A comprehensive characterization of cognitive performance, clinical symptoms, and cortical activity following mild traumatic brain injury (mTBI).

OBJECTIVE: The objective of this study was to investigate clinical symptoms, cognitive performance and cortical activity following mild traumatic brain injury (mTBI). METHODS: We recruited 30 individuals in the sub-acute phase post mTBI and 28 healthy controls with no history of head injury and compared these groups on clinical, cognitive and cortical activity measures. Measures of cortical activity included; resting state electroencephalography (EEG), task related EEG and combined transcranial magnetic stimulation with electroencephalography (TMS-EEG). Primary analyses investigated clinical, cognitive and cortical activity differences between groups. Exploratory analyses investigated the relationships between these measures. RESULTS: At 4 weeks' post injury, mTBI participants exhibited significantly greater post concussive and clinical symptoms compared to controls; as well as reduced cognitive performance on verbal learning and working memory measures. mTBI participants demonstrated alterations in cortical activity while at rest and in response to stimulation with TMS. CONCLUSIONS: The present study comprehensively characterized the multidimensional effect of mTBI in the sub-acute phase post injury, showing a broad range of differences compared to non-mTBI participants. Further research is needed to explore the relationship between these pathophysiologies and clinical/cognitive symptoms in mTBI.

Gamma connectivity predicts response to intermittent theta burst stimulation in Alzheimer's disease: a randomized controlled trial.

There is growing evidence that neural network dysfunction is a likely proximate cause of cognitive impairment in Alzheimer's disease and may represent a promising therapeutic target. Here, we investigated whether a course of intermittent theta burst stimulation (iTBS) could modulate functional connectivity and cognition in mild to moderate Alzheimer's. In a double-blind parallel randomized sham-controlled trial, 58 participants were randomized to either active or sham iTBS. Stimulation was applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, left posterior parietal cortex, and right posterior parietal cortex in every treatment session. Neurobiological (electroencephalography), cognitive, and behavioral functional assessments were undertaken at baseline and end of treatment. Cognitive and functional assessments were also conducted at 3 (blinded) and 6 month (active group only) follow-ups. Active iTBS increased resting-state gamma connectivity and improved delayed recall on an episodic memory task. Both baseline gamma connectivity and change in gamma connectivity predicted improved delayed recall following active treatment. These findings support future research into iTBS for Alzheimer's focusing on protocol optimization.

Recovery of clinical, cognitive and cortical activity measures following mild traumatic brain injury (mTBI): A longitudinal investigation.

The mechanisms that underpin recovery following mild traumatic brain injury (mTBI) remain poorly understood. Identifying neurophysiological markers and their functional significance is necessary to develop diagnostic and prognostic indicators of recovery. The current study assessed 30 participants in the subacute phase of mTBI (10-31 days post-injury) and 28 demographically matched controls. Participants also completed 3 month (mTBI: N = 21, control: N = 25) and 6 month (mTBI: N = 15, control: N = 25) follow up sessions to track recovery. At each time point, a battery of clinical, cognitive, and neurophysiological assessments was completed. Neurophysiological measures included resting-state electroencephalography (EEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG). Outcome measures were analysed using mixed linear models (MLM). Group differences in mood, post-concussion symptoms and resting-state EEG resolved by 3 months, and recovery was maintained at 6 months. On TMS-EEG derived neurophysiological measures of cortical reactivity, group differences ameliorated at 3 months but re-emerged at 6 months, while on measures of fatigue, group differences persisted across all time points. Persistent neurophysiological changes and greater fatigue in the absence of measurable cognitive impairment may suggest the impact of mTBI on neuronal communication may leads to increased neural effort to maintain efficient function. Neurophysiological measures to track recovery may help identify both temporally optimal windows and therapeutic targets for the development of new treatments in mTBI.

Investigation of neurobiological responses to theta burst stimulation during recovery from mild traumatic brain injury (mTBI).

OBJECTIVE: The ability of the brain to recover following neurological insult is of interest for mild traumatic brain injury (mTBI) populations. Investigating whether non-invasive brain stimulation (NIBS) can modulate neurophysiology and cognition may lead to the development of therapeutic interventions post injury. The purpose of this study was to investigate neurobiological effects of one session of intermittent theta burst stimulation (iTBS) to the dorsolateral prefrontal cortex (DLPFC) in participants recovering from mTBI. METHOD: Changes to neurophysiology were assessed with electroencephalography (EEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG). Digit span working memory accuracy assessed cognitive performance. 30 patients were assessed within one-month of sustaining a mTBI and 26 demographically matched controls were assessed. Participants were also assessed at 3-months (mTBI: N = 21, control: N = 26) and 6-months (mTBI: N = 15, control: N = 24). RESULTS: Analyses demonstrated iTBS did not reliably modulate neurophysiological activity, and no differences in cognitive performance were produced by iTBS at any assessment time-point. CONCLUSIONS: Factors responsible for our null results are unclear. Possible limitations to our experimental design are discussed. SIGNIFICANCE: Our findings suggest additional research is required to establish the effects of iTBS on plasticity following mTBI, prior to therapeutic application. DATA AND CODE AVAILABILITY STATEMENT: We do not have ethical approval to make this data publicly available, as our approval predated our inclusion of such approvals (which we now do routinely).

Investigating Neurophysiological Markers of Symptom Severity in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by a progressive decline in cognitive functioning for which there is a stark lack of effective treatments. Investigating the neurophysiological markers of symptom severity in AD may aid in the identification of alternative treatment targets. OBJECTIVE: In the current study we used a multimodal approach to investigate the association between functional connectivity (specifically between scalp electrodes placed over frontal and parietal regions) and symptom severity in AD, and to explore the relationship between connectivity and cortical excitability. METHODS: 40 people with AD (25 mild severity, 15 moderate severity) underwent neurobiological assessment (resting state electroencephalography (EEG) and prefrontal transcranial magnetic stimulation (TMS) with EEG) and cognitive assessment. Neurobiological outcomes were resting state functional connectivity and TMS-evoked potentials. Cognitive outcomes were scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, and a measure of episodic verbal learning. RESULTS: Greater contralateral functional theta connectivity between frontal scalp electrodes and parietal scalp electrodes was associated with poorer cognitive performance. In addition, significant correlations were seen between the contralateral theta connectivity and the N100 and P60 TMS-evoked potentials measured from electrodes over the left dorsolateral prefrontal cortex. CONCLUSION: Together these findings provide initial support for the use of multimodal neurophysiological approaches to investigate potential therapeutic targets in AD. Suggestions for future research are discussed.

Investigating neurophysiological markers of impaired cognition in schizophrenia.

Cognitive impairment is highly prevalent in schizophrenia and treatment options are severely limited. A greater understanding of the pathophysiology of impaired cognition would have broad implications, including for the development of effective treatments. In the current study we used a multimodal approach to identify neurophysiological markers of cognitive impairment in schizophrenia. Fifty-seven participants (30 schizophrenia, 27 controls) underwent neurobiological assessment (electroencephalography [EEG] and Transcranial Magnetic Stimulation combined with EEG [TMS-EEG]) and assessment of cognitive functioning using an n-back task and the MATRICS Consensus Cognitive Battery. Neurobiological outcome measures included oscillatory power during a 2-back task, TMS-related oscillations and TMS-evoked potentials (TEPs). Cognitive outcome measures were d prime and accurate reaction time on the 2-back and MATRICS domain scores. Compared to healthy controls, participants with schizophrenia showed significantly reduced theta oscillations in response to TMS, and trend level decreases in task-related theta and cortical reactivity (i.e. reduced N100 and N40 TEPs). Participants with schizophrenia also showed significantly impaired cognitive performance across all measures. Correlational analysis identified significant associations between cortical reactivity and TMS-related oscillations in both groups; and trend level associations between task-related oscillations and impaired cognition in schizophrenia. The current study provides experimental support for possible neurophysiological markers of cognitive impairment in schizophrenia. The potential implications of these findings, including for treatment development, are discussed.

Understanding individual variability in symptoms and recovery following mTBI: A role for TMS-EEG?

The pathophysiology associated with mild traumatic brain injury (mTBI) includes neurometabolic and cytoskeletal changes that have been shown to impair structural and functional connectivity. Evidence that persistent neuropsychological impairments post injury are linked to structural and functional connectivity changes is increasing. However, to date the relationship between connectivity changes, heterogeneity of persistent symptoms and recovery post mTBI has been poorly characterised. Recent innovations in neuroimaging provide new ways of exploring connectivity changes post mTBI. Namely, combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers several advantages over traditional approaches for studying connectivity changes post TBI. Its ability to perturb neural function in a controlled manner allows for measurement of causal interactions or effective connectivity between brain regions. We review the current literature assessing structural and functional connectivity following mTBI and outline the rationale for the use of TMS-EEG as an ideal tool for investigating the neural substrates of connectivity dysfunction and reorganisation post mTBI. The diagnostic, prognostic and potential therapeutic implications will also be explored.

Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users.

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.

Computerized and virtual reality cognitive training for individuals at high risk of cognitive decline: systematic review of the literature.

The aim of this study was to assess the efficacy of cognitive training, specifically computerized cognitive training (CCT) and virtual reality cognitive training (VRCT), programs for individuals living with mild cognitive impairment (MCI) or dementia and therefore at high risk of cognitive decline. After searching a range of academic databases (CINHAL, PSYCinfo, and Web of Science), the studies evaluated (N = 16) were categorized as CCT (N = 10), VRCT (N = 3), and multimodal interventions (N = 3). Effect sizes were calculated, but a meta-analysis was not possible because of the large variability of study design and outcome measures adopted. The cognitive domains of attention, executive function, and memory (visual and verbal) showed the most consistent improvements. The positive effects on psychological outcomes (N = 6) were significant reductions on depressive symptoms (N = 3) and anxiety (N = 2) and improved perceived use of memory strategy (N = 1). Assessments of activities of daily living demonstrated no significant improvements (N = 8). Follow-up studies (N = 5) demonstrated long-term improvements in cognitive and psychological outcomes (N = 3), and the intervention groups showed a plateau effect of cognitive functioning compared with the cognitive decline experienced by control groups (N = 2). CCT and VRCT were moderately effective in long-term improvement of cognition for those at high risk of cognitive decline. Total intervention time did not mediate efficacy. Future research needs to improve study design by including larger samples, longitudinal designs, and a greater range of outcome measures, including functional and quality of life measures, to assess the wider effect of cognitive training on individuals at high risk of cognitive decline.