The definitive version of this post was originally published on June 5, 2015 on the PLOS Neuroscience Community website, where I serve as an editor.
Deep brain stimulation (DBS) has been one of the biggest success stories of clinical neuroscience, thanks to its ability to reverse the symptoms of tremors, Parkinson’s disease, and a growing number of neurological and psychiatric conditions without any of the unwanted side effects of pharmacological therapies. Because DBS could in theory modulate any cerebral structure or network, researchers are starting to think about targeting cognitive functions such as memory. In a study published recently in Brain, Jonathan Miller and colleagues from University Hospitals Case Medical Center, Cleveland, OH, report on their preliminary experience with four patients in whom DBS of the fornix, the major fiber bundle of the hippocampus, improved visual-spatial memory. This first step may pave the way for more systematic explorations of the potential of DBS to improve cognitive function in patients with memory disorders. It also opens the fascinating, and slightly unsettling, possibility of intervening to boost brain capacities in healthy people—the electrical counterpart to nootropics.
In the study, Miller and colleagues recruited four patients with drug-resistant epilepsy who needed electrodes implanted in their brain in order to localize the origin of their seizures and then remove it surgically. They subjected them to batteries of memory tests, focusing on both verbal memory (e.g. the ability to learn lists of words) and visual-spatial memory (tested by asking participants to memorize a complex figure and then draw it again). During half of the testing blocks, DBS was delivered to the fornix, with the response to electrical stimulation propagating throughout the hippocampus. Importantly, the patients were unable to say whether the stimulation was turned on or off during a given block, and therefore remained blinded with respect to DBS. Miller and colleagues used novel stimulation parameters that are unusual for clinical DBS: brief electrical pulses at 200-Hz frequency were turned on and off 5 times per second (so-called theta-burst stimulation, because the theta band spans from 4 to 7 Hz). They found that the patients’ performance to the visual-spatial memory test got better with fornical DBS, whereas performance in a verbal memory and a naming task did not change consistently.
Of course, the study represents only the tiniest of first steps: with only 4 participants, the authors renounced inferential statistics altogether and simply described their patients’ performance before and after fornical DBS. The amplitude of the memory improvement remained relatively modest, and it was unexpected that it was visual-spatial memory that got better even though 3 out of the 4 patients were stimulated in the language-dominant hemisphere, which is thought to be more important for verbal than visual-spatial memory. Finally, the authors acknowledge that the fact that the stimulation was on during a complete block of neuropsychological testing prevented determining whether it improved memory encoding or retrieval (or both). Nevertheless, it is crucial that these exciting first results get published, so that further research can build upon them. I spoke with first author Jonathan Miller about his exciting work.
An interview with the authors
Your study is the first one that targeted the human fornix for deep brain stimulation (DBS) and also the first one to use theta burst stimulation. What do you think will prove the most crucial: which structure to target, or what stimulation parameters to use?
Identification of novel targets and stimulation parameters are both likely to be important for successful identification of new applications of deep brain stimulation. Most studies to date have focused on where rather than how stimulation is applied, but there is good evidence that different stimulation patterns can have very different effects. In the future I expect that there will be more attention to this in DBS research.
What differences do you see between targeting a white matter tract (the fornix in your study) versus a grey matter nucleus or region (most targets in movement disorders)?
One of the advantages of white matter stimulation is the ability to use the brain’s natural anatomic pathways to deliver stimulation to a widespread region, which is less likely with localized stimulation of discrete gray matter targets. Our study demonstrated robust evoked potentials throughout the hippocampus, so we believe we were actually stimulating a large portion of the hippocampus via the fornix. This may have implications for other DBS applications, including the traditional approaches.
DBS has recently been found to be useful for an expanding array of diseases and conditions, from Parkinson’s disease and other movement disorders to psychiatric conditions such as obsessive-compulsive disorder. Do you think that every neuropsychiatric disease could theoretically be alleviated by DBS, if only we knew where and how to stimulate? Or are there some diseases that in your opinion are not amenable to some form of neural stimulation or modulation?
Many neuropsychological and cognitive disorders are caused by abnormal interactions among structures that are not themselves abnormal. Since neuromodulation can be used to change these interactions, every brain disorder that results from circuit dysfunction can theoretically be treated using neuromodulation. The challenge is to identify the anatomic nodes in these networks for targeting and the mode of stimulation that is most effective to reverse these abnormalities.
Non-invasive electrical brain stimulation (tDCS/tACS) is currently enjoying widespread popularity. Do you foresee any use for such techniques to target brain structures involved in memory? Could they target deep-seated structures such as the fornix?
Currently, noninvasive stimulation technology such as tDCS is not able to target deep structures with enough specificity to accomplish the same effects as surgical implantation of an electrode. As technology improves, this may someday be possible.
Miller, J., Sweet, J., Bailey, C., Munyon, C., Luders, H., & Fastenau, P. (2015). Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases Brain DOI: 10.1093/brain/awv095