Key words: CAPD, Auditory Event Related Potentials (AERP), Contingent Negative Variation (CNV), LASER, problems, respiratory chain, ATP, Wire and Fire, Learning disabilities

Hypothesis for a future p200/ pattern morphology. INTRODUCTION It is well accepted that an acoustical application of a environment (noise and reverberation) in classroom conditions is a critical factor in the educational achievement of many Laser-device in patients children. Such populations being at risk for academic failure encompass children with language impairment, dyslexia, attention with symptoms of a deficits and general developmental delay (literature in 1). It is reasonable to assume, that poor neural acoustic representation developmental auditory will lead to serious problems in the maturation of the auditory pathways and hence the development of auditory processing disorder. process ability. Recent research suggests that neuroplasticity and neuromaturation are dependent on stimulation (11, 12). Therefore comprehensive management of Part II: Evaluation of CAPD should include auditory stimulation to achieve functional changes within the central auditory nervous system. clinical cases. Thus young children would be expected to benefit from a great degree of neuroplasticity. In another paper (2) we E. Friederichs focused already on the use of late event Centre for Development and Learning, Bamberg related auditory potentials (AERP´s) in Business and Economic Education, University of Bamberg, Germany documenting changes in clinical status after direct stimulation with binaural FM- devices. These data were interpreted as ABSTRACT possible effects of LASER application indicating that neuroauditory maturation The present study examined whether of auditory neurons by inducing the could be influenced by a specific changes of electrophysiological late respiratory chain of the mitochondria. intervention and could be distinctly event related potential pattern could Part II of the article now provides clinical objectified by means of late event-related be used to reflect clinical changes from data, that a LASER stimulation might be potential measures. therapeutic intervention with a LASER- useful for the clinical improvement of Recording of the Contingent negative device in a group of patients with attention (distraction) symptoms caused variation (CNV) and p200/p300 pattern symptoms of central auditory processing by auditory processing deficits. requires the patient to pay active disorder (CAPD). The contingent negative Subjects consisted of 59 patients average attention to a stimulus. Auditory event variation (CNV) and event related age 14 years (range 7-53 years) with related potentials (AERP´s) allow the auditory cortical potentials (AERP) reflect normal hearing threshold, learning evaluation of brain activities and are a synchronization of together firing wired disability and attention deficits caused presumed to be related to attention, neural assemblies responsible for auditory by central auditory processing disorder. recognition, and processes. The processing, suggesting an accelerated These patients were stimulated with a contingent negative variation (CNV) is a neuromaturation process when applying LASER-device system. Results after 10 slow negative potential decrease, which a LASER device stimulation. This was LASER stimulation sessions indicated, will appear hundreds of ms before target discussed already in Part I of this article (1), that this type of LASER-device stimulation stimulation. CNV is representing a large where a model was presented explaining significantly improved auditory CNV and number of increasing synchronous self

20 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

regulatory excitatory activity of neuron in this study. Subject age ranged from 7 sources (laser diodes). These emit at two populations and is preparing the brain for to 53 years with a mean age of 14 ± 10 different wavelengths, peak power and the following auditory stimulus. In this years. emission mode. The pulse frequency is sense CNV and p200/p300 are related to All subjects met the following criteria: for both wavelengths 1500 Hz (T-on the synchronous firing of wired neurons Hearing sensitivity better or equal to 20 mode) delivered to the auditory neurons. in order to provide the ability of reaction dB HL at 250 – 8000 Hz, German was The first one is a pulsed 905 nm laser capacity of a certain brain task. the primary language. All subjects had a diode with 25 W peak optical power Studies of brain development show that history of learning disability and attention with a pulse duration of 100 ns. The sensory stimulation in the case of the deficits. 13 patients were additionally second laser diode (808 nm) is operating visual centres of the brain is critically diagnosed with ADHD by DSM IV criteria with 1000 mW optical power with a important, and influences the actual and well controlled treated with stimulant pulse duration of 300 µs. The two laser organization of visual brain pathways. medication. In these cases CAPD was beams are emitted synchronously and Increase in visual stimulation results in considered as a comorbid condition of the propagation axes are coincident. The morphological and functional alterations ADHD. Children with and without ADHD patients received the following energy within the visual parts of the brain (4, did not demonstrate a significant different dose on both ears for 1/2 hour separately: 5). Strategies for stimulation of auditory distribution pattern of pathological 164.43 J/cm2 (according to A. Kaiser, processing disorder are usually direct auditory event related potential. This is in personal communication). remediation, environmental modifications agreement with other literature (7). Only and compensatory strategies. One of a subjects were included with an IQ-level ≥ Event Related Auditory Cortical possible new strategy for reducing the 90 measured with different appropriate Potentials (AERP) deleterious effects of auditory noise is instruments. Cortical potentials were recorded from the use of LASER light, providing discrete All subjects were administered with 26 electrodes positioned on the human wavelengths (frequencies) to improve electrophysiological tests before and after brain scalp according to the international auditory clarity and avoidance of ear 10 sessions of LASER stimulation 1 - 3 electrode placement system (10-20). pressure, tinnitus and background noise months after LASER stimulation. To maximize CNV, P200 and P300 (2,8). The purpose of direct stimulation amplitudes and stability, electrodes over of auditory processing on the level Assessment battery the central (CZ, FZ, PZ), left (C3, F3, P3, of neurostimulation is to maximize Prior to participation in the study each F7, T3, T5, P3, O1) and right (C4, F4, neural plasticity and possibly accelerate subject underwent a comprehensive P4, F8, T4, T6, O2) central, parietal and maturation, improving auditory audiologic evaluation to rule out occipital cortex parts of the brain were performance. any abnormalities of the auricle and used for evaluation. The purpose of this article is to present auditory meatus. Pure tone air and bone Electrodes were referenced to linked data from patients with developmental conduction thresholds were assessed earlobes. Vertical EOG provide control auditory-perception problems when using a Maico ST-28 clinical audiometer for blinks. Data were recorded with applying LASER light. A hypothetical (250-8000 Hz) demonstrating normal a 32–channel bio signal amplifier model is already discussed in Part I of values. Tympanometry and acoustic (Brainamps) with a frequency response this article (1) to explain the results using reflex as well otoacoustic emission testing 0.5 to 30 Hz and a A to D conversion electron modelling and proton exchange revealed normal values. All subjects were rate of 1000 Hz. Trials were corrected inside the respiratory chain. As this article required to have normal ABR tracings in for baseline and VEOG artefacts with is the second part of a two-part article it each ear. the brain vision analyser software. These is referred to the first part for reasoning data were interpreted as indicating that of this clinical evaluation. Most of the Laser application neuroauditory maturation could be literature is already cited in Part I of this The Laser source was a Multiwave Locked influenced by a specific intervention and article (1). System Laser (MLS®, ASA Srl, Vicenza, could be distinctly objectified by means Italy). It is a commercially available laser of late event related potential measures. METHODS source built in compliance with EC/EU Subject selection criteria rules, which received FDA clearance and Auditory CNV (contingent negative 59 subjects (47 males, 12 females) with is widely used in clinics. MLS® laser is a variation): normal hearing sensitivity participated class of NIR laser with two synchronized Recording of the CNV potentials was

21 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

achieved by presentation of 50 tone target tone with a stimulus duration of P2 was identified as the largest positive burst sequences (25 high frequency/ 50 ms and an ISI of 3025 msec. Prior peak between 130 and 290 ms, following low frequency 3 kHz/2 kHz and 25 to recording the event related potentials N1. P3 was identified as the highest low frequency/ high frequency 2 kHz/3 subjects were given time to practice positive peak between 250 and 600 ms kHz tone burst sequences, 75 dB HL), the tone discrimination task to become following N2. Latency was measured to respectively. Stimulus duration was 50 familiar with the while the highest peak on the wave. Amplitudes ms. The Interstimulus Interval (ISI) is listening to the rare and frequent tones were measured at the highest wave peak offered with 5 sequences of 10, 20, presented. Each session consisted of 75 relative to the prestimulus baseline: 30 40 or 50 ms. Mean reaction time presentations of the frequent tone and 25 Artefact rejection was set to ignore any and number of errors of omission and presentations of the rare tone in a random trial which the ongoing EEG exceed ± 140 commission were recorded separately sequence. Subjects were asked to push on μV. Averaging was carried out generally (not shown). 1.5 seconds prior to the a mouse button whenever an infrequent over all segments allowing comparison burst sequences a warning burst tone tone was realized. among several data sets with the same (1 kHz, 15 ms duration) was presented. Latency and amplitude measures were software. Prior to recording the event related averaged over three complete trials for This method (P300 “oddball paradigm”) potentials subjects were given time to the N1, N2, P2 and P3 components of the was specifically selected. In this case a practice the tone discrimination task to long latency response to the target tone. series of paired stimuli has to be detected become familiar with the paradigm while listening to the high/low frequency tone burst sequences presented. According to the number of errors of omission the ISI intervals were adapted to 50, 100, 150, 200 and 250 ms, respectively. Subjects Figure 1 - Composite Grand Mean CNVs before (red) and after (green) LASER application. were asked to answer either with "high" or "low" after the second tone burst was realized. CNV reflects a slow potential drift towards negativity, which will take place several hundreds of ms before target condition, preparing the processing of the following target stimulus. One CNV epoch was scored separately for tone burst (target) trial from all electrode positions. From 1120 ms on before target stimulus, a significant CNV component can be detected, representing an excitatory activation of the corresponding brain area.

Auditory P200 and P300 components: Recording of the potentials was achieved by presentation of frequent and infrequent tone bursts (75 dB HL) at a ratio of 3:1 in an “oddball paradigm”. The children were asked to recognize the infrequent stimuli. Binaural tones were presented in a random sequence with a 2.2 kHz infrequent target tone and 4 kHz frequent

22 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

which reflects additionally aspects of Differentiation and quantification take are shown in Figure 1. The two waveforms attention, discrimination and memory. place in a high sensitive fluorescence- represent the CNV locations in target condition activated cell sorter. (red: inital situation; green: after 10 binaural Laboratory analysis LASER sessions). Notice in the development ATP levels were determined in an Statistical analysis of the CNV distribution pattern the increase outsourced laboratory. Mitochondria Statistical analysis was done with a in CNV area from the frontal to the parietal are compartments of eukaryotic temporal resolution t-Test belonging to electrodes already after 10 LASER application cells. They produce by means of the the Brain Analyser software system. All sessions. A map view of CNV between the respiratory chain using oxygen, glucose analyses were performed at a p < 0.05 time interval – 300 ms to 0 ms (appearance and phosphate ATP. ATP determination level of significance. of target stimulus) illustrates the increase in is provided by measurement of the ATP excitatory activation of neuron population production in mitochondria from living RESULTS after the course of 10 sessions of LASER device T-lymphocytes of the patient. Cells with Electrophysiological results applications (Fig. 2 before and Figure 3 after adequate ATP production show after LASER application). Table 1 shows the mean addition of a specific metabolic agent CNV values of absolute CNV areas under curves a different color spectrum compared to Composite grand mean wave forms for the calculation levels before and after 10 LASER cells with decreased ATP production. experimental groups at different time intervals applications, respectively.

Figure 2 - Composite Grand Mean CNVs (mapping view -300 ms to 0 ms) before Figure 3 - Composite Grand Mean CNVs (mapping view -300 ms to 0 ms) after

23 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

Figure 4 - P200/P300 Pattern (before) Figure 5 - P200/P300 Pattern (after)

Figure 6 - C3,C4,Cz left, right and central electrode sites (before) Figure 7 - C3,C4,Cz left, right and central electrode sites (after)

24 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

P200/P300 the case of infrequent tone responses the Table 1 shows the absolute PZ amplitude Analysis of the P200 and P300 development of the classical P200/P300 mean values. It should be noticed that the components reveals a significant height distribution pattern with increase in P200 P3, P4, PZ pattern of the treated sample and morphological discrepancy between amplitude and more pronounced P300 approached more pronounced waveform the target condition (green line) and the pattern after LASER application reflecting an pattern after LASER application compared to non-target condition (red line) after the improved allocation of resources. the initial pattern giving a more convincing LASER application (Figure 5) compared argument than only looking at the absolute to the inital situation (Figure 4) level PZ levels. reflecting an increased discrimination efficiency especially at the P300 level. Table I - Pre- and post treatment mean area (µV*ms) and amplitude (μV) and latency (ms) measures for P200 Composite grand mean wave forms for and P300 of the patients taken from the graph the experimental groups at different time intervals are shown in Figures 6, 7, 8 and P200 P300 P200 P300 9. The three waveforms represent in Figure CNV (CZ)

6 the C3 (red), C4 (blue), CZ (green) and Area (µV*ms) in Figure 8 the P3 (red), P4 (blue) and Peak height (µV) latency (ms) PZ (green) non-inverting locations before LASER application, while in Figure 7 and 9 Before 190 p < 4.84 7.22 240 400 the appropriate locations are shown after 10 sessions of LASER application. Notice in After 4277 0.05 6.62 7.12 240 400

Figure 8 - P3,P4,Pz left, right and central parietal electrode sites (before) Figure 9 - P3,P4,Pz left, right and central parietal electrode sites (after)

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ATP levels an optimization of the central auditory hearing loss, while developmental ATP levels before and after intervention (% information processing. The improved hearing problems are not considered. T cells): activation pattern of the contingent Our data support this hypthosesis as negative variation (CNV) can be ATP concentration significantly increased explained by a synchronous activation after LASER application. The model is Before After p of a great amount of neurons population extensively discussed in Part I of this (assembly) which are necessary to article (1). 92.8 +/- 11.6 98.8 +/- 1.8 < 0,05 prepare for course of action. In most of the patients the CNV before The organic living brain is quite the LASER stimulation was abnormally Range 46 - 100 95.0 – 99.9 opposite of an engineered machine with evoked, severely reduced and in most of hardwired circuits that can only perform the cases absent in amplitude suggesting a limited number of actions, but during problems of the patients paying attention. ATP levels before and after intervention were the day the brain is forming / uniforming As CAPD can be a distinct disorder or significantly different, reflecting a possible new flexible neuronal networks. A group a comorbid condition of ADHD the energy dependent reaction. of neurons will be used for different success of this type of intervention purposes at different times. Tasks can seems to be independent of the type of DISCUSSION be performed using different coalitions CAPD: Children and adolescents applied Only a few studies have been found in (assemblies) of neurons (4, 5). Learning with LASER stimulation did significantly literature having focused on the use of skills are encoded in the cumulative and in different degrees benefit from this CNV and P300 potential in documenting electrical patterns resulting from the therapeutic approach whether ADHD changes in clinical status (literature in neurons firing together (4, 5). The was present or not. It seems reasonable 1). This study was designed to evaluate pattern, i.e. the population is interesting, to assume that changes in the amplitude whether development of the event not the individual cell. Cells that are, on and/or morphology of the P200/P300 related auditory event related potential whatever reason, chronically inflamed, waveforms correlate with changes of the distribution pattern would reflect any are more sensitive to red and near- clinical status. changes of the auditory processing infrared light than are well-functioning Because maturation processes in highly system resulting from LASER stimulation. cells. To heal, the body often needs to plastic brains in childhood should be Recording of the CNV requires the create new cells. The first step in cell enhanced through sensory stimulation, patient to pay active attention to a reproduction occurs when DNA replicate expectation of improvement of auditory stimulus. AERP´s are presumed to be itself. Specific wavelengths 404, 620, processing abilities could be confirmed in related to attention, recognition, and 680, 760 and 830 nm can activate DNA the current investigation. These findings memory processes. Our results revealed and RNA synthesis in cells by inducing support previous research from our group a significant improved allocation of the respiratory chain of sick neurons thus showing that children with various types resources of patients with CAPD after leading to an increased cell proliferation of learning or cognitive disorders may 10 LASER stimulation sessions. This (literature in 1). be (i) differentiated from normal control is reflected in the differential reaction Wilden et al. (8) already reported, subjects on the basis of event related on relevant and non relevant stimuli that LASER stimulation with distinct potentials and (ii) stimulation by FM- measured with the P200/P300 pattern wavelenght may vitalize the cell by devices could indeed improve auditory as well as in CNV pattern before and increasing the mitochondrial ATP processing abilities (2). Data of the control after the course of 10 LASER stimulation (adenosine-tri-phosphate)-production. subjects from this study could serve as sessions. With regard to radiation phenomena and a baseline definition. While trainings or Although some of the electrophysiological its inhanced electron flow in the cellular FM-devices usually will be applied in the changes might be attributable to normal energy transfer (respiratory chain), these morning or the afternoon as additional maturation processes, the differences authors postulated already that the educational support for the children, in CNV distribution pattern and P200/ experimentally found increase of ATP- LASER stimulation can be applied P300 from the pre-and post measures production could be explained by means independently from school schedule and can be assigned to the treatment of low-level laser light on a cellular level. may have a faster and a more sustainable intervention. This can be interpreted as Their investigations are mainly based success for the disabled children. precise discrimination efficiency and as on patients with Tinnitus and sudden Because auditory neuromaturation and

26 Hypothesis for a future application of a Laser-device in patients with symptoms of a developmental auditory processing disorder. Part II: Evaluation of clinical cases. Energy for Health [18]

neural plasticity depend on distinctive longterm follow up) have to address follow up of auditory neuromaturation auditory stimulation, “aggressive” the question whether use of AERP´s processes which was (b) induced by management of CAPD (either with or may be more sensitive for prediction LASER stimulation. without ADHD) should begin as early as of treatment outcomes as it has been Use of LASER stimulation does not possible. Studies of brain development already suggested by Walsleben et al. (6). replace other intervention measures as show that sensory stimulation of the Studies on AERP measures performed occupational therapies or other kinds of auditory centres of the brain is critically at different maturation stages and with auditory training interventions although important, and influences the actual increased number of LASER simulation they may support and possibly accelerate organization of auditory brain pathways sessions are in progress, to predict these methods. In some cases LASER (9). Increase in auditory stimulation may already possible therapeutic advantages stimulation might not be helpful. As a result in morphological alterations within of such a LASER device very early. The result of this clinical evaluation patients the auditory parts of the brain (10, 13). degree and speed of improvement and their parents need to be intensively The ability of the to between different forms of interventions involved in the decision making process reorganize continuously throughout life has still to be evaluated. using a LASER device very early to span reflects the ability to acquire new Although results of this type of improve acceptance and the beneficial skills and behaviours. Several studies investigation must be interpreted effect of such a tool. have focused on the use of the late cautiously because of the limited number auditory event-related potentials (AERPs) of subjects and possible interfering REFERENCES in documenting changes in clinical medication effects, they do suggest 1. Friederichs E. (2017). Hypothesis status. These studies emphasized the that event related potential measures for a future application of a Laser- feasibility of using P300 event related are sensitive to changes in clinical status device in patients with symptoms of potentials to document levels of auditory when applying a controlled use of LASER a developmental auditory processing dysfunction (14, 15). There are several stimulation in children/adolescents with disorder Part I: Methodological basics, studies suggesting that P300 auditory CAPD. 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