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Aging and disease    2020, Vol. 11 Issue (1) : 179-190     DOI: 10.14336/AD.2019.0511
Review Article |
The Paradoxical Effect of Deep Brain Stimulation on Memory
Shawn Zheng Kai Tan, Man-Lung Fung, Junhao Koh, Ying-Shing Chan, Lee Wei Lim*
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Deep brain stimulation (DBS) is a promising treatment for many memory-related disorders including dementia, anxiety, and addiction. However, the use of DBS can be a paradoxical conundrum—dementia treatments aim to improve memory, whereas anxiety or addiction treatments aim to suppress maladaptive memory. In this review, the key hypotheses on how DBS affects memory are highlighted. We consolidate the findings and conclusions from the current research on the effects of DBS on memory in attempt to make sense of the bidirectional nature of DBS in disrupting and enhancing memory. Based on the current literature, we hypothesize that the timing of DBS plays a key role in its contradictory effects, and therefore, we propose a consolidated model of how DBS can both disrupt and enhance memory.

Keywords memory      neuromodulation      deep brain stimulation      dementia      anxiety      addiction     
Corresponding Authors: Lee Wei Lim   
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These authors contributed equally to this work.

Just Accepted Date: 21 July 2019   Issue Date: 15 January 2020
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Shawn Zheng Kai Tan
Man-Lung Fung
Junhao Koh
Ying-Shing Chan
Lee Wei Lim
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Shawn Zheng Kai Tan,Man-Lung Fung,Junhao Koh, et al. The Paradoxical Effect of Deep Brain Stimulation on Memory[J]. Aging and disease, 2020, 11(1): 179-190.
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TargetStudyStimulation ParametersParadigmResults
Ventromedial prefrontal cortexLiu et al., 2015 [7]Single 1-h stimulation 30 mins prior to behaviour testingMorris Water Maze, Novel Object RecognitionOnly short-term memory improvement
Daily 1-h stimulation for 4 weeks, 30 mins prior to behaviour testingMorris Water Maze, Novel Object RecognitionLong-lasting benefits to memory
Tan et al., 2019 [57]Single 15-min stimulation during consolidationFear ConditioningDisruption of memory
Forniceal areaSweet et al., 2010 [124]Traumatic Brain Injury (TBI) model (also non-TBI), stimulation 15 min before and during testingDelayed non-match-to-sample swim T-mazeNo significant difference in non-TBI animals
Hescham et al., 2013 [5]6 consecutive sessions with different parameters, 2 mins before and during behaviour testingObject Location Task
Specific memory benefits in certain parameters (did not consider cumulative effects)
Hao et al., 2015 [94]Rett syndrome mice, daily 1-h stimulation for 2 weeks, not stimulated during behaviour daysMorris Water Maze, Contextual FearRescue of impaired memory
Hescham et al., 2016 [43]Single 6-h stimulation, behaviour testing 30 days after stimulationMorris Water MazeImprovement in memory
Entorhinal cortexStone et al., 2011 [41]Single 30 to 120-min stimulation, behaviour testing 10 weeks afterMorris Water MazeImprovement in memory
Xia et al., 2017 [4]Alzheimer's mice model, single 1-h stimulation, behaviour testing 1,3,6 weeks post-stimulationMorris Water Maze, Contextual FearImprovement later at 3 & 6 weeks but not at 1 week
Anterior thalamusHamani et al., 2010 [96]Stimulation during behaviour testingContextual FearImpaired memory
Stimulation immediately after behaviour testing (unknown time)Contextual FearNo significant difference
Hamani et al., 2011 [40]Cortisone-treated rats, single 1-h stimulation, behaviour testing 4/28 days after stimulationNon-Matching-to-SampleRescue of impaired memory
Table 1  Non-exhaustive list of rodent studies looking at the effects of Deep Brain Stimulation on memory.
Figure 1.  Consolidated model on how DBS can disrupt and enhance memory. In this model, DBS is applied to the mPFC, a target previously shown to be ideal for both disruption and enhancement of memory. This results in downstream effects in the hippocampus, including effects on brainwaves, neurotransmitters, and possibly neurogenesis, leading to either disruption or enhancement of memory depending on how and when DBS is applied.
[1] Breuer J, Freud S (1893). On The Psychical Mechanism of Hysterical Phenomena?: Preliminary Communication from Studies on Hysteria. Stand Ed Complet Psychol Work Sigmund Freud, Vol II Stud Hysteria:1-17.
[2] Robbins TW, Ersche KD, Everitt BJ (2008). Drug addiction and the memory systems of the brain. Ann N Y Acad Sci, 1141:1-21.
[3] Temel Y, Hescham SA, Jahanshahi A, Janssen MLF, Tan SKH, van Overbeeke JJ, et al. (2012). Neuromodulation in Psychiatric Disorders. Int Rev Neurobiol, 107:283-314.
[4] Xia F, Yiu A, Stone SSD, Oh S, Lozano AM, Josselyn SA, et al. (2017). Entorhinal cortical deep brain stimulation rescues memory deficits in both young and old mice genetically engineered to model Alzheimer’s disease. Neuropsychopharmacology, 42(13):2493-2503.
[5] Hescham S, Lim LW, Jahanshahi A, Steinbusch HWM, Prickaerts J, Blokland A, et al. (2013). Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: The role of stimulation parameters. Brain Stimul, 6(1):72-77.
[6] Hescham S, Lim LW, Jahanshahi A, Blokland A, Temel Y (2013). Deep brain stimulation in dementia-related disorders. Neurosci Biobehav Rev, 37(10):2666-2675.
[7] Liu A, Jain N, Vyas A, Lim LW (2015). Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats. Elife, 2015(4):1-21.
[8] Reznikov R, Binko M, Nobrega JN, Hamani C (2016). Deep Brain Stimulation in Animal Models of Fear, Anxiety and Post-Traumatic Stress Disorder. Neuropsychopharmacology, 41(12):2810-2817.
[9] Rodriguez-Romaguera J, Monte FHM Do, Quirk GJ (2012). Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear. Proc Natl Acad Sci, 109:8764-8769.
[10] Milad MRR, Quirk GJJ (2002). Neurons in medial prefrontal cortex signal memory for fear extinction. Nature, 420(6911):70-74.
[11] Sui L, Huang S, Peng B, Ren J, Tian F, Wang Y (2014). Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory. J Neural Transm, 121(7):773-782.
[12] Mokhtari Hashtjin M, Pirzad Jahromi G, Sadr SS, Tat M, Javidnazar D, Fakhraei N, et al. (2017). Effect of deep brain stimulation of the amygdala on post-traumatic stress disorder syndrome-induced by contextual fear conditioning in rat: Role of c-Fos protein and corticosterone hormone. Brain Stimul, 10(2):348.
[13] Langevin J-P, De Salles AAF, Kosoyan HP, Krahl SE (2010). Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res, 44(16):1241-5.
[14] Luigjes J, Van Den Brink W, Feenstra M, Van Den Munckhof P, Schuurman PR, Schippers R, et al. (2012). Deep brain stimulation in addiction: A review of potential brain targets. Mol Psychiatry, 17(6):572-583.
[15] Müller UJ, Voges J, Steiner J, Galazky I, Heinze HJ, Möller M, et al. (2013). Deep brain stimulation of the nucleus accumbens for the treatment of addiction. Ann N Y Acad Sci, 1282(1):119-128.
[16] Pierce RC, Vassoler FM (2013). Deep brain stimulation for the treatment of addiction: Basic and clinical studies and potential mechanisms of action. Psychopharmacology (Berl), 229(3):487-491.
[17] Fell J, Staresina BP, Do Lam ATA, Widman G, Helmstaedter C, Elger CE, et al. (2013). Memory modulation by weak synchronous deep brain stimulation: A pilot study. Brain Stimul, 6(3):270-273.
[18] Titiz AS, Hill MRH, Mankin EA, Aghajan ZM, Eliashiv D, Tchemodanov N, et al. (2017). Theta-burst microstimulation in the human entorhinal area improves memory specificity. Elife, 6:1-18.
[19] Miller JP, Sweet JA, Bailey CM, Munyon CN, Luders HO, Fastenau PS (2015). Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: A preliminary investigation with four cases. Brain, 138(7):1833-1842.
[20] Suthana N, Haneef Z, Stern J, Mukamel R, Behnke E, Knowlton B, et al. (2012). Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area. N Engl J Med, 366(6):502-10.
[21] Jacobs J, Miller J, Lee SA, Coffey T, Watrous AJ, Sperling MR, et al. (2016). Direct Electrical Stimulation of the Human Entorhinal Region and Hippocampus Impairs Memory. Neuron, 92(5):983-990.
[22] Merkow MB, Burke JF, Ramayya AG, Sharan AD, Sperling MR, Kahana MJ (2017). Stimulation of the human medial temporal lobe between learning and recall selectively enhances forgetting. Brain Stimul, 10(3):645-650.
[23] Lacruz ME, Valentín A, Seoane JJG, Morris RG, Selway RP, Alarcón G (2010). Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory. Neuroscience, 170(2):623-632.
[24] Halgren E, Wilson CL (1985). Recall deficits produced by afterdischarges in the human hippocampal formation and amygdala. Electroencephalogr Clin Neurophysiol, 61(5):375-380.
[25] Coleshill SG (2004). Material-Specific Recognition Memory Deficits Elicited by Unilateral Hippocampal Electrical Stimulation. J Neurosci, 24(7):1612-1616.
[26] Halgren E, Wilson CL, Stapleton JM (1985). Human medial temporal-lobe stimulation disrupts both formation and retrieval of recent memories. Brain Cogn, 4(3):287-295.
[27] Gildenberg PL (2005). Evolution of neuromodulation. Stereotact Funct Neurosurg, 83(2-3):71-79.
[28] Kringelbach ML, Jenkinson N, Owen SLF, Aziz TZ (2007). Translational principles of deep brain stimulation. Nat Rev Neurosci, 8(8):623-635.
[29] McIntyre CC, Anderson RW (2016). Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation. J Neurochem, 139:338-345.
[30] Benazzouz A, Gao DM, Ni ZG, Piallat B, Bouali-Benazzouz R, Benabid AL (2000). Effect of high-frequency stimulation of the subthalamic nucleus on the neuronal activities of the substantia nigra pars reticulata and ventrolateral nucleus of the thalamus in the rat. Neuroscience, 99(2):289-295.
[31] Dostrovsky JO, Levy R, Wu JP, Hutchison WD, Tasker RR, Lozano AM (2000). Microstimulation-Induced Inhibition of Neuronal Firing in Human Globus Pallidus. J Neurophysiol, 84(1):570-574.
[32] Ashkan K, Rogers P, Bergman H, Ughratdar I (2017). Insights into the mechanisms of deep brain stimulation. Nat Rev Neurol, 13(9):548-554.
[33] Martin SJ, Grimwood PD, Morris RGM (2000). Synaptic plasticity and memory: An Evaluation of the Hypothesis. Annu Rev Neurosci, 23:649-711.
[34] Lamprecht R, LeDoux J (2004). Structural plasticity and memory. Nat Rev Neurosci, 5(1):45-54.
[35] Altman J, Das GD (1965). Autoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol, 124(3):319-335.
[36] Leuner B, Gould E, Shors TJ (2002). Is There A Link Between Adult Neurogenesis and Learning? Hippocampus, 12(5):578-584.
[37] Epp JR, Chow C, Galea LAM (2013). Hippocampus-dependent learning influences hippocampal neurogenesis. Front Neurosci, 7:57
[38] Brummelte S, Galea LAM (2010). Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats. Neuroscience, 168(3):680-690.
[39] Toda H, Hamani C, Fawcett AP, Hutchison WD, Lozano AM (2008). The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg, 108(1):132-138.
[40] Hamani C, Stone SS, Garten A, Lozano AM, Winocur G (2011). Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp Neurol, 232(1):100-104.
[41] Stone SSD, Teixeira CM, DeVito LM, Zaslavsky K, Josselyn S a., Lozano a. M, et al. (2011). Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory. J Neurosci, 31(38):13469-13484.
[42] Pohodich AE, Yalamanchili H, Raman AT, Wan Y-W, Gundry M, Hao S, et al. (2018). Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity. Elife, 7:e34031.
[43] Hescham S, Temel Y, Schipper S, Lagiere M, Schönfeld L-M, Blokland A, et al. (2016). Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis. Brain Struct Funct, 222(2):1069-1075.
[44] Akers KG, Martinez-canabal A, Restivo L, Yiu AP, Cristofaro A De, Hsiang HL, et al. (2014). Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy. Science, 344(6184):598-602.
[45] Frankland PW, Kohler S, Josselyn S (2013). Hippocampal neurogenesis and forgetting. Trends Neurosci, 36(9):497-503.
[46] Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature, 555(7696):377-381.
[47] Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. (2018). Human Hippocampal Neurogenesis Persists throughout Aging. Cell StemCell, 22(5):589-599.
[48] Abulseoud OA, Knight EJ, Lee KH (2012). Chapter 18: Neurotransmitter Release During Deep Brain Stimulation. Deep Brain Stimulation: A New Frontier in Psychiatry, eds DenysD, FeenstraMGP, SchuurmanR (Springer), pp 193-204.
[49] Gottfries CG (1990). Neurochemical aspects on aging and diseases with cognitive impairment. J Neurosci Res, 27(4):541-547.
[50] Peters R (2006). Ageing and the brain. Postgr Med J, 82:84-88.
[51] Johansen JP, Cain CK, Ostroff LE, Ledoux JE (2011). Molecular mechanisms of fear learning and memory. Cell, 147(3):509-524.
[52] Van Dijk A, Klompmakers AA, Feenstra MGP, Denys D (2012). Deep brain stimulation of the accumbens increases dopamine, serotonin, and noradrenaline in the prefrontal cortex. J Neurochem, 123(6):897-903.
[53] Hamani C, Diwan M, Macedo CE, Brandão ML, Shumake J, Gonzalez-Lima F, et al. (2010). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. Biol Psychiatry, 67(2):117-124.
[54] Hamani C, MacHado DC, Hipólide DC, Dubiela FP, Suchecki D, MacEdo CE, et al. (2012). Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: Role of serotonin and brain derived neurotrophic factor. Biol Psychiatry, 71(1):30-35.
[55] Meneses A (2015). Serotonin, neural markers and memory. Front Pharmacol, 6:143.
[56] Cavallaro S (2008). Genomic analysis of serotonin receptors in learning and memory. Behav Brain Res, 195(1):2-6.
[57] Tan SZK, Poon CH, Chan Y-S, Lim LW (2019). Deep Brain Stimulation of the Ventromedial Prefrontal Cortex Disrupts Consolidation of Fear Memories. bioRxiv, 537514.
[58] Falowski SM, Sharan A, Reyes BAS, Sikkema C, Szot P, Van Bockstaele EJ (2011). An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression. Neurosurgery, 69(6):1281-90.
[59] Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, et al. (2017). Engrams and circuits crucial for systems consolidation of a memory. Science, 356(6333):73-78.
[60] Sesia T, Bulthuis V, Tan S, Lim LW, Vlamings R, Blokland A, et al. (2010). Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin. Exp Neurol, 225(2):302-309.
[61] Zbukvic IC, Park CHJ, Ganella DE, Lawrence AJ, Kim JH (2017). Prefrontal Dopaminergic Mechanisms of Extinction in Adolescence Compared to Adulthood in Rats. Front Behav Neurosci, 11:32.
[62] Cools R, D’Esposito M (2011). Inverted-U shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry, 69(12):e113-e125.
[63] Tan SZK, Sheng V, Chan Y-S, Lim LW (2019). Eternal Sunshine of the Neuromodulated Mind: Altering Fear Memories Through Neuromodulation. Exp Neurol, 314:9-19.
[64] Marek R, Strobel C, Bredy TW, Sah P (2013). The amygdala and medial prefrontal cortex: partners in the fear circuit. J Physiol, 591(10):2381-91.
[65] Jin J, Maren S (2015). Prefrontal-Hippocampal Interactions in Memory and Emotion. Front Syst Neurosci, 9:170.
[66] Blokland A (1995). Acetylcholine: a neurotransmitter for learning and memory? Brain Res Rev, 21(3):285-300.
[67] Hasselmo ME (2009). The Role of Acetylcholine in Learning and Memory Michael. Curr Opin Neurobiol, 16(6):710-715.
[68] Hescham S, Jahanshahi A, Schweimer J V., Mitchell SN, Carter G, Blokland A, et al. (2015). Fornix deep brain stimulation enhances acetylcholine levels in the hippocampus. Brain Struct Funct, 221(8):1-6.
[69] Liu R, Crawford J, Callahan PM, Terry A V., Constantinidis C, Blake DT (2017). Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys. Curr Biol, 27(17):2640-2646.e4.
[70] Hasselmo ME (1999). Neuromodulation: Acetylcholine and memory consolidation. Trends Cogn Sci, 3(9):351-359.
[71] Haam J, Yakel JL (2017). Cholinergic modulation of the hippocampal region and memory function. J Neurochem, 142:111-121.
[72] Luo L, Chen W-H, Wang M, Zhu D-M, She J-Q, Ruan D-Y (2008). Modulation of long-term potentiation by individual subtypes of muscarinic acetylcholine receptor in the rat dentate gyrus. Hippocampus, 18(10):989-995.
[73] Wang Y, Sherwood JL, Lodge D (2006). The α4β2 nicotinic acetylcholine receptor agonist TC-2559 impairs long-term potentiation in the dentate gyrus in vivo. Neurosci Lett, 406(3):183-188.
[74] Sawada S, Ohno-shosaku T, Yamamoto C (1994). Augmenting action of nicotine on population spikes in the dentate gyrus of the guinea pig. Neurosci Res, 20:317-322.
[75] Matsuyama S, Matsumoto a, Enomoto T, Nishizaki T (2000). Activation of nicotinic acetylcholine receptors induces long-term potentiation in vivo in the intact mouse dentate gyrus. Eur J Neurosci, 12(10):3741-3747.
[76] Riedel G, Platt B, Micheau J (2003). Glutamate receptor function in learning and memory. Behav Brain Res, 140(1-2):1-47.
[77] Izquierdo I (1991). Role of NMDA receptors in memory. Trends PharmacolSci, 12(1987):128-129.
[78] Duncan JR, Lawrence AJ (2012). The role of metabotropic glutamate receptors in addiction: Evidence from preclinical models. Pharmacol Biochem Behav, 100(4):811-824.
[79] Panaceau M, Gustafsson B (1997). NMDA receptor dependence of the input specific NMDA receptor-independent LIT in the hippocampal CA 1 region. Brain Res, 752:255-260.
[80] Tan SZK, Ganella DE, Dick ALW, Duncan JR, Ong-Palsson E, Bathgate RAD, et al. (2015). Spatial Learning Requires mGlu5 Signalling in the Dorsal Hippocampus. Neurochem Res, 40(6):1303-1310.
[81] Riedel G, Reymann KG (1996). Metabotropic glutamate receptors in hippocampal long-term potentiation and learning and memory. Acta Physiol Scaninavia, 157(1911):1-19.
[82] Jiménez-Sánchez L, Castañé A, Pérez-Caballero L, Grifoll-Escoda M, López-Gil X, Campa L, et al. (2016). Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex. Cereb Cortex, 26(6):2778-2789.
[83] Agnesi F, Blaha CD, Lin J, Lee KH (2010). Local glutamate release in the rat ventral lateral thalamus evoked by high-frequency stimulation. J Neural Eng, 7(2):26009.
[84] Tawfik VL, Chang SY, Hitti FL, Roberts DW, Leiter JC, Jovanovic S, et al. (2010). Deep brain stimulation results in local glutamate and adenosine release: Investigation into the role of astrocytes. Neurosurgery, 67(2):367-375.
[85] Staubli U, Rogers G, Lynch G (1994). Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci U S A, 91(2):777-81.
[86] Dennis TS, Perrotti LI (2015). Erasing Drug Memories Through the Disruption of Memory Reconsolidation: A Review of Glutamatergic Mechanisms. J Appl Biobehav Res, 20(3):101-129.
[87] Sederberg PB, Schulze-Bonhage A, Madsen JR, Bromfield EB, McCarthy DC, Brandt A, et al. (2007). Hippocampal and neocortical gamma oscillations predict memory formation in humans. Cereb Cortex, 17(5):1190-1196.
[88] Fell J, Ludowig E, Rosburg T, Axmacher N, Elger CE (2008). Phase-locking within human mediotemporal lobe predicts memory formation. Neuroimage, 43(2):410-419.
[89] Fell J, Klaver P, Lehnertz K, Grunwald T, Schaller C, Elger CE, et al. (2001). Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling. Nat Neurosci, 4(12):1259-1264.
[90] Lee H, Fell J, Axmacher N (2013). Electrical engram: How deep brain stimulation affects memory. Trends Cogn Sci, 17(11):574-584.
[91] Kim K, Schedlbauer A, Rollo M, Karunakaran S, Ekstrom AD, Tandon N (2018). Network-based brain stimulation selectively impairs spatial retrieval. Brain Stimul, 11(1):213-221.
[92] Ramirez S, Liu X, Lin P-A, Suh J, Pignatelli M, Redondo RL, et al. (2013). Creating a False Memory in the Hippocampus. Science, 341(6144):387-391.
[93] Ramirez S, Liu X, MacDonald CJ, Moffa A, Zhou J, Redondo RL, et al. (2015). Activating positive memory engrams suppresses depression-like behaviour. Nature, 522(7556):335-339.
[94] Hao S, Tang B, Wu Z, Ure K, Sun Y, Tao H, et al. (2015). Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature, 526(7573):430-4.
[95] Moser EI, Krober KA, Moser M-B, Morris RGM (1998). Impaired Spatial Learning after Saturation of Long-Term Potentiation. Science, 281:2038-2042.
[96] Hamani C, Dubiela FP, Soares JCK, Shin D, Bittencourt S, Covolan L, et al. (2010). Anterior thalamus deep brain stimulation at high current impairs memory in rats. Exp Neurol, 225(1):154-162.
[97] Klavir O, Prigge M, Sarel A, Paz R, Yizhar O (2017). Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex. Nat Neurosci, 20(6):836-844.
[98] Lujan JL, Chaturvedi A, McIntyre CC (2008). Tracking the mechanisms of deep brain stimulation for neuropsychiatric disorders. Front Biosci, 13:5892-904.
[99] Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al. (2006). Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology, 31(11):2384-2393.
[100] Lim LW, Prickaerts J, Huguet G, Kadar E, Hartung H, Sharp T, et al. (2015). Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry, 5(3):e535.
[101] Hoover WB, Vertes RP (2007). Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct, 212(2):149-179.
[102] Rescorla RA, Heth CD (1975). Reinstatement of Fear to an Extinguished Conditioned Stimulus. J Exp Psychol Anim Behav Process,104(1):88-96.
[103] Bouton ME (2002). Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction. Biol Psychiatry, 52(10):976-986.
[104] Barad M (2006). Is extinction of fear erasure or inhibition? Why both, of course. Learn Mem, 13(2):108-109.
[105] Bouton ME, Bolles RC (1979). Contextual control of the extinction of conditioned fear. Learn Motiv, 10(4):445-466.
[106] Baum M (1988). Spontaneous recovery from the effects of flooding (exposure) in animals. Behav Res Ther, 26(2):185-186.
[107] McNally RJ (2007). Mechanisms of exposure therapy: How neuroscience can improve psychological treatments for anxiety disorders. Clin Psychol Rev, 27(6):750-759.
[108] de Kleine R a, Rothbaum BO, van Minnen A (2013). Pharmacological enhancement of exposure-based treatment in PTSD: A qualitative review. Eur J Psychotraumatol, 4:eCollection.
[109] Farach FJ, Pruitt LD, Jun JJ, Jerud AB, Zoellner LA, Roy-Byrne PP (2012). Pharmacological treatment of anxiety disorders: Current treatments and future directions. J Anxiety Disord, 26(8):833-843.
[110] Kindt M, Soeter M, Vervliet B (2009). Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci, 12(3):256-8.
[111] Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (2008). Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res, 42(6):503-506.
[112] Monfils M-H, Cowansage KK, Klann E, LeDoux JE (2009). Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science, 324(5929):951-955.
[113] Schiller D, Monfils M-H, Raio CM, Johnson DC, Ledoux JE, Phelps E (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature, 463(7277):49-53.
[114] Torregrossa MM, Taylor JR (2013). Learning to forget: Manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology (Berl), 226(4):659-672.
[115] Klucken T, Kruse O, Schweckendiek J, Kuepper Y, Mueller EM, Hennig J, et al. (2016). No evidence for blocking the return of fear by disrupting reconsolidation prior to extinction learning. Cortex, 79:112-122.
[116] Merlo E, Milton AL, Goozee ZY, Theobald DE, Everitt BJ (2014). Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence. J Neurosci, 34(7):2422-2431.
[117] Pedreira ME, Maldonado H (2003). Protein synthesis subserves reconsolidation or extinction depending on reminder duration. Neuron, 38(6):863-869.
[118] Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003). Stability of Retrieved Memory: Inverse Correlation with Trace Dominance. Science, 301:1102-1104.
[119] Alzheimer’s Association (2015). Alzheimer’s disease facts and figures. Alzheimer’s Dement, 12(4):88.
[120] Qaseem A, Snow V, Cross Jr JT, Forciea MA, Hopkins RJr (2008). Current Pharmacologic Treatment of Dementia?: A Clinical Practice Guideline from the American College of Physicians and the American. Ann Intern Med, (148):370-378.
[121] Cummings J (2010). What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer’s disease? Biol Psychiatry, 68(10):876-878.
[122] Cummings JL, Morstorf T, Zhong K (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther, 6(4):37.
[123] Goering S, Klein E, Dougherty DD, Widge AS (2017). Staying in the Loop: Relational Agency and Identity in Next-Generation DBS for Psychiatry. AJOB Neurosci, 8(2):59-70.
[124] Sweet JA, Eakin KC, Munyon CN, Miller JP (2014). Improved learning and memory with theta-burst stimulation of the fornix in rat model of traumatic brain injury. Hippocampus, 24(12):1592-1600.
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