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Modulation of Human Memory by Deep Brain Stimulation of the Entorhinal-Hippocampal Circuitry

2020; Cell Press; Volume: 106; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2020.02.024

1097-4199

Emily A. Mankin, Itzhak Fried,

Memory and Neural Mechanisms

Neurological disorders affecting human memory present a major scientific, medical, and societal challenge. Direct or indirect deep brain stimulation (DBS) of the entorhinal-hippocampal system, the brain’s major memory hub, has been studied in people with epilepsy or Alzheimer’s disease, intending to enhance memory performance or slow memory decline. Variability in the spatiotemporal parameters of stimulation employed to date notwithstanding, it is likely that future DBS for memory will employ closed-loop, nuanced approaches that are synergistic with native physiological processes. The potential for editing human memory—decoding, enhancing, incepting, or deleting specific memories—suggests exciting therapeutic possibilities but also raises considerable ethical concerns. Neurological disorders affecting human memory present a major scientific, medical, and societal challenge. Direct or indirect deep brain stimulation (DBS) of the entorhinal-hippocampal system, the brain’s major memory hub, has been studied in people with epilepsy or Alzheimer’s disease, intending to enhance memory performance or slow memory decline. Variability in the spatiotemporal parameters of stimulation employed to date notwithstanding, it is likely that future DBS for memory will employ closed-loop, nuanced approaches that are synergistic with native physiological processes. The potential for editing human memory—decoding, enhancing, incepting, or deleting specific memories—suggests exciting therapeutic possibilities but also raises considerable ethical concerns. One of the critical challenges facing society in the 21st century is the specter of a cognitive catastrophe affecting millions of people in our midst, who face gradual loss of memory. With an increase in the aging population and the prevalence of various dementias, such as Alzheimer’s disease (AD), there is an increasing need to find therapeutic measures; yet effective pharmacological agents have not been found to provide symptomatic relief that can restore quality of life. Preservation of human memory and its enhancement when in decline are therefore major challenges for the human condition. Thus, we need to consider augmentation of human memory by introduction of neuroprosthetic devices that could interact with the human brain via electrical or chemical signals. To achieve such a bionic future, where brain and machine interface seamlessly, we need to consider specific brain networks where a direct causal role in memory processes has been established. Here, we consider external modulation of the entorhinal-hippocampal circuit, the human brain’s chief organ of declarative and episodic memory. There are two major, parallel streams of discovery implicating the medial temporal lobe (MTL), with its hippocampal-entorhinal circuitry, as the hub of declarative memory (Buzsáki and Moser, 2013Buzsáki G. Moser E.I. Memory, navigation and theta rhythm in the hippocampal-entorhinal system.Nat. Neurosci. 2013; 16: 130-138Crossref PubMed Scopus (608) Google Scholar). First, the rodent literature has made major advances in locating the circuitry of spatial memory within the MTL (Moser et al., 2008Moser E.I. Kropff E. Moser M.-B. Place cells, grid cells, and the brain’s spatial representation system.Annu. Rev. Neurosci. 2008; 31: 69-89Crossref PubMed Scopus (861) Google Scholar). Second, the MTL is also the brain’s chief circuit for transforming human and non-human primate experience into durable representations that can later be consciously retrieved. This is supported by a large body of basic science and medical discovery ranging from primate neurophysiology and lesion studies to human electrophysiology and neuroimaging studies, as well as brain lesions resulting in specific memory deficits (Squire, 2004Squire L.R. Memory systems of the brain: a brief history and current perspective.Neurobiol. Learn. Mem. 2004; 82: 171-177Crossref PubMed Scopus (1066) Google Scholar). Together, these literatures support a unified model of the role of the entorhinal-hippocampal circuitry evolving across species to support both spatial and non-spatial memory, culminating in human semantic and episodic memory. The main means of modifying brain function are chemical (pharmacological) and electrical. Electrical stimulation has thus been used to treat human brain dysfunction in disease. In particular, deep brain stimulation (DBS) is an invasive form of electrical stimulation, in which stimulating electrodes are implanted directly into the brain and can apply electric current to the surrounding brain tissue. This approach has been adopted to modulate neuronal circuits for therapeutic ends. Its use has been particularly successful in Parkinson’s disease and other movement disorders (Gross and Lozano, 2000Gross R.E. Lozano A.M. Advances in neurostimulation for movement disorders.Neurol. Res. 2000; 22: 247-258Crossref PubMed Scopus (101) Google Scholar). The use of DBS is also being explored in various neurological and neuropsychiatric disorders, such as depression, obsessive-compulsive disorder (OCD), and others, with promising results (Mclaughlin et al., 2016Mclaughlin N.C.R. Stewart C. Greenberg B.D. Deep brain stimulation for obsessive-compulsive disorder and major depressive disorder.in: Camprodon J.A. Rauch S.L. Greenberg B.D. Dougherty D.D. Psychiatric Neurotherapeutics: Contemporary Surgical and Device-Based Treatments. Springer New York, 2016: 141-163Crossref Google Scholar). More recently, several studies have addressed the challenge of applying DBS to the memory domain with the hope of ameliorating memory impairment that accompanies several disorders, such as AD, traumatic brain injury, and epilepsy. Prior to therapeutic application of DBS, electrical stimulation was commonly employed to map cortical function. Pioneered by Wilder Penfield during operations on awake patients under local anesthesia, electrical stimulation in primary motor and sensory areas evoked discrete movements or sensations, but when applied elsewhere, such as Broca’s and Wernicke’s areas or the angular gyrus, it disrupted performance on speech and language tasks (Penfield and Jasper, 1954Penfield W. Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Little, Brown, and Company, 1954Crossref Google Scholar, Penfield and Perot, 1963Penfield W. Perot P. The brain’s record of auditory and visual experience. A final summary and discussion.Brain. 1963; 86: 595-696Crossref PubMed Scopus (846) Google Scholar, Penfield and Roberts, 1959Penfield W. Roberts L. Speech and Brain Mechanisms. Princeton University Press, 1959Google Scholar). Such disruption of complex cognitive functions indicated that the stimulated sites were involved in the function tested. In addition to elucidating the brain regions generally involved in various functions, this had immediate practical applications, allowing neurosurgeons to identify functional cortex that should be avoided during surgery (Szelényi et al., 2010Szelényi A. Bello L. Duffau H. Fava E. Feigl G.C. Galanda M. Neuloh G. Signorelli F. Sala F. 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Organization of short-term verbal memory in language areas of human cortex: evidence from electrical stimulation.Brain Lang. 1978; 5: 331-340Crossref PubMed Scopus (131) Google Scholar, Ojemann, 2003Ojemann G.A. The neurobiology of language and verbal memory: observations from awake neurosurgery.Int. J. Psychophysiol. 2003; 48: 141-146Crossref PubMed Scopus (0) Google Scholar, Fried et al., 1982Fried I. Mateer C. Ojemann G. Wohns R. Fedio P. Organization of visuospatial functions in human cortex. Evidence from electrical stimulation.Brain. 1982; 105: 349-371Crossref PubMed Google Scholar). The rationale of these studies was similar to language mapping: complex functions, such as memory, should be disrupted by gross stimulation of gray matter involved. The only site with stimulation-evoked improvement of memory was, in fact, in thalamus, where stimulation of the ventrolateral nucleus during encoding resulted in improved performance on subsequent retrieval (Ojemann, 1975Ojemann G.A. Language and the thalamus: object naming and recall during and after thalamic stimulation.Brain Lang. 1975; 2: 101-120Crossref PubMed Google Scholar). Although cortical stimulation did not lead to memory improvement, upon stimulation of sites in the temporal lobe, patients occasionally reported real experiences, distinct memories, or percepts (Penfield and Perot, 1963Penfield W. Perot P. The brain’s record of auditory and visual experience. A final summary and discussion.Brain. 1963; 86: 595-696Crossref PubMed Scopus (846) Google Scholar). These experiences were characterized by vividness and authenticity (“more real than remembering”), yet two experiences were never activated concurrently, and the patients were aware that they were in the operating room. These experiences were felt to demonstrate durable representations in the temporal lobe that became accessible to human consciousness by the stimulating probe. Penfield then postulated, “There is a stream of consciousness within the brain… hidden in the interpretive areas of the temporal lobe there is a key mechanism that unlocks the past” (Penfield, 1958Penfield W. Some mechanisms of consciousness discovered during electrical stimulation of the brain.Proc. Natl. Acad. Sci. USA. 1958; 44: 51-66Crossref PubMed Google Scholar). Experiential responses evoked by cortical electrical stimulation of the temporal lobe have been described in various publications since Penfield (reviewed in Lee et al., 2013bLee H. Fell J. Axmacher N. Electrical engram: how deep brain stimulation affects memory.Trends Cogn. Sci. 2013; 17: 574-584Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar), many of these giving the impression of recalled memories surfacing on the platform of consciousness. However, these responses were sporadic and their relationship to specific neuronal circuitry difficult to dissect, especially because stimulation was presumed to affect a relatively large volume of tissue and neuropil. A recent report, however, demonstrated an ability to generate memory flashbacks in 48% of people with AD via strong (7–10 V) stimulation of the fornix and subcallosal area (Deeb et al., 2019Deeb W. Salvato B. Almeida L. Foote K.D. Amaral R. Germann J. Rosenberg P.B. Tang-Wai D.F. Wolk D.A. Burke A.D. et al.Fornix-region deep brain stimulation-induced memory flashbacks in Alzheimer’s disease.N. Engl. J. Med. 2019; 381: 783-785Crossref PubMed Scopus (0) Google Scholar). These experiences included both autobiographical, episodic memories and semantic memories in the form of concepts (e.g., patient “thinking about her daughter”). Some of these memories acquired more detail with increasing level of stimulation. These anecdotes of stimulation evoking strong memories have inspired new lines of research focused on intentionally modulating neural function to better understand the neural processes involved in memory and to explore whether such modulation could be used therapeutically. Neuromodulation is a spatiotemporal intervention in brain function that introduces electrochemical changes with a distinct temporal profile at a particular brain circuit. A great strength of electrical, compared to pharmacological, neuromodulation is its relative precision in both the spatial and temporal domains. As the entorhinal-hippocampal system, with its complex afferent and efferent fibers, is critically implicated in episodic memory, much recent work has targeted stimulation within this circuit (Figure 1). Intervention can be limited to particular stages of information processing—including encoding, consolidation, and retrieval. Alternatively, it can be delivered in a chronic manner, either continuously, cyclically, or at fixed intervals, without regard to external events. Furthermore, stimulation can be delivered independently of, or in response to, endogenous brain activity. The Circuit of Papez includes the hippocampus (a), which projects via the fimbria and fornix (b) to the mammillary bodies (c), which then project via the mammillothalamic tract (d) to the anterior nucleus of the thalamus (e). Thalamocortical fibers continue to the cingulate gyrus, from which the fibers of the cingulum (f) innervate the parahippocampal gyrus (g) and the entorhinal cortex (h), as well as many cortical areas. The circuit is completed as the entorhinal cortex projects to the hippocampus through several pathways, including the perforant path. Other components of the limbic system include the hypothalamus, amygdala (i), nucleus accumbens, and septal nuclei (j). Though not considered part of the limbic system, the nucleus basalis of Meynert (k) has also been targeted for chronic DBS for the treatment of AD, due to its large number of cholinergic projections throughout the brain. Regions that have been targeted for DBS and are reviewed here are shaded in color. The brain sketch is by Natalie Cherry, inspired by the dissections in Shah et al., 2012Shah A. Jhawar S.S. Goel A. Analysis of the anatomy of the Papez circuit and adjoining limbic system by fiber dissection techniques.J. Clin. Neurosci. 2012; 19: 289-298Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar. For each DBS study, then, it is important to consider the site, the spatial and temporal scale, the memory stage, brain state, and the settings of stimulation. Although we consider each of these separately below, it must be emphasized that these variables are not independent, and their interaction could dramatically affect the results of the study. Thus, two studies could both stimulate the same brain region and find different effects on memory if other factors differed. There is a large literature on non-invasive neuromodulation in the form of transcranial magnetic or electrical stimulation. These methods are limited in their ability to focally target a specific brain structure. Except for occasional reference to these methods, we will limit the discussion here to invasive and direct application of electrical stimulation. Similarly, we reference some animal studies that have been illuminating regarding the mechanisms by which DBS may act on memory circuits, but a thorough review of the animal literature is outside the scope of this review. As with all studies involving intracranial electrodes in humans, ethical issues limit the subject population to those for whom there is a pressing medical need for electrodes to be placed. Thus, a large number of these studies have been conducted in subjects with pharmacologically refractory epilepsy undergoing clinical seizure monitoring to identify the epileptogenic regions for possible surgical cure (e.g., Suthana and Fried, 2012Suthana N. Fried I. Percepts to recollections: insights from single neuron recordings in the human brain.Trends Cogn. Sci. 2012; 16: 427-436Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Because these patients frequently have electrodes placed in the MTL, they are good candidates for stimulation studies. It should be noted that the hippocampal-entorhinal circuit may be impaired in some epilepsy patients, so some results may not generalize to the non-epileptic population. On the other hand, many valuable insights into the function of the MTL have been derived from studies in this population, and improving memory for people with epilepsy is, in itself, a therapeutic goal. In addition, DBS has been explored as a potential treatment for a wide variety of neuropsychological diseases, including diseases characterized by cognitive impairment and memory loss—mainly AD (Lv et al., 2018Lv Q. Du A. Wei W. Li Y. Liu G. Wang X.P. Deep brain stimulation: a potential treatment for dementia in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD).Front. Neurosci. 2018; 12: 360Crossref PubMed Scopus (4) Google Scholar, Posporelis et al., 2018Posporelis S. David A.S. Ashkan K. Shotbolt P. Deep brain stimulation of the memory circuit: improving cognition in Alzheimer’s disease.J. Alzheimers Dis. 2018; 64: 337-347Crossref PubMed Scopus (1) Google Scholar), though a few trials have been conducted in Parkinson’s disease dementia (Lv et al., 2018Lv Q. Du A. Wei W. Li Y. Liu G. Wang X.P. Deep brain stimulation: a potential treatment for dementia in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD).Front. Neurosci. 2018; 12: 360Crossref PubMed Scopus (4) Google Scholar) and traumatic brain injury (TBI) (Kundu et al., 2018Kundu B. Brock A.A. Englot D.J. Butson C.R. Rolston J.D. Deep brain stimulation for the treatment of disorders of consciousness and cognition in traumatic brain injury patients: a review.Neurosurg. Focus. 2018; 45: E14Crossref PubMed Scopus (0) Google Scholar) as well. The DBS research in AD patients has focused largely on long-term (months to years), continuous stimulation with the hope that it could reverse or at least slow the progression of the disease (Table 1), whereas the research with patients with epilepsy has primarily studied whether brief stimulations within well-defined memory paradigms have an overall positive or negative effect on subsequent memory performance for that task (Table 2). All used continuous stim delivered through macroelectrode contacts. AD, Alzheimer’s disease; ADAS-cog, AD Assessment Scale-Cognitive Subscale; Am, amygdala; ANT, anterior nucleus of the thalamus; bi, bilateral; CDR_SB, clinical dementia rating sum of boxes; FX, fornix; hipp, hippocampus; MMSE, Mini Mental State Exam; NBM, nucleus basalis of Meynert; NR, not reported; PHG, parahippocampal gyrus. All were conducted in participants with refractory epilepsy undergoing seizure monitoring. Stimulation was delivered in an open-loop manner unless noted in Stage and State column. ADT, afterdischarge threshold; Am, amygdala; ERA, entorhinal area; ERP, event-related potential; FX, fornix; hipp, hippocampus; (L)TC, (lateral) temporal cortex; MIMO, multi-in, multi-out model for selecting stim pattern from neural activity (see text); MTL, (multiple sites within the) medial temporal lobe. Direct electrical stimulation of the hippocampus proper has generally been found to disrupt memory and thus confirmed the role of the hippocampus in memory function in the same manner that electrical stimulation of language areas demonstrated their role in language (Bickford et al., 1958Bickford R.G. Mulder D.W. Dodge Jr., H.W. Svien H.J. Rome H.P. Changes in memory function produced by electrical stimulation of the temporal lobe in man.Res. Publ. Assoc. Res. Nerv. Ment. Dis. 1958; 36: 227-240, discussion 241–243PubMed Google Scholar, Chapman et al., 1967Chapman L.F. Walter R.D. Markham C.H. Rand R.W. Crandall P.H. Memory changes induced by stimulation of hippocampus or amygdala in epilepsy patients with implanted electrodes.Trans. Am. Neurol. Assoc. 1967; 92: 50-56PubMed Google Scholar, Ommaya and Fedio, 1972Ommaya A.K. Fedio P. Contribution of cingulum and hippocampal structures to memory mechanisms in man.Confin. 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Other early studies stimulated multiple sites at once, so the memory impairment cannot be directly attributed to hippocampal stimulation (Halgren et al., 1985Halgren E. Wilson C.L. Stapleton J.M. Human medial temporal-lobe stimulation disrupts both formation and retrieval of recent memories.Brain Cogn. 1985; 4: 287-295Crossref PubMed Scopus (0) Google Scholar). More recent clinical opportunities to electrically stimulate in the hippocampus usually involve application of several milliamperes in a bipolar fashion through 2-mm contacts separated by a few millimeters. Such macrostimulation affects multiple neuronal layers and subregions of the hippocampus, and it is difficult to see how it could interact physiologically in a positive capacity with the delicate hippocampal neuropil. Indeed, direct hippocampal stimulation has led to neutral (Suthana et al., 2012Suthana N. Haneef Z. Stern J. Mukamel R. Behnke E. Knowlton B. Fried I. 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Recordings from hippocampal subfields CA3 and CA1 were used to model CA1 firing patterns based on CA3 activity. Later, during a delayed match to sample task, activity in CA3 was recorded, and based on the model, stimulation was applied in CA1 to mimic its expected output. This led to significantly improved performance in 6 of 7 patients, compared to a non-stimulated condition or random stimulation condition, which in fact impaired memory in some subjects. Suthana et al., 2012Suthana N. Haneef Z. Stern J. Mukamel R. Behnke E. Knowlton B. Fried I. Memory enhancement and deep-brain stimulation of the entorhinal area.N. Engl. J. Med. 2012; 366: 502-510Crossref PubMed Scopus (233) Google Scholar found that stimulation applied in the entorhinal area during a spatial navigation task improved later memory performance, even when identical stimulation in the hippocampus provided no benefit. This marked the first demonstration that stimulating a brain region that directly projects to the hippocampus might be more effective for memory enhancement than stimulating the hippocampus proper. A subsequent study using a similar task, however, found primarily impairment in the five patients who received entorhinal stimulation (Jacobs et al., 2016Jacobs J. Miller J. Lee S.A. Coffey T. Watrous A.J. Sperling M.R. Sharan A. Worrell G. Berry B. Lega B. et al.Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory.Neuron. 2016; 92: 983-990Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). The same group also found a trend toward impairment in eight patients who received stimulation in the entorhinal cortex during a verbal memory task (Jacobs et al., 2016Jacobs J. Miller J. Lee S.A. Coffey T. Watrous A.J. Sperling M.R. Sharan A. Worrell G. Berry B. Lega B. et al.Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory.Neuron. 2016; 92: 983-990Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Still, a third group found enhancement of event-related potentials in hippocampus following entorhinal area stimulation during an item-color association memory task but no behavioral effect (Hansen et al., 2018Hansen N. Chaieb L. Derner M. Hampel K.G. Elger C.E. Surges R. Staresina B. Axmacher N. Fell J. Memory encoding-related anterior hippocampal potentials are modulated by deep brain stimulation of the entorhinal area.Hippocampus. 2018; 28: 12-17Crossref PubMed Scopus (4) Google Scholar). A possible difference among these studies is the site of stimulation within the entorhinal area, which could lead to different physiological effects on hippocampus. The spatial resolution of macrostimulation may be too large to determine the anatomical extent of the stimulation or whether it involved white matter tracts, gray matter, or both (Figure 2). Additionally, extra-entorhinal regions were sometimes stimulated concurrently with entorhinal stimulation (e.g., hippocampus or parahippocampal gyrus, Jacobs et al., 2016Jacobs J. Miller J. Lee S.A. Coffey T. Watrous A.J. Sperling M.R. Sharan A. Worrell G. Berry B. Lega B. et al.Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory.Neuron. 2016; 92: 983-990Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, or perirhinal cortex, Suthana et al., 2012Suthana N. Haneef Z. Stern J. Mukamel R. Behnke E. K