Post concussion syndrome in youth:

the GABA- effects of melatonin

Play Game Trial

Traumatic Brain Injury (TBI) is one of the most common causes of neurological morbidity and it is more common in childhood and adolescence than at any other time of life (1,13,15-17). Mild TBI (mTBI) is the acute neurophysiological effect of blunt impact or other mechanical energy applied to the head, such as from sudden acceleration, deceleration or rotational forces (7,10). It accounts for 90% of all TBIs.

Epidemiological studies suggest that one in five children will experience a mTBI by the age of 10, (1,18) and 799/100 000 children under 14 years visit the emergency department (ED) with a mTBI in the US (16) and Canada (19). Falls (51%) and sports-related activities (25%) are the commonest causes (2,16,20).

There is a significant morbidity associated with mTBI in children due to Post Concussion Syndrome (PCS) (3,14,21,22) and the potential for neurodegenerative changes in later life (23,24).

We estimate that annually over a 1000 children in Canada have PCS for over a year due to a “mild” TBI.

PCS symptoms include physical (i.e. headaches, nausea, dizziness, double vision), cognitive (i.e. difficulties with attention, concentration, thinking speed
and memory), and behavioural (i.e., sleep difficulties, irritability, depression, anxiety etc.) changes from pre-injury status (2,5). We found that 11% of all children with mTBI had PCS symptoms for at least the following 3-months, in comparison to 0.5% of controls (2). Two percent of mTBI children continue to have symptoms one year later.

The pathophysiology of mTBI is well described although complex (10,32-39), but the explanations for prolonged PCS are unclear (14,32,34). The mechanisms leading to neuronal dysfunction, cell death and altered connectivity include: oxidative stress, metabolic dysfunction, neuroinflammation, axonal damage and alterations in cerebral blood flow (32,34). The pathophysiological explanations for prolonged PCS have been elusive (2,14).

Recent animal and human research suggest that the explanations for the persistent PCS symptoms may be due to alterations in neurotransmission and neuronal circuitry (31,40-46). Cortical inhibition (CI) refers to the mechanisms through which cortical output is attenuated by GABA mediated interneuron neurotransmission (50).

The recent advances in functional brain imaging help to shed light at the mechanistic level in the human but may also add more objectivity to clinical assessments (14,39,60).

  • Functional magnetic resonance imaging (fMRI) detects haemodynamic changes associated with neuronal activity (61). Using fMRI, researchers found athletes with persistent PCS displayed hypoactivation in parts of the brain (20,62-64).
  • Diffusion tensor imaging (DTI) allows us to assess the integrity of neural fibres (66). The degree of fractional anisotropy (FA) correlates with long-term cognitive and motor outcomes (39,60). 
  • Transcranial magnetic stimulation (TMS) can measure discrete cortical functional areas (71), offering non-invasive, painless mapping of motor systems (72-74). Although none have been conducted in children, a few studies have demonstrated dysfunction after concussion using TMS(75-77). 

The need for a trial 

Mechanisms in the brain

We found that children with prolonged PCS and headaches had a significant response to Melatonin treatment (161-163). Post-traumatic headaches (PTH) are thought to be particularly resistant to treatment (9,164,165). Few studies have specifically analyzed how patients respond to treatment (166,167) and none in children.Our study found that significantly more children responded to treatment with oral melatonin (83%) when compared with the other
treatments used (p<0.05). As these children were on average 10.2 months post-injury, it is very unlikely that this response was due to time alone. No serious side effects were reported.

Melatonin, naturally produced in the body by the pineal gland, has neuroprotective, analgesic, and anxiolytic properties, modulates the GABAergic system, and is a promising agent in TBI (12,13,92,104-106). Melatonin’s role in the chronological regulation of major physiological processes (e.g., the sleep wake cycle) (107-109) is well accepted. More recently, its therapeutic potential is being explored in other neurobehavioural conditions (e.g. chronic pain, headaches, anxiety, etc.) and TBI (110).

Why melatonin?

Our previous findings