29 December 2009. Better drugs are likely to be the best hope for treating schizophrenia, but two new studies remind us of the promise of behavioral training for other disorders, and thus, perhaps, for schizophrenia as well. A report in the December 10 issue of Neuron finds that a successful remedial reading program fostered communication within the cerebral cortex by building up white matter structures, and a study published by Nature online on December 9 harnessed the memory reconsolidation process to rewrite fearful memories in humans without drugs. These results hint that, someday, research may yield training-based approaches to help repair brains harmed by schizophrenia.
Building better brains
Prior studies of subjects with poor reading skills found below-normal activation of brain areas involved in reading, as well as regions of compromised white matter that could hinder communication within neural networks. Timothy Keller and Marcel Just of Carnegie Mellon University in Pittsburgh, Pennsylvania, wondered whether intensive reading instruction could reverse such abnormalities.
The researchers examined children eight to 12 years old, including 47 with poor reading skills and 25 who read well. They randomly assigned the poor readers to either a 100-hour remedial reading program or, like the good readers, to regular classroom instruction only.
To study the structure of white matter, the researchers used diffusion tensor imaging, which maps the flow of water as it navigates in, around, and through cells, allowing a particularly detailed portrait of nerve fibers (see Alexander et al., 2007 for a review). One way to analyze this diffusion is with a measure called fractional anisotropy (FA), wherein a low value means that water is moving in mostly random directions. Linear structures like nerve fibers induce water to move along them, raising the FA value. Thus, a low FA suggests less microstructural integrity, which could mean a number of things including fewer and larger nerve fibers, less myelin, and/or fewer nerve axons running parallel to each other.
Compared to subjects who read well, poor readers began the study with lower fractional anisotropy in part of the left anterior portion of the centrum semiovale (the large expanse of white matter beneath the cortex of the frontal and parietal lobes), suggesting a deficiency of white matter structures there. Those exposed to the training program not only improved their reading skills, but also their FA score in this same area. Furthermore, their reading gains correlated with the extent of change in their white matter.
Regardless of reading ability, FA in subjects who received no remedial training remained unchanged. This enabled the researchers to discount normal maturation as the cause of the changes.
Based on further analyses, Keller and Just ascribed the reason for the increased fractional anisotropy to decreased flow perpendicular to the main axis of the white matter fibers rather than increased flow along it. This would point to the training having spurred myelin growth in poor readers, perhaps by revving up neuronal firing.
“The capability to improve white matter provides a possible remediation not only for reading difficulty but also for other neurological abnormalities believed to be underpinned by deficits in anatomical connectivity, such as autism,” write Keller and Just. Since human cognition takes a village of individual neurons working together, the researchers note that even slight gains in white matter networking could lead to big performance gains.
Fear be gone
Learning what to fear helps humans and other animals avoid danger, but when fears become excessive or inappropriate in neuropsychiatric disease, they can do more harm than good. To model the learning process, studies often induce fears using a classical conditioning approach that repeatedly pairs a threatening stimulus, such as an electric shock, with a neutral one. Through this process, subjects learn to fear the neutral stimulus even when unaccompanied by shocks.
To be adaptive, fears must reflect changing conditions. Retrieving fearful memories may offer a chance to update them with new information, as part of a process called memory reconsolidation. Animal studies have used drugs at the time of reconsolidation to block the fear response, but the drugs used would have unacceptable side effects in humans.
For reconsolidation to occur, the memory must first be retrieved. In a Science paper published last May (Monfils et al., 2009), researchers in Joseph LeDoux's laboratory at New York University in New York City reported that reactivating a fearful memory, by presenting a stimulus that rats had been taught to fear, opened a six-hour window during which the researchers apparently erased the old, fear-inducing memory. They did so by presenting the previously neutral, conditioned stimulus without shocks, a process called extinction.
Elizabeth Phelps and colleagues at NYU, collaborating with LeDoux's group, suggest that a similar approach works in humans. Led by first author Daniela Schiller, they taught 65 people to fear a colored square by repeatedly pairing it with a slight wrist shock. The next day, they again presented the colored square repeatedly, but without the shocks. To gauge subjects’ fear levels, they measured skin conductance, which reflects sweating and, hence, arousal.
On the next day, subjects underwent extinction training. For some, the training happened during the six-hour reconsolidation window; for others, it occurred too late for reconsolidation. A third group underwent extinction without reactivation of their fear memories.
When shown the squares on the third day, subjects who received extinction training in time for reconsolidation showed no fear, unlike the other two groups. They remained unafraid about a year later when 19 available subjects underwent a retest.
A follow-up study showed that the extinction procedure blocked only the specific fear memory that was reactivated. It did not affect fearful memories associated with different-colored squares that had also been paired with shock.
According to Schiller and colleagues, “These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear.” They suggest that this new approach might bestow longer-lasting benefits than standard extinction procedures, which do not always stop the fear from coming back. It may prove useful for relieving specific phobias, anxiety, and traumatic memories.
Although neither of these new studies looked at schizophrenia or other psychiatric disorders, they may change the brain activity of researchers who do. They show the potential for learning-based approaches, guided by neuroscience techniques and knowledge, to lessen psychopathology and may aid the search for ways to treat the brain abnormalities seen in schizophrenia (see SRF related news story).
Yet, however promising these findings seem, cognitive remediation might not readily translate into real-world gains for people with schizophrenia. In a recent randomized, controlled trial (Dickinson et al., 2009), cognitive remediation failed to improve the daily functioning of subjects with chronic schizophrenia. It only helped them do the training exercises better. Clearly, a deeper understanding of the psychopathology of schizophrenia, and different training methods, will be necessary before patients will see any benefit.—Victoria L. Wilcox and Hakon Heimer.
Keller TA, Just MA. Altering cortical connectivity: Remediation-induced changes in the white matter of poor readers. Neuron. 2009 December 10;64:624-31. Abstract
Schiller D, Monfils M-H, Raio CM, Johnson DC, LeDoux JE, Phelps EA. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature. 2009 December 9. Abstract
Dickinson D, Tenhula W, Morris S, Brown C, Peer J, Spencer K, Li L, Gold JM, Bellack AS. A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia. AJP in Advance. 2009, December 15. Abstract