ME consensus symptoms may arise from control setpoints implemented by ventral brain neural circuits
Initial Author: Vijay Iyer, PhD (additional authors TBD)
Consensus core symptoms of Myalgic Encephalomyelitis (ME) are post-exertional malaise (PEM), orthostatic intolerance, cognitive impairment, and sleep irregularities1.
Irrespective of root cause, a systemic view is essential to ascertain what unites such a specific set of disparate symptoms. For instance, mitochondrial and neurovascular dysfunction are compelling hypotheses2 as they pertain to components spanning the body in a tissue-specific manner: neurovascular function leverages tissue-specific receptors3 while mitochondria can take tissue & even cell-type specific forms4. Conceptually, either could explain how ME dysfunction is localized to the brain, muscles, and (possibly) heart with all other organs largely normal (or variably abnormal).
Besides tissue-specificity, an alternate solution to the systemic puzzle would be central integration. The current Idea posits the ventral brain – the ‘lower’ part of the brain – is the most likely central location that could drive or perpetuate ME symptoms as a direct proximal cause.
For context, this Idea is inspired by recent reports from two longstanding ME researchers:
Komaroff posited that a hypothalamic torpor (hibernation-like) circuit could be the unifying mechanism for ME5, building upon a recent report of torpor induction in mice, another non-hibernating mammal6.
Marshall-Gradisnik and team reported the likely first 7 Tesla (7T) human MRI scanner study of ME patients, identifying enlargement of the brainstem, especially the pons7.
This Idea seeks to broaden the context, by first recognizing these brain regions (hypothalamus & brainstem) reside within the ventral brain as described in the landmark publication recently announcing the Allen Brain Cell Atlas8. This large public scientific resource identifies over 5,000 cell types via spatial transcriptomics in the whole mouse brain. A similar effort for adult human brains with lesser granularity has likewise already identified 3,000 cell types9. Importantly, both transcriptomic atlases have observed exceptional (“extraordinary”, “unexpectedly”) cell-type diversity concentrated in the ventral brain regions. Each set of authors concludes the ventral brain likely plays a host of innate survival functions largely conserved through evolution, distinct from the more divergent and adapted (speciated) functions of the dorsal brain. In short, there is ample terra incognito for neuroscience and neurology alike: specific ventral brain functions to be scientifically identified and characterized in detail.
As additional context, deep brain stimulation (DBS) has recently begun to demonstrate the human potential for treating multiple neurological disorders each mapping to distinct tightly clustered cell regions all residing within a hitherto ‘single’ anatomical region of the ventral brain, the STN or subthalamic nucleus10.
DBS however lacks the additional dimension of molecular specificity which the transcriptomic cell type maps show is paramount in the ventral brain. On the other hand, animal studies harnessing today’s advanced technologies11 for neuroscience (e.g., high-density neural probes, in vivo calcium imaging, whole brain activity mapping, optogenetics, viral tracers), are now routinely achieving functional mapping of highly specific ventral brain cell types. For instance, the hypothalamic torpor induction circuit found in rodents was termed a discrete neural circuit: it consists of molecularly-specific neurons, namely those producing the neuropeptide Qrfp, which are distributed across several hypothalamic subregions6.
Other recent example of discrete neural circuit mapping using today’s neuroscience technologies include:
Necessity of medullary reticular formation ventral part (MdV) for execution of (previously learned) forelimb fine motor tasks12
Causal role of midbrain (PPN/MRN neurons) in triggering motor cortex for initiation of planned motor tasks13
The nucleus of the solitary tract (NTS) in the medulla was revealed to contain a detailed spatial map of distinct interoceptive inputs conveyed by vagal nerve fibers, reminiscent of dorsal brain spatial maps for external sensory inputs14
Two genetically specific populations of dopamine neurons in the substantia nigra of the midbrain mediate specific motor functions (acceleration and deceleration, respectively) but not reward functions like other known dopamine cells to date15
The midbrain’s medial raphe nucleus (MRN) acts as a ‘switchboard’ between exploratory, exploitative, and disengaged states with molecularly-defined cell types for each16
Vasovagal syncope (a type of fainting) arises from molecularly-specific vagal nerve afferents (expression of NPY2R neuropeptide) from the heart to the area postrema of the medulla, with downstream syncope duration modulation by the paraventricular zone of the hypothalamus17
These examples amply demonstrate: small discrete neural populations in the ventral brain serve as surprisingly active, rich, and/or application-specific sensor or control circuitry that precisely inform, shape, and/or trigger downstream CNS function. The ventral brain can no longer be depicted as a ‘black box’ nor a passive relay station. Rather it is an active, causal player with numerous discrete (and mappable!) neural circuits.
The current Idea builds upon this insight: consensus ME symptoms of orthostatic intolerance and post-exertional malaise (PEM) may be akin to control circuit setpoints residing in the ventral brain. Vasovagal syncope is a severe & fast-acting form of orthostatic intolerance found to be both triggered & modulated by the ventral brain17 in response to a peripheral (cardiac) warning signal. Orthostatic intolerance symptoms in ME could be a more moderate and slower-acting form of pre-syncope; and the common comorbidities of orthostatic tachycardia and/or orthostatic hypotension18 could be either or both pertinent input warning signals or byproducts of the compensating control circuit. Likewise, PEM is what seems to clinician and patient alike an excessively prolonged response to the triggering exertion19. Seen from a control circuit framework, this may be a warning signal or active throttle aiming to prevent further such exertion possibly due to imperceptible physiological signals. For instance, the vagus nerve was recently found to transmit a quantitative measure of gut osmolality (which is clearly imperceptible) to the ventral brain which then gets translated (also by the ventral brain) into the experience of thirst14,20. Indeed, ME has an ‘extended relapsing course with a tendency to chronicity’21 and, anecdotally, many patients (including the author) report that one or more particular PEM episodes precipitated a sharp decline in baseline functioning; i.e., prolonged exertion throttling could underlie a protective function.
NINDS recently concluded a multi-faceted intramural study of an ME cohort characterizing two forms (one physical, one cognitive) of apparent real-time exertional throttling with some evidence (using older neuroscience technologies) this is brain-mediated22. While this putative new symptom is (importantly!) distinct from the consensus diagnostic criterion of post-exertional malaise, such real-time exertion throttling may itself be another ventral brain control circuit setpoint. Under cardiopulmonary testing, patients were ‘less likely to achieve their predicted maximal output’ (oxygenation testing) despite appearing to ‘perform to the best of their abilities’ (respiratory testing). This result may be quite important: exertion during such a paradoxical state (full effort + below-expected performance) may cause an ‘expectation mismatch’ in the (unconscious) ventral brain that could explain either or both PEM (from near-maximal exertion) and exertion throttling (during submaximal exertion). Furthermore, the finding of reduced CSF catecholamines could plausibly arise from reduced biosynthesis from its central sources (medulla and pons) within the ventral brain. Perhaps of significance: the most enlarged region detected by 7T MRI7, namely the pons, encompasses the synthesis location (locus coeruleus) of norepinephrine, the catecholamine whose reduction exhibited the greatest concordance with real-time exertional throttling.
It is important to emphasize: this Idea does not imply the ventral brain is the root cause of ME. Similarly, Wallit et al remark the root cause is likely further upstream, e.g., persistent infection, chronic immune activation, and/or microscopic mitochondrial dysfunction23. The ventral brain is the ‘gateway’ from the body to the higher-order (dorsal) brain, i.e., it is the most upstream location for the brain pathway from interoception to action. Given its location and the mounting recent evidence – of its active causal role and its diverse set of functions – the ventral brain should be a focal point for future neurological investigation of ME. Fortuitously: today’s neuroscience has the tools.
10. Hollunder, B. et al. Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation. Nat. Neurosci. (2024) doi:10.1038/s41593-024-01570-1.
16. Ahmadlou, M. et al. A subcortical switchboard for exploratory, exploitatory, and disengaged states. bioRxiv 2023.12.20.572654 (2023) doi:10.1101/2023.12.20.572654.