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Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area To the Editor: The study by Suthana and coworkers (Feb. 9 issue)1 involved patients with pharmacoresistant epilepsy who underwent implantation of intracranial depth electrodes before possible surgical resection. The authors found that stimulation of the entorhinal cortex, but not of the hippocampus proper, during the learning phase of a spatial-navigation task resulted in more efficient performance. This finding may serve as a starting point for future neuromodulatory interventions aimed at treating disorders with medial temporal-lobe dysfunction and associated cognitive dysfunction. In the context of identification of therapeutic targets, a more precise description of electrode localization, especially along the anterior-posterior axis, would considerably strengthen the findings. Spatial navigation, as tested in the current study, is functionally associated with the posterior hippocampus, as shown by long-standing evidence obtained from studies involving various species, including monkeys2 and humans.3 Electrical conduction could have affected structures that were not directly targeted by the electrodes of interest; this further underscores the importance of clarifying electrode positions in three-dimensional space for every patient.
important for higher brain functions.1 The thetaband phase has been shown to be coupled with changes in gamma-band (>80 Hz) activity; this phenomenon is called cross-frequency coupling.2 The strength of theta–gamma coupling is known to vary spatially over the cortex, depending on the task, in humans,3 and it is proportionate to learning performance in rats.4 It has been suggested that high-frequency brain activity is associated with local functional activation and that low-frequency rhythms serve to integrate activity across large regions.2 We therefore suggest that investigation of high gamma-band modulation, linked with theta-phase changes caused by entorhinal stimulation, may lead to a better understanding of memory functions. Katsuhiro Kobayashi, M.D. Harumi Yoshinaga, M.D. Yoko Ohtsuka, M.D. Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama, Japan
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Herrmann CS, Fründ I, Lenz D. Human gamma-band activ-
1. Suthana N, Haneef Z, Stern J, et al. Memory enhancement
ity: a review on cognitive and behavioral correlates and network models. Neurosci Biobehav Rev 2010;34:981-92. 2. Canolty RT, Knight RT. The functional role of cross-frequency coupling. Trends Cogn Sci 2010;14:506-15. 3. Canolty RT, Edwards E, Dalal SS, et al. High gamma power is phase-locked to theta oscillations in human neocortex. Science 2006;313:1626-8. 4. Tort AB, Komorowski RW, Manns JR, Kopell NJ, Eichenbaum H. Theta-gamma coupling increases during the learning of item-context associations. Proc Natl Acad Sci U S A 2009; 106:20942-7.
To the Editor: Suthana et al. report that memory was enhanced by electrical stimulation of the entorhinal cortex and by an association between this effect and phase resetting in theta rhythms (3 to 8 Hz). Theta rhythms are closely related to the activity of gamma (>30 Hz) frequency bands, which is
To the Editor: Suthana et al. suggest that deepbrain stimulation of the entorhinal cortex in patients with Alzheimer’s disease may be beneficial. However, the complex and incompletely understood pathophysiology of Alzheimer’s disease, such as the effect of beta-amyloid protein on synaptic plasticity,1 may limit the effect of deep-brain stimulation in persons with this disease. We suggest the histologic, molecular, and biochemical analysis of the resected mesial temporal-lobe structures (i.e., the hippocampus and entorhinal cortex) after deep-brain stimulation. We also note that, in a small trial designed to assess safety, deep-
Andres H. Neuhaus, M.D. Malek Bajbouj, M.D. Charité University Medicine Berlin, Germany
[email protected] No potential conflict of interest relevant to this letter was reported. and deep-brain stimulation of the entorhinal area. N Engl J Med 2012;366:502-10. 2. Colombo M, Fernandez T, Nakamura K, Gross CG. Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys. J Neurophysiol 1998;80:1002-5. 3. Maguire EA, Gadian DG, Johnsrude IS, et al. Navigation related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci U S A 2000;97:4398-403.
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brain stimulation of the fornix and hypothalamus in persons with Alzheimer’s disease showed no clear clinical benefit, even though activation of the entorhinal and hippocampal areas was observed.2 That said, we believe that pending replication of the study by Suthana et al., a trial of deep-brain stimulation of the entorhinal cortex in persons with Alzheimer’s disease could be considered.
heimer’s disease could be limited by various pathophysiological variables, such as buildup of proteins (beta-amyloid plaques and tau tangles) leading to impaired synaptic function and cell death. Although deep-brain stimulation has been shown to increase neurogenesis within the hippocampus,3 data are lacking from studies of its effects on protein depositions. More applicable, however, may be the potential use of deep-brain Brian J. Dlouhy, M.D. stimulation in combination with pharmaceutical University of Iowa Hospitals and Clinics interventions that are capable of potentially reIowa City, IA
[email protected] versing protein accumulation.4 We would point out that although data are lacking on the histoRajesh C. Rao, M.D. logic effects of deep-brain stimulation, they will Washington University School of Medicine be easier to investigate in animal models. All but St. Louis, MO No potential conflict of interest relevant to this letter was re- one of the brain sites undergoing deep-brain stimulation in our study were not found to be ported. part of the epileptogenic network and thus were 1. Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synap- not available for histologic analysis, since they tic plasticity and memory. Nat Med 2008;14:837-42. would not be included in surgical resection for 2. Laxton AW, Tang-Wai DF, McAndrews MP, et al. A phase I epilepsy. Even if stimulated tissue was epileptotrial of deep brain stimulation of memory circuits in Alzheimgenic and thus a target for epilepsy surgery, the er’s disease. Ann Neurol 2010;68:521-34. procedure would customarily take place several weeks after the electrodes had been removed, The Authors Reply: We agree with Neuhaus when the effects of acute short-term deep-brain and Bajbouj that electrode localization along the stimulation may be difficult to discern. anterior–posterior axis of the medial temporal Nanthia Suthana, Ph.D. lobe is important for potential therapeutic tar- Itzhak Fried, M.D., Ph.D. geting of electrodes. They note that the posterior University of California, Los Angeles hippocampus seems to be functionally associat- Los Angeles, CA ed with spatial navigation. Our electrodes were
[email protected] Since publication of their article, the authors report no furlocalized to the entorhinal white-matter area, an anterior region within the medial temporal lobe ther potential conflict of interest. that relays information to the entire anterior- 1. Suzuki WA, Amaral DG. Topographic organization of the posterior axis of the hippocampus.1,2 The poste- reciprocal connections between the monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J Neurosci rior portion of the entorhinal cortex receives and 1994;14:1856-77. 1 sends spatially relevant information, and thus 2. Witter MP. Organization of the entorhinal-hippocampal sysdeep-brain stimulation of the posterior portion tem: a review of current anatomical data. Hippocampus 1993;3: 33-44. of the entorhinal area may facilitate spatial mem- 3. Stone SS, Teixeira CM, DeVito LM, et al. Stimulation of entoory to an even larger extent. Data are lacking rhinal cortex promotes adult neurogenesis and facilitates spatial from studies with larger samples to determine memory. J Neurosci 2011;31:13469-84. 4. Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed the precise regional effects of deep-brain stimu- therapeutics rapidly clear β-amyloid and reverse deficits in AD lation along the entire longitudinal axis of the mouse models. Science 2012;335:1503-6. Correspondence Copyright © 2012 Massachusetts Medical Society. medial temporal lobe. We agree with Kobayashi and colleagues that the journal’s web and e-mail addresses: deep-brain stimulation could affect coupling beFor letters to the Editor: authors.NEJM.org tween frequencies, which we did not explore in For information about the status of a submitted manuscript: our study. They point to an exciting area of fuauthors.NEJM.org ture study. To submit a meeting notice:
[email protected] We concur with Dlouhy and Rao that the use The Journal’s web pages: NEJM.org of deep-brain stimulation in patients with Alz
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