Neuromodulation and a Reconceptualization of Autism Spectrum Disorders: Using the Locus Coeruleus Functioning as an Exemplar

Abstract

The Autism Spectrum Disorders (ASD) are a heterogeneous group of developmental disorders. Although, ASD can be reliably diagnosed, the etiology, pathophysiology, and treatment targets remain poorly characterized. While there are many atypical findings in anatomy, genetics, connectivity, and other biologic parameters, there remains no discreet hypothesis to explain the core signs as well as the very frequent comorbidities. Due to this, designing targets for treatments can only be done by assuming each symptom is a result of a discreet abnormality which is likely not the case. Neuronal circuity remains a major focus of research but rarely taking into account the functioning of the brain is highly dependent on various systems, including the neuromodulatory substances originating in the midbrain. A hypothesis is presented which explores the possibility of explaining many of the symptoms found in ASD in terms of inefficient neuromodulation using the functioning of the locus coeruleus and norepinephrine (LC/NE) as exemplars. The basic science of LC/NE is reviewed. Several functions found to be impaired in ASD including learning, attention, sensory processing, emotional regulation, autonomic functioning, adaptive and repetitive behaviors, sleep, language acquisition, initiation, and prompt dependency are examined in terms of the functioning of the LC/NE system. Suggestions about possible treatment directions are explored.

Brain Metabolite Changes After Anodal Transcranial Direct Current Stimulation in Autism Spectrum Disorder

“…Much of the recent research on ASD has focused not only on the brain structures but also on neuronal connectivity, and both underconnectivity and overconnectivity were reported based on connection lengths (London, 2018). The apparent abnormal neuronal connectivity in individuals with autistic is not fully understood.…”

“…In general, the core symptoms of ASD are impaired social communication and restricted and repetitive behaviors. Neuromodulatory changes in ASD are suspected of involving many brain regions such as the frontal, temporal, and temporoparietal lobe, insular cortex, ACC, locus coeruleus, and limbic system (London, 2018;Shepherd and Freiwald, 2018). Input from a small number of neuromodulatory cells can abruptly interrupt the activity of neural networks and reorganize the elements into new functional networks; a single neuron can participate in several networks, and a single anatomical network can mediate multiple functions (London, 2018).…”

“…Other MRS studies of ASD reported low levels of NAA in the left amygdala (Mori et al, 2013) and low levels of NAA and Glx in the left frontal cortex (Kleinhans et al, 2007). Recently, there was a hypothesis that explored the possibility of explaining the symptoms found in ASD in terms of inefficient neuromodulation using the functioning of the locus coeruleus and norepinephrine as exemplars (London, 2018).…”

Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients

“…Indeed, individuals on the autistic spectrum exhibit dysregulated behavioral states in adulthood profoundly impacting their life (11)(12)(13)(14), although we do not know when such altered states first arise. Among several neuromodulatory systems, the cholinergic system seems to be strongly and consistently perturbed in ASD (15)(16)(17)(18)(19)(20)(21)(22). Namely, cholinergic neurons in the basal forebrain of ASD patients are altered in size, number, and structure (19).…”

Neuronal Switching Between Single- and Dual-Network Activity via Modulation of Intrinsic Membrane Properties

“…Potential functions of rapid network reorganization, including switching between single and multiple oscillatory frequencies, include combining multimodal aspects of sensory perception, or multiple components of a memory for storage (Roopun et al, 2008; Wang, 2010; Akam and Kullmann, 2014). Dysfunction in these processes may lead to neurological disorders, suggested by decreased synchrony between brain regions in schizophrenia patients, and brain network dysregulation, potentially due to LC changes, in autism spectrum disorders (Uhlhaas and Singer, 2010; London, 2018). Given the many similarities in network function and plasticity from small to large networks (Haider and McCormick, 2009; Koch et al, 2011; Bargmann and Marder, 2013; Kopell et al, 2014), similar basic principles of neuronal switching in small networks will likely extend to larger, more diffuse networks.…”