WO2019033213A1 - Contingent stimulation for augmentation of memory - Google Patents

Abstract

Provided herein are methods, uses and systems for augmenting memory in a subject by delivering, via at least one electrode implanted in the hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex of the subject, an electrical stimulation to at least a portion of the subject's hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex, in response to a detected pre-determined eye movement signature associated with an event-related potential (ERP), the signature having been calibrated during a visual search task.

Description

CONTINGENT STIMULATION FOR AUGMENTATION OF MEMORY

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority from U.S. Provisional Application No. 62/545,818 filed on August 15, 2017, which is incorporated herein by reference in its entirety.

FIELD

[0002] The present disclosure relates generally to methods and systems of augmenting memory, and more particularly to methods, uses and systems of contingent stimulation of the hippocampus and other related memory structures such as the amygdala, entorhinal cortex, parahippocampus, prefrontal cortex, and temporal cortex to improve cognitive function.

BACKGROUND

[0003] Deep brain stimulation (DBS) has been widely used for Parkinson's Disease since 1991 [1], on psychosis [2], preventing seizures in patients with epilepsy [3]-[6], but has had varying results in humans during memory tasks with improvements [7]-[9] or impairments [10]- [12] (for review see [13], [14]) and limited to no success with those suffering from dementia or Alzheimer's disease [15]— [19]. Little investigation on the optimization of stimulation parameters in DBS in humans has been carried out. These parameters can include intensity of stimulation, frequency (evidence of optimizations in animals [20]), waveform shape, and timing to name a few. The current literature uses open loop stimulation, electrically stimulating without feedback [8], [10], [1 1], [21], An expanding literature has developed theorizing the importance of timing in neuronal mechanisms [22]-[25]. There is a movement towards stimulating incorporating the brain network and states as part of the approach, [26] where a major concern and limitation is timing of stimulation [14]. The theta rhythm (3-8 Hz) has been connected with cognitive processes [27]- [30], plasticity and other cellular responses occurring on its phases [31]-[35] and has been used contingently to modify performance in animals [33], [34], [36], [37].

[0004] Such theta rhythms have also been shown to interact between hippocampus and other medial temporal lobe structures and the prefrontal cortex which can mediate memory formation [94].

[0005] The hippocampal area and its substructures have been shown to have a direct association with explicit testing [43]-[46] and association with spatial location [47]-[49]. A standard model indicates memories are stored using hippocampal networks that bind together information over neocortical networks [50] and the hippocampus is activated at encoding according to standard consolidation theory [53] and multiple trace theory [54]. The hippocampus is also relevant for retrieving items not in the focus of attention or not yet consolidated in the neocortex [53]. The creative behavioural task for testing is an explicit memory task (requiring awareness at retrieval) [54] that involves hippocampus activation encoding according to the aforementioned theories.

[0006] The amygdala is another medial temporal lobe structure known for its involvement in emotion that has also been a subject of studies involving memory consolidation [95]. Activation of the amygdala has been shown to increase memory formation, can result in an increase of stress hormones which can facilitate consolidation and may modulate memory [96]. The hippocampus and amygdala are functionally connected and interact with the prefrontal cortex.

[0007] Declarative memory refers to the ability to consciously recall or recognize facts and events, and is the focus of most age-related memory issues. Explanations for these memory failures generally fault inadequate encoding and/or retrieval [62].

[0008] Neurostimulation is defined as the direct administration of electrical pulses to nervous tissue to modulate a pathologic substrate and to achieve a therapeutic effect [63]. Neuromodulation research is concerned with modulating brain activity using this externally applied 'stimulation' to either improve its function, or suppress abnormal activity (i.e. Parkinson tremors). Current clinical and most research based stimulation practices for cognition use varying open loop stimulation parameters. Experiments have also been conducted with varying stimulation parameters to investigate memory and cognition [8], [9], [1 1], [17], [64], [65] and their benefits for DBS have been reviewed [13], [66], [67]. Recorded signals from epilepsy patients have indicated that the hippocampus has a role in memory specifically when a phase reset (shift in ongoing brain oscillation) occurs at presentation of visual stimulus in electroencephalography (EEG) [68], [69], intracranial electroencephalography (iEEG) [70]-[73] and magnetoencephalography [74], [75]. Whilst in animal studies electrical stimulation at specific time points of the reset has modulated rhythm specifically inducing long term potentiation (LTP) thought to be part of encoding memory in neuroplasticity and long term depression (LTD) weakening neural synapses on peak and trough respectively and also modified behavioural outcomes [37], [76], [77]. In a recent study using open loop stimulation without feedback, offline classification was used to detect when stimulation enhanced memory performance. Based on pre image onset data in word recall there seemed to be a benefit of stimulation if the brain was in, what the authors determined was a poor encoding state (e.g. decreased high frequency power in broad band areas) [26]. Another study found stronger memory is associated with image regions that contained more fixations during encoding [78]. Other studies found that the total number of fixations is indicative of memory performance and that eye movements and fixation tasks may be indicative of behavioral performances [92], [93].

[0009] Current DBS protocols and parameters stimulate the fornix to improve memory disorders on a consistent basis with minimal feedback as to timing of the stimulus [67]. Experimental protocols working within patients with epilepsy have also shown that stimulation can also modulate memory effect when stimulating the hippocampus and entorhinal cortex using a simple on and off pulse trains [13]. Electrical stimulation in patients with epilepsy and Alzheimer's disease has been associated with improvements in behavioural outcomes as well as neuronal changes [13]. A previous study performed a spatial memory task while stimulating with 5-second trains and showed improvement when stimulating the entorhinal cortex [8], and another study [65] in DBS showed improvements with 8mA of continuous four-hour stimulation, which was determined safe. However another study on hippocampus stimulation using a single electrical pulse after a fixed time following presentation of a visual stimulus (object, face word, geometric shape) found decreased memory recall in a memory task [11]. Similarly, a study on direct electrical stimulation of the human entorhinal region and hippocampus was found to impair memory [10].

SUMMARY

[0010] The present disclosure relates to methods, uses and systems for augmenting memory in a subject by contingent stimulation of the hippocampus, amygdala, entorhinal cortex, parahippocampus, prefrontal cortex, or temporal cortex at the onset of event-related potentials (ERPs) as determined by a pre-determined eye movement signature.

[0011] A first aspect includes a method of improving memory in a subject, comprising:

tracking eye movement of the subject;

detecting a pre-determined eye movement signature, the pre-determined eye movement signature being determined during a prior calibration session and being associated with an event-related potential; and

delivering, after a lag period, an electrical stimulation to at least a portion of the subject's hippocampus, amygdala, entorhinal cortex, parahippocampus, prefrontal cortex, or temporal cortex via at least one implanted electrode, to improve the subject's memory. [0012] In an embodiment, the electrical stimulation is to at least a portion of the subject's hippocampus. In another embodiment, the electrical stimulation is to at least a portion of the subject's entorhinal cortex. In another embodiment, the electrical stimulation is to at least a portion of the subject's prefrontal cortex.

[0013] In one embodiment, the electrical stimulation is delivered after a lag period determined during the prior calibration session.

[0014] Another aspect disclosed herein includes a system for contingent neurostimulation based on a detected pre-determined eye movement signature in a subject having at least one electrode implanted in the hippocampus, amygdala, entorhinal cortex, parahippocampus, prefrontal cortex, or temporal cortex, configurable to deliver intracranial stimulation, comprising: a detector for detecting eye movement features;

a neurostimulator for generating electrical signals to the at least one electrode; and a computer in electronic communication with the detector and the neurostimulator, the computer being configured to receive eye movement data, to detect a pre-determined eye movement signature, and to instruct the neurostimulator to generate electrical signals to the at least one electrode in response to the detected pre-determined eye movement signature.

[0015] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] For a better understanding of the embodiments described herein and to show more clearly how they may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings which show at least one exemplary embodiment, and in which:

[0017] Fig. 1A is a flow diagram of the memory task. Fig. 1 B is a series of MRI-CT scans showing the electrode and its location within the hippocampus (as identified by arrows).

[0018] Fig. 2A is a series of graphs of subject 6. The first panel shows a recording of the Right Hippocampal Depth electrode 1 using fixation events. The following two panels indicate the phase coherence at significance of 0.005 after FDR correction and 0.001 on the far right showing that it is primarily after onset in the theta band. Fig. 2B is a graphic illustrating an evoked response, showing statistical significance when voltage reaches above or below threshold values (horizontal bars). Fig. 2C is a graphic showing results for two tests from the same subject (Sem 1 and Sem 2) demonstrating similar responses. It demonstrates evoked responses following fixation onset. Fig. 2D is a graphic showing event related potentials based on stimulation types, namely peak stimulation (peakStim), trough stimulation (troughStim) and random stimulation (randStim), and their evoked response in the surrounding electrodes. Each stimulation type is aligned to fixation onset. Fig. 2E is a graph showing a significant peak evoked response measured in a surrounding electrode, which indicates that the results of electrical stimulation and timing can be viewed in other electrodes and be calibrated based on downstream effects.

[0019] Figs. 3A-F are block diagrams of exemplary systems that can be used with the methods described. Fig. 3G is a diagram depicting set up infrastructure of how the stimulation is conducted.

[0020] Figs. 4A to D is a series of graphs showing event related potentials in image onset (e.g. onset of the scene) and fixation onset.

[0021] Figs. 5A and 5B are graphs showing 5 Hz oscillation with 5 pulse stimulation of 100 με biphasic pulse width.

[0022] Fig. 6A is a graph showing scene recognition by hippocampus stimulation type (n=1) averaged over immediate and delay period of testing. Fig. 6B depicts a graph showing immediate scene recognition by stimulation of prefrontal cortex (n=1).

DETAILED DESCRIPTION

Definitions

[0023] As used herein an "event-related potential" or ERP refers a measured brain response resulting from a specific sensory, cognitive, or motor event. ERPs are measured by electroencephalography (EEG) and include for example evoked responses and induced responses. ERPs can be contributed to by different frequency bands designated delta (0.5 to 3 Hz), theta (3 to 8Hz), alpha (9 to 12 Hz), beta (13-30 Hz), low-gamma (30-70 Hz) and high-gamma (70-100 Hz).

[0024] As used herein the phrase "calibration related ERP" or "calibration ERP" means an ERP evoked during a calibration to determine the timing, rhythm, intensity and/or rate of stimulation. A calibration related ERP determines timing of electrical stimulation based on saccadic eye movement. Another calibration related ERP determines intensity of ERP referred to as cortico- cortical evoked potentials (CCEP). The CCEP is evoked by stimulation which is delivered at the rate the person moved their eyes during the calibration ERP task.

[0025] As used herein, the expression "eye movement signature" refers to one or more eye movement features that associate with an event-related potential (ERP). The eye movement signature can include one or more eye movement features selected from onset of saccade, onset of fixation, saccadic duration, and fixation duration. A saccade is a quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction. A fixation is the maintaining of the visual gaze on a single location. The association with an ERP, means association with an ERP feature such as ERP timing, including for example ERP peak timing, ERP midpoint timing and/or ERP trough timing. The eye movement signature is detected using an eye tracker device tracking eye movement features during performance of a memory task. For example, the eye movement feature can be onset of fixation, which can be associated with timing an ERP peak, an ERP trough, or an ERP midpoint, as described in the Examples (see Fig. 2B). The eye movement signature is used to determine the timing of stimulation. The eye movement signature can be pre-determined, for example on the basis of a particular subject, and can be determined during a calibration session, or determined based on one or a group of subjects, for example a group having one or more common characteristics such as similar age (e.g. within 10 years of each other), similar cognitive ability (e.g. that score within 20% of each other on a cognitive task ) etc. Averages of each of the parameters, e.g. time to onset, determined during a calibration session or for a group of subjects can be used.

[0026] The term "calibration" as used herein refers to the use of a demonstration task to find the ERP due to eye movement related activity. From this ERP the skilled person can find the first significant peak and trough and use this for timing subsequent stimulation to eye movement. Such a calibration could be a demonstration of the task with a set of scenic images or simply viewing a grey screen. With respect to viewing a grey screen, a subject uses their eye movements through a grey screen to elicit an ERP for a set amount of time e.g. 5 minutes. The calibration can comprise one or more steps described in Example 3.

[0027] The term "tracking" as used herein as related to eye movement of a subject refers to following or noting eye movement of a subject by way of, for example, any eye tracking device or software on a device known to a person skilled in the art. For example, a suitable eye tracking device can include at least one of a wearable eye tracking device, an electrooculogram, and/or an electromyogram.

[0028] As used herein, the term "lag period" means the period between the onset of an eye movement signature such as fixation and event-related potential (ERP) or a particular portion thereof which is used as the timing for stimulation. For example, the lag period can range from about 20 ms to about 300 ms. The lag period can be pre-determined, for example on the basis of a particular subject to be subjected to the method, and can be determined during a calibration session, or determined based on another subject or a group of subjects, for example having one or more common characteristics such as similar age (e.g. within 10 years of each other), similar cognitive ability etc. Eye movement onset aligns to create a calibrated ERP. The lag between the eye movement onset and the onset of the selected phase (e.g. peak, trough, midpoint) or selected timepoint within that ERP can be used to time stimulations.

[0029] As used herein, the term "visual search task" means a task that requires eye movement to locate one or more objects or targets, and is associated with hippocampal activity. For example, the visual search task can be the memory task described in the Examples, objects in scene tasks such as change blindness tasks, a "Where's Waldo" type task to find a specific target, identifying certain characteristics or orientation of targets delayed to match a sample task, implicit tasks such as a visual preference learning task, or natural viewing conditions or a free natural exploration.

[0030] The term "subject" as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans.

[0031] The term "electrode" as used herein refers to a conductor through which electricity enters or leaves an object, substance, or region, for example, a region in a brain. Each electrode may become either the anode or the cathode depending on the direction of current through the cell. An electrode can be bi-polar or monopolar. A bipolar electrode is an electrode that functions as the anode at one end (e.g. tip or cell) and a return electrode is very close by, cathode is at the other end. A monopolar electrode is an electrode that functions either as anodal or cathodal with its return path a greater distance away such as a subgaleal electrode. Electrode pairs require a point of entry and return for stimulation to complete the circuit. Voltage is measured as the difference, i.e. potential, across sites, so a reference site is needed. In bipolar recordings the reference site is close by and can even be in the same structure. In monopolar recordings, the second electrode (return path) is further away. In clinical recording, such a reference is the subgaleal electrode. Anodic and cathodic stimulation refer to flow of current (by convention positive charges). Hence delivering a positive injection of current would be considered anodic stimulation, and a negative injection would be cathodic stimulation. The electrode in this case may act as either anode or cathode depending on flow or delivery of stimulation current. For example, monopolar has the cathode/negative electrode contact in the brain and the anode/positive contact in the pulse generator in the chest wall. For example, bipolar has the anode and cathode contacts in much closer proximity, both within the brain.

[0032] The term "dementia" as used herein refers to a diagnosed brain disease that causes a long-term and often gradual decrease in the ability to think and remember that is great enough to affect a person's daily functioning. It excludes Alzheimer's disease and undiagnosed or normal age related memory loss.

[0033] The term "improve" as used herein as related to memory or cognitive function refers to the ability to increase or enhance memory performance from baseline performance (i.e. without stimulation or prior to stimulation) to that with the stimulation methods based on scene recognition or basic cognitive battery of tasks described herein. For example, a subject with improved memory may have a higher rate of recollection or correct recognition of scenes.

[0034] As used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the content clearly dictates otherwise. Thus for example, a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

[0035] As used in this application and claim(s), the word "consisting" and its derivatives, are intended to be close ended terms that specify the presence of stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps.

[0036] The terms "about", "substantially" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% or at least ±10% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0037] The recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term "about."

[0038] The definitions and embodiments described in particular sections are intended to be applicable to other embodiments herein described for which they are suitable as would be understood by a person skilled in the art. For example, in the following passages, different aspects are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Methods, uses and systems for augmentation of memory

[0039] Eye movements, in particular intersaccadic fixations, have been previously associated with ongoing brain activity.

[0040] The timing of stimulus was considered by the inventors to be a key parameter for memory outcomes. In patients with epilepsy, the efficacy of contingent stimulation has been shown to stop seizures based on iEEG recordings. In this case the stimulation is provided "as needed" and not on a continual basis, essentially only during the event of a seizure occurrence

[4], [65].

[0041] Other brain structures that can be associated with memory include the parahippocampus and entorhinal cortex which can be part of afferent pathways to the hippocampus. Such areas are believed to be involved in encoding associations and space. In primates and humans, such anatomic locations have been evidenced to have single units that can fire to specific scenes or spatial locations [97], [98].

[0042] Stimulating other regions outside of the hippocampus can improve declarative memory, including the amygdala and sites outside of the medial temporal lobes [99]. Electrical stimulation of amygdala may improve memory [100]. Closed loop ventures focused on stimulating at opportune times have suggested stimulating in the hippocampus and temporal cortex may improve memory in micro and macro stimulation respectively [99], [101], [102].

[0043] Accordingly, the present disclosure relates to timed neurostimulation based on eye movement to improve cognitive function in subjects. It is demonstrated herein that coordinating the timing of hippocampal or prefrontal cortex stimulus with theta rhythms in a regulated closed loop system can augment memory in subjects including in subjects with memory impairments. [0044] A first aspect provided herein relates to a method of improving memory in a subject. The method comprises: tracking eye movement of the subject; detecting a pre-determined eye movement signature associated with an event related potential, the pre-determined eye movement signature optionally being determined during a prior calibration session ; and delivering, after a lag period, an electrical stimulation to at least a portion of the subject's hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex via at least one implanted electrode, to improve the subject's memory.

[0045] In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's hippocampus. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's amygdala. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's parahippocampus. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's entorhinal cortex. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's prefrontal cortex. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's anterior cingulate cortex. In an embodiment, the delivering of the electrical stimulation is to at least a portion of the subject's temporal cortex.

[0046] In an embodiment, the electrode is a bi-polar electrode or a monopolar electrode. In an embodiment, the electrode is a bi-polar electrode. In an embodiment, the electrode is a monopolar electrode.

[0047] Tracking eye movement of the subject, for example saccadic eye movements, can be accomplished using any eye tracking apparatus or software on a device such as a computer. Methods and apparatuses for tracking eye movement are described for example in U.S. Patent No. 6,539,263, hereby incorporated by reference in its entirety. In an embodiment, the eye movement of the subject is tracked using an eye tracking device, optionally a wearable eye tracking device, an electrooculogram, an electromyogram, and combinations thereof. For example, any camera configured to track pupillary responses may also be used.

[0048] For example, the eye movements can be tracked using a SensoMotoric Instruments iView RED-m eye tracker. The iView RED-m eye tracker can be mounted on a laptop. As described in Example 2, this set up allows viewing of the task and recording of eye movements. For example, the eye tracking device can be integrated in a computer operating system such as in Windows 10. The device can also be a wearable eye tracking device, for example the optical head-mounted display described in U.S. Application having publication no. 20130044042 A1 , which is hereby incorporated by reference in its entirety. Other ocular technologies utilizing computer in glasses, for example chip technology such as Shima by Laforge or Air Suite which allows for customizable workflows for vision based models can also be used.

[0049] Detecting the pre-determined eye movement signature can be accomplished using a recording system, for example a headset (also referred to as a headbox) such as a NeuraLynx Headbox or a Neuroscan Headbox which is in communication with one or more electrodes. The recording system acquires signals from the electrode, i.e. measuring the activity or can be used for delivering stimulation along that pathway. NeuraLynx amplifier allows for larger signal to be analyzed and used on a computer. The computer is configured to receive eye movement data and identify when the predetermined eye signature feature is recorded. As another example, a recording system such as the Xltek Natus clinical EEG system can be used and a computer that is configured to identify when the predetermined eye signature feature is recorded. The computer is further configured to deliver the stimulation after the lag period. In an embodiment, the recording system is a headset/headbox. In an embodiment, the headset/headbox is a NeuraLynx Headbox, a Neuroscan Headbox, or an Xltek Natus clinical EEG system. In an embodiment, the amplifier is a Neurolynx amplifier. The skilled person can readily recognize a suitable headset/headbox and/or amplifier to connect to the system, computer, detector, and/or neurostimulator described herein.

[0050] The pre-determined eye movement signature, in some embodiments, is a selected signature feature such as fixation onset.

[0051] In other embodiments, the pre-determined eye signature is determined for a priori for a particular subject. In embodiments where the pre-determined eye movement signature is first determined for a particular subject, it can be determined during a prior calibration session or immediately prior to a stimulation session described above.

[0052] The pre-determined eye movement signature to be used can be determined in the calibration session using electroencephalography. Electroencephalography signal refers to brain activity that is recorded for example during a calibration task. Intracranial electroencephalography is from deeper structures such as the hippocampus. Any brain activity used in conjunction with eye movement can be measured by electroencephalography, such as the ERP described. For example, the pre-determined eye movement signature to be used in a particular method can be selected eye movement features that associate with an ERP by analyzing event-related potentials recorded using for example a NeuraLynx Headbox or a Neuroscan Headbox. For example, a recording system such as the Xltek Natus clinical EEG system can be used. The headset/headbox and EEG system enables recording signals for ERP and to interface with the electrode in a brain structure to deliver stimulation once timings have been determined from the recordings.

[0053] The pre-determined eye movement signature can include one or more eye movement related features selected from onset of saccade, onset of fixation, saccadic duration and fixation duration. Other features can include the amplitude or peak velocity of saccade. The onset may be a first onset or a subsequent onset (e.g. first onset of saccade, second onset of saccade, etc).

[0054] Elements of the eye movement signature are further described below.

[0055] In some embodiments, the eye movement is tracked while the subject is performing a memory task, optionally a visual search as described herein.

[0056] Delivering the electrical stimulation can be provided by an electrical stimulation device as further described herein.

[0057] In one embodiment, the pre-determined eye movement signature is determined prior to the method described above, during a prior calibration event. In particular, eye movement signature determination comprises in an embodiment: measuring a calibration related event-related potential (ERP) in the subject in response to a calibration visual search task; and

determining association of the calibration related event-related potential (ERP) with one or more eye movement features selected from onset of saccade, onset of fixation, saccadic duration and fixation duration, and selecting the one or more eye movement features that associates with the event related potential, the selected one or more eye movement features forming the eye movement signature.

[0058] The calibration ERP for determining timing is recorded without stimulation. Such an ERP can be measured in one or multiple electrodes (e.g. based on the patient implants and for example located in a selected brain structure).

[0059] Methods and uses as described herein can also include determination of the stimulating current intensity. Determination of the stimulating current intensity can comprise applying to the at least one electrode electrical stimulation pulses, optionally with a stimulating current intensity of 10 mA or less, for example up to 8 mA, sufficient to induce evoked potentials, optionally cortico-cortical evoked potentials (CCEP). The stimulation ERP (CCEP) for determining intensity is recorded in surrounding electrodes.

[0060] Fixation periods between saccades have been shown to correlate with ERPs. As demonstrated in the Examples, fixation or saccade onset may reset theta rhythms which provide timings for subsequent peaks (long term potentiation) and troughs (long term depression) stimulation. Accordingly eye movement signatures that correlate with an ERP may provide better timing for stimulation.

[0061] Stimulation is provided in response to detecting the eye movement signature and delivery of the electrical stimulation takes place after a lag period following the pre-determined eye movement signature is detected. The lag period depends for example on the particular eye movement signature feature or features being detected as part of the eye movement signature. The lag period can be a preselected time period based on for example a plurality of subjects or a previous calibration event. For example, the lag period can be determined for a subject in a prior calibration event. In an embodiment, the lag period is between the eye movement onset and the onset of peak, trough, or midpoint phase. In an embodiment, the lag period is between the eye movement onset and a selected timepoint within that ERP from pre-determined signature. The calibration event can take place in some embodiments, immediately before the method described above.

[0062] Determination of appropriate timing of stimulation or lag period is described for example in Example 3, where the subject, during a calibration session, undergoes a calibration visual search task (such as a memory task) and is tested for example for scene recognition and targets in scene. In particular, the evoked response is analyzed offline due to fixation onset. A bootstrapping method is used, whereby the events that made up this response are randomly switched polarity, making what would be considered a random event response. This is repeated, for example 3000, times to find the maximum and minimum values of this random distribution. Anything above 97.5% of maximum values or below 97.5% of minimum values are considered significant. Significant thresholds are illustrated for example in Fig. 2B. Generally, only significant peaks and trough timings are used however if no significant values are seen in the subject, the average timings for peak and trough determined from a plurality of subjects may be used.

[0063] The calibration session involves a visual search task that includes a number of fixation events, wherein the subject can incur freely moving fixations around a scene or image. For example, the calibration session can involve at least 100 fixation events. In an embodiment, the calibration session comprises at least 100 fixation events, preferably at least 160 fixation events. [0064] The lag period is be used to set the timing of stimulation. For instance, upon detection of fixation onset, using for example an eye tracking device, the lag period begins, and once the lag period is elapsed, electrical stimulation is applied to the hippocampus, or alternatively, the amygdala, entorhinal cortex, parahippocampus, prefrontal cortex (including anterior cingulate cortex), or temporal cortex, thus timing the stimulation with an ERP or a portion thereof (for example the peak of the ERP or the trough of the ERP).

[0065] It was previously found [40] in monkeys that stimulation delivered after a 50 to100 ms delay following the end of a saccade provided most influence on local evoked potentials. In an embodiment, the lag period can range from about 20 ms to about 300 ms, about 30 ms to 200 ms or about 50 ms to about 100 ms.

[0066] In an embodiment, the calibration related ERP is detected using electroencephalography. In an embodiment, the ERP is recorded using a headset/headbox and an amplifier. In an embodiment, the headset/headbox is a NeuraLynx Headbox, a Neuroscan Headbox, or an Xltek Natus clinical EEG system. In an embodiment, the amplifier is a Neurolynx amplifier. In an embodiment, the ERP is recorded using a NeuraLynx Headbox, a Neuroscan Headbox, or an Xltek Natus clinical EEG system, and an amplifier, optionally a NeuraLynx amplifier. The skilled person can readily recognize a suitable headset/headbox and/or amplifier for methods and uses described herein.

[0067] In an embodiment, the visual search task (which can be the same or different for calibration sessions and augmenting memory sessions) is a non-invasive task and is performed on a computer screen. In an embodiment, the visual search task is memory task, for example the same as the calibration memory task, for example as described in Example 1. The visual search task performed during the contingent stimulation can be any task that involves a recall component or any recognition component. The contingent stimulation can comprise one or more steps described in Example 4.

[0068] The at least one electrode is connected to a neurostimulator for example an external neurostimulator such as the Grass Instruments neurostimulator. The at least one electrode can also be connectable to an implantable neurostimulator. The electrodes that are connected to the neurostimulator can for example be the same electrodes that are connected to the recording system (e.g. NeuraLynx Headbox). Known neurostimulators that deliver biphasic pulse stimulation and for use with implanted electrodes may be used, for example as described in U.S. Patent No. 9,403,010, which is hereby incorporated by reference in its entirety. Other neurostimulators that can modify waveforms, for example the Tucker Davis stimulator, can also be used.

[0069] In an embodiment, the stimulation of the at least one electrode occurs after a lag period following onset of a fixation.

[0070] In an embodiment, the electrode pair stimulating can be bi-polar or monopolar.

[0071] In an embodiment, the electrode in the hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the hippocampus is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the amygdala is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the parahippocampus is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the entorhinal cortex is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the prefrontal cortex is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the anterior cingulate cortex is used as cathode or anode in the electrical stimulation protocol. In an embodiment, the electrode in the temporal cortex is used as cathode or anode in the electrical stimulation protocol.

[0072] The electrode can be a micro electrode which is useful in stimulating and measuring corresponding single unit neuronal activity. In an embodiment, the electrode is a micro electrode. In an embodiment, the micro electrode stimulates and measures corresponding single unit neuronal activity. In an embodiment, the electrode is a micro electrode, wherein the micro electrode stimulates and measures corresponding single unit neuronal activity.

[0073] In one embodiment, at least one electrode is a pair of electrodes.

[0074] Accordingly, in some embodiments the neurostimulator delivers biphasic pulse stimulation via a pair of electrodes.

[0075] The number of pulses delivered can vary, as long as the pulses are sufficient to elicit hippocampus potentiation. It has been suggested that 4-5 pulses are sufficient to elicit hippocampus potentiation in vitro [87], [88], and in vivo [89]. In another study, it was determined that greater than 3 pulses in the fornix are effective at evoking responses in the hippocampus [90]. In one embodiment, the electrical biphasic pulse stimulation consists of 3 on/off pulse trains, 4 on/off pulse trains, 5 on/off pulse trains, 6 on/off pulse trains, 7 on/off pulse trains, 8 on/off pulse trains, 9 on/off pulse trains or 10 on/off pulse trains. [0076] In an embodiment, the duration of each pulse is less than about 1000 microseconds, less than about 900 microseconds, less than about 800 microseconds, less than about 700 microseconds, less than about 800 microseconds, less than about 500 microseconds, less than about 400 microseconds, less than about 300 microseconds, less than about 200 microseconds or less than about 100 microseconds.

[0077] For example, the at least one electrode delivers 1 to 5 on/off pulses trains of 100 microseconds each.

[0078] In one embodiment, the pulses are deployed by deep brain stimulation (DBS).

[0079] Theta burst stimulation at high frequency burst trains, at train rates between 3-8 Hz has been used in various models of memory [7], [91]. Theta contingent high frequency stimulation can be more effective in reducing the amount of stimulation required and may provide more effective stimulation. For example, the frequency of the stimulation pulses can range from about 50 Hz to about 5000 Hz, for example from 50 to 200 Hz.

[0080] The stimulating current intensity delivered by the at least one electrode can be, in an embodiment, pre-determined, for example prior to tracking the eye movement of the subject, for example during a calibration session. For example, the stimulating current intensity can be determined on the basis of a particular subject determined during a calibration session, or can be based on a group of subjects, having one or more common characteristics such as similar age, similar cognitive ability etc.

[0081] The desired stimulating current intensity may be pre-selected or may be tailored to a subject, for example determined in a calibration session comprising one or more steps as described in Example 3. In an embodiment, the determination of the stimulating current intensity comprises applying to the at least one electrode electrical stimulation pulses, optionally with a stimulating current intensity of 10 mA or less, for example up to 8 mA, sufficient to induce evoked potentials, optionally cortico-cortical evoked potentials (CCEP). Known neurostimulators which trigger bi-polar stimulation through the electrodes, for example as described above, may be used. For example, the Grass Instruments neurostimulator, described in Example 2, may be used.

[0082] For example, an electroencephalogram can be used to record calibration ERPs, for example CCEPs, using receiving or surrounding electrodes placed for example on the subject's head. In an embodiment, the stimulation pulse bursts can be interspersed with a rest interval of for example 2 seconds, to give the brain a rest. Once the peaks and troughs measured on the calibration ERPs are determined to be significant, using for example bootstrapping analysis, the stimulation intensity is set. For hippocampal stimulation, such intensity is determined based on the first noted CCEP in any electrode implanted in any memory related structure of the brain of a patient, for example, the hippocampal, parahippocampal or cortical electrodes. For stimulation of amygdala and other memory structures (e.g. parahippocampus, entorhinal cortex, prefrontal cortex, and temporal cortex), intensity is determined when significant CCEP is first noted in hippocampus. The resulting delay of conductivity, either from first noted significant stimulation peak or trough is subtracted from the timing of stimulation based on calibrated peak and trough from termination of saccadic eye movement.

[0083] Other structures can also be utilized. For hippocampal stimulation we utilize the first noted stimulation effects in the electrodes we have covered. This could be in cortical structures, parahippocampus, or hippocampus.

[0084] When stimulating the amygdala and other memory related structures we are trying to modulate the hippocampus, so we are specifically interested when the effect is apparent in the hippocampus.

[0085] In addition, setting the stimulating current intensity below an after-discharge threshold is thought to reduce learning and memory impairments. Methods for determining an after- discharge threshold are described in U.S. Patent No. 9,403,010, which is hereby incorporated by reference in its entirety. In an embodiment, the determination of stimulating current intensity further comprises determining the threshold required to elicit an after-discharge and reducing the current intensity, for example by about 1 mA or about 2 mA to obtain the stimulating current intensity. For example, the stimulating current intensity is set about 10% to about 30% below the after-discharge threshold.

[0086] In an embodiment, the stimulating current intensity is less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA, less than about 4 mA, less than about 3 mA, less than about 2 mA, less than about 1 mA, or less than about 0.5 mA. In another embodiment, the stimulating current intensity is about 0.5 mA.

[0087] Also provided herein is use of an eye tracking device and an electrical stimulation device that is configured for delivering an electrical stimulation after a pre-determined eye movement signature is detected for improving memory in a subject. In one embodiment, the eye tracking device and the electrical stimulation device are comprised in a system described herein.

[0088] In an embodiment, the electrical stimulation device comprises a neurostimulator which can stimulate at least one electrode. In some embodiments, the electrical stimulation device comprises a neurostimulator and at least one electrode that can be stimulated by the neurostimulator.

[0089] In an embodiment, the subject has at least one electrode implanted in the hippocampus. In another embodiment, the subject has at least one electrode implanted in the amygdala. In another embodiment, the subject has at least one electrode implanted in the parahippocampus. In another embodiment, the subject has at least one electrode implanted in the entorhinal cortex. In another embodiment, the subject has at least one electrode implanted in the prefrontal cortex. In another embodiment, the subject has at least one electrode implanted in the anterior cingulate cortex. In another embodiment, the subject has at least one electrode implanted in the temporal cortex.

[0090] In one embodiment, the at least one electrode is at least two electrodes wherein each electrode is implanted in a same or different location, for example implanted in a subject's hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, and/or temporal cortex. The prefrontal cortex includes the anterior cingulate cortex. In one embodiment, the electrode (e.g. one or more of the implanted electrodes) is in a subject's hippocampus. In one embodiment, the electrode is in a subject's amygdala. In one embodiment, the at is in a subject's parahippocampus. In one embodiment, the electrode is in a subject's entorhinal cortex. In one embodiment, the electrode is in a subject's prefrontal cortex. In one embodiment, the electrode is in a subject's anterior cingulate cortex. In one embodiment, the electrode is in a subject's temporal cortex.

[0091] In an embodiment, the subject is a mammal. In an embodiment, the subject is a human.

[0092] In an embodiment, the subject suffers from memory impairment, for example the subject may be a subject that has been diagnosed with dementia or Alzheimer's disease. In an embodiment, the subject suffers from memory impairment caused by dementia, for example the subject has been diagnosed with dementia. In an embodiment, the subject suffers from memory impairment caused by Alzheimer's disease, for example the subject has been diagnosed with Alzheimer's disease. In an embodiment, the subject suffers from memory impairment caused by epilepsy, such as temporal epilepsy, and/or aging. In an embodiment, the subject suffers from memory impairment caused by epilepsy, for example the subject has been diagnosed with epilepsy. In an embodiment, the subject suffers from memory impairment caused by aging. In one embodiment, the subject is at least 60 years old, at least 65 years old or at least 70 years old. [0093] In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's hippocampus, amygdala, entorhinal cortex, parahippocampus, prefrontal cortex, and/or temporal cortex prior to undergoing the methods described herein. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's hippocampus. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's amygdala. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's entorhinal cortex. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's parahippocampus. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's prefrontal cortex. In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's anterior cingulate cortex In an embodiment, the subject previously underwent surgery to implant at least one electrode in the subject's temporal cortex.

[0094] In an embodiment, the subject suffers from a neurological disorder, for example from epilepsy. In an embodiment, the subject suffers from seizures.

[0095] Another aspect herein disclosed is a system for contingent stimulation, based on a detected pre-determined eye movement signature in a subject having at least one electrode implanted in the hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, temporal cortex or other memory related structures configurable to deliver intracranial stimulation, comprising: a detector for detecting eye movement feature data;

a neurostimulator, for generating electrical signals to the at least one electrode; and a computer in electronic communication with the detector and the stimulator, optionally the neurostimulator, the computer being configured to receive eye movement feature data, to detect a pre-determined eye movement signature, and to instruct the stimulator, optionally neurostimulator to generate electrical signals to the at least one electrode in response to the detected eye movement signature.

[0096] As shown Fig. 3A, detector 100 detects eye movement features, neurostimulator 120 generates electrical signals to electrode 130. Computer 600 is in electronic communication with the detector 100 and the neurostimulator 120, the computer 600 being configured to receive eye movement feature data, to detect the pre-determined eye movement signature, and to instruct the neurostimulator 120 to generate, after a lag period, electrical signals to electrode 130 in response to the detected pre-determined eye movement signature.

[0097] In one embodiment, computer and stimulator is comprised on a chip.

[0098] As shown in Fig. 3B, computer 600 has a processor module 620, a memory module 640, and an interface module 660. In one embodiment, the computer comprises a processor module 620, a memory module 640 and an interface module 660.

[0099] It will be understood that in some embodiments, each of the processor module 620, the memory module 640, and the interface module 660, may be combined into fewer number of modules or may be separated into further modules. Furthermore, the processor module 620, the memory module 640, and the interface module 660, may be implemented in software or hardware, or a combination of software and hardware.

[00100] The processor module 620 controls the operation of the system. For example, the processor can be configured to identify when the predetermined eye signature feature is recorded. The process can also be configured to deliver the stimulation after the lag period. The processor module 620 may be any suitable processors, controllers or digital signal processors that can provide sufficient processing power depending on the configuration, purposes and requirements of the system. In some embodiments, the processor module 620 can include more than one processor with each processor being configured to perform different dedicated tasks.

[00101] The memory module 640 can include RAM, ROM, one or more hard drives, one or more flash drives or some other suitable data storage elements such as disk drives, etc. The memory module has unit that is used to store an operating system and programs as is commonly known by those skilled in the art. For instance, the operating system provides various basic operational processes for the operator unit. The programs include various user programs so that a user can interact with the operator unit to perform various functions such as, but not limited to, viewing and manipulating data as well as sending messages as the case may be.

[00102] The memory module 640 may further include one or more databases for storing information relating to, for example, biological and/or patient data or standards or controls. In some embodiments, one database may be used to store this information. In some other embodiments, one database may be used to store, for example, information related to group buy offers (e.g., a group buy offer database) and another database may be used to store, for example, information related to group buy participants (e.g., a group buy participant database). [00103] The interface module 660 may be any interface that enables the promotion system to communicate with other devices and systems. In some embodiments, the interface module 660 can include at least one of a serial port, a parallel port or a USB port. The interface module 660 may also include at least one of an Internet, Local Area Network (LAN), Ethernet, Firewire, modem or digital subscriber line connection. Various combinations of these elements may be incorporated within the interface module 660.

[00104] For example, the interface module 660 may receive input from various input devices, such as a mouse, a keyboard, a touch screen, a thumbwheel, a track-pad, a track-ball, a card- reader, voice recognition software and the like depending on the requirements and implementation of the system.

[00105] Each of the computing devices may be any networked device operable to connect to the network. A networked device is a device capable of communicating with other devices through a network such as the network. A network device may couple to the net-work through a wired or wireless connection.

[00106] Fig. 3C shows computer 200 embedded in detector 100. The computer 200 embedded in detector 100 is in electronic communication with neurostimulator 120, the computer 200 being configured to receive eye movement feature data, to detect the pre-determined eye movement signature, and to instruct the neurostimulator 120 to generate, after a lag period, electrical signals to electrode 130 in response to the detected pre-determined eye movement signature

[00107] Fig. 3D shows computer 300 embedded in neurostimulator 120. The computer 300 embedded in neurostimulator 120 is in electronic communication with detector 100, the computer 300 being configured to receive eye movement feature data, to detect the pre-determined eye movement signature, and to instruct the neurostimulator 120 to generate, after a lag period, electrical signals to electrode 130 in response to the detected pre-determined eye movement signature.

[00108] Fig. 3E shows computer 400 embedded in detector 100, and computer 500 embedded in neurostimulator 120. The detector 100 or the computer 400 embedded in detector 100 is in electronic communication with neurostimulator 120, or with computer 500 in neurostimulator 120, the computer 400 or 500 being configured to receive eye movement feature data, to detect the pre-determined eye movement signature, and to instruct the neurostimulator 120 to generate, after a lag period, electrical signals to electrode 130 in response to the detected pre-determined eye movement signature. [00109] Fig. 3F shows computer 199 is external to detector 100 and neurostimulator 120. The computer 199 is in electronic communication with neurostimulator 120, the computer 199 being configured to receive eye movement feature data, to detect the pre-determined eye movement signature, and to instruct the neurostimulator 120 to generate, after a lag period, electrical signals to electrode 130 in response to the detected pre-determined eye movement signature.

[00110] In an embodiment, the system describe herein comprises a computer, a detector, and a neurostimulator. In an embodiment, the computer 200, 400 or 600 or is embedded in the detector 100. In an embodiment, the computer 200, 500, or 600 is embedded in the neurostimulator 120. In an embodiment, the computer 200, 400, 500, or 600 is embedded in the detector 100 and the neurostimulator 120. In an embodiment, the computer 199 or 600 is external to the detector 100 and the neurostimulator 120. In an embodiment, the computer described herein comprises a processor module, a memory module and an interface module. In an embodiment, the computer is connected to or further comprises a recording system and/or an amplifier described herein. In an embodiment, the computer measures ERP.

[00111] The detector can be a video-based eye tracker, for example an EyeLink 1000 eye tracking device or other eye tracking device described herein. The detector should be able to detect eye movements within at least 30 ms of eye actually moving occurring with >90% accuracy. This would enable stimulation if ERP peak/trough occurs after that time. Sampling frequency is at least 120 Hz, and preferably 500Hz or above.

[00112] In an embodiment, the detector is an eye tracking device, optionally a wearable eye tracking device, an electrooculogram, an electromyogram, and combinations thereof, or a video- based eye tracker, optionally EyeLink 1000 eye tracking device. In another embodiment, the detector is a camera configured to track pupillary responses. In an embodiment, the detector detects eye movements within at least 30 ms of eye actually moving occurring with >90% accuracy. In an embodiment, sampling frequency is at least 120 Hz, and preferably 500Hz or above.

[00113] The neurostimulator is a device that provides electrical stimulation to nerves. They can be any controllable unit that provides electric currents, for example a stimulation generator that generates electrical stimulation to an electrode. The neurostimulator can be a pulse generator that generates neurostimulation pulses. The neurostimulator may house a battery that powers the device. The neurostimulator can also be an external neurostimulator, a Grass Instruments neurostimulator, an implantable neurostimulator, or Tucker Davis stimulator. The stimulator can also be a voltage stimulator. The stimulator can be an implantable device for example Neuropace that stores EEG data in stimulator itself. In an embodiment, the neurostimulator is a stimulation generator, a voltage stimulator, a pulse generator, external neurostimulator, a Grass Instruments neurostimulator, an implantable neurostimulator, Tucker Davis stimulator, a voltage stimulator, an implantable stimulator, optionally Neuropace.

[00114] If the neurostimulator is not recording the ERP and detecting it then it is coupled to a recording device such as a computer.

[00115] The computer may include at least a processor, memory and interface, and may be an electronic tablet device, a personal computer, workstation, server, portable computer, mobile device, personal digital assistant, laptop, smart phone, WAP phone, an interactive television, video display terminals, gaming consoles, and portable electronic devices or any combination of these. In an embodiment, the computer is a processor, memory and interface, an electronic tablet device, a personal computer, workstation, server, portable computer, mobile device, personal digital assistant, laptop, smart phone, WAP phone, an interactive television, video display terminals, gaming consoles, and portable electronic devices or combination thereof. The computer is able to instruct for amplifying and recording signals and measuring an ERP. Such a computer can be connected to an amplifier such as Neuralynx to record eye detected movements and calibrate timings of an ERP. The computer can communicate and is capable of connecting with a detector, e.g. an eye tracking device, as well as to detect eye movements from the detector, and trigger the neurostimulator based on recorded ERP. In an embodiment, the computer is connected to an amplifier, optionally a Neuralynx amplifier. In an embodiment, the computer amplify and record signals and measure ERP. In an embodiment, the computer communicates or is connected to a recording system, optionally a headset/headbox, and/or an amplifier. The skilled person can readily recognize a suitable amplifier to connect with the system describe herein.

[00116] The computer may have one or more memory tasks including tasks described herein stored therein.

[00117] The system can be used in any of the methods described herein and comprise one or more of the components described herein including in the Examples.

[00118] In one embodiment, the system is for performing a method or use described herein.

[00119] In one embodiment, the neurostimulator is instructed by the computer to generate electrical signals after a lag period. In one embodiment, the neurostimulator is configured to receive instructions to generate electrical signals after a lag period optionally following detection of an eye movement signature such as onset of a fixation.

[00120] In an embodiment, the at least one electrode delivers between 3 and 10 on/off pulse trains. In yet another embodiment, the at least one electrode delivers 3, 4, 5, 6, 7, 8, 9 or 10 on/off pulse trains.

[00121] In an embodiment, the duration of each pulse delivered by the at least one electrode is less than about 1000 microseconds, less than about 500 microseconds, less than about 400 microseconds, less than about 300 microseconds, less than about 200 microseconds or less than about 100 microseconds.

[00122] In one embodiment, the at least one electrode delivers 1 to 5 pulses of 100 microseconds each. In another embodiment, the at least one electrode delivers 5 pulses of 100 microseconds each.

[00123] In an embodiment, the stimulating current intensity delivered by the at least one electrode is less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA or less than about 4 mA.

[00124] The stimulation by an electrode can impact brain structures outside of the stimulation location. Therefore, intensity first elicits an effect measured through a significant cortico-cortical evoked potential (CCEP) in brain structures outside of the stimulation location. The determination of significance of such a response/CCEP is undertaken by the same bootstrapping method as described herein for the eye movement response event-related potential (ERP). For hippocampal stimulation, this functionally relevant or significant CCEP is detected in other brain structures of which an electrode has been implanted in the patient. The bootstrapping method creates a distribution of possible ERP values. A functionally relevant CCEP is where the measured CCEP is significant from that distribution of ERP values. Anything above 97.5% of maximum values or below 97.5% of minimum values are considered significant, and therefore functionally relevant. In an embodiment, the stimulating current intensity is determined by functionally relevant CCEP when stimulating the hippocampus as recorded in cortical locations or in the hippocampus when stimulating structure of afferent pathways. The structures of afferent pathways to hippocampus include parahippocampus, entorhinal cortex, prefrontal cortex, or amygdala. In an embodiment, the structure of afferent pathways is parahippocampus, entorhinal cortex, prefrontal cortex, or amygdala. [00125] For the other memory related brain structure stimulation we are interested when such an intensity elicits significant response in hippocampus. This intensity determination is done by delivering stimulation at a pseudo saccade rhythm and rate based on the participants own saccade rate during the calibration/demonstration task. The pseudosaccade rhythm is the averaged saccade rhythm during the task. For example, if 3 saccades per second on average is determined, stimulation is then delivered three times per second to get stimulation intensity when stimulating based on the eye movement.

[00126] In one embodiment, the computer comprises at least one of a processor or programmable computer configured for performing a method or use as described herein. In one embodiment the computer receives input data comprising eye movement feature data, or detects the pre-determined eye movement signature, and generates output information comprising stimulating current intensity or instructs the neurostimulator to generate, after a lag period, electrical signal to the least one electrode in response to the detected pre-determined eye movement signature. In one embodiment, the system comprises an eye tracking device, optionally a wearable eye tracking device, an electrooculogram, an electromyogram, and combinations thereof, in communication with a processor or programmable computer as described herein.

[00127] The embodiments of the systems and methods described herein may be implemented in hardware or software, or a combination of both. These embodiments may be implemented in computer programs executed on programmable computers, each computer including at least one processor, a data storage system (including volatile memory or non-volatile memory or other data storage elements or a combination thereof), and at least one communication interface. For example and without limitation, the programmable computers (also referred to as computing devices) may be a server, network appliance, embedded device, computer expansion module, a personal computer, laptop, personal data assistant, cellular telephone, smart-phone device, tablet computer, a wireless device or any other computing device capable of being configured to carry out the methods described herein.

[00128] In some embodiments, the communication interface may be a network communication interface. In embodiments in which elements are combined, the communication interface may be a software communication interface, such as those for inter-process communication (IPC). In still other embodiments, there may be a combination of communication interfaces implemented as hardware, software, and combination thereof. [00129] Program code may be applied to input data to perform the functions described herein and to generate output information. The output information is applied to one or more output devices, in known fashion.

[00130] Each program may be implemented in a high level procedural or object oriented programming and/or scripting language, or both, to communicate with a computer system. However, the programs may be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language. Each such computer program may be stored on a storage media or a device (e.g. ROM, magnetic disk, optical disc) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. Embodiments of the system may also be considered to be implemented as a non-transitory computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

[00131] Furthermore, the system, processes and methods of the described embodiments are capable of being distributed in a computer program product comprising a computer readable medium that bears computer usable instructions for one or more processors. The medium may be provided in various forms, including one or more diskettes, compact disks, tapes, chips, wireline transmissions, satellite transmissions, internet transmission or downloadings, magnetic and electronic storage media, digital and analog signals, and the like. The computer useable instructions may also be in various forms, including compiled and non-compiled code.

[00132] Also provided are systems and methods described herein for use to improve memory of a subject suffers from memory impairment caused by dementia, Alzheimer's disease, epilepsy, or aging. In an embodiment, the systems and methods described herein are for use to improve memory of a subject diagnosed with dementia, Alzheimer's disease or epilepsy. In an embodiment, the subject suffers from (e.g. has been diagnosed with) memory impairment, optionally dementia or Alzheimer's disease. In an embodiment, the subject suffers from dementia. In an embodiment, the subject suffers from Alzheimer's disease. In another embodiment, the subject suffers from neurological disorder, for example from epilepsy. In an embodiment, the subject suffers from seizures.

[00133] The present invention is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Examples

Example 1 : Memory task framework

[00134] Patients in the epilepsy monitoring unit with implanted electrodes in their hippocampus performed a memory task to search for one of two targets in a scene and were questioned about scenes and the targets in them (Fig. 1A). Subjects were implanted with recording electrodes and confirmed via MRI-CT scan to have an electrode within the hippocampus (Fig. 1 B). Implementation of surgical stereo depth electrodes was found to usually enable more than two contacts to be implanted within multiple portions of the hippocampus. The task framework is described.

[00135] The task is an explicit memory task (requiring awareness at retrieval). Free eye movements can be indicative of memory and hippocampal activation. Subjects search freely through scenes, moving their eyes between fixation points, known as saccades. Each scene is shown for four seconds in 40 scene blocks and is subsequently tested in memory with 40 novel scenes randomly interspersed.

[00136] To ensure numerous saccades, embedded targets were added in the scenes that subjects must search. These saccades enable to find events for an eye movement related event related potential (ERP) where the appropriate timings of peak and trough can be used for stimulation. Targets are embedded in the scenes using an objective structure similarity metric [81], a more stable unique image quality index model [82], which has been used to camouflage images in scenes incurring longer time to detection and more saccades in scene than other embedding algorithms [83]. The designed task incorporates many scenes in a short period of time, incurs many saccadic eye movements and fixations. The task has undergone a number of iterations to enhance its success in assessing memory in a short period of time including optimizing stimuli (scenes and targets) and scene time (see Table 1).

Table 1

Total number of Excluded

Task iteration Type of Subject

subjects subjects

Optimizing Targets Healthy Controls 17 2

6 (2 iEEG and 4

Testing Task In Patient iEEG and Scalp EEG 1

Scalp EEG) No Closed Loop iEEG 6 0

Closed Loop Stimulation iEEG 6 0

[00137] Closed loop stimulation refers to the method described herein. No closed loop refers to just looking at the event related potentials.

[00138] It was found that a reset in rhythms can be induced from fixation or saccade onset (Fig. 2A). The subsequent peak and trough timing can accordingly be used for stimulation. A bootstrap method with 3000 iterations [84] was used to show the significance of peaks of the evoked response, while the phase concentration using Rayleigh statistic and false discovery rate (FDR) correction (p<0.001) showed at which frequencies phase is concentrated due to eye movement event and thus suggest a reset of activity in the theta band.

[00139] These targets can also be tested in the retrieval trials which is an added associative memory component also considered to be dependent on hippocampus [44]. In retrieval, subjects are presented with yes/no responses to indicate memory and association of target to scene rather than being given a forced choice with both targets as a yes/no cue is thought to be more hippocampal reliant than forced choice recognition [55]. Memory performance is evaluated based on corrected recognition and d' a sensitivity metric that takes into account both hit rates and false alarms. This task is different than other known intracranial studies as it does not implicitly measure memory as an optimal path to store, [58], [8] incorporates free viewing as opposed to word recall [26], and has room for memory performance modulation Sternberg probe >95% accuracy [27].

Example 2: Calibration session

[00140] To obtain the evoked response and appropriate timings, subjects perform a calibration session searching through scenes. Stimulations are timed to peak and trough based on the eye movements in a recognition memory task. To calibrate intensity of stimulation, electrodes from the surrounding areas and their response to stimulation are measured.

Determination of stimulation timing

[00141] Obtaining stimulation timings from the hippocampal electrodes was done through a calibration session, in which saccadic eye movements were recorded during a sample viewing of the memory task (described in Example 1) to detect the evoked response and find individual specific timings. (Fig. 2B and 2C). [00142] To find event related potentials, fixation events were averaged to find peak and trough timings of significance which ranged from 28-215ms. To detect these timings, an eye tracking device such as a video-based eye tracker (for example, the EyeLink 1000 eye tracking device) was used as it can detect eye movement fixation events within 32 ms of onset.

[00143] Stimulation was carried out on peak and trough since it was hypothesized that this may ameliorate the timed stimulations for at least two reasons: 1) Electrode location can switch polarity of the signal and 2) For some locations of Hippocampus, peak may be beneficial to encoding while trough may be beneficial to recall and vice versa.

Determination of stimulation intensity

[00144] To ensure appropriate stimulation parameters cortico-cortical evoked potentials (CCEP) were used, to ensure the stimulation caused an effect downstream of the stimulation. Intensity did not exceed 8mA [11], and evoked a response at less than 3 mA [26]. Intensity is calculated using the five pulses at 0.1 ms pulse width with an inter trial stimulus interval similar to average saccade rate. This saccade rate was obtained through the scene search.

[00145] To obtain a relevant response downstream from the stimulation, 1 to 5 pulses, 0.1 ms pulse width were used at an average fixation rate (e.g. 2-3 per second on average) to mimic the stimulation during the experiment. Increments of 0.5 mA were used until a significant response was obtained in the surrounding electrodes. These parameters are used in the same searching task with new scenes shuffling stimulation timing to isolate stimulation as the independent variable for subsequent memory performance analysis.

[00146] 60 pulses of stimulation were required on average to induce a visible change at approximately 8mA [41]. Also, to determine the stimulation parameters to be used, the after- discharge threshold was first determined. Once the after-discharge threshold was established the current was reduced by 1-2 mA to prevent occurrence of after-discharge.

[00147] It was found that the average peak time after reset ranges from 28 ms to greater than 100 ms. An eye tracker, such as a video-based eye tracker, that is able to detect for example at least 80% or at least 90% of the timed events can be used, such as for example the EyeLink 1000 eye tracking device.

[00148] Scenes were shuffled. An example of scene shuffling is provided in Table 2. Since there is a tendency to have preferential memory for initial scenes or recent scenes, shuffling through possible combinations mitigates effects of scene preference, targets in scene, or recency effect. Table 2

[00149] Some subjects may not exhibit reset. Mitigation strategies can include using the median time of patient population peak and troughs if a subject did not exhibit reset. As well, if timing was less than 32ms, stimulation occurred only within a certain phase difference of the detected peak and trough.

[00150] A block diagram of the methodology, detailing stimulation task setup with patient and incorporating stimulation, is shown in Fig. 3G. The subject's table incorporates a laptop and SMI iView RED-m eye tracker enabling the viewing of memory task and recording of eye movements for real time detection of events and further offline analysis. Real time events are then sent through parallel port connection Cart One (Synchronizing data collection and events) and in stimulation session Cart Two (triggering stimulation). Cart one is the Neuralynx Headbox where subjects' brain signals are connected from electrodes and recorded at 16 kHz sampling rate for each electrode. Cart Two is a Grass neurostimulator that triggers bi-polar stimulation through the electrodes which are connected to the Neuralynx Headbox. Each trigger sends a biphasic pulse of stimulation intensity which can be set to range from 0.5 to 17.5 mA and pulse width can be set between 100-500 microseconds.

[00151] A specific implementation of the calibration session is described in Example 3.

Example 3: Calibration Session Protocol

[00152] 1. Connect patient to device (see the block diagram of Fig. 3G):

a. Transfer electrodes to research recording system

b. Set up memory task on laptop on patient table

c. Calibrate eye tracker to get eye tracking during scenes d. Explain behavioural paradigm

[00153] 2. Calibrate Reset and Event Related Potential for peak and trough stimulation timings: a. Run memory search task with 40 scenes, 4 seconds each, assuming minimum of 1 fixation in the 4 seconds (usually rate of fixations is a minimum 2/sec), minimum 160 fixations. Subject with <160 fixations has shown significant evoked response. This task is designed to get the subject used to a memory task where scene recognition and targets in scene are tested and to find timings for the evoked fixation response.

b. Find an electrode within the hippocampus which exhibits ERP (e.g. significant peaks and troughs based on bootstrapping), and if multiple electrodes in the hippocampus optionally select the one with stronger phase locking in theta band. The metric used for phase locking detection can be for example an observation independent metric inter trial phase coherence (ITPC) transformed using Rayleigh's statistic.

For example, the normal ITPC or average vector of angles for an event at 200ms would be 0.6 a highly synchronous event and larger ITPC, while at 800ms the angles of the event are dispersed and therefore a low value 0.091. To take into account variances in number of events, this value is squared and multiplied by the total fixations, known as ITPCz. The highest value for a hippocampal electrode in this case in the theta to alpha band region (3-15 Hz) during the post fixation period will be used. If no significant band is found: the average of significant peak/trough times of collected subjects as stimulation time after fixation is used. Times of first peak/trough have currently ranged from 28ms to 215ms. An example of evoked potential responses (ERP) in image and fixation onset is shown in Fig. 4C and 4A, respectively. Anything above or below the horizontal thresholds is considered significant in the individual subject ERP. These peaks and troughs of the signal would be the example used if no significant band is found.

If the delay for detected fixation is greater than the time of the peak/trough, (i.e. the EyeLink eye tracking device can detect with 32ms delay from fixation onset, but the peak may be for example at 28 ms): If within 45 degrees or optionally 90 degrees of that trough and peak signal, the stimulation can take place immediately, otherwise wait for the second peak or trough of the signal, even if not significant.

[00154] 3. Calibrate Intensity using electrode selected from step 2:

a) Three options exist for intensity calibration. 1) stimulate until after discharge is exhibited similar to previous literature or up to maximum intensity 8 mA.

2) To ensure the stimulus is actually causing downstream effect, cortical-cortico evoked potentials (CCEP) will be measured from other recording electrodes. 60 pulses of stimulation were required on average to induce a visible change at approximately 8mA.

3) Use 3-5 stimulation pulses in accordance with a high frequency burst of stimulation between 50 to 5000 Hz. These will be safe biphasic pulses ranging from 100-1000 microseconds in length for each biphasic pulse. This would enable the stimulation to land on the appropriate peak or trough (e.g., a pulse stimulation width of about 100 microseconds and a frequency of about 50 Hz would generate a high frequency burst stimulation akin to theta burst stimulation). The setting used in this example was: bursts of 5 stimuli with inter trial stimulus of period approximating saccade period with interburst interval of 2 seconds (to give the brain a rest). 12 of these = 60 stimuli. CCEP were computed at different current levels to see if CCEP were evoked in other contacts (using current steps of 0.5mA starting at 0.5 mA). This provided the minimal current that gave significant CCEP, or 1 mA less than the current that evokes after-discharge. b) Example stimulation intensities are shown in Fig. 5A and 5B. (During testing, the stimulation intensity used was 3mA) Fig. 5A and 5B show that a biphasic pulse stimulation of 5 pulses at 100 microseconds could provide desired oscillation. Stimulation evoked response in surrounding electrodes can be visually seen as well as averaged to see evoked response. The CCEP can be also bootstrapped reversing polarity randomly for trials around its onset after removing stimulation artifact to see if the peaks and troughs are significant. Once intensity reach where evoked response is evident, than stimulation intensity is be set.

Example 4: Contingent stimulation

Subjects

[00155] The subjects included were temporal lobe epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring. All subjects had previously undergone surgical insertion of intracranial depth electrodes within the hippocampus, amygdala, parahippocampus, or prefrontal cortex.

Methods [00156] Once the timings and intensity as described in Example 3 were established, the memory task was carried out, with relevant timed electrical stimulation to visual stimulus presentation and eye movements focused on timings based on calibration session and phase reset. The visual search task is a non-invasive task and is performed on a computer screen. The task involves looking at a computer laptop and reading words, looking at pictures, viewing scenes and some involve a simple computer game. An iView RED-m eye tracker is used to track eye movement. Each study session lasts between 1 and 2 hours with each trial within lasting 10-30 minutes.

[00157] In the case of stimulating the anterior cingulate cortex (i.e. prefrontal cortex), determination of intensity involves stimulating the anterior cingulate cortex at saccade rate and noting when such intensity was significant in the hippocampus. Stimulating location in timing is similar to saccade onset. This is to calibrate intensity of deliver stimulation in a rhythmic fashion at an individual's eye movement rate, analyze response and determine if significant. Once the intensity that elicits a significant response in the hippocampus is determined, this intensity is used for stimulating the anterior cingulate cortex. There is a delay of onset of significance between stimulation at the anterior cingulate cortex and when such intensity is observed in the hippocampus. To account for this, if possible, this delay can be subtracted from stimulation timing for peak and trough.

[00158] To ensure the potentiation is possible, stimulation was carried out using 5 pulses, each having a 0.1 ms pulse width for bi-phasic pulses. The stimulation intensity was 3 mA.

[00159] During the memory task, all 40 searched scenes (as described in Examples 2 and 3) and 40 novel scenes are shown in random order. The subject is asked whether any scene was shown before. If the subject answers yes, he is asked about the target embedded in the scene. Analysis of both scene recognition and target memory based on the stimulation type is carried out, as shown in Fig. 6. Four behavioural sections with contingent stimulation are as follows: Stimulation Type 1 corresponds to peak stimulation; Stimulation Type 2 corresponds to trough stimulation, Stimulation Type 3 corresponds to Random Stimulation (either yoked from other eye tracker or Gaussian timing based off of fixation); and Stimulation Type 4 corresponds to no stimulation (sham stimulation).

[00160] The test session is similar to the calibration session. The scenes are shuffled to reduce recent memory effects.

Results [00161] As shown in Fig. 6, stimulation using a closed loop system was found to be feasible. Scene recognition was analyzed based on the stimulation type. Stimulation on peak and trough (stimulation type 1 and 2, respectively) created scene recognition performance of 80 and 90%, respectively. Random stimulation induced 70% scene recognition and scenes that lacked stimulation had 75% performance. Testing was performed on over 80 scenes (e.g. 20 scenes per stimulation type), in orders 1 , 2, 3, 4 and 4, 3, 2, 1 for stimulation in two separate tests over two testing times. Fig. 6B shows results from stimulation of anterior cingulate cortex, which is part of the prefrontal cortex.

[00162] While this disclosure has been particularly shown and described with reference to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[00163] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

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Claims

We claim:

1. A method of improving memory in a subject, comprising:

tracking eye movement of the subject;

detecting a pre-determined eye movement signature associated with an event-related potential (ERP), the pre-determined eye movement signature optionally being determined during a prior calibration event; and

delivering, after a lag period optionally determined during the prior calibration event, an electrical stimulation to at least a portion of the subject's hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, and/or temporal cortex via at least one implanted electrode, to improve the subject's memory.

2. The method of claim 1 or any claim herein, wherein the electrical stimulation is to at least a portion of the subject's hippocampus, entorhinal cortex, or prefrontal cortex and/or the at least one implanted electrode is in the subject's hippocampus, entorhinal cortex, and/or prefrontal cortex.

3. The method of claim 1 or 2 or any claim herein, wherein the electrical stimulation is to at least a portion of the subject's hippocampus and/or the at least one implanted electrode is in the subject's hippocampus.

4. The method of claim 1 or 2 or any claim herein, wherein the electrical stimulation is to at least a portion of the subject's entorhinal cortex and/or the at least one implanted electrode is in the subject's entorhinal cortex.

5. The method of claim 1 or 2 or any claim herein, wherein the electrical stimulation is to at least a portion of the subject's prefrontal cortex and/or the at least one implanted electrode is in the subject's prefrontal cortex.

6. The method of any one of claims 1 to 5 or any claim herein, wherein the prior calibration event comprises:

measuring a calibration related event-related potential in the subject in response to a visual search task, preferably a memory task; and

determining association of the calibration related event-related potential with one or more eye movement features selected from onset of saccade, onset of fixation, saccadic duration and fixation duration, the one or more eye movement features forming the eye movement signature.

7. The method of claim 6 or any claim herein, wherein the lag period is determined during the prior calibration event and comprises measuring the time period between onset of the predetermined eye movement signature and onset of the calibration related event-related potential, optionally peak, trough or midpoint timing or other selected timepoint.

8. The method of any one of claims 1 to 7 or any claim herein, wherein the lag period is about 20 ms to about 300 ms.

9. The method of any one of claims 1 to 8 or any claim herein, wherein the eye movement of the subject is tracked using an eye tracking device, optionally a wearable eye tracking device, an electrooculogram, an electromyogram, and combinations thereof, or a video-based eye tracker, optionally EyeLink 1000 eye tracking device.

10. The method of any one of claims 1 to 9 or any claim herein, wherein the pre-determined eye movement signature is detected by an eye tracking device comprising an internal processor or by a computer configured to receive eye movement feature data and to detect the predetermined eye movement signature.

1 1. The method of any one of claims 1 to 10 or any claim herein, wherein the at least one electrode delivers the electrical stimulation as a biphasic pulse stimulation.

12. The method of claim 11 or any claim herein, wherein the biphasic pulse stimulation consists of 3, 4, 5, 6, 7, 8, 9 or 10 on/off pulse trains.

13. The method of claim 1 1 or 12 or any claim herein, wherein the duration of each pulse is less than about 1000 microseconds, less than about 500 microseconds, less than about 400 microseconds, less than about 300 microseconds, less than about 200 microseconds or less than about 100 microseconds.

14. The method of claim 1 1 or any claim herein, wherein the at least one electrode delivers 1 to 5 pulses of 100 microseconds each.

15. The method of any one of claims 1 to 14 or any claim herein, wherein the electrical stimulation current intensity is determined during the prior calibration event and comprises: applying to the at least one electrode electrical stimulation pulses, optionally with a stimulating current intensity of 8 mA or less, sufficient to induce evoked potentials, optionally cortico- cortical evoked potentials; and

optionally determining an after-discharge threshold in the subject and reducing the stimulating current intensity by about 1 mA or about 2 mA to obtain the stimulating current intensity.

16. The method of claim 15 or any claim herein, wherein the stimulating current intensity is less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA or less than about 4 mA, less than about 3 mA, less than about 2 mA, less than about 1 mA or about 0.5 mA.

17. The method of any one of claims 1 to 16 or any claim herein, wherein the subject suffers from memory impairment, optionally diagnosed with dementia or Alzheimer's disease.

18. The method of any one of claims 1 to 16 or any claim herein, wherein the subject suffers from epilepsy.

19. The method of any one of claims 1 to 18 or any claim herein, wherein the method is performed in an in-patient context or in an out-patient context.

20. The method of any one of claims 1 to 19 or any claim herein, comprising implanting in the subject's hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex the at least one electrode prior to tracking the eye movement of the subject.

21. The method of claim 20 or any claim herein, wherein the implanting of the at least one electrode is in the subject's hippocampus.

22. The method of claim 20 or any claim herein, wherein the implanting of the at least one electrode is in the subject's prefrontal cortex.

23. The method of claim 20 or any claim herein, wherein the implanting of the at least one electrode is in the subject's temporal cortex.

24. A system for contingent neurostimulation based on a detected pre-determined eye movement signature in a subject having at least one electrode implanted in the hippocampus, amygdala, parahippocampus, entorhinal cortex, prefrontal cortex, or temporal cortex configurable to deliver intracranial stimulation, comprising:

a detector for detecting eye movement features;

a neurostimulator for generating electrical signals to the at least one electrode; and a computer in electronic communication with the detector and the neurostimulator, the computer being configured to receive eye movement feature data, to detect the predetermined eye movement signature, and to instruct the neurostimulator to generate, after a lag period, electrical signals to the at least one electrode in response to the detected predetermined eye movement signature.

25. The system of claim 24 or any claim herein, wherein the detector is an eye tracking device, optionally a wearable eye tracking device, an electrooculogram, an electromyogram, and combinations thereof, a video-based eye tracker, optionally EyeLink 1000 eye tracking device.

26. The system of claim 24 or any claim herein, wherein the neurostimulator is a stimulation generator, a pulse generator, external neurostimulator, a Grass Instruments neurostimulator, an implantable neurostimulator, Tucker Davis stimulator, a voltage stimulator, an implantable stimulator, optionally Neuropace.

27. The system of claim 24 or any claim herein, wherein the computer is a processor, memory and interface, an electronic tablet device, a personal computer, workstation, server, portable computer, mobile device, personal digital assistant, laptop, smart phone, WAP phone, an interactive television, video display terminals, gaming consoles, and portable electronic devices or combination thereof.

28. The system of claim 24 or any claim herein, wherein electrode is a bi-polar electrode or a monopolar electrode.

29. The system of claim 24 or any claim herein, further comprises a recording system and an amplifier.

30. The system of claim 29 or any claim herein, wherein the recording system is an headset.

31. The system of claim 30 of any claim herein, wherein the headset is a NeuraLynx Headbox, a Neuroscan Headbox, or an Xltek Natus clinical EEG system.

32. The system of claim 31 or any claim herein, wherein the amplifier is a NeuraLynx amplifier.

33. The system of any one of claims 24 to 32 or any claim herein, wherein the lag period is about 20 ms to about 300 ms.

34. The system of any one of claims 24 to 33 or any claim herein, wherein the neurostimulator delivers electrical biphasic pulse stimulation to the at least one electrode.

35. The system of claim 34 or any claim herein, wherein the at least one electrode delivers 3, 4, 5, 6, 7, 8, 9 or 10 on/off pulse trains.

36. The system of claim 34 or 35 or any claim herein, wherein the duration of each pulse delivered by the at least one electrode is less than about 1000 microseconds, less than about 500 microseconds, less than about 400 microseconds, less than about 300 microseconds, less than about 200 microseconds or less than about 100 microseconds.

37. The system of claim 34 or any claim herein, wherein the at least one electrode delivers between 1 and 5 pulses of 100 microseconds each.

38. The system of any one of claims 24 to 37 or any claim herein, wherein the stimulating current intensity delivered by the at least one electrode is less than about 8 mA, less than about 7 mA, less than about 6 mA, less than about 5 mA or less than about 4 mA.

39. The system of any one of claims 24 to 38 or any claim herein, wherein the stimulating current intensity is determined by functionally relevant cortico-cortical evoked potentials when stimulating the hippocampus as recorded in cortical locations or in the hippocampus when stimulating structure of afferent pathways, wherein the structure of afferent pathways is parahippocampus or entorhinal cortex.

40. The system of any one of claims 24 to 39 or any claim herein, wherein the system is for use in a subject that suffers from memory impairment, optionally diagnosed with dementia or Alzheimer's disease.

41. The system of claim 40 or any claim herein, wherein the system is for use in a subject suffers from/diagnosed with dementia.

42. The system of claim 40 or any claim herein, wherein the system is for use in a subject suffers from Alzheimer's disease.

43. The system of any one of claims 24 to 42 or any claim herein, wherein the system is for use in a subject suffers from epilepsy.