Closed-Loop Interruption of Hippocampal Ripples through Fornix Stimulation in the Non-Human Primate

BACKGROUND Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. OBJECTIVE The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. METHOD Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. RESULTS The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. CONCLUSION Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit.

[1]  István Ulbert,et al.  Input-Output Features of Anatomically Identified CA3 Neurons during Hippocampal Sharp Wave/Ripple Oscillation In Vitro , 2013, The Journal of Neuroscience.

[2]  Eran Stark,et al.  Predicting Movement from Multiunit Activity , 2007, The Journal of Neuroscience.

[3]  J. Aggleton,et al.  Differential cognitive effects of colloid cysts in the third ventricle that spare or compromise the fornix. , 2000, Brain : a journal of neurology.

[4]  K. Heilman,et al.  Korsakoff's syndrome resulting from bilateral fornix lesions , 1977, Neurology.

[5]  Victor A. F. Lamme,et al.  Synchrony and covariation of firing rates in the primary visual cortex during contour grouping , 2004, Nature Neuroscience.

[6]  R. Vertes,et al.  Phase relations of rhythmic neuronal firing in the supramammillary nucleus and mammillary body to the hippocampal theta activity in urethane anesthetized rats , 1997, Hippocampus.

[7]  P. Brown,et al.  The functional role of beta oscillations in Parkinson's disease. , 2014, Parkinsonism & related disorders.

[8]  D. Gaffan,et al.  Impaired Recency Judgments and Intact Novelty Judgments after Fornix Transection in Monkeys , 2004, The Journal of Neuroscience.

[9]  D. Gaffan,et al.  Amnesia in man following transection of the fornix. A review. , 1991, Brain : a journal of neurology.

[10]  R. Vertes,et al.  Characterization of neurons of the supramammillary nucleus and mammillary body that discharge rhythmically with the hippocampal theta rhythm in the rat , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  J. Fell,et al.  Ripples in the medial temporal lobe are relevant for human memory consolidation. , 2008, Brain : a journal of neurology.

[12]  Morris Moscovitch,et al.  Hippocampal contributions to recollection in retrograde and anterograde amnesia , 2006, Hippocampus.

[13]  Bin Deng,et al.  Closed-Loop Control of the thalamocortical Relay Neuron's Parkinsonian State Based on Slow Variable , 2013, Int. J. Neural Syst..

[14]  J. Aggleton,et al.  Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function , 2011, Hippocampus.

[15]  G. Buzsáki,et al.  tFast Network Oscillations in the Hippocampal CA1 Region of the Behaving Rat , 1999, The Journal of Neuroscience.

[16]  John P. Aggleton,et al.  Understanding retrosplenial amnesia: Insights from animal studies , 2010, Neuropsychologia.

[17]  G. V. Van Hoesen,et al.  Interhemispheric pathways of the hippocampal formation, presubiculum, and entorhinal and posterior parahippocampal cortices in the rhesus monkey: The structure and organization of the hippocampal commissures , 1985, The Journal of comparative neurology.

[18]  C. Houser,et al.  Heterogeneity of the supramammillary–hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences , 2010, The European journal of neuroscience.

[19]  Richard C Saunders,et al.  Origin and topography of fibers contributing to the fornix in macaque monkeys , 2007, Hippocampus.

[20]  Itzhak Fried,et al.  Large-Scale Microelectrode Recordings of High-Frequency Gamma Oscillations in Human Cortex during Sleep , 2010, The Journal of Neuroscience.

[21]  R. Wennberg,et al.  A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease , 2010, Annals of neurology.

[22]  Charles L. Wilson,et al.  Hippocampal and Entorhinal Cortex High‐Frequency Oscillations (100–500 Hz) in Human Epileptic Brain and in Kainic Acid‐Treated Rats with Chronic Seizures , 1999, Epilepsia.

[23]  H. Harris,et al.  The Rat , 1958, Nature.

[24]  J. Born,et al.  Sustained increase in hippocampal sharp-wave ripple activity during slow-wave sleep after learning. , 2008, Learning & memory.

[25]  G. Buzsáki,et al.  Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus , 2014, Proceedings of the National Academy of Sciences.

[26]  H DAITZ,et al.  Note on the fibre content of the fornix system in man. , 1953, Brain : a journal of neurology.

[27]  Szabolcs Káli,et al.  Mechanisms of Sharp Wave Initiation and Ripple Generation , 2014, The Journal of Neuroscience.

[28]  Matthijs A. A. van der Meer,et al.  Hippocampal Replay Is Not a Simple Function of Experience , 2010, Neuron.

[29]  J. O’Neill,et al.  The reorganization and reactivation of hippocampal maps predict spatial memory performance , 2010, Nature Neuroscience.

[30]  D. Amaral,et al.  Amygdalo‐cortical projections in the monkey (Macaca fascicularis) , 1984, The Journal of comparative neurology.

[31]  D. Simpson.  THE EFFERENT FIBRES OF THE HIPPOCAMPUS IN THE MONKEY , 1952, Journal of neurology, neurosurgery, and psychiatry.

[32]  R. Young,et al.  Brain stimulation. , 1990, Neurosurgery clinics of North America.

[33]  P. Robert,et al.  Symptomatic treatment of memory decline in Alzheimer's disease by deep brain stimulation: a feasibility study. , 2013, Journal of Alzheimer's disease : JAD.

[34]  Daniela Montaldi,et al.  A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory , 2008, Nature Neuroscience.

[35]  N. Logothetis,et al.  A combined MRI and histology atlas of the rhesus monkey brain in stereotaxic coordinates , 2007 .

[36]  John P. Aggleton,et al.  Intact negative patterning in rats with fornix or combined perirhinal and postrhinal cortex lesions , 2000, Experimental Brain Research.

[37]  Suneil K. Kalia,et al.  Rapid Modulation of Protein Expression in the Rat Hippocampus Following Deep Brain Stimulation of the Fornix , 2015, Brain Stimulation.

[38]  W. Lipski,et al.  Sensing-enabled Hippocampal Deep Brain Stimulation in 2 Idiopathic Nonhuman Primate Epilepsy 3 4 , 2022 .

[39]  B. Givens,et al.  Stimulation‐induced reset of hippocampal theta in the freely performing rat , 2003, Hippocampus.

[40]  Amanda Parker,et al.  The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys , 1997, Neuropsychologia.

[41]  Andreea Oliviana Diaconescu,et al.  Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. , 2012, Archives of neurology.

[42]  Margaret F. Carr,et al.  Hippocampal SWR Activity Predicts Correct Decisions during the Initial Learning of an Alternation Task , 2013, Neuron.

[43]  D. Gaffan,et al.  Addition of fornix transection to frontal-temporal disconnection increases the impairment in object-in-place memory in macaque monkeys , 2008, The European journal of neuroscience.

[44]  Rajesh C. Rao,et al.  Memory enhancement and deep-brain stimulation of the entorhinal area. , 2012 .

[45]  Satoshi Ikemoto,et al.  Mesopontine median raphe regulates hippocampal ripple oscillation and memory consolidation , 2015, Nature Neuroscience.

[46]  G. Buzsáki.  Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning , 2015, Hippocampus.

[47]  Seth Love,et al.  Memory loss resulting from fornix and septal damage: impaired supra-span recall but preserved recognition over a 24-hour delay. , 2008, Neuropsychology.

[48]  W M Cowan,et al.  Subcortical afferents to the hippocampal formation in the monkey , 1980, The Journal of comparative neurology.

[49]  M. Zugaro,et al.  Learning-Induced Plasticity Regulates Hippocampal Sharp Wave-Ripple Drive , 2014, The Journal of Neuroscience.

[50]  Charles L. Wilson,et al.  Cell Type-Specific Firing during Ripple Oscillations in the Hippocampal Formation of Humans , 2008, The Journal of Neuroscience.

[51]  S. Bressler,et al.  Reversal of theta rhythm flow through intact hippocampal circuits , 2014, Nature Neuroscience.

[52]  Philip G. F. Browning,et al.  Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection , 2009, Cerebral cortex.

[53]  Jadin C. Jackson,et al.  Hippocampal Sharp Waves and Reactivation during Awake States Depend on Repeated Sequential Experience , 2006, The Journal of Neuroscience.

[54]  Philip G. F. Browning,et al.  Learning and retrieval of concurrently presented spatial discrimination tasks: role of the fornix. , 2004, Behavioral neuroscience.

[55]  J. Aggleton,et al.  Rats' processing of visual scenes: effects of lesions to fornix, anterior thalamus, mamillary nuclei or the retrohippocampal region , 2001, Behavioural Brain Research.

[56]  L. Swanson,et al.  The projection of the supramammillary nucleus to the hippocampal formation: An immunohistochemical and anterograde transport study with the lectin PHA‐L in the rat , 1984, The Journal of comparative neurology.

[57]  M. W. Brown,et al.  Episodic memory, amnesia, and the hippocampal–anterior thalamic axis , 1999, Behavioral and Brain Sciences.

[58]  E. Rolls.  Diluted connectivity in pattern association networks facilitates the recall of information from the hippocampus to the neocortex. , 2015, Progress in brain research.

[59]  U. Heinemann,et al.  Adrenergic modulation of sharp wave‐ripple activity in rat hippocampal slices , 2012, Hippocampus.

[60]  T L Babb,et al.  Increased glucose metabolism during long-duration recurrent inhibition of hippocampal pyramidal cells , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[61]  Thilo Womelsdorf,et al.  Sharp Wave Ripples during Visual Exploration in the Primate Hippocampus , 2015, The Journal of Neuroscience.

[62]  Attila I. Gulyás,et al.  Generation of physiological and pathological high frequency oscillations: the role of perisomatic inhibition in sharp-wave ripple and interictal spike generation , 2015, Current Opinion in Neurobiology.

[63]  I. Whishaw.  The Septohippocampal System and Path Integration , 2000 .

[64]  Mark D'Esposito,et al.  Amnesia following traumatic bilateral fornix transection , 1995, Neurology.

[65]  D. Gaffan,et al.  Place memory and scene memory: effects of fornix transection in the monkey , 2004, Experimental Brain Research.

[66]  J. T. Erichsen,et al.  Hippocampal–anterior thalamic pathways for memory: uncovering a network of direct and indirect actions , 2010, The European journal of neuroscience.

[67]  M. Wilson,et al.  Disruption of ripple‐associated hippocampal activity during rest impairs spatial learning in the rat , 2009, Hippocampus.

[68]  Robert Chen,et al.  The mechanisms of action of deep brain stimulation and ideas for the future development , 2015, Progress in Neurobiology.

[69]  D. Gaffan,et al.  Correlation of fornix damage with memory impairment in six cases of colloid cyst removal , 2006, Acta Neurochirurgica.

[70]  N. Inagaki,et al.  In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis , 1991, Naunyn-Schmiedeberg's Archives of Pharmacology.

[71]  D. Gaffan,et al.  Dissociated effects of perirhinal cortex ablation, fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe , 2004, Experimental Brain Research.

[72]  John P. Aggleton,et al.  Interleaving brain systems for episodic and recognition memory , 2006, Trends in Cognitive Sciences.

[73]  P. Gloor,et al.  The human dorsal hippocampal commissure. An anatomically identifiable and functional pathway. , 1993, Brain : a journal of neurology.

[74]  Charles L. Wilson,et al.  High‐frequency oscillations recorded in human medial temporal lobe during sleep , 2004, Annals of neurology.

[75]  R. Vertes,et al.  Extrinsic modulation of medial septal cell discharges by the ascending brainstem hippocampal synchronizing pathway , 1994, Hippocampus.

[76]  G. Buzsáki,et al.  Selective suppression of hippocampal ripples impairs spatial memory , 2009, Nature Neuroscience.

[77]  D. Durand,et al.  Low‐frequency electrical stimulation of a fiber tract in temporal lobe epilepsy , 2013, Annals of neurology.

[78]  N. McNaughton,et al.  Mapping the differential effects of procaine on frequency and amplitude of reticularly elicited hippocampal rhythmical slow activity , 1993, Hippocampus.

[79]  H. Steinbusch,et al.  Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: The role of stimulation parameters , 2013, Brain Stimulation.

[80]  L. Frank,et al.  Awake Hippocampal Sharp-Wave Ripples Support Spatial Memory , 2012, Science.

[81]  A. Lozano,et al.  The rationale for deep brain stimulation in Alzheimer’s disease , 2016, Journal of Neural Transmission.

[82]  T. Bussey,et al.  Conditional motor learning in the nonspatial domain: effects of errorless learning and the contribution of the fornix to one-trial learning. , 2005, Behavioral neuroscience.

[83]  B. McNaughton,et al.  EEG sharp waves and sparse ensemble unit activity in the macaque hippocampus. , 2007, Journal of neurophysiology.

[84]  L. Acsády,et al.  Principal cells are the postsynaptic targets of supramammillary afferents in the hippocampus of the rat , 1994, Hippocampus.

[85]  G. Buzsáki,et al.  High-Frequency Oscillations in the Output Networks of the Hippocampal–Entorhinal Axis of the Freely Behaving Rat , 1996, The Journal of Neuroscience.

[86]  R. Vertes.  Major diencephalic inputs to the hippocampus: supramammillary nucleus and nucleus reuniens. Circuitry and function. , 2015, Progress in brain research.

[87]  R. Wennberg,et al.  Memory enhancement induced by hypothalamic/fornix deep brain stimulation , 2008, Annals of neurology.