Hey guys, especially thehamma
Well, at least no one can say I didn't try to simplify things.

I hate talking in sceintific jargon, because I believe it just makes things needlessly more complicated, but since you are really asking for it (and it is your right by the way, so more power to you

) then ok, here goes.
Fatigue has some metabolic causes, but for CNS fatigue the most important is an increase in the plasma concentration ratio of free tryptophan to branched-chain amino acids. (Other fatigue causes identified in various medical literature being hypoglycemia, phosphocreatine level decrease, proton accumulation, and glycogen depletion in the muscle, etc.)
As Bryan mentioned quite early on in HST, CNS fatigue is not muscle fatigue. As researchers have fully clarified, CNS fatigue is not fatigue in the motile muscles themselves, and in fact is different from the so called tiredness feeling caused by physical (muscular) fatigue and, also another fact, certain related CNS fatigue (like CFS) can be generated in a state that is not accompanied by physical fatigue. CNS results from fatigue that occurs in a large portion of intercerebral control circuits caused by suppression in the level of voluntary exciting, which are suppressed in the number of motor units to the level of voluntary neuromuscular junction - muscle fibers and the firing frequency (as previously stated, it's not really about the fatigue in the motile muscles themselves)
Let's go to the really interesting part. Research has proven that fatigue in the CNS doesn't show a reduction in the serotonergic system function in the central and peripheral nerves but, in contrast, an enhanced nerve transmission response and this implies a relation to a change in the transmission of extracellular fluid 5-HT (5-hydroxytryptamine) that depends on an increase in tryptophan. So what's the big deal?
Tryptophan, which is a causal substance of the fatigue, is transferred from the peripheral system (in blood) to the central system (brain) through the blood-brain barrier (L-system transporter) to give inhibiting (negative) information to the CNS. In other words, an excessive amount of tryptophan or 5-HT in the brain suppresses the CNS, causes a reduction in the motor system output that is released through pyramidal tracts and x-motor neurons. It is this mechanism that causes the fatigue phenomena (central fatigue) derived from the CNS.
To verify such research, some researchers, particularly Dr. Eric Newsholme, from Oxford University, and Dr. Takanobu Yamamoto, from Tezukayama University, experimented with suppressing trytophan uptake to alleviate central fatigue. The results? Great. They found that specific inhibitors of the L-system transporter on the blood-brain barrier (BBB) make it possible to suppress the fatigue in the CNS. They also found two components they they determined were therapeutically effective in suppressing this CNS fatigue: BCH and BCAA's.
Simply put, going to failure (that literally means you don't get enough rest), increases the trytophan uptake significantly (read: tremendously), and without enough necessary nutrition (BCAA's as identified), this also increases the extracellular fluid 5-HT, and an excessive amount of tryptophan or 5-HT in the brain suppresses the CNS, causes a reduction in the motor system output that is released through pyramidal tracts and x-motor neurons.
Going to failure once doesn't necessarily mean CNS fatigue will immediately set in. Nobody ever said that. But if failure becomes the goal of every workout (and every exercise), you are pretty sure that unless you drank all the BCAA's in California, CNS fatigue will be your bestfriend
You may also check out the following articles to find out more:
1.) The role of tryptophan in fatigue in different conditions of stress; Castell LM, Yamamoto T,
Phoenix J, Newsholme EA; Adv Exp Med Biol. 1999;467:697-704
2.) Changes in the albumin binding of tryptophan during postoperative recovery: a possible link
with central fatigue?; Yamamoto T, Castell LM, Botella J, Powell H, Hall GM, Young A,
Newsholme EA; Brain Res Bull. 1997;43(1):43-6
3.) Diminished central fatigue by inhibition of the L-system transporter for the uptake of
tryptophan; Yamamoto T, Newsholme EA; Brain Res Bull. 2000 May 1;52(1):35-8
4.) The effect of tryptophan deficiency in the brain on rat fatigue levels: a rat model of fatigue
reduction; Yamamoto T, Newsholme EA; Adv Exp Med Biol. 2003;527:527-30
5.) The plasma level of some amino acids and physical and mental fatigue; Newsholme EA,
Blomstrand E; Experientia. 1996 May 15;52(5):413-5
6.) Tryptophan, 5-hydroxytryptamine and a possible explanation for central fatigue; Newsholme
EA, Blomstrand E; Adv Exp Med Biol. 1995;384:315-20
7.) Physical and mental fatigue: metabolic mechanisms and importance of plasma amino acids;
Newsholme EA, Blomstrand E, Ekblom B; Br Med Bull. 1992 Jul;48(3):477-95
8.) Characterisation of L-tryptophan transporters in human placenta: a comparison of brush
border and basal membrane vesicles; Kudo Y, Boyd CA; J Physiol. 2001 Mar 1;
531(Pt 2):405-16
9.) Amino acids and central fatigue; Blomstrand E; Amino Acids. 2001;20(1):25-34
Hope this satisfies your curiosity. Regards!

-JV