• BrainSightAI Team

The Dopamine Serotonergic Pathway

Surgical interventions such as stereotactic radiosurgery and magnetic resonance-guided focused ultrasound, and neuromodulatory interventions such as deep brain stimulation (DBS) and vagal nerve stimulation, have been under investigation to remediate psychiatric conditions resistant to conventional therapies involving drugs (Cabrera et al., 2019).


There has been even more interest in brain mapping with the latest article on deep brain stimulation being used for depression (Wu et al., 2021). All these made us further think about how VoxelBox could be used for psychiatric conditions. Conversations with advisors led us to this paper and to deeper conversations on the intersection between clinical, research and VoxelBox. Here's a summary of what we learnt.


Microscopic brain mapping in psychiatric disorders

Over the years, psychiatric disorders have been systematized and classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM). It has become the standard tool with which psychiatrists, psychologists, researchers and other mental health professionals diagnose and communicate about these disorders (Regier, Kuhl & Kupfer, 2013).


Since psychiatric disorders have long been established to be a function of disturbances in neurotransmitter levels and regulation, research in the field of psychopharmacology and neuro techniques - like brain mapping - to modulate and assess synapses and neurotransmission has provided rich insights (Ceccarini, 2020; Kato et al, 2013). The interplay of the mechanisms of neurotransmission, localization and regulation has led to targeted research in understanding the systems of major neurotransmitters, and how they are affected in psychiatric disorders. The contribution of dopaminergic, serotonergic and opioidergic systems are generally studied to find dysregulation and modulation of neurocircuitry that underlies psychoses (Puryear et al, 2019).


Thus, in spite of the DSM’s conquest over the field of psychiatry, complex clinical cases require psychiatrists to examine neurotransmitter levels.


A brief history of neurotransmitter testing for psychiatric disorders

Research documenting the excretion of urinary neurotransmitters and their metabolites in humans dates back to 1951, when Von Euler published a number of papers on this subject (Von Euler and Helner, 1951). As a result, the first clinical application of neurotransmitter testing tested the role of norepinephrine and its metabolites as biomarkers of an adrenal tumor known as pheochromocytoma (Engel and Von Euler, 1951).


Since then, a compelling number of studies have employed urinary neurotransmitter testing for examining psychological disorders. These studies provide evidence supporting three key points: changes in urinary neurotransmitter, excretion correlates with disease states, and therapeutic effectiveness.


Neurotransmitter testing has shown positive results in relation to diagnosis of mental disorders. A study on Autistic children had higher levels of urinary dopamine excretion and low levels of urinary norepinephrine excretion relative to non-autistic controls (Barthelemy et al., 1988). Another study examined the relationship between depression and anxiety symptoms and urinary norepinephrine excretion. The results showed a significant positive relationship between the Beck Depression Inventory and Spielberger State-Trait Anxiety Inventory and levels of urinary norepinephrine excretion (Hughes et al., 2004). Studies on other conditions like ADHD, Schizophrenia, Bipolar Disorder etc. are ongoing.


When it comes to treatment, neurotransmitter testing can guide clinicians decisions. Most medicines given to alleviate symptoms of psychiatric disorders are neuro-modulators. The pharmacodynamics of these molecules help us understand the role of these neuro-transmitters.

  • For example, schizophrenia – In 1970, the dopamine hypothesis of schizophrenia was formulated, when the antipsychotic and antimanic effects of DA receptor blockade agents suggested that psychotic and manic symptoms are related to a dysregulation of dopaminergic activity. Hence the etiology of schizophrenia was traced to excessive transmission at DA receptors.

  • An updated model of schizophrenia combined subcortical hyper-dopaminergia with prefrontal hypo-dopaminergia, which behaviorally results in the attribution of aberrant salience to stimuli.

  • During the mid-1960s, mood effect of molecules which modify the serotonin (5-HT) metabolism gave rise to the monoamine theory of affective disorders, which assumed a relationship between depression and decreased levels of centrally available neurotransmitters

How are neuro-transmitter levels tested in Indian settings?

In India, the levels of metabolites of the neurotransmitter in the cerebrospinal fluid (CSF) are commonly measured using spectrophotometry and enzyme assay methods like the Enzyme Linked Immunosorbent Assay (ELISA) (Radhakrishnan & Andrade, 2010).


Further research in assessing the neurological basis of psychiatric disorders has improved with developments in brain imaging. Using CT scans for cognitive dysfunction, MRI and EEG for predicting the response towards antidepressant, Positron Emission Tomography (PET) scans to study in schizophrenia etc. has started to become the norm (Radhakrishnan & Andrade, 2010).


Unfortunately, these methods have not found application at the clinical level due to high costs, technical difficulties and relatively low spatial and temporal resolution.


Can resting-state fMRI help in understanding neuro-transmitter signaling?

Conio et al. (2020) hypothesize that alterations in neurotransmitter signaling result in a subcortical–cortical functional reorganization, which leads to Resting State Networks (RSNs) disbalancing, finally manifesting in distinct psychopathological states.

Hence, we can use RSN’s (particularly Default Mode Network (DMN), Sensorimotor Network (SMN) and Salience Network (SN)) to understand the neurotransmitter signaling, particularly 5- hydroxytryptamine (HT) signaling and Dopamine (DA) signaling.


What are the correlations?


(Benedetta Conio et al.,Mol Psychiatry . 2020 Jan; 25(1):82-93)

  • A deficit in 5-HT signaling and/or functional dis-connection of raphe nuclei (RNI) may result in DMN deficit with relative predominance of SMN–SN activity, manifesting in psychomotor excitation, excessive salience to sensory stimuli and externally focused thought, i.e., manic state.

  • A deficit in DA signaling and/or functional disconnection of dopaminergic substantia nigra (SNc) – ventral tegmental area (VTA) may result in SMN–SN deficit with relative predominance of DMN activity, manifesting in psychomotor inhibition, reduced salience to stimuli and internally focused thought, i.e., depressive state.

  • Finally, hyperactive DA signaling may result in over-activity of SMN–SN, manifesting in excessive salience attribution to irrelevant stimuli, perceptual distortions, psychomotor agitation, and thought disturbances, i.e., psychotic state.

The underlying basis

“According to the reviewed and empirical data, neurotransmitter signaling impacts the functional configuration/ connectivity (i.e., FC) and activity (i.e., fALFF/neuronal variability) of RSNs. Dopaminergic SNc-related nigrostriatal pathway is mainly connected with SMN and VTA-related mesocorticolimbic pathway with SN, whereas serotonergic RNi- related pathways are connected with SMN and DMN. SNc- related FC is positively correlated with SMN activity, whereas RNi-related FC is negatively correlated with SMN activity (tilting the networks balance toward the DMN). DA signaling is associated with increase in FC and activity in SMN and SN, whereas 5-HT signaling is associated with decreased SMN and increased DMN activity.” (Conio et al., 2020)


It is well established that the the dynamics associated with the regulation of the levels of neurotransmitters contribute to the pathogenesis of most of the psychiatric disorders. However, it is not always feasible to directly estimate their levels. The FC and activity of task negative networks from rsfMRI are able to provide an indirect association between the neurotransmitter levels and their contribution in disease pathogenesis.


We are building VoxelBox, a platform that uses state of the art technologies and helps researchers and clinicians understand macroscopic brain function at the click of a button.

VoxelBox is envisioned as an indication-agnostic platform to map an individual’s structural and functional connectome and compare it against the healthy connectome. Over and above it, the platform uses AI to classify the resultant connectomic patterns and anomalies. If you are interested by the questions we are trying to answer and would like to get involved, please write to us at collaborationa@brainsightai.com

References

  1. Barthelemy, C., Bruneau, N., Cottet-Eymard, J. M., Domenech-Jouve, J., Garreau, B., Lelord, G., ... & Peyrin, L. (1988). Urinary free and conjugated catecholamines and metabolites in autistic children. Journal of Autism and Developmental Disorders, 18(4), 583-591. https://doi.org/10.1007/BF02211876

  2. Cabrera, L. Y., Courchesne, C., Kiss, Z., & Illes, J. (2019). Clinical Perspectives on Psychiatric Neurosurgery. Stereotactic and functional neurosurgery, 97(5-6), 391–398. https://doi.org/10.1159/000505080

  3. Conio, B., Martino, M., Magioncalda, P. et al. Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry 25, 82–93 (2020). https://doi.org/10.1038/s41380-019-0406-4

  4. Engel, A., & Von Euler, U. S. (1950). Diagnostic value of increased urinary output of noradrenaline and adrenaline in phaeochromocytoma. The Lancet, 256(6630), 387. https://doi.org/10.1016/S0140-6736(50)91342-0

  5. Hughes, J. W., Watkins, L., Blumenthal, J. A., Kuhn, C., & Sherwood, A. (2004). Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. Journal of psychosomatic research, 57(4), 353-358. https://doi.org/10.1016/j.jpsychores.2004.02.016

  6. Kato, T. A., Yamauchi, Y., Horikawa, H., Monji, A., Mizoguchi, Y., Seki, Y., Hayakawa, K., Utsumi, H., & Kanba, S. (2013). Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry. Current medicinal chemistry, 20(3), 331–344. https://doi.org/10.2174/0929867311320030003

  7. Radhakrishnan, R., & Andrade, C. (2010). The evolution of Indian psychiatric research: An examination of the early decades of the Indian Journal of Psychiatry. Indian journal of psychiatry, 52(Suppl 1), S19–S25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146197/

  8. Regier, D. A., Kuhl, E. A., & Kupfer, D. J. (2013). The DSM-5: Classification and criteria changes. World psychiatry : official journal of the World Psychiatric Association (WPA), 12(2), 92–98. https://doi.org/10.1002/wps.20050

  9. Von Euler, U. S., & Hellner, S. (1951). Excretion of noradrenaline, adrenaline, and hydroxytyramine in urine. Acta Physiologica Scandinavica, 22(2‐3), 161-167. https://doi/abs/10.1111/j.1748-1716.1951.tb00765.x

  10. Wu Y, Mo J, Sui L, Zhang J, Hu W, Zhang C. (2021). Deep Brain Stimulation in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis on Efficacy and Safety. Frontiers in Neuroscience. Vol 15, pp 257. https://www.frontiersin.org/articles/10.3389/fnins.2021.655412/full