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The pathophysiology behind the "knockout punch", though generally thought to be a simple concept of shutting down the brain because of a suddent impact of energy, is in reality, a complicated one. Knowledge of the anatomy and physiology of the brain, though helpful in understanding this, is way beyond the scope and ambition of this article. But one quote, from a neurologist experienced with post traumatic brain injuries, puts the overall concept of the brain into perspective. FYI, axons are the nerve cells that, by numbers of millions and millions, all interact and interconnect to form the almost gelatinous mass of the brain. The brainstem is the area between the brain, which lies in the skull, and the spinal cord, which transmits the information down to the rest of the body.

The first time I was up close to a "living brain" was about 20 years ago during surgery in a young man with intractable epilepsy. I was amazed when I touched its surface with my finger-so soft! I don't know why I was surprised, but somehow I expected something so important to be more substantial than what looked and felt like a big chunk of pulsating, grey Jello.

I think that memory of the brain's velvet vulnerability motivated me to write about boxing and other contact sports. When observing a roundhouse blow, I imagine that precious glob of tissue shuddering in its pool of cerebrospinal fluid, veins and arteries stretched to the point of tearing, axons shearing, and just a bit of a twist on the brainstem, maybe enough for a knockout. While boxing may have other merits, protecting the brain isn't one of them. (The high speed collision of two NFL helmets also makes me wince.)  Andrew Wilmer MD

There appear to be at least 3 different mechanisms for a knockout:

1. Stimulation of the trigeminal nerve, vagus nerve, or carotid sinus causes a reflex drop in heart rate, cerebral blood vessel constriction, and peripheral blood vessel dilatation, a "neurovascular knockout." This knockout occurs because of a neural reflex drop in cerebral perfusion, either because of localized blood vessel constriction, or a drop in cardiac output because of a slower heart rate (bradycardia) or a drop in blood flow return to the heart because of dilation of neurally induced dilation of blood vessels throughout the body.

2. Strikes to the side of the head or the angle of the jaw from a punch known as a "hook" result in rotational forces that can disrupt brain function by one of four hypothetical mechanisms: a) twisting of the brainstem with disturbance of the reticular activating system, b) stimulation of the trigeminal nerve, c) activation of the carotid sinus, and d) diffuse axonal injury. The reticular activating system is a small area in the brainstem which controls "wakefulness" and the sleep wake cycle.

3. The "pummeling knockout," which occurs without loss of consciousness, but with dissociation and confusion. This type of knockout is believed to be caused by traumatic disruption of neuronal activity. Traumatic disruption includes shearing of axonal connections, localized edema which inhibits neural functioning, and disruption of neural cell membrane function which effectively shuts down function of brain nerve cells.

Of course knockouts may present concomittantly with cerebral contusions, subdural hematomas, epidural hematomas, intracerebral hematomas and concussions. These are discussed elsewhere. Let us continue with an evaluation of a analysis of the damage suffered by amateur boxers who are subject to non-knockout blows to the head.


In 2006, a landmark study was performed on boxers in Sweden, which identified the increased level of certain proteins in the cerebrospinal fluid, in young healthy boxers, who had suffered blows to the head during boxing matches. No knockout blows were identified, yet these young amateur boxers demonstrated evidence of neural injury. I quote the highlights of the study, initally published in Sweden, here.

Study Details

Professional boxing is associated with risk for long-term neurologic injury.The development of chronic neurologic symptoms in this setting was originally referred to as the punch-drunk syndrome or dementia pugilistica. The terminology has evolved with time, and the entity is now termed chronic traumatic brain injury and occurs in approximately 20% of professional boxers.The clinical manifestations vary depending on the accumulated number of blows to the head, career duration, performance as a boxer, and ability to withstand many hits.According to some studies, amateur boxers also show neuropsychologic and neuroimaging evidence of chronic traumatic brain injury,although at a lower incidence than in professional boxers. There is, however, lack of consensus in the scientific literature, possibly because the expected effects are less severe in amateur boxing compared with professional boxing owing to less exposure to repetitive head trauma because of shorter bouts and the mandatory use of protective headgear.

Studies of chronic traumatic brain injury in boxers have been based on identification of the cumulative late effects of repeated hits to the head, such as brain atrophy and cognitive disturbances or neuropathologic abnormalities. To our knowledge, no study has examined the short-term effects of amateur boxing on the brain in direct connection to a bout. We conducted a study to identify and monitor brain injury associated with amateur boxing by cerebrospinal fluid (CSF) analyses of biochemical markers for neuronal and astroglial injury in a cohort of amateur boxers after a bout and after extended rest from boxing. A control group of 10 healthy nonathletic subjects was included for comparison of long-term biochemical evidence for neuronal impairment in amateur boxers.

Fourteen Swedish amateur boxers (11 men and 3 women; age [mean ± SD], 22 ± 3.8 years) were enrolled in the study. Ten healthy male nonboxers with no known history of head trauma (age [mean ± SD], 30 ± 6.3 years) were included as control subjects. The study was approved by the Ethics Committee for Medical Research at Göteborg University, Göteborg, Sweden, and written informed consent was obtained from all participants. Cerebrospinal fluid was collected in polypropylene tubes by lumbar puncture (LP) through the L3-4 or L4-5 interspace. In boxers, LP was performed both 7 to 10 days after boxing and after a 3-month period of rest from boxing. One boxer refused the second LP. Only 1 LP was performed in each of the healthy control subjects. Seven to 10 days was chosen as the optimal length of time for detection of a change in biomarker levels as a result of a bout on the basis of CSF biomarker kinetics in a study of stroke. All CSF samples were stored at –80°C pending analysis. The participants were examined physically and neurologically before LP. All were healthy and showed no signs of focal neurologic injury. The number and severity of hits to the head were assessed by interviewing the boxers when examined 7 to 10 days after a bout. Because a score in amateur boxing is counted for hits to any part of the front or sides of the head or body, it was impossible to use the total score of the opponent as a measure of hits to the head. The severity of hits was divided into 2 categories: more than 15 hits to the head or grogginess during or after a bout, and 15 or fewer hits to the head and no grogginess during or after the bout. None of the boxers received a knockout hit.

Cerebrospinal fluid total tau (T-tau) concentration was determined using a sandwich enzyme-linked immunosorbent assay (ELISA) (Innotest hTAU-Ag; Innogenetics, Gent, Belgium) specifically constructed to measure all tau isoforms irrespective of phosphorylation status, as previously described.8 Phosphorylated tau in CSF was determined using a sandwich ELISA specific for tau phosphorylated at threonine  Cerebrospinal fluid concentrations of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP) were analyzed using previously described ELISA methods. The detection limit for the NFL ELISA was 125 ng/L. beta-Amyloid proteins 1-40 (Abeta[1-40]) and 1-42 (Abeta[1-42]) concentrations were determined by ELISA as previously described. Albumin levels in CSF were measured by immunonephelometry on an Immage immunochemistry system (Beckman Coulter Inc, Fullerton, Calif).

After a bout, there was a marked increase (4.1-fold) in the CSF levels of NFL compared with levels detected in the same individuals after a 3-month rest from boxing. The CSF levels of T-tau and GFAP also were significantly increased after a bout compared with after a 3-month rest from boxing (1.5-fold and 1.3-fold, respectively.

The NFL and GFAP, but not T-tau, concentrations were significantly higher in boxers after a bout than in nonathletic control subjects. No significant differences in biomarker concentrations were detected between boxers after the 3-month rest period and control subjects, except for NFL, which remained significantly elevated despite absence from boxing (mean ± SD, 208 ± 108 ng/L vs =125 ng/L; P = .001). The NFL, T-tau, and GFAP concentrations were higher in boxers who had received many hits (>15) or high-impact hits to the head compared with boxers who reported few hits. With the exception of NFL, boxers who received few hits had biomarker levels statistically indistinguishable from those in control subjects. Levels of phosphorylated tau and Abeta(1-40) and Abeta(1-42), markers that reflect molecular changes in Alzheimer disease, were not significantly altered in boxers after a bout compared with after rest or levels detected in the nonathletic control subjects. No significant differences in CSF albumin concentrations were detected, indicating that amateur boxing does not significantly impair the blood-brain barrier function.


The current study contributes new information about brain injury risks in amateur boxing. Data suggest that participation in an amateur boxing bout is directly associated with neuronal and astroglial damage, as reflected by the increase in NFL, T-tau, and GFAP concentrations in CSF. The findings that the increase in these CSF biomarkers is most pronounced in boxers who receive many hits or high-impact hits to the head and that the CSF levels show normalization after 3 months of rest from boxing indicate that the changes are directly related to brain trauma inflicted by hits to the head. The high correlation between biomarker changes in individual boxers supports this interpretation.

The most pronounced change was a marked increase in CSF NFL after a bout that also correlated with the severity of received hits, while a similar but less pronounced increase was found for CSF T-tau. Both NFL and tau are important constituents of neuronal axons. The CSF levels of these proteins increase in disorders with neuronal and axonal degeneration and damage, and the increase is known to correlate with the size of the brain lesion. When applied to the results of this study, the increases in NFL and T-tau probably reflect damage to neuronal axons from hits to the head during a bout. An increase after a bout was also found for CSF GFAP, which is an intermediate filament protein mainly expressed in astrocytes, for which it constitutes a selective marker. This finding suggests that there is also astroglial damage caused by amateur boxing. Similarly, in acute brain trauma, a marked increase in serum GFAP concentration was recently found. This increase also correlated with clinical outcome.

A large body of evidence supports the belief that professional boxers who have been exposed to repetitive head trauma are at increased risk for developing Alzheimerlike pathologic findings, with hyperphosphorylation of tau and formation of tangles and deposition of Abeta into plaques. We, therefore, tested whether amateur boxing results in any changes in CSF biomarkers reflecting these pathogenic processes, that is, elevated phosphorylated tau concentration and decreased Abeta(1-42) concentration and the ratio of Abeta(1-42) toAbeta(1-40). No significant changes were detected; hence, our data provide no evidence for any acute disturbances in these systems in amateur boxers.

In conclusion, our study results suggest that amateur boxing impairs axonal and astroglial integrity. The molecular changes detected are likely to be even more pronounced in professional boxers and in boxers who have received a knockout punch.

Henrik Zetterberg, MD, PhD, Department of Experimental Neuroscience, Section of Neurochemistry, Sahlgrenska University Hospital