Non invasive oscillatory stimulation treatment for combating late-life accelerated cognitive decline Preservation of cortical network synchronicity and executive cognitive functions in prodromal neurodegenerative dementia Oded Meiron, Ph.D. Head of Electrophysiology & Neurocognition lab at Clinical Research Center for Brain Sciences, Herzog Hospital, Jerusalem

Overall Research goal: Inducing positive neurocognitive modulations in humans using novel noninvasive brain stimulation treatments: normalizing electrophysiological activity and enhancing cognition

Difference map of theta power (4–6 Hz) between conditions manipulation and retention during the entire delay period of 2000 ms is depicted. Griesmayr et al., 2010 Neurobiology of Learning and behavior

In a pilot study(Meiron et al In a pilot study(Meiron et al., in preparation): After examining 100 Healthy Adults ages 18 to90: Natural age-related decay in prefrontal executive attention functioning: significant inverse association between WM accuracy scores and age throughout the entire adult-life span (r = -.693, p < .001) Douaud et al., 2014, PNAS Douaud et al. (2014) using structura; MRI Identified an age related to whole Gray matter deterioration corresponding with decline in executive attention function: Spatially specific network of neocortical, limbic and paralimbic regions lateral prefrontal cortex, frontal eye field, intraparietal sulcus, superior temporal sulcus, posterior cingulate cortex, and medial temporal lobe showing monotonic decrease in whole gray matter from ages 40 to 90: associated with episodic memory deficits Douaud et al., 2014, PNAS

Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients (Lindenberg et al., 2010, Neurology) :transcranial direct current stimulation(tDCS)

Datta et. al. Brain Stim 2009

Physiological Basis of Transcranial Direct Current Stimulation (Stagg and Nitsche, 2011, Neuroscientist) 1)tDCS does indeed modulate synaptic strength within the cortex, and evidence points to the involvement of intracortical neurons. 2) “excitatory (anodal) tDCS causes locally reduced GABA while inhibitory (cathodal) stimulation causes reduced glutamatergic neuronal activity with a highly correlated reduction in GABA” (Stagg, 2009, Journal of Neuroscience)

Executive attention assessment: Verbal working memory performance (Meiron et al, 2013) Normal cognitive ageing is associated with mild to moderate WM deficits

O. Meiron, M. Lavidor (2013) ; Brain Stimulation Unilateral prefrontal direct current stimulation effects are modulated by working memory load and gender Illustration of online high-load WM accuracy enhancement

Meiron O, Lavidor M (2013): Bilateral Transcranial Alternating Current Stimulation (tACS) of the Dorsolateral Prefrontal Cortex Enhances Verbal Working Memory and Promotes Episodic Memory After-effects. In Working Memory:

Promotes Episodic Memory After-effects

Meiron O, Lavidor M: Prefrontal oscillatory stimulation modulates access to cognitive control references in retrospective metacognitive commentary. Clinical Neurophysiology 2014; 125:77-82

Using EEG, neurocognitive function, and personalized tACS protocols to delay MCI and the onset of dementia: Alzheimer’s disease. Evidence that ageing is related to lower resting EEG alpha power (i.e., amplitude of alpha). An increase in resting theta power is not directly related to normal late-life ageing but more likely a result of late-life neurological diseases (Klimesch, 1999, Finnigan and Robertson, 2011). Recent data indicates that a decrease in induced theta amplitude occurs in progressive mild cognitive impairment (MCI) patients versus stable-MCI patients and could be utilized as biomarker of rapid cognitive decline (Deiber et al., 2009). Distinct transcranial current frequencies (induced by tACS) might contribute to local excitability in humans (Kirov et al., 2009, Zaehle, Rach and Herrmann, 2010, Schutter & Hortensius, 2010, Meiron and Lavidor, 2013a,b), and may prove beneficial for delaying the onset of neurodegenerative diseases such as progressive MCI and AD

Enabling Technology Behaviorally-based electrophysiological biomedical device to denote the prognosis of accelerated MCI symptoms versus normal ageing deficits Personalized tACS treatment to enhance and help maintain cognition and functional capacity in normal ageing individuals and prodromal dementia patients, as well as identifying and treating those with more pronounced neurocognitive deficits

Boggio et al.,, 2013

Neurology August 12, 2008 vol. 71 no. 7 493-498 (Ferrucci et al) Transcranial direct current stimulation improves recognition memory in Alzheimer disease Neurology August 12, 2008 vol. 71 no. 7 493-498 (Ferrucci et al) Temporal-parietal cortex Neuroenhancement of the Aging Brain: Restoring Skill Acquisition in Old Subjects ANN NEUROL 2013;73:10–15(Zimerman et al, 2013) Motor cortex

Discrepancies in task-related EEG oscillatory cortical interactions Envisioned product: Designed to arrest or postpone pathological neurodegenerative ageing: Innovative in its objective capability for early detection and prevention of accelerated cognitive decline in the ageing population. Personalized repetitive oscillatory electrical stimulation treatment protocols to preserve adequate working memory function and delay possible progression of MCI symptoms Identify functional EEG frequencies that correspond to optimal executive attention performance within a certain age-range Discrepancies in task-related EEG oscillatory cortical interactions Diagnose executive attention deficits Define performance-related electrophysiological biomarkers of premorbid accelerated neurocognitive decline.

Thanks for listening Special Thanks: 1) Mr. Lawrence Normie , Gerontech 2) Organizing Committee 3) Scientific Committee 3) Clinical Research Center for Brain Sciences, Herzog Hospital, Jerusalem