Roma are in turmoil after a 4-1 loss at Atalanta last weekend, having won only twice in their past eight matches to sit seven points below fourth-place Lazio in sixth spot in the standings.
But Ledesma has played in 12 Rome derby matches and knows that form will count for nothing.
"The derby is a special game, a unique emotion," Ledesma said. "When you go on to the pitch you forget everything: standings, the league and other results. The fans make you understand how important it is, the rest doesn't matter at all. In fact, when you are behind in the standings you are even more motivated.
"In the derby, you have to keep a cool head and a warm heart. You have to keep calm even if your heart is beating a million times a second.
"You have to try to think about what you have to do, about what has to be done on the pitch, otherwise you'll do something that has nothing to do with a football game."
Roma are likely to have Daniele De Rossi back after he was dropped for theAtalanta game as punishment for turning up late to a meeting.
Francesco Totti, the captain, is also set to feature despite being injured in training. Totti crumpled to the ground following a late tackle from Cicinho, and it was initially feared he had fractured his foot. But the striker could return to some form of training on Thursday afternoon.
Simone Perrotta remains a bigger doubt with an ankle injury, while Pablo Osvaldo and Marco Cassetti are suspended.
Lazio are without key players Senad Lulic, Lorik Cana, Luciano Zauri and Stefan Radu, but are hopeful the French defender Abdoulay Konko will be passed fit in time.
Lazio won the derby for the first time in five years in October, beating Roma 2-1, and will now be looking to do the double over their city rivals for the first time in 14 years.
The two played out a 1-1 draw at San Siro last weekend, with both sides controversially failing to have goals awarded. Milan will feel the most aggrieved after Sulley Muntari's header travelled several yards over the goal line.
Milan's players will have to put thoughts of what might have been to the back of their minds as they visit a Palermo side which, although woeful on their travels, have won four of their past five home matches in Sicily.
However, Milan will be boosted by the return of their star striker Zlatan Ibrahimovic, who returns from a three-match ban for slapping the Napoli defender Salvatore Aronica.
Philippe Mexes sits out the first of his three-match ban after video evidence showed he struck the Juventus striker Marco Borriello, his former Roma teammate.
Milan, the leaders and defending champions, are a point above the unbeaten Juventus but have played a game more.
Inter Milan head into tomorrow's home game with Catania in the midst of a crisis.
Claudio Ranieri's men are on a run of eight matches without a win, including seven defeats in which they have failed to score.
Ranieri would be closer to becoming Inter's second managerial casualty this campaign with another loss, after having replaced Gian Piero Gasperini five games into the season.