Traditionally, diagnosis of musculoskeletal signs and symptoms, tends to weigh in the direction of descriptions of all kinds of altered morphology of structural origin, but the structural diagnosis is often only a small part of a more complex and highly diversified overall picture. Structural, tissue related, diagnosis is under scrutiny since it doesn’t necessarily always play an important role and many studies show false positive findings in the asymptomatic population and recovery of function and symptoms don’t necessarily imply a contemporary recovery of the structural morphology. Musculoskeletal signs and symptoms not necessarily are indications of distinct and singular musculoskeletal pathology, that may therefore require different reasoning strategies and therapeutic approaches. All the physiological processes in the human body are controlled by the PNEI systems and interact strongly with all the processes of the human body, including tissue related conditions as well as signs and symptoms.

So, how can we be sensitized towards recognizing non-structural involvement and open our clinical reasoning processes towards other potential factors of PNEI involvement in neuro-musculoskeletal signs and symptoms? Is it all related to structural diagnosis and structural pathology, or are some of the patients suffering from musculoskeletal signs and symptoms having PNEI system dominance?

Without doubt, the homeostatic and metabolic equilibrium which is controlled and require continuous adjustments is the most important and vital function of the PNEI systems. 

PNEI systems do not function independently and in isolation, but strongly interact and use complex feedback systems and bidirectional crosstalk influencing and sustaining each other in trying to maintain homeostasis. 

The spectrum of challenging situations for maintaining system homeostasis and metabolic health vary widely and spread from unfavorable genetics, inherited or acquainted forms of sensory sensitivity, presence of inherited or acquired pathology, are the consequences of an unhealthy lifestyle and may involve psychological traits to potential healthy persons with overtraining syndrome. Often there is not one single reason for the presence of health challenging situations but the presence of causal pluralism where the whole system is in charge and not necessarily only one single entity is at fault. 

It seems therefore wise to concentrate on the rehabilitation of lost function and consecutive recovery of symptoms, keeping the door open for involved PNEI factors if possible and not only on recovery of local structural morphology which may imply biased, single entity, reasoning and monomodal management.

The role of the gut microbiome, the muscle, bone, body weight and body fat, the nervous system, gender and sex hormones, lifestyle factors and musculoskeletal pathology their interactions with PNEI systems at different age groups are introduced. The use of Pharmacological products and potential side effects are being discussed. 

The most reliable health related biomarkers are being presented. 

Potential clinical patterns which might present a dominance towards systemic PNEI involvement are discussed, as well as several potential and promising treatments methods.