Changes in Brain Activity as a Function of Scalp and Subcutaneous Electrical Stimulation Parameters in Epileptic Patients
Phase: NA
Conditions: Epilepsy
Sponsor: Semmelweis University

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
1 / 40 
Document title: 
Clinical trial data and documents 
The name of the study 
Changes in brain activity as a function of scalp and 
subcutaneous electrical stimulation parameters in epileptic 
patients 
Original permission number: OGYÉI/9674/2021
Date of original acceptance: 04/06/2021
Permission number of revised protocol: NNGYK/4245/2025
Date of last revision: 01/13/2025
Name of the sponsor/investigation manager: Dr. habil Erőss Loránd 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
2 / 40 
In case of a multicenter investigation, a resolution from the relevant Ethics Committee of 
the State party to the EEA Agreement (if applicable). 
 The study is not multicentric, so this point is not applicable. 
15) The clinical trial plan, which includes
a) Purpose of the study (testing effectiveness)
The objective of this study is to evaluate the effects of spatially and temporally targeted 
transcranial 
stimulation—specifically, 
Intersectional 
Short 
Pulse 
(ISP) 
stimulation 
administered via extracranial and subgaleal electrodes—on epileptic brain phenomena, 
 and EEG activity in subjects 
with epilepsy. We aim to assess the tolerability, safety, and preliminary effectiveness of 
ISP stimulation by systematically optimizing stimulation parameters. In patients 
participating in the extended three-phase study design, we will evaluate the practicality 
and effectiveness of closed-loop automatic stimulation. This stimulation will be precisely 
controlled by a fine-tuned seizure detection algorithm, with efficacy determined primarily 
by the reduction in the frequency of clinically observable epileptic seizures. 
Furthermore, we aim to refine the precision of deep brain targeting for transcranial 
stimulation by employing individualized MRI and neuronavigation-based localization 
techniques. 
b) Accurate, objective definition of the goals to be achieved
First objective is to determine the accuracy and feasibility of electrode placement under the 
scalp. We will perform patient-specific MRI-based estimations of current distribution in 
epileptic patients. These estimations, combined with neuronavigation positioning, will inform 
the precise placement of implanted electrodes. 
Our second aim is to investigate the dose-response and tolerance relationships: 
•

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
3 / 40 
•
in epileptic patients. Targeted ISP stimulation will be applied to cortical areas using
standardized parameters to evaluate its efficacy and safety.
During the study, subjective sensations experienced by the patients will be systematically 
recorded, both to identify potential side effects and to evaluate sensory experiences induced 
by the stimulation.
 Additionally, changes in epileptic spike 
frequency on EEG recordings will be monitored. 
Our third objective is to determine whether stimulation triggered very early in seizure onset, 
via an automated seizure detection algorithm, is more effective in terminating seizures or 
preventing their generalization compared to stimulation initiated at later stages of the seizure. 
This involves the detection of epileptic seizures in patients and customization of the seizure 
detection algorithm to their individual EEG patterns. The accuracy of this seizure detection 
will be validated using EEG segments from both seizure-free intervals and intervals with 
artificially introduced EEG artifacts.  
An additional objective of this study is to modulate epileptic seizures through 
spatially and temporally targeted transcranial stimulation delivered via implanted 
electrodes. Seizure episodes will be recorded through the stimulation electrodes and 
automatically detected. Detected seizures will then be targeted for intervention using 
timed ISP pulses delivered at previously established safe intensities. The effectiveness of 
stimulation will be evaluated by comparing the duration of seizures treated with ISP 
stimulation to untreated seizures. For patients enrolled in the three-phase experimental 
protocol, we will further compare clinically observed seizure frequencies during periods of 
active stimulation and control periods without stimulation. 
c) Description of study method (e.g. double-blind, randomised, etc.)
Interventional, open label observational clinical trial. 
d) Description of the investigation procedure
We will use a previously developed electronic system capable of delivering precisely 
controlled Intersectional Short Pulse (ISP) stimulation. This device can simultaneously record 
EEG signals from electrodes placed externally on the scalp or subgaleally, without significant 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
4 / 40 
 
distortion due to its wide dynamic range. Recorded signals will undergo real-time adaptive 
signal processing to remove stimulation-related electrical artifacts, thereby preserving the 
integrity and clinical relevance of the EEG data. 
In the current study, we will employ our validated (1) signal processing system to investigate 
the impact of transcranial stimulation on resting-state and pathological brain activities, 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
5 / 40 
Procedures for Patients with Epilepsy 
Patients will primarily be recruited from the epilepsy outpatient clinic at SEINK. Eligibility 
includes drug-resistant epilepsy patients who have been determined unsuitable for resective 
surgery based on established clinical criteria (as detailed in the inclusion criteria). 
Upon providing informed consent after thorough explanation of the study, participants will 
undergo assessments conducted at the SEINK facilities. Patients will be enrolled based on the 
availability of resources in the Video-EEG testing laboratory. 
The investigation consists of multiple sequential stages: 
Stage I: MRI Scanning and Neuronavigation 
Patients will first undergo an MRI scan to guide precise electrode placement using 
neuronavigation technology. The MRI protocol, lasting no more than 60 minutes, will include 
routine clinical sequences (3D MPRAGE T1, FLAIR) to obtain high-resolution anatomical images 
necessary for creating individualized neuronavigation maps.  
Stage II: Electrode Positioning and Planning 
The exact electrode positions will be determined based on patient-specific 3D head models 
derived from MRI images. Neuronavigation (Neural Navigator, Brain Science Tools BV) will 
ensure accurate and reproducible placement of electrodes at predefined cortical targets.  

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
6 / 40 
Stage III: Electrode Implantation and ISP Stimulation 
Electrode implantation and subsequent neurophysiological and cognitive assessments, 
including ISP stimulation, will be performed in the Video-EEG laboratory at SEINK’s Neurology 
Department.  
Two alternative protocols are available for conducting the investigation: 
In the first protocol, patients will participate for a maximum duration of 30 days, during which 
hospitalization is continuous, under the following conditions: 
1) Seven days after electrode implantation, a surgical assessment of wound healing is
performed to ensure proper healing and the absence of infection risk. If the outcome of this
evaluation is satisfactory, the investigation may continue.
2) Fourteen days after implantation, the wound check described in point 1 will be repeated. If
results are satisfactory, the investigation period may be extended for two additional 7-day
intervals. Thus, the total duration of participation can reach up to 30 days, including 2 days
dedicated to preparatory examinations, surgery, and system installation, followed by up to 28
days allocated for EEG monitoring, seizure recording, and ISP stimulation.
During rapid, pulse-like electrical stimulation, the risk of potential tissue damage is not 
determined solely by stimulation intensity, power density, or duration individually, but rather 
by the total charge density transferred to cellular membranes over the stimulation period—

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
7 / 40 
essentially, the combination of these parameters. In practice, this means that a longer, low-
intensity stimulus and a shorter, high-intensity stimulus can produce equivalent effects. For 
example, intraoperative cortical stimulation often uses a short duration of 0.1 ms at 
approximately 100 mA intensity, whereas transcranial stimulation typically involves several 
milliseconds at lower intensities (1–2 mA), both potentially resulting in similar charge 
densities. For our electrical stimulation experiments, instruments specifically developed by 
Neunos ZRt will be utilized. During ISP stimulation, electrodes with a surface area of 19.6 mm² 
will be implanted subgaleally (beneath the scalp) to reduce charge density, thereby minimizing 
patient discomfort and avoiding potential injury. Standard subdural electrode strips (Ad-Tech 
Medical Instrument Corporation, WI, USA; models MS08R-IP10X-0JH and MS08R-IP10X-000) 
will be used. 
Electrode insertion will be carefully planned and performed by an experienced neurosurgeon 
under general anesthesia. Electrodes will be inserted subcutaneously through small skin 
incisions. 
Electrodes will be positioned beneath the scalp but superficial to the skull bone. The electrode 
strips remain stable once positioned subgaleally, secured only by absorbable sutures. 
Electrode cables will be externalized percutaneously using a tunneling needle, exiting away 
from the primary skin incision site to minimize infection risk. 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
8 / 40 
Following electrode insertion, externalisation of electrode leads, layered closure of the skin, 
and recovery from anesthesia, a CT scan is performed to verify the exact positioning of the 
electrodes. The patient is then transferred to the video-EEG unit. After a brief postoperative 
recovery period, the externalised electrode leads are connected to the Neunos SeizureSTOP™ 
system. 
. The subgaleal 
electrodes are simultaneously connected to both the clinical EEG recording system and the 
Neunos system, allowing concurrent monitoring. 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
9 / 40 
 Although the stimulation parameters used 
in the proposed paradigms differ, the charge density transferred during a single stimulation 
cycle at any electrode does not exceed the safe limit used by commercially used and already 
approved stimulation methods . (3) 
Before, during and after the stimulation, EEG measurements will be performed to investigate 
the spectral properties of brain activity and, through them, the electrophysiological efficacy 
of the stimulation. EEG analysis will be performed off-line,
The planned 3+1 stimulation paradigms are as follows: 
III./1. ISP Parameter Dependence of Subjective Tolerability of Stimulation 
The tolerance test will be performed on the morning following electrode implantation, or—in 
the case of patients enrolled in the three-phase (ambulatory) protocol—the morning after 
hospital admission. This timing ensures adequate recovery of the surgical site, patient 
comfort, and minimizes the potential influence of residual anesthetic effects on test 
outcomes. 
The objective of this test is to evaluate how individual ISP stimulation parameters, beyond 
stimulation intensity alone, influence subjective tolerability. The results obtained will guide 
the optimization of ISP stimulation parameters for subsequent clinical use, aiming to achieve 
maximum therapeutic efficacy while minimizing patient discomfort. 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
10 / 40 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
11 / 40 
III./2. Measurement of Patient-Specific ISP Sequence Tolerance 
Therapeutic stimulation is delivered by rapidly connecting specific groups of electrodes, 
forming a tailored ISP sequence. Based on the outcomes of the previous test (III./1), we 
identify the electrode pairs within the sequence capable of safely delivering the highest 
stimulation intensity without causing discomfort. Spatial targeting is guided by directing 
stimulation specifically towards the patient's presumed seizure-triggering cortical area. When 
creating the ISP stimulation sequence, preference is given to electrode pairs demonstrating 
higher tolerability to ensure optimal spatial selectivity. 
Prior to initiating therapeutic stimulation, we determine the maximum tolerable stimulus 
intensity for the finalized ISP sequence. This determination accounts for the patient’s 
individual anatomy and the tolerance thresholds identified for each electrode pair. 
Procedure: Subjects are positioned comfortably, either seated in a reclining chair or lying in 
their hospital beds during the measurement. 
After programming the selected ISP stimulation sequence, stimulation is initiated at an 
intensity of 5 mA. The amplitude is incrementally increased in steps of 0.5–2 mA, and the 
patient's reported sensory experiences and subjective discomfort levels are digitally recorded 
using a Visual Analog Scale (VAS). A pause of at least 5 seconds is maintained between each 
stimulus. Stimulation parameters match those used for seizure management:
The stimulation intensity continues to be gradually increased until the patient reaches an 
painful level (VAS = 10), which the patient deems higher than acceptable for anti-seizure 
treatment or until the maximum safe charge density is achieved. The highest intensity level 
associated with acceptable discomfort (VAS = 9) immediately preceding intolerable pain is 
designated as the subject's individual tolerance threshold and represents the maximum 
allowed therapeutic stimulation intensity for seizure control in that ISP sequence. 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
12 / 40 
 
In cases involving multiple ISP sequences (e.g., multifocal epilepsy), individual tolerance 
thresholds are determined separately for each sequence. The tolerance assessment 
procedure typically requires up to 5 minutes per ISP sequence. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
13 / 40 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
14 / 40 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
15 / 40 
III./6. The Ability of Closed-Loop Administration of ISP to Stop Pathological (Epileptic) 
Brain Rhythms 
One desired outcome of this study is to investigate that accurately parameterized and 
precisely timed ISP stimulation can effectively modulate pathological brain activity. As 
demonstrated previously in animal models,(1) such stimulation may impact epileptic activity 
by arresting seizures, shortening seizure duration, preventing seizure propagation (including 
bilateral spreading), and modifying seizure spectral composition. According to existing 
literature, these effects strongly correlate with long-term therapeutic efficacy of this method 
(35). 
The Measurement Procedure: 
1. To assess changes in seizure frequency and severity, a paper-based seizure diary is
maintained by the patient starting at least 30 days prior to electrode implantation (if
available), and continuing for at least 60 days after implantation. This diary records the daily
number and type of seizures, patient comments, and medication usage. The three-phase
study design (ambulatory) also enables detailed analysis of changes in electrophysiological
activity through continuous EEG monitoring data.
2. Examination of the effects of ISP stimulation on neurophysiological properties of epileptic
seizures. The primary objective of this set of measurements is to statistically compare seizure
durations with and without ISP stimulation, thereby evaluating the efficacy of the
intervention. An additional goal is to validate and refine the performance of the automatic

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
16 / 40 
seizure detection algorithm. Together, these objectives will further establish the feasibility and 
safety of the closed-loop stimulation method. 
In the first protocol (the maximum 30-day, in-hospital-only study), EEG monitoring is 
conducted using the Neunos system employed in previous studies, alongside standard clinical 
EEG equipment. During the monitoring period, patients will be housed within the SEINK Video-
EEG monitoring unit. They will be permitted mobility consistent with standard clinical 
procedures, allowing them to move within the hospital as directed by clinicians. The total 
monitoring period—from implantation to hospital discharge—is limited to 30 days and is 
divided into the following phases: 
1. Initial (Control seizure recording) Phase: Lasting at least 5 days (including the implantation
day), this phase involves continuous EEG recording without stimulation. Spontaneous seizures
and resting EEG activity are documented, and individual tolerance assessments
 are conducted as detailed previously. Collected EEG data, combined with clinician-
annotated seizure onset and offset times, serve as training data for the automated seizure 
detection algorithm. 
2. Semi-Automatic Stimulation Phase: After completing the detector training, the semi-
automatic ISP stimulation mode is activated. Here, when the seizure detector triggers an alert,
the investigator initiates stimulation manually after verifying seizure onset through real-time
EEG and video monitoring. If a seizure occurs without detector activation, the investigator
may manually trigger stimulation based on clinical judgment. ISP stimulation intensity settings
are based on patient-specific tolerance thresholds established in prior testing phases. During
this phase, the accuracy of seizure detection (specificity, sensitivity, false detection rate) is
evaluated against clinician-defined seizure epochs, and detection parameters are adjusted
accordingly.
3. Automatic Closed-Loop Stimulation Phase: Once the clinician confirms reliable seizure
detection performance (specificity >90%, sensitivity >90%, false detection rate <1/h), the ISP
system proceeds to automatic closed-loop stimulation. EEG and video streams continue to be
closely monitored by the investigator, who retains the ability to manually intervene and stop
or initiate stimulation to address any false positives or negatives.
4. ISP Stimulation Procedure During Seizures: When seizure activity is identified—either
automatically by the detector or manually by the supervising clinician—the pre-configured ISP
stimulation sequence is activated. Post-stimulation, EEG signals are momentarily obscured by
stimulation artifacts (lasting 1-2 seconds). Once the artifact period passes, the seizure detector 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
17 / 40 
resumes EEG analysis. If ongoing seizure activity is detected, the clinician visually confirms and 
may repeat stimulation. 
Multiple stimulation sequences (each consisting of three half-sine pulses) can be administered 
per seizure, with sufficient intervals between sequences to enable clear EEG analysis post-
artifact. Individual stimulation pulses are 
The cortical target for stimulation is initially set by the clinician, based on the 
identified epileptic focus and with careful consideration of minimizing side effects to 
adjacent deep brain structures. ISP stimulation sequences are always individually 
tailored to patient-specific tolerance thresholds. 
In the second protocol, in the three-phase study design, patients will participate for a 
maximum of 90 days (3 days in hospital; up to 30 days at home with EEG recording without 
stimulation; up to 30 days at home with EEG recording and seizure detection without 
stimulation; up to 30 days in hospital with stimulation) to evaluate longer-term efficacy. The 
objectives of the two at-home phases are: firstly, to record sufficient baseline EEG and 
seizure data required to train the seizure detection algorithm and collect non-stimulated 
control seizures; secondly, to fine-tune the seizure detection algorithm and validate its 
performance 
(sensitivity and false-positive rate). These preparations will ensure safe and effective closed-
loop ISP stimulation during the final hospital phase. 
The test phases are conducted under the following conditions: 
1) Three days after electrode implantation, the patient remains hospitalized, the system is
installed, and the hospital staff assesses wound healing (proper healing, no infection
risk). If the evaluation is positive, the study continues.
2) If the wound condition is satisfactory, the hospital and technical staff prepare the patient
and, if necessary, their relatives for the home phase of the study:
a. The patient receives thorough instructions on using the system at home, including
guidance on daily activities, comfort, hygiene, sleep, and mobility.
b. The patient is provided with necessary equipment: modular device storage bag, external
batteries, battery charger, and a waterproof bag.

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
18 / 40 
c. The patient receives detailed instructions on maintaining cleanliness of the cable exit site
and symptoms requiring immediate staff notification.
d. Patients and relatives are provided with immediate contact details for technical and
medical support.
3) The patient spends the registration phase (up to 30 days) at home under the following
conditions:
a. The system operates only in EEG recording mode, without stimulation or seizure
detection, recording EEG signals continuously (24/7).
b. The modular neurostimulator is stored in a dedicated backpack, with externalized cables
connected directly to the device inside. The patient replaces the external battery daily based
on audible device notifications. A factory-designed, mechanically safe connector cable is
used, which disconnects safely under excessive tension, avoiding damage to cables or scalp
stitches.
c. Electrode cables may be temporarily disconnected for activities such as cleaning or
washing. In such cases, the head unit collecting cables must be placed in a provided
waterproof bag. Upon reconnection, EEG recording automatically resumes.
d. Hospital staff conduct phone check-ins every other day to confirm patient wellbeing and
address any concerns. If feedback is positive, the study continues.
e. A qualified healthcare professional inspects the wound condition every 7 days (or more
frequently if clinically required), either at home or hospital, assessing for proper healing and
absence of infection risk (mild inflammation may be acceptable). Dressings are changed, and
the wound area treated accordingly. If the outcome is positive, the study continues.
f. If signs of wound infection are detected, the patient is immediately examined by the
surgical team at the hospital and treated according to medical guidelines. Patient safety
remains the priority; the team may decide to continue with conservative treatment (topical
or systemic antibiotics) or immediately terminate the study and explant electrodes.
g. The study must also be terminated immediately if the patient experiences discomfort,
pain, or any other issues that prompt withdrawal, even without visible complications.
h. To adequately train a highly reliable seizure detection algorithm, recording an adequate
number of seizures with good-quality data is essential. The duration required for this phase

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
19 / 40 
depends on the individual patient's seizure frequency. When sufficient data is obtained, this 
phase may be shortened, subject to investigator review and agreement. 
4) During the initial registration phase, technical staff review EEG recordings daily,
annotating seizure activity and any EEG artifacts. Annotated data is used to train the seizure
detection algorithm. The trained algorithm is activated during a scheduled hospital visit
without delivering stimulation at this stage. During the same visit, wound status is assessed
again (proper healing, no risk of infection, mild inflammation acceptable). If this check is
satisfactory, the study continues.
5) In the following seizure detector tuning phase, the patient spends another period at home
under conditions described in point 3. During this up-to-30-day phase, EEG signals and
automated detector decisions are continuously recorded. This data allows long-term
monitoring and further tuning of detector performance as needed. Detector efficacy is
evaluated offline through recorded data analysis (sensitivity, specificity, false detection rate).
6) Upon reaching a sufficient number of detected seizures and statistically acceptable
detector accuracy (>90% specificity, >90% sensitivity, false detection rate <1/h), the study
may proceed earlier to the next phase, shortening the 30-day duration. The final decision on
study pipeline progress is made collaboratively by the clinical investigators.
7) Following the second home phase (seizure detector tuning), the patient returns to the
hospital for up to 30 days for the final stimulation phase, similar to the first case described
above. During this phase, stimulation-related testing is performed. Unlike the first case, no
additional control seizure recordings or detector training are required, as these steps were
completed previously. The stimulation phase begins immediately following the
determination of individual tolerance thresholds.
IV) The conclusion of the will occur no later than 30 days after implantation. The exact duration 
of participation is determined jointly by the patient and the clinical team. At the end of the
study period, the implanted electrodes are removed under local scalp-blockade, and the skin
is closed in anatomical layers.
After participation in the three-phase study, slight scarring may develop around the implanted 
electrodes, which can make atraumatic removal of the electrode strips more difficult. In such 
cases, and based on the neurosurgeon's judgment, a pulsed radiofrequency (RF) dissection 
device may be used. This technique allows the strips to be removed without causing tissue 
damage and without damaging the explanted device, ensuring that no part of the implant 
remains under the skin (36). 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
20 / 40 
V) During the follow-up phase, any delayed adverse effects or medium-term changes in
epileptiform activity will be monitored and recorded to provide additional safety data. The
follow-up plan is detailed in Chapter 16g).
e) Factors Affecting the Outcome of the Test (e.g., Other Diseases)
Patients eligible for inclusion in the study may present with comorbidities, such as memory 
or mood disorders, depending on their specific epilepsy type. The etiology of epilepsy in 
the patient population is expected to be heterogeneous; however, autoimmune etiologies 
are strictly excluded.  Each patient will serve as their own control, and all results will be 
analyzed individually prior to any pooled analysis. Therefore, the presence of 
comorbidities in a participant is not expected to introduce bias into the study results. 
Additionally, patients with severe internal medicine conditions or progressive brain 
pathologies will be excluded from the study. 
Data sheet sample, algorithm, written instructions for the evaluation of the study 
Data recorded during electrophysiological measurements are analyzed using commercially 
available
 software 
 and 
. EEG signals 
during stimulation are cleaned and pre-processed using a proprietary signal filtering 
algorithm(1). Statistical tests are performed using
1. Planned Statistical Analysis
The following statistical analyses are planned to evaluate the results of the study. The 
primary endpoint is the feasibility and safety of the method. Secondary endpoints include 
determining the effect of stimulation on epileptiform activity. 
1.1. 1.1. Incidence of adverse events during the study 
In patients with epilepsy, side effects/adverse events will be closely monitored. Patients will 
be instructed to report any adverse effects throughout the study. Additionally, side effects will 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
21 / 40 
be assessed and recorded twice daily (morning and evening) during hospitalization, and every 
other day during home visits. Surgical- and stimulation-related adverse events will be 
recorded separately. Although the likelihood of unexpected events after discharge is low, 
patients will be actively queried during follow-up visits (see Chapter 16g) for any such 
occurrences. 
1.2. Tolerance Testing of Individual Stimulus Intensity 
Tolerance Analysis in Epileptic Subjects 
For epilepsy patients, we will assess intra- and inter-subject variability in stimulus tolerance 
for each electrode sublocation. The dependence of tolerable intensity on the anatomical site 
of stimulation will be analyzed at both individual and group levels. 
Because ISP sequences are uniquely customized for each patient and vary significantly, their 
tolerance levels are not comparable across subjects; therefore, no statistical analyses will be 
conducted for ISP sequence tolerance data. 
1.3. Statistical Analysis of the Effect of ISP on Epilepsy 
The primary therapeutic goal of ISP stimulation is to reduce or terminate seizures by 
modulating their onset through electrical stimulation. While a statistically significant 
therapeutic effect is not expected during the study period (given that neuromodulation effects 
often manifest over weeks or months), we expect to observe trend-level changes. The 
following variables will be tracked and analyzed: 
1.3.1. Change in Seizure Rate 
1.3.1.1. Seizure Rate Change Calculated from the Seizure Diary 
Seizure frequency will be tracked using a patient-maintained seizure diary for 30 days 
before implantation (if available) and for at least 60 days post-implantation. In cases of 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
22 / 40 
 
long-lasting stimulation effects observed during hospitalization, a reduction in seizure 
frequency may be noted. The diary will include details on seizure types and frequencies, 
enabling tracking of total seizure burden as well as changes in specific seizure types—
offering insight into potential long-term effects of ISP stimulation. 
1.3.1.2. Seizure Rate Variation Calculated from Video-EEG Analysis (In-Hospital Only) 
During hospitalization, continuous video-EEG monitoring from implanted electrodes will 
be reviewed. The clinician annotates all observed epileptic events.
 
 
The number and types of seizures in the control phase will 
be compared to those during the stimulation phase, allowing inference of acute effects. 
1.3.1.3. Epileptiform EEG Activity and Seizure Rate Variation Calculated from Continuous 
EEG Recording Analysis in the Three-Phase Study 
Continuous EEG data collected during the up to 60-day pre-stimulation period (registration 
+ seizure detector tuning) and during the stimulation phase (up to 30 days in hospital) will 
be analyzed. This data allows for a comparison of interictal and ictal phenomena over a 
longer timeframe, enabling a more statistically robust assessment than the shorter video-
EEG analysis described in 1.3.1.2. 
1.3.2. Investigation of the Effect of ISP Stimulation on the Length of Electrographic 
Seizure Patterns 
The duration of electrographic seizures recorded via EEG will be measured, and the effect 
of ISP stimulation on seizure duration will be evaluated. Two experienced clinicians will 
independently identify seizure onset and offset, reaching a consensus on duration. Focal 
and generalized phases will be analyzed separately, and total seizure duration will also be 
assessed. A reduction in seizure duration will indicate potential long-term therapeutic 
benefit. 
1.3.3. Investigation of the Effect of ISP Stimulation on the Spectral Composition of 
Electrographic Seizure Patterns 
Changes in the spectral profile of seizure activity are a sensitive indicator of 
neuromodulatory impact. Spectral analysis will be conducted 
 
 
Spectral features of control (non-stimulated) and stimulated seizures 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
23 / 40 
 
will be compared for each patient. Clinician-annotated timestamps will define baseline 
and seizure windows for spectrogram generation. 
1.3.4. Examining the Impact of ISP Stimulation on Seizure Severity and Propagation 
We will analyze whether ISP stimulation alters the severity or progression of seizures. 
Seizures will be classified by two clinicians in consensus into: Focal aware seizures, Focal 
seizures with impaired awareness, Focal to bilateral tonic-clonic seizures (secondary 
generalized seizures). The analysis will determine whether ISP stimulation can acutely 
prevent seizure generalization. 
 
1.4. Evaluating the Performance of the Seizure Detector 
Post-recording, the automated seizure detector's performance will be benchmarked 
against expert clinician annotations,
 
 
 
g) Follow-up plan  
Follow-up will be conducted through a combination of in-person visits and remote 
consultations (telephone or video call), as follows: 
• Control 1 (10–14 days after explantation): In-person neurosurgical follow-up visit, 
including suture removal. 
• Control 2 (10–14 days after explantation): In-person epileptological follow-up, 
recording of any side effects, and review of the seizure diary. 
• Control 3 (first month after explantation): Telephone epileptological follow-up, 
recording of side effects, and review of the seizure diary. 
• Control 4 (second month after explantation): Telephone epileptological follow-up, 
recording of side effects, and review of the seizure diary. 
• Control 5 (third month after explantation): Telephone epileptological follow-up, 
recording of side effects, and review of the seizure diary. 
• Control 6 (sixth month after explantation): In-person epileptological follow-up, 
recording of side effects, and review of the seizure diary. 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
24 / 40 
 
Clinical visits for study participants will be conducted according to standard medical practice. 
As outlined in the patient information leaflet (provided prior to study participation and at 
hospital discharge), patients are instructed to report any adverse events to the investigating 
clinician by phone—even between scheduled visits—and especially during the first 30 days 
following study completion. 
h) Scientific, Medical, and Technical Justification for Carrying Out the Study 
Modification of brain function through electrical stimulation—commonly referred to as 
electrical neuromodulation—is a well-established treatment for several neuropsychiatric 
conditions, including depression, movement disorders (e.g., Parkinson’s disease), epilepsy, 
and obsessive-compulsive disorder (5)(6)(7). One of the key advantages of neuromodulation 
is its ability to deliver targeted, systemic treatment with minimal side effects. Both the 
stimulation site and parameters can be adjusted, allowing for highly individualized treatment 
planning.  
In many of these conditions, the electric field is applied directly to selected deep brain 
structures in a method known as deep brain stimulation (DBS) (8). DBS has been approved by 
both U.S. and European regulatory authorities for various indications, and hundreds of 
thousands of patients have undergone this therapy, with the number continuing to rise (9). In 
DBS, electrodes are surgically implanted into the brain and cannot be repositioned without 
another invasive procedure. While the method offers high targeting precision, it is inherently 
invasive and restricts target flexibility. 
Non-invasive neuromodulation methods that avoid neurosurgery also exist. Transcranial 
electrical stimulation (TES) (10) and transcranial magnetic stimulation (TMS) (11) have both 
been investigated and applied clinically. However, these techniques offer limited penetration 
to deep brain structures or require complex and bulky equipment (12). 
Neuromodulation therapies rely on two main mechanisms of action. The first involves direct 
modulation of neuronal function through the applied electric field, typically by increasing 
neuronal firing rates and synchronizing activity to the stimulation frequency (13). Depending 
on the frequency, this can result in excitation or functional inhibition of the target area (14). 
These effects persist only during stimulation, and abnormal brain activity typically returns 
shortly after the stimulus ends. 
The second mechanism leverages plasticity: changes in neural firing patterns activate long-
term plastic processes that can lead to sustained inhibition of pathological activity and a 
lasting return to normal function (15). This true neuromodulation is exemplified in TMS 
therapy for depression, where patients often experience long-term improvement—even 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
25 / 40 
 
months after receiving thousands of stimulation pulses (11). Achieving such effects requires 
repetitive stimulation, which implies the need for portable or implantable systems the patient 
can use regularly. 
However, current TMS systems are large and non-portable, requiring repeated visits to clinical 
facilities. A promising alternative is electrical stimulation, yet its main limitation is the poor 
penetration of electric fields into the brain. For instance, with the commonly used transcranial 
direct current stimulation (tDCS) at therapeutic levels (1–2 mA), most of the current is shunted 
outside the skull (Liu, 2018). Increasing current or frequency can cause discomfort or pose a 
risk of inducing epileptic seizures at certain frequencies (16). 
Prior research conducted at the University of Szeged has shown that Intersectional Short Pulse 
Stimulation (ISP) can safely and effectively stimulate the cortex using low extracranial charge 
densities (17). This method applies extremely brief electrical pulses distributed in space and 
time at several kHz to the target region, creating a modifiable electrical field with controlled 
frequency and minimal scalp current—making it tolerable for patients. Additionally, by 
employing a specialized signal filtering algorithm, EEG activity can be recorded even during 
stimulation. Studies have shown that ISP above 4.5 mA selectively modulates continuous brain 
rhythms, such as the posterior alpha oscillation (1). 
The goal of the current study is to further refine the technical parameters for precise brain 
targeting using the ISP technique and to define the optimal design and stimulation conditions 
for delivering effective and safe deep brain stimulation. We specifically aim to evaluate 
stimulation frequencies comparable to those used in high-frequency DBS therapy.  
e) Selection criteria of study participants  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
26 / 40 
 
 
 
 
Epilepsy patients: 
Potential study subjects will be selected from among epilepsy patients treated at the epilepsy 
outpatient clinic of the National Institute of Clinical Neuroscience (SEINK). Only adult patients 
aged 18 years or older will be considered. 
Eligible participants will include individuals with drug-resistant epilepsy, specifically those 
diagnosed with generalized or focal epilepsy, who have undergone comprehensive clinical 
assessments—including non-invasive or invasive EEG monitoring, neuropsychological testing, 
and epilepsy protocol-compliant cranial MRI, FDG-PET/CT, FDG-PET/MRI, and/or ictal SPECT 
scans—and have been deemed unsuitable for resective epilepsy surgery by a multidisciplinary 
epilepsy surgery team. Patients with a confirmed autoimmune etiology will be excluded. In 
cases where the cause of epilepsy is unknown, autoimmune processes must be ruled out 
through serological testing if not already completed. The neurologists participating in the 
study will be responsible for identifying potential participants and informing them about the 
research. Final eligibility is determined based on clinical findings and the patient’s specific 
epilepsy type. Importantly, all diagnoses will be established independently—prior to any 
consideration of study participation—and solely in the best interest of the patient’s health, in 
alignment with the Hippocratic Oath. 
 
Selection Criteria 
• Age between 18–65 years 
• Diagnosis of drug-resistant focal epilepsy, with unsuitability for resective epilepsy 
surgery confirmed by an interdisciplinary team based on: 
o Non-invasive or invasive EEG 
o Neuropsychological assessment 
o Brain MRI (epilepsy protocol) 
o FDG-PET/CT or FDG-PET/MRI and/or ictal SPECT 
• Diagnosis of focal epilepsy or idiopathic generalized epilepsy 
• On antiepileptic treatment 
• ≥4 focal seizures per month, or 
• Frequent spike-wave activity on EEG (minimum 10 seconds per hour) 
• Patient must be capable of caring for the surgical wound, and the home 
environment must support study requirements in terms of hygiene and compliance 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
27 / 40 
 
 
Exclusion Criteria 
• Age under 18 years 
• Patient is eligible for resective epilepsy surgery or has unclear surgical candidacy 
• Autoimmune epilepsy etiology 
• The presence of therapy-resistant or untreated psychiatric symptoms at the time 
of inclusion (e.g., depression, severe anxiety), as well as a history of suicide or 
psychotic episodes. 
• Progressive brain lesions (MRI), serious internal medical conditions, or clinically 
significant coagulopathies 
• Presence of electrically active implanted medical devices, including: 
o Pacemakers 
o Implantable cardioverter defibrillators 
o Any other electrical energy-transmitting medical device 
o Pregnancy 
• All women of childbearing potential must have a negative pregnancy test 
• History of traumatic brain injury, skull injury, or stroke not automatically 
exclusionary, but such cases require consultation with both the investigating 
physician and the Neunos technical support team 
• Metal implants generally contraindicated; all such cases must be evaluated 
individually by the investigating physician and Neunos technical support team 
 
f) Identification and justification of the number of participants in the study  
Based on the experience gained from our previous study (1), we plan to enroll 30 patients 
with drug-resistant epilepsy, characterized by either generalized spike-wave EEG patterns 
or focal epileptic seizures.
 
 
 
Identification of the assets under investigation 
 
 
 
 
 
 
 
 
 
g) Identification of other devices not subject to the test but bearing the CE conformity 
marking 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
28 / 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
h) Identification of Other Devices Not Subject to the Test but Not Bearing the CE 
Conformity Marking, with a Detailed Description of How the Safety of the Test Can 
Be Ensured 
No additional devices that lack CE conformity marking are involved in this study. 
Therefore, no further safety considerations are required in this context.. 
 
i) Risk analysis and risk assessment, detailed assessment of the likely risks and side 
effects, how to avoid or reduce them 
The studies to be presented in this protocol involve the following risk factors: 
1) The safety risk associated with MRI is minimal, with very few incidents reported over the 
past 20 years. Earplugs are provided for noise protection. The primary safety concern with 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
29 / 40 
 
MRI is the mechanical force exerted by the magnetic field on ferromagnetic materials. Any 
such materials must be removed from the vicinity of the subject prior to entering the MR 
environment. If removal is not possible, the subject will be excluded from the study. A detailed 
screening questionnaire (see Appendix) will be completed before entering the MR zone 
(console room), and access will be granted only after confirming the absence of ferromagnetic 
materials. 
2) Transcranial magnetic stimulation (TMS) involves passing an electric current through a coil 
placed on the scalp, generating a variable magnetic field for a brief period. Among repetitive 
TMS procedures, high-frequency stimulation carries a known risk of inducing seizures. 
However, in this study, only low-frequency or single-pulse TMS will be applied, which has not 
been associated with similar risks. 
2) Electrophysiological tests involve recording electroencephalographic (EEG) activity in 
response to spontaneous and stimulus-related brain signals. These recordings do not interfere 
with brain function and are considered minimally risky. 
3) The main risks associated with electrode implantation are local infection and subgaleal 
bleeding. To minimize these, strict aseptic and antiseptic procedures will be followed 
throughout the surgical and postoperative periods. Outside the operating theatre, sterile 
dressings will not be removed unless medically indicated (e.g., for wound checks conducted 
in hospital or at home as part of the study protocol). Antibiotic prophylaxis will be 
administered perioperatively. According to current guidelines and clinical trial data, 
postoperative antibiotic prophylaxis is not recommended (37). 
To reduce the risk of subgaleal hemorrhage, electrodes will be implanted by experienced 
neurosurgeons, with design and placement guided by anatomical and safety considerations. 
If significant bleeding or infection occurs, the procedure will be halted and electrodes 
removed. Based on the literature, these complications are rare. 
During the maximum 2 × 30-day home-based phases of the study, regular wound inspections 
will be conducted by hospital nursing staff to ensure wound integrity. Notably, long-term 
externalized neuromodulation systems, such as spinal cord stimulation (SCS) devices for 
chronic pain, also involve percutaneous components. In a large randomized controlled trial 
(PROMISE RCT (38)), the infection rate was 5.2% (9 of 174 patients). Compared to SCS systems, 
the present study's design is less prone to infection: cables exit through the scalp, which is 
well vascularized, and electrodes are placed extracranially, under the scalp. 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
30 / 40 
 
Other long-term external systems, such as bone-conduction hearing aids (39) and brain-
machine interfaces (40), also involve chronic connections through the scalp and rarely require 
non-conservative treatment for infections—even over long periods of use. 
4) The risks associated with transcranial electrical stimulation are somewhat higher than those 
in points 1 and 2. Both animal and human studies confirm that electrical stimulation affects 
cortical excitability. Anodal stimulation increases neuronal firing rates, while cathodal 
stimulation decreases it (Bindban et al., 1964; Creutzfeldt et al., 1962; Purpura and McMurty, 
1965; Ward and Weiskrantz, 1969). In humans, direct current (DC) stimulation applied to the 
motor cortex has been shown to alter motor-evoked potentials elicited by TMS (18), as well 
as modulate early visual processing—such as contrast sensitivity and visual evoked potentials 
(19). 
Additional studies confirm that stimulation effects on cortical excitability can persist beyond 
the stimulation period, likely due to plastic changes in the brain. These have been successfully 
leveraged in learning enhancement (20) and in the treatment and rehabilitation of 
neurological conditions (21)(22). 
To date, transcranial stimulation has been regarded as safe, with no serious side effects 
reported in a significant body of literature. The stimulation is typically painless, as the large 
electrode surface area produces a low charge density, supported by existing research (23). 
Nonetheless, several safety aspects must be considered: 
High-frequency stimulation has the potential to induce seizures in epilepsy patients (16). This 
risk is mitigated by using continuous video-EEG monitoring under clinical supervision. During 
the initial three sessions—when stimulation is not seizure-triggered—patients will remain on 
antiepileptic medication. If seizure activity occurs during this phase, the neurologist may 
terminate the study and administer treatment according to protocol. In the fourth session, 
seizure provocation (e.g., medication tapering) will follow established video-EEG protocols, as 
decided by the treating physician team. To prevent false stimulation during non-seizure 
events, stimulation will only be activated after manual confirmation by the investigator. 
During all phases, medical care follows current clinical standards: 
Patients are maintained on antiepileptic drugs throughout hospitalization. If seizure risk is 
elevated (e.g., due to stimulation), a neurologist will remain present at all times. 
Emergency treatment protocols include: 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
31 / 40 
 
First-line: IV benzodiazepines (diazepam, clonazepam, lorazepam) 
Second-line: IV antiepileptics (levetiracetam, valproate, lacosamide) 
 In case of status epilepticus, anesthesia and ICU admission may be required. 
Electrode heating is also considered, but is unlikely with the surface area and charge density 
used in this trial. This has been confirmed in previous studies (18). Given that only ~50% of the 
current reaches the brain through the skull, the likelihood of heating is even lower. 
There is no evidence that long-term stimulation causes structural harm. A 2004 study by 
Nitsche et al. found no signs of edema, blood-brain barrier disruption, or anatomical changes 
on MRI. Similarly, EEG readings and serum neuron-specific enolase levels did not indicate 
neuronal damage (18). Repeated daily stimulation has also been shown to be safe, with no 
adverse effects reported in the literature (24).  
Finally, the study carries inherent risks related to the two surgical procedures and the 
presence of a foreign body beneath the scalp. All surgical interventions will be performed 
using minimally invasive techniques. The choice between general anesthesia and local scalp-
block will be determined by the anesthesiologist, with preference for local methods to 
minimize risk.  
Potential hypersensitivity reactions to medications administered during surgery will be 
handled per clinical protocols. If such a reaction occurs, the study will be terminated for that 
patient. 
Subgaleal hematoma may develop due to the foreign body or manipulation of the subgaleal 
space. Hematoma status will be routinely monitored. If excessive bleeding is detected, 
electrodes will be removed and the hematoma managed according to clinic protocols. 
Infection risk due to surgery or externalized components will be minimized through 
prophylactic treatment with second-generation oral cephalosporins during the single-phase 
hospitalization. If infection occurs, the electrodes will be removed, and appropriate treatment 
administered per clinical guidelines. 
j) Analysis and Justification of the Acceptability of the Planned Performance and the 
Likely Risks and Side-Effects Ratio 
The significance of ISP brain stimulation lies in its ability to deliver targeted deep brain 
stimulation non-invasively or with minimal invasiveness, eliminating the need to open the 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
32 / 40 
 
skull. The ISP stimulator under investigation is a compact, high-efficiency portable device, 
capable of reaching and modulating brain regions that traditionally required neurosurgical 
access. This approach represents a potential paradigm shift in neuromodulation—
providing a feasible alternative to invasive surgical procedures and large-scale, stationary 
magnetic stimulation technologies.  The medical utility of this research is clear, and its 
potential for industrial application follows directly from the study’s findings. If successful, 
the method could broaden therapeutic options for drug-resistant epilepsy and related 
neurological conditions. 
Brain stimulation techniques have long been established as clinical diagnostic tools for 
epilepsy, especially in identifying evoked pathological responses, after-discharges, and 
provoked seizures (25). However, conventional transcranial electrical stimulation cannot 
be performed during standard scalp video-EEG procedures due to technical limitations. 
The device used in this study overcomes these challenges by allowing for simultaneous 
EEG recording and spatially precise stimulation. This capability can enhance the diagnostic 
process by providing additional functional information about the epileptogenic focus. 
Seizures elicited during the study may also offer valuable diagnostic insights. 
Through this investigation, we may demonstrate the therapeutic potential of spatially and 
temporally targeted neurostimulation, paving the way for a novel, effective treatment 
option for patients with drug-resistant epilepsy. Should chronic ISP neuromodulation 
prove viable and the study results support its efficacy for an individual patient, the data 
collected from this clinical video-EEG study may serve as a personalized screening tool to 
guide future therapy planning. 
 
 
 
Given the low incidence of expected adverse events, and in light of the potential long-term 
benefits, the risk-to-benefit ratio of this study is considered acceptable and ethically 
justified. 
 
Copies of certificates of qualification of the staff who carried out the tests  
See Annex 4  
k) Patient information and informed consent 
See Annexes 6, 7, 12, 13, 15, 16  

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
33 / 40 
 
l) Procedure to be followed in the event of an unforeseen event, list of persons to be 
notified, deadline for notification 
Patients enrolled in the study will be closely monitored throughout the brain stimulation 
procedures at the healthcare facility (SEINK). Participation in the study will not interfere with 
the patients’ standard clinical care. During ISP stimulation, patients will be observed under the 
standard clinical video-EEG monitoring protocol, which runs concurrently with the 
investigational procedures. As such, no additional or special monitoring procedures are 
required beyond those routinely applied in clinical practice. In the event of epileptic seizures 
occurring as unexpected adverse events, management will follow the established clinical 
protocol, as detailed in Section 16/n of this document. 
m) Criteria for stopping a clinical trial  
Participation in the protocol will be immediately suspended upon the subject's request, 
without the need for justification. Additionally, participation will be discontinued if the 
subject's cooperation is found to negatively impact their clinical care or the course of their 
illness. Under no circumstances should participation in the protocol interfere with the 
patient’s current or future medical care. 
n) Confirmation of a Health Care Provider Conducting a Clinical Trial to Cover the 
Indemnity of the Research Before the Start of the Research Activity, in Accordance 
with the Risks Covered by the Research Liability Insurance Contract  
As experimental stimulation cannot be separated from the diagnostic process, the same 
insurance conditions apply to this intervention as to other patients in clinical practice.  
o) research equipment and staff  
Both the material and human resources required for the research are fully in place. The 
facilities at SEINK are well-equipped with the necessary personnel, instrumentation, and 
infrastructure to conduct the planned investigations. The ISP stimulators to be tested, along 
with the electrophysiological recording systems, are housed at SEINK. The institute also 
operates a fully functional video-EEG monitoring unit as part of its routine clinical services, 
where all study-related recordings can be performed under standard clinical protocols. The 
neurologists and researchers involved in the project possess significant expertise, and their 
longstanding experience in working with epilepsy patients ensures the scientific and clinical 
robustness of the study. Their contributions to the field include decades of clinical practice 
and a strong track record of high-quality international scientific publications in the area of 
brain stimulation. 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
34 / 40 
 
On the scientific and technical side, the instrument development, experimental design, and 
data analysis are grounded in collaborative research with New York University, further 
reinforcing the study’s credibility. The study will be designed, conducted, documented, and 
reported in full compliance with Good Clinical Practice (GCP) guidelines, ensuring ethical 
integrity and scientific validity throughout. 
p) Draft text of the call for applications and description of the recruitment method 
 
 
 
Epilepsy patients: 
Patients included in the study will be drug-resistant individuals with focal epilepsy who have 
been deemed unsuitable for resective epilepsy surgery. This determination will be made by 
an interdisciplinary epilepsy team, based on comprehensive evaluations including non-
invasive or invasive EEG monitoring, neuropsychological assessments, and imaging studies 
performed according to epilepsy protocols—such as cranial MRI, FDG-PET/CT, FDG-PET/MRI, 
and/or ictal SPECT scans. Eligible patients will be selected from the clinical database 
maintained at the SEINK epilepsy outpatient clinic. Identified candidates will be offered 
participation in the study. The neurologists involved in the project will be responsible for both 
selecting potential participants and informing them about the study. Eligibility will be 
determined based on detailed clinical evaluations, including confirmation of epilepsy type and 
suitability for the study. Importantly, diagnosis and eligibility assessments are made prior to 
any offer of participation, and are conducted independently, in the best interests of the 
patient’s health and recovery, and in full accordance with ethical medical standards, including 
the Hippocratic Oath.  
16) Quality assurance certificate for clinical investigations of devices and active implants in 
risk class III  
No active implant is involved in the study.  
The electrodes manufactured by 
 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
35 / 40 
 
 
 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
36 / 40 
 
 

SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic
__________ 
clinic director
DR. HABIL. LORÁND ERŐSS
Clinical Investigation Protocol
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu
Tel: (+36-1) 467-9301
semmelweis.hu
37 / 40 
17) In the case of a multicentre study, the opinion already issued by the Ethics Committee
of the EEA State Party on the study, if available
The study is not multicentric, so this point is not meaningful. 
18) Annexes
Annex 
Title 
1 
Declaration of admission 
2 
Authorisation from the manufacturer to the investigator-
in-charge 
3 
Manufacturer's declaration of conformity 
4 
Documents of the investigators 
5 
CV of the Principal Investigator 
6 
Factsheet 
7 
Declaration of consent 
8 
Liability insurance - SEINK 
9 
Liability insurance - NEUNOS 
10 
Declaration of Helsinki 
11 
Data protection statement 
12 
Patient information for volunteers 
13 
Declaration of consent for volunteers 
14 
Call for volunteers 
15 
Informed consent - for participation in the three-phase 
trial 
16 
Patient information leaflet - for participation in the three-
phase trial 

 
SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
38 / 40 
 
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SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
39 / 40 
 
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SEMMELWEIS UNIVERSITY 
Neurosurgery and Neurointerventional Clinic 
__________ 
clinic director 
DR. HABIL. LORÁND ERŐSS 
Clinical Investigation Protocol 
 
 
Address: 1145 Budapest, Amerikai út 57. 
Postal address: 1085 Budapest, Üllői út 26.; 1428 Budapest, 
Pf. 2. 
E-mail: titkarsag.amerikaiut@semmelweis.hu 
Tel: (+36-1) 467-9301 
semmelweis.hu 
 
 
40 / 40 
 
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