Tick, tick, tick.

It’s a familiar sound to neurologists, who have grown accustomed to watching the clock as they hurry to get tissue plasminogen activator on board in ischemic stroke patients.

If Dr. Steven Cramer proves correct, a second timer may soon be ticking, this one measuring in days or weeks a limited “golden” period in which combined restorative therapies and rehabilitation efforts should be initiated to achieve maximum effect.

“Therapeutic windows open and close,” stressed the University of California, Irvine (UCI), professor of neurology during a presentation at the meeting.

Comparing brain plasticity after stroke to that seen in early development, Dr. Cramer emphasized the need for pairing restorative therapeutic targets with behavioral conditioning, and doing it all at the optimal time.

Nature provides its own best rationale, propelling “most of the action” in spontaneous recovery within a month post-stroke, he said.

In animal models, brain response to a unilateral lesion is rapid and intense, Dr. Cramer explained.

“We see inflammation and a wealth of growth events that look very much like a developing brain. It’s an excitable brain,” ushering in building blocks for repair and regrowth of cells, dendrites, and synapses.

“Some people look at this and say these are molecular underpinnings of spontaneous recovery. Some people look at this and say, these are therapeutic targets, because if these are the components that are the backbone of spontaneous repair, amplifying these sorts of processes could lead to enhanced outcomes compared to the natural processes.”

Quickly administered stand-alone treatments have indeed been shown to mimic and expand on this natural boost to early recovery, but Dr. Cramer predicted far more will happen if active rehabilitation is added to the mix.

“When the brain is fertile to undergo repair, whatever substance you give has maximum effect if it is paired with the right kind of experience,” Dr. Cramer said.

“If you sprinkle your best restorative pixie dust on the brain, you’re not going to get the same effect as if you pair it with some kind of behavioral shaping.”

“Pixie dust” may soon come in the guise of growth factors; monoclonal antibodies; existing drugs such as amphetamines, levodopa, or SSRIs; or cell-based therapies, he said.

Similarly, on the rehabilitation side, labs around the world – including Dr. Cramer’s at UCI – are experimenting with robot-assisted movement devices that show moderate but nonetheless impressive results when used long after a stroke.

UCI’s Hand-Wrist Assisting Robotic Device (HWARD, see www.strokerobot.com

For example, the HWARD device at UCI currently helps chronic stroke patients do such engaging activities as playing blackjack, and soon will move into their homes for round-the-clock skill-building athletics and games, Dr. Cramer said.

A pilot study of the HWARD robot found significant arm and hand functional improvement in 13 patients who had a hemiparetic stroke a mean of 2.9 years prior to the study. The improvement was noted on changes in their performance on the Action Research Arm Test and the arm motor score of the Fugl-Meyer Assessment (Brain 2008;131:425-37).

In a recent study of another device, researchers at the VA Medical Center and Brown University in Providence, R.I., randomized 127 chronic stroke patients to usual care, intensive traditional physical therapy, or robot-assisted physical therapy that involved more than 1,000 upper limb movements per session.

The robot-assisted group trended toward a significant improvement in Fugl-Meyer Assessment scores, while function declined in the usual care group over the 12-week trial.

Notably, the trial’s participants were enrolled an average of 5 years following their strokes, with a range of 6 months to 24 years.

Dr. Cramer’s suggestion is that it might make more sense to strike while the iron is hot. And he warns, it may not be hot very long after a stroke.

“Repair is an organizational problem, and it’s time sensitive,” he said.

In fact, some candidates for repair boosting – gamma-aminobutyric acid (GABA) agonists, for example – are “excellent targets in the first few hours, but wait a few days and these become toxic.”

Just as injured brains may be receptive early on to neurochemical or cellular assistance, they also may need early reinforcement of experiences at risk of being lost forever.

This is the time when robotic assistance of movements, applied multiple times, may be especially useful in properly selected patients, especially those with evidence of abundant preserved regions of the corticospinal tract.

“It takes a lot of practice to make the brain better,” he said.

Perhaps, he said, that practice should begin during the “black box” period, during the 90 days following hospital discharge. In fact, Dr. Cramer and his colleagues are now enrolling up to 72 patients who had a hemiparetic stroke within the past 11-26 weeks in a phase II trial of 3 weeks of therapy with the HWARD robot.

Dr. Cramer disclosed that he has received grant support and has served as a paid consultant for GlaxoSmithKline, and has also consulted for PhotoThera, Allergan, Pfizer/CogState, and Johnson & Johnson.