A method for operating a brain stimulation system, associated operating module and stimulation system

Abstract

The present invention relates to a method (100) for operating a brain stimulation system, the method comprising selecting (110) an envelope frequency comprised between about 25 Hz and 35 Hz; generating (120) a stimulation signal corresponding to a dichotic auditory stimulus comprising a primary stimulus and a secondary stimulus, wherein the primary stimulus comprises an amplitude-modulated carrier sound modulated by the envelope frequency; transmitting (130) the stimulation signal to a sound-emitting module configured to emit the dichotic auditory stimulus. The invention also concerns an operating module and a brain stimulation system related to the method (100).

Description

[0001] A method for operating a brain stimulation system, associated operating module and stimulation system

[0002] FIELD OF THE INVENTION

[0003] The present invention concerns a method for operating a brain stimulation system. The present invention also concerns a brain stimulation system implementing such a method.

[0004] The brain stimulation system implementing the method of the invention can be used to treat conditions characterized by a reduced or impaired phonological processing, such as dyslexia.

[0005] BACKGROUND OF THE INVENTION

[0006] Dyslexia is a frequent neurodevelopmental disorder of genetic origin that affects the schooling and psychological development of about 7% of children, and results in persistent reading and writing difficulties that are extremely challenging from childhood to adulthood, particularly in literate societies with intense written exchanges. The predominant cause of dyslexia lies in a phonological deficit, the ability to process the sounds of language, which most prominently impacts phonemic processing. This capacity allows representing and mentally manipulating phonemes, the smallest speech sounds, which in some languages such as Italian have a direct correspondence with alphabetic letters (e.g. / a / or / i / ). As learning to read requires the correct mapping of phonemes onto graphemes, impaired phonemic representation hampers reading acquisition. This explains why dyslexia is diagnosed around the age at which children learn reading.

[0007] Current solutions to alleviate this deficit consist almost exclusively of behavioral auditory and reading training (Frey, Aline, et al., Brain Sciences 9.4 (2019): 91 ; Loo, Jenny Hooi Yin, Stuart Rosen, and Doris-Eva Bamiou, Ear and hearing 37.1 (2016): 38-47) provided by a professional speech therapist. A standard solution is the application GraphoLearn, which is a tool that essentially retrains children on phonology and reading but that is not based on advanced neurophysiological data, and hence does not address the neurological cause of the phonological difficulties. Other clinical interventions that are currently being explored are for instance the upregulation of the visual word form area, an area of the brain that is involved in letter / grapheme processing. However, no reading improvement has been shown to date using this method (Haugg, Amelie, et al., Scientific

[0008] Reports 13.1 (2023): 9195).

[0009] Previous neuroscientific studies using electroencephalography to measure the electrical activity of the brain have associated dyslexia with a deficit in the oscillatory activity in the 25-35 Hz range, the so-called low-gamma band (Lehongre, Katia, et al., Neuron 72.6 (2011): 1080-1090; Lallier, Marie, et al., Clinical Psychological Science 5.2 (2017): 379-401 ; Di Liberto, Giovanni M., et al., NeuroImage 175 (2018): 70-79; Lizarazu, Mikel, et al., Human brain mapping 36.12 (2015): 4986-5002; Lizarazu, Mikel, et al., Cortex 137 (2021): 160-178; Marchesotti, Silvia, et al., PLoS Biology 18.9 (2020): e3000833). The involvement of this frequency band is particularly relevant as it corresponds to the phonemic encoding rate, as the key cues for phonemic discrimination occur within frames of approximately 30-40 ms. Lehongre, Katia, et al. and Marchesotti, Silvia, et al. (loc. cit.) provided pioneering work in two separate studies showing that individuals with dyslexia have reduced activity in the low-gamma oscillation band around 30 Hz in the left hemisphere as compared to good readers, ascertaining the reliability of this finding. In Marchesotti, Silvia, et al. (loc. cit.), normal brain response typically found in good readers was restored in individuals with dyslexia by applying transcranial alternating current stimulation (tACS, a widely used non-invasive electric brain stimulation method) delivered at 30 Hz to the left auditory cortex in dyslexic individuals to boost the oscillatory activity at this specific frequency. This study highlighted for the first time the causal role of low-gamma oscillation in phonemic processing. The stimulation was shown to be effective in increasing the amplitude of the oscillations specifically at 30 Hz and in the left hemisphere, together with improving phonemic perception and reading skills. Importantly, these behavioral improvements were absent when the tACS stimulation was faked or delivered at another frequency (i.e. 60 Hz), thereby proving the selectivity of using an intervention targeting oscillations specifically at 30 Hz.

[0010] Nevertheless, using stimulation approaches such as tACS requires specific equipment and procedures, which hinder their applicability outside of specialized institutions, such as for a domestic use in children. In addition, tACS is sometimes considered too invasive by the users or their relatives, and for a use in young children. A less invasive and more practical solution to assist subjects in need, such as subjects suffering from dyslexia, is therefore highly desirable. SUMMARY OF THE INVENTION

[0011] One of the aims of the invention is to solve the above-mentioned issues and to provide a solution that is both less invasive and more practical to assist subjects in need, such as subjects suffering from dyslexia.

[0012] For this purpose, the invention relates to a method for operating a brain stimulation system, the method comprising:

[0013] - selecting an envelope frequency comprised between about 25 Hz and 35 Hz;

[0014] - generating a stimulation signal corresponding to a dichotic auditory stimulus comprising a primary stimulus and a secondary stimulus, wherein the primary stimulus comprises an amplitude-modulated carrier sound modulated in amplitude by the envelope frequency;

[0015] - transmitting the stimulation signal to a sound-emitting module configured to emit the dichotic auditory stimulus.

[0016] Thanks to these features, the method according to the invention allows to operate a brain stimulation system.

[0017] Previous studies have shown that individuals with dyslexia present a specific deficit in the brain activity around 30 Hz in the left auditory cortex as compared to good readers (Lehongre, Katia, et al. ; Marchesotti, Silvia, et al. (loc. cit.)).

[0018] Marchesotti, Silvia, et al. (loc. cit.) recently showed that by using transcranial alternating current stimulation (tACS) delivered within the 25-35 Hz range, specifically at 30 Hz, to the left auditory cortex, reading skills and phonemic perception could be improved in adults with dyslexia. By measuring the brain response through electroencephalography (EEG), a specific enhancement of neural oscillations at 30Hz in the left auditory cortex after the electrical stimulation was observed. TACS also induced a re-lateralization of low- gamma oscillatory activity to the left superior temporal cortex by reducing activity in the right one, towards the inter-hemispheric balance typically found in normo-readers. The stimulation was effective on phonemic perception but not on syllabic perception, indicating the specificity of the intervention. Phonemic perception and reading improvement were absent when the tACS stimulation was faked or delivered at another frequency. These results highlight the potential of boosting brain activity specifically at 30 Hz in left auditory cortex. The inventors of the present invention conjectured discovered that by using a specific auditory stimulus, a similar brain oscillation boost was achievable, opening the way to a non-invasive sound-based method for targeting the neural mechanism involved in conditions characterized by a reduced or impaired phonological processing, such as dyslexia, with potential to alleviate the phonological deficit and the consequent reading impairment in subjects suffering from such conditions. The conjecture was confirmed in a proof-of-concept study performed in adults (Marchesotti et al. unpublished).

[0019] The invention encompasses a specific approach to deliver the sounds referred to as “dichotic stimulation”, wherein specific sounds are delivered only to the right ear (also referred to herein as primary stimulus), thereby activating the opposite brain hemisphere, the left auditory cortex (Bryden, M. Philip, and M. Barbara Bulman-Fleming, Behavioural Brain Research 64.1-2 (1994): 119-129; Kimura, Doreen, Cortex 3.2 (1967): 163-178; Saoud, Houda, et al., Journal of Neuroscience 32.1 (2012): 275-281), and balancing the potentially unpleasant monaural sensation. A dichotic auditory stimulus as used herein refers to the fact that the stimulus comprises two different sounds (e.g. a primary and a secondary stimulus), each of which is to be delivered to one of the two ears of a subject simultaneously.

[0020] The term “about” as used in “comprised between about 25 Hz and 35 Hz” is equivalent to a variation of ± 2 Hz from any one of the end values in such a range.

[0021] In some embodiments, the method according to the invention further comprises the step of receiving a response signal from a sensing module configured to detect a brain activity in response to the dichotic auditory stimulus. In some embodiments, the method according to the invention further comprises the step of quantifying the effect of the dichotic auditory stimulus on the response signal to allow a selection of the envelope frequency which maximizes the detected brain activity.

[0022] Thanks to these features, the effect of the dichotic auditory stimulus on the response signal can be monitored, and based on the quantification performed, the stimulus can be further controlled and adapted if required. In some embodiments, the detection of a brain activity comprises the detection of an electrical activity from the left auditory cortex. In some embodiments, the detection of a brain activity is measured at least at the vertex of the brain.

[0023] In some embodiments, the method according to the invention further comprises the step of transmitting the response signal and / or data related to the quantification of the response signal to a storage medium.

[0024] Thanks to these features, the response signal and / or data related to the quantification of the response signal can be stored and accessed remotely to allow any subsequent analysis of interest (such as the adaptation of the stimulation frequency within the operating range for an optimal effect) or monitored by a third party such as a speech therapist.

[0025] In some embodiments, the carrier sound has a frequency selected within the speech frequency range (e.g. 400 to 3500 Hz). In some embodiments, the carrier sound is continuous. In some embodiments, the carrier sound is a pure tone (e.g. equal to 440 Hz) or a complex harmonic or inharmonic tone in the above-mentioned frequency range.

[0026] In some embodiments, the primary stimulus comprises a plurality of noise intervals, preferably pink noise intervals, spaced in the amplitude-modulated carrier sound. In some embodiments, each of said noise interval comprised in the primary stimulus has a duration comprised between 0 sec and 10 sec, preferably of about 1 sec, and each amplitude- modulated carrier sound interval has a duration comprised between 0 sec and 10 sec, preferably of about 1 sec. Accordingly, in a preferred embodiment, the primary stimulus comprises a plurality of 1 sec long pink noise intervals regularly spaced with 1 sec long amplitude-modulated carrier sound intervals, wherein the carrier sound is of 440 Hz and is modulated by an envelope frequency comprised between about 25 Hz and 35 Hz, preferably between about 27 Hz and 33 Hz, more preferably between 27 Hz and 33 Hz. It is to be understood that the total duration of the dichotic auditory stimulus is dictated by the primary stimulation signal and can be configured accordingly. The term “about” as used in relation to an amount of time such as “about 1 sec” is equivalent to a variation of ± 10% of this value. In some embodiments, the envelope frequency is comprised between about 25 Hz and 35 Hz, about 25 Hz and 34 Hz, about 25 Hz and 33 Hz, about 26 Hz and 35 Hz, about 26 Hz and 34 Hz, about 26 Hz and 33 Hz, about 27 Hz and 35 Hz, about 27 Hz and 34 Hz and between about 27 Hz and 33 Hz. In some embodiments, the secondary stimulus comprises any sound differing from the primary stimulus. In some embodiments, the secondary stimulus does not comprise any amplitude-modulated sound. In preferred embodiments, the secondary stimulus comprises or consists of a constant pink noise.

[0027] In some embodiments, the dichotic auditory stimulus is configured to allow delivery of the primary stimulus to the right ear and of the secondary stimulus to the left ear of a subject. In some embodiments, the primary stimulus and the secondary stimulus comprised in the dichotic auditory stimulus as described herein are configured to be simultaneously delivered to the right and left ear of a subject, respectively.

[0028] In some embodiments, the method according to the invention further comprises the step of carrying out an entertainment activity in parallel to transmitting the stimulation signal to the sound-emitting module. In some embodiments, the entertainment activity comprises a visual stimulation via an interface. In some embodiments, the entertainment activity comprises a video game. In some embodiments, the entertainment activity comprises a drawing game.

[0029] In some embodiments, the invention relates to a computer program comprising software instructions which, when executed by a computer, carry out the method according to the invention.

[0030] The invention also relates to an operating module implementing the method according to the invention. Accordingly, in some embodiments, the invention relates to an operating module comprising:

[0031] - a processing module configured to select an envelope frequency comprised between about 25 Hz and 35 Hz and to generate a stimulation signal corresponding to a dichotic auditory stimulus comprising a primary stimulus and a secondary stimulus, wherein the primary stimulus comprises an amplitude-modulated carrier sound modulated by the envelope frequency; and

[0032] - a transmission module configured to transmit the stimulation signal to a soundemitting module configured to emit the dichotic auditory stimulus.

[0033] The invention further relates to a brain stimulation system comprising the operating module according to the invention. In some embodiments, the brain stimulation system of the invention further comprises: - a sound-emitting module configured to provide the primary stimulus to the right ear of a subject and the secondary stimulus to the left ear of the subject;

[0034] - a sensing module configured to detect a signal generated by the brain of the subject in response to the dichotic auditory stimulus; and

[0035] - a receiving module configured to receive the detected signal.

[0036] In some embodiments, the brain stimulation system according to the invention further comprises:

[0037] - a headset comprising the sound-emitting module and the sensing module; and

[0038] - a computing device configured to be connected to the headset and comprising the processing module, the transmission module and the receiving module.

[0039] In some embodiments, the computing device is a mobile device selected among a smartphone, a tablet or a laptop.

[0040] In some embodiments, the brain stimulation system according to the invention is a portable brain stimulation system. Alternatively, the brain stimulation system can be a fixed (or non-portable) brain stimulation system.

[0041] The invention further relates to the use of the brain stimulation system according to the invention for the treatment of a medical condition. For this purpose, stimulations are provided to a subject in need thereof by using the brain stimulation system according to the invention. Accordingly, in some embodiments, the invention relates to the use of the brain stimulation system according to the invention for the treatment of a medical condition of a subject suffering from the medical condition. In some embodiments, the invention relates to the brain stimulation system according to the invention for use in the treatment of a medical condition. In some embodiments, the brain stimulation system according to the invention is configured for treating a medical condition. In some embodiments, the invention provides a method for treating a subject suffering from a medical condition by brain stimulation using the brain stimulation system according to the invention. In preferred embodiments, said medical condition is a condition characterized by a reduced or impaired phonological processing. In some embodiments, the condition characterized by a reduced or impaired phonological processing is selected from the group consisting of dyslexia and receptive aphasia. In further preferred embodiments, the medical condition is dyslexia.

[0042] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, and / or decreasing the dose of one or more other medications required to treat the disease. The use of the present invention contemplates any one or more of these aspects of treatment. A “subject” as used herein is a human. In some embodiments, the subject is a child, preferably aged up to 18, up to 17, up to 16, up to 15, up to 14, up to 13, up to 12, up to 11 , up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 year(s) old.

[0043] In some embodiments the invention relates to the use of the brain stimulation system according to the invention for modulating brain activity of a subject. For this purpose, stimulations are provided to the subject by using the brain stimulation system according to the invention. In some embodiments the invention relates to a method of modulating the brain of a subject, the method comprising stimulating the brain of the subject by using the brain stimulation system according to the invention.

[0044] In some embodiments the invention relates to the use of the brain stimulation system according to the invention for modulating brain oscillations of a subject. For this purpose, stimulations are provided to the subject by using the brain stimulation system according to the invention.

[0045] In some embodiments, the uses of the brain stimulation system described herein involve repeated stimulations (or sessions of stimulations). Accordingly, in some embodiments, the brain stimulation system according to the invention is configured to provide a session of stimulations to a subject. In some embodiments, the treatment is 20 min of stimulation per day. The frequency as well as the total duration of a session (or treatment) can be adapted depending on the needs of the subject. In some embodiments, the brain stimulation system according to the invention is configured to provide the primary stimulus and the secondary stimulus comprised in the dichotic auditory stimulus simultaneously to the right and left ear of a subject, respectively.

[0046] BRIEF DESCRIPTION OF THE DRAWINGS The invention and its advantages will be better understood upon reading the following description, which is given solely by way of non-limiting examples, and which is made with reference to the appended drawings, in which:

[0047] Figure 1 is a schematic view of a portable brain stimulation system according to an embodiment of the invention;

[0048] Figure 2 is a schematic view of an operating module comprised in the mobile computing device of the portable brain stimulation system of Figure 1 .

[0049] Figure 3 is a block diagram of the method according to the invention for operating a portable brain stimulation system, said method being implemented by the operating module of Figure 2.

[0050] Figure 4 shows an experimental setup in which the brain stimulation system of Figure 1 is applied. Figure 4a illustrates a dichotic auditory stimulation delivered to a subject as applied in Experiment 1 and Experiment 2. Figure 4b is a detailed view of the right ear sound stimulus applied in these experiments.

[0051] Figure 5 shows results obtained in Experiment 1 , where the experimental setup of Figure 4 was used on healthy subjects.

[0052] Figure 6 shows results obtained in Experiment 2, where the experimental setup of Figure 4 was used on subjects diagnosed with dyslexia.

[0053] DETAILED DESCRIPTION OF THE INVENTION

[0054] Referring to Figure 1 , a portable brain stimulation system 10 according to an embodiment of the invention is shown, the system 10 comprising a headset 1 configured to be coupled to a computing device 2.

[0055] The headset 1 comprises a sound-emitting module 18 allowing the emission of an auditory stimulus. The headset 1 can be any portable device capable of delivering sound in proximity of the ears of a subject 4, such as headphones. Preferably, the headset 1 further comprises a sensing module 20 suitable for measuring a brain activity of the subject 4 wearing the headset 1. Although in the present examples sound is delivered by a portable device such as the headset 1 , it should be understood that the sound can be equivalently delivered by a suitable fixed (or non-portable) device.

[0056] The sound-emitting module 18 allows emission of an auditory stimulus based on a stimulation signal provided by a transmission module 16. Accordingly, the sound-emitting module 18 can include a receiver for receiving the stimulation signal. Alternatively, the sound-emitting module 18 receives the stimulus signal from a separate receiver comprised in the headset 1. As will be further detailed below in relation to the method 100 of the invention, the auditory stimulus is a dichotic auditory stimulus comprising a primary stimulus 26 and a secondary stimulus 28, wherein the primary stimulus 26 comprises an amplitude- modulated carrier sound modulated by an envelope frequency.

[0057] The sensing module 20 allows to detect signals such as electric activity generated by the brain of the subject 4 in response to stimuli provided by the system 10, in particular in response to the auditory stimulus from the sound-emitting module 18. Although primarily intended to monitor the activity of the brain in response to an auditory stimulus, it is to be understood that the sensing module 20 also allows to detect brain signals at any time during use of the brain stimulation system 10, such as for monitoring brain activity before, during and after the delivery of an auditory stimulus. The sensing module 20 can for instance be an electroencephalography (EEG) sensor. Preferably, the sensing module 20 comprises one or more EEG electrodes, preferably dry EEG electrodes. The sensing module 20 is preferably a non-invasive sensor. In preferred embodiments, the sensing module 20 is configured to at least detect a brain activity at the vertex of the brain of the subject 4. The sensing module 20 can include a transmission module for sending the detected signals to a receiving module 14 comprised in the mobile computing device 2. Alternatively, the sensing module 20 is configured to send the detected signals to the receiving module 14 by a separate transmission module comprised in the headset 1.

[0058] The computing device 2 comprises an operating module 9 configured to execute the method 100 according to the invention. The operating module 9 is illustrated in more detail in Figure 2.

[0059] As such, the computing device 2 can be any device suitable for carrying out the method 100 further described below. For example, the computing device 2 can be a mobile device such as a smartphone, a tablet or a laptop. Alternatively, the computing device 2 may be a fixed solution. The computing device 2 can be configured to communicate with a storage medium 5 and with the headset 1 to allow an exchange of data between these components. Accordingly, the mobile computing device 2 can be configured to transfer data measured via the sensing module 20 or computed by the operating module 9 in relation to the subject 4, to the storage medium 5. In some embodiments, the mobile computing device 2 is further configured to display information relating to the subject 4 during use of the system 10 via an interface, or to provide a visual stimulus to the subject 4 in parallel to the auditory stimulus. The interface can allow further controlling of the computing device 2.

[0060] The storage medium 5 is for example a remote database which is configured to store data measured during use of the portable brain stimulation system 10, in particular data measured via the sensing module 20 or computed by the operating module 9 in relation to the subject 4. The storage medium 5 can be configured to allow secured remote access to the stored data by a third party such as a speech therapist.

[0061] Referring to Figure 2, the operating module 9 comprises a processing module 12, a receiving module 14, a transmission module 16 and an optional entertainment module 22.

[0062] Each of modules 12, 14, 16 and 22 can be at least partially implemented as a software. In such a case, the computing device 2 further comprises a memory for storage of such software and a processor allowing execution of this software. Alternatively or in addition, at least one of modules 12, 14, 16 and 22 is implemented at least partially as a programmable logic circuit such as a FPGA (Field Programmable Gate Array) or ASIC (Application-Specific Integrated Circuit).

[0063] In some embodiments, the operating module 9 can present a software package which can be purchased and installed on the computing device 2.

[0064] The processing module 12 allows to select an envelope frequency, in particular an envelope frequency comprised between 25 Hz and 35 Hz. The selection of this envelope frequency can be based on a predetermined algorithm or rationale, or on an input from another module comprised in the operating module 9. Preferably, the envelope frequency is selected based on the signal from the sensing module 20 received by the receiving module 14, separately for each subject and thus adapted to each individual. The processing module 12 further allows to generate a stimulation signal corresponding to a dichotic auditory stimulus. Said dichotic auditory stimulus comprises a primary stimulus 26 and a secondary stimulus 28, wherein the primary stimulus 26 comprises an amplitude-modulated carrier sound modulated by the selected envelope frequency. The secondary stimulus 28 can comprise any sound differing from the primary stimulus. Preferably, the secondary stimulus 28 does not comprise any amplitude-modulated sound. More preferably the secondary stimulus comprises or consists of a pink noise. As used herein, the term “pink noise” refers to a noise whose intensity is inversely proportional to frequency over a specified range to give a constant energy per octave.

[0065] The receiving module 14 allows to receive signals from the headset 1 , in particular signals relating to measurements taken on the subject 4 by the sensing module 20.

[0066] The transmission module 16 allows to transmit the generated stimulation signal to the sound-emitting module 18. The transmission can be carried out by wire or wirelessly using any suitable means to this effect. For example, a radio-frequency communication protocol such as Bluetooth® can be used.

[0067] The optional entertainment module 22 allows to generate entertainment content to visually entertain the subject 4 in parallel to the delivery of the auditory stimulus. For example, the entertainment module 22 can be configured to generate and provide visual stimulation to the subject 4 via an interface of the computing device 2. Such visual stimulation encompasses information relating to the signals measured by the sensing module 20 and video games for providing behavioral therapy to the subject 4 in combination to the auditory stimulus.

[0068] The operating module 9 allows to execute a method 100 according to the invention for operating a brain stimulation system 10 which will now be further described with reference to Figure 3 showing a block diagram of its steps.

[0069] In a first step 110, the processing module 12 selects an envelope frequency comprised between about 25 Hz and 35 Hz, preferably between about 27 Hz and 33 Hz, more preferably between 27 Hz and 33 Hz. The selection of the envelope frequency can be based on a predetermined algorithm or rationale. In some embodiments, the envelope frequency is selected in this range of frequencies to maximize brain activity, more particularly brain oscillations in the left auditory cortex. Such brain oscillations can be measured by the sensing module 20 in step 150 of the method 100. In the following step 120, the processing module 12 generates a stimulation signal corresponding to a dichotic auditory stimulus. Said dichotic auditory stimulus comprises a primary stimulus 26 and a secondary stimulus 28, wherein the primary stimulus 26 comprises an amplitude-modulated carrier sound modulated by the envelope frequency selected in step 110. The amplitude modulation to generate the primary stimulus 26 can be achieved by any modulation means known to the skilled person in the art. In some embodiments, the carrier sound can be a pure tone comprised between 400 Hz and 3500 Hz, such as equal to 440 Hz. In some embodiments, the amplitude-modulated carrier sound has noise characteristics (spans the speech frequency range 400-3500 Hz). In some embodiments, the primary stimulus 26 comprises a plurality of noise intervals, preferably pink noise intervals, regularly spaced in the amplitude-modulated carrier sound. In some embodiments, each of said noise interval comprised in the primary stimulus 26 has a duration comprised between 0 sec and 10 sec, preferably of about 1 sec, and each amplitude-modulated carrier sound interval has a duration comprised between 0 sec and 10 sec, preferably of about 1 sec. Accordingly, in a preferred embodiment, the primary stimulus 26 comprises a plurality of 1 sec long pink noise intervals regularly spaced with 1 sec long amplitude-modulated carrier sound intervals, wherein the carrier sound has a frequency of 440Hz and is modulated by an envelope frequency comprised between about 25 Hz and 35 Hz, preferably between about 27 Hz and 33 Hz, more preferably between 27 Hz and 33 Hz. Such a primary stimulus 26 is represented in Figure 4b. It is to be understood that the total duration of the dichotic auditory stimulus is dictated by the stimulation signal and can be configured accordingly. The secondary stimulus 28 can comprise any sound differing from the primary stimulus 26. Preferably the secondary stimulus 28 comprises or consists of a constant pink noise. Such a secondary stimulus 28 is represented in Figure 4a. All sound levels are set to a comfortable level of about 50 dB above hearing threshold (HL) never exceeding 70 dB SPL (Sound Pressure Level).

[0070] In the following step 130, the transmission module 16 transmits the stimulation signal generated in step 120 to the sound-emitting module 18 to generate and deliver the dichotic auditory stimulus to the subject 4.

[0071] In the following step 140, the sensing module 20 detects a brain activity in response to the delivered dichotic auditory stimulus. Various parameters of the brain activity are encompassed in this detection, and the resulting signals will be collectively referred to as the response signal detected by the sensing module 20. As described above, the sensing module 20 is preferably a non-invasive sensor capable of measuring an electrical brain activity, such as for instance an EEG sensor comprising an array of electrodes, preferably dry electrodes. The sensing module 20 is further particularly suited or configured to detect electrical activity from the left auditory cortex. The detected response signal is then transmitted to the operating module 9 by the sensing module 20, or alternatively by a transmission module comprised in the headset 1. The operating module 9 therefore receives the response signal. For this purpose, the operating module 9 can comprise a receiving module 14 configured to communicate with the processing module 12.

[0072] In the following step 150, the response signal is processed by the processing module 12 to quantify the effect of the dichotic auditory stimulus on the response signal. This processing can include time-frequency analysis of the response signal, and any other signal processing operation commonly used in the art such as the power, the coherence and the phase-locking value of the brain signals. The output data of this processing can then be used for a subsequent selection of an envelope frequency in step 110.

[0073] In the following step 160, the processing unit 12 transmits the response signal and / or data related to the processing performed in step 150 via the transmission module 16 to the storage medium 5.

[0074] The step 170 is an optional entertainment step. In this step 170, the entertainment module 22 generates entertainment content to visually entertain the subject 4 in parallel to the delivery of the auditory stimulus from the transmission module 16 to the sound-emitting module 18. The entertainment module 22 can therefore be configured to generate and provide visual stimulation to the subject 4 via an interface, preferably an interface of the computing device 2.

[0075] In some embodiments, the method 100 is applied to calibrate the portable brain stimulation system 10 for a specific subject. In such cases, a plurality of envelope frequencies (between 25 Hz and 35 Hz) is selected and tested for maximal brain activity response according to the method 100. Upon identifying a frequency inducing maximal brain activity response, the method 100 can be repeated and said identified frequency is selected (and maintained) in any subsequent occurrence of step 110, such as for different subsequent stimulation sessions (or treatments) provided to the subject. In others embodiments, the envelope frequency can be adapted and selected for each repetition of the stimulation. An example of implementation of the method 100 in a portable brain stimulation system 10 is provided in Experiments 1 and 2 detailed below. Results of these experiments are shown in Figures 4 to 6

[0076] Experiment 1 : neural response to dichotic stimulation

[0077] The effect of a dichotic auditory stimulation on brain oscillations was tested in healthy normally hearing subjects. Participants (n = 5) were exposed to a 20-minute dichotic stimulation at a stimulus modulation frequency that was set for all participants at 30 Hz. Brain response was measured before and immediately after the stimulation by means of a 256-channels EEG system.

[0078] The auditory stimulation consisted of an amplitude-modulated pure tone carrier (440 Hz), modulated by an envelope frequency corresponding to the 30 Hz stimulus frequency. This stimulus was delivered to the right ear of the subjects (primary stimulus 26) and a pink noise was delivered to the left ear (secondary stimulus 28). To avoid attenuation effects in the neural response due to habituation, the stimulation to the right ear was provided in bursts of 1 second regularly spaced with 1 second of pink noise, while the noise stimulation in the left ear was continuous. Figure 4 illustrates the stimulus configuration for the 30 Hz stimulus. The dichotic nature of the stimulus is represented in Figure 4a showing the primary stimulus 26 and the secondary stimulus 28. Details of the primary stimulus 26 are shown in Figure 4b, where the box 30 shows a zoomed view of the amplitude-modulated sound at 30Hz.

[0079] Results

[0080] Figure 5 shows the measured auditory steady state response (ASSR) in time to amplitude-modulated sounds delivered at different frequencies (i.e. 28, 30, 32, 40 and 58 Hz). The average neural response in the time domain to the amplitude-modulated sounds shows the stereotypical onset and offset evoked potentials (Figure 5a) as recorded through electrode Cz (Figure 5b). Figure 5b shows the topography of the activity over the scalp around the first positive peak (P200), with electrode Cz characterized by the strongest peak- to-peak response amplitude.

[0081] The values represented in Figure 5c correspond to average response over the portion of the signal between the onset and offset of the auditory stimulation (grey area in Figure 5a), which is modulated by the frequency of the stimuli. It is possible to observe this modulation with the naked eye from the EEG channel Cz: the brain oscillations synchronize with the frequency of the auditory stimuli (Figure 5a).

[0082] The two curves in Figure 5c corresponds to the measures observed before (S1) and after (S2) a 20 min dichotic auditory stimulation at 30 Hz. As can be seen, the magnitude of brain oscillations at 30 Hz and in the neighboring frequencies (28, 30, 32, 40 Hz) increases, whereas a higher frequency chosen as a control (58 Hz) is not affected by the stimulation, and on average shows a decrease. The fact that the increase occurs not only at 30 Hz but in the surrounding frequencies supports the potential of a personalized frequency of stimulation.

[0083] Experiment 2: auditory stimulation improves phonemic processing

[0084] In this experiment, the effectiveness of the dichotic auditory stimulation on behavioral performance was evaluated in a separate group of individuals who received a diagnosis of dyslexia from a speech therapist (n = 5). Linguistic tests specifically targeting the abilities that are impaired in dyslexia before and after a 20-minute dichotic auditory stimulation were performed. The dichotic auditory stimulation was delivered as described in Experiment 1.

[0085] To evaluate the efficacy of the stimulation on phonological processing and reading, language tests that are commonly used by speech therapists and that were used in previous studies (Marchesotti, Silvia, et al. (loc. cit.)) were performed. These tests probe phonemic processing, syllabic short-term memory, phonological and lexical structure processing, and reading skills taking into account lexical knowledge. An appropriate test to evaluate specifically phonemic perception at the base of the dyslexic impairment is the pseudo-word reading test, which was applied in this experiment.

[0086] Results

[0087] The number of phonemic errors in reading 32 pseudo-words was evaluated. The normalized performance before and after auditory stimulation is shown in Figure 6. Strikingly, performance improves after the 20 minutes of auditory stimulation in all participants (T4 = 3.5, p < 0.05, d = 1.59).

Claims

CLAIMS1. A method (100) for operating a brain stimulation system (10), the method comprising:- selecting (110) an envelope frequency comprised between about 25 Hz and 35 Hz;- generating (120) a stimulation signal corresponding to a dichotic auditory stimulus comprising a primary stimulus (26) and a secondary stimulus (28), wherein the primary stimulus (26) comprises an amplitude-modulated carrier sound modulated by the envelope frequency;- transmitting (130) the stimulation signal to a sound-emitting module (18) configured to emit the dichotic auditory stimulus.

2. The method according to claim 1 , further comprising:- receiving a response signal from a sensing module (20) configured to detect (140) a brain activity in response to the dichotic auditory stimulus.

3. The method according to claim 2, further comprising:- quantifying (150) the effect of the dichotic auditory stimulus on the response signal to allow a selection of the envelope frequency which maximizes the detected brain activity.

4. The method according to any one of claims 2 or 3, wherein the detection of a brain activity comprises the detection of an electrical activity from the left auditory cortex.

5. The method according to any one of claims 2 to 4, wherein the detection of a brain activity is measured at least at the vertex of the brain.

6. The method according to any one of claims 2 to 5, further comprising:- transmitting (160) the response signal and / or data related to the quantification of the response signal to a storage medium (5).

7. The method according to any one of the preceding claims, wherein the carrier sound has a frequency selected between 400 Hz and 3500 Hz, advantageously equal to e.g. 440 Hz.

8. The method according to any one of the preceding claims, wherein the primary stimulus (26) comprises a plurality of pink noise intervals spaced in the amplitude-modulated carrier sound, preferably each pink noise interval having a duration of about 1 sec, and each amplitude-modulated carrier sound having a duration of about 1 sec.

9. The method according to any one of the preceding claims, wherein the secondary stimulus (28) comprises a pink noise, preferably consists of a pink noise.

10. The method according to any one of the preceding claims, further comprising:- carrying out an entertainment activity (170) in parallel to transmitting the stimulation signal to the sound-emitting module (18).

11. An operating module (9) comprising:- a processing module (12) configured to select an envelope frequency comprised between about 25 Hz and 35 Hz and to generate a stimulation signal corresponding to a dichotic auditory stimulus comprising a primary stimulus (26) and a secondary stimulus (28), wherein the primary stimulus comprises an amplitude-modulated carrier sound modulated by the envelope frequency; and- a transmission module (16) configured to transmit the stimulation signal to a soundemitting module (18) configured to emit the dichotic auditory stimulus.

12. A brain stimulation system (10) comprising the operating module (9) according to claim 11 , the brain stimulation system being preferably portable.

13. The brain stimulation system (10) according to claim 12, further comprising:- a sound-emitting module (18) configured to provide the primary stimulus (26) to the right ear of a subject (4) and the secondary stimulus (28) to the left ear of the subject (4);- a sensing module (20) configured to detect a signal generated by the brain of the subject in response to the dichotic auditory stimulus; and- a receiving module (14) configured to receive the detected signal.

14. The brain stimulation system (10) according to claim 13, comprising:- a headset (1) comprising the sound-emitting module (18) and the sensing module (20); and- a computing device (2) configured to be connected to the headset (1) and comprising the processing module (12), the transmission module (16) and the receiving module (14).1915. The brain stimulation system (10) according to any one of claims 12 to 14 for use in the treatment of a condition characterized by a reduced or impaired phonological processing, such as dyslexia or receptive aphasia.

Images