DLPFC function and a potential treatment target to enhance DLPFC function and working memory in patients with AD.

Effects of Extended Cannabis Abstinence on Cognitive Outcomes in Cannabis Dependent Patients with Schizophrenia vs Non-Psychiatric Controls.

Cross-sectional studies of the effects of cannabis on cognition in schizophrenia have produced mixed results. Heavy and persistent cannabis use in schizophrenia is a common clinical problem, and effects of controlled abstinence from cannabis in these patients have not been carefully evaluated. The present study sought to determine the effects of cannabis abstinence on cognition in patients with schizophrenia and co-occurring cannabis dependence. We utilized a 28-day cannabis abstinence paradigm to investigate the state-dependent effects of cannabis on select cognitive outcomes in cannabis-dependent patients with schizophrenia and non-psychiatric controls. Nineteen patients and 20 non-psychiatric male cannabis-dependent participants underwent 28 days of cannabis abstinence. Cognition was assessed on day 0, 14, and 28 using a comprehensive neuropsychological battery. Clinical symptoms were assessed weekly. Abstinence was facilitated by contingency reinforcement confirmed by twice weekly urinalysis. Forty-two percent of patients and 55% of controls achieved end-point abstinence (p=0.53), which was biochemically-verified (day 28 urinary THC-COOH <20 ng/ml). In this preliminary study, schizophrenia-abstainers demonstrated improvements in Hopkins Verbal Learning Test-Revised (HVLT-R) performance over time [F(2,14)=4.73, p<0.03] (d=1.07). Lesser improvements on HVLT-R were observed in non-psychiatric control abstainers (d=0.66), and with abstinence on other cognitive test measures, in both patients and controls. Verbal memory and learning may improve in schizophrenia and control subjects with cannabis abstinence, but larger more definitive studies are needed. Our findings underscore the importance of developing effective interventions for cannabis use disorders in schizophrenia.

Differential effects of cannabis dependence on cortical inhibition in patients with schizophrenia and non-psychiatric controls.

BACKGROUND: Cannabis is the most commonly used illicit substance among patients with schizophrenia. Cannabis exacerbates psychotic symptoms and leads to poor functional outcomes. Dysfunctional cortical inhibition has been implicated in the pathophysiology of schizophrenia; however, the effects of cannabis on this mechanism have been relatively unexamined. The goal of this study was to index cortical inhibition from the motor cortex among 4 groups: schizophrenia patients and non-psychiatric controls dependent on cannabis as well as cannabis-free schizophrenia patients and non-psychiatric controls. METHODS: In this cross-sectional study, GABA-mediated cortical inhibition was index with single- and paired-pulse transcranial magnetic stimulation (TMS) paradigms to the left motor cortex in 12 cannabis dependent and 11 cannabis-free schizophrenia patients, and in 10 cannabis dependent and 13 cannabis-free controls. RESULTS: Cannabis-dependent patients with schizophrenia displayed greater short-interval cortical inhibition (SICI) compared to cannabis-free schizophrenia patients (p = 0.029), while cannabis-dependent controls displayed reduced SICI compared to cannabis-free controls (p = 0.004). SICI did not differ between cannabis dependent patients and cannabis-free controls, or between dependent schizophrenia patients compared to dependent controls. No significant differences were found for long-interval cortical inhibition (LICI) or intra-cortical facilitation (ICF) receptor function, suggesting a selective effect on SICI. CONCLUSION: These findings suggest that cannabis dependence may have selective and differing effects on SICI in schizophrenia patients compared to controls, which may provide insight into the pathophysiology of co-morbid cannabis dependence in schizophrenia.

Effects of varenicline on motor cortical plasticity in non-smokers with schizophrenia.

BACKGROUND: Nicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia. METHODS: Varenicline (0.5mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1Hz to the left motor cortex and measured every 15min for two hours post-PAS. RESULTS: There was a significant diagnosis × medication interaction on peak potentiation (F (3, 34)=6.04, p<0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects. CONCLUSIONS: These preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia.

Deficits in GABAA receptor function and working memory in non-smokers with schizophrenia.

BACKGROUND: Although altered gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathophysiology of schizophrenia, it is unclear whether the influence of GABA on working memory processes is confounded by nicotine use in this population. It is therefore crucial to evaluate working memory and its underlying mechanisms in non-smokers with schizophrenia to eliminate the confounding effects of nicotine on behavior and neurophysiology. METHODS: In this cross-sectional study, working memory was assessed using the verbal N-back task, while GABAergic function was assessed through motor cortical inhibition using single and paired-pulse transcranial magnetic stimulation (TMS) to the left primary motor cortex in 11 non-smokers with schizophrenia and 13 non-smoker healthy subjects. RESULTS: Similar to previously published studies, working memory performance was significantly impaired in the 3-back condition in patients with schizophrenia compared to healthy subjects (p=0.036). In addition, GABAA receptor function was significantly reduced in schizophrenia as assessed by short interval cortical inhibition (SICI) (p=0.005). A positive correlation was found between GABAA inhibition and working memory performance on the 3-back task (r(23)=0.55, p=0.006), suggesting that greater GABAA inhibition is associated with better performance on tasks of working memory. CONCLUSIONS: Our findings highlight the role of GABAA receptor dysfunction in working memory and the pathophysiology of schizophrenia, and may represent a selective characteristic of schizophrenia. Moreover, these findings suggest a potential therapeutic role for targeting GABA receptor activity to improve cognition and quality of life in patients with schizophrenia.

Cost and incidence of social comorbidities in low-risk patients with community-acquired pneumonia admitted to a public hospital.

CONTEXT: There are up to 1 million patients treated in acute-care hospitals for community-acquired pneumonia (CAP), with an estimated annual cost > 8 billion dollars. A newly validated CAP outcomes prediction rule developed by Fine and colleagues has been advocated as a guide to hospitalization decisions. OBJECTIVE: To evaluate the clinical characteristics, costs of care, and resource utilization of patients with low-risk CAP at an urban public hospital serving an indigent population. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study from June 1, 1994 to May 31, 1996. MAIN OUTCOME MEASURES: Clinical characteristics and costs of care of patients with low-risk CAP and features associated with low-risk CAP in this population. RESULTS: A total of 522 patients were identified at the time of hospital admission as having CAP; 97 patients (19%) were HIV positive on hospital admission and excluded. Of the remaining 425 patients, 253 patients (60%) were classified as pneumonia severity index (PSI) class I-III (low risk). Of the patients with low-risk CAP, only four patients (1.6%; 95% confidence interval, 0.4 to 4.0%) died during hospitalization. Low-risk CAP was both costly and accounted for significant resource use (35.4% of total CAP costs, and 45% of all CAP bed days). Of the patients with low-risk CAP, there were 138 patients (55%) who could potentially have been treated as outpatients (absence of altered mental status, hypotension, hypoxia on hospital admission, or direct ICU admission). However, 49% of these patients had a history of alcoholism, 20% had a blood alcohol level > 50 mg/dL, and 44% were homeless. CONCLUSIONS: A significant proportion of the patients admitted with CAP to a public hospital had low-risk CAP and accounted for a significant proportion of the CAP bed days and costs. The use of the PSI accurately predicted which patients would be at low risk for death; however, the utility of using the PSI to reduce low-risk CAP hospital admissions would have been of limited benefit. High rates of homelessness, substance abuse, and medical needs not captured in the PSI would preclude many of these patients from unsupervised outpatient treatment.