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Transcranial Photobiomodulation for the Treatment of Children with Autism Spectrum Disorder (ASD): A Retrospective Study


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Children with Autism Spectrum Disorder (ASD) face several challenges due to deficits in social function and communication along with restricted patterns of behaviors. Often, they also have difficult-to-manage and disruptive behaviors. At the moment, there are no pharmacological treatments for ASD core features. Recently, there has been a growing interest in non-pharmacological interventions for ASD, such as neuromodulation. In this retrospective study, data are reported and analyzed from 21 patients (13 males, 8 females) with ASD, with an average age of 9.1 (range 5–15), who received six months of transcranial photobiomodulation (tPBM) at home using two protocols (alpha and gamma), which, respectively, modulates the alpha and gamma bands. They were evaluated at baseline, after three and six months of treatment using the Childhood Autism Rating Scale (CARS), the Home Situation Questionnaire-ASD (HSQ-ASD), the Autism Parenting Stress Index (APSI), the Montefiore Einstein Rigidity Scale–Revised (MERS–R), the Pittsburgh Sleep Quality Index (PSQI) and the SDAG, to evaluate attention. Findings show that tPBM was associated with a reduction in ASD severity, as shown by a decrease in CARS scores during the intervention (p < 0.001). A relevant reduction in noncompliant behavior and in parental stress have been found. Moreover, a reduction in behavioral and cognitive rigidity was reported as well as an improvement in attentional functions and in sleep quality. Limitations were discussed as well as future directions for research.
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Citation: Pallanti, S.; Di Ponzio, M.;
Grassi, E.; Vannini, G.; Cauli, G.
Transcranial Photobiomodulation for
the Treatment of Children with
Autism Spectrum Disorder (ASD): A
Retrospective Study. Children 2022,9,
755. https://doi.org10.3390//
Academic Editor: Benedetto Vitiello
Received: 8 April 2022
Accepted: 19 May 2022
Published: 20 May 2022
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Transcranial Photobiomodulation for the Treatment of Children
with Autism Spectrum Disorder (ASD): A Retrospective Study
Stefano Pallanti 1, 2, *, Michele Di Ponzio 1, Eleonora Grassi 1, Gloria Vannini 1and Gilla Cauli 3
1Neurodevelopment Division, Istituto di Neuroscienze, 50121 Florence, Italy; (M.D.P.); (E.G.); (G.V.)
2Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
3Asst Fatebenefratelli Sacco, 20154 Milan, Italy;
Children with Autism Spectrum Disorder (ASD) face several challenges due to deficits
in social function and communication along with restricted patterns of behaviors. Often, they also
have difficult-to-manage and disruptive behaviors. At the moment, there are no pharmacological
treatments for ASD core features. Recently, there has been a growing interest in non-pharmacological
interventions for ASD, such as neuromodulation. In this retrospective study, data are reported
and analyzed from 21 patients (13 males, 8 females) with ASD, with an average age of 9.1 (range
5–15), who received six months of transcranial photobiomodulation (tPBM) at home using two
protocols (alpha and gamma), which, respectively, modulates the alpha and gamma bands. They
were evaluated at baseline, after three and six months of treatment using the Childhood Autism
Rating Scale (CARS), the Home Situation Questionnaire-ASD (HSQ-ASD), the Autism Parenting
Stress Index (APSI), the Montefiore Einstein Rigidity Scale–Revised (MERS–R), the Pittsburgh Sleep
Quality Index (PSQI) and the SDAG, to evaluate attention. Findings show that tPBM was associated
with a reduction in ASD severity, as shown by a decrease in CARS scores during the intervention
(p< 0.001). A relevant reduction in noncompliant behavior and in parental stress have been found.
Moreover, a reduction in behavioral and cognitive rigidity was reported as well as an improvement
in attentional functions and in sleep quality. Limitations were discussed as well as future directions
for research.
autism spectrum disorders; ASD; photobiomodulation; LED; near-infrared; NIR; neuro-
1. Introduction
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition typically
characterized by deficits in social and communicative behaviors as well as repetitive patterns
of behaviors (APA 2013) [
]. In addition to such core symptoms, several children and
adolescents with ASD also present severe behavioral difficulties, including aggression, self-
injurious behavior, tantrums, irritability and sleep problems, which usually interfere with
their education and development as well as the wellbeing of caregivers (Hill et al., 2014;
Soke et al., 2016; Baglioni et al., 2016) [
]. Moreover, people with ASD showed attentional
and executive function deficits (Gargaro et al., 2011; Demetriou et al., 2019) [5,6].
While the cause of autism is uncertain, the most widely accepted explanation is that it
is a complex neurodevelopmental disorder characterized by brain network abnormalities.
EEG has shown local overconnectivity and long-range underconnectivity, also involving
the corpus callosum (Barttfeld et al., 2011) [
]. fMRI studies revealed altered functional
connectivity in the default mode network (DMN), a network with a role in interoceptive
awareness and mind wandering and which was implicated in social-cognitive deficits of
autism (Harikumar et al., 2021; Broyd et al., 2009) [8,9].
Children 2022,9, 755.
Children 2022,9, 755 2 of 12
The main goal of therapy for children with ASD is the improvement of socio-relational
and communication skills. This goal is pursued through a combination of interventions, such
as speech therapy, parent training, social skills training and cognitive-behavioral therapy
(Chahin et al., 2020) [
]. In the presence of emotional and behavioral dysregulation, a
pharmacological approach is often considered (Eissa et al., 2018; Pallanti et al., 2015) [
Although some medications such as risperidone and aripiprazole have an effect on ASD-
related irritability and aggression (DeVane et al., 2019) [
], they also have important side
effects including sedation, anticholinergic effects, metabolic alterations, weight gain and
involuntary movements (DeVane et al., 2019) [
]. Moreover, they do not target the core
features of ASD.
Recently, there has been a growing interest in the potential of non-invasive brain stimu-
lation in neurodevelopmental disorders, thanks to their ability to modulate neuroplasticity
and enhance cognitive, behavioral and socio-emotional processes (Finisguerra et al., 2019;
Enticott, Pallanti and Hollander, 2018) [14,15].
Among new neuromodulation approaches, transcranial photobiomodulation (tPBM)
is characterized by the noninvasive delivery of low-level light, transcranially. Light pen-
etrates the skin and the skull and then is absorbed into the brain tissue by specific chro-
mophores, such as water, oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), myoglobin,
melanin, cytochromes, and flavin. The target for light within single neurons is the mito-
chondria, where tPBM stimulates cytochrome c oxidase. The consequence is that light
enhances mitochondrial activity and hence ATP synthesis, leading to an activation of
transcription factors associated with increased functional activity (Salehpour et al., 2018;
Mitrofanis and Henderson, 2020) [
]. Coherently, research has shown that tPBM boosts
brain energy metabolism as well as cognition in preclinical (Mochizuki-Oda et al., 2002;
Konstantinovic et al., 2013) [18,19]
and clinical studies, (Maiello et al., 2019) [
]. tPBM has
been effectively applied in post-stroke rehabilitation (Yang et al., 2018) [
], in patients with
TBI (Figueiro Longo et al., 2020) [22] and depression (Askalsky and Iosifescu, 2019) [23].
As far as safety is concerned, in a randomized-controlled study, which included about
1000 patients with stroke (Hacke et al., 2014) [
], no significant difference in side effects
was reported between active and sham stimulation with tPBM. Other studies reported
transient headaches, insomnia, irritable mood and a strange taste in the mouth as the most
common side effects (Cassano et al., 2018; 2019) [
]. The risk of thermal injury following
tPBM is minimal and mostly dependent on the parameters and device used (Caldieraro
and Cassano, 2019) [27].
Specifically, concerning ASD in adults, a recent study by Ceranoglu and colleagues
(2022) [
] also reported no side effects, with the exception of one out of six patients
who developed a transient headache. They suggested beneficial effects of twice-a-week
Transcranial Light Emitting Diode (LED) Therapy (TLT), a form of PBM, on core social
deficits associated with ASD in adult patients aged 18–55 years, as shown by the reduction
in the restricted interests and repetitive behavior subscale of the Social Responsiveness
Scale (SRS-2) and on measures of social emotional competence and global functioning, with
a good tolerability and adherence rate.
Furthermore, tPBM could also be safely and efficiently used in children and adolescents,
considering that several studies used PBM to treat pediatric samples with no reported or
minimal side effects (Leisman et al., 2018; Mannu et al., 2019; Salgueiro et al., 2021; Noirrit-
Esclassan et al., 2019; Santos et al., 2017) [
]. Furthermore, phototherapy, of which PBM
is a variant—although the wavelength used in phototherapy is lower than in tPBM—has
also been widely adopted in neonates (Faulhaber et al., 2019) [
] and, although some
reported side effects, many were transient and mild.
Concerning ASD specifically, Leisman and colleagues (2018) [
] treated children and
adolescents with ASD administering low-level light therapy (a form of PBM) to the base of the
skull and temporal areas eight times for 5 min and no side effects that necessitate discontinuation
of the therapy were reported. All the participants were evaluated with the Aberrant Behavior
Children 2022,9, 755 3 of 12
Checklist (ABC) and there were no dropouts. Resultsshow a decreased irritability after treatment,
suggesting the potential of PBM also in treatment of children with ASD.
Based on these preliminary findings, tPBM has been prescripted for home-based
treatment of children and adolescents with ASD on the basis of the principle of the good
clinical practice. Previously, PBM has been used efficiently and without side effects in other
studies for home treatment (Chao, 2019; Gavish and Houreld, 2019) [
]. In our study,
the type of tPBM employed (Vielight
Neuro Alpha/Gamma stimulator) stimulates the
default mode network (DMN) (Vielight, 2020) [
] and not only the temporal lobe, as was
the case in the study by Leisman and collegues (2018) [29].
Psychometrical data were collected. Here, they are reported and analyzed retrospec-
tively, with the aim to examine the clinical profile of children and adolescents with ASD
before and after treatment with tPBM.
2. Materials and Methods
2.1. Participants
Clinical data of children and adolescent patients with a diagnosis of ASD according to
DSM-5 criteria were extracted from databases containing information on patients of the
psychiatric clinic at the Istituto di Neuroscience, Florence (Italy). It is important to mention
that the database contains only the data of patients who accepted treatment among all the
ones to which was proposed. The diagnosis was confirmed with the Autism Diagnostic
Interview–Revised (ADI–R) and a CARS (Schopler et al., 1980) [
] total score of no less
than 30. tPBM was added to ongoing behavioral or pharmacological treatments, which
were unchanged for at least 1 month at the date of the start of the stimulation and remained
unchanged throughout the stimulation period. Demographical data as well as ongoing
treatments are reported in Table 1.
Table 1.
Demographical data of the patients as well as comorbidities and ongoing treatments (ADHD,
Attention Deficit Hyperactivity Disorder; SAD, Social Anxiety Disorder; ODD, Oppositional Defiant
Disorder; CBT, Cognitive-Behavioral Therapy).
1 9 M ADHD Omega-3; Melatonin; Probiotics;
Phosphatidylserine CBT; Speech therapy
Melatonin; Probiotics; Phosphatidylserine
CBT; Parent Training
3 7 F ODD Probiotics CBT; Speech Therapy
4 6 F SAD Omega-3 CBT
5 12 M ADHD Omega-3; Probiotics; Phosphatidylserine CBT; Speech Therapy
6 7 F ADHD Melatonin; Phosphatidylserine CBT; Speech Therapy
7 15 M Omega-3; Melatonin; Probiotics CBT; Speech Therapy
8 14 M SAD Melatonin CBT; Speech Therapy
9 7 M ODD CBT; Speech Therapy;
Parent Training
10 7 M ODD; SAD Omega-3; Melatonin; Probiotics
11 8 M Melatonin
12 5 F SAD CBT; Speech Therapy
13 8 F ODD Omega-3 CBT
14 8 M ADHD Phosphatidylserine CBT; Speech Therapy
15 10 M ADHD Probiotics; Phosphatidylserine
16 11 F ADHD; SAD Omega-3; Phosphatidylserine CBT; Speech Therapy
17 7 F ADHD Omega-3; Melatonin; Probiotics;
Phosphatidylserine CBT; Speech Therapy
18 7 M Omega-3; Melatonin CBT; Speech Therapy;
Parent Training
19 14 F ADHD; SAD Omega-3; Probiotics; Phosphatidylserine CBT; Speech Therapy
20 14 M CBT; Speech Therapy
21 10 M ADHD Melatonin; Phosphatidylserine CBT; Speech Therapy
After the complete description of the study to participants’ parents, written informed
consent was obtained in accordance with the Declaration of Helsinki.
Children 2022,9, 755 4 of 12
2.2. Stimulation
tPBM was delivered using the commercially available Vielight
Neuro Alpha/Gamma
brain photo biomodulation stimulator. Two stimulator devices were used: alpha and
gamma. The alpha stimulator device delivers 810 nm near infrared light pulsing at 10 Hz
via the transcranial LED clusters placed on the Photo-Bio-Modulation helmet. The 10 Hz
correlates with alpha brain waves which are produced by the brain during meditation
and relaxation states. The gamma stimulator pulses light at 40 Hz light pulsing frequency
and delivers 810 nm near infrared light via the transcranial LED clusters placed on the
helmet. The frequency of gamma stimulation simulates neural gamma waves which
are correlated with increased cognitive activities. Both protocols were used in order to
exploit the advantages of both and increase attention, improve sleep and reduce irritability
and rigidity.
The device is composed of a wearable headset (see Figure 1) with features microchip-
boosted transcranial LED diodes. The tPBM headset consists of four clusters. According
to the 10–20 EEG system, the frontal cluster should be positioned over FPz, the posterior
cluster over Cz and the two lateral ones over T3 and T4. In this way, the four LEDs deliver
the NIR to the subdivisions of the DMN: the medial prefrontal cortex, the precuneus area,
and left and right angular gyrus (Vielight, 202) [
]. The intranasal application is positioned
in the left or right nostril with the clip on the outside to deliver light to the ventral section
of the brain, specifically to the ventromedial PFC. The support pads should fall naturally
into place around the ears.
Figure 1.
Positioning of the tPBM on the head, which is composed of a helmet and a nasal stimulator.
LED diodes emit non-thermal, non-laser light at an intensity that penetrates the scalp,
skull, and meninges to a depth of ~40 mm, stimulating cortical brain areas (Jagdeo et al., 2012;
Tedford et al., 2015) [
] and is powered by three rechargeable NiMH batteries. The
posterior transcranial LEDs have a power of 100 milliwatts (mW) and the anterior tran-
scranial has a power of 75 mW. Each posterior transcranial LED has a power density of
100 mW/cm
and the anterior transcranial LED of 75 mW/cm
. The beam spot size of
Children 2022,9, 755 5 of 12
each LED is approximately 1 cm
. The energy delivered by posterior transcranial LEDs
is 60 joules (J) and the anterior transcranial LED delivers 45. The energy density of the
posterior transcranial LEDs is 60 J/cm
and 45 J/cm
for the anterior transcranial LED.
The hamma and alpha stimulator devices delivered 240 J during a 20-minute treatment
session. For both gamma and alpha stimulations, an intranasal neurostimulator was used
to simultaneously stimulate ventral brain areas. The intranasal neurostimulator has an
810 nm
wavelength near infrared light LED that delivers NIR through the nasal channel.
The intranasal LED has a power of 25 mW and a power density of LED of 25 mW/cm
The energy delivered by the intranasal LED is 15 Joules; the energy density is 15 J/cm
Light parameters are summarized in Table 2.
Table 2. Parameters of the Vielight PBM device (LED, Light-Emitting Diode).
Device Parameter LED
Transcranial LEDs
Transcranial LED Intranasal LED
Power output 100 mW 75 mW 25 mW
Power density 100 mW/cm275 mW/cm225 mW/cm2
Energy delivered 60 J 45 J 15 J
Energy density per LED
60 J/cm245 J/cm215 J/cm2
The stimulation is painless, non-invasive, and well-tolerated. The PBM devices used
in this study are considered to be non-regulated, “low risk general wellness products,’
according to the “General Wellness: Policy for Low Risk” published by the Food and Drug
Administration in September 2019 [41].
2.3. Procedure of Administration
Patients received tPBM treatments at home for 5 days a week, for 6 months (from
November 2020 to April 2021). Parents were trained in how to position the tPBM device
and administer the protocols. For the first at-home session, parents were asked to contact
the staff via videocall so that could be possible to control the correct administration of the
protocols and, if necessary, correct possible mistakes. Parents were retrained when necessary
and they were contacted every week by the staff to assess for adverse events. An alpha and
a gamma protocol were administered each day, one in the morning and one in the evening.
Each session had a duration of 20 min, during which children were involved in stimulating
activities (such drawing, coloring, reading, playing games, or doing homework).
2.4. Baseline and Follow-Up Assessments and Outcome Measures
Baseline assessments were performed before the first tPBM session and repeated after
three and six months. Safety and tolerability were monitored by assessing adverse events
and vital signs weekly.
The primary outcome was the change from baseline to 3- and 6-month in the Childhood
Autism Rating Scale (CARS) (Schopler et al., 1980; 1988) [
]. The CARS consists of
14 domains
assessing behaviors associated with autism, with a 15th domain rating the general
impression of autism. Total score ranges from 15 to 60, with scores below
30 indicating
absence of autism, a score ranging between 30 and 36.5 indicating mild-to-moderate autism,
and scores higher than 37 indicating severe autism (Schopler et al., 1988) [42].
Secondary outcomes were measured using the Home Situation Questionnaire-ASD
(HSQ-ASD), the Autism Parenting Stress Index (APSI), the SDAG (Scala per i Disturbi
di Attenzione/Iperattivitàper Genitori (ADHD rating scale for Parents)), the Montefiore
Einstein Rigidity Scale–Revised (MERS–R) and the Pittsburgh Sleep Quality Index (PSQI).
HSQ-ASD (Chowdhury et al., 2015) [
] is a 24-item parent-rated measure of noncompliant
behavior in children with ASD. The scale yields per-item mean scores of 0 to 9 (higher
Children 2022,9, 755 6 of 12
is worse). APSI (Silva and Shalock, 2012) [
] is a 13-item parent-rated measure, which
assesses parenting stress in three categories: core social disability, difficult-to-manage
behavior, and physical issues. SDAG was completed by the parents. Nine items (marked
with odd numbers) explore Inattention (subscale In), and nine items (marked with even
numbers) explore Hyperactivity/Impulsivity (subscale H/I). The frequency and intensity
of the 18 ADHD symptoms are rated on a 4-point Likert scale from 0 to 3 (0, never, 1,
sometimes, 2, often, 3, very often).
MERS–R measures three domains: behavioral rigidity, cognitive rigidity and protest
domain. Behaviors are rated on a scale from 0 to 4. All three domains consist of four items.
Regarding behavioral rigidity and cognitive rigidity, the items are: 1, Time spent engaging
in behavior; 2., Interference due to behavior; 3, Distress due to disruption of behavior; 4,
Degree of control. Regarding the protest domain, the items are: 1, Time spent protesting; 2,
Interference due to protest; 3, Severity of protest; 4, Effort for redirection.
PSQI (Buysse et al., 1989) [45] is a standardized self-administered questionnaire, that
in this case was completed by parents. It aims to assess sleep problems and its quality.
2.5. Statistical Analysis
The baseline demographic and clinical characteristics of the sample were tabulated with
descriptive statistics. Parametric and non-parametric tests were used according to variables’
distribution to analyze changes in scores over time. For all statistical analyses, the alpha level
of significance was set at 0.05. All the statistical analyses were performed using the statistical
programming language R (version 4.0.5) (R Core Team. R: A Language and Environment for
Statistical Computing. Vienna: R Foundation for Statistical Computing (2021)).
3. Results
The study included 21 patients (13 males, 8 females). The average age was 9.1 (range 5–15).
As CARS scores, MERS scores and Inattention subscale of SDAG scores were normally
distributed (verified through the Shapiro–Wilk test), one-way repeated measures ANOVA
was used to determine whether there were differences in scores during time. CARS results
(see Figure 2) showed that they were statistically significantly different at the different
time points during tPBM intervention (F (2,40) = 137.143, p< 0.001,
g = 0.02). Pairwise
comparisons using the Bonferroni correction showed that there was a decrease in CARS
score from pre-intervention to three months (p< 0.001) and from pre-intervention to six
months (p< 0.001) as well as from three to six months (p< 0.001).
Figure 2. CARS mean scores at the three timepoints (***: p-value < 0.001).
MERS scores (see Figure 3) showed that they were statistically significantly different at
the different time points during tPBM intervention (F (2,40) = 116.308, p< 0.001,
g = 0.55).
Pairwise comparisons using the Bonferroni correction showed that there was a decrease in
Children 2022,9, 755 7 of 12
MERS score from pre-intervention to three months (p< 0.001) and from pre-intervention to
six months (p< 0.001) but not from three to six months (p> 0.05).
Figure 3. MERS mean scores at the three timepoints (***: p-value < 0.001; ns, not significant).
SDAG scores (see Figure 4) showed that they were statistically significantly different at
the different time points during tPBM intervention (F (2,40) = 39.966, p< 0.001,
g = 0.574).
Pairwise comparisons using the Bonferroni correction showed that there was a decrease in
SDAG scores from pre-intervention to three months (p< 0.001) and from pre-intervention
to six months (p< 0.001) as well as from three to six months (p< 0.001).
Figure 4. SDAG mean scores at the different timepoints (***: p-value < 0.001).
As HSQ-ASD, APSI and PSQI scores were not normally distributed, a Friedman test
was run to determine whether there were differences in scores during treatment. HSQ-ASD
scores (see Figure 5) were statistically significantly different at the different time points
during t-PMB intervention (
2(2) = 38, p= < 0.001, W = 0.905). Post hoc analysis revealed
statistically significant differences in the scores between baseline and mid- (p< 0.001), and
post-treatment (p< 0.001), and also between mid- and post-treatment (p< 0.01).
Children 2022,9, 755 8 of 12
Figure 5.
Median scores of HSQ-ASD and ASPI at the three timepoints (***: p-value < 0.001;
**: p-value < 0.01; ns, not significant).
A statistically significant difference has also been found in APSI scores (see Figure 4)
during intervention (
2(2) = 39.4, p
0.001, W = 0.938). In this case, post hoc analysis re-
vealed statistically significant differences in the scores between baseline and mid- (
p< 0.001
and post-treatment (p< 0.001), but not between mid- and post-treatment (p> 0.05).
PSQI scores (see Figure 6) were statistically significantly different at the different
time points during t-PMB intervention (
2(2) = 18.9, p
0.001, W = 0.451). Post hoc
analysis revealed statistically significant differences in the scores between baseline and
mid- (p< 0.01), and post-treatment (p< 0.01), but not between mid- and post-treatment.
Figure 6. Median scores of PSQI at the three timepoints (**: p-value < 0.01; ns, not significant).
As far as safety is concerned, in our study, tPBM sessions were well tolerated: we had
no dropouts, and no patient experienced seizures or syncope, neurological complications,
or other major adverse effects. Occasional headache has been reported by two patients
(9.5% of patients), but the intensity did not require tPBM discontinuation.
4. Discussion
The main result of this retrospective study is the reduction in ASD severity as shown
by the decrease in CARS scores after the intervention. Then, a reduction in cognitive
and behavioral rigidity, measured through the MERS–R, and an increase in sleep quality,
measured through the PSQI, were observed. Importantly, attention improved too, as shown
by the reduction in the scores of the inattention subscale of the SDAG. A relevant reduction
in noncompliant behavior as measured by HSQ-ASD has been also found.
Children 2022,9, 755 9 of 12
It is noteworthy to mention that these improvements, which have a great impact on
patients’ lives, allow for a decrease in parental stress, as measured through the APSI, a
result that could lay the foundation for a quieter, more effective growth environment.
It is likely, even if not demonstrable at the moment, that these effects are a consequence
of the combination of the two protocols, alpha and gamma. Indeed, increased relaxation, a
feature of the alpha protocol, would allow for a reduction in rigidity and sleep improvement,
while enhanced cognition effect, an effect of the gamma protocol, would account for
improvements in attentional functions.
The positive effects of tPBM are therefore in line with those reported by Ceranoglu
and colleagues (2022) [
] on adults with ASD, despite the different protocols, devices and
evaluation tools used. Moreover, results are consistent with the study by Leisman and
colleagues (2018) [
]. Regardless, in our study tPBM stimulates not only the temporal lobe
but the DMN, and this can explain the effects reported here that also concern rigidity and
attention. It is significant to report that the device used in our study and the one used in
the study by Leisman (Leisman et al., 2018) [
] are different, although they are all forms of
photobiomodulation. In this study, the device uses LEDs, while in the other one laser light
is used. They differ mainly in light emission. Laser is characterized by coherence while
LED is characterized by non-coherence. (Heiskanen and Hamblin, 2018) [
] Nevertheless,
the basic working principle is the same in both and their effects are similar (Brochetti et al.,
2017) [
]. For our study, we have decided to employ LEDs for the ease of using them at
home and because of the lower safety concern associated with their use (Vielight Device
emits non-thermal light). Moreover, LEDs can irradiate larger areas of tissue, which is
particularly suitable for brain stimulation and specifically for frontal regions stimulation
(Salehpour et al., 2018) [
]. In addition, an intranasal light delivery method has also
been employed in this study in order to overcome the penetration limitation of LEDs in
comparison to laser.
Results regarding improved attention are consistent with a previous study (Jahan et al.,
2019) [
], which reported that light irradiation with 850 nm LED source on the right prefrontal
cortex improved attentional performance. Despite the significant results, further studies are
needed to confirm attention improvements through an evoked potential evaluation.
Improvement in autism severity, which eventually corresponds to an improved co-
habitation with their relatives, as a consequence of tPBM, as reported here, could also be
explained due to the potential effect over electrophysiological oscillations. Indeed, EEG
power abnormalities in autism have been reported (Wang et al., 2013) [
] and recently,
tPBM has been shown to modulate neural oscillations (Wang et al., 2019; Zomorrodi et al.,
2019) [
]. Future studies might deeply investigate this point, by studying the potential
correlation between improvements in autism severity and EEG changes.
Importantly, the results of this retrospective study suggested that tPBM is safe, since
all participants tolerated the stimulations well, even if this technique was previously
associated with treatment-emergent side effects, such as headache, strange taste in mouth
and decreased appetite (Cassano et al., 2019) [26].
Despite the interesting results, these findings should be evaluated considering some
limitations. Results could be partly explained by the placebo effect. Indeed, some elements
including regular contact between patients and therapists, and patients‘ expectations to
benefit from treatment (in this case parents’ expectations) have been widely reported in the
literature as contextual factors that can determine an improvement in symptomatology as
the treatment itself (Brody 2018; Kjær et al., 2020) [52,53]. Therefore, further research with
well-designed studies, including a double-blind administration of the intervention, and a
placebo group, is warranted.
Future studies might use neuroimaging techniques, which could help to understand
whether the clinical improvement reported here is associated with functional or matura-
tional changes at the level of a specific network, as has been shown in Alzheimer’s disease,
where the improvement in clinical manifestation after tPBM treatment was associated with
a reduction in tau and beta-amyloid levels (Chao, 2019) [
]. Furthermore, additional tools
Children 2022,9, 755 10 of 12
that are also able to measure other domains characterizing the ASD might be employed,
in order to better understand, for example, whether the tPBM had a better effect on other
cognitive domains, such as language.
In conclusion, tPBM represents a promising intervention for children and adolescents
with ASD, considering also its practicality and the freedom of movement it offers. If other
studies will confirm our findings, tPBM could represent a promising device for moving
forward to a more precision medicine approach, on the road to personalized treatment in
the realm of neurodevelopmental disorders.
Author Contributions:
Conceptualization: S.P.; Formal analysis: M.D.P.; Investigation: S.P., E.G.,
M.D.P.; Data curation: S.P., E.G., M.D.P.; writing—original draft preparation: S.P., M.D.P., E.G., G.V.,
G.C.; Writing—Revision and editing: S.P., M.D.P.; Supervision: S.P., G.C. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement:
The data presented in this study are available on request from the
corresponding author. The data are not publicly available due to privacy.
The authors would like to thank the Clinical Neuoscience Onlus and Care4Autism
for their support.
Conflicts of Interest:
The authors declare no conflicts of interest with respect to the research, author-
ship, and/or publication of this article.
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Importance: Preclinical studies have shown that transcranial near-infrared low-level light therapy (LLLT) administered after traumatic brain injury (TBI) confers a neuroprotective response. Objectives: To assess the feasibility and safety of LLLT administered acutely after a moderate TBI and the neuroreactivity to LLLT through quantitative magnetic resonance imaging metrics and neurocognitive assessment. Design, setting, and participants: A randomized, single-center, prospective, double-blind, placebo-controlled parallel-group trial was conducted from November 27, 2015, through July 11, 2019. Participants included 68 men and women with acute, nonpenetrating, moderate TBI who were randomized to LLLT or sham treatment. Analysis of the response-evaluable population was conducted. Interventions: Transcranial LLLT was administered using a custom-built helmet starting within 72 hours after the trauma. Magnetic resonance imaging was performed in the acute (within 72 hours), early subacute (2-3 weeks), and late subacute (approximately 3 months) stages of recovery. Clinical assessments were performed concomitantly and at 6 months via the Rivermead Post-Concussion Questionnaire (RPQ), a 16-item questionnaire with each item assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). Main outcomes and measures: The number of participants to successfully and safely complete LLLT without any adverse events within the first 7 days after the therapy was the primary outcome measure. Secondary outcomes were the differential effect of LLLT on MR brain diffusion parameters and RPQ scores compared with the sham group. Results: Of the 68 patients who were randomized (33 to LLLT and 35 to sham therapy), 28 completed at least 1 LLLT session. No adverse events referable to LLLT were reported. Forty-three patients (22 men [51.2%]; mean [SD] age, 50.49 [17.44] years]) completed the study with at least 1 magnetic resonance imaging scan: 19 individuals in the LLLT group and 24 in the sham treatment group. Radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) showed significant time and treatment interaction at 3-month time point (RD: 0.013; 95% CI, 0.006 to 0.019; P < .001; MD: 0.008; 95% CI, 0.001 to 0.015; P = .03; FA: -0.018; 95% CI, -0.026 to -0.010; P < .001).The LLLT group had lower RPQ scores, but this effect did not reach statistical significance (time effect P = .39, treatment effect P = .61, and time × treatment effect P = .91). Conclusions and relevance: In this randomized clinical trial, LLLT was feasible in all patients and did not exhibit any adverse events. Light therapy altered multiple diffusion tensor parameters in a statistically significant manner in the late subacute stage. This study provides the first human evidence to date that light therapy engages neural substrates that play a role in the pathophysiologic factors of moderate TBI and also suggests diffusion imaging as the biomarker of therapeutic response. Trial registration: Identifier: NCT02233413.
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There have been significant changes in the way Autism has been defined especially in the last decade. The changes encompass criteria over a spectrum rather than individual diagnoses based on clusters of criteria. With these changes, there has been a push for earlier screening and diagnosis to be made to ensure individual impacted by the deficits have ample time and opportunity to receive the services they need. Additionally, with the changes that have come up, screening tools and assessments have also been changed and improved to assist with the increasing demand of early screening. Screeners have been created to help in primary care settings so physicians can gauge the severity of symptoms and refer patients to the appropriate resources. The assessment and diagnostic process for Autism involves a large battery including parental interviews and forms, the ADOS-II, and a multitude of other intellectual assessments to get a full picture of what the individual is experiencing. Once an individual is diagnosed with Autism, the interventionist team, physicians, and clinicians assist the family in finding the appropriate resources and treatment plan. There are several evidence-based therapies that exist that have been effective in improving the quality of life of individuals with Autism Spectrum Disorder diagnoses. Although several interventions and therapies exist, there are some potential interventions some use that need to more research to know how truly effective they are.
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Paula Askalsky,1 Dan V Iosifescu1,2 1Department of Psychiatry, NYU Langone School of Medicine, New York, NY, USA; 2Clinical Research Division, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USACorrespondence: Dan V IosifescuDepartment of Psychiatry, NYU School of Medicine, One Park Avenue, 8th Floor, New York, NY 10016, USATel +1 646-754-5156Email Dan.Iosifescu@nyumc.orgAbstract: Major depressive disorder (MDD) is a prevalent condition associated with high rates of disability, as well as suicidal ideation and behavior. Current treatments for MDD have significant limitations in efficacy and side effect burden. FDA-approved devices for MDD are burdensome (due to repeated in-office procedures) and are most suitable for severely ill subjects. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. In this paper, we review a novel neuromodulation strategy, transcranial photobiomodulation (t-PBM) with near-infrared light (NIR). The scope of our review includes the known biological mechanisms of t-PBM, as well as its efficacy in animal models of depression and in patients with MDD. Theoretically, t-PBM penetrates into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow. Animal and human studies, using a variety of t-PBM settings and experimental models, suggest that t-PBM may have significant efficacy and good tolerability in MDD. In aggregate, these data support the need for large confirmatory studies for t-PBM as a novel, likely safe, and easy-to-administer antidepressant treatment.Keywords: low-level light therapy, photobiomodulation, near infrared radiation, major depressive disorder, depression
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This review presents an outline of executive function (EF) and its application to autism spectrum disorder (ASD). The development of the EF construct, theoretical models of EF, and limitations in the study of EF are outlined. The potential of EF as a cognitive endophenotype for ASD is reviewed, and the Research Domain Criteria (RDoC) framework is discussed for researching EF in ASD given the multifaceted factors that influence EF performance. A number of executive-focused cognitive models have been proposed to explain the symptom clusters observed in ASD. Empirical studies suggest a broad impairment in EF, although there is significant inter-individual variability in EF performance. The observed heterogeneity of EF performance is considered a limiting factor in establishing EF as a cognitive endophenotype in ASD. We propose, however, that this variability in EF performance presents an opportunity for subtyping within the spectrum that can contribute to targeted diagnostic and intervention strategies. Enhanced understanding of the neurobiological basis that underpins EF performance, such as the excitation/inhibition hypothesis, will likely be important. Application of the RDoC framework could provide clarity on the nature of EF impairment in ASD with potential for greater understanding of, and improved interventions for, this disorder.
Objective: To assess the efficacy and safety of transcranial photobiomodulation (tPBM) in adults with autism spectrum disorder (ASD). Methods: Adults with high-functioning-ASD, between 18 and 59 years of age, were enrolled to receive twice a week tPBM for 8 weeks in an open-label single group design. ASD symptom severity was assessed at baseline, midpoint, and end-point, by clinician-, self-, and informant-rated measures. Treatment response was defined as a ≥30% reduction in Social Responsiveness Scale-2nd Edition (SRS-2) total score and ASD Clinical Global Impression-Improvement score ≤2. Any possible adverse events were recorded at each visit. Paired-samples t-test analyses were performed. Results: Eleven participants were enrolled, and 10 participants (9 males; 30.0 ± 11.9 years) completed the study. One participant withdrew consent before baseline. All 10 completers were included in efficacy and safety analyses. Five participants (50%) met responder criteria at end-point. Overall, 8-week tPBM was associated with significant reduction in SRS-2 total scores at end-point (SRS-2: -30.6 ± 23, p < 0.001) particularly in Social Awareness (-3.0 ± 1.9, p < 0.001), Social Communication (-10.3 ± 6, p < 0.001), Social Motivation (-5.0 ± 2.4, p < 0.001), and Restricted/Repetitive Behaviors (-7.4 ± 4.1, p < 0.001). There were statistically significant improvements at end-point in Global Assessment of Functioning scores (+12.8 ± 4.2, p < 0.001) and Quality of Life Enjoyment and Satisfaction Questionnaire scores (+6.0 ± 7.9, p = 0.02). Three participants experienced transient, mild side effects (insomnia, headache, and warmth at treatment application site). No adverse events required changes in tPBM protocol. Adherence rate was 98%. Conclusions: tPBM is a safe and feasible treatment approach that has the potential to treat core features of ASD. Further research is necessary and warranted. Identifier: NCT03724552.
Functional magnetic resonance imaging (fMRI) has been widely used to examine the relationships between brain function and phenotypic features in neurodevelopmental disorders. Techniques such as resting state functional connectivity (FC) have enabled the identification of the primary networks of the brain. One fMRI network in particular, the default mode network, (DMN), has been implicated in social-cognitive deficits in Autism Spectrum Disorders (ASD) and attentional deficits in Attentional Deficit Hyperactivity Disorder (ADHD). Given the significant clinical and genetic overlap between ASD and ADHD, surprisingly, no reviews have compared the clinical, developmental, and genetic correlates of DMN in ASD and ADHD and here we address this knowledge gap. We find that, compared to matched controls, ASD studies show a mixed pattern of both stronger and weaker FC in the DMN and ADHD studies mostly show stronger FC. Factors such as age, IQ, medication status, and heredity affect DMN FC in both ASD and ADHD. We also note that most DMN studies make ASD versus ADHD group comparisons and fail to consider ASD+ADHD comorbidity. We conclude, by identifying areas for improvement and by discussing the importance of using transdiagnostic approaches such as the Research Domain Criteria (RDoC) to fully account for the phenotypic and genotypic heterogeneity and overlap of ASD and ADHD.
Background: The diagnosis of sleep bruxism (SB) in children is difficult due to the lack of a polysomnographic protocol for this population. Moreover, the gold standard treatment [occlusal splint (OS) therapy] has limitations, as adequate use depends on the child's cooperation. The etiology of SB may include stress factors. Salivary cortisol is a biomarker used as a noninvasive method to evaluate the response to stress. Besides physiological aspects, it is also important to investigate morphological aspects, such as masticatory muscle strength. The aim of the present study was to determine the occurrence of bite marks on the buccal mucosa in children as a complementary sign for the diagnosis of SB and investigate and the effectiveness of photobiomodulation as an alternative treatment for this condition. Methods: Seventy-six children 6-12 years of age were divided into four groups: G1-with SB and submitted to laser therapy over acupuncture points (λ = 786.94 nm, 20 sec per point, fluency = 33.5 Jcm2, energy = 1 J, number of points = 12); G2-with SB, use of OS, G3-with SB and submitted to sham laser therapy; and G4-control group without SB. Clinical signs (bite marks on buccal mucosa and headaches), bite force (BF), and salivary cortisol (biomarker of stress) were evaluated before and after treatment. Statistical analysis involved the Kolmogorov-Smirnov, Shapiro-Wilk, and analysis of variance (ANOVA) tests. Results: Bite marks on the buccal mucosa were significantly associated with SB (p < 0.001). A statistically significant difference was found between the frequency of children with headache before and after treatment in G1 (p = 0.0005) and G2 (p = 0.0001), with no significant differences between the two groups (G1 and G2). The children in G1 had lower BF on both sides compared to the other groups. In the intragroup analysis after treatment, all groups exhibited an increase in salivary cortisol levels. Conclusions: Bite marks on the buccal mucosa can be used as a complementary sign for the clinical diagnosis of SB. Children with SB responded well to photobiomodulation therapy, as evidenced by the reduction in BF and reports of headache.
Objective: Our aim was to test the anxiolytic effect of transcranial photobiomodulation (t-PBM) with near-infrared light (NIR) in subjects suffering from generalized anxiety disorder (GAD). Background: t-PBM with NIR is an experimental, noninvasive treatment for mood and anxiety disorders. Preliminary evidence indicates a potential anxiolytic effect of transcranial NIR. Methods: Fifteen subjects suffering from GAD were recruited in an open-label 8-week study. Each participant self-administered t-PBM daily, for 20 min (continuous wave; 830 nm peak wavelength; average irradiance 30 mW/cm2; average fluence 36 J/cm2; total energy delivered per session 2.9 kJ: total output power 2.4 W) broadly on the forehead (total area 80 cm2) with an LED-cluster headband (Cerebral Sciences). Outcome measures were the reduction in total scores of the Hamilton Anxiety Scale (SIGH-A), the Clinical Global Impressions-Severity (CGI-S) subscale and the Pittsburgh Sleep Quality Index (PSQI) subscales from baseline to last observation carried forward. Results: Of the 15 recruited subjects (mean age 30 ± 14 years; 67% women), 12 (80%) completed the open trial. Results show a significant reduction in the total scores of SIGH-A (from 17.27 ± 4.89 to 8.47 ± 4.87; p < 0.001; Cohen's d effect size = 1.47), in the CGI-S subscale (from 4.53 ± 0.52 to 2.87 ± 0.83; p < 0.001; Cohen's d effect size = 2.04), as well as significant improvements in sleep at the PSQI. t-PBM was well tolerated with no serious adverse events. Conclusions: Based on our pilot study, t-PBM with NIR is a promising alternative treatment for GAD. Larger, randomized, double-blind, sham-controlled studies are needed.
Background: Transcranial photobiomodulation (t-PBM) consists in the delivery of near-infrared light (NIR) to the scalp, directed to cortical areas of the brain. NIR t-PBM recently emerged as a potential therapy for depression, although safety of repeated treatments has not been adequately explored. Objective: This study assessed incidence of side effects, including weight and blood pressure changes, during repeated sessions of NIR t-PBM using a light-emitting diode source. Methods: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder. Eighteen individuals received NIR t-PBM (n = 9) or sham (n = 9) twice weekly for 8 weeks. Side effects were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry. In 14 individuals (nNIR = 6 vs. nsham = 8), body weight and systemic blood pressure were recorded at baseline and end-point. Results: More subjects in the NIR t-PBM group experienced side effects compared to sham, but only a trend for statistical significance was observed (χ2 = 3.60; df = 1; p = 0.058). The rate of side effects described by participants as "severe" in intensity was low and similar between the treatment groups (χ2 = 0.4; df = 1; p = 0.53), with no serious adverse events. Most side effects resolved during the study and treatment interruption were not required. Changes in weight and systolic blood pressure across groups were neither significant nor approached significance. In the NIR t-PBM group, diastolic blood pressure increased and reached statistical-however not clinical-significance (5.67 ± 7.26 vs. -6.13 ± 6.88; z = -2.40, p = 0.016). Conclusions: This small-sample, exploratory study indicates repeated sessions of NIR t-PBM might be associated with treatment-emergent side effects. The systemic metabolic and hemodynamic profile of repeated t-PBM appeared benign. Future studies with larger samples and longer follow-up are needed to more accurately determine the side-effect profile and safety of NIR t-PBM.