WO2023172450A2

WO2023172450A2 - Transcranial direct current stimulation for treating depression

Info

Publication number: WO2023172450A2
Application number: PCT/US2023/014479
Authority: WO
Inventors: Giulio Ruffini; Maria BIAGI; Ricardo SALVADOR
Original assignee: Neuroelectrics Usa Corporation
Priority date: 2022-03-07
Filing date: 2023-03-03
Publication date: 2023-09-14
Also published as: WO2023172450A3

Abstract

In various aspects and embodiments, the present disclosure provides a treatment for depression that comprises applying transcranial direct current stimulation (tDCS). According to aspects of the disclosure, the tDCS employs electrode montages to stimulate the left dorsolateral prefrontal cortex (1DLPFC), and which comprise multiple anodes and/or multiple cathodes.

Description

TRANSCRANIAL DIRECT CURRENT STIMULATION FOR TREATING DEPRESSION

PRIORITY

This application claims priority to and benefit from U.S. Provisional Patent Application Ser. No. 63/317,098, filed on March 7, 2022, the entire contents of which are incorporated by reference herein.

BACKGROUND

Major depressive disorder (MDD) is a debilitating mental illness for millions of people. Unfortunately, treatment options for depression are very limited and psychotherapy and pharmacological treatments may not work, especially for treatment resistant patients. Accordingly, methods for treatment of depression, including MDD, are needed, including methods that may be practiced in the home.

Transcranial direct current stimulation (tDCS) is a non-invasive, brain stimulation treatment that uses direct electrical currents to modulate excitability of specific targets in the brain. A constant, low intensity current is passed through electrodes placed over the head which modulates neuronal activity. There are two types of stimulation with tDCS: anodal and cathodal stimulation. Anodal stimulation acts to excite neuronal activity while cathodal stimulation inhibits or reduces neuronal activity. While tDCS has been proposed for treatment of conditions such as depression, electrode montages (including electrode positions and injected currents) that are both safe and effective (including for frequent at- home use by non-professionals) are needed.

SUMMARY OF THE INVENTION

In various aspects and embodiments, the present disclosure provides a treatment for depression that comprises applying transcranial direct current stimulation (tDCS). According to aspects of the disclosure, the tDCS employs electrode montages to stimulate the left dorsolateral prefrontal cortex (1DLPFC), and which comprise multiple anodes and/or multiple cathodes. In an aspect, there is provided a method of treating depression, which comprises applying tDCS to the patient using a multi electrode montage exciting the left dorsolateral prefrontal cortex. In an aspect, there is provided a method of treating depression, which comprises applying tDCS to the patient using an electrode montage exciting the left dorsolateral prefrontal cortex, where the electrode montage comprises cathodes at one or more of T7 and AF4 (based on 10-10 international system).

In various embodiments, the patient has major depressive disorder (MDD). In still other embodiments, the patient has 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.

In various embodiments, an anode of the electrode montage is positioned at F3 and/or AF3 (based on the 10-10 system). For example, the electrode montage may have multiple anodes, including anodes positioned at both F3 and AF3. In some embodiments, the electrode montage has 2 anodes (e.g., positioned at F3 and AF3). In various embodiments, the electrode montage has as at least 4 electrodes. In various embodiments, the electrode montage has no more than 6 electrodes. In some embodiments, the electrode montage has 4 electrodes. In various embodiments, the electrode montage has an equal number of anodes and cathodes.

In these or other embodiments, cathodes in the electrode montage are positioned at one or more of T7 and AF4. In some embodiments, the electrode montage has a cathode positioned at each of T7 and AF4. An exemplary electrode montage consists of anodes positioned at AF3 and F3 and cathodes positioned at T7 and AF4.

In various embodiments, the current intensity of any anode is at least about 1.00 milliamps (mA). In some embodiments, the current intensity of any anode 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 anode is no more than about 2.00 mA. In some embodiments, the maximum current intensity of any anode is about 1.70 mA. In various embodiments, the method of this disclosure uses 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 an exemplary embodiment, the currents per electrode in the montage are (1) about 1.41 mA at AF3, (2) about 1.70 mA at F3, (3) about -1.41 mA at T7, and (4) about -1.70 mA at AF4.

In various embodiments, the tDCS 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 (e.g., about 25 minutes or about 30 minutes).

Generally, the tDCS is applied in multiple sessions. For example, the tDCS can be applied for at least 5 sessions. Sessions can be performed at a set frequency, or a variable frequency. In some embodiments, sessions are performed at least once per week, such as once, twice, or three times per week (i.e., 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 or 3 times) on the same day. In some embodiments, sessions are performed twice daily or three times daily on average. In exemplary embodiments, sessions are performed about daily or about weekly.

Sessions can be performed for a definite period (such as two weeks, one month, two months, six months, or one year), or can be performed indefinitely, or as needed to combat symptoms of depression.

Other aspects and embodiments will be apparent from the following detailed description. BRIEF DESCRIPTION OF THE FIGURES

FIG. la shows the target for excitation by tDCS according to this disclosure (filled rectangle). The target was conceived as a region surrounding the most relevant hotspot for transcranial magnetic stimulation (TMS). The transparent rectangle represents a buffer area to account for variability of the TMS hotspot positions on brains of different subjects, which could have different size and morphologies. FIG. lb shows the hotspots remapped on the cortex of a default subject brain. FIG. 1c shows the final target map used for determining the multi electrode montage. FIG. Id shows the overlap of the final target map and the TMS hotspots on the default subject brain.

FIG. 2 shows determination of a 4-electrode montage for excitation of the target with a maximum intensity per electrode of 1.70 milliamps.

FIG. 3 illustrates the nomenclature for electrode positions using the International 10- 10 System.

FIG. 4 is a graph depicting the distribution of MADRS scores of the patient population at baseline, Week 4, Week 8, and 4-Weeks post treatment.

FIG. 5 is a graph depicting the distribution of QIDS-SR scores of the patient population at baseline, Week 4, Week 8, and 4-Weeks post treatment.

FIG. 6 is a graph depicting the distribution of Q-LES-Q-SF scores of the patient population at baseline, Week 4, Week 8, and 4-Weeks post treatment.

DETAILED DESCRIPTION

In an aspect, there is provided a method of treating depression, which comprises applying tDCS to the patient using a multi anode electrode montage exciting the left dorsolateral prefrontal cortex, such as the MNI coordinates described herein. In an aspect, there is provided a method of treating depression, which comprises applying tDCS to the patient using an electrode montage exciting the left dorsolateral prefrontal cortex, where the electrode montage comprises cathodes at one or more of T7 and AF4 (based on 10-10 international system). The disclosure provides a system for treatment of depression, comprising an electrode montage as described herein. 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 the target area (in this case, the IDLPFC), via the component of the electrical field orthogonal to the cortical surface E_n, while providing other locations (non-target) an E_n absolute magnitude that is lower to limit the effects outside the target.

The basic mechanism for transcranial current stimulation (tCS) may be through the coupling of electric fields to elongated form-factor neurons such as pyramidal cells. The role of other types of neurons (e.g., interneurons such as basket cells) or other brain cells such as glia, is less understood. Physically, the external electric field forces the displacement of intracellular ions (which move to cancel the intracellular field), altering the neuron’s internal charge distribution and as a result modifying the transmembrane potential difference. For a long, straight fiber with a space constant Z (mm) in a homogenous electric field, the transmembrane potential difference is largest at the fiber termination, with a value than can be approximated by X • n^A, where n^A is the unit vector defining the fiber axis. This is an expected first-order result, with a spatial scale provided by the membrane space constant and directions by field and fiber orientation. See Ruffini G., et al. [3],

In accordance with this disclosure, placement of the electrodes uses the International 10-10 system, as illustrated in FIG. 3. 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.

In various embodiments, the patient has major depressive disorder (MDD). In still other 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.

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.

In some embodiments, the patient is diagnosed with depression. In some embodiments, the patient is diagnosed with depression by self-report, or by evaluation by a healthcare provider. For example, a patient may be diagnosed with depression by the Hamilton Rating Scale for Depression used by a healthcare provider. The Hamilton Rating Scale for Depression is used to quantify the severity of symptoms of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. In various embodiments, the patient may have mild depression, moderate depression, or severe depression, according to the Hamilton Rating Scale for Depression.

In embodiments, the patient’s depression is evaluated using the Columbia-Suicide Severity Rating Scale. The Columbia-Suicide Severity Rating Scale (C-SSRS) is used to evaluate suicidal ideation and behavior. See Nilsson M., et al. [8]

In embodiments, the patient’ s depression is evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS). The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. See Montgomery and Asberg [7], In embodiments, the patient’s depression is evaluated using the Quick Inventory of Depressive Symptomatology (QIDS-SR). The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) is a self-report measure covering depressive symptoms incorporating nine Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnostic criteria for major depressive disorders. See Rush et al., [9],

In embodiments, the patient’s depression is evaluated using the Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is a self-report measure designed to obtain sensitive measures of the degree of enjoyment and satisfaction experienced by patients in various areas of daily functioning. See Endicott et al., [10],

In accordance with this disclosure, patients may be male or female, and may be of any age, including child, adolescent, and adult (including the elderly).

In various embodiments, an anode of the electrode montage is positioned at F3. In some embodiments, an anode of the electrode montage is positioned at AF3. For example, the electrode montage may have multiple anodes, including anodes positioned at both F3 and AF3. In some embodiments, the electrode montage has 2 anodes (e.g., positioned at F3 and AF3). In other embodiments, the electrode montage has 3 anodes or 4 anodes.

In various embodiments, the electrode montage has at least 3 electrodes, such as at least 4 electrodes, or at least 5 electrodes. In various embodiments, the electrode montage has no more than 6 electrodes. In some embodiments, the electrode montage has 4 electrodes. In various embodiments, the electrode montage has an equal number of anodes and cathodes.

In these or other embodiments, at least one cathode in the electrode montage is positioned at one or more of T7 and AF4. In some embodiments, the electrode montage has a cathode positioned at each of T7 and AF4.

An exemplary electrode montage consists of anodes positioned at AF3 and F3, and cathodes positioned at T7 and AF4.

In various embodiments, the current intensity of any anode is at least about 1.00 milliamps (mA). In some embodiments, the current intensity of any anode 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 anode is at least about 2.00 mA. In some embodiments, the maximum current intensity of any anode is about 1.70 mA.

In various embodiments, the method of this disclosure uses a total injected current intensity of at least about 2.00 mA. As used herein, total injected current intensity is the sum of all the currents in all the anodes. 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.

In accordance with aspects and embodiments, the electrode montage targets for excitation the left dorsolateral prefrontal cortex of the brain, including one or more hotspot for the treatment of depression. Hotspots include MNI coordinates (in millimeters) 1 : [-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],

The dorsolateral prefrontal cortex (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 (Grimm et. al., 2008). In various embodiments, the tDCS 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.

Generally, the tDCS is applied in multiple sessions. For example, the tDCS can be applied for at least 5 sessions. In some embodiments, the tDCS is applied for at least 10 sessions, at least 15 sessions, or at least 20 sessions. Sessions can be performed at a set frequency, or variable frequency. In some embodiments, sessions are performed at least once per week, such as once, twice, or three times per week (i.e., 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 or 3 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 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 semi weekly.

Sessions can be performed for a definite period (such as one month, two months, six months, or one year), or can be performed indefinitely, or as needed to combat symptoms of depression.

In embodiments, the patient is concomitantly treated with medication. In embodiments, the patient is concomitantly treated with one or more antidepressants. In embodiments, the antidepressants are selected from one or more of selective serotonin reuptake inhibitor (SSRI), serotonin- norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants. In embodiments, non-limiting examples of selective serotonin reuptake inhibitors (SSRIs) include citalopram (Celexa), escital opram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), fluvoxamine CR (Luvox CR), paroxetine (Paxil), paroxetine CR (Paxil CR), sertraline (Zoloft).

In embodiments, non-limiting examples of serotonin-norepinephrine reuptake inhibitors (SNRIs) include desvenlafaxine (Pristiq), duloxetine (Cymbalta), venlafaxine (Effexor), venlafaxine XR (Effexor XR), milnacipran (Savella), and levomilnacipran (Fetzima).

In embodiments, non-limiting examples of tricyclic antidepressants (TCAs) include amitriptyline (Elavil), desipramine (Norpramin), doxepine (Sinequan), Imipramine (Tofranil), nortriptyline (Pamelor), am oxapine, clomipramine (Anafranil), maprotiline (Ludiomil), trimipramine (Surmontil), and protriptyline (Vivactil).

In embodiments, non-limiting examples of atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone (Serzone), trazodone (Desyrel, Oleptro), vilazodone (Viibryd), and vortioxetine (Brintellix).

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.

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

EXAMPLES

Example 1 :

In this Example, a multichannel montage was used for excitation of the left dorsolateral prefrontal cortex (1DLPFC) by tDCS. The montage search was performed with maximum total injected current of 4.00 mA and maximum number of electrodes of 4. The montage is intended to be useful for home applications.

The target map was based upon hotspots for treatment of depression by TMS as identified by Trapp N., et al. (1). FIG. la shows the target for excitation (filled rectangle). The transparent rectangle in FIG. la represents a buffer area to account for variability of the hotspots and central target position in heterogeneous population. The brain MNI coordinates of the points encompassed by the target were mapped onto the cortical surface of a default subject brain (FIG. lb). The brain MNI (x,y,z) coordinates, in millimeters, of the TMS hotspots (reported in [1]) were: 1 :[-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], With these positions as reference, the complete target map was manually drawn as in FIG. 1c. FIG. Id shows the overlap of the TMS points identified on the cortex, with the final complete target map.

The whole target area was set to activation with the target electric field (En^targct) at 0.75V/m, with weight 20 in the central region of interest and weight 18 in the surrounding buffer region. The rest of the cortex was left unstimulated with weight 2. See FIG. 2. A maximum number of 4 electrodes were used, so that the montage can be more easily implemented in a home system. Moreover, using only the 4 electrodes, spaced apart, may reduce the chances of bridging, in particular between electrodes of different polarity, which can occur when non-professional users apply conductive gel to positions that are too close.

The modeled values of the montage were evaluated on a default head model. See US 9,694, 178, which is hereby incorporated by reference. Stimulation parameters and electrode locations are determined 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. The current per electrode, 1.70 mA, is well below the safety limit and should be tolerable for most patients.

The final solution is shown in FIG. 2 on the cortex of a template brain (Colin27). On this referenced cortex, the surface average value of the orthogonal component of the electric field on the whole target is E_n= 0.194 V/m, with E_n=0.284 V/m in the central target and 0.175 V/m on the surrounding region. In the rest of non-stimulated cortex, E_n remains low (0.00185 V/m). Error with respect to no intervention (ERNI) of the solution is -109672 mV²/m². See Salvador R., et al. [6],

Table 1 (below) presents a summary of the 4-channel montage.

Example 2:

A study was conducted using the 4-channel montage of Table 1 involving 37 at-home stimulation sessions (30-minutes each) of multichannel excitatory tDCS targeting the left dorsolateral prefrontal cortex (DLPFC) administered over 8 weeks, with a follow-up period of 4 weeks following the final stimulation session.

The primary efficacy measure for this study was the median of percentage change (MPC) from baseline to the end of the 4-week post-treatment period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS) (FIG. 4). A descriptive analysis of the MADRS at each visit; baseline, week 4, week 8 and at 4-week post-treatment visit, was also presented. This analysis was performed for both the Intention-to-Treat (ITT) and the Per Protocol (PP) sets. The MADRS scoring criteria is listed below.

MADRS scoring criteria:

O to 6: No depression 7 to 19: Mild depression

20-34: Moderate depression 35-59: Severe depression

60: Very severe depression

MADRS score percentage change is evaluated using the formula below

The Final value refers to the MADRS score recorded in each visit.

According to the scoring criteria, the smaller the MADRS score, the less severe the depression. Therefore, by doing (baseline value - final value), the percentage change represents a decrease in the MADRS score (i.e., an improvement of the depressive disorder).

Table 2: MADRS score at each visit

4-week post Baseline Week 4 Week 8 treatment

MADRS (ITT set)

Total no-missing n 34 34 33 33

0-6 No depression n (%) 7 (20.6%) 6 (18.2%) 5 (15.2%)

7-19 Mild depression n (%) 14 (41 .2%) 24 (72.7%) 27 (81 .8%)

20-34 Moderate depression n (%) 26 (76.5%) 13 (38.2%) 3 (9.1 %) 1 (3.0%)

35-59 Severe depression n (%) 8 (23 5%)

60 Very severe depression

Missing n 0 0 1 1

MADRS (PP set)

Total no-missing n 33 33 33 33

0-6 No depression n (%) 7 (21 .2%) 6 (18.2%) 5 (15.2%)

7-19 Mild depression n (%) 14 (42.4%) 24 (72.7%) 27 (81 .8%)

20-34 Moderate depression n (%) 25 (75.8%) 12 (36.4%) 3 (9.1 %) 1 (3.0%)

35-59 Severe depression n (%) 8 (24 2%)

60 Very severe depression

Missing n 0 0 0 0

Secondary efficacy endpoints were also evaluated using the response rate of MADRS score (Table 3), percentage change in MADRS (Table 4), change from baseline to 4-week follow-up in the participant-rated QIDS-SR score (FIG. 5) and change from baseline to 4- weekfollow-up in the Quality-of-Life Enjoyment and Satisfaction Questionnaire ShortForm (Q-LES-Q-SF) (FIG. 6).

Table 3: Rate of improvement according to MADRS score

ITT set (n=34)

Observed >50% Improvement (a decrease of 50%) in

MADRS score¹

Total no-missing N 33

Yes n (%) 24 (72.7%)

No n (%) 9 (27.3%)

Missing N 1

Response rate (RR) % 72.7%

¹>50% Improvement in MADRS score from baseline to the last visit (4-week post treatment).

Patient MADRS scores were analyzed according to observed >50% improvement in MADRS score from baseline to 4-week post treatment. In Table 3, “Yes” represented that MADRS score decreased 50% or more according to MADRS score percentage change from baseline to 4-week post treatment; “No” represented MADRS score’s decrease from baseline to 4-week post treatment was inferior to 50%.

Table 4: Percentage change in MADRS score at each visit

Percentage

Percentage Percentage change change change at 4-week post at week 4 at week 8 treatment

MADRS score n 34 33 33 percentage change

(ITT set)

Mean (SD) 43.3 (33.9) 55.0 (26 1) 63.6 (19.3)

Median (Q1 , Q3) 32.3 (22.2, 76.9) 45 8 (38.5, 76.7) 64.5 (48.6, 72.4)

Min, Max -55, 94 16, 100 29, 100

Missing 0 1 1

Note that the percentage change is measured from baseline and expressed as a decrease in the MADRS s core.

That is, positive values mean the MADRS score decreased, and negative values mean the MADRS score i ncreased.

The percentage change in MADRS score from baseline to the end of week 4 of treatment, to the end of week 8 of treatment, and to the end of the 4-week follow-up period, calculated for all study subjects (Table 4).

The change from baseline to 4-week follow-up in the participant-rated Quick Inventory of Depressive Symptomatology (QIDS-SR), were also evaluated at the same time points as the MADRS (FIG. 5). A descriptive analysis of QIDS-SR at each visit was also presented. The QIDS-SR scoring criteria is listed below. QIDS-SR scoring criteria:

0 to 5: Normal

6 to 10: Mild

11 to 15 : Moderate

16 to 20: Severe 21 or more: Very severe

The change from baseline to 4-week follow-up in the Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) was also evaluated at the same time points as the MADRS (FIG. 6). A descriptive analysis of Q-LES-Q-SF at each visit was also presented. The formula for calculating the Q-LES-Q-SF score is listed below.

Percentage maximum possible score of Q-LES-Q-SF:

(raw score — minimum score') (raw score — 14)

- - _: - - - — - — ¹ - -xlOO = - - - -xlOO (maximum possible raw score - minimum score) 56

EQUIVALENTS

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

All patents and publications referenced herein are hereby incorporated by reference in their entireties. Exemplary publications are listed below in the “REFERENCES” section and throughout the above disclosure.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. REFERENCES

1. Trapp N., et al., Reliability of Targeting Methods in TMS for Depression: Beam F3 vs. 5,5 cm. Brain Stimulation (2020).

2. Ruffini G., et al., Transcranial current brain stimulation (tCS): models and technologies. IEEE Trans. Neural. Syst. Rehabil. Eng. Vol. 21 (2013).

3. Miranda PC, et al., The electric field in the cortex during transcranial current stimulation. NeuroImage Vol. 30 (2013).

4. Ruffini G., et al., Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields. NeuroImage (2014).

5. Grimm S., et al., Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biol Psychiatry. 2008 Feb; 63(4):369— 76.

6. Salvador R., et al., Personalization of Multi-electrode Setups in tCS/tES: Methods and Advantages. Brain and Human Body Modeling (2021).

7. Montgomery S.A. and Asberg M., A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382-389 (1979).

8. Nilsson M. et al., Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide. Version 2,0. (2013)

9. Rush J, et al., The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological psychiatry vol. 54,5 (2003): 573-83

10. Endicott, J et al., Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacology bulletin vol. 29,2 (1993): 321-6.

Claims

1. A method for treating depression in a patient, comprising: applying transcranial direct current stimulation (tDCS) to the patient using a multi anode electrode montage exciting the left dorsolateral prefrontal cortex.

2. The method claim 1, wherein the depression is major depressive disorder, persistent depressive disorder, bipolar disorder, seasonal affective disorder, psychotic depression, peripartum (postpartum) depression, premenstrual dysphoric disorder, situational depression, atypical depression, treatment resistant depression.

3. The method of claim 2, wherein the depression is major depressive disorder.

4. The method of any one of claims 1 to 3, wherein an anode is positioned at F3.

5. The method of any one of claims 1 to 4, wherein an anode is positioned at AF3.

6. The method of any one of claims 1 to 5, wherein the electrode montage has 2, 3, or

4 anodes.

7. The method of any one of claims 1 to 5, wherein the electrode montage has at least 3 electrodes.

8. The method of claim 7, wherein the electrode montage has at least 4 electrodes.

9. The method of claim 7, wherein the electrode montage has at least 5 electrodes.

10. The method of any one of claims 6 to 8, wherein the electrode montage has no more than 6 electrodes, and optionally 4 electrodes.

11. The method of any one of claims 1 to 10, wherein the electrode montage has a cathode positioned at one or more of T7 and AF4.

12. The method of claim 11, wherein the electrode montage has a cathode positioned at T7 and AF4.

13. The method of claim 12, wherein the electrode montage consists of anodes positioned at AF3 and F3, and cathodes positioned at T7 and AF4.

14. The method of any one of claims 1 to 13, wherein the current intensity of any anode is at least about 1.00 milliamps (mA).

15. The method of claim 14, wherein the current intensity of any anode is at least about 1.25 mA.

16. The method of claim 14, wherein the current intensity of any anode is at least about 1.50 mA.

17. The method of claim 14, wherein the maximum current intensity of any anode is about 2.00 mA.

18. The method of claim 17, wherein the maximum current intensity of any anode is about 1.70 mA.

19. The method of any one of claims 1 to 18, wherein the total injected current intensity is at least about 2.00 mA.

20. The method of claim 19, wherein the total injected current intensity is at least about 3.00 mA.

21. The method of claim 20, wherein the total injected current intensity is no more than about 5.00 mA.

22. The method of claim 21, wherein the total injected current intensity is no more than about 4.00 mA.

23. The method of claim 22, wherein the currents per electrode are: (1) about 1.41 mA at AF3, (2) about 1.70 mA at F3, (3) about -1.41 mA at T7, and (4) about -1.70 mA at AF4.

24. A method for treating depression in a patient, comprising: applying transcranial direct current stimulation (tDCS) to the patient using an electrode montage exciting the left dorsolateral prefrontal cortex, the electrode montage comprising cathodes at one or more of T7 and AF4.

25. The method claim 24, wherein the depression is major depressive disorder, persistent depressive disorder, bipolar disorder, seasonal affective disorder, psychotic depression, peripartum (postpartum) depression, premenstrual dysphoric disorder, situational depression, atypical depression, treatment resistant depression.

26. The method of claim 25, wherein the depression is major depressive disorder.

27. The method of any one of claims 24 to 26, wherein the electrode montage has at least two anodes.

28. The method of claim 27, wherein the electrode montage has 2, 3, or 4 anodes.

29. The method of claim 27 or 28, wherein an anode is positioned at F3.

30. The method of any one of claims 24 to 29, wherein an anode is positioned at AF3.

31. The method of claim 30, wherein the electrode montage has at least 4 electrodes.

32. The method of claim 31, wherein the electrode montage has at least 5 electrodes.

33. The method of any one of claims 24 to 31, wherein the electrode montage has no more than 6 electrodes, and optionally 4 electrodes.

34. The method of claim 33, wherein the electrode montage has a cathode positioned at T7 and AF4.

35. The method of claim 34, wherein the electrode montage consists of anodes positioned at AF3 and F3, and cathodes positioned at T7 and AF4.

36. The method of any one of claims 24 to 35, wherein the current intensity of any anode is at least about 1.00 milliamps (mA).

37. The method of claim 36, wherein the current intensity of any anode is at least about 1.25 mA.

38. The method of claim 37, wherein the current intensity of any anode is at least about 1.50 mA.

39. The method of claim 37 or 38, wherein the maximum current intensity of any anode is about 2.00 mA.

40. The method of claim 39, wherein the maximum current intensity of any anode is about 1.70 mA.

41. The method of any one of claims 24 to 40, wherein the total inj ected current intensity is at least about 2.00 mA.

42. The method of claim 41, wherein the total injected current intensity is at least about 3.00 mA.

43. The method of claim 42, wherein the total injected current intensity is no more than about 5.00 mA.

44. The method of claim 43, wherein the total injected current intensity is no more than about 4.00 mA.

45. The method of claim 44, wherein the currents per electrode are: (1) about 1.41 mA at AF3, (2) about 1.70 mA at F3, (3) about -1.41 mA at T7, and (4) about -1.70 mA at AF4.

46. The method of any one of claims 1 to 45, wherein the tDCS is applied for a duration of at least five minutes.

47. The method of claim 46, wherein the tDCS is applied for a duration of at least ten minutes.

48. The method of claim 46 or 47, wherein the tDCS is applied for a duration of no more than two hours.

49. The method of claim 48, wherein the tDCS is applied for a duration of no more than 1 hour.

50. The method of any one of claims 46 to 49, wherein the tDCS is applied for a duration of from about 10 minutes to about 1 hour.

51. The method of claim 50, wherein the tDCS is applied for a duration of from about 20 minutes to about 40 minutes.

52. The method of claim 50, wherein the tDCS is applied for a duration of about 15 minutes, about 20 minutes, about 30 minutes, or about 45 minutes.

53. The method of any one of claims 46 to 52, wherein the tDCS is applied in a plurality of sessions.

54. The method of claim 53, wherein the tDCS is applied for at least 5 sessions.

55. The method of claim 53, wherein the tDCS is applied for at least 10 sessions.

56. The method of claim 53, wherein the tDCS is applied for at least 15 sessions or at least 20 sessions.

57. The method of any one of claims 53 to 56, wherein the tDCS sessions are applied at least once per week.

58. The method of claim 57, wherein the tDCS sessions are applied at least two or three times in at least one week.

59. The method of claim 58, wherein at least two sessions are performed on consecutive days, and optionally at least 2, 3, 4, or 5 consecutive days.

60. The method of any one of claims 46 to 56, wherein the regimen is performed at least twice on at least one day.

61. The method of any one of claims 46 to 57, wherein sessions are performed about weekly or about daily.

62. The method of any one of claims 46 to 57, wherein sessions are performed about twice daily or three times daily on average.

63. The method claims 62, wherein the sessions are performed no more than three times a day.