This paper (2017) argues that 5-HT2A agonists should be investigated as a potential treatment for functional neurological disorders.

Abstract

“Functional neurological disorders are frequently encountered in clinical practice. They have a poor prognosis and treatment options are limited. Their etiology is unknown, but leading theories propose a disturbance of somatic self-representation: the mind perceives dysfunction of a body region despite intact motor and sensory pathways. Central to this model is the concept of an abnormal top-down cognitive influence upon sensorimotor function. There is growing interest in the use of 5-HT2A agonists in the management of neuropsychiatric conditions. Recent studies have shown that these agents induce changes in neural activity that disrupt hierarchical brain dynamics and modulate networks subserving self-related processing. Converging evidence suggests they may hold unique therapeutic potential in functional neurological disorders. This is of importance given the considerable personal and societal burden of this condition and we argue a clinical trial to test this hypothesis is warranted.”

Authors: Alexander Bryson, Olivia Carter, Trevor Norman & Richard Kanaan

Notes

This paper matches well with the systematic review on this topic by Butler and colleagues (2020).

Summary

FNDs are neurological symptoms without underlying structural pathology that exist on the borderland of neurology and psychiatry. 5-HT 2A agonists have recently emerged as a plausible adjunct therapy for major depression, anxiety, and drug addiction.

FNDs are psychiatric conditions that may take varied forms including hemiparesis, visual impairment, or movement disorders. Treatment options are limited, and the prognosis is unfavorable, and clinicians have historically adopted a distrustful attitude toward these patients.

Functional magnetic resonance imaging (fMRI) and behavioral studies have demonstrated that patients with functional motor symptoms experience a loss of volitional control over a body part, and that they show a tendency to divert attentional resources onto the self.

A preoccupation with somatic symptoms is associated with increased fMRI activity within the ventromedial prefrontal cortex, precuneus and insula. These regions serve introspective cognitive functions including somatic self-representation and the retrieval of self-imagery.

FNDs may be caused by aberrant somatic self-representation, perhaps induced through heightened self-monitoring, exerting excessive influence over normal motor function. This is reflected in abnormal DMN and supplementary motor cortex activity, and a perceived loss of self-agency.

The brain generates our experience of reality through predictive representations of the self and environment, which are compared and updated against somatic and exteroceptive sensory input, forming posteriors. An intervention capable of disrupting both hierarchical brain dynamics and self-representation could confer a therapeutic benefit.

The 5-Ht 2A Receptor: Single Neurons and Neural Circuits

Serotonin (5-HT) regulates cortical function via widely projecting axons acting on a diversity of receptor subtypes. The 5-HT 2A and 5-HT 1A receptors exert the greatest influence over cortical function.

Cortical circuits are incompletely understood, but increased firing rates and spontaneous excitatory postsynaptic potentials have been observed in slice recordings of pyramidal cells. 5-HT 2A agonists may also enhance the power of gamma-frequency local field potential recordings, possibly due to enhanced synchrony within populations of parvalbumin-positive interneurons.

Brain activity in higher-order modules is reduced by 5-HT 2A agonists, whereas activity in lower-order modules is increased. This produces a flattening of the brain’s hierarchical topography and may explain intrusive sensory experiences and feelings of loss of separation from the environment.

A 5-HT 2A agonist weakens the influence of higher-order cognitive processes upon lower-order sensorimotor function, and enhances the influence of neural activity from lower-order regions upon higher-order regions. This may resolve a pathological influence of the mind over the body, leading to an improvement of symptoms.

Summary and Future Directions

There is strong interest in the therapeutic potential of 5-HT 2A agonists in mood disorders and drug addiction. A study is needed to examine the use of these agents in refractory functional hemiparesis in the absence of psychiatric comorbidity, in conjunction with best-practice treatment including physiotherapy and psychotherapy.

Psychological mechanisms of medically unexplained symptoms include: a) serotonin-receptor-mediated regulation of membrane excitability in the central nervous system b) serotonin receptor-mediated inhibition of memory function c) a combination of the above d) and e)

Brown RJ, Brunt N, Poliakoff E, Lloyd DM, Danquah AN, Miles E, Holmes E, Poliakoff DM (2010), Bullmore E, Sporns O (2009), Burke MJ, Ghaffar O, Staines WR, Downar J, Feinstein A (2014). Buzsaki G, Wang XJ, Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ (2016) investigated the effects of psilocybin on the brain. Patients with symptoms “unexplained by organic disease” are more likely to be disabled, distressed and unemployed than patients with symptoms explained by organic disease. Conversion disorders are psychiatric and psychotherapeutic disorders characterized by muscle weakness, sensory and gait disorders, and increased self-monitoring during imagined movements.

Motor imagery is a window into the mechanisms and alterations of the motor system, and it is altered connectivity between the prefrontal and sensorimotor cortex in conversion paralysis, and abnormal sense of intention preceding voluntary movement in patients with psychogenic tremor. Psilocybin, a serotonergic hallucinogen, affects alpha oscillations, N170 visual-evoked potentials, and visual hallucinations in the brain. It also affects the function of basal forebrain parvalbumin neurons, which regulate cortical gamma band oscillations.

Motor conversion disorder is associated with decreased action-effect binding, decreased sense of agency, and dual task interference. The authors review the mechanisms underlying functional neurological disorders and discuss treatment options. Broadband cortical desynchronization underlies the human psychedelic state, and is associated with ego-dissolution, medically unexplained symptoms, and loss of sensory attenuation in patients with functional (psychogenic) movement disorders. Puig MV, Celada P, Diaz-Mataix L, Artigas F, Puig M V, Gulledge AT (2011) Serotonin modulates fast-spiking interneuron and synaptic transmission in the rat medial prefrontal cortex.

Synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors is involved in the default mode of brain function, and the thick-tufted layer 5 pyramidal neuron is involved in the DOI activity in the four-plates test-retest paradigm. Rucker JJ, Jelen LA, Flynn S, Frowde KD, Young AH (2016) Review of psychoedelics in the treatment of unipolar mood disorders, Saulin A, Savli M, Lanzanberger R (2012) Serotonin and molecular neuroimaging in humans using PET, Stone J, Carson A, Sharpe M (2010).

The corticothalamocortical circuit drives higher-order cortex in the mouse, and multiple layer 5 pyramidal cell subtypes relay cortical feedback from secondary to primary motor areas in rats. Conversion disorders are characterized by abnormal parietal function, attention to self, supplementary motor complex, limbic activity, and motor preparation. Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat prefrontal cortex.