Loss of the ability to transform present experience to what can be later remembered is one of the most dreaded afflictions of the human condition. It is present in various neurological disorders including temporal lobe epilepsy, traumatic brain injury and other hippocampal injuries such as those occurring during stroke, cardiac arrest, or encephalitis. It is also one of the first features of Alzheimer's Disease (AD) which affects millios of people in the US and worldwide, and is an unwelcome companion of the aging process becoming an increased burden on individual and society. Decades of research have established that declarative memory, the ability to remember recently experienced facts and events, depends on the hippocampus and associated structures in the medial temporal lobe (MTL), including the entorhinal cortex. In particular, understanding the role of the hippocampus and its relationship to afferent input from the entorhinal cortex is of considerable significance, as insul to this connective circuitry is very early and disproportionally affected in temporal lobe epilepsy AD and other neurological disorders, resulting in profound effects on memory. The applicant's laboratory has been the leader in single neuron physiology of the human MTL and recently published findings in the New England Journal of Medicine showing dramatic spatial memory enhancement when deep brain stimulation (DBS) of the human entorhinal area was given during the learning phase [13]. The present project will characterize the mechanisms of DBS through simultaneous recording of single neuron and local field potentials (LFPs). The project utilizes a rare opportunity to record the activity of single neurons and LFPs from depth electrodes implanted in patients with intractable epilepsy in order to identify the seizure focus fr potential surgical cure. A primary objective is to characterize the effect of DBS on learning vs. recall phases of memory, including both spatial and non-spatial memory, in addition to understanding its longitudinal effects. The project will elucidate the complex relationship between single neuronal responses, LFP oscillations, and DBS that underlies memory enhancement. Lastly the project will investigate variations in memory enhancement associated with changes in electrode placement through the use of high-resolution magnetic resonance imaging and high-resolution diffusion tensor imaging. By these three lines of investigation the project will develop insight into the mechanisms of memory enhancement associated with DBS in humans, contribute to the understanding of the MTL and its role in memory, and ultimately provide novel therapeutic approaches to human memory disorders.
Loss of the ability to transform present experience to what can be later remembered is one of the most dreaded afflictions of the human condition and is present in a variety of neurological disorders including temporal lobe epilepsy, traumatic brain injury, and is one of the first features of Alzheimer's Disease (AD) affecting approximately 10% of individuals over the age of 65, with increasing devastating costs to individual and society. Both epilepsy of medial temporal lobe (MTL) origin and AD affect entorhinal-hippocampal circuitry in the human MTL resulting in substantial compromise to learning and memory systems. Except for temporary and mild symptomatic relief by a few pharmaceutical agents, there are currently no therapeutic measures to alleviate the cognitive impairment experienced by victims of memory and cognitive disorders. Using deep brain stimulation (DBS) simultaneously with single-unit and local field potential recordings in humans we strive to develop a detailed understanding of the mechanisms of memory enhancement induced by DBS in the entorhinal region of MTL, and to contribute to novel transformative therapeutic approaches to treat memory disorders in humans.
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| Nir, Yuval; Andrillon, Thomas; Marmelshtein, Amit et al. (2017) Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med 23:1474-1480 |
| Titiz, Ali S; Hill, Michael R H; Mankin, Emily A et al. (2017) Theta-burst microstimulation in the human entorhinal area improves memory specificity. Elife 6: |
| M Aghajan, Zahra; Schuette, Peter; Fields, Tony A et al. (2017) Theta Oscillations in the Human Medial Temporal Lobe during Real-World Ambulatory Movement. Curr Biol 27:3743-3751.e3 |
| Fried, Itzhak (2016) Brain Stimulation in Alzheimer's Disease. J Alzheimers Dis 54:789-91 |
| Fried, Itzhak (2015) Brain stimulation and memory. Brain 138:1766-7 |
| Ison, Matias J; Quian Quiroga, Rodrigo; Fried, Itzhak (2015) Rapid Encoding of New Memories by Individual Neurons in the Human Brain. Neuron 87:220-30 |
| Hill, Michael R H; Fried, Itzhak; Koch, Christof (2015) Quantification and classification of neuronal responses in kernel-smoothed peristimulus time histograms. J Neurophysiol 113:1260-74 |
| Miller, Jonathan F; Fried, Itzhak; Suthana, Nanthia et al. (2015) Repeating spatial activations in human entorhinal cortex. Curr Biol 25:1080-5 |
| Tankus, Ariel; Fried, Itzhak; Shoham, Shy (2014) Cognitive-motor brain-machine interfaces. J Physiol Paris 108:38-44 |
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