Cognition and Aging

Non-invasive Brain Stimulation for Cognition and Aging. In modern psychiatry, dysfunctional brain networks are considered the neural substrates of mental disorders. These networks can be precisely targeted with TMS, a non-invasive, FDA-cleared treatment with minimal side effects. In one meta-analysis and one review paper, we assess the state of the field with regard to using repetitive TMS protocols to modulate brain networks and cognition. Another application of TMS is to probe the brain to identify dysfunctional brain networks, for example in the case of post-surgery delirium. This work is based on a conceptual model of delirium as the result of a stressor in an individual with pre-existing deficits in connectivity and/or atypical mechanisms of plasticity. The identification of pre-operative predictors of post-operative delirium can help stratify individual risk and identify novel therapeutic targets for interventions to prevent delirium or mitigate its impact in predisposed individuals. My work demonstrates the feasibility of gathering EEG and TMS in individuals scheduled to undergo elective surgery to identify neurophysiologic signatures of vulnerability to post-operative delirium. I present preliminary experimental evidence that EEG and TMS-EEG of cerebral oscillatory activity and cortical plasticity, which are non-invasive and scalable neurophysiological measures, identify individuals at risk of post-operative delirium.

  1. Ross, J.M., Santarnecchi, E., Lian, S.L., Fong, T.G., Touroutoglou, A., Cavallari, M., Travison, T.G., Marcantonio, E.R., Libermann, T.A., Schmitt, E., Inouye, S.K.*, Shafi, M.M.*, & Pascual-Leone, A.* (Accepted). Neurophysiologic predictors of individual risk for post-operative delirium after elective surgery. Journal of the American Geriatrics Society.
  2. Pabst, A., Comstock, D.C., Mede, B., Proksch, S., Ross, J.M., & Balasubramaniam, R. (2022). A systematic review and meta-analysis of the efficacy of intermittent theta burst stimulation (iTBS) on cognitive enhancement. Neuroscience and Biobehavioral Reviews, 135, 104587.
Figure 1. Post-surgical delirium is associated with increased morbidity, lasting cognitive decline, and loss of functional independence. Within a conceptual framework that delirium is triggered by stressors when vulnerabilities exist in cerebral connectivity and plasticity, we previously suggested that neurophysiologic measures might identify individuals at risk for post-surgical delirium (Shafi et al., 2017, JAGS). We demonstrate the feasibility of the approach and provide preliminary experimental evidence of the predictive value of such neurophysiologic measures for the risk of delirium in older persons undergoing elective surgery (Ross et al., 2022, JAGS). Electroencephalography (EEG) and transcranial magnetic stimulation (TMS) were collected from 23 patients prior to elective surgery. Resting-state EEG spectral power ratio (SPR) served as a measure of integrity of neural circuits. TMS-EEG metrics of plasticity (TMS-plasticity) were used as indicators of brain capacity to respond to stressors. Presence or absence of delirium was assessed using the Confusion Assessment Method (CAM). We included individuals with no baseline clinically relevant cognitive impairment (MoCA scores ≥21) in order to focus on subclinical neurophysiological measures. In patients with no baseline cognitive impairment (N=20, age = 72±6), 3 developed post-surgical delirium (MoCA = 24±2.6) and 17 did not (controls; MoCA = 25±2.4). Patients who developed delirium had pre-surgical resting-state EEG power ratios outside the 95% confidence interval of controls, and 2/3 had TMS-plasticity measures outside the 95% CI of controls. Consistent with our proposed conceptual framework, this pilot study suggests that non-invasive and scalable neurophysiologic measures can identify individuals at risk of post-operative delirium. Specifically, abnormalities in resting-state EEG spectral power or TMS-plasticity may indicate sub-clinical risk for post-surgery delirium. Extension and confirmation of these findings in a larger sample is needed to assess the clinical utility of the proposed neurophysiologic markers, and to identify specific connectivity and plasticity targets for therapeutic interventions that might minimize the risk of delirium. Figure from Ross et al., 2022, JAGS.

Figure 2. Intermittent theta-burst stimulation (iTBS) has been used to focally regulate excitability of neural cortex over the past decade – however there is little consensus on the generalizability of effects reported in individual studies. Many studies use small sample sizes (N < 30), and there is a considerable amount of methodological heterogeneity in application of the stimulation itself. This systematic meta-analysis aims to consolidate the extant literature and determine if up-regulatory theta-burst stimulation reliably enhances cognition through measurable behavior. Results show that iTBS – when compared to suitable control conditions — may enhance cognition when outlier studies are removed, but also that there is a significant amount of heterogeneity across studies. Significant contributors to between-study heterogeneity include location of stimulation and method of navigation to the stimulation site. Surprisingly, the type of cognitive domain investigated was not a significant contributor of heterogeneity. The findings of this meta-analysis demonstrate that standardization of iTBS is urgent and necessary to determine if neuroenhancement of particular cognitive faculties are reliable and robust, and measurable through observable behavior. Figure from Pabst et al., 2022, Neurosci. Biobehav. Rev.