Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)

Figures & data

Figure 1 Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE) diagnoses and conditions.

Notes: Developmental learning disorder, learning disorders with impairment in reading, written expression, or mathematics; ESSENCE-associated conditions, behavioural phenotype syndromes (eg Down’s syndrome, fragile X syndrome and premutation FraX, sex chromosome anomalies, tuberous sclerosis complex, 22q11 deletion syndrome, Prader-Willi and Angelman syndrome, neurofibromatosis, foetal alcohol spectrum disorder/syndrome, valproate acid syndrome), neurological conditions and disorders (eg epilepsy or seizures, cerebral palsy, disorders of muscles), severe early-onset mental disorders (eg early-onset bipolar disorder, schizophrenia, disruptive mood dysregulation disorder).

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; DCD, developmental (motor) coordination disorder; ASD, autism spectrum disorder; RAD, reactive attachment disorder; DSED, disinhibited social engagement disorder; ARFID, avoidant-restrictive food intake disorder; PANS, paediatric acute-onset neuropsychiatric syndrome; PANDAS, paediatric acute-onset neuropsychiatric disorder associated with streptococcal infection; OCD, obsessive-compulsive disorder.

Table 1 ADHD and ASD Symptoms and Plausible Orexin/Hypocretin System (Orx-S) Involvement

Main Symptom Domain of ADHD/ASD	ADHD and ASD	Plausible Role of Orx-S
Arousal	Deficient and/or excessive arousal pathways may be linked to ADHD^Citation10 Within RDoC matrix, deficit in arousal/regulatory system (eg, biological rhythm) in ADHD^Citation7 Altered HPA axis function in ADHD and ASD^Citation63,Citation64 Constellation of symptoms described as “brain fog” among patients with ASD^Citation65 Children with hyperactive/impulsive symptoms of ADHD have higher pupil dilation in response to happy faces^Citation66 Children with ASD show “decreased pupil responses to human faces” and differ in tonic pupil size from age-matched controls^Citation67 Pupillometry may differ in individuals with and without ASD^Citation68	“Orexin is a key component of the arousal system”^Citation36 Monoaminergic neurons in the brainstem are strongly excited by orexin neurons^Citation69 Orexin activates the HPA axis^Citation36 “Brain fog” may be linked to impairments in Orx-S^Citation70 Orx-A might modulate pupil size^Citation71
Wakefulness and sleep	Shared neuronal mechanisms (with increased Orx-S activity) proposed to underly insomnia in patients with ASD and ADHD^Citation17	Orexin neurons “modulate sleep and wakefulness”^Citation35
Sensorimotor system, sensory processing, and perception	Many children with ASD and ADHD show motor impairments^Citation72 Fine motor skill difficulties are common in pediatric ADHD^Citation73 Many children with NDDs may have DCD^Citation72 Sensorimotor deficits have an impact on the performance of daily living skills in preschool children with ASD, impacting their autonomy^Citation74 Atypical sensory-processing is a common feature of ADHD and ASD^Citation75 Sensory abnormalities: core ASD diagnostic criterion^Citation21,Citation22,Citation75 Altered perceptual functions in ADHD (ie, olfactory detection threshold)^Citation76 Children with ASD show altered olfactory function^Citation77 Volitional eye movement control is associated with ADHD traits^Citation78 Subtle language and social processing differences in eye movement studies in ASD found^Citation79	Loss of orexin neurons likely involved in the pathophysiology of some movement disorders^Citation50 Orexin neurons are sensorimotor controllers^Citation80 Orx-S exerts excitatory effect on dopamine neurons in the ventral tegmental area^Citation81 Sensory-evoked and self-generated movements are regulated by the orexin neurons^Citation80 Orx-S relates to spontaneous physical activity^Citation24 Orx-S might orchestrate central motor control^Citation51 Orexin possibly modulate olfactory perception^Citation82 Orx-A might modulate eyelid position, and possibly convergence movements and eye alignment^Citation71
Impulsivity and compulsivity	Impulsivity and compulsivity are present in ADHD and ASD^Citation26	In narcolepsy with orexin deficiency, “selective impairment of alerting network” exists^Citation83 Orexins are associated with stereotypic behaviors^Citation12 Orx-S might be involved in compulsive and repetitive behaviors^Citation49,Citation84 Potential therapeutic use of orexin antagonists to reduce motor impulsivity induced by psychostimulants^Citation62
Reward, motivation, and feeding	Within RDoC matrix, deficit in positive valence systems (eg, sustained responsiveness to reward) in ADHD^Citation7 Dopamine reward pathway disruption is likely “associated with motivation deficits in ADHD”^Citation85 Within RDoC matrix, deficit in negative valence systems (eg, frustrative non-reward) in ADHD^Citation7 Deficiencies in the mesolimbic reward pathway might underlie impaired social skills in children with ASD^Citation86 Individuals with ASD exhibit atypical neural processing of “social, non-social, and potentially restricted interest rewards”^Citation87 Reward system dysfunction has been suggested to support the emergence and maintenance of ASD symptoms (social and non-social)^Citation88 Atypical eating behaviors are more common among children with ASD, than in children with other disorders or with typical development^Citation89 Association between eating disorders/eating pathology and ADHD in adolescents^Citation90 Positive association between body mass index and ADHD^Citation91	Orexin neurons might modulate the reward system^Citation24 Orexins might have a role in translating motivational activation into adaptive behavior^Citation44 Orexin has a role in feeding behaviors^Citation92 Orx-S regulates dietary preferences and the anticipation of food rewards^Citation93 Presence of orexin cells in the lateral hypothalamus, a crucial site of food intake regulation^Citation48 Orexin-based therapeutics have been proposed to increase food intake in patients with anorexia nervosa^Citation25 Orexin signaling disruption leads to increased body mass index^Citation94 Orexin neurons may promote foraging behavior^Citation95 Orexin might be seen as promotor of homeostatic eating^Citation95
Fear and social play	Social deficits may be affected by hypothalamic atrophy in ASD^Citation96 Morphofunctional alterations of the hypothalamus have been implicated in ASD's pathophysiology, particulary atypical socio-emotional behaviours^Citation97 Unusual fears common in ASD^Citation98 Fear circuits' abnormalities during extinction learning and recall have been reported in ADHD^Citation99 Within RDoC matrix, deficit in systems for social processes (eg, social communications) in ADHD^Citation7	Orx-S might modulate expression of social play behavior and fear^Citation45,Citation100 Activity of orexin neurons might promote “emotional arousal or fear-related responses” upon presentation of emotional stimuli^Citation24 Orx-S' regulatory role in social (fear) behavior is partly sex-dependent^Citation45 Orx-S dysregulation might have a contribution in the etiology of anxiety disorders and fear^Citation101 Orexin neurons might modulate behavioral fear expression^Citation60 Orx-S may modulate conditioned fear^Citation102 Orexin deficiency might probably affect social behaviour and emotional regulation^Citation103
Executive functions and memory	Working memory is impaired in ASD^Citation104 Within RDoC matrix, deficit in cognitive systems (eg, working memory) in ADHD^Citation7 Using RDoC framework, common thinking patterns and behaviours in ASD (eg, rigidity of thinking, impaired attention) may represent cognitive features^Citation4	Orexin transmission is possibly “involved in executive functions”^Citation62 and other cognitive functions, such as cognitive flexibility, the activation of learning, and the acquisition and consolidation of memory^Citation12,Citation27,Citation94 Orexin deficiency modulates particular cognitive flexibility's phases^Citation105 Orexin has a sexually dimorphic role in regulating cognitive flexibility^Citation105 Orx-A may enhance some cognitive deficits^Citation13 Orexin agonists may hypothetically benefit individuals with “age-related cognitive decline, attention disruptions caused by sleep deprivation or circadian dysregulation, and ADHD”^Citation27

Abbreviations: ASD, autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; Orx-S, orexin/hypocretin system; NDDs, neurodevelopmental disorders; Orx-A, orexin-A/hypocretin-1; DCD, developmental coordination disorder; HPA, hypothalamus-pituitary-adrenal; RDoC, Research Domain Criteria.

Table 2 Proposed Role of the Orx-S in Disorders and Conditions Associated with ESSENCE

Symptoms, Conditions, Disorders, or Diagnoses	Proven or Plausible role of Orx-S in the Context of Presented Symptoms, Generating Orx-S Dysfunction Hypotheses
OCD	OCD symptoms may be linked to orexinergic system and its interactions with the dopaminergic systems (based on results from animal models)^Citation49
Some types of epileptic seizures	The mean serum Orx-A levels in patients with some types of epileptic seizures were found to be significantly higher compared to those with non-epileptic seizures^Citation144
RAD/DSED	Serum Orx-A levels seem to be attachment-related; positively associated with secure attachment scores and negatively with insecure (avoidant, anxious/ambivalent) attachment total scores in healthy individuals^Citation145
BPS	Orx-A was found to be significantly decreased in individuals with Down’s syndrome^Citation146 Orexin might have a role in sleep dysfunction in an animal model of tuberous sclerosis complex^Citation147 Lower levels of cerebrospinal fluid orexin in patients with Prader–Willy syndrome compered to control subjects^Citation148
FAS/FASD	Orx-A neurons areas and volumes were significantly smaller in groups not exposed to prenatal alcohol than in the group with chronic alcohol exposure, while orexinergic boutons' density in the anterior cingulate cortex was lower in the chronic alcohol group than in the other groups (in an animal model)^Citation149 Embryonic ethanol exposure, although low-dose, had various, ongoing, and asymmetric effects on the early development of orexin neurons in the hypothalamus, which resulted in abnormalities of “their ultimate location that may contribute to behavioral disturbances”^Citation150 Excessive orexinergic neuron activity contributes to motor hyperactivity among animals after a perinatal alcohol exposure; however, the antagonism of Orx1R may alleviate these symptoms^Citation151
PANS/PANDAS	Symptomatic overlap between sleep problems in PANS with other sleep disorders, such as narcolepsy and Kleine–Levin syndrome,^Citation152 could also suggest an Orx-S dysfunction in the pathogenesis of sleep alterations in PANS,^Citation70 as it has been suggested that orexin dysregulation also plays a role in the pathophysiology of Kleine–Levin syndrome^Citation153 Sleep, motor, and cognitive symptoms in PANS^Citation152 imply that Orx-S dysfunction might plausibly have a role in the development of PANS^Citation70 Some children with NT1 also have high ASLO titers^Citation50 implying hypothetically that Orx-S dysfunction might play a role in the PANDAS, as well
Catatonia and Stiff-Man Syndrome	Catatonia, long considered a motor disorder, might be also understood as an evolutionary-based fear response (“Scared Stiff”)^Citation154 and thus potentially connected with orexin, as Orx-S has a role in the context of fear (ie, in fear memory and impaired freezing response)^Citation8,^Citation28,Citation155 Orexin reduction is associated with reduction in motor control^Citation53 Akinetic catatonia may be associated with GAD65 antibodies^Citation156 Most patients with Stiff-Man syndrome have serum GAD65 antibodies^Citation157 Orexin neurons activate the GAD65 network of the LH submodule which governs physical activity and overactivation in GAD65LH cell leads to hyperlocomotion^Citation158 thus, GAD65 may suggest a “common pathway” how Orx-S dysfunction is related to catatonia and Stiff-Man syndrome, and ESSENCE-related conditions with motor symptoms
ME/CFS	Symptoms of ME/CFS such as chronic fatigue, post-exertional malaise, and “brain fog”^Citation107 might be associated with Orx-S dysfunction Post-COVID-19 syndrome, called as “long COVID” have features that might follow ME/CFS^Citation159 Autoantibodies may contribute to both ME/CFS and post-COVID illness symptoms^Citation159 Orexin receptor antibodies (of importance for sleep and fatigue)^Citation159 were found in patients with COVID-19^Citation160 showing that ME/CFS might potentially be connected with Orx-S dysfunction Described clinical observation of several symptoms overlapping between CFS and ASD, including brain fog and fatigue, although not proven in one study^Citation161 CFS is one of the indications that might be approached with orexinergic agents^Citation27
Fibromyalgia	Fibromyalgia is associated with a variety of symptoms, including non-refreshing sleep, debilitating fatigue, joint stifness and irritable bowels;^Citation162 symptoms that might be associated with Orx-S such as fatigue, sleep^Citation159 and gastrointestinal functions^Citation163,Citation164 Higher incidence of NDDs has been observed in juvenile fibromyalgia^Citation162 ADHD and certain fibromyalgia subtypes might have etiological pathways in common^Citation165 The orexin antagonist, suvorexant, has shown efficacy in improving sleep time and reducing next-day pain sensitivity in patients with fibromyalgia and comorbid insomnia^Citation119
Connective tissue disorders, HSD/hEDS	Connective tissue disorder (ie, hEDS) may underlie ESSENCE-related problems during childhood^Citation166 HSD/hEDS may be associated with anxiety disorders, chronic pain, fatigue, and ADHD/ASD,^Citation167,Citation168 all of this might be associated with Orx-S dysfunction

Abbreviations: ESSENCE, Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations; OCD, obsessive-compulsive disorder; Orx-S, orexin/hypocretin system; Orx-A, orexin-A; Orx1R, orexin type 1 receptor; ASD, autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; RAD, reactive attachment disorder; DSED, disinhibited social engagement disorder; BPS, behavioral phenotype syndromes; PANS, pediatric acute-onset neuropsychiatric syndrome; PANDAS, pediatric acute-onset neuropsychiatric disorder associated with streptococcal infection; FAS, fetal alcohol syndrome; FASD, fetal alcohol spectrum disorder; ME, myalgic encephalomyelitis; CFS, chronic fatigue syndrome; HSD, hypermobility spectrum disorder; hEDS, hypermobile Ehlers–Danlos syndrome; GAD65, glutamic acid decarboxylase 65; ASLO, anti-streptolysin O; COVID-19, coronavirus disease 2019; LH, lateral hypothalamus; NT1, narcolepsy type 1 or narcolepsy with cataplexy.

Table 3 Research Questions Regarding the Role of Orx-S Dysfunction in ESSENCE, that Require Further Studies

Research Questions Based on Proposed Explanation Model	ADHD and ASD in the Context of Research Question	Rationale for Proposed Orx-S Dysfunction Role in ESSENCE
Orx-S dysfunction role in the field of Immunopsychiatry	Potential role of neuroinflammation in the pathophysiology of ADHD has been supported by a recent review^Citation171 Associations between parental autoimmune diseases and ASD or ADHD in offsprings^Citation172,Citation173 Anti-sense transcript to the HLA-DQB1 locus on chromosome 6 is elevated roughly twofold in people with ADHD^Citation174 Recent study with a large dataset suggested the role of HLA genes in ASD and intellectual disability^Citation175 HLA polymorphisms can possibly distinguish regressive and non-regressive ASD^Citation176 HLA-DPA1*01-DPB1*04 sub-haplotype “may exert a protective effect against regression”^Citation176 Serum GAD65 autoantibodies were found in some children with ASD or ADHD^Citation177	Orx-A may reduce the production of pro-inflammatory cytokines, suggesting its immunomodulatory role^Citation164 Connection between the Orx-S, “the HPA-axis, and associated glucocorticoid secretion and/or sympathetic tone” may point toward the influence of orexin signaling pathways on peripheral immune function^Citation27,Citation178 Sleep, stress, and peripheral immune responses interact robustly, highlighting orexin's central role in this relationship^Citation27 HLA and the T-cell receptor variants have strong predisposing effects on the destruction of orexinergic cells, and this destruction may be considered an autoimmune event^Citation179 HLA-DPB1*04:02 shows the strongest protection from narcolepsy^Citation180 Orexin activates the GAD65 network of the LH submodule which governs physical activity^Citation158
Orx-S dysfunction may be associated with alterations of the microbiome-gut-brain axis	Microbiome-gut-brain axis alterations might be responsible for the appearance of NDDs in children (ie, in ADHD)^Citation181 Association between alteration of gut microbiota composition and ASD has been suggested by recent meta-analysis^Citation182	During gastrointestinal inflammation, Orx-A has potential role as one of central mediators of the microbiota-gut–brain interactions^Citation183
Interplay between vitamin D and steroids with Orx-S may explain their role in NDDs	Steroid abnormalities of various kinds (cortisol, testosterone, estrogens, progesterone, and vitamin D) have been linked with ASD, suggesting an underlying cholesterol-steroid hormone pathway^Citation184	Several possible mechanisms proposed to explain association between vitamin D deficiency and high risk of sleep disorders, one of which pointed to vitamin D receptor expression in human brain areas that play important roles in sleep regulation, such as the hypothalamus^Citation185 Orexin stimulates adrenocorticotropin and the secretion of corticosteroids^Citation12 Orexin receptors have been detected in many peripheral tissues, such as adrenal glands and male reproductive tract^Citation29,Citation170 Sexual dimorphism of the Orx-S^Citation29,Citation105 “Orexin stimulation induces an increased steroidogenesis”^Citation170 Orx-S might “act in a steroid-sensitive manner” on activation of the mesolimbic dopaminergic system^Citation81 Orx-S relate to testosterone production^Citation186 Orexin receptor mRNA in the adrenal glands was four-fold higher than in the male animal brain^Citation29
Potential of orexin for orchestrating heart rate variability	Children with ADHD may exhibit an autonomic dysfunction - HRV's overall reduction and sympatovagal imbalance^Citation187 Different HRV measures may give significant insights into sustained attention, as well as in the impairments of behavioral and emotional regulation in ADHD^Citation188 HRV as indicator of “flexible and adaptive autonomic response systems”, has become a crucial part of the pathogenetic triad in proposed unifying theory for ASD^Citation189	HRV during periods of non-stress was associated with greater stress resilience^Citation190 HRV belongs to the RDoC arousal domain^Citation8 Chronic lack of orexin results in a “blunted circadian variation of heart rate”^Citation191 Orx-S “integrates diverse inputs modulating arousal”^Citation27 and controls some key features of cardiovascular “homeostatic output”^Citation192,Citation193
CACNA1C, as a novel explanation model for pathogenesis of some psychiatric disorders, could associates with the Orx-S dysfunction	CACNA1C gene is associated with various psychiatric conditions^Citation194 Association between CACNA1C voltage-gated calcium channel gene, autism, ADHD, schizophrenia and bipolar disorder^Citation195	Sleep disorders (eg, insomnia and narcolepsy) have been associated with polymorphisms in the CACNA1C gene^Citation194 CACNA1C gene encodes the alpha-1 subunit of L-type Ca^2+ channels (Cav1.2) and their depletion seems to attenuate Orx-A “mediated excitation of wake-related neurons”, in animal models^Citation194

Abbreviations: ESSENCE, Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations; OCD, obsessive-compulsive disorder; Orx-S, orexin/hypocretin system; Orx-A, orexin-A; ASD, autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; HPA, hypothalamus-pituitary-adrenal; HLA, human leukocyte antigen; HRV, heart rate variability; NT1, narcolepsy type 1; NDDs, neurodevelopmental disorders; GAD65, glutamic acid decarboxylase 65; LH, lateral hypothalamus.

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