Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Corrigendum: Patterned hippocampal stimulation facilitates memory in patients with a history of head impact and/or brain injury.

[This corrects the article DOI: 10.3389/fnhum.2022.933401.].

Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury.

RATIONALE: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). METHODS: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject's medical history was unknown to the experimenters until after individual subject memory retention results were scored. RESULTS: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. CONCLUSION: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

Hippocampal CA1 and CA3 neural recording in the human brain: validation of depth electrode placement through high-resolution imaging and electrophysiology.

OBJECTIVE: Intracranial human brain recordings typically utilize recording systems that do not distinguish individual neuron action potentials. In such cases, individual neurons are not identified by location within functional circuits. In this paper, verified localization of singly recorded hippocampal neurons within the CA3 and CA1 cell fields is demonstrated. METHODS: Macro-micro depth electrodes were implanted in 23 human patients undergoing invasive monitoring for identification of epileptic seizure foci. Individual neurons were isolated and identified via extracellular action potential waveforms recorded via macro-micro depth electrodes localized within the hippocampus. A morphometric survey was performed using 3T MRI scans of hippocampi from the 23 implanted patients, as well as 46 normal (i.e., nonepileptic) patients and 26 patients with a history of epilepsy but no history of depth electrode placement, which provided average dimensions of the hippocampus along typical implantation tracks. Localization within CA3 and CA1 cell fields was tentatively assigned on the basis of recording electrode site, stereotactic positioning of the depth electrode in comparison with the morphometric survey, and postsurgical MRI. Cells were selected as candidate CA3 and CA1 principal neurons on the basis of waveform and firing rate characteristics and confirmed within the CA3-to-CA1 neural projection pathways via measures of functional connectivity. RESULTS: Cross-correlation analysis confirmed that nearly 80% of putative CA3-to-CA1 cell pairs exhibited positive correlations compatible with feed-forward connection between the cells, while only 2.6% exhibited feedback (inverse) connectivity. Even though synchronous and long-latency correlations were excluded, feed-forward correlation between CA3-CA1 pairs was identified in 1071 (26%) of 4070 total pairs, which favorably compares to reports of 20%-25% feed-forward CA3-CA1 correlation noted in published animal studies. CONCLUSIONS: This study demonstrates the ability to record neurons in vivo from specified regions and subfields of the human brain. As brain-machine interface and neural prosthetic research continues to expand, it is necessary to be able to identify recording and stimulation sites within neural circuits of interest.

Using the Principles of Multisensory Integration to Reverse Hemianopia.

Hemianopia can be rehabilitated by an auditory-visual "training" procedure, which restores visual responsiveness in midbrain neurons indirectly compromised by the cortical lesion and reinstates vision in contralesional space. Presumably, these rehabilitative changes are induced via mechanisms of multisensory integration/plasticity. If so, the paradigm should fail if the stimulus configurations violate the spatiotemporal principles that govern these midbrain processes. To test this possibility, hemianopic cats were provided spatially or temporally noncongruent auditory-visual training. Rehabilitation failed in all cases even after approximately twice the number of training trials normally required for recovery, and even after animals learned to approach the location of the undetected visual stimulus. When training was repeated with these stimuli in spatiotemporal concordance, hemianopia was resolved. The results identify the conditions needed to engage changes in remaining neural circuits required to support vision in the absence of visual cortex, and have implications for rehabilitative strategies in human patients.

Interhemispheric visual competition after multisensory reversal of hemianopia.

Unilateral lesions of visual cortex have the secondary consequence of suppressing visual circuits in the midbrain superior colliculus (SC), collectively producing blindness in contralesional space ("hemianopia"). Recent studies have demonstrated that SC visual responses and contralesional vision can be reinstated by a non-invasive multisensory training procedure in which spatiotemporally concordant visual-auditory pairs are repeatedly presented within the blind hemifield. Despite this recovery of visual responsiveness, the loss of visual cortex was expected to result in permanent deficits in that hemifield, especially when visual events in both hemifields compete for attention and access to the brain's visuomotor circuitry. This was evaluated in the present study in a visual choice paradigm in which the two visual hemifields of recovered cats were simultaneously stimulated with equally valent visual targets. Surprisingly, the expected disparity was not found, and some animals even preferred stimuli presented in the previously blind hemifield. This preference persisted across multiple stimulus intensity levels and there was no indication that animals were less aware of cues in the previously blind hemifield than in its spared counterpart. Furthermore, when auditory cues were combined with visual cues, the enhanced performance they produced on a visual task was no greater in the normal than in the previously blind hemifield. These observations suggest that the multisensory rehabilitation paradigm revealed greater inherent visual information processing potential in the previously blind hemifield than was believed possible given the loss of visual cortex.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall.

OBJECTIVE: We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient's own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. APPROACH: We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MAIN RESULTS: MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. SIGNIFICANCE: These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.