Effects of Neurobiological Therapy With Asymmetric Radio-electric Conveyer (REAC) in Diffuse Axonal Injury: a Randomized Controlled Trial.
Phase: PHASE2
Conditions: Traumatic Brain Injury
Sponsor: University of Sao Paulo

 
 
EFFECTS OF RADIO ELECTRIC ASYMMETRIC CONVEYER (REAC) NEUROBIOLOGICAL 
TREATMENTS IN DIFFUSE AXONIAL INJURY: A RANDOMIZED, DOUBLE-BLIND CLINICAL 
TRIAL 
 
 
Unique Protocol Id: 84791824.8.0000.0068 
Date: October/15/2025 
 

 
 
Abstract 
Background: Severe traumatic brain injury, particularly diffuse axonal injury (DAI), often 
leads to lasting neurological issues. Cerebral dysfunction in DAI can be evaluated by 
monitoring cerebral electrical activity (CEA) through EEG. The radio electric asymmetric 
conveyer (REAC) is a noninvasive method designed to rebalance cellular polarity via 
endogenous bioelectric fields and modulate CEA. This technique may alter CEA, which 
can be detected using quantitative EEG (qEEG). 
Objective: To assess qEEG changes following DAI and brain wave alterations after a REAC 
protocol in this group. 
Methods: In this prospective, randomized, double-blind clinical trial, adult (≥18 y.o.) DAI 
patients will be assigned to active or sham groups for 19 sessions of either true or sham 
REAC following ICU discharge. Interventions include one Neuro Postural Optimization 
session and 18 NPPO-BWO-G sessions (up to four per day). The main outcome is to 
evaluate changes in qEEG patterns through population brain electrical mapping after 
REAC therapies. Additionally, voluntary adults (≥18 y.o.) with no history of neurological 
diseases will be submitted to the same protocol to further comparisons between qEEG 
patterns. 
Keywords: cognitive dysfunction; diffuse axonal injury; radio electric asymmetric 
conveyer; rehabilitation; traumatic brain injury. 
 
 

 
 
LIST OF ACRONYMS AND ABBREVIATIONS 
 
ANOVA ........................................................................................... analysis of variance 
ANP ............................................................................. neuropsychological assessment 
BDNF ......................................................................... brain-derived neurotrophic factor 
Beta-APP ...................................................................... Beta-Amyloid-Precursor-Protein 
BVMT ........................................................................... Brief Visuospatial Memory Test 
CE ................................................................................................... cortical excitability 
CRT .............................................................................. cognitive rehabilitation therapy 
CONSORT .................................................... Consolidated Standards of Reporting Trials 
cTBS ........................................................................ continuous theta burst stimulation 
DAI ................................................................................................ diffuse axonal injury 
DWI ................................................................................... diffusion weighted imaging 
EEG…………………………………………………………………………………………….electroencephalogram 
EMP ......................................................................................... motor evoked potential 
FIC ........................................................................................... intracortical facilitation 
GABA .................................................................................. gamma-aminobutyric-acid 
GRE ......................................................................................................... gradient echo 
HVLT ................................................................................. Hopkins verbal learning test 
LAT .......................................................................................... traumatic axonal injury 
LED .............................................................................................. Light-Emitting Diode 
LLLT ............................................................................................ Low Level Light/Laser 
LM ......................................................................................... Resting Motor Threshold 
LTD ............................................................................................ Long-Term Depression 
LTP ........................................................................................... Long-Term Potentiation 
M1 ................................................................................................. primary motor area 
MRI .................................................................................. magnetic resonance imaging 
MSC ........................................................................... minimum state of consciousness 
NMDA ........................................................................................ N-Methyl-D-Aspartate 
PDC ..................................................................................... prefrontal dorsolateral cortex 
PET ............................................................................... positron emission tomography 

 
 
PVS ..................................................................................... persistent vegetative state  
RCT ......................................................................................... randomized clinical trial 
STAITER ............................................................................. state-trait anxiety inventory 
SIII ........................................................................ short interval intracortical inhibition 
TC ............................................................................................. computed tomography 
TBI .............................................................................................. traumatic brain injury 
TD ........................................................................................................ diffusion tensor 
TF3D ................................................................... three-dimensional fiber tractography 
TMT .................................................................................................... trail making test 
 
 
 

 
 
LIST OF UNITS 
 
μA ................................................................................................................. microAmpere 
Cm .................................................................................................................... centimetre 
Ms .................................................................................................................... millisecond 
ºC ................................................................................................................. degree Celsius 
T ................................................................................................................................. Tesla 
Db ........................................................................................................................... decibel 
Mv ......................................................................................................................... miliVolt 
Hz .............................................................................................................................. Hertz 
V .................................................................................................................................. Volt 
m .............................................................................................................................. meter 
 
 

 
 
 
 
LIST OF FIGURES 
 
Figure Y. Evaluations and interventions performed during the study. 
Figure X ........................................................................................ CONSORT flow diagram

7 
 
INTRODUCTION 
 
Traumatic brain injury (TBI) is a leading cause of death and disability globally, 
significantly affecting the quality of life for patients and caregivers [1-3].  
In the United States, traumatic brain injury is the leading cause of death for people aged 
1 to 45 and a major risk factor for morbidity and mortality in polytrauma cases [4].  
Although epidemiological data in Brazil are limited, studies indicate that TBI is a 
significant public health issue, primarily impacting the country's young and economically 
active population [5, 6]. 
Automobile accidents and falls are primary causes of traumatic brain injury, with 
incidence rates highest among young adults (20 to 29 years) and individuals over 80 
years old [4-6].  
TBI is a highly heterogeneous condition, with multiple classification systems that 
emphasize distinct aspects such as the underlying mechanism of injury, clinical severity, 
radiological characteristics, and pathophysiological processes. These classifications play 
an important role in standardizing data collection, identifying prognostic factors, and 
informing the selection of appropriate therapeutic approaches tailored to individual 
cases. 
From a pathophysiological perspective, traumatic brain injury (TBI) causes damage 
through primary lesions—direct energy transfer to the brain at trauma—and secondary 
effects, which involve cellular and molecular changes occurring for hours to weeks post-
injury [7, 8]. 
Diffuse axonal injury (DAI) is a type of lesion in TBI that leads to significant brain 
dysfunction and affects roughly 40% of patients, making it a leading cause of 
neurological problems in survivors [9-11].  
Clinically, it is defined as a coma lasting more than 6 hours after TBI, excluding cases 
caused by ischemic brain injury or intracranial masses [10, 12]. Gennarelli et al.'s 1982 
study described DAI in primates as a range of injuries mainly involving brain white matter 

8 
 
damage [9]. In 1989, Adams established objective criteria for classifying DAI from an 
anatomopathological perspective into three categories: mild, moderate, and severe 
[10]. In each case, the principal form of structural damage is axonotomy (axon injury), 
which may occur immediately at the time of trauma (primary) or subsequently 
(secondary), following a series of biomolecular events [13-15].  
Detecting this condition during routine exams in TBI patients can be challenging, as DAI-
related abnormalities are often missed by standard CT or MRI scans and may require 
advanced imaging techniques to identify structural changes in the central nervous 
system [16-23]. 
From a neurological perspective, TBI can result in a wide range of cognitive, behavioral, 
and sensory-motor changes that may affect the patient's quality of life. Cognition 
encompasses the processes involved in acquiring knowledge and includes factors such 
as thought, language, memory, reasoning, and task execution, which are considered 
important for intellectual development [24, 25].  
Although TBI is strongly linked to cognitive dysfunction, effective treatment remains 
difficult. While cognitive rehabilitation therapies have shown benefits in some studies, 
results are inconsistent [26-29].  
Drug therapies for post-TBI cognitive disorders have proven ineffective [30]. The limited 
effectiveness of conventional cognitive rehabilitation in DAI patients has led to the 
exploration of new therapies. Neuromodulation techniques, both invasive and 
noninvasive, offer promising options by targeting specific brain regions to alter activity 
and support recovery. 
Radio electric asymmetric conveyer (REAC) technology is a noninvasive technique that 
was first described by Rinaldi and Fontani [31, 32]. REAC neurobiological modulation 
with specific protocols such as neuro-postural-optimization (NPO) and neuro-psycho-
physical-optimization – brain wave optimization-G (NPPO-BWO-G) is a safe, established 
technique with proven therapeutic benefits for various neurological and psychiatric 
disorders [33-40].  

9 
 
Given the significant brain damage and multiple disabling neurological sequelae, in 
severe TBI patients, combined with the limited efficacy of conventional pharmacological 
and cognitive rehabilitation interventions, REAC may be a promising therapeutic 
approach for affected patients. We will conduct a randomized clinical trial to assess 
REAC's effects in patients with DAI. 
 
GOALS 
Primary Endpoint 
• To evaluate the qEEG changes in patients with subacute/chronic DAI, following 
REAC neuromodulation. 
Secondary Endpoint 
• To evaluate the qEEG changes in adults free of neurological conditions, following 
REAC neuromodulation. 
• To evaluate cognitive and humor changes in adults free of neurological 
conditions, following REAC neuromodulation. 
 
 
 

10 
 
LITERATURE REVIEW 
TBI Classifications 
TBI is typically a heterogeneous condition being classified by clinical severity, 
mechanism of injury and pathophysiology, all of which are relevant to properly 
determine treatment and prognosis. 
From a clinical point of view, TBI is classified as mild, moderate and severe 
depending on the duration of the loss of consciousness, level of consciousness on the 
Glasgow Coma scale and the presence or absence of post-traumatic amnesia, as well as 
its duration. However, knowledge of other information, such as history of exogenous 
intoxication, use of sedatives and neuromuscular blockers, as well as orotracheal 
intubation, is essential to avoid misclassification of TBI [41, 42]. 
Gennarelli et al. (1982) classified the injuries caused by TBI into 5 major groups: 
skull fractures, focal lesions, diffuse lesions, penetrating injuries and explosion injuries. 
Diffuse lesions differ from focal lesions in that they usually do not present macroscopic 
structural damage. This type of injury causes diffuse brain dysfunction and affects about 
40% of patients with severe TBI [9, 43]. Basically, this type of injury is the result of two 
basic mechanisms: by contact and inertial (acceleration). Contact injuries require the 
occurrence of direct trauma of the skull against another object. On the other hand, 
inertia injuries, commonly called acceleration injuries, are due to sudden and intense 
movement of the skull, regardless of the occurrence of impact of the skull against 
external structures. It is worth mentioning that, of the 3 possible types of acceleration 
(translational, rotational and angular), the angular type is the one that is most associated 
with DAI because in this mechanism there is a combination of translational and, mainly, 
rotational movements, causing diffuse brain injury [44, 45]. 
From the histopathological point of view, the 3 main tissues involved in TBI 
(bone, vessels and cerebral parenchyma) differ considerably with regard to their 
tolerances to compression, tension and shear. Because of these different inertia 
properties of the affected tissues, the brain is susceptible to abrupt rotational forces. In 
this way, when the skull undergoes a sudden rotation, the superficial layers of the brain 
(closest to the skull) are accelerated (or braked) before the deep ones, producing a shear 

11 
 
stress. As a consequence, this mechanism can cause the rupture of axons and vessels in 
various regions of the brain, notably in the white fibers of projection, cortico-subcortical 
transition, dorsolateral rostral regions of the brainstem, corpus callosum, hippocampus 
and cerebellum [46-48]. 
Regarding the pathophysiology, the brain lesions observed in TBI can be divided 
into two broad categories that are distinct, but closely related to each other: primary 
and secondary lesion. This classification guides most of the treatments in current clinical 
practice. For example, surgical treatment of primary brain lesions, such as the removal 
of an intracranial hematoma, is one of the main measures instituted in the treatment of 
these patients in the acute phase. Likewise, the identification, treatment and prevention 
of secondary brain lesions is the main focus of therapy instituted within neurological 
intensive care centers in patients with severe TBI. 
The deleterious effects observed in TBI are the result of the primary injury, that 
is, of the immediate trauma in the brain tissue and dependent on physical phenomena, 
added to the secondary lesions, which are those that follow the aggression that occurred 
at the first moment, being dependent on biomolecular and pathophysiological 
processes [7]. 
Although the mechanisms of primary injury are numerous and heterogeneous, 
they are all the result of external mechanical forces transferred to the intracranial 
structures. The severity of the primary injury depends on the intensity and temporal and 
spatial distribution of the insult. More intense, long-lasting and therefore more severe 
aggressions usually cause neuronal necrosis while mild injuries result in apoptosis[8]. 
On the other hand, secondary injuries involve complex biological processes and 
include all the cascading molecular mechanisms that follow the moment of trauma and 
that can last for hours or even days. These mechanisms include neurotransmitter-
mediated 
excitotoxicity, 
electrolyte 
disturbances, 
mitochondrial 
dysfunction, 
inflammatory response, and cell death (necrosis and apoptosis).  
At first, the excess release of glutamate, the main excitatory neurotransmitter of 
the central nervous system, leads to the phenomenon of glutamatergic excitotoxicity 
mediated by NMDA (N-Methyl-D-Aspartate), culminating in processes of neuronal 
dysfunction and death [49-52]. This process induces the accumulation of calcium ion in 

12 
 
the neuronal intracellular compartment, promoting inflammation, mitochondrial 
dysfunction and apoptosis, and may even trigger and potentiate oxidative stress through 
the phenomenon of spreading cortical depression [7, 53-56]. 
In addition to the events involving glutamate, there is evidence that GABA 
(gamma-aminobutyric acid), the main inhibitory neurotransmitter of the cerebral 
cortex, is also involved in the process of secondary injury related to TBI. Studies in rats 
have demonstrated the recovery of sensory and motor functions, as well as better 
cognitive performance and increased survival, in animals undergoing GABAergic neuron 
transplantation [57, 58]. Demirtas-Tatlidede et al. [25] described the occurrence of 
excess GABA-mediated inhibition in the subacute phase of TBI, which could explain the 
arousal alterations seen in this population. 
Diffuse axonal injury 
General aspects and terminology 
DAI accounts for almost one-third of deaths due to TBI. DAI is considered the 
main risk factor for morbidity and mortality of TBI victims, being the main cause of coma, 
neurological sequelae and chronic disorders of the level of consciousness (vegetative 
state and minimal state of consciousness) after TBI [10-12]. 
The spectrum of DAI ranges from its mildest form (concussion), when there are 
only changes in neuronal function but without damage to the cellular structure, to the 
most severe cases, when diffuse axonal damage occurs at the microscopic level in 
addition to macroscopic findings[12]. 
The terminology of the DAI was clarified by Geddes et al. [59]. The definitions 
suggested by the author are: 
● Traumatic Axonal Injury (TAI): axon injury caused by trauma. The extent can vary 
greatly and may affect only small foci up to extensive lesions of the cerebral 
parenchyma. 
● Diffuse Traumatic Axonal Injury (DTAI): originally called "DAI"", this represents 
the most severe form of this spectrum. 
● Diffuse Axonal Injury (DAI): initially described as a syndrome clinicopathological 
of patients unconscious from the moment of TBI, without expansive intracranial 

13 
 
lesions and with diffuse lesion of the axons in the brain, including the brainstem 
[60].  Ideally, the traumatic etiology of axonal damage should always be cited 
when the term is used to describe a neuropathological diagnosis. 
For didactic purposes and considering the consecration of the term DAI in clinical 
practice, we will use this term to describe the extensive diffuse axonal brain lesion 
resulting from TBI. 
Generally, these lesions result from the involvement of the white matter when 
subjected to rotational forces, as well as through the effect of acceleration and 
deceleration on the brain parenchyma, exerting shear stress on the fibers and, 
consequently, axonal injury [43, 46, 47, 61]. 
 
Pathology 
The diagnosis of DAI can only be confirmed through anatomopathological 
examination (APE). Adams et al. [10] developed a classification to assess the severity of 
DAI based on macroscopic and microscopic findings of silver-impregnated brain tissue 
(Table 1): 
Table 1 - Adams classification (1989) according to anatomopathological criteria 
DAI Grade I  
(light) 
Microscopic changes in the white matter of the cerebral hemispheres, 
corpus callosum, brainstem, and occasionally cerebellum. 
DAI grade II  
(moderate) 
Grossly evident lesions on the corpus callosum, usually as punctate 
hemorrhages 
DAI grade III  
(severe) 
In addition to the findings present in grade II, additional focal lesions in 
the dorsolateral regions of the rostral portion of the brainstem, with 
involvement of the superior cerebellar peduncle. 
DAI – Diffuse Axonal Injury 
At first, the microscopic changes of DAI are imperceptible in conventional APE. 
In 1993, Gentleman et al. [62] described a robust immunoreactivity method, capable of 
identifying changes present in the axonal lesion within only a few hours of the trauma. 
Through immunohistochemistry, it was possible to detect focal accumulations of beta-

14 
 
amyloid precursor protein (beta-APP - beta-amyloid precursor protein) two hours after 
TBI, while axon varicose veins and axonal swelling could be seen after 12 to 24 hours. 
When compared to preparations impregnated by silver, the immunohistochemistry 
technique proved to be superior and able to identify more exuberantly the lesions in the 
axons, becoming considered the gold standard technique for detection of DAI [11, 62]. 
Subsequently, some studies demonstrated that immunoreactivity to beta-APP was not 
exclusive to DAI but was also described in other forms of brain injury, such as hypoxic-
ischemic lesions [63, 64]. 
 
Pathogenesis of DAI 
In DAI, the basic structural damage is axonotomy. Two basic mechanisms are 
implicated in this process: primary and secondary axonotomy. Primary axonotomy 
occurs immediately after tissue trauma and causes the influx of calcium into neurons 
and activation of proteases. Human studies have detected histological lesions between 
4 to 6 hours after trauma [13]. Secondary axonotomy, on the other hand, begins hours 
after tissue injury and can last for years [14, 15, 46]. The failure of cell repair 
mechanisms, or the subsequent occurrence of ischemic lesions, results in disconnection 
of the distal axonal segment. Axoplasmic transport continues and this blockage due to 
axonal disconnection results in accumulation of material at the proximal end to the axon 
breaking point, causing localized axonal edema, also referred to as axonal bulb [65]. 
Although the magnitude of the trauma is apparently directly correlated with the severity 
of the axonal damage, secondary axonotomy seems to have greater relevance in TBI-
related axonopathy [66]. 
 

15 
 
 
Source: Greer JE et al., 2013[67] 
Figure 2 – DAI rapidly induces secondary axonotomy 
In a model of fluid percussion in rats, after the impact on the brain there was the 
formation of axonal dilatations (bulbs) (arrowheads) early as 15 minutes after the injury 
(a – c). Several injured fibers showed clear evidence of disconnection (b), although many 
demonstrated some degree of axonal continuity (a,c). In addition, the formation of the 
bulbs can be seen at various locations along the axon, both distal (a,b) and proximal (c) 
relative to the cell body. Range: 10 μm.  
 
Clinical Aspects 
DAI is defined from a clinical point of view as a state of coma after TBI that lasts 
for more than 6 hours, excluding cases related to ischemic brain lesions or intracranial 

16 
 
expansive lesions [10, 12]. Typically, patients with DAI are unconscious from the 
moment of impact, do not present a lucid interval and remain with severe impairment 
of the level of consciousness for a variable period of hours. Even those patients with less 
severe brain injury can regain the level of consciousness with definitive sequelae. 
Gennarelli et al. classified diffuse traumatic brain injuries into 4 groups: mild, 
moderate (or classical), severe concussion, and DAI [10]. DAI can also be classified as 
mild, moderate or severe, and mild DAI occurs in 8% of severe TBI. In this type, the coma 
lasts from 6 to 24 h and after the trauma and the victims may evolve with psychological 
or neurological deficits. The evolution is variable: 78% of the cases evolve favorably, 2% 
have severe sequelae, 1% evolve with persistent vegetative state (PVS) and death occurs 
in about 15% of the patients. Moderate DAI, present in 20% of severe TBIs, is 
characterized by coma for more than 24 hours and recovery is often incomplete. The 
evolution is favorable in 59% of the victims, with severe sequelae in 12%, PVS in 5% and 
fatal evolution in up to 24% of the cases. Finally, severe DAI occurs in 16% of severe TBI 
and is characterized by a coma lasting days or weeks. These patients have frequent signs 
of brainstem dysfunction and dysautonomia (systemic arterial hypertension, 
hyperhidrosis, and hyperthermia). The evolution is favorable in only 28% of cases; 14% 
have severe sequelae, 7% progress to PVS and 57% die. 
 
Radiological Aspects 
Although patients with DAI usually present exuberant clinical alterations, the 
abnormal findings in a considerable part of the cases are not identified by the techniques 
of computed tomography (CT) or conventional magnetic resonance imaging (MRI) of the 
brain. 
Despite the limitations of conventional routine imaging techniques, some 
macroscopic changes may suggest the presence of DAI: 
● Focal lesions of the corpus callosum, seen as hemorrhagic foci. Occasionally 
these hemorrhages can rupture the interventricular septum, causing ventricle 
hemorrhage. 

17 
 
● Focal lesions in the dorsolateral quadrants of the rostral portions of the 
brainstem. Small hemorrhagic lesions can also be seen near the superior 
cerebellar peduncles. 
● "Gliding Contusions": punctate hemorrhagic lesions affecting the parasagittal 
white matter in the upper portion of the cerebral hemispheres, usually in the 
transition zone between the white and gray matter. They are often bilateral and 
asymmetrical. 
T2/FLAIR-weighted brain MRIs (Fluid Attenuated Inversion Recovery), particularly 
in the coronal and sagittal sections, are useful in the detection of DAI involving the 
corpus callosum and the fornix, two areas difficult to be analyzed in routine 
examinations obtained in the axial plane [16]. 
Focal lesions of the corpus callosum and dorsolateral rostral portions of the 
brainstem present in grade II and III DAI's may be visible in conventional neuroimaging 
studies. However, in patients with grade I DAI, these techniques may not show any 
abnormalities. 
Diffusion sequence-weighted MRI (DWI - diffusion weighted imaging) measures 
the random motion, also known as Brownian motion, of water molecules in brain tissue. 
Because of its sensitivity for detecting acute stretch injuries, diffusion has been 
particularly useful in detecting DAI [17, 19-21]. Diffusion is able to detect more DAI-
related lesions than T2-weighted images fast spin echo and/or T2 gradient echo (GRE) 
T2* within the first 48 hours after injury. 
Diffusion tensor (DT) MRI has shown utility in assessing white matter integrity. 
This technique allows the determination of fractional anisotropy (FA), which measures 
the preferential movement of water molecules within the axons present in the white 
matter, with respect to their degree and direction (axis) of the diffusion of the water 
molecule. PA values range from 0 to 1, with 0 referring to completely isotropic diffusion 
(e.g. Water) and the value 1 related to diffusion only in a single direction, i.e., maximum 
anisotropy [22, 23]. In addition to PA, the integrity of white matter fibers can be 
measured with the use of three-dimensional tractography of white fibers (TF3D). 
However, few studies have sought to correlate the findings of 3D TF in patients with DAI 

18 
 
and more research is needed so that this technique can be incorporated into the clinical 
routine of investigation of these patients [18, 68-72]. 
 
Cognitive changes due to TBI and treatment 
Cognitive impairment resulting from TBI is considered one of the most severe 
and debilitating neurological sequelae in this population, and may occur even in patients 
with mild TBI [24]. 
Cognitive sequelae are those in which there is impairment of attention, 
concentration, memory, verbal fluency, planning, decision-making, reasoning and 
problem solving, which may assume a persistent character and prevent the individual 
from reestablishing their independence or returning to their usual activities before the 
TBI [73, 74]. Although DAI can cause motor or sensory deficits, cognitive sequelae are 
more related to the individual's dependence, occurring in up to 65% of victims of severe 
TBI [75]. Of these, about 43% of patients have cognitive dysfunctions for more than 6 
months and in more severe cases, even basic activities of daily living, such as preparing 
a meal and driving, are compromised [76]. 
Among the cognitive alterations observed in patients with TBI, the impairment 
of executive functions draws a lot of attention. This term refers to the set of higher-
order cognitive skills capable of planning, executing and monitoring a series of actions 
aimed at achieving a goal. This cognitive domain depends fundamentally on the 
prefrontal cortex and its circuitry, being extremely important for the quality of life of the 
individual, since it directly influences everyday acts, such as performance at work or in 
interpersonal relationships [77]. Given the high prevalence of such cognitive disorders, 
it is not surprising that the frontal lobe, or the connections to this brain region, are 
particularly vulnerable to TBI [78]. For example, disturbances in working or planning 
memory may be seen in patients with focal lesions in the dorsolateral prefrontal cortex 
or in projections (white matter) between the lateral frontal region and posterior regions 
[21]. 
Memory disorders after DAI also deserve to be highlighted, since they are highly 
prevalent in this population, affecting up to 40 to 60% of victims of severe TBI. In fact, 

19 
 
TBI broadly affects the most diverse aspects of memory and presents a striking 
characteristic: the pattern of memory impairment is much more similar to that found in 
patients with frontal injury than individuals with amnesia [79]. In 2005, Mathias and 
Mansfield [80] compared 25 TBI victims with 25 healthy individuals matched for age and 
sex and found that the patients had worse performance in explicit memory. These same 
findings have been demonstrated in other studies, indicating memory disorders to be 
highly prevalent after DAI, affecting up to 40 to 60% of victims of severe TBI. In fact, TBI 
broadly affects the most diverse aspects of memory and presents a striking 
characteristic: the pattern of memory impairment is much more similar to that found in 
patients with frontal injury than individuals with amnesia [79].  
Although the pathophysiological mechanism is not well understood, the 
cognitive changes found in these patients seem to be related to the impairment of 
circuits involving several neurotransmitters, such as serotonin, glutamate, dopamine, 
norepinephrine and acetylcholine [81]. In the acute phase of TBI there is a massive 
production and release of acetylcholine in combination with other neurotransmitters 
such as glutamate, catecholamines and serotonin, which contributes to the clinical 
disorders observed at this stage (changes in the level of consciousness, executive 
dysfunctions and memory impairment) [82, 83]. However, in chronic disorders affecting 
these cognitive domains, acetylcholine seems to be the most relevant neurotransmitter 
involved [81, 84]. After experimental studies demonstrated the impairment of 
cholinergic pathways after TBI in the 1990s, Dewar and Graham and Murdoch et al. [85, 
86] conducted seminal studies postmortem in humans and demonstrated the 
pathophysiology of cholinergic dysfunctions observed in TBI victims. Despite the relative 
normalization of most neurotransmitters, cholinergic function remained chronically 
reduced, which was apparently directly related to the cognitive disorders observed [84-
86].  
The spontaneous cognitive recovery of DAI victims is well documented in the 
literature. Despite memory impairment after TBI, many patients have spontaneous 
recovery of cognitive functions. This is a well-known and reported phenomenon in the 
medical literature. Zaninotto et al., [87] followed 18 patients with DAI for 12 months 
after trauma and documented a significant improvement in verbal fluency at the 12th 

20 
 
month, compared to the performance obtained at the 6th month. Three years later, the 
same authors reported data from 40 patients with DAI and observed spontaneous 
improvement in visuospatial memory as a function of time at the end of the 1st year 
after TBI [88]. In addition to the spontaneous cognitive gain observed, many studies 
have demonstrated improvement in additional cognitive performance when submitted 
to cognitive rehabilitation therapies (CRT) [89-91]. In 2009, Rohling et al. [89] published 
a review showing improvement of memory in TBI and stroke patients who underwent 
CRT, being this benefit markedly in the domains of attention training, visuospatial 
memory and language. CRT is a term that describes treatments developed to improve 
cognitive performance, either by restoring lost cognitive functions or learning 
compensatory strategies. Specific CRTs have been developed for resolution of disorders 
of memory, attention, communication, and executive functions. In addition, a 
committee to evaluate CRTs for TBI patients was created by the Institute of Medicine in 
the United States [92]. This same committee evaluated the studies on specific CRT for 
executive functions and described a wide variety of different strategies employed, 
predominantly compensatory and applied in victims of moderate to severe TBI, and 
concluded that there is evidence that goal-guided training Goal Management Training, 
using previously planned tasks as guides for the planning and execution of new tasks, 
promotes positive effects on the performance of this domain cognitivo.Com relation to 
CRT for memory, Rohling et al. [89] questioned the benefit of this therapeutic strategy, 
since it did not find significant changes. However, few studies that were part of this 
meta-analysis specifically evaluated the memory domain, making it difficult to reach a 
definitive conclusion on this topic. In 2014, Elliott and Parente [93] published a meta-
analysis evaluating the efficacy of CRT for the treatment of memory deficit in patients 
with TBI and stroke, including new studies, and revisited the data published by Rohling 
et al. in 2009 [89]. This time, the results indicated moderate and significant memory 
improvement with CRT, especially in the working memory component. Regarding the 
techniques used, it was demonstrated that the most recently described strategies, using 
digital resources such as the internet, were not superior to the protocols traditionally 
used [29]. 

21 
 
To date, studies evaluating pharmacological treatments for cognitive changes 
resulting from TBI have failed to demonstrate a clear benefit of this therapeutic modality 
[94]. Extrapolating the findings of studies in patients with mild cognitive impairment, a 
known risk factor for Alzheimer's disease, that evaluated possible drug treatments for 
dementia, it was seen that the strategies studied failed to demonstrate this benefit. Still, 
no medication for this purpose has been approved for clinical use by the United States 
Food and Drug Administration (FDA) [95-97]. In contrast to most published studies, 
donepezil (an acetylcholinesterase inhibitor) can be used as an attempt to control 
symptoms in patients with severe and debilitating cognitive conditions, although its 
efficacy is still questionable [98]. 
 
Neuromodulation Methods in TBI 
The International Neuromodulation Society (www.neuromodulation.com) 
defines therapeutic neuromodulation as: "Alteration of nerve activity through targeted 
delivery of stimulus, such as electrical stimulation or chemical agents, to specific 
neurological sites of the body". The limited results with conventional cognitive 
rehabilitation techniques motivated studies evaluating invasive and non-invasive 
neuromodulation strategies, as follows: Transcranial Magnetic Stimulation (TMS), 
Transcranial Direct Current Stimulation (tDCS), Low Intensity Laser Therapy and Light 
Emitting Diode (LLLT - Low-Level Light/Laser and LED - Light-Emitting Diode) Transcranial 
and Deep Brain Stimulation, the latter of which is an invasive technique. Among these, 
tDCS is the intervention currently with the largest number of clinical studies published 
on the subject [99]. However, most of the current evidence is case reports or case series, 
and the few randomized and covert clinical trials have a small sample size, allowing for 
limited analyses. 
Given the various neuromodulation techniques described, an important question 
still to be answered is which of the strategies offers the best results. In fact, there is no 
data available that answers this question. Many topics still need to be explored: 1) 
effectiveness of these techniques when compared to each other; 2) the peculiarity of 
each of the methods that may be advantageous for the treatment in TBI; 3) safety and 

22 
 
tolerability; 4) consider the various biological processes that occur in the different 
phases of TBI, identifying favorable moments ("therapeutic windows") for the institution 
of a certain technique and 5) combining different modalities can optimize the final 
product. 
 
Radio electric asymmetric conveyer 
The REAC technology is a noninvasive, personalized approach to neuromodulation that 
has been investigated as a possible treatment for various neurological and psychiatric 
conditions. 
REAC technology, in contrast to traditional neuromodulation methods that generally 
target specific neural pathways, operates by using very low-intensity asymmetrically 
conveyed radio electric fields to modulate the endogenous bioelectric field. This field 
includes the electrical activity of all body cells. The process is carried out with a REAC 
device, which produces an asymmetric radioelectric field, while the asymmetric 
conveyor probe interacts with the body's bioelectric field. 
The main function of REAC technology is to affect endogenous bioelectric activity and 
cellular polarity. Cells maintain an internal and membrane charge imbalance, creating 
an electrical gradient that supports various cellular processes. The asymmetric 
radioelectric field generated by REAC can interact with this charge imbalance, which may 
result in changes to endogenous bioelectric activity and cellular polarity, potentially 
influencing neural communication. 
REAC technology has demonstrated therapeutic promise for neurological and 
psychiatric conditions, and ongoing research suggests it may play a growing role in 
neuromodulation. 
 
Clinical protocols 
REAC technology provides several therapeutic protocols for neuro modulation and bio 
modulation. These protocols are used to address mood, behavior, motor control, and 
pain disorders, as well as in reparative and regenerative medicine. 

23 
 
Safety and Recommendations 
The obtained certifications (CE and ANVISA) and existing studies confirm that the 
treatments of REAC technology are safe and effective when used as intended and by 
qualified professionals. 
General considerations 
REAC is a noninvasive technology that utilizes low-intensity radio electric (RE) 
emissions to interact with biological tissues. 
Physical aspects 
The physical aspects of Radio Electric Asymmetric Conveyer (REAC) treatments 
involve a noninvasive interaction of low intensity RE emissions with the patient's body. 
The device features a unique ACP that convey the RE field to the target area. 
REAC treatments are non-invasive and painless. Patients typically lie or sit comfortably 
while the ACP is placed on specific areas of the body based on the treatment protocol. 
The treatment sessions duration can vary depending on the targeted condition and 
treatment plan. Overall, the physical aspects of REAC treatments involve the application 
of low power RE energy through a specialized probe to potentially influence cellular 
processes. 
Adverse effects 
No adverse effects have been reported to date. However, transient expected 
side effects that are part of the therapeutic response may occur, such as mild axial 
instability, asthenia, and mood swings. 
Contraindications 
At present, no specific contraindications to REAC neuromodulation treatments 
have been identified. However, it is recommended to avoid application in patients with 
pacemakers and pregnant women. 
Ethical Aspects related to the use of REAC technology treatments. 
Widespread axonal damage currently has no effective therapy. REAC 
neuromodulation treatments are safe and non-invasive and have been shown to 

24 
 
produce improvements in other neurodegenerative diseases. Based on these premises, 
there are no apparent ethical concerns. 
Regulation 
The devices used in this study are the BENE Model 110 devices, which have 
obtained both CE and ANVISA (Brazilian regulatory agency) certification. 
 
Table 3 – Possible therapeutic applications for REAC in TBI 
Therapeutics 
Neuro postural optimization NPO and Neuro Psycho Physical 
Optimization 
– 
Brain 
Wave 
Optimization-G 
(NPPO-BWO-G) 
treatments 
Enhance: 
• Motor recovery 
• Cognitive rehabilitation (memory, language, executive functions) 
• Treatment of post-concussion syndrome 
• Reduction of depression, anxiety, and post-traumatic stress symptoms 
• Treatment of chronic disorders of the level of consciousness  
• Painful syndromes  
 
REAC in cognitive, mood, behavior, and motor disorders. 
Radio Electric Asymmetric Conveyer (REAC) technology is a relatively new 
approach to neuromodulation, aiming to influence the nervous system through the 
application of radio electric fields asymmetrically conveyed, using precise 
administration procedures. These specific treatments have proven useful and effective 
in numerous mood, behavior and movement control disorders [33-40, 100-134].  

25 
 
 
MATERIAL AND METHODS 
Series 
Participants will be prospectively included of both genders, between 18 and 60 
years of age. Eligibility criteria is described in Tables 4 and 5. 
Table 4 - Inclusion criteria 
1. Clinical-radiological diagnosis of diffuse axonal lesion 
2. Traumatic brain injury suffered for at least one (1) week 
3. Be hospitalized at the neurotraumatology section at the Hospital das Clínicas 
Complex of the Medical School of the University of São Paulo (HCFMUSP) 
 
Table 5- Exclusion criteria 
1. History of addictive behavior and/or serious psychiatric illnesses 
2. Presence of bone defects in the skullcap 
3. Uncontrolled epilepsy 
4. Carriers of implanted metallic or electronic devices: cardiac pacemaker, stents, 
epidural or deep brain electrodes, cochlear implants, drug infusion systems or 
intracranial clips 
5. Next of kin refusal to participate in any of the stages of the study, as well as to be 
randomly allocated to one of the groups 
6. Next of kin refusal to provide the free and informed consent for participation 
7. Gestation 
8. Severe, uncontrolled systemic disease 

26 
 
9. Magnetic resonance imaging of the brain with findings not compatible with DAI or 
demonstrating the presence of expansive intracranial lesion. 
 
The clinical diagnosis of DAI is defined as a state of coma after TBI, lasting at least 
6 hours, after exclusion on imaging of intracranial lesions with mass effect or significant 
ischemic brain lesions. At hospital admission, all patients underwent head CT as a 
standardized routine of hospital care for patients with moderate and severe TBI. In 
addition, all patients underwent magnetic resonance imaging of the brain to identify 
injuries suggestive of DAI, as well as to rule out other causes of brain injury that could 
justify the patient's clinical picture. 
Recruitment and adherence strategies 
The participants will be recruited when hospitalized at the Neurotraumatology 
Clinic of the Hospital das Clínicas Complex of the Medical School of the University of São 
Paulo (HCFMUSP). Overall admission and in-hospital records will be collected of each 
patient who meet the inclusion criteria. Patients will complete the minimum period of 6 
months of TBI of follow-up. 
In this study, REAC will be performed a single session of Neuro Postural 
Optimization (NPO), and 18 Neuro Psycho Physical Optimization – Brain Wave 
Optimization-G (NPPO-BWO-G) treatment sessions for 4 daily sessions. Each next of kin 
will receive written instructions with the date and time of the next sessions in order to 
avoid misunderstandings. 
Search locations 
The study will be conducted within the HCFMUSP, in São Paulo - SP, which has 
2400 beds distributed among its 8 specialized institutes and 2 auxiliary hospitals 
(www.hc.fm.usp.br). The research locations in the various stages of the study are 
described in Table 6: 
 
Table 6 - Stages of the study and the respective places where they will be carried out 

27 
 
Stage of the study 
Location 
Purpose 
Patient selection 
ICU - Neurotraumatology 
 
Electroencephalogram 
ICU - Neurotraumatology 
Brain waves mapping 
Brain MRI 
Central Institute  
DAI diagnostic 
REAC 
ICU - Neurotraumatology 
Intervention 
DAI: diffuse axonal injury, ICU: intensive care unit, MRI: magnetic resonance imaging, 
REAC: radio-electric asymmetric conveyer. 
Study design 
This is a prospective, randomized, double-blind, placebo-controlled clinical trial.  
According to the hypotheses of the present study, the sample size calculation was made 
considering an alpha error of 5% and based on other studies with similar design [135-
140]. We estimate that 30 patients should complete the follow-up and be included in 
the statistical analyses. However, lack of adherence could be a problem. Thus, we 
estimate losses at 20% and calculated a final sample size of 36 participants. Subjects 
with no history of chronic neurological disorders will also be included and separated of 
DAI patients but submitted to the same protocols. After meeting the eligibility criteria, 
the participants will follow the steps of the study as described in Table 7. 
 
Table 7 - The study steps 
Patient selection 
Medical record, radiology, participation consent 
Step 1 (pre-intervention) 
qEEG, TCD and brain4care up to 3 days before the 
start of REAC sessions 
Step 2 (intervention) 
NPO (single session) 
Step 3 (intervention) 
NPPO-GW (18 sessions) 
Step 4 (post-intervention) 
qEEG up to 3 days after the end of REAC sessions 

28 
 
Follow-up discharge, 3m and 6m mRankin, GOSE, DASS 21 
qEEG: quantitative electroencephalogram, TCD: transcranial Doppler, REAC: radio-
electric asymmetric conveyer, NPO: neuro-postural optimization, NPPO-GW: gamma-
waves neuro psycho physical optimization. 
 
Randomization 
A participant will select patients according to DAI criteria and obtain consent for 
participation with the next of kin for each eligible patient. Following, qEEG examinations 
will be performed. Up to three days after finishing NPPO-BWO sessions, a second 
acquisition of qEEG will be performed. All participants will be blinded between active 
and sham until the study is finished. 
 
Participants will be randomly divided in a 1:1 ratio into two groups:  
1. Active 
2. Sham 
The randomization process will be done in blocks interchanged, with the size of each 
block equal to four. The computerized system available in www.randomization.com will 
be used. For the persistence of allocation concealment, all evaluations will be performed 
using a database containing the group with a label "A" and "B". Consequently, all 
analyses were made without possible presumptions as to the allocation of the group.  
 
Masking of Groups 
In order to maintain masking in the study, the REAC device has a very similar 
shape, size, color, weight and emits very similar sounds. The participants and their 
families will not know which group the patient has been included up to the conclusion 
of the study. The entire process of selection, interview, neuropsychological evaluation 
and intervention with REAC will be similar in the groups, differing only the type of device 
used. The neuropsychologist responsible for the application of the neuropsychological 
tests will be unaware of the allocation of the intervention group.  

29 
 
Ethics 
The project will be submitted to the Research Ethics Committee of the Hospital 
das Clínicas da Faculdade de Medicina da Universidade de São Paulo. 
All responsibles for the patients will have full knowledge of the objectives and 
methods of the experiment and consented through written signature of the informed 
consent form. They will be informed about the experimental character of the proposed 
intervention, expected risks and benefits, as well as their random inclusion in one of the 
treatment groups (active and Sham). They will be aware that they could request their 
exclusion from the research at any time, without this interfering on the care that this 
patient receives in the institution. 
The study will be conducted according to the requirements of the institution's 
ethics committee and also based on the recommendations established in the 
Declaration of Helsinki (1964), as amended in Tokyo (1975), Venice (1983) and Hong 
Kong (1989). 
The therapeutic application of REAC will be carried out according to the ethical 
principles established in the aforementioned declarations and in the ethics standards of 
the Ministry of Health (C.N.S. Resolution no. 196 10/10/96). The ethical foundations and 
guidelines for the clinical application of REAC followed the basic precepts of treatment 
with this technique according to the International Conference on REAC Safety 
Consensus, held in March 2008 in Siena, Italy. 
This study will be registered in ClinicalTrials.Gov (www.clinicaltrials.gov), one of 
the most reliable sources of consultation on clinical studies in the world. This is the U.S. 
government agency responsible for centralizing and updating information about studies 
that have been registered on this platform and that are underway around the world.  
 
Procedures 
Quantitative Electroencephalogram 
Purpose: Documenting brain waves patterns pre and post interventions. 

30 
 
Patients will be submitted qEEG testing before starting the REAC protocols and 
then after finishing the last session. For data collection, EEG examinations were 
performed using an international 10-20 electrode placement system. The examination 
will last 30 minutes, 15 minutes with eyes open and 15 minutes with eyes closed (relaxed 
wakefulness. The digital 19-channel Nihon Kohden® EEG 1200 version 01.71 (Nihon 
Kohden, Tokyo, Japan) will be used., The channels follow the 10-20 system: seven 
located in the frontal lobe (Fz, Fp1, Fp2, F3, F4, F7 and F8), three in the center (Cz, C3 
and C4), four in the temporal lobe (T3, T4, T5 and T6), three in the parietal lobe (Pz, P3 
and P4) and two in the occipital lobe (O1 and O2). For quantitative analysis, the data 
were converted using the Neuromap of the Neuroworkbench software, transferred to 
Matlab vR2002b and treated with the EEGlab v2023.0116 software. After being 
imported into EEGLAB, the spatial coordinates of each electrode will be inserted 
according to the 10-20 system. The signals were referenced using the average between 
the channels. The baseline was automatically removed using a 0.5Hz 117 high-pass filter. 
Artifacts are automatically rejected and incorrect data periods removed. Finally, the 
Independent Component Analysis is performed. 
Processing 
Using EEGlab's Darbeliai tool, the power spectral density of each channel is 
calculated for four bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-32 Hz), 
in which the absolute power will be determined. The relative power analysis will be 
performed using the Fast Fourier Transform FFT. 
OUTCOMES 
Primary: 
Observe if there are significant changes in the electroencephalographic pattern, 
compared between the groups.  
Secondary:  
Observe if there are: 
Significant clinical improvement determined by the mRankin and GOSE scales 
between the groups. 

31 
 
 
Statistical analysis 
Categorical variables will be presented in absolute values and relative 
frequencies, while continuous variables will be described in measures of central 
tendency and dispersion. All analyses will be performed under the intention to treat. 
The Kolmogorov-Smirnov test will be used to verify the parametric nature of the 
quantitative values observed in the battery of neuropsychological tests. The repeated 
measures related to the items neuropsychological assessment and cortical excitability 
will be compared through ANOVA-type analyses (analysis of variance) of two factors for 
repeated measures and the interaction test between the groups considered to test the 
null hypothesis[141, 142]. 
To compare the delta (Δ) values between the intervention groups, the Mann-
Whitney test will be used. The comparison of the frequency of adverse effects according 
to the intervention groups will be performed using Pearson's chi-square. The Wilcoxon 
Rank-Sum test will be performed in the intra-group comparison regarding pre-
intervention 
(E1) 
and 
post-early 
intervention 
(E2) 
performance 
in 
the 
neuropsychological assessment. 
Statistically significant findings are those with a p-value or probability of type I 
error lower than 5%. The control of blinding will be done with the analysis of agreement 
with Cohen's kappa. The sample size is based on the TMT part B scores obtained after 
the intervention (E2). The analyses were performed using Microsoft Excel 2010 and IBM 
SPSS (Statistical Package for Social Sciences) v.21.0. 
 

32 
 
Funding 
The present study will receive no funding. Device/software manufacturers will 
support the project providing their methods to be used in the study.  
Chronogram 
June 2024- Protocol submission. 
Recruitment: One year. 
Data analysis: Three months. 
Publishing results: Manuscript submission to publication one month later. 
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medidas repetidas. In: Editor (ed)^(eds) Book Análise não-paramétrica de dados 
ordinais com 
medidas repetidas. Universidade de São Paulo, City, pp.  
 
 
 

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APPENDIX 
 
Extended Glasgow Recovery Scale (GOS-e) 
The Glasgow Recovery Scale (GOS) is a global scale for the functional evolution of TBI 
patients. The Extended GOS provides more detailed categorization into eight 
categories: Use of the structured interview is recommended to facilitate consistency in 
classification. 
(8) Total recovery: this category includes individuals who resumed normal life without 
any alteration or complaint consequent to the trauma. Return to productivity is not a 
basic parameter for inclusion in this category.  
(7) Good recovery: refers to individuals who have resumed normal life with the 
presence of mild physical or mental disabilities. As in the previous category, the return 
to productivity is not a basic parameter for inclusion in the category.  
(6) Moderate disability: "independent but incapable". They can perform the basic 
activities of self-care and other essential activities to maintain independence without 
help, by themselves, with or without difficulties in the execution. The basic point of 
differentiation for good recovery is that individuals who are included in these 
categories are not able to resume all activities performed prior to the trauma.  
(5) Marked moderate disability: "independent but incapable". It can perform the basic 
activities of self-care and the essential activities to maintain independence, with the 
help of devices or in an environment in which there are modifications to enable its 
realization.  
(4) Severe-moderate disability: "conscious but dependent." Is able to maintain the 
basic activities of self-care, but to perform one or more, essential activities to maintain 
independence, needs the help of another person. 

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(3) Severe disability: "Conscious but dependent." You can't maintain the basic activities 
of self-care without the help of someone else. You need help with at least one of these 
activities. 
(2) Persistent vegetative state (PVS): does not demonstrate evidence of significant 
responsiveness. He does not obey simple commands or utter any words. Differentiate 
from other conditions in which there is extreme reduction in responsiveness.  
(1) Death: death as a result of trauma. 
(a) Basic self-care activities: bathing, feeding, moving within the room/place where one 
is, taking care of one's excretory function, dressing, shaving, brushing teeth, combing.