Treatment of neuropsychiatric disorders

Abstract

In various aspects and embodiments, the present disclosure provides a method for treating a neuropsychiatric disorder in a subject undergoing a treatment or protocol that induces plasticity.

Description

[0001] TREATMENT OF NEUROPSYCHIATRIC DISORDERS

[0002] PRIORITY

[0003] This Application claims priority to and the benefit of US Provisional Application No. 63 / 624,598, filed January 24, 2024, which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] Neural plasticity is a mechanism of neuronal adaptation that is disrupted in neuropsychiatric conditions such as but not limited to Major Depressive Disorder (MDD) depression. Changes in neural dynamics, connectivity and neural plasticity (as well as metaplasticity) are induced by stress and other stimuli, which play a role in the onset and development of neuropsychiatric conditions. Pathologies such as MDD are increasingly seen as resulting from dysfunction in plasticity. The nuanced interaction between the brain’s neurophysiology and the emergent brain activity underlies the pathophysiology of mood disorders, often resulting in a persistent and maladaptive rigidity in cognitive and emotional processes. Such changes to the brain’s neurophysiology can be explained through the CANAL framework whereby pathological plasticity, often caused by a traumatic event, asserts itself and dominates brain activity, driving a deepening minimum in the dynamical landscape.

[0006] While interventions, including psychedelics, have been observed to induce neural plasticity, detailed mechanisms of neural plasticity are not well understood. Methods and systems are needed for better harnessing neural plasticity for therapeutic purposes.

[0007] DESCRIPTION OF THE FIGURES

[0008] FIG. 1 is an illustration of multiscale digital twin modeling: (a) Multiscale modeling of physics and physiology for the creation of whole-brain models; (b) data assimilation to personalize the model and use for optimization of therapy.

[0009] FIG. 2 illustrates therapy using a neurotwin model: (A) Autoencoders can be used to process subject data and project it into its latent space, where it can be clustered and patients stratified; (B) Personalization and optimization of the neurotwin model for a patient can be carried out in latent space, with optimization functions in this space; (C) The process for personalization and optimization of models. Personalization can start from an archetype, a model built using large amounts of data that represents a starting point. Data from different sources and types can be assimilated into the model using a loss function in latent space, where model -generated data and real subject data are projected. Similarly, the brain stimulation optimization function can be designed in latent space, where a “healthy region” has been identified. Finally, model-based biomarkers can be used for the stratification of patients.

[0010] FIG. 3 is an illustration of the schematics for mapping out brain circuits involved in depression symptoms and using personalized stimulation in treatment.

[0011] FIG. 4 is an illustration of the schematics for mapping and treating epileptic networks.

[0012] DETAILED DESCRIPTION OF EMBODIMENTS

[0013] In various aspects and embodiments, the disclosure provides a method for treating a neuropsychiatric disorder in a subject undergoing a treatment or protocol that induces plasticity. In various embodiments the method comprises providing a transcranial electrical stimulation (tES) electrode montage designed to stimulate one or more brain networks affected by said treatment that induces plasticity, and applying the tES with the electrode montage.

[0014] According to this aspect, there is also provided a method for designing an electrode montage for a subject, the electrode montage designed to modify excitability of a plurality of target regions of the subject’s brain, such as target regions affected by the treatment that induces plasticity. According to this aspect, the electrode montage is selected for the subject using one or more computational head models (which may be personalized as described further below). In embodiments, the method comprises providing a head model and determining an electrode montage that stimulates the targets according to simulations using the model.

[0015] As used herein, the term “electrode montage” refers to a configuration of electrodes comprising the number, location, and type of electrodes, as well as electrode current. In the aspects and embodiments, the present disclosure improves the effectiveness of tES for neuromodulation for the treatment of neuropsychiatric disorders, such as MDD and others. The method leverages the complementary capabilities of tES and psychoactive substances, such as psychedelics or neuropl astogens (e.g., non-hallucinogenic psychoplastogens), to enhance neural plasticity. tES can instigate and leverage beneficial neural plasticity through gentle perturbations in brain activity over multiple sessions, thereby creating clinically relevant after-effects. However, its efficacy is often limited by the gradual nature of these induced changes. Psychoactive substances, such as psychedelics, enhance neural plasticity during both acute and post-acute phases, making them promising candidates for co-administration with tES. The synergistic action of tES and psychoactive substances can accelerate and intensify neural plasticity-mediated changes in target brain networks, thereby offering a potentiated clinical impact. This combined treatment protocol provides a new avenue for rapidly and sustainably modifying neural circuits, thus offering enhanced therapeutic outcomes.

[0016] The underlying mechanisms governing therapeutic interventions for MDD and other neuropsychiatric disorders, as well as their possible synergistic effects if used in combination, are yet to be fully explored. In particular, while non-invasive brain stimulation can modify brain dynamics and elicit plastic effects, psychedelics may further enhance circuital effects by boosting plasticity and increasing brain dynamics complexity, rendering the system more receptive and malleable to stimulation. In embodiments, the present disclosure provides for the development of whole-brain computational models for diagnosis and personalization of treatment. The models are personalized by assimilating structural and functional neuroimaging data (e.g., anatomical and diffusion MRI, fMRI, EEG, etc.) and are designed to reflect the pathology of the patient with sufficient detail for developing personalized, optimized treatments, which can include both brain stimulation (e.g., tES) and pharmacological interventions.

[0017] In some embodiments, the treatment or protocol that induces plasticity comprises therapy with a neuropl astogen agent. Numerous neuropl astogen agents (e.g., medications that induce plasticity) are known. In embodiments, the neuroplastogen comprises one or more of a psychedelic agent, an antidepressant, an anti-anxiety agent, a stimulant, an antipsychotic agent, and a mood stabilizer agent.

[0018] In embodiments, the neuropl astogen is a psychedelic agent. Psychedelics such as psilocybin and LSD act as agonists or partial agonists for serotonin 5 hydroxytryptamine 2A (5-HT2A) receptors, specifically targeting Layer V cortical pyramidal neurons. These drugs can cause a swift reconfiguration of neural dynamics. In embodiments, the psychedelic is selected from one or more of ketamine, 3,4-methylenedioxymethamphetamine (MDMA), scopolamine, esketamine, 2C-B, N,N-dimethyltryptamine (DMT), LSD, mescaline, psilocybin, psilocin, and ibogaine.

[0019] Psychedelics can induce acute and post-acute plastic effects. The acute plastic effects can be represented by rapid state-independent changes in connectivity parameters. This results in the flattening or de-weighting of the brain’s dynamical landscape. Such flattening allows for the exploration of a wider range of states, eventually creating new minima through state-dependent plasticity. As the psychedelic action fades out, the landscape gradually transitions towards its initial state but with lasting changes due to the alteration of dynamics during the acute state and acute enhanced plasticity. The post-acute plastic effects can be described as a “window of plasticity” characterized by a period of enhanced plasticity. In this post-acute phase, the landscape is more malleable to internal and external influences.

[0020] Psychedelics may mediate their effects by altering the balance between stability and plasticity in neural networks through metaplasticity. By acting on the serotonergic receptors, they trigger a cascade of neurochemical events, subsequently facilitating the reorganization of entrenched neural patterns. This alteration of the neural network during the acute phase can be interpreted as a rapid deformation or flattening of the landscape that allows the trapped state to escape and access more adaptive cognitive and emotional patterns. The acute phase is believed to be followed by an extended window of enhanced malleability of the landscape, otherwise known as a “window of plasticity,” where treatments such as tES can further influence dynamics and alter the pathological rigidity characteristic of various brain disorders.

[0021] 5-HT2A receptors are strongly expressed in the pyramidal neurons of the cortex along a steep anteroposterior gradient. When psychedelics bind to these receptors, they can lead to a gradual increase in the excitability of these pyramidal neurons — depolarizing them and making them more susceptible to excitatory inputs such as those associated with glutamate receptors — much as the gain knob in an amplifier. This increased excitability and susceptibility to inputs can lead to changes in the firing patterns of these neurons and alterations in the overall neural circuit activity.

[0022] This abrupt shift induced by psychedelics can be thought of as a transformation of the phase space’s geometry, allowing the neural state to explore new trajectories. Such changes in connectivity correspond to a flattening of the dynamical landscape or a destabilization of it. The instantaneous modification of the landscape is, however, ephemeral, gradually fading as the acute effects of the psychedelics wear off. The system returns to near its original geometrical configuration but with lasting influences brought about by the plastic changes resulting from the exploration of new trajectories in the acute phase. These residual changes are due to Hebbian plasticity that arises from the co-activation of neurons during the psychedelic acute stage.

[0023] Evidence suggests the existence of a post-acute phase following psychedelic exposure characterized by a period of enhanced plasticity. This phase can be interpreted as an extended window of malleability of the landscape, which could have profound implications for therapy. Such a window of plasticity has been related to increased neurogenesis and upregulation of Brain-Derived Neurotrophic Factor (BDNF). The activitydependent release of BDNF plays a crucial role in selectively strengthening active synapses while weakening inactive ones, a critical process for Hebbian-type plasticity. This means that in the post-acute period, the landscape would be more responsive to state changes (itself influenced by external factors), offering a potential mechanism for the long-lasting changes reported after psychedelic experiences. Such external influences can be environmental / sensory inputs, psychotherapy, or neuromodulatory invasive or non-invasive brain stimulation techniques such as tES.

[0024] In embodiments, the neuropl astogen that is employed is a Serotonin-Norepinephrin Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI). Non-limiting examples of SSRIs include citalopram (CELEXA), escital opram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine (LUVOX), fluvoxamine CR (LUVOX CR), paroxetine (PAXIL), paroxetine CR (PAXIL CR), and sertraline (ZOLOFT). Non-limiting examples of SNRIs include desvenlafaxine (PRISTIQ), duloxetine (CYMBALTA), venlafaxine (EFFEXOR), venlafaxine XR (EFFEXOR XR), milnacipran (SAVELLA), and levomilnacipran (FETZIMA).

[0025] In embodiments, the neuropl astogen is a tricyclic antidepressant (TCA), such as amitriptyline (ELAVIL), desipramine (NORPRAMIN), doxepine (SINEQUAN), Imipramine (TOFRANIL), nortriptyline (PAMELOR), amoxapine, clomipramine (ANAFRANIL), maprotiline (LUDIOMIL), trimipramine (SURMONTIL), and protriptyline (VIVACTIL).

[0026] In embodiments, the neuropl astogen is an atypical antidepressant, such as bupropion (WELLBUTRIN), mirtazapine (REMERON), nefazodone (SERZONE), trazodone (DESYREL, OLEPTRO), vilazodone (VIIBRYD), and vortioxetine (BRINTELLIX). In embodiments, the neuropl astogen is d-cycloserine.

[0027] In other embodiments, the neuropl astogen is a stimulant (e.g., an agonist of the cholinergic system), such as but not limited to nicotine, or comprises amphetamine (e.g., ADDERALL) or lisdexamfetamine.

[0028] In embodiments, the neuropl astogen is an antiepileptic such as memantine (EBIXIA, NEMDATINE, VALIOS), lamotrigine (LAMICTAL), diazepam (DIASTAT, VALIUM), levetiracetam (KEPPRA, DESITREND), and valproic acid (BELVO, DEPAKOTE, DYZANTIL, CONVULEX, SYONELL).

[0029] In these or other embodiments, the treatment or protocol that induces plasticity comprises (or further comprises) electroconvulsive therapy (ECT). ECT is a psychiatric treatment that induces brain plasticity, and which is used for treating severe depression, such as depression that is unresponsive to medications. ECT is also used for treatment of other neuropsychiatric conditions, such as bipolar disorder and schizophrenia. ECT exerts its effects by inducing controlled seizures.

[0030] In embodiments, the tES comprises transcranial direct current stimulation (tDCS) or transcranial Alternating Current Stimulation (tACS). tDCS is a type of transcranial stimulation where the stimulation currents are held constant. tDCS produces effects on neuronal excitability by increasing or decreasing the strength of the electric field. tDCS generates weak electrical currents and electric fields measured in volts per meter that modulate neuronal activity in the brain. The multichannel stimulation is designed to excite or inhibit one or more target areas via the component of the electrical field orthogonal to the cortical surface En, while providing other locations (non-target) an Enabsolute magnitude that is lower to limit the effects outside the target. tES can influence the dynamics of brain activity by altering the excitation / inhibition ratio of selected brain regions and modifying trajectories of brain activity. Given that human brain activity impacts structure via the plasticity mechanism, tES, if properly designed, can modify brain connectivity with therapeutic value. However, the effects of tES are at the same time limited by the plasticity state of the brain. For this reason, it is usually necessary to employ many tES sessions to achieve the desired outcome.

[0031] For tDCS a low, constant current stimulates specific areas of the brain. The current is delivered through electrodes placed on the scalp. For MDD, tDCS often targets the left dorsolateral prefrontal cortex (DLPFC). tDCS has shown promise in MDD (nodal tDCS of the left DLPFC) with the right orbitofrontal cathode, but variability in results across montages and studies leaves much room for improvement. For example, recent results in a large study using a traditional bipolar frontal montage in partially refractory patients have led to a disappointing result.

[0032] DLPFC is connected to the subgenual cingulate cortex (SGC) and other limbic regions. This connectivity suggests that modulating the activity of the DLPFC may have downstream effects on mood regulation and emotional processing through its connections with these limbic areas. Accordingly, a model-driven approach, based on computational models of brain dynamics, might be used to design optimized treatments. Understanding the etiology of MDD and the affected brain circuits can help inform more targeted and precise interventions, ultimately leading to improved patient outcomes.

[0033] In some embodiments, brain networks for stimulation are selected based on the distribution of receptors for a neuroplastogen agent. In embodiments, the receptors are serotonin, dopamine, or acetylcholine receptors or transporters. In embodiments, the receptors comprise one or more of NMD A Receptors, BDNF / TrkB pathway receptors, mTOR Pathway receptors, AMP AR, 5-HT receptors, GluR receptors, Sigma-1 Receptors, Sigma-2 Receptors, Cannabinoid Receptors, Opioid Receptors, and receptors of the cholinergic system. For example, in some embodiments, the receptors comprise 5-HT receptors, such as 5-HT2A receptors or 5-HT1A Receptors. Receptors for various neuroplastogen agents and their average distribution with the brain are known in the art. In embodiments, a target map can be created based on the receptor distribution in the brain, and the map used for determining an electrode montage for fES stimulation (in accordance with this disclosure). Brain regions with high distribution of receptors can be prioritized to impact target brain networks.

[0034] In embodiments, the brain networks for stimulation comprise cortical targets and / or subcortical targets. In embodiments, the electrode montage modifies the excitability of one or more of such targets without substantial excitation outside the targets.

[0035] In embodiments, the targets for stimulation can be defined by a physician or according to known information concerning a subject’s pathology, including but not limited to receptor distribution within the brain and locations of target brain networks. In embodiments, the target regions (such as affected networks) are defined by empirical data obtained from the subject or a representative cohort. In embodiments, the targets for tES are identified by one or more of EEG, SEEG, MEG, PET and MRI (e.g., obtained for the subject or a representative cohort). In embodiments, the tES targets one or more of the salient network (SN), fronto-parietal network (FPN), dorsolateral attention network, and default mode network (DMN). In embodiments, target networks comprise one or more regions such as subgenual cingulate cortex, ventromedial prefrontal cortex, and dorsolateral prefrontal cortex (e.g., left DLPFC). In embodiments, a target network comprises a causal network described in Siddiqi et al.

[0060] , which is hereby incorporated by reference in its entirety.

[0036] In embodiments, this disclosure involves personalization of therapy using a model- driven approach, where data is assimilated into mechanistic multiscale models. FIG 1. These neurotwin models combine physical and physiological models of brain function for optimization of therapy. Protocols can be personalized using neurotwin models to better identify the brain circuits of interest and account for patient heterogeneity (patient subtypes), including anatomical and physiological differences, and optimize therapy accordingly. Neuropsychiatric disorders ultimately result from network (circuit) dysfunctions. Computational models allow the design of therapies to target dysfunctional circuits and their resulting symptoms.

[0037] The personalization process starts with the creation of a phy si co-phy si ologi cal model of the patient’s head and brain to be able to simulate the generation of EEG, fMRI (e.g., BOLD), or other data, the propagation of electrical currents or electrical fields generated by brain stimulation technology, and the interaction of neural populations with the induced electric field. FIG. 2. The model architecture also represents the effects of neuroplastogens, such as psychedelics, ideally both on dynamics (concurrent) and plasticity (concurrent and aftereffects). Model outputs may also include symptoms (e g., anhedonia) provided a map between circuit dysfunction and symptomatology is provided.

[0038] For example, the model can be personalized by assimilating multimodal neuroimaging data, including anatomical MRI, diffusion MRI, functional MRI (BOLD, ASL), EEG, SEEG, or any other measurements the model can reproduce. If appropriate, the model may also simulate and use semiology (behavioral or first-person symptoms from personal reports) data. Alternatively, personalization can leverage limited patient data combined with larger human databases to provide personalized treatment. For example, group data can be used to estimate anatomical or physiological characteristics if some of the patient data is not available (aMRI or dMRI, for example).

[0039] To personalize the model, in embodiments an autoencoder (e.g., a variational autoencoder) can be used to process subject data and project it into its latent space, where the data can be compared to model-simulated data in a principled way. In embodiments, semiology data can help start the personalization process from a biotype archetype of the model. Once the model is personalized, the effects of the intervention (e.g., tES) can be evaluated in silico. In embodiments, a latent space analysis is used to specify an optimization function, that is, where in phase space is the healthy region that the intervention should bring the dynamics to.

[0040] According to this disclosure, the etiology of MDD or other neuropsychiatric disorder is evaluated for stratification and personalization of treatment. Once relevant circuits (e.g., networks) are selected or identified, more precise treatment strategies using tES can be adopted. tES can instigate beneficial neural plasticity through gentle perturbations in brain activity over multiple sessions, thereby creating clinically relevant aftereffects. However, its efficacy is often limited by the gradual nature of these induced changes. tES combined with neuroplastogen (e.g., psychedelics) may provide a powerful combination to treat depression and other psychiatric disorders, where each has already demonstrated some potential to treat depression independently.

[0041] The combination of psychedelics with optimized tES is especially interesting from the point of view of enhanced plasticity. After administration of psychedelics, the window of increased neuroplasticity appears to open within a few hours and may last a few days, with resulting plastic changes surviving for at least a month. Furthermore, because plastic changes occur in an experience-dependent manner, experiences people have during this time may have a greater psychological impact than they otherwise would. Thus, psychoactive substances, such as psychedelics, can significantly enhance neural plasticity during both the acute and post-acute phases, making them promising candidates for co-administration with optimized or personalized tES according to this disclosure.

[0042] Thus, a model-driven therapeutic approach leveraging the synergistic action of tES and psychoactive substances can potentially accelerate and intensify neural plasticity, thereby offering a potentiated clinical impact. This combined treatment concept provides a new avenue for rapidly and sustainably modifying neural circuits, thus offering enhanced therapeutic outcomes in neuropsychiatric disorders such as, but not limited to, MDD.

[0043] In embodiments, a head model is created from an image or scan of the subject’ s head (as known in the art), such as with one or a combination of MRI, CT, DW-MRI, fMRI, fNTRS, PET, rs-fcMRI, EEG, MEG, SEEG, and SPECT. Head models can be biophysical head models that model passive tissues, or in embodiments can be hybrid models created from a combination of imaging modalities to model the subject’s unique brain dynamics.

[0044] In embodiments, the head model is created using an MRI, and the model represents the geometry of the patient’s head and their passive electrical properties. These models are built from automatic segmentation of Tlw-MRIs, or Tlw and T2w-MRIs (preferably with full head coverage), into different tissues: scalp, skull, cerebrospinal fluid (CSF, including the ventricles), gray matter (GM), and white matter (WM). Certain types of lesions can also be represented in the head model, such as corticotomies, strokes, brain tumors, skull scar tissue and titanium implanted plates. In embodiments, target regions can be mapped to the head model for tES montage determination.

[0045] In embodiments, currents, electrode locations, and electrode numbers are determined for montages using such a head model with electric field modeling. See U.S. Patent No. 9,694,178, the entire disclosure of which is hereby incorporated by reference. In such embodiments, tissue boundaries are derived from MR images (scalp, skull, cerebrospinal fluid (CSF) including ventricles, Grey Matter and White Matter), and the finite element method is used to calculate the electric potential in the head, subject to the appropriate boundary conditions. Tissues are assumed to be uniform and possibly isotropic (although anisotropy can also be modeled), and values for their electric conductivity are taken from the literature or measured using techniques such as electrical impedance tomography (EIT) or Magnetic Resonance Electrical Impedance Tomography (MREIT).

[0046] In embodiments, the head model comprises an electric field characteristic target map for the subject’s cortex, and includes the target regions and desired values for the electrical field at each of the target regions to modulate excitation of said target regions. In various embodiments, the head model further comprises a weight map for the cortical surface specifying a degree of relative importance for each of the target regions and the rest of the cortex for the purposes of modulating excitability. In embodiments, the modulating excitation of the targets can increase activity of one or more target brain networks.

[0047] As used herein, a “target map” defines desired values for the electric field at multiple spatial and temporal points for stimulation. Targets can be defined based on a coordinate system relative to the cortical surface, with target values for normal and / or tangential components of electric field to the cortex, or, more generally, by a spatiotemporal field in the brain.

[0048] The electrode montage can be identified using algorithms to optimize currents, for example, as well as the number and location of electrodes given appropriate constraints, such as the maximum current at any electrode and the maximum total injected current. For example, an electrode montage and stimulation parameters to be provided can be determined using a target map of a cortical surface specifying desired values for the electric field at each (spacetime) point. Further, the determination of an electrode montage and stimulation parameters to be provided can employ a weight map providing the degree of relative importance of each location in the target map, and a set of constraints on the number of electrodes and their currents. In embodiments, the weighted target map of the cortical surface is generated by prioritizing the areas in the target map for optimization purposes. For example, a higher weight is given to those brain areas considered to be more important for the particular application of neurostimulation.

[0049] In embodiments, the electrode montage comprises optimal currents and optimal number and locations for a plurality of electrodes to globally inhibit excitability of the target regions. In embodiments, the optimal currents and optimal number and locations for the plurality of electrodes is calculated under constraints regarding the total current injected into the brain by all electrodes at any time. In embodiments, the optimal currents and optimal number and locations for the plurality of electrodes is calculated under constraints regarding a maximal current at each electrode. In embodiments, the electrode montage impacts the excitability of the plurality of target regions without substantial excitation outside the target regions. For example, the electrode montage may comprise optimal currents and optimal number and locations for a plurality of electrodes to globally impact excitability of one or more target regions or networks.

[0050] In embodiments, the calculation of stimulation parameters and electrode locations is performed under constraints regarding maximal electrode number, maximal or minimal current at each electrode, and the total current injected into the brain by all electrodes at any time. In embodiments, the calculations are performed under additional constraints including holding the current in an electrode at a constant fixed value.

[0051] In embodiments, the calculation of stimulation parameters (e.g., current intensity for tDCS) uses least squares. In embodiments, the present method comprises using constrained least squares to optimize current intensities. In embodiments, the calculation of optimal electrode locations and / or optimal electrode numbers employs a genetic algorithm. Exemplary genetic algorithms are described, for example, in U.S. Patent No. 9,694,178, the entire disclosure of which is hereby incorporated by reference. The genetic algorithm can be based on the definition of a solution by a “DNA” binary string (in this case of dimension N- 1) specifying the electrode locations and number, and stimulation parameters, and may employ as an optimization function the least squares error, i.e., the one with the best possible current configuration for the chosen electrode locations. Cross-over and mutation functions are defined to ensure that the offspring of solutions do not violate the constraint of maximal number of electrodes in the solution. Once a DNA string is specified (i.e., a particular montage), its fitness can be computed by inverting the solution for that particular montage. Solutions with more than the maximal number of electrodes desired are penalized strongly. The genetic algorithms with specifically designed fitness, cross-over and mutation functions, converge quickly and reliably to a solution.

[0052] In some embodiments, the head model is a template head model, which is either a single model from a different subject or a group optimized model. These embodiments are useful, for example, where an MRI of the subject is not available. For example, the head model can be a single model from a different subject, and selected based on one or more criteria that match the subject, such as age, gender, and head measurements. Other criteria such as ethnicity may also be used. For example, in embodiments the template head model is from an individual that is similar in age to the subject, for example, ±25%, or ±20%, or ±15%, or ±10% of the age of the subject. In embodiments, the head model is selected at least according to age of the subject and one or more head measurements, such as one or more (or all) measurements selected from nasion-to-inion distance, tragus-to-tragus distance, and head coronal perimeter. These morphometric measurements help to ensure that the current intensity and electric field modeling according to the head model will be similar for the subj ect. In certain embodiments, these measurements are each within ±20%, ± 15%, or ± 10% between the selected head model and the subject.

[0053] In some embodiments, the head model is a group-optimized head model. For example, the group-optimized head model can be prepared from a group of template head models matched for the subject based on the one or more criteria (as described). In embodiments, the template head models for group optimization are selected at least according to age of the subject and one or more measurements selected from nasion-to-inion distance, tragus-to-tragus distance, and head coronal perimeter (as described). For group- optimized approaches, the montage is selected to minimize the average of ERNI across all the subjects.

[0054] In some embodiments, the head model is a hybrid model prepared with MRI and one or more of EEG, DW-MRI, DTI, and fMRI (e.g., BOLD) to model the subject’s unique neural dynamics (e.g., connectivity).

[0055] In embodiments, the brain model comprises neural mass models (NMM) coupled to create a Brain Network Model (BNM). NMMs represent the average activity of populations of neurons. NMMs are mathematical representations of the dynamics of the average membrane potential and firing rate of a population of neurons. In other embodiments, the BNM is constructed using Wilson and Cowan models, or mean field models. The Wilson- Cowan model describes the evolution of excitatory and inhibitory activity in a synaptically coupled neuronal network. Mean-field models can reproduce local neural dynamics elicited by different cortical inputs and can accurately predict population-specific activity patterns. In some embodiments, Ising models or Hopf models are employed. BNMs are created through an ensemble of neural population models (e.g., NMMs) and are informed by anatomical connectivity, which can be inferred from various neuroimaging techniques, such as diffusion MRI-based tractography. EEG, SEEG, and fMRI data can also be used.

[0056] In embodiments, a BNM is created using the following steps. Structural data (such as from an Tlw-MRI and / or T2w-MRI) is obtained and used to prepare a biophysical head model that represents the geometry of the patient’s head and the passive electrical properties. The biophysical head model comprises segmentation of the different tissues: scalp, skull, cerebrospinal fluid, gray matter, and white matter. The biophysical head model in embodiments also comprises lesions if present, such as one or more of corti cectomy, stroke, brain tumor, skull scar tissue, and titanium implanted plate. Using measured data such as from DW-MRI (diffusion-weighted MRI), connectivity is inferred between different regions of the subject’s brain in the head model. In some embodiments, the connectivity of various regions is inferred from DW-MRI using DTI (diffusion tensor imaging). A BNM is created by placing in various regions (or nodes) of the head model, a mathematical model (e.g., NMM) to represent brain activity and connectivity at and between the various regions. The NMMs and their ensembles can be constructed to recapitulate, for example, measured EEG, SEEG, and / or fMRI activity, and to represent the neural activity of each region. The model parameters can be tuned to model the actual measured data and the subject’s symptoms as closely as possible. In embodiments, the head model is based on MRI to determine biophysical structures, and DW-MREDTI to infer connectivity and construct NMMs and their ensembles (i.e., construct the BNM). In embodiments, the subject’s connectivity or other model parameters are tuned using EEG and / or SEEG data to simulate as closely as possible the subject’s neural activity.

[0057] In embodiments, the Brain Network Model simulates brain activity or behavioral outcomes (symptoms) in response to the treatment or protocol and / or the tES. The simulation may comprise simulating acute and / or long term plasticity effects. In embodiments, the Brain Network Model simulates altering of neural dynamics and / or connectivity in response to the treatment or protocol (e.g., pharmacological intervention) and / or the tES. Modeling such neural dynamics and underlying mechanisms are further described in Ruffini G. et al., Neural Geometrodynamics. Complexity, and Plasticity: A Psychedelics Perspective, Entropy 2024, 26, 90; and Ruffini G, Castaldo F, Lopez-Sola E, Sanchez-Todo R, Vohryzek J. The Algorithmic Agent Perspective and Computational Neuropsychiatry: From Etiology to Advanced Therapy in Major Depressive Disorder. Entropy. 2024; 26(11):953. In embodiments, the electrode montage is selected to increase plasticity of target networks in the Brain Network Model.

[0058] In embodiments, the stimulation is designed to optimize a loss function based on a representation of the desired clinical outcome, including neurophysiological, neuroimaging, dynamical or clinical symptoms. In embodiments, in a personalized electrode montage the loss function is created around the electric field as the target. In embodiments, in epilepsy the loss function is a measure of the probability or spread of seizures. In embodiments, in MDD the loss function is defined in terms of electric field, activity of a region, the activity of a network, other dynamical features of the network (e.g., spectral features, criticality or complexity features), or semiology or symptoms. For example, in the case of MDD, the model may provide a symptom output such as the probability of anhedonia.

[0059] In embodiments, the head model for the subject includes a representation of their brain connectivity (e.g., derived from dMRI), adjusted by data assimilation (e.g., EEG, clinical data, or plasticity probing through techniques such as rTMS TMS-MEP), which can be through minimization of a loss function matching model generated data and the data to be assimilated. To deal with multiple parameter optimization, techniques such as genetic algorithms or Bayesian optimization, or gradient descent, as used in deep learning can be used. In embodiments, the head model reflects pathological features, effects of tES (acute and long term / plasticity), and effects of neuroplastogen drugs (acute and long term). The model is used to simulate the effects of stimulation to select the best solution (e.g., comprising montage, currents, duration, and potentially scheduling) for each subject. The solutions will consider anatomy, circuital elements affected (and not affected) in the patient, and plasticity mechanisms and characteristics of the subject.

[0060] In embodiments, to assess the fitness of a particular montage according to this disclosure, a target map is first created to comprising the desired excitability or activity of selected regions or networks (as described). A weight map is also created to prioritize the targets as already described. Electric field distribution is estimated for the montage (e.g., as described using the biophysical model), and the ERNI is calculated using the target and weight maps. In embodiments, the electric field distribution is used in the personalized brain network model to simulate its effects. From these simulations, metrics such as probability of seizure or seizure spread, activity of a region or network, probability of relevant symptoms, and induction of plasticity can be extracted.

[0061] For example, in such embodiments, the method can comprise: preparing a target map comprising targets for impacting excitability of one or more regions or networks; preparing a weight map indicating the relative importance of the targets; estimating an electric field distribution for an electrode montage and calculating ERNI based on the target and weight maps; and simulating the effects of the electric field distribution using a brain network model using any of the outputs described herein.

[0062] In embodiments, to find the optimal montage, an evolutionary algorithm is used to optimize the desired model output while minimizing the ERNI. The evolutionary algorithm can be based on a parameter vector that defines the positions of the active electrodes and their currents (as described). Such parameter vector can be designed to ensure that the solutions being assessed do not violate constraints regarding the total injected current, maximum number of electrodes, and current conservation constraints. In addition, repair functions can be designed to ensure that the assayed montages do not violate the maximum current per electrode constraint. This evolutionary algorithm, with designed mutation and cross-over functions, can reliably converge to a solution.

[0063] In embodiments, the neuropsychiatric disorder is selected from major depressive disorder (MDD), post-traumatic stress disorder (PTSD), addiction disorders (e.g., opioid or alcohol addiction, or other addiction), anorexia, epilepsy, schizophrenia, bipolar disorder (BD), attention deficit hyperactivity disorder (ADHD), anxiety, cognitive deficit disorders, eating disorders, mania, migraine, Parkinson disease, sleep disorders, attention deficit disorders, delirium, dementia, mood disorders, neurodegenerative conditions, palsies and Alzheimer’s disease.

[0064] In embodiments, the neuropsychiatric condition is epilepsy. In embodiments, the neuroplastogen for treatment of epilepsy is selected from Acetazolamide, Brivaracetam, Cannibadiol, Carbamazepine, Cenobamate, Clobazam, Clonazepam, Clorazepate, Corticotropin, Diazepam, Eslicarbazepine acetate, Ethotoin, Ethosuximide, Felbamate, Fenfluramine, Fosphenytoin, Gabapentin, Lacosamide, Lamotrigine, Levetiracetam, Lorazepam, Methsuximide, Midazolam, Oxcarbazepine, Perampanel, Phenobarbital, Phenytoin, Pregabalin, Primidone, Rufinamide, Stiripentol, Tiagabine, Topiramate, Valproate, Vigabatrin, and Zonisamide. In embodiments, the tES is selected for reducing excitability of one or more regions or networks such as an epileptogenic region and a propagation network. In embodiments, the target regions comprise one or more targets outside the epileptogenic region and / or propagation network. Methods for selecting target regions and networks and preparing whole brain models (e.g., neurotwins) to simulate intervention is described in U.S. provisional application 63 / 608,606, which is hereby incorporated by reference in its entirety.

[0065] For example, in embodiments, ibogaine is administered to a subject for treatment of addiction (such as opioid addiction), and which can act through receptors such as NMDA receptors, Sigma-2 receptors, serotonin transporter, and opioid receptors (the distribution of which can be used for designing the montage). In embodiments, the neuropsychiatric disorder is MDD. MDD is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Management of MDD typically involves psychotherapy and / or pharmacological treatments (i.e., antidepressants). Treatment resistant patients do not respond to antidepressant therapy.

[0066] In some embodiments, the patient has a depression classified as persistent depressive disorder, bipolar disorder, seasonal affective disorder, psychotic depression, peripartum (postpartum) depression, premenstrual dysphoric disorder, situational depression, atypical depression, or treatment-resistant depression.

[0067] For example, depression (e.g., MDD) or other condition can be treated according to the present disclosure by applying tES to the subject using a multi-electrode montage exciting at least the left dorsolateral prefrontal cortex (DLPFC), as well as one or more identified networks.

[0068] The DLPFC is an area in the prefrontal cortex. The DLPFC has connections with the orbitofrontal cortex, as well as the thalamus, parts of the basal ganglia (specifically, the dorsal caudate nucleus), the hippocampus, and primary and secondary association areas of neocortex (including posterior temporal, parietal, and occipital areas). The DLPFC is also the end point for the dorsal pathway which effects how the brain interacts with stimuli. The DLPFC may be responsible for executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. The DLPFC is also the highest cortical area that is involved in motor planning, organization and regulation. The DLPFC is thought to modulate depression under the prefrontal asymmetry theory of depression, which states that right prefrontal activity is higher than left in depressed patients.

[0069] In some embodiments, an anode is positioned at F3 and / or AF3 (based on the 10-10 international system). In embodiments, the electrode montage has a cathode positioned at T7 and / or AF4. In embodiments, the electrode montage includes anodes positioned at AF3 and F3, and cathodes positioned at T7 and AF4.

[0070] The International 10-10 system is a method for standardized placement of electrodes. The 10-10 system correlates external scalp locations with the underlying cortical areas. Electrode sites are identified with a letter to identify the lobe, or area of the brain. Regions of the brain are labeled as pre-frontal (Fp), frontal (F), temporal (T), parietal (P), occipital (O), and central (C). The International 10-10 system also identifies (z) sites; A “z” (zero) refers to an electrode placed on the midline sagittal plane of the skull, (Fpz, Fz, Cz, Oz) and is present mostly for reference / measurement points. The International 10-10 system uses even-numbered electrodes for the right side of the head, whereas odd numbers refer to electrodes placed on the left.

[0071] In accordance with aspects and embodiments, the electrode montage targets for excitation at least the left dorsolateral prefrontal cortex of the brain, including one or more hotspots for the treatment of depression. Hotspots include MNI coordinates (in millimeters) l:[-40.6, 41.7, 34.3; -41.5, 41.1, 33.4], 2:[- 39.3, 46.2, 27.5;-41.3, 48.9, 27.7 ], 3:[-50, 30, 36], 4:[-33.6, 30.8, 51.1]. See WO 2023 / 172450, which is hereby incorporated by reference in its entirety. In embodiments, these hot spots are modified based on the model (e.g., optimized for the subject), and modified (including optionally by addition of further targets) to excite selected networks.

[0072] In embodiments, the electrode montage has at least 3 cathodes. In embodiments, the electrode montage has 4, 5, or 6 cathodes. In embodiments, the electrode montage has at least 6 electrodes or at least 7 electrodes. In embodiments, the electrode montage has no more than 8 electrodes, and optionally 4 electrodes. In embodiments, the electrode montage has from 2 to about 6 electrodes. In some embodiments, the electrode montage has a plurality of anodes (e.g., from 2 to 6, or from 2 to 4, anodes).

[0073] In embodiments, the maximal voltage of the electric field of the montage is about 23 volts per meter. In embodiments, the maximal voltage of the electric field is about 20 volts per meter, or about 21 volts per meter, or about 22 volts per meter, or about 23 volts per meter, or about 24 volts per meter, or no more than about 25 volts per meter.

[0074] In various embodiments, the current intensity of any cathode is at least about 1.00 milliamps (mA). In some embodiments, the current intensity of any cathode is at least about 1.25 mA or at least about 1.50 mA, or at least about 1.75 mA. In embodiments, the maximum current intensity of any cathode is about 2.00 mA. In various embodiments, the method of this disclosure uses a total injected current intensity of at least about 2.00 mA. In some embodiments, the total injected current intensity is at least about 3.00 mA, or at least about 4.00 mA. In some embodiments, the total injected current intensity is no more than about 5.00 mA or no more than about 4.00 mA. In some embodiments, the total injected current intensity is half the sum of the absolute values of all the currents.

[0075] Generally, the tES is applied in multiple sessions. In some embodiments, the tES is applied for at least 5 sessions, at least 10 sessions, at least 15 sessions, or at least 20 sessions. Sessions can be administered continually. Sessions can be performed at a set frequency, or variable frequency. In embodiments, the frequency of the sessions is selected from (or varies within) the range of bimonthly (e.g., every other month) to three times daily. In some embodiments, sessions are performed at least once per week, such as once, twice, or three times per week (e.g., on average). In some embodiments, at least two sessions are performed on consecutive days. In some embodiments, sessions are performed on at least 2, 3, 4, or 5 consecutive days. In these or other embodiments, sessions can be performed multiple times (such as 2 to 20 times, or from 2 to 10 times) on the same day. In some embodiments, sessions are performed twice daily or three times daily on average. In some embodiments, sessions are performed no more than three times on any day. In exemplary embodiments, sessions are performed about daily or about weekly. In some embodiments, sessions are performed about bimonthly, monthly, semimonthly, biweekly, weekly, or semiweekly, daily, or more than daily, and any number of periodic sessions there between. In embodiments, at least 5, or at least 10, or at least 20 session are performed within three days.

[0076] In embodiments, the tDCS (per session) is applied for a duration of at least about 5 minutes (i.e., per session), or at least about 10 minutes, or at least about 15 minutes, or at least about 20 minutes, or at least about 30 minutes, or at least about 45 minutes. In various embodiments, the tDCS is applied for a duration of no more than about 2 hours (i.e., per session), or for no more than about 1 hour. In some embodiments, the tDCS is applied for a duration of from about 10 minutes to about 1 hour. In some embodiments, the tDCS is applied for about 20 minutes to about 40 minutes. In embodiments, the tDCS is applied for a duration of about 15 minutes, about 20 minutes, about 30 minutes, or about 45 minutes. Sessions can be performed for a definite period (such as one month, two months, six months, or one year), or can be performed indefinitely.

[0077] In embodiments, the method is designed to leverage at least post-acute plasticity effects of the neuropl astogen. For example, the method can involve one or more cycles where a single high dose of a neuropl astogen (e.g., a psychedelic) is followed by several days, several weeks, or months of targeted tES leveraging the enhanced plasticity. For example, in embodiments, at least five or at least 10 tES sessions are performed over no more than three days of administering the neuropl astogen. In embodiments, the tES is performed at home. The cycles can be repeated for maintenance of the effects. In embodiments, tES is delivered at least daily (e.g., for at least three or at least five days per week), for from one to four weeks, after the single high dose. In embodiments, no more than 20, or no more than 12, or no more than 10 tES sessions are employed per cycle.

[0078] In embodiments, the method is designed to leverage at least acute plasticity effects of the neuropl astogen. For example, tES can be applied within 24 hours after the administration of the neuroplastogen, which is optionally a low dose or a microdose. In some embodiments, the tES is applied within about 15 hours, or within about 12 hours, or within about 10 hours, or within about 8 hours, or within about 6 hours, or within about 4 hours of the administration of the low dose or microdose. In some embodiments, tES can be delivered at least daily (e.g., at least one, at least three, or at least five sessions per day, and / or for three to seven or for five to seven days per week), and for at least one, two, three, or four weeks, or for as long as necessary. In embodiments, the synergy between the therapies allows for the effects to be seen within one, two, or three cycles. In embodiments, no more than 20, or no more than 12, or no more than 10 tES sessions are employed, or are employed per cycle.

[0079] In embodiments, the present disclosure provides a tDCS system for treating the neuropsychiatric condition in a subject, comprising an electrode montage that modifies the excitability of a plurality of target regions of the subject’s cortex. The system further comprises a head model as described herein, and can be applied in a method for treating neuropsychiatric conditions.

[0080] In other aspects and embodiments, a tES system comprising an electrode montage for use in treating neuropsychiatric disorder in a subject according to this disclosure. The tDCS methods and systems described herein can employ systems that are described in US 9,694,178, US 10,463,855, US 2020 / 029119, and US 2021 / 0031034, which are hereby incorporated by reference in their entireties.

[0081] As used herein, the term “about” is defined as ± 5% of the associated numerical value, unless the context requires otherwise.

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Claims

CLAIMS:

1. A method for treating a neuropsychiatric disorder in a subject undergoing a treatment or protocol that induces plasticity comprising: providing a transcranial electrical stimulation (tES) electrode montage designed to stimulate one or more brain networks affected by said treatment that induces plasticity, and applying the tES with the electrode montage.

2. The method of claim 1, wherein the treatment or protocol that induces plasticity comprises therapy with a neuropl astogen agent.

3. The method of claim 2, wherein the neuroplastogen comprises one or more of a psychedelic agent, antidepressant agent, anti-anxiety agent, stimulant, antipsychotic agent, and mood stabilizer agent.

4. The method of claim 3, wherein the neuroplastogen is a psychedelic agent selected from one or more of Ketamine, MDMA, Scopolamine, 2C-B, DMT, LSD, mescaline, psilocin, and ibogaine.

5. The method of claim 3, wherein the neuroplastogen is a stimulant, which is optionally nicotine.

6. The method of claim 3, wherein the neuroplastogen is a Serotonin-Norepinephrin Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI).

7. The method of any one of claims 1 to 6, wherein the treatment or protocol that induces plasticity comprises electroconvulsive therapy (ECT).

8. The method of any one of claims 1 to 7, wherein the treatment or protocol that induces plasticity comprises sensory inputs.

9. The method of any one of claims 1 to 8, wherein the brain networks are selected based on the distribution of receptors for a neuroplastogen agent, which are optionally serotonin, dopamine, or acetylcholine receptors or transporters.

10. The method of claim 9, wherein the receptors comprise one or more of NMD A Receptors, BDNF / TrkB, mTOR Pathway, AMP AR, 5-HT receptors, GluR receptors, Sigma- 1 Receptors, Sigma-2 Receptors, Cannabinoid Receptors, Opioid Receptors, and receptors of the cholinergic system.

11. The method of claim 10, wherein the receptors comprise 5-HT receptors, which are optionally 5-HT2A receptors or 5-HT1A Receptors.

12. The method of any one of claims 1 to 11, wherein the brain networks comprise cortical targets and / or subcortical targets.

13. The method of claim 12, wherein the electrode montage modifies the excitability of one or more targets without substantial excitation outside the targets.

14. The method of any one of claims 1 to 13, wherein the tES comprises transcranial direct current stimulation (tDCS), transcranial Alternating Current Stimulation (tACS), or transcranial magnetic stimulation (TMS).

15. The method of claim 14, wherein the targets for tES are identified by one or more of SEEG, EEG, MEG, PET and MRI.

16. The method of any one of claims 1 to 15, wherein the electrode montage is designed using a head model.

17. The method of claim 16, wherein the head model is created from one or a plurality of images or scans selected from MRI, CT, DW-MRI, fMRI, fNIRS, PET, rs-fcMRI, EEG, MEG, SEEG, and SPECT.

18. The method of claim 16 or 17, wherein the head model comprises: an electric field characteristic target map for the subject’s cortex, said target map including the brain targets and desired values for the electrical field at each of the brain targets to modulate excitation of said brain targets; and a weight map for the cortical surface specifying a degree of relative importance for each of the brain targets and the rest of the cortex for the purposes of modulating excitability.

19. The method of claim 18, wherein the electrode montage comprises optimal currents and optimal number and locations for a plurality of electrodes to globally increase or decrease excitation of the brain targets.

20. The method of claim 19, wherein the optimal currents and optimal number and locations for the plurality of electrodes is calculated under constraints regarding the total current injected into the brain by all electrodes at any time.

21. The method of claim 19 or 20, wherein the optimal currents and optimal number and locations for the plurality of electrodes is calculated under constraints regarding a maximal current at each electrode.

22. The method of claim 16 or 17, wherein the head model is prepared from an image or scan of the subject’s brain, and optionally where the image or scan is an MRI, and optionally comprises a Tlw-MRI and / or a T2w-MRI.

23. The method of claim 22, wherein the MRI image or scan comprises a Tlw-MRI and / or T2w-MRI with full head coverage.

24. The method of claim 22 or 23, wherein the head model comprises one or more of a cortical resection geometry, skull defect(s), and / or implants of the subject’s head.

25. The method of any one of claims 22 to 24, wherein the head model is a hybrid model prepared with MRI and one or more of SEEG, EEG, DW-MRI, DTI, and fMRI.

26. The method of claim 16 or 17, wherein the head model is a template head model, which is either a single model from a different subject or a group head model.

27. The method of claim 26, wherein the head model is a single model from a different subject, and selected based on one or more criteria selected from: age, gender, and head measurements.

28. The method of claim 27, wherein the head model is selected at least according to age of the subject and one or more head measurements selected from nasion-to-inion distance, tragus-to-tragus distance, and head coronal perimeter.

29. The method of claim 26, wherein the template head model is a group head model.

30. The method of claim 29, wherein the group head model is prepared from a group of template head models matched for the subject based on one or more criteria selected from: age, gender, and head measurements.

31. The method of claim 30, wherein the template head models are selected at least according to age of the subject and one or more measurements selected from nasion-to-inion distance, tragus-to-tragus distance, and head coronal perimeter.

32. The method of any one of claims 22 to 25, wherein the group head model is created from a plurality of models created from the subject’s neuroimaging data.

33. The method of claim 32, wherein the group head model is prepared based on neuroimaging and empirical data measured for the subject.

34. The method of any one of claims 22 to 33, wherein the head model is a brain model comprising neural mass models, neural field models, or mean field models coupled to create a Brain Network Model.

35. The method of claim 34, wherein the subject’s connectivity or other model parameters are tuned using one or more of SEEG, EEG, DW-MRI, DTI, and fMRI data.

36. The method of claim 34 or 35, wherein the Brain Network Model simulates brain activity in response to the treatment or protocol and / or the tES, optionally comprising simulating acute and / or long term plasticity effects.

37. The method of claim 36, wherein the Brain Network Model simulates altering of neural dynamics and / or connectivity in response to the treatment or protocol and / or the tES.

38. The method of any one of claims 1 to 37, wherein the neuropsychiatric disorder is selected from major depressive disorder (MDD), post-traumatic stress disorder (PTSD), addiction disorders, anorexia, epilepsy, schizophrenia, bipolar disorder (BD), attention deficit hyperactivity disorder (ADHD), anxiety, cognitive deficit disorders, eating disorders, mania, migraine, Parkinson disease, sleep disorders, attention deficit disorders, delirium, dementia, mood disorders, neurodegenerative conditions, palsies and Alzheimer’s disease.

39. The method of claim 38, wherein the neuropsychiatric disorder is MDD.

40. The method of claim 39, wherein MDD is treated by applying tDCS to the subject using a multi anode electrode montage exciting at least the left dorsolateral prefrontal cortex.

41. The method of claim 40, wherein an anode is positioned at F3 and / or AF3.

42. The method of claim 40 or 41, wherein the electrode montage has a cathode positioned at T7 and / or AF4.

43. The method of any one of claims 40 to 42, wherein the electrode montage includes anodes positioned at AF3 and F3, and cathodes positioned at T7 and AE4.

44. The method of any one of claims 1 to 43, wherein the tES stimulation comprises more than one session, with the frequency of the sessions being from about bimonthly to about three times daily.

45. The method of claim 44, wherein sessions occur at a frequency of about bimonthly, about monthly, about semimonthly, about biweekly, about weekly, about semiweekly, about daily, or about twice daily, or a combination thereof.

46. The method of claim 44 or 45, wherein the tES stimulation is applied for a duration of at least 5 minutes.

47. The method of claim 46, wherein the tES stimulation is applied for a duration of at least 10 minutes, or at least 15 minutes, or at least 20 minutes, or at least 25 minutes, or at least 30 minutes.

48. The method of claim 47, wherein the tES is applied for a duration of no more than 2 hours in a session.

49. The method of claim 47, wherein the tES is applied for a duration of no more than 1 hour in a session.

50. The method of any one of claims 47 to 49, wherein the tES is applied for a duration of from about 10 minutes to about 1 hour in a session, or tES is applied for a duration of from about 20 minutes to about 40 minutes in a session.

51. The method of any one of claims 44 to 50, wherein the tES regimen is applied after the administration of a high dose of a neuropl astogen agent.

52. The method of any one of claims 44 to 50, wherein the tES is applied within 24 hours after the administration of the neuroplastogen, which is optionally a low dose or a microdose.

53. A tES system comprising an electrode montage for use in treating neuropsychiatric disorder in a subject according to a method of any one of claims 1 to 52.

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